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A n a t o m y o f th e
Maxillofacial Region in the

T h ree Pl a n e s o f Se c t i o n
Christos Angelopoulos, DDS, MS
KEYWORDS
! Cone beam computed tomography ! Maxillofacial anatomy ! Maxillofacial region
! Multiplanar imaging
KEY POINTS
! Multiplanar imaging-reformatting (MPR) has significantly increased the diagnostic accu-
racy and efficiency of the knowledgeable dental professional.
! Reviewing the dental and maxillo-facial structures in all perspectives may reveal hidden
aspects of relevant disease and may enhance diagnosis.
! The novelty of the diagnostic tool (CBCT) and the unfamiliarity of the generated sectional
images make knowledge of the anatomy mandatory.
! Major anatomical structures, commonly seen in CBCT routine scans are reviewed as well
as related pathology, including the para-nasal sinuses, neck and cervical spine, skull base
and more.
INTRODUCTION
Multiplanar imaging has offered an unparalleled diagnostic approach when dealing

with an unknown entity (pathologic or not) that has stood as a diagnostic challenge.
This concept is inherent to volumetric type of data (computed tomography [CT],
cone beam computed tomography [CBCT], magnetic resonance imaging) and has
offered the diagnostician the unique ability to generate images (sections) at different
planes (flat or curved). Because a volume of data has been acquired and stored by
CBCT, this data can be reformatted or realigned and several different types of images
can be synthesized in any way the diagnostician requires,1 thus eliminating the super-
imposition of the area or entity under investigation with other neighboring structures
and allowing its assessment from all perspectives. With multiplanar imaging, the diag-
nostician/operator can re-create images in different planes (flat or curved) with very
simple functions, increasing the diagnostic efficiency in the hands of the knowledge-
able individual in an unparalleled way (Fig. 1).2
Oral and Maxillofacial Radiology, College of Dental Medicine, Columbia University, 208 E, 51st
Street, Ste#121, New York, NY 10022, USA
E-mail address: angelopoulosc@gmail.com
Dent Clin N Am 58 (2014) 497–521

http://dx.doi.org/10.1016/j.cden.2014.03.001 dental.theclinics.com
0011-8532/14/$ – see front matter ! 2014 Elsevier Inc. All rights reserved.
498 Angelopoulos
Anatomy of the Maxillofacial Region 499
Undoubtedly, multiplanar imaging, as provided by cone-beam imaging, is a novelty

for the dental professional: most dentists and specialists, with only a few exceptions,
are not familiar with diagnostic imaging in different planes, although they are keen on
interpreting projectional images as those produced by traditional dental imaging mo-
dalities (intraoral radiography and panoramic radiography). Sectional images (tomo-
graphic images) reveal the spatial relationship of the various known anatomic
structures in the maxillofacial region, which was more or less lost in projectional
imaging.
In this article the appearance of several anatomic structures of the maxillofacial re-
gion as well as the head and neck region in general is reviewed; these structures are
analyzed in all 3 basic tomographic planes (axial, coronal, sagittal). Additional recon-
structed images may be used to view certain anatomic areas from all aspects. To re-
view the anatomy of the maxillofacial region in a systematic way, the maxillofacial
region is divided into smaller areas of interest. Emphasis in this topographic anatomic
review is placed on areas that may demonstrate a higher incidence of occult disease.
Emphasis is also on structures outside the dentoalveolar region. The anatomy of
dental and dentoalveolar structures has been thoroughly reviewed elsewhere.2
NOSE AND PARANASAL SINUSES
The paranasal sinuses are 4 pairs of air-filled osseous cavities that surround the nose
and the orbits and that belong to the maxillary (maxillary sinuses), ethmoid (ethmoid air
cells), frontal (frontal sinuses), and sphenoid (sphenoid sinuses) bones, respectively.
Paranasal sinuses are best assessed in coronal sections; in fact, coronal images are
the most appropriate for the evaluation of anatomic structures that have a posteroan-
terior orientation. The maxillary, ethmoid, and sphenoid sinuses as well as the nasal
cavity and certain structures in the skull base will be optimally imaged in these views.
In this review, the anatomic structures of interest ventrally to dorsally (or anterior to
posterior) are reviewed (see Figs. 21–26).
At the level of maxillary premolars, the coronal images section through the frontal si-
nuses, the orbits, the anterior aspect of the maxillary sinuses, the ethmoid air cells, and
the nasal cavity. The various anatomic structures of interest are addressed by means of
importance to the dental professional (anatomic proximity to dental structures).
The nasal cavity is seen as a pyramidal-shaped air cavity that is divided in 2 distinct,
fairly symmetric, noncommunicating air cavities by the nasal septum. Each one of
them is separated further into smaller, blind (open) chambers by 3 elongated or
arch-shaped osseous projections that originate from its lateral walls: these are the
inferior, middle, and superior nasal conchae or turbinates, which border the inferior,
middle, and superior nasal meatuses (chambers) (Fig. 2). Only the inferior concha is
an independent facial bone; the rest are parts of the ethmoid bone. Although they
are lined by 2 to 3 mm of mucosa, there are identifiable air passageways that guide
the inhaled air to the paranasal sinuses. Shape alterations of the nasal chambers
=
Fig. 1. (A) The 3 standard planes of section: axial, coronal, and sagittal of the maxillofacial
region. These sectional images are the first to be reconstructed by any CBCT or MSCT (multi-
slice CT) scanner and serve as the basis for numerous other reconstructions based on the
diagnostic needs. Vertical and horizontal lines across the images guide the user at of the
actual location of each section. (B) Panoramic reconstruction and related cross-sectional im-
age. These images can be generated with very simple functions using the CBCT scanner’s
software applications. Their goal is to approach the region of concern from all perspectives.
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Fig. 2. Coronal section of the face, approximately at the molar level, depicting the nasal
cavity at its best. The nasal septum, in this case, is deviated to the left, causing a marked
asymmetry between the right and left nasal cavities, this often affects the patency of the
nasal passageways and may also be affected by the shape and size of the nasal turbinates
as well as the mucosal lining of the turbinates (seen as a dotted line). The white arrow shows
the left maxillary sinus ostium (draining site of the sinus cavity). EB, ethmoid bulla, the
inferior-most ethmoid air cell; INT, inferior nasal turbinate; MNT, middle nasal turbinate
(in this case, this is pneumatized and called concha bullosa); O, orbits.
and the septum may affect the flow of air through the nose and may be associated with
upper airway obstructive phenomena (ie, sleep apnea). In fact, a deviated nasal
septum is a common cause of sleep apnea (see Fig. 2). The nasal turbinates may
sometimes be pneumatized; in this case, instead of a dense bony process, the nasal
turbinate is presented as an extension of the ethmoid air cells, filled with air, and sur-
rounded by a thin corticated border. This phenomenon is considered an anatomic
variant, and the pneumatized turbinate is best known as “concha bullosa,” and is
more frequently seen in the middle nasal turbinates; its incidence ranges between
15% and 45%. Conchae bullosa may be inflamed because they are communicating
with the ethmoid air cells; however, their presence does not seem to affect the path-
ogenesis of sinus inflammation (sinusitis).3 Sometimes, conchae bullosa may
contribute to upper airway obstruction because they may obliterate the air passage-
ways in the nasal cavity (see Fig. 2).
Another prominent osseous canal is identified in the coronal sections through the
anterior third of the nasal cavity: the nasolacrimal duct, which originates at the floor/
medial wall of the orbit, opens into the inferior nasal meatus (Fig. 3), and drains tears
form the orbit into the inferior meatus.
The maxillary sinuses are the largest among the various paranasal sinuses (Figs. 4–6).
These air cavities belong to the maxillary bone. As all air cavities will be displayed as
uniform dark or black because air is depicted as a very low density structure in
computed tomography (CT or CBCT). The presence of any other appearance than black
may represent pathologic abnormality in the air cavity. Almost pyramidal in shape, with
the base of the pyramid being the medial wall or the wall that is shared with the nasal
cavity and the tip of the pyramid being the zygomatic process of the maxilla (anterior
end of the zygomatic arch). The other sides of the pyramid are the superior wall (roof
of the maxillary sinus), which is shared with the orbit, the lateral wall, the anterior
wall, and the posterior wall. CBCT images may provide a detailed evaluation of the
integrity of the walls of the maxillary sinuses as well as the presence of disease in the
air cavities. The posterior superior alveolar neurovascular canals may be sometimes
Fig. 3. Coronal section of the face, at approximately the premolar level. The structures visu-
alized at this level are the orbits (O), frontal sinuses (FS), the oral cavity (OC), the anterior
walls of the right (R) and left (L) maxillary sinuses and nasolacrimal ducts, marked by the
green arrows.
be seen on the lateral wall of the maxillary sinus as a small, pinhead-size, low-density
areas (in coronal images) running almost parallel to the floor of the sinus and turning
cephalad (superior) in the premolar region (in panoramic reconstructions). Its diameter,
as with all vascular canals, may provide information as far as it concerns its bleeding
potential if injured during sinus grafting procedures (see Fig. 4).
The draining sites of the maxillary sinuses (maxillary sinuses’ ostia) are likely to be
visualized in coronal images toward the anterior third of the sinus cavities (from front
to back) and may not be both identifiable in the same coronal plane. The ostium of the
maxillary sinus is a small opening in the medial wall of the maxillary sinus (or lateral wall
of the nasal cavity) toward the superior aspect, leading into the ethmoid infundibulum,
a narrow passageway that opens into the middle nasal meatus; it is formed partially by
the ethmoid bone (ethmoid bulla-superior) and a thin pointy osseous process on the
lateral wall of the nasal cavity known as the uncinate process. The maxillary sinus
and the anterior ethmoid air cells drain into the middle nasal meatus through the infun-
dibulum.4,5 The maxillary sinus ostium and the infundibulum are parts of the ostiomea-
tal complex, a broader anatomic unit that serves as the draining site of the maxillary,
anterior ethmoid, and frontal sinuses. Slightly higher, in the same sections, the drain-
ing path of the frontal sinus is identified; this is known as the frontal recess. The narrow
arch-shaped passageway between the ethmoid bulla and the middle turbinate just su-
perior to the infundibulum is the hiatus semilunaris, named so because of its curved,
almost semilunar shape, in the sagittal views (see Fig. 5). This hiatus semilunaris con-
nects the ethmoid infundibulum to the frontal recess. The semilunar hiatus is the final
segment of the drainage pathway from the maxillary sinus and ethmoidal infundibulum
to the middle meatus.6 The narrow and delicate nature of the above-mentioned drain-
ing sites makes them vulnerable to possible blockage when inflammation occurs in
their vicinity. Moreover, their close proximity to each other renders them possible
paths for spread of infection. Identification of the draining sites and assessment of
their integrity is important in patients who will undergo maxillary sinus grafting proce-
dures. Blockage of the draining site may prevent the aeration of the sinus cavity and
result in accumulation of inflammatory products into the sinus (see Fig. 6). This fine
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Fig. 4. (A) Panoramic reconstruction and related cross-sectional images of the right poste-
rior maxilla for the assessment of the lateral wall of the maxillary sinuses before a grafting
procedure. The small, low-density (almost pinhead in size) area (red arrows) is the osseous
canal for the posterior superior alveolar (PSA) neurovascular bundle (artery, vein, and
nerve). (B) Panoramic reconstructions along the lateral wall of the maxillary sinus illustrate
clearly the course of neurovascular canal of PSA (red arrows) from posterior to anterior. The
bleeding potential of any vessel is proportional to its diameter.
Fig. 5. (A, B) Coronal section of the face, at the level of maxillary sinuses/nasal cavity
(approximate maxillary molar level) depicting the maxillary sinuses at best. These images
are optimal for the evaluation of the integrity of the floor and walls of the sinuses and nasal
cavities. The draining site of the maxillary sinus is known as ostium (red arrows) and is nar-
row, opening on the medial wall of the maxillary sinus to the medial nasal meatus (cham-
ber). The medial wall ends in a pointy osseous projection known as uncinate process
(stars). The ostium opens into a narrow canal, the ethmoidal infundibulum (green dotted
line). Part of the infundibulum is a thin curved canal, the shape of which is affected by its
proximity to the ethmoid bulla; this is the hiatus semilunaris (white dotted line). All of
the above participate in a broader unit often identified as ostiomeatal complex or unit
(green dash-marked cycle), including the draining sites of the maxillary sinuses, frontal
sinuses, and anterior and middle ethmoid sinuses (all drain in the middle nasal meatus).
EB, ethmoid bulla; INT, inferior nasal turbinate; MNT, middle nasal turbinate.
and delicate anatomy of the ostiomeatal complex may be grossly altered if sinus sur-
gery has occurred (Fig. 7).
The ethmoid air cells or sinuses are numerous, small, mostly square, air cavities that
are separated by thin bony walls, grouped in 2 orthogonal prisms located on either
side of the superior nasal cavities, and run parallel to the nasal cavities through their
entire length (from front to back). They are bordered from the orbits with the lamina
papyracea, a paper-thin osseous wall, and from the nasal cavities with the superior
and middle nasal turbinates (Fig. 8). The anterior and middle ethmoid air cells drain
into the middle nasal meatus, whereas the posterior ethmoid air cells drain into the su-
perior nasal meatus (Fig. 9).
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Fig. 6. (A) Coronal sections through the maxillary sinuses showing the presence of inflam-
matory tissue (collection of soft tissue in density content) in the left maxillary sinus and
thickening of the mucosal lining of the floor and walls of the right maxillary sinus. Note
the inflammatory tissue is rather extensive and has blocked draining passageway (ostium)
(green arrow). (B) Coronal section through the sinuses showing extensive inflammatory
changes in the sinus cavities of the right and left maxillary sinuses. Flat surfaces on the
(soft in density) content of sinuses may indicate coexistence of fluid in sinus cavity (air/fluid
level) (red arrows). In this case, however, the evaluation of the maxillary sinuses is incom-
plete and a more extended field of view should be used.
Fig. 7. Coronal section of the maxillary sinuses (approximate maxillary molar level): the
nasal architecture as well as the ethmoid sinuses is dramatically altered; in addition, the
ostia of the right and left maxillary sinuses are widened to facilitate drainage, the result
of extensive sinonasal surgery.
Fig. 8. (A–C) Axial (A), coronal (B), and sagittal (C) views of the ethmoid sinuses and sphe-
noid sinuses (A, C). The ethmoid sinuses are composed of numerous, thin-walled air cells the
complexity of which gave them the name of ethmoid labyrinth. Other structures visualized
included the sphenoid sinuses (SS), the lamina papyracea (thin wall separating the ethmoid
sinuses from the orbit, green arrow), the inferior nasal turbinate (INT), and the middle nasal
turbinate (MNT).
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Fig. 9. (A, B) The drainage path of the anterior ethmoid air cells (white dotted line) and
middle ethmoid air cells (green dotted line) is depicted in coronal (A) and in sagittal (B) sec-
tions of the anterior/middle ethmoid air cells. This path clearly opens to the middle nasal
meatus.
The sphenoid sinuses are the posterior-most air cavities and belong to the sphenoid
bone. Their shape is similar to that of a truncated pyramid with its base being the bony
roof of the nasopharynx; its roof, the sella turcica (pituitary fossa), and its lateral walls
border the cavernus sinuses on either side of the body of the sphenoid bone. The
sphenoid sinuses drain to the superior nasal meatus through a small opening in their
anterior wall, the spheno-ethmoidal recess (Fig. 10).
Important anatomic entities, such as the optic canal, the foramen rotundum, and the
vidian canal, are closely related to the sphenoid sinuses and will be addressed in later
discussion in the anatomic review of the skull base (see Figs. 25 and 26).
The frontal sinuses are 2 funnel-shaped air cavities identified superior to the ethmoid
air cells and the nasal cavities and belong to the frontal bone. They demonstrate a
great deal of variation in shape and size. A septum, which is frequently deviated, sep-
arates the right from the left and asymmetry between the 2 is not uncommon. They
drain into the middle nasal meatus through the frontal recess, a thin passageway,
part of the ostio-meatal complex (discussed earlier).
The orbits are visualized toward the anterior third of the face as well as the ethmoid
air cells, the most anterior part of which is sectioned at this level. These views are
excellent for the assessment of the integrity of the osseous walls of the orbits and their
borders. A short osseous canal seen originating from the floor of the orbit and directed
inferomedially to the anterior wall of the maxillary sinus is the infraorbital foramen,
which accommodates the infraorbital nerve (Fig. 11). Lamina papyracea, a paper-
thin osseous diaphragm that belongs to the ethmoid bone and serves as the medial
orbital wall, stands as the boundary between the orbit and the ethmoid air cells (see
Figs. 6A and 8B).
Fig. 10. (A–C) Axial (A), coronal (B), and sagittal (C) views of the sphenoid sinuses (SS). The
green dotted line shows the draining path of the sphenoid sinuses to the superior nasal
meatus through a narrow opening on the anterior wall known as sphenoethmoidal recess
(green arrow).
Unfortunately, the soft tissue contrast of CBCT is inadequate for the assessment of
the orbital content (eye globe, fat, and musculature of the eye globe).
Inflammation is by far the most common pathologic entity among the ones affecting
the paranasal sinuses. Moreover, it seems that it is a frequent occult pathologic entity
in CBCT scans prescribed for other diagnostic concerns.7,8
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Fig. 11. (A, B) Coronal (A) and sagittal (B) views through the floor of the orbits and maxillary
sinuses. Ovoid osseous canals seen on the floor of the orbits are the infraorbital foramina
(green arrows). Also notice the inflammation in the left maxillary sinus. Nasolacrimal canal
(stars).
NECK AND CERVICAL SPINE
A considerable portion of the patient’s neck and cervical spine may be included in an
extended field-of-view scan of the maxilla and mandible or of the mandible toward the
inferior end of the scan. Axial images are best for the evaluation of the visible parts of
the neck and cervical spine as well as the skull base, although a combination of recon-
structed images in all 3 planes (axial, coronal, and sagittal) may be used to assess a
region of interest fully.
Most times, the portion of the neck that is visualized in a CBCT includes the supra-
hyoid neck (above the hyoid bone). A few osseous structures and mostly soft tissue
structures are present at that level (Fig. 12). The inferior border of the anterior
mandible may be sectioned at this level and may be visualized toward the upper
border of the image. The hyoid bone and the third or fourth cervical vertebra (these
vertebrae are almost indistinguishable at that level in axial sections) are the only other
bony structures seen toward the inferior end of the imaging volume. The sequential
axial images of the neck are dominated by soft tissue structures, the visualization of
which is generally limited because of reduced soft tissue contrast in CBCT images.
In fact, soft tissue structures often blend together in the various reconstructed images,
a fact that renders CBCT inadequate for the diagnosis of soft tissue pathologic abnor-
mality. However, sometimes, soft tissues are identifiable and this may vary in different
CBCT scanners.
The soft tissue structures identified in that level include the sternocleidomastoid
muscle (SCMs) bilaterally, the geniohyoid muscles, as well as the submandibular sali-
vary glands. Most of the time only the contour of these structures is discernible and,
although their visualization is not adequate for possible disease involvement, they may
be used as anatomic landmarks for orientation. In the center of the neck lies the only
readily identifiable soft tissue structure: the airway; this is a semicircular, very low-
density (dark) area bordered by the hyoid bone (ventrally) and the vertebral column
Fig. 12. (A) Axial CBCT image at the level of the hyoid/C3 vertebra. (B) The same axial image
as the one on the left with some identifiable neck anatomic structures outlined. (Despite the
fact that the soft tissue contrast of cone-beam tomography is not optimal for the diagnosis
of soft tissue pathologic abnormality, some of the neck anatomic landmarks are visualized.)
The neck spaces, because they are mainly occupied by fat, appear of a lower density in com-
parison to the neighboring musculature. Note that this is the approximate location of the
major blood vessels of the neck; their precise location cannot be clearly seen without the
utilization of intravenous administration of contrast media. Knowledge of the topographic
location of the major neck anatomic structures will assist the diagnostician to determine the
origin of the various pathologic entities that may develop on the neck. C3, an axial section
of the third cervical vertebra; CA, carotid arteries; E, epiglottis; F, fatty tissue; GH, genio-
hyoid muscle; H, hyoid bone (note the almost modular appearance of the hyoid bone
that can imitate a fracture); IJV, internal jugular vein; M, inferior border of the anterior
mandible; S/M, submandibular salivary glands.
(dorsally). The airway is separated almost in 2 halves by a soft tissue structure, cres-
cent in shape (most often), the epiglottis.
Approximately at this level, the common carotid artery bifurcates into 2 main
branches, the internal carotid and external carotid arteries, which supply the brain
and face of each side, respectively. The most reliable reported landmarks to indicate
the level at which bifurcation occurs are the C3/C4 level and the superior border of the
thyroid cartilage of the larynx; however, variation is not uncommon (see Fig. 12). The
blood vessel is accompanied by the internal jugular vein (the bigger blood vessel of the
neck) and the vagus nerve to form the neurovascular bundle of the neck. The location
of the bundle in the axial images of the neck, at the level of C3-C4, is posterolaterally to
the airway and anteromedially to the sternocleidomastoid muscle (SCM) (Fig. 13). Su-
perior to the bifurcation, the carotid artery branches are less distinguishable due their
reduced diameter.
Despite that the major blood vessels of the neck discussed above are rarely distin-
guished from the rest of the soft tissues of the neck in CBCT images because of the
limited soft tissue contrast, familiarity of the course of the blood vessel on the lateral
neck is crucial to identify pathologic conditions inside or in the vicinity of the blood
vessels, such as carotid artery atheromatosis, a pathologic condition in which calcified
deposits (atheromas) accumulate on the internal wall of the blood vessel;9 this grad-
ually reduces the flexibility and functionality of the blood vessel. Carotid artery athero-
matosis demonstrates a fairly high incidence rate in older age groups and has been
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Fig. 13. Axial section of the neck at the level of C3/C4 vertebral bodies with contrast-
enhanced CT. The circulating contrast medium is depicted with a high-density fact that
makes the blood vessels and other anatomic structures supplied by the blood with contrast
well-identifiable. ECA, external carotid arteries; EJV, external jugular vein; F, subcutaneous
fat; GH, geniohyoid muscle; ICA, internal carotid arteries; IJV, internal jugular vein; MH,
mylohyoid muscle; SMG, submandibular salivary gland; VA, vertebral arteries.
associated with an increased risk of stroke. These calcifications most frequently occur
within 10 to 15 mm of the bifurcation (above or below). Sometimes they have a clear
tubular appearance that makes them more readily identifiable than not. Other times
they look more like a cluster of calcifications in the region (Figs. 14 and 15).
Fig. 14. Axial section of the neck at the level of C3/C4 vertebral bodies showing an athero-
matous plaque (green arrow) in the left common carotid artery almost tangential to the an-
teromedial aspect of the left SCM (red dotted outline). The other smaller calcifications seen
on either side of the airway are calcifications in the thyroid cartilage complex (yellow
arrows).
Fig. 15. Axial section (A) and coronal section (B) of the neck at the level of C3/C4 vertebral
bodies showing atheromatous plaques (green arrows) in the common carotid arteries bilat-
erally. Variation as far as size and shape is frequent.
Other types of neck calcifications may include calcifications in the thyroid cartilage
complex, stylohyoid ligament calcifications, sialoliths, and tonsiloliths (Figs. 16 and
17). Some may resemble carotid artery calcifications; however, the appearance and
location most of the times will assist in determining the origin of the calcification.
Apart from the visualization of the corresponding cervical vertebrae (depending on
the level of the axial sections) and the mandibular bone, axial images of the floor of the
mouth reveal minimal information about the soft tissue structures in the region
(Fig. 18).
Sagittal images of the neck are best for the assessment of the cervical spine and the
airway (Fig. 19A). The cervical spine is partially only visualized in CBCT scans (C1–C5).
The normal (healthy) appearance of the vertebral bodies includes a fairly square body,
a thin cortical outline, a cancellous component of homogenous density, and a fairly
symmetric spacing between the vertebrae visible in the scan. However, pathologic ab-
normality associated with the cervical spine and other irregularities is not uncommon
(see Fig. 19B). Often the above are incidental findings in scans that were prescribed
for different reasons.
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Fig. 16. Bilateral calcifications at the level of the floor of the mouth (axial and coronal im-
ages) (arrows). Note the superficial location of the calcifications in relationship to the
airway. These were tonsilar calcifications or tonsiloliths and have been associated with recur-
rent inflammation of the tonsils as well as halitosis.
Fig. 17. Single, round calcification in the left submandibular space (arrows); this was a silao-
lith in the left submandibular salivary gland.
Fig. 18. Axial cut of the mandible toward the lower half of the mandibular body. At that
level, the C3 vertebra is depicted. The red arrows mark the right and left transverse foramen
(or foramen transversarium). Contiguous transverse foramina form a canal that hosts the
vertebral artery during its ascending course toward the endocranium. Note that due to
inadequate soft tissue contrast, it is impossible to distinguish different soft tissue structures
in the mouth. FOM, floor of the mouth; VF, vertebral foramen.
The airway is presented as a low-density (black), tubular-shaped structure, which

may vary in width and lies just ventrally to the cervical part of the vertebral column.
The position of the epiglottis, the laryngeal opening below the epiglottis, as well as
the position of the tongue may have an effect on the diameter of the airway in several
locations. CBCT images are very useful in the evaluation of the airway and the factors
that may cause restrictions in the airflow in sleep-apnea cases (Fig. 20).10,11
Shape alterations of the airway in the various levels may trigger alerts for possible
disease. In fact, soft tissue pathologic abnormality around the borders of the airway
may have an effect on the shape of the airway (Fig. 21).
MIDFACE AND SKULL BASE
The midfacial structures as well as the skull base are reviewed next in a series of
axial sections (Figs. 22–27). This review starts at the level of the floor of the maxillary
sinuses and the base of the maxillary alveolar bone. Apart from the apices of the
maxillary teeth, the hard palate, and the floor of the maxillary sinuses, the superior
foramina (anteriorly) and the greater and lesser palatine foramina are visualized at
that level. The superior foramina are the entrance of the nasopalatine canal and
are located on the floor of the nasal cavity (inferior meatus); they host the nasopala-
tine nerve, which exists through the incisive foramen on the palatal aspect of the
maxillary midline between the central incisor teeth. The greater and lesser palatine
foramina serve as the passageways to the greater and lesser palatine nerves and
vessels, which will run the hard palate from posterior to anterior just superior to
the palatal roots of the maxillary molars on the soft tissue in a palatal mucosa (see
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Fig. 19. (A) Midsagittal cut of the face and neck. Sagittal sections are best for the evaluation
of the visible portion of the cervical spine and the airway. C2, 2nd cervical vertebral axis;
the superior end of C2 is the odontoid process, which is articulated with the atlas (C1) and
the skull base; C3, third; C4, fourth. FS, frontal sinus; NPC, nasopalatine canal; S, sella turcica;
SS, sphenoid sinus. The yellow arrows mark the hard palate and the green arrows mark the
soft palate. The elongated, slightly curved, low-density area anterior to the cervical spine is
the airway. (B) Sagittal image of the cervical spine and the airway; large osseous masses (green
arrows) on the ventral aspect of the C4, C5 are osteophytes, signs of degenerative joint disease
in the visible portion of the cervical spine. Other signs of degenerative joint disease (arthritis)
include loss of intervertebral space, erosive changes, subchondral cyst formation, and
sclerosis.
Fig. 22). Their identification during palatal surgery and palatal flap elevation is impor-
tant. Similarly to several other important anatomic structures, they will not always be
visualized in CBCT scans.
The nasopharyngeal aspect of the airway dominates the center of the axial cuts of
the midface. Its shape and size vary and may be affected by neighboring anatomic
structures in the vicinity. A deep depression on the lateral walls of the nasopharynx
bilaterally is the Eustachian tube, the tube that communicates and balances the air
Fig. 20. A thick sagittal cut visualized in 3 dimensions to assess the airway (blue). Several
software programs (mostly third party) offer specific utilities that simplify airway evaluation
as well as measurements, volume, and analysis.
pressure between the inner ear and external ear (see Figs. 22 and 23). Just posterior to
the Eustachian tube, separated only by soft tissue projection (torus tubarius), lies the
pharyngeal recess or fossa of Rosenmueller. This region almost always will appear
into the maxillary CBCT scans and it is imperative to be included in the evaluation.
Further dorsally, an ovoid or ellipsoid structure is visualized toward the anterior aspect
of the foramen magnum; this is the odontoid process of the axis (C2) (see Fig. 19A).
Several very important anatomic structures are identified posterior to the midface, in
the skull base (see Figs. 24–27; Figs. 28 and 29). These structures are the mandibular
condyles, external auditory canals, mastoid processes (partially visualized), bilaterally,
and the sphenoid sinus almost in the center of the axial image. Anteromedial to the
mandibular condyles lie 2 important foramina: the foramen ovale (larger one) and
the foramen spinosum (smaller one). The former hosts the third division of the trigem-
inal nerve (V3), the mandibular nerve, and the latter, the middle meningeal artery.
At the same level, simply by slightly changing the reformatting angle to make the
sections more parallel to the skull base, additional very important anatomic structures
will appear: one of the most important anatomic regions of the skull base is the pter-
ygopalatine fossa (PPF), which is identified in contact with the posterior wall of the
right and left maxillary sinuses. The PPF represents a major crossroad in the skull
base: in the PPF open 2 large osseous channels: the Vidian canal (or pterygoid canal),
which hosts fibers of the petrosal nerves, and the foramen rotundum, which carries the
maxillary nerve (V2). With the PPF as a passageway, the middle cranial fossa commu-
nicates with the orbits (through the inferior orbital fissure), with the paranasal sinuses
through the sphenopalatine foramen, the infratemporal fossa, and the nasal cavity.
Through this crossroad, inflammation from the orbits, nasal cavity, sinuses, and oral
cavity can be transferred into the middle cranial fossa and vice versa. The
516
Fig. 21. Axial (top) and coronal (bottom) sections of the airway showing marked asymmetry
between the right and left lateral walls with the right posterolateral wall shifted medially.
This shift is evident in the coronal view (arrows). Often, airway shape alterations may be
associated with soft tissue growths in the region and may require further investigation.
Fig. 22. (left) Axial section at the level of the roots of the maxillary teeth. (right) Axial sec-
tion slightly superior to the other section, at the level of the floor of the maxillary sinus. The
green arrows show the pharyngeal opening of the Eustachian tube, which helps in equal-
izing the pressure between the 2 sides of the eardrum. The red arrows mark the fossa Rose-
nmuller. GLPF, greater and lesser palatine foramina; HP, hard palate; MS, maxillary sinus; OC,
oral cavity; SF, superior foramina, the starting point of the nasopalatine canal; TT, torus
tubarius, a soft tissue process on either side of the nasopharynx (NF) separating the Eusta-
chian tube from the fossa Rosenmuller.
Fig. 23. Axial section at the level of the maxillary sinuses/mandibular rami demonstrating
major structures of the maxillary sinus, nasal cavity, and nasopharynx at the axial plane.
INT, inferior nasal turbinate; (L)MR, left mandibular ramus; MS, maxillary sinus; N/F, naso-
pharynx; PP, lateral and medial pterygoid plates; ZP, zygomatic process of the maxilla. The
red arrows mark the Eustachian tube, and the round shaded region, the general site of fossa
Rossenmuller and torus tubarius.
identification of the PPF and assessment of the integrity of its margins are absolutely
necessary if this structure is demonstrated in the CBCT scan.12,13
Just posterior to the foramen ovale and medial to the mandibular condyle lies the
carotid canal, on either side of the skull base. The 2 canals converge toward the
base of the sphenoid, where they pass close to the cavernous sinus before they
ascend.
Fig. 24. Axial section at the level of the maxillary sinuses (superior third) demonstrating ma-
jor structures of the maxillary sinuses, nasal cavity, and skull base at the axial plane.
Co, mandibular condyle; FO, foramen ovale; FS, foramen spinosum; IO, infraorbital canal;
JF, jugular foramen (or jugular fossa); Ma, mastoid air cells; MNC, middle nasal concha;
NL, nasolacrimal duct; SS, sphenoid sinus; ZA, zygomatic arch. The blue arrow indicates
the external auditory canal.
518 Angelopoulos
Fig. 25. Axial section at the level of the maxillary sinuses (superior third) (same as Fig. 17,
but slightly higher) demonstrating additional anatomic details about the skull base. MNC,
middle nasal concha; SS, sphenoid sinus. The green arrows mark the walls of a thin channel
known as the “Vidian canal” or pterygoid canal. The yellow arrows mark the course of the
carotid canals that appear to be converging toward the base of the sphenoid bone. PPF is a
region of importance in the skull base. It is the passageway from the middle cranial fossa to
the orbit, face, sinuses, and vice versa. Disease processes may be transferred from the middle
cranial fossa to other sites (mentioned above) through the PPF. Similarly, disease originated
extracranially may be transferred to the endocranium through the PPF.
Fig. 26. Axial image of the head at level of the orbits (inferior third). The section depicts the
roof of the maxillary sinuses (MS) bilaterally and the ethmoid sinuses (ES), just medial to the
maxillary sinuses. Note the fine and delicate air cells that form the ethmoid sinuses; this fine
and complicated architecture has given the name of ethmoid labyrinth to the ethmoid air
cells. The circular depressions toward the posterolateral walls of the sphenoid sinuses (SS),
which can be seen in its magnitude in this image, represent the continuation of the carotid
canals (CC) as they are entering the cavernous sinus of the lateral border of the base of the
sphenoid bone. Note the septations, present in the sphenoid sinus, seen in this image. The
section very clearly illustrates the relationship between the PPF, the inferior orbital fissure
(IOF), and the temporal fossa (yellow dotted area). Last, the green arrows mark the course
of the right and left foramen rotundum. IAC, internal auditory canal; MCF, middle cranial
fossa; PCF, posterior cranial fossa.
Fig. 27. Axial section of the head at the level of the orbits (superior half). The posterior
opening of the orbits is divided by the superior orbital fissure (SOF) and the optic canal
(yellow arrows). The orientation of the optic canals is toward the sella, where the optic
chiasma takes place. ACP, anterior clinoid processes; PCP, posterior clinoid processes.
At the same level, almost in contact with the posterior border of the external auditory
canals and medially to the mastoid air cells, the jugular foramina are located. Also
known as jugular fossae (due to their large size), they are well-defined, wide, corti-
cated canals that serve as the passage points for the ninth (glossopharyngeal), tenth
(vagus), eleventh (accessory) cranial nerves as well as the jugular vein, among others.
Variation in their shape and size as well asymmetry is not uncommon.
More cephalad axial sections (see Fig. 26) will show the orbits, the ethmoid sinuses,
and the sphenoid sinuses. The posterior opening of the orbits at that level is the inferior
orbital fissure, which communicates with the PPF as mentioned earlier.
The ethmoid sinuses are made up of numerous, small, thin-walled, air cells sepa-
rated by the vomer bone (nasal septum) in the midline. Their complicated anatomy
gave them the characterization of the ethmoid labyrinth. The larger sphenoid sinuses
are located just posterior (dorsally) to the ethmoid sinuses. They occupy the base of
the sphenoid bone (basisphenoid) and their thinned osseous walls are in contact
with some rather important anatomic entities: the carotid canals (posterolaterally)
and the foramina rotunda/PPF (anterolaterally). Anatomic variation and the presence
of septations are often the rule rather than the exception.
Fig. 28. Coronal section through the sphenoid sinus (SS). CP, coronoid process of the
mandible; NP, nasopharynx. The yellow arrows show the Vidian canal (pterygoid canal)
and the red arrows show the foramen rotundum.
520 Angelopoulos
Fig. 29. Coronal section through the sphenoid sinus (just posterior to section in Fig. 25). NP,
naso-pharynx; SS, sphenoid sinus. The dotted lines mark the course of the foramen ovale
bilaterally.
The most superior (cephalad) axial sections will reveal the upper half of the orbits,
the temporal fossa, and partially the middle and the posterior cranial fossae. The con-
cavities seen toward the posterolateral orbital walls are the temporal fossae; they are
anatomic depressions into the temporal bone and serve as the attachment point for
the temporalis muscle (see Fig. 27).
At this level, the orbital apex (posterior opening of each orbit) appears to be splitting
into 2 distinct openings: a lateral opening, which is rather wide and opens into the
anterior cranial fossa (superior orbital fissure), and a narrower medial opening, which
is longer and directed posteromedially toward the sella turica (optic canal). In fact, the
2 optic canals are converging toward the sella turcica, where they finally unite. The
convergence point is the optic chiasma where the 2 optic nerves (content of the optic
canals) cross each other’s course.
The posterior clinoid processes (also identified at that plane) are 2 small osseous
tubercles, which demonstrate a transverse orientation form the dorsal boundary of
the sella turcica. They show a great deal of variation in shape and size, deepen the
sella, and serve as attachment points (see Fig. 27).
The goal of the above anatomic review of the maxillofacial region was 2-fold: to shed
some light into structures and anatomic landmarks that were “lost,” in some ways, in
projectional imaging and discuss their location, course, and relationship with neigh-
boring structures in 3 dimensions; and also to illustrate the effects of disease in known
anatomic boundaries (canals, foramina, osseous cavities, soft tissue contours) that,
sometimes, may be the only signs of developing pathologic abnormality.
The successful identification of an unknown entity lies in the ability of the observer to
approach it from all perspectives, using fully the potential of the multiplanar imaging. It
is strongly recommended that to take advantage of the CBCT images in full, the diag-
nostician should be able to understand and apply the concept of multiplanar reformat-
ting to the highest degree. It is in our hands to reveal the information related to each
diagnostic task. In other words, our diagnostic efficiency is based on our sound knowl-
edge of anatomy and on our skills to retrieve relevant diagnostic information.
REFERENCES
1. Angelopoulos C, Scarfe WC, Farman AG. A comparison of maxillofacial CBCT

and medical CT. Atlas Oral Maxillofac Surg Clin North Am 2012;20(1):1–17.
Fan et al. BMC Oral Health (2022) 22:69
https://doi.org/10.1186/s12903-022-02074-9
CASE REPORT Open Access
Uncontrollable bleeding after tooth

extraction from asymptomatic mild hemophilia
patients: two case reports
Guo Fan1, Yi Shen1, Yu Cai1,2, Ji-hong Zhao1,2 and Yang Wu1,2*
Abstract
Background: Uncontrollable bleeding after tooth extraction usually occurs in patients with coagulation diseases,
including hemophilia, von Willebrand’s disease, vitamin K deficiency, platelet deficiency, and taking anticoagulant
drugs. Hemophilia A is an X-linked recessive disorder caused by insufficiency of coagulation factor VIII. Mild hemo-
philia, defined by factor level between 0.05 and 0.40 IU/mL, is characterized by uncontrollable hemorrhage after
trauma or invasive operations. Some mild hemophiliacs may remain undiagnosed until late adulthood. Therefore,
surgical management of these patients may be relatively neglected. These case reports describe two uncontrollable
bleeding patients with unknown mild hemophilia A after tooth extraction.
Case presentation: This paper reports 2 cases of persistent bleeding after tooth extraction under local anesthesia
which could not be completely stopped by routine treatments. Both of them denied prior illness and injury, allergies,
anticoagulant medication history, systemic and family illness. The APTT and other coagulation screening tests of the
two patients before surgery were normal. Finally, they were diagnosed with mild hemophilia A via coagulation factor
assays. The patients acquired complete hemostasis by receiving coagulation factor supplement therapy in hemato-
logic department.
Conclusion: Mild hemophilia is marked by subclinical, asymptomatic and even normal coagulation test results.
The purpose of these case reports is to bring dental professionals’ attention that APTT test alone cannot be used to
exclude mild hemophilia, and provide reasonable evaluation and treatment procedures of bleeding patients after
tooth extraction.
Keywords: APTT, Mild hemophilia A, Persistent bleeding, Tooth extraction, Case reports
Background or prolonged bleeding after minor trauma and abnor-

Hemophilia is an X-linked, recessive, bleeding disorder mal coagulation test results. Coagulation screening tests
caused by deficiency of blood coagulation factor VIII. The are widely recommended to evaluate the risk of bleed-
incidence is estimated to be 24.6 in 10,000 males. It’s con- ing before oral and maxillofacial surgery [1, 2]. Platelet
ventionally marked by occasional spontaneous bleeding count, activated partial thromboplastin time (APTT) and
prothrombin time (PT) are the major indicators. How-
ever, some mild bleeding disorders are often "subclini-
*Correspondence: wuyang83@whu.edu.cn cal" and the patients may experience increased bleeding
1
The State Key Laboratory Breeding Base of Basic Science of Stomatology only in the setting of trauma or surgical operations. Even
(Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry
of Education, School and Hospital of Stomatology, Wuhan University, 237
worse, according to the World Federation of Hemophilia
Luoyu Road, Wuhan 430079, China (WFH), whether the coagulation tests can accurately
Full list of author information is available at the end of the article
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permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
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regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
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Fan et al. BMC Oral Health (2022) 22:69 Page 2 of 8
assess the coagulation status of mild hemophilia patients (Table 1: 1 year ago). Despite that fact, he denied prior
is still controversial [3]. illness and injury, allergies, anticoagulant medication his-
Many studies have confirmed that these indicators tory, systemic and family illness.
cannot accurately intimate the coagulation function of Coagulation screening tests were performed before
patients due to some internal (patient’s physical condi- tooth extractions. The international normalized ratio
tion and some special coagulation diseases) or external (INR), PT, APTT and platelet count were within the nor-
(unregulated collection and processing of the sample) mal range (Table 1: Day 0). Under articaine infiltration
reasons [3, 4]. A patient with coagulation dysfunction anesthesia and lidocaine block anesthesia, two wisdom
might present "normal" laboratory examination results teeth were then routinely removed within 20 min. The
[3]. Similarly, an abnormal APTT result doesn’t always wound was sutured with 2–0 unabsorbable sutures and
indicate abnormal coagulation function because of inter- compressed with sterile gauze as usual.
nal or external influence. Several hours later, the patient developed continuous
Generally, most hemophilia patients are diagnosed bleeding at the lower extraction site (#48). Because of
preoperatively and tooth extractions are performed with the poor hemostasis effect of sterile gauze compression,
a personalized hemostasis management plan. After per- we used a gelatin sponge (a tough and porous absorbable
forming a literature review, we found 2 cases of mild sponge-form material that makes the platelets adhere to
hemophilia after oral invasive surgery (tooth extrac- the network and break down, thus leading to the release
tion [5] and electrosurgical resection of pericoronal flap of thrombokinase [10]) to fill up the extraction site and
[6]), while the two case reports lack preoperative APTT sutured tightly to stop bleeding.
results. There are some patients with normal preopera- Second postoperative day, the patient had recurrent
tive APTT results who had uncontrollable bleeding after intermittent bleeding at both extraction sites. Each time
surgeries (including tonsillectomy [7], ocular trauma [8], the bleeding was relieved by sterile gauze compres-
thyroidectomy [9]), and they were diagnosed with mild sion. Fifth postoperative day, we performed coagulation
hemophilia A by factor assays eventually. screening tests again. The results showed that APTT
This paper reports 2 cases of persistent bleeding after and fibrinogen (FIB) were beyond the normal range
tooth extraction which could not be completely stopped (Table 1: Day 5). Then we began to consider whether
by routine treatments. Neither of them had a bleeding there was a coagulation system disease, despite nor-
history. More specifically, their preoperative coagula- mal results obtained at day 0. Through a more detailed
tion function tests showed "normal" laboratory examina- history inquiry, the patient recalled that his elder male
tion results. Due to the poor effect of various hemostasis cousin had "some problems in blood coagulation" before.
methods, we suspected that the patients had hemophilia We suggested he check the coagulation factor level at the
and recommended a coagulation factor testing. Finally, hematology department.
they were diagnosed with mild hemophilia A via coagula- Seventh postoperative day, severe persistent bleeding
tion factor assays. Mild hemophilia is relatively uncom- occurred again in both two sites. Neither sterile gauze
mon compared with moderate to severe hemophilia compression nor the local application of hemostatic
which are characterized by spontaneous bleeding. It is drugs could stop bleeding. We removed the original
generally believed that APTT can detect this coagulation sutures under local anesthesia, cleaned the socket, filled
disorder before surgery. However, we described two cases the alveolus nest tightly with iodoform gauze, and then
of mild hemophilia with a normal preoperative APTT sutured tightly to achieve hemostasis.
result. The purpose of these case reports is to deepen
the oral surgeon’s understanding of the preoperative
coagulation screening tests, raise clinicians’ awareness of
diagnostic tests and provide reasonable evaluation and Table 1 The coagulation test results of Case 1 at different time
points
treatment procedures for bleeding patients with potential
mild hemophilia after tooth extraction. 1 year ago Day 0 Day 5 Day 7
APTT (s) 43.1 (20–38) 32.3 (20–38) 53.5 (28–43.5) 50.2 (20–47.1)
Case presentation PT (s) 11.3 (9–14) 9.4 (9–14) 13.1 (11–16) 14 (10–16.9)
Case 1 TT (s) 17.3 (13–20) 16.6 (13–20) 15.5 (14–21) 14.9 (12.9–22.9)
A healthy 29-year-old man came to our hospital and INR 1.03 (0.8–1.3) 0.8 5(0.8–1.3) 1.01 (0.8–1.31) 1.12 (0.9–1.22)
asked for the removal of his impacted wisdom teeth (#18 FIB (g/L) 4.53 (2–4) 3.25 (2–4)
and #48) because of recurrent local inflammation. He FVIII:C% 10 (70–150)
mentioned that he went to the hospital a year ago because APTT activated partial thromboplastin time, PT prothrombin time, TT thrombin
of bleeding gums and found abnormal blood coagulation time, INR international normalized ratio, FIB fibrinogen, FVIII factor VIII, s seconds
The difference in reference value range (in the brackets) might be attributed to
different coagulation tests devices among different medical institutions.
Table 2 The coagulation test trsults of Case 2 at different time points

Day 0 Day 3 Day 4 Day 5 Day 7
APTT (s) Normal (data missing) 66.4 (28–43.5) 50.0 (20–38) 58.5 (20–47.1)
PT (s) 12.8 (11–16) 12.2 (9–14) 13.5 (10–16.9)
TT (s) 14.7 (14–21) 17.2 (13–20) 14.1 (12.9–22.9)
INR 0.98 (0.8–1.31) 1.11 (0.8–1.3) 1.02 (0.9–1.22)
FIB (g/L) 4.8 (2–4) 4 (2–4)
FVIII:C% 5 (70–150) 3 (70–150)
APTT activated partial thromboplastin time, PT prothrombin time, TT thrombin time, INR international normalized ratio, FIB fibrinogen, FVIII factor VIII, s seconds
The difference in reference value range (in the brackets) might be attributed to different coagulation tests devices among different medical institutions.
The factor assays showed FVIII value decreased (Day routine methods could not stop bleeding until iodoform
7, FVIII: 10%), while the level of FII, FV, FVII, FIX, FX, gauze was used to fill the extraction sockets.
FXI, FXII were in the normal range (data not shown). The Based on the experience of Case 1, we suspected this
patient was diagnosed with mild hemophilia A. patient may be suffering from an asymptomatic coagu-
At last, the patient acquired complete hemostasis after lation dysfunction and suggested he had factor assays
receiving twice coagulation factor supplement therapy immediately.
(day 8 and 12, 400 IU of native plasma derived factor The factor assays performed on days 5 and 7 diag-
VIII). Iodoform gauze was safely removed 14 days after nosed mild hemophilia A and the concentration of FVIII
operation. Until the 28th day of postoperative follow-up, decreased continuously from 5 to 3% (Table 2: Day 5, Day
the patient had no hemorrhage again. 7). At last, the patient received FVIII supplement therapy
to achieve a favorable prognosis without bleeding.
Case 2
A 41-year-old man underwent extraction of his right
mandibular second molar (#47) with severe periodonti- Discussion and conclusions
tis at a dental clinic, followed by continuous bleeding. He Hemophilia is an X-linked congenital bleeding disorder
told the doctor that he had a physical examination a week characterized by a deficiency of coagulation factor VIII
ago and there were no abnormalities in his blood tests (FVIII), called hemophilia A (80–85% of all hemophilia
(data was missing) or other systemic diseases. Compress- cases), or factor IX (FIX), called hemophilia B (15–20% of
ing with sterile gauze, extraction site suturing and injec- all hemophilia cases) [3]. Hemophilia usually affects only
tion of 2.0 IU Hemocaogulase Bothrops Atrox were used, males who inherit an affected maternal X chromosome,
but failed to achieve hemostasis. The APTT value was while female patients are rare. Estimated prevalence at
significantly increased to 66.4 s (normal, 28.0 to 43.5 s) in birth is 24.6 cases per 100,000 males for all severities of
the blood coagulation tests (Table 2: Day 3). hemophilia A, and the definite diagnosis of this disease is
When the patient came to our hospital (Day 4), we factor assays or other appropriate specific investigations,
observed #47 alveolar cavity bleeding with swelling local such as genetic testing [3].
gingival, and residual root of the lower right first molar According to the circulating level of FVIII, hemophilia
(#46). Radiographs confirmed the #47 socket was empty. A can be classified as mild (5–40 IU/dL or 5–40% of
Coagulation function tests showed APTT prolonged normal), moderate (1–5 IU/dL or 1–5% of normal), and
to 50.0 s (normal 20–38 s) (Table 2: Day 4). The patient severe (< 1 IU/dL or < 1% of normal), and the constitu-
denied prior illness and injuries, allergies, anticoagulant tion ratio was mild 51%, moderate 25% and severe 21%
medication history, systemic and family diseases. respectively [3, 11]. Severe hemophilia usually has spon-
Although the APTT value exceeded the normal taneous bleeding into joints, muscles and soft tissues at
range, it did not reach the alarm value of our hospi- an early age, and those with moderate hemophilia have
tal (APTT > 100.0 s, PT > 30.0 s). We suspected that the occasional spontaneous bleeding or prolonged bleed-
bleeding might be related to the inflammatory granu- ing after minor trauma or surgery [11]. These two types
lation tissue in the extraction socket. Therefore, we of hemophilia are easy to diagnose according to medical
removed #46 residual root, gently cleaned both #46 and history and clinical symptoms.
#47 sockets and sutured the wound under local anes- Patients with mild hemophilia usually do not have
thesia. Then the situation was similar as in Case 1. All spontaneous bleeding, but only bleed abnormally
after major surgery or trauma [11]. Therefore, they are
Table 3 Interpretation of false APTT results

False negative results Strenuous exercise, stress, inflammation, or pregnancy [16–18]
The type of reagent used for the test [4]
Compensatory of other higher level clotting factors [19]

Inappropriate storage and handling conditions [3]
False positive results FXII deficiency [20]

Transient appearance of LAC [14, 21]
The reduction of coagulation factors because of massive blood loss [22]
Inappropriate storage and handling conditions [3]
LAC lupus anticoagulant
probably unaware of hemophilia before tooth extraction, Above all, APTT test results alone cannot be used to
leading to uncontrollable postoperative bleeding. exclude the presence of mild hemophilia. This disease will
Accurate diagnosis of hemophilia is essential to appro- bring great challenges to oral surgeons due to its ambigu-
priate management and treatments. The APTT testing ous clinical symptom and the unreliability of APTT test.
is conventionally used for assessing the contact factor The diagnostic tests of hemophilia are factor assays and
pathway of blood coagulation, screening deficiencies in other specific investigations like genetic assessment. Oral
intrinsic pathway, monitoring unfractionated heparin surgeons should be acquainted with these technologies
(UFH) therapy, as well as screening lupus anticoagulant and give timely advice to patients with potential bleeding
(LA) and assessing thrombosis risk [12]. It is consid- disorders.
ered to be a "global" coagulation test, which can indicate Many guidelines suggest that it is not recommended
intrinsic and common pathway abnormalities or defects, to perform indiscriminate coagulation screening tests
including hemophilia [13]. Clinically APTT alone is gen- before surgery or other invasive procedures to predict
erally considered to be an appropriate test for predicting postoperative bleeding in unselected patients [1]. A
individual bleeding risk during surgery [14]. detailed preoperative inquiry of medication history and
However, studies found that APTT may not be able to previous bleeding symptoms may be more useful than
exclude mild hemophilia. Luciá et al. [7] reported uncon- coagulation screening tests to predict the risk of bleed-
trollable bleeding in a boy who underwent tonsillectomy ing after tooth extraction [14] (Table 4). This is particu-
at the age of 4, but no abnormalities were found in coag- larly important for patients with potential hemophilia.
ulation tests including bleeding time (BT), APTT and Abnormal gingival bleeding, a common oral disease, may
prothrombin, while the patient was diagnosed with mild indicate coagulation dysfunction like hemophilia, plate-
hemophilia by coagulation factor assays at the age of 29. let deficiency, von Willebrand’s disease, and the use of
Hallet et al. [8] also reported a 12-year-old boy with an antithrombotic drugs, including fluindione, furosemide,
injured left eye. He had a normal preoperative APTT at amiodarone, paroxetine or ketoprofen [23].
38 s (normal range 27–39 s), while his FVIII:C level was The National Institute for Health and Care Excellence
25 IU/dL (mild hemophilia > 5–40 IU/dL; 5–40% of nor- (NICE) recommends tests of hemostasis for patients with
mal), and the boy was diagnosed with mild hemophilia a history of abnormal bleeding, anticoagulant medication
eventually. As exhibited in our case report, the preop- or liver disease [27, 28]. Because abnormal results may
erative APTT test results were within the normal range indicate a significant underlying hemostatic dysfunction
in Cases 1 and 2, while both were eventually diagnosed and it would also provide a useful baseline for the moni-
with mild hemophilia by factor assays. The latest guide- toring of factor VIII titer postoperatively [28]. Giuseppe
lines from WFH clearly state that APTT test results alone et al. [14] reviewed 7606 patients and found that the risk
cannot be used to exclude the presence of mild hemo- of uncontrollable postoperative bleeding increased only
philia A or B, because APTT may be within the normal when the APTT ratio > 1.3 (the reported therapeutic
range in some cases of mild hemophilia [3].In addition, APTT range divided by the control value for the reagent,
the results of APTT testing can be influenced by many normal range 0.82–1.20), while a slight APTT prolonga-
factors, resulting in false positive or false negative results, tion (APTT ratio, 1.2–1.3) can be considered at "low risk
and may lead to inappropriate precautionary measures or of bleeding" irrespectively of the type of surgery.
misjudgment, respectively [15] (Table 3).
Table 4 Detailed preoperative inquiry for suspicious patients

Preoperative inquiry Contents
Previous bleeding symptoms Continuous bleeding

Muscle hematoma, joint bleeding, easy bruising, gingival bleeding
Uncontrollable bleeding after undergoing surgical procedures
Family history Tracking back to more than three generations, especially the male members
Systemic diseases Liver disease: anemia, reduced hepatic synthesis of procoagulant factors,
and increased fibrinolytic activity [24]
Kidney disease: decreasing platelet function [25]
Medication history Aspirin, heparin, clopidogrel and warfarin [26]
We divide the patients into the following situations Etiologies and managements of bleeding after tooth
for reference according to preoperative inquiry and rel- extraction
evant blood tests:
1) Failure to follow postoperative instructions: inad-
1) Having a history of hemophilia: for these patients, a equate pressure of compressed gauze or eating too
general surgical treatment plan from hematologists hot food may lead to blood oozing from the extrac-
and comprehensive examination of coagulation function site. It’s advisable to continue compressing with
tion are necessary before tooth extraction. gauze until there is no more bleeding.
2) Having a history of abnormal bleeding: regular coag- 2) Lax suture: Slow bleeding can be seen from the
ulation screening tests should be performed before wound. Reinforce suture under local anesthesia until
surgery. Routine surgical operations can be carried there is no bleeding, observe for an hour with gauze
out on the patients with normal results; abnormal compressed before discharging the patient.
test results should be evaluated by hematologists 3) Alveolar bone fracture: small fragments should be
before surgery. removed while the larger fracture pieces with suf-
3) Without bleeding history: for the patients without ficient blood supply should be retained by resetting
bleeding history, preoperative coagulation tests are and fixing.
not necessary. Routine treatments can be carried 4) Osseous bleeding: small-scale fractures of the alveo-
out, but bleeding disorders should be considered if lar bone due to excessive force during tooth extrac-
the patients have uncontrollable bleeding like in the tion and the removal of bone resistance by the tur-
cases reported. bine may cause the nourishing blood vessels in the
alveolar bone to rupture. Usually, it can be found
Considering the relatively low incidence rate of during the operation. Aspirating to determine the
hemophilia and high expense, it is not recommended bleeding site, a flat instrument (such as an elevator
to perform coagulation factor assays immediately for or periosteal raspatory) or Mitchell’s trimmer [31]
patients with abnormal bleeding after tooth extraction. can be used to burnish local cancellous bone to help
Routine coagulation screening tests are recommended compress for hemostasis in the area [32].
to rule out underlying severe disease. Meanwhile, sur- 5) Infection: A large area of infection causes granulation
geons should evaluate the etiologies of bleeding, and tissue to form at the base of the socket, which may
then deal with them respectively. Acute arterial hemor- impair clotting and result in bleeding profusely [32].
rhage after tooth extraction may be related to the rup- The management of postoperative infection involves
ture of large vessels in maxillofacial bone or soft tissue, thorough irrigation of the wound site, curettage of
or the less common but more critical vascular anoma- infected granulation tissue and appropriate antibiot-
lies such as pseudoaneurysm or vascular malformation ics [33, 34]. Incision and drainage of the abscess are
[29]. This acute bleeding can’t be managed effectively by required with abscess formation.
local compression or packing of the socket. However,
most patients with postoperative bleeding present with In addition to active local treatments, oral surgeons
slow and continuous oozing which can be controlled by can use hemostatic drugs or materials around the tooth
local interventions [30]. The recommended local treat- extraction socket, or systemically, to control hemor-
ment procedures are provided for reference (Fig. 1). rhage, including tranexamic acid, oxidized cellulose,
thrombin, fibrin sealant, gelatin sponge, and HemCon
Fig. 1 The procedures for bleeding patients after tooth extraction
bandage, a special dental dressing [26, 35–37]. In addi- and hemostasis urgently in salvage treatment of hemor-
tion, paracetamol/acetaminophen can be used for pain rhagic arteriovenous malformations in jaws [42].
relief to alleviate the patient’s anxiety. It’s important In conclusion, tooth extraction is the most frequent
to note that NSAID (non-steroidal anti-inflammatory invasive procedure in general population [43], and it
drugs), including ibuprofen, are not recommended in is likely to be the most common surgical procedure
hemophilia because it will aggravate the existing bleed- required in people with hemophilia, especially those
ing disorder by inducing platelet dysfunction [38]. For living in countries with restricted resources [44]. As
patients with severe trauma or bleeding caused by an oral surgeon, it’s important to ensure the safety of
tooth extraction, antibiotics should be prescribed to the operation, perform timely treatment for bleed-
prevent infection [39]. ing patients and provide reasonable suggestions for
If the patient still bleeds after the above interven- patients with potential bleeding disorders.
tions, a packed iodoform gauze can be placed in the Coagulation screening tests including APTT alone
extraction socket with figure-of-eight sutures. At the are not entirely reliable, especially for asymptomatic
same time, the patient should be sent to the depart- mild hemophilia patients. A detailed preoperative
ment of hematology for detailed coagulation function inquiry is more useful than unselective preoperative
examinations. tests. We divided patients into the following three cat-
As a last-ditch emergency material, iodoform gauze egories based on the results of coagulation tests and
can supply continuous and reliable physical pressure postoperative bleeding: (1) for the normal patients, rou-
by fixing to adjacent soft tissue or tooth because of tine tooth extraction treatment can be carried out; (2)
its relative incompressibility compared with conven- for the bleeding patients with normal coagulation tests
tional hemostatics, such as gelatin sponge or HemCon results, local hemostatic therapy can be performed; (3)
bandage. Moreover, after contacting with tissue fluid hemophilia and other coagulation disorders should be
and blood, the iodoform can slowly decompose free considered if the results are abnormal and conventional
iodine, which has a bactericidal effect. Iodoform has treatments fail.
little irritation to tissues, and the effects of promoting
granulation tissue regeneration will promote the heal-
Abbreviations
ing of tooth extraction wounds [40]. This unabsorbable FVIII: Factor VIII; APTT: Activated partial thromboplastin time; PT: Prothrombin
material needs to be removed 10–14 days after surgery. time; INR: International normalized ratio; FIB: Fibrinogen; TT: Thrombin time; s:
Iodoform gauze is usually used to stop bleeding and Seconds; UFH: Unfractionated heparin; LA: Lupus anticoagulant; BT: Bleeding
time; NSAID: Non-steroidal anti-inflammatory drugs.
prevent infection in emergency management of high-
energy shell fragment midface complex injuries [41]
18347819, 2014, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/adj.12199 by Baskent University, Wiley Online Library on [10/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Australian Dental Journal
The official journal of the Australian Dental Association
Australian Dental Journal 2014; 59: 296–301
doi: 10.1111/adj.12199
Protocol in managing oral surgical patients taking

dabigatran
O Breik,* A Cheng,† PJ Sambrook,‡ AN Goss§
*Registrar, Oral and Maxillofacial Surgery Unit, Royal Adelaide Hospital, Adelaide, South Australia.
†Senior Registrar, Oral and Maxillofacial Surgery Unit, Royal Adelaide Hospital, Adelaide, South Australia.
‡Head of Unit, Oral and Maxillofacial Surgery Unit, Royal Adelaide Hospital, Adelaide, South Australia.
§Professor, The University of Adelaide and Emeritus Consultant, Oral and Maxillofacial Surgery Unit, Royal Adelaide Hospital, Adelaide,
South Australia.
ABSTRACT
New anticoagulants are being introduced into the market. These drugs are orally administered, have predictable pharma-
cokinetics and dose response, do not require monitoring and have an acceptable safety profile when used appropriately,
and so avoid many of the disadvantages and possible complications of warfarin and heparin. Dabigatran is the most
widely used, and has been approved by the Therapeutic Goods Administration. The use of dabigatran will likely increase
in the coming years, and so it is important for dentists to be aware of its mechanism of action, the possible complica-
tions, and how to reverse the bleeding if it occurs. This review discusses dabigatran and reports on our experience of five
cases, and provides practical clinical advice on how to manage patients on dabigatran who require dental treatment,
particularly extractions.
Keywords: Anticoagulants, bleeding, dabigatran, extractions, oral surgery.
Abbreviations and acronyms: aPTT = activated partial thromboplastin time; DVT = deep venous thrombosis; FFP = fresh frozen
plasma; INR = International Normalized Ratio; LMWH = low molecular weight heparin; PT = prothrombin time; TGA = Therapeutic
Goods Administration; TT = thrombin clotting time; UFH = unfractionated heparin.
(Accepted for publication 24 November 2013.)
carefully monitored to ensure therapeutic dosing.

INTRODUCTION
Also, low molecular weight heparin (LMWH) – such
Anticoagulants are among the most commonly used as enoxaparin – needs to be administered subcutane-
medications in our community. They are predomi- ously, which makes it useful in the hospital setting
nantly prescribed to patients at risk of venous throm- but limits its application in the outpatient setting.
boembolism (history of previous thromboembolism, To find alternatives to heparin and warfarin, signifi-
immobilized hospital patients, patients after major cant research has gone into the development of new
surgery, pregnancy, etc.), or those at risk of embolic classes of anticoagulants. Several novel agents have
strokes (patients with atrial fibrillation, prosthetic undergone large scale clinical trials to compare their
heart valves). The most common anticoagulant efficacy and safety profiles to current anticoagulants.
encountered in outpatient oral surgical and dental These novel agents operate on targeted inhibition of
practice is warfarin. The use of warfarin is associated specific proteins or proteases of the coagulation
with many difficulties including its delayed onset of cascade such as thrombin and activated factor Xa. A
action, individualized dosing regimens, many drug detailed discussion of these is beyond the scope of this
and food interactions, and the need for regular article, but references to some key studies have been
monitoring and adjustment. The other main anticoag- provided.1–3 The thrombin inhibitors have been the
ulants are the heparins, which are mainly used in the main focus of research, and one of the agents
hospital environment. They are also not ideal dabigatran (Pradaxa®) has Therapeutic Goods
anticoagulants, mainly because unfractionated heparin Administration (TGA) approval since November 2008
(UFH), needs to be administered parenterally or for post-orthopaedic surgery thromboprophylaxis.4 It
subcutaneously, it has long-term side effects such as has also been approved by the TGA for prevention of
osteoporosis and thrombocytopenia, and must be thromboembolism associated with atrial fibrillation
296 © 2014 Australian Dental Association
Protocol for patients on dabigatran
since April 2011.5 As this drug has made its way into Hence the dose needs to be adjusted in patients with
our hospitals and the community and are being pre- creatinine clearance of <50 ml/min, and the drug is
scribed by general practitioners, it is important for all contraindicated in patients with creatinine clearance
medical and dental practitioners to be aware of these of <30 ml/min.14 Dabigatran is not metabolized by
drugs, how they work, how to administer them, and cytochrome p450, and it displays low protein binding
most importantly how to deal with complications aris- (approximately 35%), and so the risk of drug interac-
ing from them. tion is low.15
The major advantages of dabigatran are that it is
orally administered, and it has predictable pharmaco-
Thrombin inhibitors
kinetics and dose response. For the prescribing medi-
The antithrombotic activity of the heparins is medical practitioner, this allows a fixed dose regimen in
ated by their ability to potentiate the activity of anti- most patients without the need for routine monitoring
thrombin III. Normally the inactivation of thrombin of anticoagulant effect.16
by antithrombin III is a slow process, but after con- Most of the initial clinical studies performed have
formational change induced by heparin, antithrombin been non-inferiority trials comparing dabigatran with
irreversibly binds to and inhibits the active site of enoxaparin for thromboprophylaxis after orthopaedic
thrombin. The antithrombin activity is potentiated surgery, or dabigatran and warfarin for atrial fibrilla-
1000 times its normal activity.6 This binding of the tion. The studies comparing dabigatran with enoxapa-
heparin-antithrombin complex to thrombin requires rin demonstrated non-inferiority of dabigatran with
access to multiple binding sites on the thrombin com- enoxaparin, and similar rates of bleeding.17,18 In the
plex. The binding is impaired when the thrombin is RE-LY study comparing dabigatran with warfarin in
already bound to fibrin, limiting the capacity for the patients with atrial fibrillation, at the dabigatran dose
inhibition of fibrin-bound thrombin, which is still of 110 mg twice daily, there was similar efficacy in
capable of further thrombus growth.7 Since direct preventing thromboembolism and stroke as compared
thrombin inhibitors are independent of antithrombin, with warfarin (to target INR 2-3), but statistically
they are able to inhibit soluble circulating thrombin significant reduced rates of major bleeding, which is
and thrombin which are bound to fibrin. very promising.19 Table 1 compares the properties of
The univalent direct thrombin inhibitors such as dabigatran and warfarin.
ximelagatran and dabigatran reversibly bind only to As dabigatran acts on thrombin mediated conver-
the active site on the thrombin molecule, inhibiting sion of fibrinogen to fibrin, it has an effect on all of
both free and clot bound thrombin.8,9 Direct thrombin the routine coagulation assays. However, the different
inhibitors also have an antiplatelet effect by reducing tests seem to behave differently with increasing con-
the thrombin mediated activation of platelets.10 One of centrations of dabigatran.20 Prothrombin time (PT)
the early direct thrombin inhibitors ximelagatran and in turn the International Normalized Ratio (INR)
(Exantra®) demonstrated a good safety profile and rea- are not normally affected by dabigatran, but at very
sonable efficacy compared with enoxaparin for throm- high doses may be elevated up to an INR of 2.0.16
boprophylaxis in major orthopaedic surgery,11 but There appears to be a relationship between increasing
with long-term use the drug appeared to be hepatotoxic dabigatran levels and prolongation of the activated
with prolonged elevation of liver function tests.12 partial thromboplastin time (aPTT). At peak concen-
tration, the aPTT is approximately two-fold that of
control, and 12 hours later (trough level), the aPTT is
Dabigatran etexilate
approximately 1.5-fold that of control. As a general
The direct thrombin inhibitor dabigatran etexilate has rule, a normal aPTT suggests minimal drug is present,
recently been investigated in large multicentre trials whereas a significantly prolonged aPTT at trough, or
for orthopaedic thromboprophylaxis and demon- at peak time suggests that there is excess drug16
strated sound safety and efficacy. Dabigatran etexilate (Table 2). Other more accurate tests can also be
is a low molecular weight prodrug of dabigatran, a ordered such as thrombin clotting time (TT) and
potent molecule that specifically and reversibly inhib- serum dabigatran levels,16 but for practice outside of
its free and clot-bound thrombin. When taken orally, the hospital setting, the aPTT should be sufficient to
it has a bioavailability of 6.5%, terminal half-life of determine if the dose effect of dabigatran will cause
12 to 17 hours, with its peak plasma volume 2–3 significant bleeding or not.
hours after administration.13 Eighty per cent of circu-
lating dabigatran is cleared renally, with the remain-
Cases
der conjugated and excreted via the bile. Patients with
a moderate or severe decline in renal function exhibit We report the outcome of five patients on dabigatran
reduced clearance and elevated plasma concentration. who underwent tooth extractions. Cases 1–3 were for
© 2014 Australian Dental Association 297
O Breik et al.
Table 1. Comparison between warfarin and thromboprophylaxis due to atrial fibrillation. The
dabigatran dabigatran was continued. Tooth 24 was extracted
without complication and the socket was sutured
Property Warfarin Dabigatran
tightly. There was no significant intraoperative or
Administration Oral Oral postoperative bleeding.
Dosing Individualized – Fixed dose
highly variable dependent
on renal function
Onset of Action 36–72 hours 2–4 hours
Case 2
Duration of Action 48–96 hours 24 hours
Elimination half-life 20–60 hours 14–17 hours
Eighty year old male referred for extraction of tooth
Interactions Yes – many Possible interaction 36. He was taking dabigatran for atrial fibrillation.
drugs and foods with drugs that Dabigatran was continued. Tooth 36 was extracted
impair renal
function
and the socket sutured without significant intraopera-
Clearance/ Metabolized by Renally cleared tive bleeding. The patient reported minor postopera-
Metabolism hepatic route tive bleeding for three hours not significant to warrant
Bleeding risk Significant Significant – not
worse than
the patient returning to the hospital. Bleeding was
warfarin or controlled by pressure.
enoxaparin in
RCTs
Monitoring INR checked Not needed Case 3
fortnightly
Bridging Needed due to Not needed Sixty-seven year old male referred for extraction of
anticoagulation initial procoagulant
effect
tooth 17. His medical history included ischaemic
Reversibility Vit K, fresh frozen Partially reversed heart disease, atrial fibrillation, hypertension and
plasma, prothrombin with haemodialysis gout. He was taking 110 mg dabigatran daily. Dabig-
complex concentrates (60% after
2 hours)
atran was continued and tooth 17 was extracted and
the socket sutured and packed with SurgicelTM. There
was no significant intraoperative or postoperative
bleeding encountered.
Table 2. Summary of correlation between coagulation
test results and bleeding risk
Case 4
Test result Bleeding risk
Seventy-two year old female referred for extraction of
aPTT and TT normal No drug effect present
aPTT normal or slightly + Drug effect present, multiple teeth – 44, 46 and 35. Her medical history
prolonged and TT abnormal but likely low level included hypertension, type 2 diabetes mellitus and
aPTT and TT abnormal ++ Drug effect present atrial fibrillation. She was taking 110 mg dabigatran
aPTT = activated partial thromboplastin time; TT = thrombin time. daily. The dabigatran was stopped 48 hours preopera-
tively and the teeth were extracted without complica-
tion. There was no significant intraoperative or
single tooth extractions and cases 4 and 5 were for postoperative bleeding noted.
multiple tooth extractions. A summary of the cases is
provided in Table 3.
Case 5
Eighty-four year old male referred for left sided facial
Case 1
swelling secondary to multiple abscessed teeth. His
Seventy-eight year old male referred for extraction of dentition was found to be grossly carious. His medical
tooth 24. He was taking dabigatran 110 mg daily for history included hypertension, type 2 diabetes mellitus
Table 3. Summary of cases
Case Age Gender Reason for Dabigatran Procedure Postop complications
dabigatran management
1 78 M AF Continued Extraction 24 None

2 81 M AF Continued Extraction 36 Minor postop bleed
3 67 M AF Continued Extraction 17 None
4 72 F AF Ceased 48 hrs Extraction of multiple None
preop teeth – 44, 46, 35
5 84 M AF Continued Extraction of 18 teeth Severe postop bleeding
under GA and drainage requiring suturing under
of abscess anaesthetic and ceasing dabigatran

and atrial fibrillation. His medications included ator- taken. Referral to an oral and maxillofacial surgeon
vastatin, digoxin and 110 mg dabigatran daily. Preop- should be strongly considered for patients with history
erative coagulation studies revealed an elevated INR of renal failure, patients needing invasive surgical pro-
of 1.5 and aPTT of 47 seconds. The dabigatran was cedures likely to have a high risk of bleeding, or those
not ceased preoperatively. He was taken to theatre patients who are also on other anticoagulants or anti-
and 18 teeth were extracted under a general anaes- platelet agents (such as clopidogrel or aspirin). The
thetic as well as drainage of the facial abscess. Intra- surgeon will liase with the patient’s physician to con-
operatively it was noticed that he had significant sider temporary cessation of the dabigatran 24 hours
bleeding and the wounds were sutured tightly. Postop- (two half-lives) before the procedure is recommended.
eratively but while still in hospital, he had significant The aPTT or TT should be checked preoperatively to
haemorrhage necessitating a return to theatre for fur- ensure the drug effect is reduced. If aPTT is still pro-
ther suturing and haemorrhage control. The dabiga- longed, then a further 24 hours may be required to
tran was then ceased, and the bleeding stopped 24 reduce the risk of bleeding.
hours later. Cessation of dabigatran or any anticoagulant
The cases of single tooth extractions were managed should only be made in consultation with the patient’s
without ceasing the dabigatran and there were no epi- general practitioner/cardiologist, who will weigh up
sodes of significant postoperative bleeding. Case 4 the risk of bleeding from the proposed procedure with
reports the successful extraction of multiple teeth after the risk of thrombosis/stroke in each individual
ceasing dabigatran for 48 hours, but ceasing the patient. For patients who are on dabigatran for atrial
dabigatran for 24 hours would have been equally fibrillation without a history of a previous stroke,
effective. Case 5 reports significant postoperative stopping the dabigatran for 24 hours is considered
bleeding in a patient who underwent a full clearance relatively safe. For patients with a history of recent
of his remaining dentition while still taking dabiga- deep venous thrombosis (DVT), pulmonary embolism,
tran. The bleeding ceased after stopping the dabiga- or embolic strokes, it may be dangerous to cease the
tran for 24 hours. The following section describes the dabigatran. The treating physician may decide to use
current management protocol we recommend for alternative anticoagulation such as heparin preopera-
managing patients taking dabigatran. tively as these have established protocols for oral sur-
gical management. The timing of cessation of the
dabigatran also depends on the patients renal func-
Management protocol
tion.16,22 Dabigatran has a short half-life (14–17
When considering the management of these patients, hours) and so in otherwise healthy patients with nor-
it is essential to always keep in mind that stopping mal renal function, stopping the dabigatran 24 hours
the dabigatran leads to an increased risk of stroke or (two half-lives) before the operation is adequate time
venous thrombosis in these patients. Intraoral bleeding to reduce the risk of bleeding to normal. If the patient
can often be managed and is rarely catastrophic, but has a history of renal impairment, they are likely to
a stroke can be permanently debilitating. need the dabigatran stopped 2–5 days before the oper-
ation depending on their renal function.16 Checking
coagulation tests such as aPTT preoperatively will
Elective treatment
help determine if the dabigatran has been stopped for
long enough. Patients with severe renal impairment
General dental procedures
should not be prescribed dabigatran but sometimes
For simple procedures with a minor bleeding risk such this is overlooked and these patients often have
as scaling, restoration with use of a matrix band, severely deranged coagulation markers and can bleed
endodontic treatment, or single tooth extractions, the spontaneously.23 It is important to keep in mind that
dabigatran will likely not need to be stopped like dabigatran will mainly be indicated in elderly patients,
warfarin.21 For single uncomplicated tooth extrac- and in these patients renal function may deteriorate
tions, local haemostatic measures such as mechanical without notice. Persistently abnormal coagulation
pressure, suturing and topical haemostatic agents studies in patients who have ceased dabigatran for
(such as GelfoamTM or SurgicelTM) should be adequate more than 24 hours should prompt practitioners to
to control the bleeding. assess renal function for possible progressive renal
impairment.
If the dabigatran is ceased, it can be restarted when
Multiple extractions
the risk of postoperative bleeding is minimal, usually
For patients undergoing multiple extractions, due to 24–48 hours after surgery. When restarting the dabig-
the increased bleeding risk, patients should be assessed atran, the anticoagulant effect reaches its optimum
by their own physician before the procedure is under- level within two hours of administration.
O Breik et al.
Emergency surgery in the absence of tissue factor.25 In a rat-tail model,

addition of rFVIIa significantly reduced bleeding time
Oral and maxillofacial surgical emergencies that need
and aPTT associated with a high dose of dabigatran
prompt surgical intervention such as acute odontogenic
in a dose-dependent manner.16 However, no adequate
infections with risk of airway compromise or haemor-
studies on human subjects have been performed to
rhaging facial fractures will require immediate referral
firmly establish the usefulness of rFVIIa in bleeding
to the nearest tertiary referral centre. Currently, there is
patients on dabigatran. In the case of an emergency,
no effective reversal agent for dabigatran.
rFVIIa or other agents can be considered in consulta-
In the situation where emergency surgery is needed
tion with the haematology team. See Table 4 for a
in a patient taking dabigatran, then haemodialysis
summary of the management protocol for patients on
should be considered. Dabigatran can be cleared with
dabigatran seeking oral surgical management.
dialysis because of its limited plasma protein binding.
The guidelines proposed in this paper are based on
The mean percentage of the drug removed was 62%
the fact that an effective reversal agent is still not
at two hours and 68% at four hours as shown in an
available. With further surgical experience on patients
open label study on patients with end stage renal fail-
taking the drug, and the advent of a simple, effective
ure after taking 50 mg of dabigatran.16 A recent case
reversal agent, these guidelines will likely change. At
report described the safe use of haemodialysis for
this stage, the protocol proposed here is similar to the
reversal of dabigatran in a patient requiring ortho-
protocol for the treatment of patients on warfarin
tropic heart transplantation.24
with additional precautions for patients undergoing
In the case of a patient presenting with bleeding
multiple extractions in the same appointment due to
while on dabigatran, the dabigatran should be ceased,
the higher bleeding risk. Future clinical research is
mechanical pressure should be applied, and intravascu-
required to determine if these guidelines are effective,
lar volume should be maintained with intravenous
or if stopping dabigatran preoperatively for all
fluid replacement and blood products such as fresh
patients is required to reduce bleeding complications.
frozen plasma. This maintains adequate renal perfu-
sion enhancing removal of the drug from the circula-
tion. If all else fails, haemodialysis must be considered.
SUMMARY
Several agents have been considered for reversal of
dabigatran but they are lacking any adequate studies Dabigatran is a direct thrombin inhibitor that is likely
in human subjects. The use of blood products like to become more widely prescribed due to its ease of
fresh frozen plasma (FFP) will not reverse the antico- use. Due to its more predictable pharmacokinetics,
agulant effect of dabigatran. This is because the circu- and standard dose regimens, stopping and recom-
lating dabigatran will inhibit any newly transfused mencing the dabigatran is easier and causes less risk
thrombin. Recombinant factor VIIa (rFVIIa) is a than warfarin. These decisions should still only be
potent procoagulant and general haemostatic agent made in conjunction with the patient’s general medi-
that can initiate haemostasis at sites of bleeding by cal practitioner. The protocol recommends not stop-
directly activating thrombin on the surface of platelets ping the dabigatran for standard procedures such as
Table 4. Summary of management of oral surgical patients taking dabigatran

Guidelines
Dental procedures and - Not necessary to discontinue use of dabigatran in patients with normal renal function
uncomplicated simple - Local haemostatic measures need to be applied – mechanical pressure, suturing and
tooth extractions local haemostats
Extraction of multiple - Consider referral to an oral and maxillofacial surgeon
teeth or elective oral/ - In consultation with the patient’s physician, will consider discontinuing dabigatran or
maxillofacial surgical changing to another anticoagulant preoperatively
procedures or patients - If normal renal function will discontinue dabigatran 24 hours before procedure
taking other anticoagulants - Consider checking aPTT preop
or antiplatelet agents - If abnormal renal function, consider discontinuing for 48 hours or longer depending on
degree of renal impairment16
- Local haemostatic measures should be used
- Can recommence dabigatran 24–48 hours after operation
Emergency oral/maxillofacial - Refer immediately to a tertiary referral centre
surgical procedures or - Cease dabigatran, mechanical pressure, maintain intravascular volume with fluid
patients presenting with resuscitation and blood products such as FFP
severe haemorrhage - Contact haematology for consideration of rFactor VIIa administration or other agents
- Consider haemodialysis

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high-dose factor VIIa is independent of tissue factor. Br J Hae-
7. Liaw PCY, Becker DL, Stafford AR, Frenburgh JC, Weitz JI. matol 1997;99:542–547.
Molecular basis for the susceptibility of fibrin-bound thrombin to
inactivation by heparin cofactor II in the presence of dermatan 26. South Australian Health. Pathology Haemostasis/Thrombosis
suphate but not heparin. J Biol Chem 2001;276:20959–20965. Group Dabigatran Guidelines. Available at: http://www.sahealth.
sa.gov.au/wps/wcm/connect/eea3550048fb0a5f895afd7675638bd8/
8. Hauel NH, Nar H, Priepke H, Ries U, Stassen JM, Wienen W. DabigatranClinicalGuidelines-2-PHCS-PSS-20120223.pdf?MOD=
Structure-based design of novel potent nonpeptide thrombin AJPERES&CACHEID=eea3550048fb0a5f895afd7675638bd.
inhibitors. J Med Chem 2002;45:1757–1766.
27. Oral and Dental Expert Group. Therapeutic guidelines: oral
9. Wienen W, Stassen JM, Priepke H, Ries UJ, Hauel N. In-vitro and dental. Version 2. Melbourne: Therapeutic Guidelines Lim-
profile and ex-vivo anticoagulant activity of the direct thrombin ited, 2012.
inhibitor dabigatran and its orally active prodrug, dabigatran e-
texilate. Thromb Haemost 2007;98:155–162.
10. Xiao Z, Theroux P. Platelet activation with unfractionated hep- Address for correspondence:
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molecular weight heparin and with a direct thrombin inhibitor. Dr Omar Breik
Circulation 1998;97:251–256. Registrar
11. Evans HC, Perry CM, Faulds D. Ximelagatran/Melagatran: a Oral and Maxillofacial Surgery Unit
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2005;46:1986–1995. Email: omar.breik@gmail.com

Journal of the Formosan Medical Association (2018) 117, 979e986
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.jfma-online.com
Original Article
Management of dental extractions in

patients on warfarin and antiplatelet
therapy
Shin-Yu Lu*, Liang-Ho Lin, Shui-Sang Hsue
Oral Pathology and Family Dentistry Section, Department of Dentistry, Kaohsiung Chang Gung
Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
Received 5 August 2018; received in revised form 14 August 2018; accepted 20 August 2018
KEYWORDS Background/Purpose: Planning dental extractions for Taiwanese patients on antithrombotic

Dental extractions; therapy remains controversial. This study aimed to examine management of dental extraction
Warfarin; in patients on warfarin and antiplatelet therapy.
Aspirin; Methods: Subjects comprised 1331 patients, with (1) 60 on warfarin with intentional normal-
Clopidogrel ized ratio (INR) below 4.0 (warfarin continued: 28 patients/33 occasions; warfarin stopped
and switched to heparin under hospitalization: 32 patients/37 occasions); (2) 183 on antiplate-
let therapy (aspirin: 125 patients/185 occasions; clopidogrel: 42 patients/65 occasions; dual
therapy: 16 patients/24 occasions); and (3) a control group of 1088 patients/1472 occasions
without any antithrombotic therapy. The patient’s clinico-demographic parameters, warfarin
effectiveness (dose and INR levels) and antiplatelet therapy, number and type of dental
extraction and incidence of postoperative bleeding were investigated.
Results: Incidence of postoperative bleeding in the warfarinized group (warfarin continued:
9.1%; warfarin stopped: 8.1%) was higher than in the antiplatelet group (aspirin: 1.1%; clopido-
grel: 3.1%; dual antiplatelet: 4.2%), and the control group (0.7%), but these differences were
not significant and unrelated to INR or number and type of dental extraction. Postoperative
hemorrhage was managed successfully by repacking with Gelfoam impregnated with tranexa-
mic acid powder in most patients.
Conclusion: The study indicated that there is no need to interrupt warfarin (INR<4.0) and an-
tiplatelet therapy before dental extractions in Taiwanese patients. A sufficient hemostasis
could be obtained using local measures. This approach can save these individuals from
becoming exposed to the risk of thromboembolism and the inconvenience of bridging anticoa-
gulation with heparin.
Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
* Corresponding author. Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Niaosong, Kaohsiung, 833, Taiwan, ROC. Fax: þ886
7317123 x8288.
E-mail address: jasminelu@adm.cgmh.org.tw (S.-Y. Lu).
https://doi.org/10.1016/j.jfma.2018.08.019
0929-6646/Copyright ª 2018, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
F 2 A( DB 1B A 2 2C )2B C 1 E AB C A 2/ 3 ,B E A 3AD2A
A AB 2 DB 0 C A DB B F C DC A BB A C ,B E A. ( A CB A B AE
980 S.-Y. Lu et al.
Introduction moderate-intensity anticoagulation (INR 2.0e3.0) for most

indications of warfarin, such as prophylaxis and treatment
To routinely stop warfarin or antiplatelet therapy for 3e10 of venous thrombosis, pulmonary embolism, and prevention
days before dental extraction in order to avoid the risk of of systemic embolism secondary to valvular heart disease or
bleeding is common among physicians and dentists. It has AF.16,17 The exceptions that require high intensity anti-
been assumed that discontinuing antithrombotic medica- coagulation (INR 3.0e4.5) are patients with mechanical
tions for a short period presents negligible risk to the pa- heart-valve prostheses.
tient. But, the rebound hypercoagulable state with Taiwan Health and Welfare reported that cerebrovas-
increased thrombin activity after stopping warfarin and cular disease remained the top 3 leading causes of death in
progressive recovery of platelet function with excessive recent 10 years.18e20 Among the stroke population,
thromboxane A2 activity plus decreased fibrinolysis after approximately 15% are related to atrial fibrillation
interrupting aspirin are associated with the risk of (AF).20e22 Studies suggest that AF patients without any
thromboembolism,1e6 thereby exposing the patient to a preventive treatment increase the risk of stroke five-
higher risk of recurrent thrombosis, stroke, myocardial fold.22e26 Such cardioembolic strokes are often fatal or
infarction (MI), and other coronary events.6e15 Collet et al. severely disabling.27,28 Guidelines recommend warfarin or
reported that nine of 475 MI patients (1.9%) had dis- novel oral anticoagulants (NOACs) for ischemic stroke pa-
continued aspirin therapy within 15 days prior to intended tients related to AF.24 Among nonvalvular AF patients, an
surgery.12 Wahl reported that of 493 patients undergoing INR of 2.0 or greater reduces not only the frequency of
542 cessations of warfarin for dental surgery, only five ischemic stroke but its severity and the risk of death from
(1.0%) had serious embolic complications, but four of them stroke as well.27 Randomized trials have shown that
died.3e5 The present researchers have experienced a mor- warfarin reduces the relative risk of stroke by 64% while
tality risk occurring in a 68-year-old Taiwanese female with anti-platelet agents only reduces this risk by 22%.22e30 But,
hypertension, diabetes, and a stroke after cessation of underprescription or underdose of warfarin was observed
warfarin. She reported being asked to stop warfarin for 5 worldwide.24 warfarin therapies are problematic with many
days prior to extraction of a mobile premolar. Two days disadvantages including unpredictable response, numerous
after tooth extraction, she was sent to the emergency room drug-drug or drug-food interactions, narrow therapeutic
because of sudden onset of chest tightness, cold sweating, range requiring routine coagulation monitoring and there-
dizziness, and dyspnea. An acute MI with total occlusion of fore frequent dose adjustment, slow onset/offset of ac-
right coronary artery was diagnosed, and a percutaneous tion, genetic variation, and finally the concerns of bleeding
coronary intervention was performed. We also witnessed complications.4 A national representative cohort study has
three strokes occurring in two diabetic females with hy- shown a progressive increase in the use of warfarin among
pertension and one male with atrial fibrillation (AF) who Taiwanese patients over time. But, usage rates (24.7%) are
had been instructed to stop taking aspirin 7 days before a still low when compared with Western populations (36.6%e
single dental extraction. The chronological link between 65.0%).24,26 The use of antithrombotic therapy improved
acute thromboembolic events and aspirin or warfarin after NOACs became available. But, the majority of AF
withdrawal may not have been a matter of chance. patients still received antiplatelet agent for emboli stroke
Most Western studies do not recommend interrupting prevention.24
antiplatelet and warfarin therapy or replacing warfarin Prophylactic aspirin use in the United States has been
with heparin before dental extraction if the international estimated at 33% in high-risk individuals (e.g., those with
normalized ratio (INR) levels <4.0 are maintained. Thus no coronary artery disease, MI, stroke, or peripheral vascular
marked differences in the incidence or volume of post- disease), 16% in those with multiple cardiovascular disease
extraction bleeding happen.1e11 Stopping warfarin for 2 (CVD) risk factors, and 12%e49% in those with dia-
days might increase the risk of thromboembolic events7,8 betes.12e19 Diabetes is a complex metabolic disease with
The risk is difficult to estimate, but is probably between increased macrovascular and microvascular complications,
0.02% and 1%.3,4 Warfarin has a long half-life of 48e72 h and which are often the leading causes of deaths in patients
delayed-onset of 76e96 h of action after cessation as well with type 2 diabetes.19
as restarting treatment. Accordingly, patients may have at Antiplatelet therapy was reported to have reduced the
least 2e3 days of sub-therapeutic anticoagulation around overall mortality of vascular disease by 15% and non-fatal
the time of surgery, increasing the risk of thromboembolic vascular complications by 30%.12 Dual therapies with aspirin
events.3e11 If patients with INR <4 could be treated and clopidogrel have a synergistic antiplatelet effect, as
routinely without altering their warfarin regime, then it is the two drugs affect platelet aggregation by different
possible that most dental extractions could be done in mechanisms. Compared with aspirin alone, dual antiplate-
general practice on the same day as regular INR blood let therapy can provide an additional 20% reduction in the
monitoring. This would be more convenient, cost-effective, relative risk of MI or stroke.29
and quicker for the patients, and would help to reduce In Taiwan, the debate about continuing or stopping
hospital waiting lists for bridging anticoagulation with warfarin or antiplatelet therapy prior to dental extraction
heparin. has been going on for a long time, with opinions varying
The optimal therapeutic range of warfarin therapy var- between institutions and doctors. In over 25 years of clin-
ies for different indications and for patients with various ical practice, the present researchers have not withheld
characteristics. Both the British Society for Hematology and warfarin and antiplatelet therapy in any of their patients
the American College of Chest Physicians recommend seeking dental extractions. Perioperative bleeding has been
Dental extractions on warfarin and antiplatelet therapy 981
shown not to differ significantly between patients who divided into antiplatelet and warfarinized groups. The an-
continue warfarin and single or dual antiplatelet therapy tiplatelet group comprised 183 patients, of whom 125 were
and those who stop it of their own accord. on aspirin (100 mg/day), 42 were on clopidogrel (75 mg/
The aim of this retrospective study was to evaluate the day), and 16 were on dual therapy (100 mg aspirin plus
incidence of postoperative bleeding after dental extrac- 75 mg clopidogrel) (Table 1). The warfarinized group
tions in patients without interrupting warfarin or anti- comprised 60 patients, of whom 32 were hospitalized for
platelet therapy and in patients whose warfarin were replacement of warfarin with heparin, and 28 were out-
temporarily replaced with heparin. patients without interrupting warfarin therapy (Table 2).
The 32 consecutive inpatients on warfarin for heart-valve
replacement were referred from a cardiac surgeon who
Patients and methods arranged for them to stop taking warfarin and administered
bridging anticoagulation with heparin several days before
The study was approved by the Institutional Review Board extractions, with mean preoperative INR (range) from a
and comprised a total of 1363 consecutive subjects who level of 2.30 (1.32e3.12) brought down to 1.14
underwent dental extractions at the Family Dentistry (1.04e1.32). After the extractions, they resumed taking
Department of Kaohsiung Chang Gung Memorial Hospital warfarin on the same day. All 32 patients were hospitalized,
between January 2010 and June 2014. Data were retrieved at least for one week, for observation. The 28 outpatients
from the chart notes made at each visit, and the following were using warfarin for heart valve replacement (11 pa-
factors were investigated: patient’s clinico-demographic tients), AF (6 patients), ischemic cerebrovascular or heart
parameters (gender, age, dental disease, and medical disease (6 patients), venous thrombosis (2 patients), liver
illness), warfarin effectiveness (dose and INR levels) and transplant (2 patient), and heart transplant (1 patient).
antiplatelet therapy, number and type of dental extraction They were instructed not to alter their warfarin dose in any
(simple or complicated extraction), and incidence of post- way before dental extraction, and did not have their INR
operative bleeding. Any patient who had an INR> 4.0, had evaluated as it had been measured within several days,
combined antiplatelet and warfarin therapy or platelet with an average preoperative INR (range) of 1.95
counts below 6 " 104/mm,3 had liver disease or any sys- (1.06e3.08) (Table 2). Patients with cardiac valvular dis-
temic disease affecting postoperative bleeding and coagu- ease or organ transplant were administered an appropriate
lopathies, or had withdrawn warfarin or antiplatelet regime of antibiotic prophylaxis, according to the recom-
therapy by themselves was excluded from the study. A total mendations of the American Heart Association.31 All pro-
of 32 patients were excluded from the study because of cedures were planned in liaison with patients’ medical
stopping antiplatelet therapy (25 patients) and warfarin practitioners and informed consent.
(three patients) by the individuals themselves, having an All dental extractions were performed with minimal in-
INR>4 (two patients), or with platelet counts below vasion, and inflammatory granulation tissue was curetted
6 " 109/I (two patients). completely. Each extraction was carried out under local
A convenience sample of 1088 patients without any anesthesia using 2% (20 mg/mL) lidocaine hydrochloride
antithrombotic therapy comprised the control group. A with 1/80,000 (12.5 mg/ml) epinephrine. Extraction was
total of 243 patients on antithrombotic therapy were considered complicated when the tooth was removed using
Table 1 Dental extractions in the control group without taking antiplatelet or warfarin therapy and the antiplatelet group
maintained on continuing antiplatelet therapy.
Antiplatelet group (n Z 183) Control group (n Z 1088) P-value
Gender (Male/Female) M (110), F (73) M(513), F (575) 0.79
Mean age (range, y) 72.0 (20e94) 48.9 (9e95) 0.94
Number of tooth extractions (occasions) 548 (274) 2487 (1472)
Number of tooth extractions (postoperative bleeding) 548 (5) 2487 (10)
Number of simple extractions 489 (5) 1669 (7) 0.81
Number of complicated extractions 59 (0) 818 (3) 0.80
Mean number of teeth extracted per case 2.0 1.7 0.98
Reason of extraction (postoperative bleeding)
Periodontitis 190 (3) 576 (5) 0.03a
Deep caries or residual roots 350 (2) 1298 (2) 0.26
Impaction 8 (0) 613 (3) 0.40
Postoperative bleeding (number of patients/occasions) 5/274 (1.8%) 10/1472 (0.7%) 0.07b
Aspirin 2/185 (1.1%) 0.49
Clopidogrel 2/65 (3.1%) 0.50
Aspirin þ clopidogrel 1/24 (4.2%) 0.43
a
Postoperative bleeding was significantly higher in patients with periodontitis (P Z 0.03).
b
No significant difference in the incidence of postoperative bleeding was found between the antiplatelet group and the control group
(P Z 0.07).
982 S.-Y. Lu et al.
Table 2 Dental extractions in the inpatient group for bridging anticoagulation with heparin after stopping warfarin and the
outpatient group maintained on continuing warfarin therapy.
Inpatient group Outpatient group P value
(stopping warfarin) (32 cases) (continuing warfarin) (28 cases)
Gender (Male/Female) M (17), F (15) M(16), F (12)
Mean age (range, y) 56.7 (37e81) 63.3 (31e88) 0.547
Main indication for warfarin (patient no.) 32 28
Heart valve replacement 31 11
Atrial fibrillation 0 6
CVA/CAD or PAD/DVT 0 8
Liver or heart transplantation 0 3
Mitral valve Stenosis 1 0
Prophylactic antibiotic prophylaxis 32 14
Warfarin mean dose (mg) 3.44 # 1.54 2.84 # 1.35 0.165
INR mean (before extraction) 2.30 # 0.39 1.95 # 0.55 0.189
Range (patient no. with INR>2.5) 1.32e3.12 (10) 1.16e3.08 (7)
Reduced after cessation of warfarin 1.14 # 0.18
No. of tooth extractions (occasions) 130 (37) 77 (33)
No. of simple extraction 110 68
No. of complicated extraction 20 9
Mean no. of teeth extracted-per case 3.5 2.3 0.820
Cause of extraction (postop. hemorrhage)
Periodontitis 52 (2) 30 (2) 0.531
Deep caries or residual roots 74 (1) 46 (1) 0.787
Impaction 4 1 0.594
Postoperative hemorrhage 3/37 (8.1%) 3/33 (9.1%) 1.000*
(no. of patients/occasions)
Abbreviation: CAD, Coronary artery disease; CVA, Cerebral vascular accident; DVT, deep vein thrombosis; PAD, Peripheral arterial
disease.
*The incidence of postoperative bleeding between the inpatient group and the outpatient group indicated no significant difference
(p Z 1.000).
additional surgical procedures such as mucoperiosteal flap extraction type and the incidence of postoperative
reflection, tooth separation, and bone cutting. The stan- bleeding in relation to warfarin and single or dual anti-
dard hemostatic measure in each extraction site was platelet therapy between these groups were analyzed using
packed with Gelfoam and followed by compression with dry Fisher’s exact test or the c2 test, as appropriate. Statistical
gauze pack. Suturing was not performed routinely unless significance was set at a P-value of less than 0.05.
indicated, depending on the extent of the wound. Imme-
diate bleeding was recorded if hemostasis was not achieved
by dry gauze compression for 10 min; in such cases the Results
socket was repacked with Gelfoam impregnated with tra-
nexamic acid (TXA) powder. If this failed, sutures were The results of the study and patient clinico-demographic
inserted and the patients were kept under observation for data are summarized in Tables 1e4. A total of 1331 patients
the next 30 min before being discharged. who underwent 3242 dental extractions on 1816 occasions
Patients were given a leaflet outlining the usual post- were divided into three groups: (1) control group, n Z 1088
extraction instructions and a 24-h on-call emergency tele- (513 male and 575 female, mean age 48.9 years, range
phone number to contact in case of any serious hemor- 9e95 years) who underwent 2487 teeth extractions on 1472
rhage. Patients who had bleeding 1 h after extraction and occasions (mean 1.7 per occasion, range 1e12); (2) anti-
needed to return to the hospital were considered cases of platelet group, n Z 183 (110 male and 73 female, mean age
delayed bleeding. Patients who were able to manage the 72.0 years, range 20e94 years) who underwent 548 teeth
bleeding themselves at home were not included. All pa- extractions on 274 occasions (mean 2.0 per occasion, range
tients were reviewed by telephone call 24 h later or at 1e7); and (3) warfarinized group, n Z 60 (27 women and 33
clinical follow-up 7 days postoperatively in order to check men, mean age 59.8 years, range 31e88 years) who were
on the following: the occurrence of any delayed bleeding, further divided into two sub-groups including the inpatient
adequacy of the gauze pressure packing in stopping group requiring 130 teeth extracted on 37 occasions (mean
bleeding, and need for professional help. 3.5 per occasion, range 1e13) and the outpatient group
Data were analyzed using SPSS Statistics version 19.0 requiring 77 teeth extracted on 33 occasions (mean 2.3 per
software (SPSS Inc., Chicago, IL, USA). One-way analysis of occasion, range 1e8). There were no significant differences
variance (ANOVA) was used to analyze age and mean among these groups in terms of sex distribution, age,
number of extracted teeth. Categorical data such as number of tooth extractions and type of extraction, or dose
Table 3 The incidence of postoperative bleeding among patients maintained on continuing warfarin (INR<4.0) and anti-
platelet therapy.
Warfarin continuing Antiplatelet therapy continuing P-value
Aspirin Clopidogrel Aspirin þ clopidogrel
Total patients 28 125 42 16
Total dental extractions (Occasions) 77 (33) 361 (185) 138 (65) 49 (24)
Postoperative bleeding 9.1% (3/33) 1.1% (2/185) 3.1% (2/65) 4.2% (1/24) 0.0599
(Bleeding patients/occasions)
The incidence of postoperative bleeding in the warfarin group (9.1%) was higher than that in the antiplatelet groups (aspirin: 1.1%;
clopidogrel: 3.1%; dual antiplatelet: 4.2%); however, these differences were not significant (p Z 0.0599).
Table 4 Main indications for warfarin and antiplatelet therapy in patients of the study.
Main indication Warfarin Antiplatelet agents Total patients
Aspirin Clopidogrel Aspirin plus clopidogrel
Coronary artery disease 0 51 11 14 76 (31.3%)
Cerebral vascular accident 0 35 22 1 58 (23.9%)
Heart valve replacement 42 (91.3%) 2 2 0 46 (18.9%)
Atrial fibrillation 6 (28.6%) 14 (66.7%) 0 1 21 (8.7%)
PAD/DVT 8 3 2 0 13 (5.3%)
Hypertension 0 10 1 0 11 (4.5%)
Diabetes 0 7 2 0 9 (3.7%)
Liver or heart Transplantation 3 3 2 0 8 (3.3%)
Mitral valve stenosis 1 0 0 0 1 (0.4%)
Total 60 125 42 16 243
% 24.7% 51.4% 17.3% 6.6% 100%
Abbreviation: PAD, peripheral arterial disease; DVT, deep vein thrombosis.
Warfarin therapy was used in 91.3% of patients with heart valve replacement, but only in 28.6% of patients with atrial fibrillation. Aspirin
was the most used drug (51.4%), followed by warfarin (24.7%), clopidogrel (17.3%), and dual antiplatelet (6.6%).
of warfarin and each INR category (all P-values >0.05, Local hemostasis with Gelfoam sponge was sufficient in
Tables 1 and 2). The incidence of postoperative bleeding in most patients. Seventeen confirmed cases of immediate
the warfarinized groups (warfarin continued: 3/33, 9.1%; postoperative bleeding could be managed by repacking
warfarin stopped: 3/37, 8.1%) was higher than in the anti- with Gelfoam impregnated with TXA powder followed by
platelet group (aspirin: 2/185, 1.1%; clopidogrel: 2/65, pressure, and suturing was not necessary. The wounds were
3.1%; dual antiplatelet 1/24, 4.2%), and in the control group sutured only in those who had undergone surgical extrac-
(10/1472, 0.7%); however, the differences were not signif- tions of teeth with flap elevation, including three patients
icant (Table 3). in the control group and one warfarinized patient with
Ten patients in the control group and five patients in the immediate postoperative bleeding.
antiplatelet group and five patients in the warfarinized Aspirin was the most used drug (51.4%), followed by
group had immediate postoperative bleeding. One inpa- warfarin (24.7%), clopidogrel (17.3%), and dual antiplatelet
tient in the warfarin withdrawal group who received simple (6.6%) (Table 4). Most patients were taking single anti-
extraction of seven teeth had delayed oozing from one of platelet therapy for the prevention of primary or secondary
the sockets on the 2nd day postoperatively. None of the CVD, including 14 (66.7%) out of 21 AF patients receiving
outpatients reported any delayed bleeding necessitating a aspirin alone. Dual therapy was assumed in 14 patients with
return to the hospital. Among the 20 patients with imme- coronary drug-eluting stents, one AF patient, and one ce-
diate postoperative bleeding, 17 cases were simple ex- rebrovascular accident (CVA) patient. Warfarin was used in
tractions rather than invasive dental procedures, and 12 most patients with heart valve replacement from cardiac
cases involved periodontitis. With respect to the reasons surgeons (Table 4). Among 60 warfarinized patients, only 17
for extraction, periodontitis was found to be associated (28%) cases had INR>2.5, and 22 (37%) cases showed INR<2.
with postoperative bleeding. In the warfarinized group, the
INR levels at the time of postoperative hemorrhage ranged
from 1.21 to 2.15 among three outpatients and below 1.15 Discussion
in three inpatients. For seven outpatients without inter-
rupting warfarin (INR>2.5), 13 teeth were extracted in Most Western studies have reported that over 99% of
seven occasions, but postoperative hemorrhage did not anticoagulated patients have had no postoperative oral
occur. bleeding that have required more than local hemostatic
984 S.-Y. Lu et al.
measures, with no cases of morbidity or fatality.5,6 But, easily with the application of pressure. However, the risk of
there were 22 embolic complications (0.8% of cessations), stent thrombosis in drug-eluting stents is increased in the
including 6 fatal events (0.2% of cessations) among 2673 perioperative setting and is strongly associated with the
patients whose warfarin dose was reduced or withdrawn cessation of antiplatelet therapy.9,30
for undergoing 2775 dental procedures.5 We once experi- Evidences have supported a platelet rebound phenom-
enced a female patient who was rescued from acute MI enon after abrupt aspirin withdrawal.6$9,11 This rebound
with total occlusion of the right coronary artery by period is characterized by increased thromboxane produc-
percutaneous coronary intervention 2 days after tooth tion, decreased fibrinolysis, and a resultant clinical pro-
extraction because her warfarin had been stopped for 5 thrombotic state.12e14 The mean platelet life-span being
days prior to the procedure. All these evidences indicate 7e10 days, about 50% of normally functioning platelets are
that discontinuing warfarin could lead to lethal throm- recovered within 5 days after aspirin withdrawal, while
bosis. Although the thromboembolic risk is small, the platelet thromboxane biosynthesis recovers more rapidly,
outcome exceeds the risk of oral bleeding, even when with its urinary thromboxane metabolites close to normal
surgery is extensive. levels after 3 days.12,29 The mean delay in stroke and MI
The postoperative bleeding incidence of 9.1% in the after aspirin cessation is approximately 10 days (range 4e17
dental outpatient group without interrupting warfarin was days), which is consistent with the time interval of the
about the same as 8.1% in the inpatient group with stopping platelet rebound effect.35 Ferrari et al. reported that 51 of
warfarin and bridging with heparin. Studies have indicated 383 coronary artery disease (CAD) patients were admitted
that heparin bridging therapy may result in a similar rate of for acute coronary syndrome (ACS) events within 1 month
bleeding or thromboembolic events.5,7,32 This study pro- (mean 10 days) after stopping aspirin therapy, for an inci-
vides additional evidence on the subject. None of the pa- dence among CAD patients of 13% and an overall incidence
tients with immediate or delayed postoperative bleeding of 4% (51 of 1236 patients).35 Collet et al. reported that
required blood transfusion or parenteral TXA or reduction nine of 475 MI patients had discontinued aspirin therapy
of warfarin dose or administration of vitamin K. Most within 15 days prior to intended surgery.12 These patients
postoperative hemorrhage can be successfully managed by had been treated by aspirin for a long time for a coronary
repacking with Gelfoam plus TXA powder which is safe, insufficiency and were perfectly stable until aspirin inter-
simple, and less troublesome than TXA mouthwash for ruption.12 We have witnessed two strokes occurring in two
several days.33 Sutures are usually unnecessary. The INR diabetic patients whose aspirin therapy was interrupted for
levels in six patients with postoperative hemorrhage were 5e7 days before dental extractions. Atherosclerosis ac-
not markedly high at the time of dental extraction. counts for approximately 80% of all diabetic mortality, and
Contrarily, seven outpatients with INR>2.5, postoperative about 75% of this is a consequence of CAD; the remaining
hemorrhage did not occur. Blinder et al. divided 249 pa- 25% results from cerebrovascular and peripheral vascular
tients undergoing dental extractions into five groups, based disease.36 The incidence of aspirin poor responders in-
on lowest to highest INR levels. There was no significant creases in diabetic patients, suggesting an active proin-
difference in the incidence of postoperative bleeding be- flammatory background likely responsible for a continued
tween the groups and the INR value did not significantly platelet hyperactivity.36 These facts suggest that aspirin
affect the incidence of postoperative bleeding,34 which was cessation might lead to serious thrombosis, particularly in
compatible with our results.10 patients with diabetes or CVD and indications for aspirin
The heparin in the inpatient group was discontinued for treatment.
a minimum of 6 h preoperatively and resumed 12e24 h The individual stroke risk stratification in AF patients can
after surgery, along with regular preoperative dosage of be quantified based on the CHA2DS2-VASc scores (conges-
warfarin until INR was back to the optimal therapeutic tive heart failure, hypertension, age %75 (doubled), dia-
level. This required hospitalization for 1 week at least and betes mellitus, prior stroke or transient ischemic attack
careful monitoring; however, this put the patients at risk of (doubled), vascular disease, age 65e74, female).37 AF pa-
postoperative thromboembolism as warfarin may require tients at high risk of stroke can benefit from anti-
several days to reach the therapeutic levels required. coagulation therapy, and the use of aspirin or dual
Heparin administration had an uncontrollable risk factor antiplatelet therapy is less effective, unless in patients
and carried a higher degree of complexity and discomfort with ACS and receiving stenting therapy.19e26 In spite of the
for the patients.32 Warfarin regime, therefore, should not data, more than three-quarters of high-risk patients among
be interrupted for most dental surgery. Then, most cases Chinese populations with nonvalvular AF were not anti-
requiring dental extraction can be treated on an outpatient coagulated or had poor INR control.38 In the study, two-
basis, which can save valuable time and resources in hos- thirds of AF patients received aspirin alone, and over one-
pital care. third of warfarinized patients did not achieve sufficient
The incidence of postoperative bleeding in the anti- INR therapeutic range. This may reflect poor anti-
platelet groups (aspirin: 1.1%; clopidogrel: 3.1%; dual an- coagulation control, highlighting opportunities for
tiplatelet 4.2%) was less than that in the warfarin groups improved stroke prevention with alternative strategies,
(warfarin continued: 9.1%; warfarin stopped: 8.1%). such as novel oral anticoagulants (NOACs), and the impor-
Furthermore, postoperative hemorrhage in most cases was tance of continuous antiplatelet therapy throughout the
minimal. Park et al. reported that dental extractions were perioperative period of dental surgery. For patients with
safe without stopping dual or triple antiplatelet agents in established CVD, especially those taking aspirin or other
coronary drug-eluting stent patients; only two of 100 (0.2%) antiplatelet agents for thrombotic prophylaxis, this should
had postoperative bleeding, which could be controlled be considered a critical therapy.18,26e30,35e38
The dentist today is seeing an increasing number of 11. Lu SY, Tsai CY, Lu SN, Lin LH. Dental extraction without stopping
ambulatory patients on warfarin and antiplatelet therapy single or dual antiplatelet therapy: results of a retrospective
to prevent thrombosis who require dental surgery. Our cohort study. Int J Oral Maxillofac Surg 2016;45:1293e8.
findings provide valuable medical education to dentists and 12. Collet JP, Montalescot G. Premature withdrawal and alterna-
tive therapies to dual oral antiplatelet therapy. Eur Heart J
physicians, as well as patients, that warfarin and anti-
2006;8:46e52.
platelet cessation preoperatively may invite a remote but 13. Gerstein NS, Schulman PM, Gerstein WH, Petersen TR, Tawil I.
fatal risk of thromboembolism. Bleeding complications, Should more patients continue aspirin therapy perioperatively?
while inconvenient, do not carry the same risks as throm- Clinical impact of aspirin withdrawal syndrome. Ann Surg 2012;
boembolic complications. Sufficient hemostasis can be ob- 255:811e9.
tained using local measures. Whenever possible, the 14. Collet JP, Himbert D, Steg PG. Myocardial infarction after
therapeutic levels of warfarin (INR <4) or antiplatelet aspirin cessation in stable coronary artery disease patients. Int
therapy should not be interrupted before most dental J Cardiol 2000;76:257e8.
extractions. 15. Yasaka M, Naritomi H, Minematsu K. Ischemic stroke associated
with brief cessation of warfarin. Thromb Res 2006;118:290e3.
16. Hirsh J, Fuster V, Ansell J, Halperin JL. American heart Asso-
Conflicts of interest ciation/American College of cardiology foundation guide to
warfarin therapy. Circulation 2003;107:1692e711.
The authors have no conflicts of interest relevant to this 17. Baglin TP, Keeling DM, Watson HG. Guidelines on oral anti-
coagulation (warfarin): third edition e 2005 update. Br J
article.
Haematol 2006;132:277e85.
18. Chen PC, Lip GYH, Yeh G, Lin HJ, Chien KL. Risk of bleeding and
Acknowledgments stroke with oral anticoagulation and antiplatelet therapy in
patients with atrial fibrillation in Taiwan: a nationwide cohort
study. PLoS One 2015;10, e0125257.
The study was supported in part by a CMRP research grant 19. You JH, Chan FW, Wong RS, Cheng G. Is INR between 2.0 and
from the Chang Gung Memorial Hospital, Kaohsiung, Taiwan 3.0 the optimal level for Chinese patients on warfarin therapy
(CMRPG8C0642 to Shin-Yu Lu) after proper Institutional for moderate-intensity anticoagulation. Br J Clin Pharmacol
Review Board approval. 2005;59:582e9.
20. Lin YP, Tan TY. Do NOACs improve antithrombotic therapy in
secondary stroke prevention in nonvalvular atrial fibrillation?
Appendix A. Supplementary data Medicine (Baltimore) 2015;94:e1627.
21. Murasaki K. Guideline for management of anticoagulant and
Supplementary data related to this article can be found at antiplatelet therapy in cardiovascular disease (JCS2009). Nihon
https://doi.org/10.1016/j.jfma.2018.08.019. Rinsho 2011;69:567e71.
22. Chiang CE, Wu TJ, Ueng KC, Chao TF, Chang KC, Wang CC,
et al. 2016 Guidelines of the Taiwan heart rhythm society and
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Intern Med 1998;158:1610e6. teristics of hospitalized patients with atrial fibrillation in Taiwan:
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5. Wahl MJ, Pinto A, Kilham J, Lalla RV. Dental surgery in anti- Compliance with antithrombotic prescribing guidelines for
coagulated patients–stop the interruption. Oral Surg Oral Med patients with atrial fibrillation-a nationwide descriptive study
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Available online at www.sciencedirect.com
ScienceDirect
British Journal of Oral and Maxillofacial Surgery 59 (2021) 633–642
Review
Antibiotic prophylaxis in oral and maxillofacial surgery: a
systematic review
T. Milic, P. Raidoo ∗ , D. Gebauer
Royal Perth Hospital, Department of Oral and Maxillofacial Surgery, Oral Health and Equity, Department of Human Sciences, Victoria Square, Perth,
WA 6000
Received 12 March 2020; accepted 15 September 2020
Available online 23 September 2020
Abstract
Surgical site infections are a complication of oral and maxillofacial procedures, with the potential for significant morbidity and mortality. Use
of preoperative, perioperative, and postoperative antibiotic prophylaxis to reduce the incidence of surgical site infections must be balanced
with considerations of a patients’ risk of antibiotic-related adverse events. This review aimed to provide evidence-based recommendations
for antibiotic prophylaxis. Searches were conducted using MEDLINE, the Cochrane Library, EMBASE, and PUBMED for maxillofacial
procedures including: treatment of dental abscesses, extractions, implants, trauma, temporomandibular joints, orthognathics, malignant and
benign tumour removal, and bone grafting, limited to articles published since 2000. A total of 98 out of 280 retrieved papers were included
in the final analysis. Systematic reviews were assessed using AMSTAR criteria. Randomised controlled trials were assessed for bias using
Cochrane Collaborative tools. The overall quality of evidence was assessed using GRADE. Prophylactic antibiotic use is recommended in
surgical extractions of third molars, comminuted mandibular fractures, temporomandibular joint replacements, clean-contaminated tumour
removal, and complex implants. Prophylactic antibiotic use is not routinely recommended in fractures of the upper or midface facial thirds.
Further research is required to provide recommendations in orthognathic, cleft lip, palate, temporomandibular joint surgery, and maxillofacial
surgical procedures in medically-compromised patients.
Crown Copyright © 2020 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights
reserved.
Keywords: antibiotic; maxillofacial; oral; prophylaxis; review
Introduction risk of SSI is dependent on factors such as the duration of

surgery, wound class, and the patient’s American Society of
Surgical site infection (SSI) is a common complication of Anesthesiologists (ASA) score. Increased risk of surgical site
oral or maxillofacial surgery. SSIs are defined as those which infection is generally accepted as an indication for antibiotic
occur within 30 days of a surgical operation, or within one prophylaxis.
year for patients who have had implants placed.1 They can Antibiotic prophylaxis is used to reduce the risk of SSI
cause significant postoperative morbidity and mortality.2 The and the associated morbidity and mortality. At the same
time, antibiotic resistance has been identified as a significant
threat to global public health.3 When antibiotic prophylaxis
∗ Corresponding author at: 11 Robin Warren Dr, Murdoch, WA 6150. Tel.: is indicated, the selection of antibiotic type and timing of pro-
(08) 6152 2222. phylaxis are specific to the procedure and likely population
E-mail addresses: tihana@live.com.au (T. Milic), of organism(s). Studies indicate the identification of strains
priyanka.raidoo@my.jcu.edu.au (P. Raidoo), dietergebauer@hotmail.com with reduced susceptibility to amoxicillin with short-duration
(D. Gebauer).
https://doi.org/10.1016/j.bjoms.2020.09.020
0266-4356/Crown Copyright © 2020 Published by Elsevier Ltd on behalf of The British Association of Oral and Maxillofacial Surgeons. All rights reserved.
634 T. Milic et al. / British Journal of Oral and Maxillofacial Surgery 59 (2021) 633–642
therapies,4 or even after a single dose.5 Therefore, signifi- systematic reviews, and randomised controlled trials (RCT),
cant efforts have been made in the development of restricted comparing different antibiotic protocols or antibiotics com-
antibiotic policies and procedures, to ensure the use of antibi- pared with antimicrobial treatments were included. Level 3-5
otics is restricted to cases in which the incidence and risk evidence was sought if higher-level evidence was lacking for
of infection are great and the consequences of infection are a specific procedure. Letters to the editor were included when
significant. they included scientific evidence. Abstracts were included
Antibiotics also have an additional financial cost to both if they contained information on infection rates using pro-
patient and healthcare provider. Costs of antibiotic treatment phylactic systemic antibiotic treatment in comparisons to
may influence prescribing habits and patient compliance. control (or placebo) following maxillofacial or oral surgery.
Healthcare expenditure pertaining to antibiotic use in both Maxillofacial procedures considered in this review included:
private and public sectors needs to be evaluated when con- treatment of dental abscesses, dental extractions, implants,
sidering evidence-based management of SSI. trauma, TMJ, orthognathic, malignant and benign tumour
Recent systematic reviews have suggested that some evi- removal, and bone grafting. Further details can be found
dence exists for the beneficial use of prophylactic antibiotics in Supplemental Table 2. Clean was defined as a proce-
in a limited number of maxillofacial surgeries, however, qual- dure in which an incision was made without breaking sterile
ity of evidence may be lacking in certain procedures.6,7 The technique during which the respiratory or alimentary tracts
scope of the current review includes the full portfolio of max- were not entered. Clean-contaminated referred to an incision
illofacial surgeries performed in metropolitan hospitals, that which was made through which the respiratory or alimentary
has not been covered in its entirety to our knowledge in recent tracts were entered under controlled conditions but with no
systematic reviews. contamination encountered.9
The aim of the study was to systematically review the
current literature and examine whether the use of preopera- Data collection process
tive, perioperative, or postoperative antibiotic prophylaxis in
patients undergoing oral and maxillofacial surgeries of SSI is The first author collected the data. Studies were analysed
supported. The timing of prophylactic antibiotics was defined for risk of bias. Results were synthesised. The data were re-
as per Morris and Kellman8 as preoperative (from the time reviewed and assessed independently by the second author to
of injury up to two hours prior to surgical intervention), peri- confirm accuracy and currency.
operative (from two hours before surgical intervention until
completion of surgery) or postoperative (from the completion
of the surgical procedure). The study also aimed to iden- Risk of bias of individual studies
tify evidence-based antibiotic regimens for use in oral and
maxillofacial surgery. Systematic reviews were assessed as having low, moderate,
or high risk of bias according to AMSTAR criteria.10,11 Ran-
domised controlled trials were assessed for bias using the risk
of bias tool developed by Cochrane Collaboration.
Methods
Information sources, search, and study selection Synthesis of results
Searches were conducted in MEDLINE (OVID), the This is a systematic review of the published literature. No
Cochrane Library (Wiley), EMBASE and PubMed in meta-analysis was performed due to anticipated heterogene-
June 2019 using the following MESH terms ("Antibiotic ity between studies. The overall quality of evidence was
Prophylaxis"[Majr]) AND ("Surgery, Oral"[Mesh] OR "Oral assessed using the GRADE method.12 A strong recommen-
Surgical Procedures"[Mesh] OR “Head, Neck, Surgery” dation was defined where the majority of published literature
[Mesh] OR “Dental Implant, Infection”[Mesh] OR “Extrac- of level II and above supported the recommendation.
tion, Infection”[Mesh]. In addition, we performed a hand
search of systematic reviews and more recent research arti-
cles. Searches were not restricted by language, but were Results
limited to studies conducted in humans that contained
information on surgical site infections. Articles describing Study selection
endocarditis in susceptible individuals were excluded. The
inclusion and exclusion criteria for individual parts of this A total of 531 papers were retrieved. Of these, 251 duplicates
review are listed in Supplemental Table 1, online only. This were excluded following abstract review. Of the remaining
systematic review was not registered. 280 papers, 98 were included in the final systematic review
Abstracts were retrieved and reviewed by two independent (Supplementary Figs. 1–8, online only). Included studies
authors. Published data was only included. Meta-analyses, are cited in each section of the systematic review.
T. Milic et al. / British Journal of Oral and Maxillofacial Surgery 59 (2021) 633–642 635
Table 1
Recommendations – third molar extractions
Antibiotic use - Yes (strong recommendation)
1. There is a lack of clear evidence regarding optimal timing of prophylaxis (preoperative, intraoperative, postoperative).
2. A single dose of preoperative antibiotics may reduce the incidence of infection following surgical extraction of third molars. This should be
balanced against the risks of antibiotic adverse effects and the potential for antibiotic resistance (strong recommendation).
Antibiotic type and dose
3. If there is indication for systemic antibiotic prophylaxis, administer amoxicillin or amoxicillin and clavulanic acid preoperatively (strong
recommendation).
For patients undergoing surgical extraction by osteotomy of lower mandibular third molar teeth, a single dose of 2 g preoperative oral amoxicillin
may reduce the incidence of SSI (strong recommendation).
Amoxicillin [Cost Range Private/Public $0.26-$0.32 per 2 g/dose]
4. Clindamycin is not recommended for prophylaxis in Australia except in those who are allergic to penicillin (weak recommendation).
Recommendations – extractions excluding third molars
5. No randomised controlled trials or systematic reviews were located on which to base a recommendation. Further research is required in this
area.
Extractions Andreasen’s systematic analysis identified a significant

reduction in infection rates with the use of preoperative
No studies were found evaluating antibiotic prophylaxis for antibiotics in patients with mandibular fractures.45 Postop-
tooth extractions other than third molars.13 A total of 31 erative antibiotics used more than 24 hours after the repair
relevant studies were included.14–44 For third molar extrac- of mandibular fractures showed no significant benefit.44,45,52
tions (clean-contaminated surgery), prophylactic antibiotic Preoperative and postoperative antibiotics in upper and mid-
use was considered based on the depth of impaction, need facial trauma are not routinely recommended.8,46 This is
for osteotomy, trauma to the surrounding tissues, and postop- also highlighted by the meta-analysis performed by Habib
erative inflammation. A lack of clear evidence regarding the showing that the use of postoperative antibiotics does not
optimal timing of prophylaxis (preoperative, intraoperative, significantly decrease the likelihood of infection.55 Recom-
or postoperative) was apparent. Complications of surgery mendations are summarised in Table 2.
included infection and alveolar osteitis.18,21 One meta-
analysis demonstrated that preoperative antibiotics reduced
Temporomandibular joint surgery
the rate of dry socket and wound infection.22 Two systematic
reviews were included; Ramos, who combined 21 clinical tri-
Temporomandibular joint surgery was defined as including
als to assess the efficacy of systemic antibiotics in preventing
total joint replacements, arthrocentesis, arthroscopy, arthro-
dry socket and infections after third molar extractions, and
plasty, condylectomy, and injections of autologous blood.
Lodi et al.15,20 These two systematic reviews suggest that
Infections occurred in 1.5% to 4.5% of patients who under-
prophylactic antibiotics reduced the infection risk by 60% to
went TMJ total joint replacements. National and international
70% post extraction.15,20 However, the incidence of postop-
published literature indicated that these infections were most
erative infection in patients undergoing third molar removal
commonly caused by S. aureus, S. epidermidis, Peptostrep-
is estimated to be less than 1%, so the adverse effects of
tococcus sp, or P. aeruginosa. No high-level evidence was
antibiotics (which have been stated to occur in 6% to 7% of
found for the use of antibiotic prophylaxis in TMJ surgery;
patients) and the potential risks of antibiotic resistance must
however, some authors have suggested that perioperative IV
be considered.18 Despite this, the majority of publications
antibiotic prophylaxis, starting within the first hour prior to
in this context support the use of prophylactic antibiotics in
surgery, does reduce the risk of surgical site infection.58–61
patients undergoing third molar extractions.14 Recommenda-
Four relevant studies were included58,62–64
tions are summarised in Table 1.
Potential prophylactic antibiotics for TMJ replacement
surgery include perioperative use of cefazolin 1 g (< 80 kg),
2 g (60 to 120 kg), 3 g (> 120 kg) every two to five hours; clin-
Maxillofacial trauma
damycin 900 mg every three to six hours; cefuroxime 1.5 g
every three to four hours; or vancomycin 15 mg/kg every
The decision to use antibiotic prophylaxis in maxillofacial
six to twelve hours.62,63 Therapeutic concentrations of IV
trauma depends on the type of fracture (open, which have
antibiotics should be maintained until the time of surgical
communication with the oral cavity or skin surface; or closed,
closures.63 Recommendations are summarised in Table 3.
which have reduced infection rates), its planned treatment
(open or closed reductions), and the location of the fracture
(mandibular fractures are more likely to become infected). Dental implants
Antibiotic prophylaxis in this setting is thought to act against
bacteria that enter the wound prior to surgery.45 Fifteen rel- Dental implants are widely used, long-term, aesthetic treat-
evant studies were included8,44–57 ment for patients with partially or completely edentulous
Table 2
Recommendations – maxillofacial trauma
Antibiotic use
Preoperative - Yes (strong recommendation)
1. Preoperative antibiotics are recommended for comminuted mandible fractures (strong recommendation).
2. Preoperative antibiotics are not routinely recommended for upper and midface fractures (weak recommendation).
Perioperative - Yes (strong recommendation)
3. Perioperative antibiotics are recommended in all facial thirds (strong recommendation).
Postoperative - No (strong recommendation)
4. Postoperative antibiotics are not recommended for mandibular fractures beyond 24 hours (strong recommendation).
5. Postoperative antibiotics are not routinely recommended for upper and midface fractures (weak recommendation).
6. The evidence for prophylactic antibiotics in patients with premorbid acute or chronic sinusitis with midface fractures is poor. Antibiotics are
not routinely recommended in this setting (weak recommendation).
Antibiotic dose
Administer amoxicillin 2 g po perioperatively or penicillin V po (strong recommendation). Amoxicillin [cost range private/public $0.26-$0.32
per 2 g/dose]
Penicillin V [Cost Range Private/Public $0.32-$0.60 per 2 g/dose]
Table 3
Recommendations – temporomandibular joint surgery (Bosco et al)
Preoperative - Yes (weak recommendation)
1. Antibiotic use one hour prior to surgery may reduce the risk of surgical site infection in TMJ replacements (weak recommendation). No
recommendations can be made for other types of TMJ surgery.
Perioperative - Yes (weak recommendation)
2. Maintenance of a therapeutic antibiotic concentration until wound closure may reduce the risk of surgical site infection in TMJ replacements
(weak recommendation). No recommendations can be made for other types of TMJ surgery.
Postoperative - No (weak recommendation)
3. There is limited evidence supporting postoperative antibiotic dosing.
Antibiotic dose
1. For TMJ replacement surgery, perioperative use of cefazolin 1 g (<80 kg), 2 g (60 to 120 kg), 3 g (>120 kg) every two to five hours; or
clindamycin 900 mg every three to six hours; or cefuroxime 1.5 g every three to four hours; or vancomycin 15 mg/kg every six to twelve hours
(weak recommendation).
Cefazolin [cost range private/public $0.72-$3.16 (1 g), $1.44-$6.32 (2 g), $2.16 - $9.48 (3 g)]
Clindamycin [cost range private/public $19.8-$39.87 per 900 mg/dose]
Vancomycin [cost range private/public $10.41-$12.45per 1500 mg/dose]
Cefuroxime [cost range private/public $2.40-$4.02 per 1.5 g/dose]
jaws. Implant success rates following surgery are high Orthognathic surgery
(between 95% and 99%), with failure often associated with
surgical trauma, lack of initial stability, or infection.65 Nine- Orthognathic surgery was defined as including reconstruc-
teen relevant studies were included.6,44,65–82 Overall, the tive surgery, maxillomandibular advancement, and surgical
quality of evidence for the use of prophylactic antibiotics correction of facial asymmetry. Clean-contaminated proce-
in dental implant surgery is moderate. dures would be expected to have higher infection than rates
There was moderate level evidence to suggest that pre- in non-contaminated surgeries. Twenty-two relevant publica-
operative prophylactic antibiotics reduce the risk of implant tions were included.17,44,85–104
loss by up to 2%.6,31,32 However, included studies have vary- It appears that procedures in the mandible are at greater
ing risks of bias. Patients who smoked appeared to be at risk of postoperative infection than other maxillofacial
greater risk of infection.6 Therefore, prophylactic antibiotic procedures.88,105 Overall, the quality of evidence for pro-
use is probably not required for single implant placement in phylactic antibiotic use was low in this setting, and there
low-risk patients.83 were mixed results. In studies with a low risk of bias, one
Where prophylactic antibiotics are warranted, 2 g of pre- study reported a benefit of preoperative antibiotics in bimax-
operative amoxicillin has been shown to provide the same illary surgery,90 while another suggested no benefit following
reduction in the number of implant failures as 1 g of preop- postoperative antibiotics.94 Of importance, Zijderveld et al
erative amoxicillin and an additional two-day postoperative conducted the only placebo controlled trial, and this had to
course.70 As the potential for antibiotic-related adverse be ceased early due to a large difference in infection rates
events increases with duration of exposure,84 preoperative between the treatment arms. Although the difference may
dosing is recommended in this setting. Recommendations have been due to preoperative versus postoperative antibi-
are summarised in Table 4. otic prophylaxis, a lack of consistency in the definition of
Table 4
Recommendations – implants
Antibiotic use - Yes (strong recommendation)
1. For single implant placement in healthy uncompromised patients, antibiotic prophylaxis is not recommended (strong recommendation).
2. In complex cases such as those requiring grafting or multi-implant placement, the beneficial effect of antibiotic prophylaxis cannot be
excluded, but should be considered in the context of emerging antibiotic resistance and adverse reactions (strong recommendation).
Preoperative antibiotics - Yes (strong recommendation)
3. Where prophylactic antibiotics are deemed necessary, preoperative amoxicillin is recommended (strong recommendation)
Postoperative antibiotics - No (weak recommendation)
4. There is limited evidence supporting postoperative antibiotic dosing. Therefore, postoperative antibiotics are not routinely recommended at
this time (weak recommendation)
Antibiotic dose
5. Administer 2 g amoxicillin one hour preoperatively for patients undergoing complex dental implants (strong recommendation).
Amoxicillin [cost range private/public $0.20- $0.32 per 2 g/dose]
Table 5 1.7 mg/kg IV q8h, and clindamycin 900 mg IV q8h), but

Recommendations – orthognathic surgery lacked a placebo control, thus the underlying effect of pro-
Antibiotic use phylactic antibiotics could not be determined.108 Despite this,
Preoperative - Yes (weak recommendation) Russell and Goldberg, as well as recent meta-analyses, have
1. Preoperative antibiotics reduce the risk of surgical site infection
(Weak Recommendation).
suggested little evidence for antibiotic use beyond the first
Postoperative - Yes (weak recommendation) 24 hours.106–108 Recent systematic reviews and RCTs have
2. There is limited evidence supporting postoperative antibiotic noted that clindamycin prophylaxis alone may be inferior to
dosing. A 3-day regimen of postoperative antibiotics may reduce the other antibiotic therapies, and a risk factor for SSI.106,107,109
risk of surgical site infection compared to 1 day (weak Further research is required to identify an effective alternative
recommendation).
3. Further research is required in this area.
to clindamycin in penicillin-sensitive patients.106,107
According to Kreutzer et al, benefits of antibiotic prophy-
laxis in clean head and neck surgery do not outweigh the risks
infection between the Zijderveld et al and Tan et al stud- of adverse events, as SSIs occur in less than 1%.7 A meta-
ies may have accounted for the differences in their findings. analysis by Ariyan et al found no significant reduction in
One study suggested that preoperative antibiotics were ben- SSIs for clean head and neck surgery with antibiotic prophy-
eficial in sagittal split osteotomies.91 A 2017 RCT by Davis laxis, and an effective duration could not be determined.86
et al found that three days of postoperative cefazolin and Recommendations are summarised in Table 6.
cephalexin decreased SSI compared to one day, with an NNT
of 10. The trial did not include a placebo group that received Cleft lip and palate surgery
no antibiotic therapy.87
Further research on the use of preoperative or postop- A cleft lip and palate may develop during pregnancy and
erative prophylactic antibiotics for orthognathic surgery is is repaired in stages of surgical treatment. There is lim-
required.86 Recommendations are summarised in Table 5. ited data regarding antibiotic prophylaxis in the repair of
cleft lip, palate, or alveolus. No national or international
Oral and maxillofacial pathology evidence-based guidelines exist. The incidence of postopera-
tive infection following cleft lip or palate surgery is 1.3%.119
Oral and maxillofacial pathology describes a heterogenous Risks are primarily associated with the length of operation.
group of conditions with differences in the perplexity of A 2008 survey of cleft surgeons in the UK found that
operation. Due to the diversity in the extent of procedures, a majority used antibiotic prophylaxis for cleft lips, and a
this review included papers focused separately on clean slightly lower proportion use prophylaxis for repair of a cleft
and clean-contaminated head and neck surgery. Eight rele- palate.120
vant studies were included.86,106–112 The majority of studies One randomised controlled trial was included, which
supported the consideration of preoperative prophylactic examined postoperative antibiotic prophylaxis for cleft palate
antibiotic therapy for patients undergoing oral or maxillo- surgery (five days of amoxicillin 50 mg/kg/day IV, maxi-
facial surgery who had a significant underlying condition, or mum 1.5/day, divided into three doses postoperatively). All
who were immunocompromised (such as patients undergoing patients were given a single dose of intraoperative cefuroxime
radiotherapy or chemotherapy).7,113–118 IV. 5 days of postoperative antibiotics in this patient group
Russell and Goldberg’s systematic review was limited to decreased the incidence of fistulas from 17.1% – 10.7%.
five randomised clinical trials comparing various antibiotic However, a high percentage of patients were lost to follow up.
regimes (cefazolin 500 mg or 2 g IV q8h, cefoperazone 2 g The wider applicability of these study results to a Western set-
IV q8h, cefotaxime 2 g IV q8h, moxalactam 2 g IV q8h, ting is questionable.121 Recommendations are summarised in
clindamycin 600 mg IV q8h with or without gentamycin Table 7.
Table 6
Recommendations – oral and maxillofacial pathology
Clean-contaminated surgery
Antibiotic use - Yes (weak recommendation)
1. Single dose preoperative prophylactic therapy is recommended for patients undergoing clean-contaminated surgery for removal of tumours (weak
recommendation).
Antibiotic dose
1. Administer cefazolin 2 g IV q8 h, cefoperazone 2 g IV q8 h, cefotaxime 2 g IV q8 h, clindamycin 600 mg IV q8 h with or without gentamicin
1.7 mg/kg IV q8 h, ampicillin-sulfabactam 1.5 g or clindamycin 900 mg IV q8 h for patients undergoing clean-contaminated surgery for removal of
tumours (weak recommendation).
Cefazolin [cost range private/public $1.44 -$6.32 per 2 g/dose]
Clindamycin [cost range private/public $9.4-$12 per 600 mg/dose]
Clindamycin + Gentamicin [cost range private/public $14.08-$28.01 per 600 mg/120 mg clindamycin/gentamicin dose]
Clindamycin [cost range private/public $14.1-$39.87 per 900 mg/dose]
Ampicillin-Sulfabactam- N/A in Australia. Piperacillin/tazobactam used alternatively. [cost range private/public $3.45-$5.00 per 400/500 mg/dose]
Cefotaxime- [cost range private/public $1.75 per 1 g dose]
Ceftriaxone [cost range private/public $0.60 per 1 g/dose]
Cefoperazone- N/A in Australia
2. Doses should be administered for no more than 24 hours (strong evidence).
Clean surgery (including thyroidectomy, parotidectomy, submandibular gland surgery, neck dissection without oral access)
Antibiotic use - No (weak recommendation)
1. Antibiotic prophylaxis is not routinely recommended for clean head and neck surgery (weak recommendation).
Table 7 grafting or multiple implants are involved, and for clean-

Recommendations – cleft lip and palate surgery contaminated tumour removal. Prophylactic antibiotic use
1. There is insufficient information upon which to base a is not routinely recommended after fractures of the upper
recommendation for prophylactic antibiotics in cleft lip and palate or midface facial thirds. Further good quality research is
surgery.
2. Postoperative antibiotics may reduce the risk of surgical site
required to allow recommendations for patients undergoing
infection (weak evidence). orthognathic, cleft lip and palate, temporomandibular joint
3. Further research is needed in this area. surgery (other than TMJ replacement), and for all maxillofa-
cial surgical procedures in medically-compromised patients.
Table 8 In Australia, current guidelines do recommend the prophy-
Recommendations – medically-compromised patients lactic use of antibiotics in patients undergoing head and neck
There is insufficient information upon which to base a recommendation surgery in which an incision is made through the oral, nasal,
for prophylactic antibiotics in patients who are medically compromised. pharyngeal, or oesophageal mucosa.123 The recommended
regimen is cefazolin 2 g within 60 minutes of surgical inci-
sion, with metronidazole 500 mg within 60 minutes before
Medically-compromised patients surgical incision for incision involving mucosal surfaces.123
Patients with immediate hypersensitivity to penicillins are
Evidence of the use of antibiotic prophylaxis in medically- recommended clindamycin 600 mg IV within 60 minutes
compromised patients to prevent surgical site infections in prior to the surgical incision.123 In light of our review of the
oral and maxillofacial procedures is limited. One randomised evidence, we suggest that prophylactic antibiotics are limited
control study was included by Lopes et al evaluating prophy- to those surgeries that are at high risk of SSI, and for which
laxis in dentally-invasive procedures in patients with cancer there is evidence for prophylactic use (see above).
or solid-organ transplants. Procedures included exodontia, Overall, we support the Therapeutic Guidelines’ recom-
or periodontal scaling/root planning and prophylaxis was mendation that:
amoxicillin as a single 500 mg 2 h preoperative dose versus
500 mg 2 h preoperative and additional dose 8 h later. No SSIs 1 Antibiotic prophylaxis should not be used unless there is
occurred in either group.122 Recommendations have been a clear indication to do so.
summarised in Table 8. 2 The optimal time for preoperative IV administration is
within 60 minutes prior to surgical incision.
3 A single preoperative dose of antibiotic is sufficient for the
Discussion majority of procedures.
Based on currently available evidence identified in this sys- Key limitations of this review are identified below, how-
tematic review, prophylactic antibiotic use is recommended in ever it must be noted that the quality of evidence of the use
the surgical extraction of third molars, comminuted mandibu- of antibiotic prophylaxis in some maxillofacial procedures
lar fractures, TMJ replacement, complex implants in which is limited. We support the need for further good quality ran-
domised controlled trials in this field. The findings of this Appendix A. Supplementary data
review must be interpreted in the context of the broader
factors influencing the risk/benefit decision regarding pro- Supplementary material related to this arti-
phylactic antibiotic use. This includes factors at the patient cle can be found, in the online version, at
level (such as the likely degree of microbial contamination of doi:https://doi.org/10.1016/j.bjoms.2020.09.020.
the surgical sites, type of procedure, the duration of operation,
and the likely pathogenic organism124 (supplemental Table
3); balanced against the risk of antibiotic-related adverse
events at the patient level and antimicrobial resistance at the References
population level.
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The Journal of Arthroplasty 37 (2022) 1223e1226
Contents lists available at ScienceDirect
The Journal of Arthroplasty

journal homepage: www.arthroplastyjournal.org
Commentary
Antibiotic Prophylaxis for Prosthetic Joint Patients Undergoing

Invasive Dental Procedures: Time for a Rethink?
Bryan D. Springer, MD a, *, Larry M. Baddour, MD b, Peter B. Lockhart, DDS c,
Martin H. Thornhill, MBBS, BDS, PhD c, d
a
OrthoCarolina Hip and Knee Center and Atrium Musculoskeletal Institute, Charlotte, NC
b
Division of Infectious Diseases, Departments of Medicine and Cardiovascular Disease, Mayo Clinic College of Medicine, Rochester, MN
c
Department of Oral Medicine, Carolinas Medical Center e Atrium Health, Charlotte, NC
d
Unit of Oral & Maxillofacial Medicine Surgery and Pathology, School of Clinical Dentistry, University of Sheffield, Sheffield, UK
a r t i c l e i n f o a b s t r a c t
Article history: Background: In the United States, it has been common practice to recommend that dentists provide
Received 30 January 2022 antibiotic prophylaxis (AP) before invasive dental procedures (IDPs) to prevent late periprosthetic joint
Received in revised form infections (LPJIs) in patients who have prosthetic arthroplasties despite lack of evidence for a causal
3 February 2022
relationship between IDP and LPJI and a lack of evidence for AP efficacy.
Accepted 6 February 2022
Available online 11 February 2022
Methods: A recent study quantified the IDP incidence over the 15-month period prior to LPJI hospital
admissions in the United Kingdom for which dental records were available. A case-crossover analysis
compared IDP incidence in the 3 months before LPJI admission with the preceding 12 months. The
Keywords:
arthroplasty
English population was used because guidelines do not recommend AP and any relationship between
infection IDPs and LPJI should be fully exposed.
antibiotic prophylaxis Results: No significant positive association was identified between IDPs and LPJI. Indeed, the incidence of
dental procedures IDPs was lower in the 3 months before LPJI hospital admission than that in the preceding 12 months.
guidelines Conclusion: In the absence of a significant positive association between IDPs and LPJI, there is no
prevention rationale to administer AP before IDPs in patients with prosthetic joints, particularly given the cost and
inconvenience of AP, the risk of adverse drug reactions, and the potential for unnecessary AP use that
promotes antibiotic resistance. These results should reassure orthopedic surgeons and their patients that
dental care of patients who have prosthetic joints should focus on maintaining good oral hygiene rather
than on recommending AP for IDPs. Moreover, it should also reassure those in other countries where AP
is not recommended that such guidance is sufficient.
© 2022 Elsevier Inc. All rights reserved.
Replacing arthritic joints with prostheses is one of the great this number is increasing rapidly with approximately 4 million new
advances of modern medicine with 2.9 million joint arthroplasties hip and knee arthroplasties projected annually by 2030 [5].
performed annually worldwide [1,2]. Successful joint arthroplasties Although a vast majority of joint arthroplasties are successful,
improve quality of life and provide pain relief, mobility, and inde- periprosthetic joint infections (PJIs) remain one of the leading
pendence for patients. There are already greater than 7 million causes of arthroplasty failure. Early infections, defined as occurring
people with prosthetic arthroplasties in the United States [3,4], and within 3 months of joint arthroplasty, are likely due to wound
contamination at the time of surgery. Early-infection rates in the
1950s were approximately 12%; since then, perioperative antibiotic
prophylaxis (AP) administered before joint arthroplasty and
One or more of the authors of this paper have disclosed potential or pertinent laminar airflow operating rooms have reduced this to around 1%-2%
conflicts of interest, which may include receipt of payment, either direct or indirect, [4,6e8] and refocused attention on late PJIs (LPJIs), which occur
institutional support, or association with an entity in the biomedical field which
greater than 3 months after joint arthroplasty surgery. Although
may be perceived to have potential conflict of interest with this work. For full
disclosure statements refer to https://doi.org/10.1016/j.arth.2022.02.014. relatively uncommon, LPJIs are most likely due to hematogenous
* Address correspondence to: Bryan D. Springer, MD, OrthoCarolina Hip and Knee spread of infection from a distant site.
Center, Atrium Musculoskeletal Institute, 2001, Vail Avenue, Suite 200A, Charlotte,
NC 28207.
https://doi.org/10.1016/j.arth.2022.02.014
0883-5403/© 2022 Elsevier Inc. All rights reserved.
1224 B.D. Springer et al. / The Journal of Arthroplasty 37 (2022) 1223e1226
The economic, societal, and personal costs of PJI are substantial. such an association exists. In 1977, Waldman et al [32] performed a
The cost of treating PJIs is 4 to 6 times that of the original arthro- retrospective case review of 62 patients with late periprosthetic
plasty [9e12] and was projected to reach $1.62 billion annually in knee joint infection and identified 7 (11%) of them with a tempo-
the United States by 2020 [13] without accounting for personal and rally associated IDP. In a related study, LaPorte et al [33] temporally
societal costs of long-term disability and impact on the patient associated 3 of 52 (6%) late periprosthetic hip joint infections with
quality of life [14]. PJI is, therefore, of major concern for the 28,000 IDPs. However, neither study included a control group, making it
orthopedic surgeons in the United States and the greater than 7 impossible to draw conclusions regarding a possible association
million individuals who have prosthetic arthroplasties [3,4]. between IDPs and LPJI. In contrast, a case-control study by Kaan-
Following the successful reduction in early PJI rates, there was a dorp et al [34] reported that none of the 37 LPJI cases had under-
resultant desire to identify ways of reducing LPJI, particularly those gone an IDP in the previous 3 months, but 10% of controls had. In a
due to hematogenous spread of infection from other anatomic sites. similar study of 42 Medicare patients with LPJI by Skaar et al [35],
Not surprisingly, orthopedic surgeons recognized the efforts of the only 4 (9.5%) had undergone an IDP in the previous 3 months as
American Heart Association to reduce the risk of infective endo- compared with 15.9% of controls. However, differences were not
carditis (IE) following invasive dental procedures (IDPs) as a para- statistically significant in either study. In the largest study, Berbari
digm that could have applicability to PJI prevention. et al [28] found that 48% of 303 patients with PJI had undergone an
The use of AP to prevent IE in susceptible individuals undergo- IDP in the previous 2 years compared with 34% of 318 controls, but
ing IDPs had become well-established following a series of guide- a high proportion had received AP. A subanalysis of those who had
lines first published by the American Heart Association in 1955 and not received AP, however, identified 33 (11%) patients with PJI who
supported by the American Dental Association [15]. By the 1970- had an IDP in the previous 2 years compared with 49 (14%) controls.
80s, this led orthopedic surgeons to call for dentists to give AP to None of the differences were statistically significant, and each study
patients with prosthetic joints undergoing IDPs [16e19], a practice had a small sample size with a resultant lack of statistical power.
supported by greater than 90% of US orthopedic surgeons at the The case-control studies also suffered from selection bias and risk
time [20,21]. However, unlike IE, where 30%-40% of cases are due to factors confounding between cases and controls. Furthermore,
hematogenous spread of oral bacteria, mainly oral viridans group there was confounding owing to the widespread use of AP in the
streptococci (OVGS) [22e26], these bacteria account for few cases populations studied. In addition, recall bias for IDPs was a limita-
of LPJI. tion in some studies.
Although, joint prostheses remain at infection risk throughout a However, a recent study by our group has produced more
patient’s life, LPJI resulting from hematogenous seeding of bacteria conclusive evidence regarding the possible relationship between
from a remote site is rare. In the largest study that examined this IDPs and subsequent LPJI [36]. This study included all 9427 LPJI
scenario, a cohort of 6101 patients who underwent arthroplasty hospital admissions in the United Kingdom between December
(4002 hip arthroplasties and 2099 knee arthroplasties) were fol- 25th, 2011 and March 31st, 2017, for whom dental records were
lowed for a mean period of 70 months [27]. During this time, 553 available. This cohort is more than 30 times larger than that in any
had distant infections, mainly cystitis episodes, pneumonia, skin previous study, and calculations showed that it had more than
and soft tissue infections, gastrointestinal infections, and so on, and sufficient statistical power to detect any clinically significant asso-
there were also 3 dental abscesses. Although there were 71 PJIs in ciation between IDPs and LPJI. Furthermore, confounders caused by
the cohort (incidence 71 of 6101 ¼ 1.16%), only 7 (0.01%) of these AP use in previously investigated populations were avoided by
were secondary to a remote infection, and none of these were using the English population, where use of AP to prevent LPJI has
dental in origin [27]. Therefore, the risk of hematogenous spread of never been advocated [30]. Thus, any association between IDPs and
infection from a distant site to a prosthetic joint was low and may LPJI should have been fully exposed. Recall bias was eliminated by
have been responsible for only approximately 10% of all PJIs (7/71). inclusion of health records of all events and their timing. Addi-
Moreover, dental-related “seeding” appears uncommon. tionally, a major advantage of the case-crossover design used in this
Microbiological studies also suggest OVGS are an uncommon study was the avoidance of selection bias since each individual
cause of LPJI. An analysis of 14 large studies of PJI microbiology, served as their own control, and it also implicitly accounted for
including >2400 patients who had hip or knee arthroplasty in- potential confounders (eg, differences in oral hygiene, comorbid-
fections, found that 54% of all PJIs were attributable to Staphylo- ities, age, gender, etc.) [37,38]. The study showed that there was no
cocci, but only 8% to Streptococci, with other causes including association between IDPs and subsequent LPJI. Indeed, there was a
Enterococci (3%), aerobic gram-negative bacteria (9%), anaerobes lower incidence of IDPs in the three months prior to LPJI (incidence
(4%), other (3%), polymicrobial infection (15%), and culture negative rate ratio ¼ 0.89, 95% confidence interval (CI) ¼ 0.82-0.96, P ¼ .002)
(14%) [27]. Despite accounting for less than 10% of PJIs, Strepto- than in the preceding 12 months [36]. Furthermore, a sensitivity
coccus is a diverse genus with only a few species included as OVGS, analysis showed that when the exposure window for IDPs was
and few studies have examined streptococcal species in sufficient extended to 4 or 5 months before LPJI hospital admission, there was
detail to quantify the prevalence of OVGS. Two investigations with still no significant association between IDPs and subsequent LPJI
the largest cohorts published to date identified only 3% of 339 and [36].
4.9% of 281 PJI cases due to OVGS [28,29]. If there is no significant association between IDPs and subse-
Overall, recognizing that there are so few cases of PJI due to quent LPJI, then how do we account for the very small proportion of
OVGS, any benefit of AP in preventing LPJI following IDPs is likely to PJI due to OVGS? The reality is that oral bacteria do not only enter
be extremely limited. For this reason, many countries no longer the vascular circulation during IDPs, but also do so during common
recommend AP coverage of IDPs for those patients who have daily activities such as tooth brushing, flossing, and other oral hy-
prosthetic arthroplasties, including Australia, Brazil, Canada, giene procedures [39e41]. This may also occur during mastication,
Denmark, France, the Netherlands, Norway, Portugal, and the particularly if there is tooth mobility [40,42]. However, the fre-
United Kingdom including England, Scotland, Wales, and Northern quency with which bacteremia occurs is influenced by an in-
Ireland [30]. dividual’s oral hygiene status and periodontal health [29,40,43].
For AP to be effective, a positive causal association must exist Those patients who have good oral hygiene and little or no gingival
between IDPs and LPJI, and currently, supporting data are lacking inflammation are less likely to experience bacteremia following
[31]. Moreover, only five studies have previously evaluated whether daily activities than those who have poor oral hygiene. The
B.D. Springer et al. / The Journal of Arthroplasty 37 (2022) 1223e1226 1225
frequency of such bacteremia, particularly in those who have poor Conclusions

oral hygiene, is likely to pose a far more important overall risk for
OVGS PJI than an occasional dental office procedure [28,41,44]. These data suggest there is no rationale for patients who have
However, it is neither practical nor sensible to attempt to cover prosthetic joints to receive AP before IDPs. Indeed, the risk of
frequent daily events with APdeven in those patients who have adverse drug reactions and contributions to the development of
poor oral hygiene. It does, however, seem reasonable to improve antibiotic resistance suggest that continuing this practice is likely to
oral hygiene and eradicate disease around the teeth in all patients be harmful to individual patients and to society, in general. Thus,
who have prosthetic joints to reduce episodes of OVGS bacteremia orthopedic surgeons in many countries have accepted that AP
[29,40]. Indeed, the Berbari study found that patients with more should not be recommended for prosthetic joint patients under-
than one dental hygiene visit were 30% less likely to develop a going IDPs. Moreover, there is no evidence that the incidence of LPJI
prosthetic hip or knee infection, although the study was not suffi- is any higher in the countries where AP is not advocated.
ciently large for this difference to be statistically significant [28]. Therefore, it is time to consider recommending against the use
It can be argued that just as obesity, diabetes mellitus, immu- of AP before IDPs to prevent LPJI in the United States and instead to
nosuppression, and rheumatoid arthritis are considered risk factors focus on the importance of eradicating dental-related disease and
associated with PJI, poor oral hygiene should also be considered as a establishing good oral hygiene in patients who have prosthetic
risk factor [4]. joints. This is something that dentists and orthopedic surgeons
In the absence of a positive association between IDPs and should strongly support to benefit their patients.
subsequent LPJI, there is no rationale for providing AP in those
with prosthetic arthroplasties undergoing IDPs for LPJI prevention.
This conclusion is also supported by the only study to evaluate AP References
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International Journal of Dentistry
Volume 2021, Article ID 6667624, 10 pages
https://doi.org/10.1155/2021/6667624
Review Article
Antibiotic Therapy in Dentistry
Hanie Ahmadi,1 Alireza Ebrahimi,2 and Fatemeh Ahmadi 3
1
Student Research Committee, School of Dentistry, Shiraz University of Medical Sciences, Shiraz, Iran
2
Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
3
School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
Correspondence should be addressed to Fatemeh Ahmadi; ahmadi_f@sums.ac.ir
Academic Editor: Lucio Goncalves
Copyright © 2021 Hanie Ahmadi et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Dental caries, pulpal necrosis, trauma, and periodontal diseases can result in dental infections which could have severe con-
sequences that affect both soft and hard tissues of the oral cavity. Dental infections commonly present with symptoms of pain,
fever, and swelling. Surgical and endodontic treatments are the early management of infected teeth, followed by antibiotic therapy.
Some alternative methods also exist for treating infection such as low-level laser therapy and photodynamic therapy. Antibiotics
are generally used in dental procedures to treat odontogenic infections, nonodontogenic infections, local infection, focal infection,
and prophylaxis. Antibiotic prophylaxis is prescribed for patients with immunosuppressed conditions, infective endocarditis,
metabolic disorders, and patients with prosthetic joints. To reduce the complications of unnecessary antibiotic prescriptions
especially bacterial resistance, comprehensive guidelines should be established. It has been noted that only about 12% of dentists
adequately and correctly prescribe antibiotics, which shows the importance of comprehensive guidelines. Antibiotics prescription
may result in some adverse effects such as hypersensitivity reactions and dermatological and allergic disorders. Furthermore,
unnecessary prescription of antibiotics could result in several serious sequelae, for example, bacterial resistance, gastric and
hematological problems, and diversion of bacterial microbiota. The present review attempts to summarize the indications of
antibiotic therapy in dentistry and discuss the common types of antibiotics that are routinely used in dental practice based on
pharmacologic classes. Moreover, types of antibiotics that are considered safe during pregnancy and childhood are also reviewed.
1. Background be treated as soon as possible, as they may lead to severe and

irrecoverable consequences such as osteomyelitis, brain
Orofacial infections are commonly categorized as odonto- abscess, airway obstruction, carotid infection, sinusitis,
genic and nonodontogenic. The conditions that originate septicemia, meningitis, cavernous sinus thrombosis, orbital
within a tooth and dental supporting structures are called abscess, and loss of vision [5]. It has been noted that the most
odontogenic infections. On the other hand, teeth structures common prevalent feature of orofacial infections are den-
are not involved in nonodontogenic infections [1, 2]. Dental toalveolar abscess [3].
caries, pulpal necrosis, dental trauma, and periodontal Dental infections could be cured by surgical interven-
diseases can result in dental infections which could have tions, endodontics therapy, and antibiotic prescriptions [4].
severe consequences that affect both soft and hard tissues of The early surgical management of the infected tooth should
the oral cavity. According to a previous study, Gram-positive be carried out to prevent further consequences; this may
cocci are responsible for about 65% of orofacial infections, include debridement, irrigation, and incision and drainage
and Gram-negative bacilli could be found in 25% of patients’ (I&D) in severe cases [6]. Furthermore, in patients with the
oral specimens [3]. Orofacial infections mostly occur during signs of systemic involvement, administration of intrave-
the age of 21–40; besides, the prevalence of the disease is not nous antibiotics according to bacterial cultures and sensi-
gender-related [1, 4]. tivity is suggested [5, 7]. Present guidelines indicate that
Dental infections are commonly presented by symptoms antibiotics should be prescribed after the elimination of the
of pain and swelling in the oral area. These infections should infectious sources. These should be prescribed for 2-3
2 International Journal of Dentistry
consecutive days after surgical treatments. Longer durations Table 1: Different rates of antibiotic prescription by dentists [10].
of antibiotic therapy were not found to be significantly Antibiotic Prescription rate (%)
beneficial and are not recommended [8]. This could result in
Amoxicillin 51.1
the unnecessary prescription and a longer duration of an- Amoxicillin + clavulanic acid 24
tibiotic therapy that may have serious consequences [9]. Clindamycin 6.6
Previous studies demonstrated that about 12% of den- Azithromycin 5.3
tists adequately prescribe antibiotics as a prophylactic in- Clarithromycin 4.4
tervention and treatment [7]. In this regard, previous reports Doxycycline 3.6
have mentioned that the most common antibiotic that is Spiramycin 2.2
prescribed in dental practice is amoxicillin followed by Erythromycin 1.2
amoxicillin and clavulanic acid (Table 1) [10]. Antibiotics Ciprofloxacin 0.2
prescription may result in some adverse effects such as Cefadroxil 0.1
hypersensitivity reactions and dermatological and allergic Minocycline 0.1
Cefuroxime 0
disorders [11]. Furthermore, unnecessary prescription of
Others 1.1
antibiotics could result in several serious complaints, for
example, bacterial resistance, gastric and hematological
problems, and diversion of bacterial microbiota [12, 13].
Besides, this could lead to oral bacterial resistance which is with metabolic disorders (such as diabetes and splenec-
considered a growing concern in dentistry and medicine as tomies), patients with prosthetic joints, in-dwelling cath-
well. To prevent these problems, antibiotics should be eters, neurosurgical shunts, valvular heart diseases, surgical
prescribed in a narrow spectrum and be limited to acute pulmonary shunts, hypertrophic cardiomyopathy, mitral
infections. Moreover, further education and investigation valve prolapsed, and prosthetic heart valves [19, 20]. In
should be conducted to prevent and reduce the problem of susceptible patients, some procedures enhance the risk of
antibiotic resistance [14]. infection such as dental extraction, surgical periodontal
Since a few decades ago, the rate of odontogenic in- procedures, dental implant placement, reimplantation of
fections has tended to be decreasing. This could be because teeth, endodontic procedures or endodontics surgeries,
of the rising education of individuals about oral hygiene and subgingival placement of antibiotic fibers or strips, and
the development of oral healthcare products [4]. Conversely intraligamentary local anesthetic injections [19]. Prophy-
to the abovementioned fact, the orofacial infections are still laxis for healthy patients is also suggested in special dental
considered as a worldwide problem. The lack of sufficient practices, such as surgery for benign tumors, bone grafting,
strategies for antibiotic prescription in dentistry has been a implant placement, periapical surgery, and removal of
concern for many dental practitioners, and more education impacted teeth [20].
is needed in this regard [14]. To decrease the prevalence of Antibiotic prescription is recommended in acute in-
dental infection and its consequences, comprehensive fection conditions such as necrotizing ulcerative gingivitis,
guidelines are needed for the treatment of the condition. stage III-grade C/incisor-molar pattern periodontitis (for-
In this review, we aim to provide some applicable data merly referred to as localized aggressive periodontitis), acute
for dentists to prescribe appropriate types of antibiotics. At periapical abscess, cellulitis, local or systemic spreading of
first, common types of antibiotics that are considered safe infection in the periodontal abscess, pericoronitis, peri-
during pregnancy and childhood are mentioned. Then, the implantitis, infection of deep fascial layers of the head and
common cases that need antibiotic therapy or prophylaxis neck, and in the case of fever and/or malaise [6, 20, 21].
and the most useful and commonly used antibiotics in
dentistry are reviewed (Figure 1). 3. Antibiotic Use in Pediatric Dentistry
2. Indications of Antibiotics Anatomical and physiological differences between children
and adults such as the amount of their body water and fat,
Antibiotics are suggested in the cases of prophylaxis for local the maturation of the immune system, the volume of pro-
and focal infections, besides, for the treatment of odonto- tein, and the level of liver enzymes should be considered
genic and nonodontogenic infections [13, 15]. Antibiotics while prescribing antibiotics for children [22]. Dentists treat
are not indicated for all odontogenic infections; they should children with antibiotics to reduce the risk of bacteremia
not be used instead of removal of the source of infections caused by dental infections; however, antibiotic therapy
[16]. In the case of infection, I&D, debridement, and end- should not be used as an alternative method for elimination
odontic management followed by systemic antibiotic ther- of an infection source [23]. Furthermore, antibiotic resis-
apy are recommended [17]. Moreover, the practitioners tance owing to inappropriate use, prescribing antibiotics in
should also bear in mind that the antibiotic prophylaxis is the wrong situation and for a too long period in children is a
indicated in a few specified conditions [18]. Figure 2 global concern [24]. Therefore, dental practitioners should
summarizes the indications of antibiotics in dental practice. be aware of proper antibiotic choices and indications of
Antibiotic prophylaxis is a necessary option in cases of antibiotic therapy for children under 13 years [24]. Common
immunosuppressed patients, patients with a history of types and forms of antimicrobial agents used in pediatric
cancer, individuals with infective endocarditis, patients dentistry are listed in Tables 2 and 3.
International Journal of Dentistry 3
The most commonly used antibiotics

in dentistry
Beta-lactamase
Nitroimidazole Macrolides Lincosamide Fluoroquinolones Tetracycline
antibiotics
Penicillin Cephalosporin Metronidazole Erythromycin Clindamycin Ciprofloxacin
Penicillin v Azithromycin Moxifloxacin
Amoxicillin Clarithromycin
Co-amoxiclav
Ampicillin
Figure 1: The most commonly used antibiotics in dentistry.
them [26]. It should be also noted that most of the dental

Treatment of odontogenic procedures are not emergencies and can be postponed after
infections delivery; however, acute dental infections should be man-
aged during pregnancy [25–27].
The drug prescription during the pregnancy should be
done more cautiously, as the inappropriate prescription
Treatment of could irrecoverably harm the fetus. In dental practice, the
nonodontogenic infections main agents that are commonly used during pregnancy and
are considered to be safe during this period are analgesics,
Indications of antibiotics
anesthetic agents, and antibiotics [26]. Food and Drug
Administration (FDA) has classified drugs into 5 groups (A,
Prevention of focal
infection
B, C, D, and X) based on their risk factors during pregnancy
(Table 4), and most of the antibiotics are classified to be in
class B of FDA arrangement [28]. Furthermore, the pregnant
patients should receive a complete adult dose with the usual
Prevention of local length of treatment [27].
infection
5. The Most Common Prescribed Antibiotics

Figure 2: Indications of antibiotics in dental practice.
5.1. Beta-Lactams. Beta-lactam antibiotics are the antimi-
crobial agents that contain beta-lactam ring in their molecular
4. Antibiotic Therapy during Pregnancy structure (this ring includes a three-carbon and one-nitrogen
cyclic amine structure) [7, 29]. This group of antibiotics is
The physiological changes of pregnancy can affect the bactericidal agents that act against many Gram-positive,
condition of the oral cavity such as increasing the risk of Gram-negative, and anaerobic bacteria via inhibiting the
gingivitis and pyogenic granuloma [25]. Preventive or synthesis of the cell wall [7]. Beta-lactam antibiotics are
therapeutic interventions during this period should be categorized into five classes: penicillin, cephalosporins,
carried out to preserve the health of both mother and her penems, carbapenems, and monobactams [30].
neonate, enhance maternal oral health, and reduce children’s The overuse and misuse of penicillin and cephalosporins
future oral problems [26]. In this regard, it has been has resulted in an increased rate of bacterial resistance,
mentioned that the mothers with poor oral hygiene who caused by the production of beta-lactamase. Moreover, the
have a higher number of microorganisms in their saliva, risk of resistance might be increased if penicillin is ad-
especially Streptococcus mutans, can easily transmit the ministered simultaneously with other antibiotics, for in-
infection to the infant causing several serious problems for stance, metronidazole [31]. Allergic reactions caused by the
Table 2: Therapeutic antibiotic dose for children.

Agent Situation Dose Maximum dose Available forms
Tablet 125 mg, capsule 250 mg and
First choice in 20–40 mg/kg/day,
Amoxicillin 2 g/day 500 mg, and oral suspension 125 mg/
dental infection e8 h
5 ml and 250 mg/5 ml
1000–2800 mg
Amoxicillin + clavulanic Failure of first Tablet 375 mg, 625 mg, and 1000 mg
amoxicillin/143–400 mg
acid choice antibiotic and oral suspension 228.5 mg/5 ml
clavulanic acid
Penicillin 10–20 mg/kg/day,
Clindamycin Suspension 75 mg/5 ml
hypersensitivity e6 h
Tablet 125 mg, 250 mg, and 500 mg,
Necessity of broad- 25–100 mg/kg/day, capsule 250 mg, 500 mg, and 750 mg,
Cephalexin
spectrum action e6_8 h and oral suspension 125 mg/5 ml and
250 mg/5 ml
Tablet 200 mg, 250 mg, 400 mg, and
Metronidazole Anaerobic bacteria 30 mg/kg/day, 8 h 2 g/day 500 mg, infusion solution 500 mg/5 ml,
and oral suspension 200 mg/5 ml
Table 3: Antibiotic prophylaxis regimen for children.

Agent Situation Administration route Dosage
Amoxicillin First choice Oral 50 mg/kg
Ampicillin or Unable to take
IM or IV 50 mg/kg
cefazolin/ceftriaxone oral medication
Allergic to penicillin or
Cephalexin oral 50 mg/kg
ampicillin
Clindamycin 20 mg/kg
Azithromycin/
15 mg/kg
clarithromycin
Allergic to penicillin and ampicillin and unable to
Cefazolin/ceftriaxone IM or IV 50 mg/kg
take medication orally
Clindamycin 20 mg/kg
Table 4: FDA risk classes of antibiotics used during pregnancy.

Category risk factor Antibiotics Side effects
A
Satisfactory well-controlled studies on humans showing no
hazard to the fetus
B Amoxicillin
Animal studies demonstrate no risk, but no human studies have
Cephalexin
been performed or human studies have demonstrated no risk
Chlorhexidine
Clindamycin
Erythromycin
Metronidazole
Penicillin
Azithromycin
C Ciprofloxacin Chondrotoxic in growing rats
Studies on animals establishing fetal hazards and no exact studies on human being Moxifloxacin Chondrotoxic in growing rats
Clarithromycin Increased risk of miscarriage
D Doxycycline Intrinsic dental staining
Evidence of risk to the fetus can be used in exceptional cases or circumstances Tetracycline Intrinsic dental staining
X
The hazards of using the drug in pregnant women far more than the benefits
release of immunoglobulin E (IgE) mediators are among the the orogastrointestinal normal microbiota causing candi-
common side effects of beta-lactams and might include diasis or even Clostridium difficile infection [42].
rashes, pruritis, and even anaphylactic shock [29].
5.2.4. Ampicillin. Ampicillin is categorized as a broad-
5.2. Penicillin. Penicillin is a narrow-spectrum antibiotic spectrum beta-lactam antibiotic that has bactericidal activity
that was discovered from a rare variant of Penicillium [7]. The drug antibacterial activity mostly covers the Gram-
notatum [32]. The most common types of penicillin that are positive bacilli, but it acts less effectively than amoxicillin [6].
being administered for treatment of odontogenic infections Moreover, ampicillin mainly acts against aerobic bacteria,
are penicillin V, amoxicillin, and amoxicillin/clavulanic acid, and it could be simultaneously prescribed with metroni-
and studies show that they have almost the same efficacy dazole to more efficiently fight anaerobic bacteria of
regarding the treatment of dental infections [21]. According odontogenic infections [43]. The agent is commonly used for
to previous investigations, nearly 70% of bacteria isolated patients who cannot orally take drugs, and the prophylaxis
from odontogenic infections were susceptible to penicillin dosage is 2 mg IV or intramuscular (IM) half an hour before
[33]. Commonly, penicillin is considered to be the first-line the procedure [20]. Furthermore, ampicillin-sulbactam
drug and the gold standard for the treatment of odontogenic could be prescribed 3 g intravenously every 6 hours [29]. The
infections because of its cost-effectiveness, low incidence of coadministration of ampicillin and clindamycin could in-
side effects, and appropriate antimicrobial activity [21, 34]. crease the risk of pseudomembranous [44].
Despite these benefits, the drug might cause various side
effects in certain patients, including rash, nausea, gastric
5.2.5. Cephalosporin. Cephalosporins are classified in beta-
irritation, diarrhea, and hypersensitivity reactions such as
lactam antibiotics and can inhibit the biosynthesis of bac-
skin reactions [13]. It has been mentioned that about 10% of
terial cell walls [38]. Cephalosporins can act against aerobic
people might present some levels of hypersensitivity to the
bacteria, and their combination with metronidazole could
drug; however, 90% of them can tolerate penicillin [34].
cover both aerobic and anaerobic bacteria [43]. Cephalexin
Should the patients have a history of hypersensitivity to the
and cefazolin are among the most commonly prescribed
drug or a positive skin test, clindamycin could be admin-
first-generation cephalosporins in dental practice [45].
istered instead of penicillin [21].
Cephalexin could be prescribed for penicillin-allergic pa-
tients, with the dosage of 2 g orally 1 h before dental pro-
5.2.1. Penicillin V. Compared with penicillin G, penicillin V cedures [20]. Cefazolin is suggested for patients who are
stays for a longer time in blood circulation [12]. Tablet of 500 allergic to penicillin and cannot take the medication by
milligrams (mg) penicillin V is recommended every 6 hours mouth, with the dosage of 1 g IV or IM 30 minutes before the
taking by mouth [17]. Moreover, 2–4 g penicillin V every 4–6 procedure [20]. Older studies recommended not to use
hours combined with 500 mg metronidazole intravenous cephalosporins in penicillin-allergic patients, while more
(IV) or orally every 8 hours could also be prescribed [31]. recent investigations showed that there is little cross-activity
between penicillin and cephalosporins [46]. Studies also
mentioned that while the cephalosporins have few side ef-
5.2.2. Amoxicillin. Amoxicillin is a penicillin antibiotic that
fects and better antimicrobial activity, amoxicillin is still the
acts against Gram-negative bacilli [6, 35]. Amoxicillin is
drug of choice for the treatment of odontogenic infections
commonly considered to be the first line of treatment in
[46, 47]. The patients who were treated with cephalosporins
nonallergic patients [36]. It is the most frequently prescribed
might have higher risks of colonization of Candida albicans
antibiotic accounting [37]. Some practitioners also prefer to
and yeast [48].
administer the combination of amoxicillin and metroni-
dazole or amoxicillin/clavulanate to treat odontogenic in-
fection [38, 39]. The therapeutic dosage for amoxicillin is 5.3. Nitroimidazoles. Nitroimidazoles are commonly ad-
500 mg every 8 hours or 1000 mg every 12 hours [21]. ministered to treat parasitic and anaerobic bacterial infec-
tions. Nitroimidazoles include metronidazole, nimorazole,
and tinidazole [49, 50]. It has been noticed that dental
5.2.3. Amoxicillin with Clavulanic Acid (Co-Amoxiclav).
practitioners tend to prescribe metronidazole for the
Amoxicillin with clavulanic acid (co-amoxiclav) is a broad-
treatment of acute infections, as it has great antianaerobic
spectrum antibiotic that is believed to be the second most
bacterial activity and low risk of toxicity [49, 50].
prescribed antibiotic by dentists [9]. It has been shown that
all the bacteria that were extracted from an odontogenic
abscess were susceptible to the agent [33]. Besides, in the 5.3.1. Metronidazole. Metronidazole has bactericidal ac-
case of amoxicillin resistance, the administration of co- tivity and acts against anaerobic microorganisms by
amoxiclav or metronidazole is suggested [40]. A high dose of inhibiting the nucleic acid synthesis; the agent also
co-amoxiclav (875/125 mg every 8 hours or 2000/125 mg showed antiprotozoal activity and does not disrupt the
every 12 hours) is a proper choice in the cases of severe protective aerobic microbiota [50, 51]. Combined ad-
odontogenic infections, such as abscess and pulpitis [41]. ministration of amoxicillin and metronidazole could
The dental practitioners should be aware that the drug could cover most of the oral bacteria [43]. Prescription of this
result in some levels of hepatotoxicity; besides, it can change combination or metronidazole is also recommended for
the treatment of periodontal infections [40, 52, 53]. The 5.4.3. Clarithromycin. Clarithromycin is a broad-spectrum
drug is commonly prescribed with a dosage of 500–750 mg antibiotic that is considered to be the new generation of
every 8 hours [21]. erythromycin [65]. Clarithromycin is a bacterial protein
The dental practitioners should bear in mind that synthesis inhibitory and matrix metalloproteinase (MMP)
metronidazole can interact with some agents such as alcohol regulating activities that could fight against intracellular
(causes nausea, vomiting, and abdominal cramp), disulfi- pathogens by penetrating the cells [66]. Among the mac-
ram, warfarin, and hydantoin anticonvulsants [50]. The rolides, the agent is believed to have the greatest effect
agent might also result in serious side effects, such as sei- against anaerobic Gram-positive bacilli [6]. Hence over, the
zures, anesthesia, or paresthesia of the limbs in certain prescription of clarithromycin can be a logical approach for
patients [21]. Two cases with metronidazole resistance have suppressing the pulp and periodontal infections [67, 68].
been reported in Scotland: one was an infection of the knee However, clarithromycin is not usually recommended as the
joint (with anaerobic streptococci that is found in dental first-line treatment and is used instead of penicillin in pa-
abscess and periodontal disease) and the other was Bac- tients who cannot tolerate the gold standard treatment of
teroides thetaiotaomicron bloodstream infection [51]. penicillin [62].
The standard dose for prophylaxis is 500 mg orally 1
hour before the dental procedure [46]. The most common
5.4. Macrolides. Macrolides have a macrocyclic lactone ring, side effects of clarithromycin are gastrointestinal compli-
which are bacteriostatic agents that inhibit protein synthesis; cations, such as nausea and diarrhea [61]. It is indicated that
these agents have translation modulators that act against clarithromycin has some new effects such as modulating
bacterial ribosomes [54–56]. Macrolides mainly act against myocarditis, cardiac rejection, and change of inflammatory
beta-hemolytic streptococci [57]. Macrolides should not be signs [67].
coadministered with clindamycin, since these have the same
target point and antagonistic effects [56]. Moreover, mac-
rolides should not be prescribed in patients with progressive 5.5. Lincosamides. Lincosamides are bacteriostatic agents
cirrhosis, as this could result in liver failure and even death that mostly fight against Gram-positive anaerobic patho-
[42]. gens, by binding to the functional spot of the bacterial ri-
bosome and restricting the protein synthesis [69, 70].
Lincomycin and clindamycin are the drugs that are classified
5.4.1. Erythromycin. Erythromycin has bacteriostatic ac- in the group of lincosamides antibiotics [71]. Studies showed
tivities and is commonly prescribed for dental caries and that clindamycin has a greater effect against infections
dental plaque [55, 56, 58]. The most common microor- compared with other lincomycin [69]. The coadministration
ganism that causes dental caries is Streptococcus mutans, of lincomycin and erythromycin is not suggested, as these
which is highly sensitive to erythromycin [59]. Erythro- two drugs have an antagonistic effect against each other [72].
mycin can inactivate the caries, and it also can decrease the While, among lincosamides, the prescription of clindamycin
growth and formation of dental plaque [60]. is more common than the others [70].
Erythromycin should be prescribed with a dosage of
250–500 mg every 6 hours [13]. However, the drug is not
regularly recommended as it could cause several short-term 5.5.1. Clindamycin. Clindamycin is a broad-spectrum bac-
and long-term adverse effects, such as gastrointestinal teriostatic antibiotic that covers both aerobic and anaerobic
problems, hepatotoxicity, and also bacterial resistance [61]. pathogens [73, 74]. The drug is the newer generation of
Moreover, the drug is contraindicated in patients taking lincomycin, and it has suitable potency against bone, joint,
simvastatin or colchicine and also in patients who suffer and odontogenic infections [73, 74]. As showed by the
from porphyria [62]. previous investigations, nearly 75% of all bacteria causing
odontogenic infections are sensitive to the drug [33].
Clindamycin could be prescribed in the case of persistent
5.4.2. Azithromycin. Azithromycin is a bacteriostatic anti- infections, as it has more efficacies in comparison with
biotic that has a great potency against Gram-negative penicillin and metronidazole [73]. Besides, it has been
pathogens and is considered to be the safest among the shown that the bacterial resistance rates against penicillin are
macrolides [56, 63]. The drug is not suggested as the first-line higher comparing to clindamycin [75]. Moreover, the agent
treatment of odontogenic infections and is usually pre- could be administered IV or IM, besides, oral ingestion [76].
scribed as an alternative in penicillin-allergic patients Clindamycin is also an excellent choice for patients who
[63, 64]. have an allergy to beta-lactam group antibiotics. The ther-
The dosage of the drug is 500 mg once a day for three apeutic dosage of the drug is 600 mg or 300 mg every 8 hours
days, in case of therapeutic prescription, and 500 mg 1 hour orally or intravenously [2, 6, 13]. The drug is also a proffered
before the oral procedure, in case of prophylactic admin- alternative for prophylaxis in penicillin-allergic patients for
istration [13, 46]. The common side effects of azithromycin prophylaxis [20]. The usual prophylactic dose is 600 mg
include nausea, diarrhea, and gastrointestinal disorders, and before procedure orally or 600 mg intravenously in both
it should not be prescribed in erythromycin-allergic patients penicillin-allergic patients and those who cannot take
[21, 56, 63]. medication by mouth [20]. Furthermore, more recent
studies showed that clindamycin might reduce the risk of dry prophylactically prescribed to beta-lactam-allergic patients
socket after extraction [46]. to prevent bacteremia [64]. However, moxifloxacin is not
The most common side effects of clindamycin are used as the first-line treatment because of its high price and
vomiting, nausea, diarrhea, exanthem, jaundice, hepatitis, is usually prescribed when the first-line antibiotics and
neutrophil reduction, eosinophilia, agranulocytosis, blood surgical procedures are failed [46, 79]. The effective dose of
platelet count change, and pseudomembranous colitis the agent to control odontogenic infections is 400 mg once a
[68, 70]. The agent is contraindicated for cirrhotic patients day [79]. The major concern is that the drug could affect
and for patients with a history of ulcerative and pseudo- cartilage maturation; hence, it must not be in pregnant and
membranous colitis [73, 75, 76]. adolescent patients [56].
5.6. Fluoroquinolones. Fluoroquinolones are broad-spec- 5.7. Tetracyclines. Tetracycline is a bacteriostatic antibiotic
trum bactericidal antibiotics that mostly act against Gram- that is active against Gram-positive and Gram-negative
negative bacilli, Gram-positive aerobic cocci, and anaerobic bacteria, acting by blocking the synthesis of protein through
organisms, by preventing the synthesis of DNA [77–80]. binding to the ribosomal subunit [89]. The drug could be a
Fluoroquinolones are commonly prescribed for non- reasonable prescription for the treatment of periodontal
odontogenic infections, such as respiratory, genitourinary diseases, as it has anti-inflammatory activity, collagenase
tract, joint, and bone infections [78]. These agents have a inhibition potential, and bone resorption inhibitory ca-
higher capacity of penetration into tissue in comparison with pacity; besides, it could help the fibroblasts to attach to the
other commonly prescribed antibiotics in dental practice root surface [90].
[81]. Tetracycline is recommended in cases of periodontal
The side effects of this class of antibiotics include diseases, improving marginal attachment and enhancing
gastrointestinal reactions and cartilage, joint, tendon, bone graft [56, 90]. The drug has a long half-life, preserves its
and the central nervous system involvement [82, 83]. antimicrobial activity for a long time, and is released from
Fluoroquinolones must not be prescribed for children the tooth surface gradually [90]. However, the agent is not
because of the possibility of chondrotoxicity in devel- commonly suggested for the treatment of odontogenic in-
oping cartilage and for patients who use theophylline, as fections because of the widespread resistance of pathogens
this could result in serious complications, for example, and several side effects, including photosensitivity, nausea,
seizure [79]. vomiting, diarrhea, loss of appetite, hepatotoxicity, and
discoloration of primary and permanent teeth [46, 91]. The
prescription of the drug for young children and pregnant
5.6.1. Ciprofloxacin. Ciprofloxacin is among the second
women is not recommended because it can cause intrinsic
generation of fluoroquinolone antibiotics and is active
tooth staining during the calcification phase [56, 92]. Be-
against Gram-positive and Gram-negative pathogens
sides, tetracycline must not be prescribed for patients with
[53, 77]. This antibiotic showed excellent antibacterial po-
active liver diseases [20].
tency, whilst having minimum side effects [56, 84, 85]. The
drug is usually administered orally with a dosage of 500 mg
every 12 hours to treat odontogenic infections [20]. The most 6. Conclusion
common side effect of ciprofloxacin is gastrointestinal
problems, including, nausea, vomiting, and diarrhea [21]. Antibiotic therapy is crucial to control dental infections after
Dental practitioners should take the patients’ history as if surgical interventions such as incision, drainage, and pulp
they have been using theophylline because the drug inter- debridement. Dentists prefer to prescribe amoxicillin and
action could result in severe consequences [86]. The initial metronidazole or co-amoxiclav to control dental infections.
signs of theophylline toxicity in these patients are nausea and Moreover, clindamycin is an alternative drug in penicillin-
vomiting, which should not be confused with the side effects allergic patients. The accurate information about oral mi-
of ciprofloxacin [86]. croorganisms, the character of oral infections, and the
pharmacokinetics of antibiotics reduce the risk of incorrect
antibiotic prescription. Some alternative methods exist for
5.6.2. Moxifloxacin. Moxifloxacin is a broad-spectrum treating infection such as low-level laser (LLL) therapy and
bactericidal agent and a fourth-generation fluoroquinolone. photodynamic therapy (PDT).
The drug acts against aerobic, anaerobic, Gram-positive, and Previous studies show the effectiveness of LLL therapy
Gram-negative bacteria and is commonly administered to on infected wounds; moreover, it can reduce inflamma-
control chronic bronchitis, pneumonia, skin infections, and tion and bacterial proliferation. PDT has been successfully
bacterial sinusitis [53, 75]. Prior investigations showed that used to eliminate pathogens and treat localized infections
most of the bacterial populations found in odontogenic such as periodontal infections, abscesses, oral and dental
infections are susceptible to moxifloxacin [33]. infections, wound, burn, and ear infections. Accurate use
Moxifloxacin can be considered as a good choice to treat of antibiotics is crucial for the treatment of dental in-
odontogenic and periodontal infections as well, since it has fections; accordingly, comprehensive antimicrobial pre-
high penetration capacity through periodontal and bone scribing guidance should be established for dental
tissues [56, 81, 87, 88]. Moreover, this could be professionals.
Reviews
Dental treatment of post-myocardial infarction patients:

A review of the literature
Leczenie stomatologiczne pacjentów po przebytym zawale
mięśnia sercowego – przegląd piśmiennictwa
Renata Samulak-Zielińska1,A,B,D,F, Elżbieta Dembowska1,D–F, Piotr Lizakowski2,B,D–F
1
Departament of Periodontology, Pomeranian Medical University in Szczecin, Poland
2
Specialist Medical Practice in Szczecin, Poland
A – research concept and design; B – collection and/or assembly of data; C – data analysis and interpretation;
D – writing the article; E – critical revision of the article; F – final approval of the article
Dental and Medical Problems, ISSN 1644-387X (print), ISSN 2300-9020 (online) Dent Med Probl. 2019;56(3):291–298
Address for correspondence

Renata Samulak-Zielińska
Abstract
E-mail: renata.samulak.zielinska@gmail.com Patients who have suffered a heart attack often require dental treatment. The inflammation of the oral
cavity not only reduces the quality of life, but also negatively affects the course of ischemic heart disease.
Funding sources
None declared
Dental treatment in patients with a history of myocardial infarction seems complicated, since these patients
require special consideration with regard to the timing and form of dental treatment as well as to the
Conflict of interest precautions required. Patients at risk of cardiac complications that are greater than the benefits of dental
None declared treatment should be identified and only the most urgent conditions should be treated. The aim of this study
was to present the latest guidelines for dental treatment in patients who have suffered myocardial infarc-
Received on January 2, 2019 tion. We reviewed the available literature explaining when dental treatment can be undertaken, whether
Reviewed on February 20, 2019 antibiotic prophylaxis is required, whether the patient can be anesthetized locally, and how to provide the
Accepted on May 8, 2019
maximum safety during the visit. The principles of the surgical treatment of patients receiving drugs that
affect hemostasis were also reviewed.
Published online on September 30, 2019
Key words: dental care, oral anticoagulants, antibiotic prophylaxis, myocardial infarction
Słowa kluczowe: opieka stomatologiczna, doustne antykoagulanty, profilaktyka antybiotykowa, zawał
mięśnia sercowego
Cite as
Samulak-Zielińska R, Dembowska E, Lizakowski P. Dental
treatment of post-myocardial infarction patients: A review
of the literature. Dent Med Probl. 2019;56(3):291–298.
doi:10.17219/dmp/109232
DOI
10.17219/dmp/109232
Copyright
© 2019 by Wroclaw Medical University
This is an article distributed under the terms of the
Creative Commons Attribution 3.0 Unported License (CC BY 3.0)
(https://creativecommons.org/licenses/by/3.0/)
292 R. Samulak-Zielińska, E. Dembowska, P. Lizakowski. Dental treatment after myocardial infarction
Introduction Needs (CPITN), 38.6% of them have a score of 3 and 46%
a score of 4, meaning they are in urgent need of periodon-
The number of patients with general diseases requiring tal treatment.6 Questions concerning the safety of dental
dental treatment is on the increase. According to the esti- treatment of patients after myocardial infarction need to
mates presented in Bhateja’s report, out of 36,729 patients be addressed.
of Dental College and Hospital in Mathura, India, 58%
had a history of cardiovascular disease.1 Such patients re-
quire an individualized treatment plan and the continuous Material and methods
monitoring of oral health. The current state of knowledge
indicates that inflammation in the oral cavity, particularly To identify key words, a Population, Intervention,
periodontitis, affects the general state of health, including Comparison and Outcome (PICO) question was for-
the development and course of atherosclerosis. Cardiovas- mulated as: What are the safety rules for dental care
cular disease has an inflammatory origin. Firstly, there is of patients following myocardial infarction? A compre-
an increase in the level of pro-inflammatory mediators in hensive search of the MEDLINE (PubMed), Scopus and
response to the presence of Gram-negative lipopolysac- Google Scholar electronic databases was undertaken in
charides (LPSs), C-reactive protein (CRP), interleukin 1β January 2019 to find relevant articles, using the follow-
and interleukin 6 (IL-1β and IL-6), tumor necrosis facing search terms: [dental care OR dental anesthesia OR
tor alpha (TNF-α), fibrinogen, and matrix metallopro- tooth extraction] AND [myocardial infarction OR isch-
teinase 9 (MMP-9). These substances contribute to the emic heart disease]. The timeframe was 2000–2019. Ad-
destabilization of the atherosclerotic plaque.2 Secondly, ditionally, a manual search of the bibliographies of full-
there is a cross-reaction of the patient’s antibodies with text articles was also conducted. The guidelines of the
heat shock protein (HSP) present in the damaged vascu- American Heart Association (AHA), American College
lar endothelium and atherosclerotic plaques. This leads to of Cardiology (ACC), European Society of Cardiology
the continuation of the inflammatory process, and thus to (ESC), and Polish Society of Cardiology were also re-
the progression of the disease. Cross-reactivity is triggered viewed. We considered reviews, systematic reviews,
by the presence of oral bacteria Porphyromonas gingivalis guidelines and statements of dental and cardiological as-
and Tannerella forsythia, whose HSP is in 60% homolo- sociations, randomized controlled trials (RCTs) as well
gous to HSP found in mammals.3 Thirdly, direct bacterial as cohort, case and cross-sectional studies. Papers with
mechanisms (e.g., bacterial enzyme activity) contribute to abstracts written in English or Polish were included. Let-
the progression of cardiovascular disease. Bacterial DNA ters, book chapters, case reports, and studies without an
of Tanerella forsythia, Porphyromonas gingivalis, Aggrega- abstract or with no full text available were not included.
tibacter actinomycetemcomitans, and Prevotella interme- Only publications addressing the protocol for the treat-
dia has been found in the atherosclerotic plaque.4 Finally, ment of post-myocardial infarction patients were ana-
the concept of ‘vascular endothelial activation’ can explain lyzed. Articles dealing with the influence of oral inflam-
the mechanism underlying inflammatory-induced athe- mation on cardiovascular disease or the effects of dental
rosclerotic plaque formation. The LPS binding, bacterial treatment on general health were excluded.
outer membrane vesicles, fimbriae, and other bacterial an- The limitations of this review include the open PICO
tigenic structures have an impact on the local and systemic question, the broad spectrum of relevant issues requiring
host response. This leads to the upregulation of endothe- urgent explanation, and the restriction to cardiological
lial cell receptors followed by monocyte adhesion to the society guidelines and reviews rather than RCTs. Taking
vascular wall. Monocytes migrate into the subendothelial all this into account, only some of the Preferred Reporting
space, absorb low-density lipoprotein cholesterol (LDL-C) Items for Systematic Reviews and Meta-Analyses (PRIS-
and become foam cells. After their apoptosis, lipids are ac- MA) rules could be fulfilled. The study selection was
cumulated in the vessel wall, covered by matrix and ac- conducted independently by 2 reviewers (PL and RSZ),
companied by smooth muscle cell proliferation, which is with any disagreements resolved by the 3rd reviewer (ED).
induced by invasive periodontal pathogens. The enzyma- A total of 37 articles were included in the review. No me-
tic degradation of the extracellular matrix results in plaque ta-analyses or systematic reviews were found.
rupture, the exposure of prothrombotic components and Our findings were compatible with those presented by
subsequent thrombus formation, which ultimately leads to Napeñas et al. at a panel of experts during World Work-
blood vessel occlusion.4 This results in a need for treat- shop on Oral Medicine VI.7 They stated that “with a lack
ment of oral cavity diseases as well as in intensive efforts of consensus statements, guidelines, or systematic re-
toward periodontal disease prevention in patients with views focused on these specific issues related to dental
cardiovascular diseases.5 treatment for patients with cardiovascular diseases, the
The need for periodontal treatment is significant vast majority of current recommendations are not linked
among Polish patients after myocardial infarction. With to levels of evidence and are presumably derived from ex-
regard to the Community Periodontal Index of Treatment pert opinion”.7
Dent Med Probl. 2019;56(3):291–298 293
Appropriate time to start dental treatment amines that burden the already damaged heart muscle,
which means caution might not always be the safest solu-
in post-myocardial infarction patients
tion. The priority is to cure inflammation in the oral cavi-
Dental procedures are classified as minor surgical pro- ty, as it can cause pain similar to angina pectoris, with the
cedures of a low cardiovascular risk. The risk of death or same characteristic pain radiation. In addition, painful
myocardial infarction within 30 days of a dental procedure inflammation hinders food intake and interrupts sleep,
is less than 1%. However, a patient after a heart attack is resulting in a significant reduction in the quality of life.11
at high risk of recurrence of cardiovascular events. Only Endodontic treatment, conservative treatment, non-sur-
considering patients with acute ST-elevation myocardial gical periodontal treatment, or prophylactic treatment
infarction (STEMI), the risk of in-hospital death ranges are considered procedures entailing a low risk of compli-
from 4% to 14% and the annual mortality after a surgical cations. In addition, the risk decreases in stable periods
intervention is 10%.8 Over 70% of relapses occur in the of coronary heart disease or after heart failure, when the
1st month after the initial incident. The risk of recurrence symptoms have a constant intensity, are predictable and
depends on the severity of the disease, type of disease, occur only after intense physical activity. A good deter-
treatment applied, and possible complications of the in- minant of the patient’s condition is a lack of chest pain
farction.5 for 2 weeks and satisfactory test results.12 Most authors
The most burdened group of patients are those treated recommend a cautious 4–6-week period after myocardial
conservatively − currently only a small number, due to the infarction to stabilize the disease.13 During this period, the
pressure of cardiac society guidelines pertaining to ear- most indispensable procedures, such as extractions, the
ly invasive treatment. In these cases, the natural course drainage of abscesses or pulpotomies can be performed
of the disease lasts for more than 6 weeks.9 This is the in a hospital setting. After this period, unless the cardio-
period needed for a post-infarction scar to form, to cre- logist recommends otherwise, complex dental treatment
ate collateral circulation and to restore the contractility can be carried out.13
of the damaged (but not necrotic) areas of the myocar-
dium. To avoid late infarction complications, all proce- Antibiotic prophylaxis
dures excluding emergency treatment should be avoided
in this period. This also applies to dental surgery. Former
AHA guidelines extended this period to 6 months, during Another issue is antibiotic prophylaxis prior to treat-
which avoiding dental surgery was recommended, as the ment, associated with the risk of bacteremia in patients
risk of complications was considered the highest in this who have suffered myocardial infarction. Patients with
period.10 angina pectoris, cardiovascular events or coronary artery
Due to advances in cardiac management in the last bypass surgery (bypass grafts) are classified as patients at
2 decades, these limitations are no longer recommended. low risk of infective endocarditis, and therefore antibiotic
Firstly, there is widespread access to the invasive methods prophylaxis is not indicated.14 The same applies to stent-
of treatment of infarctions, allowing the immediate reper- injected patients. Guidelines set by the Polish Dental As-
fusion of tissues, thus avoiding early and late complica- sociation and the National Antibiotic Protection Program
tions. In addition, on the 2nd day after myocardial infarc- in 2019 continue to support the 2015 guidelines of ESC
tion patients are subjected to early cardiac rehabilitation; on the prevention and treatment of infective endocardi-
this is continued after discharge in rehabilitation centers, tis (Table 1). They recommend the use of antibiotics in
where patients undergo fitness tests in the 1st month a number of situations, including the presence of an ar-
of convalescence. When the patient’s test tolerance is tificial prosthetic valve, the presence of artificial material
found to be good, the risk of recurrence is considered low, used to repair the valve (e.g., a mitral ring) and cyanotic
and if the attending physician does not find otherwise, congenital heart disease. In the cases of congenital heart
there are no contraindications to dental treatment.5 Pa- defects repaired with artificial material, prophylaxis is
tients who had myocardial infarction in the past and are recommended for 6 months after surgery, or perma-
in a stable period of coronary heart disease do not need nently if the defect has not been completely corrected
stress tests and can be assessed on the basis of an inter- and there is intracardiac leakage. The guidelines do not
view. In terms of metabolic equivalents of task (METs), include a history of myocardial infarction or bypass sur-
efficiency at 4 METs is sufficient to qualify the patient for gery as posing an increased risk of infection. They limit
dental procedures. high-risk dental procedures to those in which the conti-
Patients at risk of cardiac complications exceeding the nuity of the mucous membranes is disrupted and the risk
benefits of dental treatment should be identified and only of injury to the gingival or periapical area is present. Such
the most urgent conditions should be treated. However, procedures require antibiotic prophylaxis only in select-
pain and inflammation, which may be a consequence ed cases mentioned above.15,16 However, some authors
of avoiding dental treatment as a precaution against car- recommend antibiotics in the case of invasive proce-
diac complications, are a source of endogenous catechol- dures up to 30 days after the cardiological intervention.17
Table 1. Comparison of guidelines for the antibiotic prophylaxis of endocarditis
Polish Dental Association

AHA 2007 ESC 2015
and National Antibiotic Protection Program
American Heart Association20 European Society of Cardiology15
201916
– patients with a prosthetic heart valve or who have had – patients with any prosthetic valve, – patients with an artificial heart valve, including
a heart valve repaired with prosthetic material including a transcatheter valve, or those those implanted percutaneously, or patients
– patients with a history of endocarditis in whom any prosthetic material was who have been treated with artificial material
– patients with a heart transplant with abnormal heart used for cardiac valve repair for valve repair
valve function – patients with a previous episode – patients after an episode of infective
– patients with certain congenital heart defects, including: of infective endocarditis endocarditis
• cyanotic congenital heart disease (birth defects, – patients with congenital heart defects: – patients with congenital heart disease,
with oxygen levels lower than normal) that has not • any type of cyanotic congenital heart including:
been fully repaired, including children who have had defects • patients with a congenital cyanotic heart
surgical shunts and conduits • any type of congenital heart defects defect
• a congenital heart defect that has been completely repaired with prosthetic material, • patients after the repair of a congenital
repaired with prosthetic material or a device, for the whether placed surgically or by malformation of the heart with artificial
first 6 months after the repair procedure percutaneous techniques material, both during surgery and using
• repaired congenital heart disease with residual • up to 6 months after the procedure transcutaneous techniques for up to 6
defects, such as persisting leaks or abnormal flow at or • lifelong if a residual shunt or valvular months after surgery, or lifelong if residual
adjacent to a prosthetic patch or prosthetic device regurgitation remains leakage or valve regurgitation remains
In each case, the benefits and risks of possible antibiotic incidence of myocardial infarction, and late afternoon
usage should be balanced. It should be noted that in post- hours, when fatigue and stress levels are high, should be
myocardial infarction patients there may be indications avoided.
for antibiotic prophylaxis resulting from other concomi- During dental procedures, a supine position should be
tant diseases.18 The most important factors in the preven- avoided, as it leads to the return of blood from peripheral
tion of infective endocarditis are good oral hygiene and areas to the central circulation system and may overload
oral inflammation prophylaxis.19,20 pulmonary circulation. In cases of systolic heart failure
following myocardial infarction, this overload may result
Rules for safe dental treatment in the aggravation of heart failure, including pulmonary
edema after re-verticalization, and further contribute
The basics of safe dental treatment of patients with to orthostatic syncope.8 The patient should continue to
cardiovascular diseases comprise a detailed medical his- take the medication before the appointment as directed
tory, including complaints, allergies, medications, and by the attending physician. If the patient’s regular the-
specialist recommendations. It is important to monitor rapy includes nitrates, the patient should bring them. In
the patient’s condition and to interrupt the procedures cases of anxiety disorders and stress, the administration
when the patient becomes restless or cardiac problems of 5–10 mg of diazepam is recommended the night prior
arise. An angina attack can occur in the dental chair due to the visit and 1–2 h before the treatment. In this case,
to stress, pain and anxiety triggers.3 Pain can be felt in the the patient should not drive a motor vehicle.5
jaw, from where it can radiate to the neck and throat, so
in some cases, the patient and the dentist may interpret it Local anesthesia
as toothache. If the patient experiences retrosternal pain,
the procedure should be interrupted, and sublingual ni-
troglycerin (0.4–0.8 mg) and oxygen (3L/min) should be Another important aspect of dental treatment is lo-
administered. If the pain subsides within 5 min, the ap- cal anesthesia. If the patient’s condition is stable and the
pointment can be continued or postponed to the next day. medication is taken as prescribed, there are no contra-
If the pain persists after 5 min, nitrates should be given indications for local anesthesia with adrenaline. Patients
again. If there is no improvement after 15 min since the with ischemic heart disease are more vulnerable to the
first symptoms occurred, a re-infarction should be sus- negative effects of the release of endogenous adrena-
pected, and in this situation the patient should be trans- line as a result of severe pain during surgery than they
ferred as soon as possible to an emergency department.5 are to a small amount of adrenaline in an anesthetic.22
Psychological and physiological stress during dental A visit to the dental office is a stressful event, meaning
appointments has the potential to significantly alter he- the level of endogenous catecholamines increases more
modynamic stability. Therefore, a stress-reduction proto- than after the administration of anesthesia.23 The level
col is suggested for post-myocardial infarction patients, of endogenous adrenaline is naturally the highest be-
including profound local anesthesia, preoperative or in- tween 8 and 11 a.m., so the visits should not be in the
traoperative sedation and excellent post-operative analge- morning.9 Vanderheyden et al. showed that the highest
sia.21 The dental visit should be short − up to 30 min − and increase in the level of adrenaline is associated with the
in the middle of the day. Morning hours, with the highest beginning of the visit and the treatment itself.24 However,
Dent Med Probl. 2019;56(3):291–298 295
during the administration of anesthesia and immediately Hemostasis

after the injection, increases in adrenaline levels were
not observed.24 This means that most of the adrenaline
is of endogenous origin, hence the reduction of stress Today the risk of complications of dental procedures is
and good, effective anesthesia are indicated. Moreover, dependent more on the anticoagulant therapy used than on
local anesthetics without vasoconstrictors do not pro- the severity of coronary heart disease. Patients who have had
vide satisfactory hemostasis or anesthesia during dental acute myocardial infarction always take medications that
procedures.25 However, it is recommended not to exceed affect hemostasis.27 Depending on the indications, these
0.04 mg of adrenaline, which corresponds to 2 1.8-cc are either antiplatelet drugs, vitamin K antagonists or new
cartridges of an anesthetic with adrenaline at a dilution non-vitamin K antagonist oral anticoagulants (NOACs).
of 1:100,000.14 If it is necessary to administer more an- The discontinuation of therapy with these drugs is asso-
esthesia, subsequent portions should be administered ciated with a high risk of complications, including death.
without a vasoconstrictor. Intravascular anesthesia This risk far exceeds the risk of increased bleeding during
should be avoided.4 The use of intrapulpal and intraos- and after surgery. In addition, a surgical intervention itself
seous anesthesia is contraindicated, as this could lead to increases the risk of deep vein thrombosis. Double anti-
the excessive absorption of adrenaline.9 For this reason, platelet therapy (DAPT) is aimed at preventing thrombosis
retraction cords impregnated with adrenaline should be in the coronary artery. The risk of thrombosis lasts until
avoided. However, in the case of untreated, unregulated the atherosclerotic plaque stabilizes (a process taking about
arythmias or unstable angina, vasoconstrictor substan- 4–6 weeks) or − in the case of stent implantation − until it
ces are contraindicated. Similarly, caution with the use is covered with the vascular endothelium (the convention-
of vasoconstrictors is indicated in patients with pace- al limit for metal stents is 1 month, and for coated stents
makers, especially implantable automatic defibrillators.23 6–12 months). Double antiplatelet therapy includes acetyl-
Elad et al. showed that local anesthesia using 4% articaine salicylic acid (ASA) and an inhibitor of the P2Y12 glycopro-
hydrochloride with adrenalin 1:200,000 is as safe as local tein receptor (clopidogrel, prasugrel or ticagrelor) (Table 2).28
anesthesia with 2% lidocaine and adrenalin 1:100,000 in In cases when there is also a risk of cardiac embolism (atrial
cardiovascular patients.26 They observed neither severe fibrillation, intracardiac thrombus) or concomitant venous
adverse effects nor cardiac ischemic changes on electro- thromboembolism, DAPT treatment is supplemented with
cardiography (ECG) in either group.26 an oral anticoagulant.28
Table 2. Recommendations for patients receiving drugs that affect hemostasis depending on the risk of excessive bleeding after dental procedures28
Patients on ASA Patients on oral

Risk of bleeding in dental procedures Patients on NOACs
and/or clopidogrel anticoagulants
Low risk of excessive bleeding:
1. conservative and endodontic treatment;
2. supragingival scaling;
continue therapy continue therapy
3. periodontal pocket probing;
without check if INR < 3 without
4. air polishing;
any changes any changes
5. extraction of 1 tooth or teeth that are loose;
6. single implant placement;
7. laser evaporation of oral mucosa lesions.
Moderate risk of excessive bleeding:
1. subgingival scaling;
2. root debridement;
3. frenulectomy; stop therapy with rivaroxaban
4. periodontal flap surgery; – 24 h before surgery,
5. guided tissue regeneration; continue therapy and with dabigartan – 1–2 days
6. tooth extraction with flap elevation; without check if INR < 3 before surgery
7. extraction of impacted teeth; any changes
8. root resection; restart therapy 24–48 h after
9. vestibuloplasty; surgery
10. several implant placement;
11. closed sinus lift procedure;
12. excisional or incisional biopsy.
High risk of excessive bleeding: stop therapy with rivaroxaban
continue therapy with ASA
1. soft tissue augmentation with free gingival grafts – 24 h before surgery,
or connective tissue grafts; stop therapy with P2Y12 inhibitors check if INR = 2–2.5
and with dabigartan
2. placement of 6–8 implants in the edentulous 24–72 h before surgery convert to heparin – 1–2 days before surgery
alveolar ridge; only in selected cases
in patients at high risk of thrombosis, restart therapy 24–48 h
3. bilateral open sinus lift procedure;
consider glycoprotein IIa/IIIa inhibitors after surgery
4. oncological, orthognathic and reconstructive surgery.
ASA – acetylsalicylic acid; NOACs – non-vitamin K antagonist oral anticoagulants.

Coronary angiography is routinely performed in pa- achieved by pressure, suturing, applying collagen sponges,
tients with acute coronary syndrome, and if the coronary or prescribing tranexamic acid. As mentioned above, the
artery responsible for myocardial infarction is identified, discontinuation of antiplatelet therapy is the main cause
a revascularization procedure is performed. Coronary an- of late stent thrombosis, which can result in serious com-
gioplasty is the most common one, with the implantation plications, including death (in up to 45% of cases) and
of an anti-proliferative eluting stent, coated with a cyto- significant damage to the heart.32 The safety of surgical
static agent that inhibits cell division. This limits the indental procedures during antiplatelet therapy was con-
flammatory process and the formation of restenosis in the firmed by Park et al.33 Among 100 patients undergoing
vessel, but at the same time slows down the epithelializa- combined antiplatelet therapy with ASA, clopidogrel and,
tion of the stent and prolongs the need for DAPT. New in some cases, with the addition of cilostazol, only 2 pa-
drug-eluting stents require the use of 2 antiplatelet drugs tients had increased post-operative bleeding after tooth
for about 6 months, or 12 months if they are implanted extraction and in both, it was enough to apply pressure
due to acute coronary syndrome. This is a conventional to stop the bleeding.31 Dodson demonstrated that the
time period to allow the vascular endothelium to grow. amount of bleeding measured during invasive procedures
The earlier discontinuation of therapy may result in acute was similar in the group of patients who suspended their
thrombosis in the stent, myocardial infarction and death. ASA therapy for 7 days before tooth extraction and in
In exceptional situations, metal stents are used; their epi- patients who continued their ASA therapy.32 However,
thelialization takes 1 month.28 Buhatem Medeiros et al. showed that patients on DAPT
The time limits for DAPT were modified by the ESC presented a larger volume of bleeding during invasive
guidelines published in 2017.28 Two scales were created to procedures than patients not using these medications.34
establish a safe date for ending the treatment. The PRE- Local hemostatic methods were sufficient to control the
CISE-DAPT score is used for stent implantation based on bleeding and there were no post-operative bleeding com-
the results of laboratory tests (hemoglobin, leukocytes, plications in any of the presented cases.34 When in doubt,
creatinine clearance) and the patient’s data (age, history it is recommended to check prothrombin time (PT), par-
of bleeding), and indicates either a brief (3–6 months) or tial thromboplastin time (PTT) and the number of plate-
extended (12–24 months) use of DAPT. Longer therapy lets. If PT and PTT are found to be within the normal
may be beneficial and may lower the risk of stent closing. range and the number of platelets exceeds 100,000/mm3,
However, the duration of therapy depends on individual surgery can safely be performed.31 In more complicated
factors (e.g., age, comorbidities, left ventricular ejec- surgical procedures with a moderate bleeding risk, pa-
tion fraction (LVEF), bleeding risk, or smoking) as well tients should be maintained on aspirin, while P2Y12 in-
as on the procedure technique (implanted stent caliber, hibitor therapy should be discontinued.30
type of substance released, presence of a stent in the vein Vitamin K antagonists warfarin and acenocoumarol are
bridge).28,29 used in conditions associated with coronary heart disease,
In 2016, Pruszczyk et al. published (in Polish) a paper de- including the prophylaxis of venous thromboembolism,
tailing a protocol for preparing patients on anticoagulants and in patients with arythmias, artificial valves, throm-
for dental surgical procedures.30 It follows the guidelines bophilia, and antiphospholipid syndrome.35,36 In these
set out by ESC and the European Association for Cardio- cases, the administration of vitamin K antagonists should
Thoracic Surgery (EACTS).28 Most dental procedures are not be stopped before any dental procedures – including
defined as low-risk in terms of blood loss, and hemosta- procedures of a higher risk of bleeding – if the patient’s
sis can be achieved through the use of local hemostatic international normalized ratio (INR) <3 24 h before the
agents. There is a greater risk of blood loss associated with planned procedure.34 If the patient’s INR > 3, the attend-
major reconstructive procedures, bone block transplants, ing physician should adjust the therapy to achieve a lower
implantological procedures, extractions of more than INR.30 The withdrawal of oral anticoagulants does not
3 teeth, treatment with the elevation of the mucoperiosteal guarantee that bleeding will not occur; serious bleeding
flap, soft tissue augmentation procedures, connective tis- occurs also in patients who have never taken anticoagu-
sue grafts, and open sinus lift procedures. The 4 criteria lants. Only 0–3.5% of cases of excessive bleeding are so
for abundant post-operative bleeding are: bleeding lasting severe that they cannot be controlled with local measures.
longer than 12 h, forcing the patient to report to the dental A higher risk of death or permanent disability is associ-
office or the emergency room, hematoma or bruising, and ated with the discontinuation of anticoagulant treatment.
need for a blood transfusion.30 In a relapse of venous thromboembolism, the risk of death
The effect of antiplatelet therapy may double the bleed- is 6% and of permanent disability 2%. In the case of arte-
ing time, but in most cases, it remains within the normal rial embolism, the former risk is 20% and the latter 40%.37
range or only slightly over it.30 The results of the plate- It should be emphasized that there is no description in
let aggregation test might be abnormal, although with- the literature of any case of death or permanent disability
out clinical consequences.31 Prolonged bleeding time resulting from massive bleeding after a dental procedure
is not a major clinical problem, since hemostasis can be in a patient taking anticoagulants. It should be borne in
Dent Med Probl. 2019;56(3):291–298 297
mind that during anticoagulant therapy, the administra- taken 6 weeks after myocardial infarction. It is important
tion of tetracyclines, erythromycin, clarithromycin, and to eliminate pain, so local anesthesia with a vasodilator
metronidazole is contraindicated.9 in a dose not exceeding 0.04 mg should be used. Anti-
Newer anticoagulants are direct inhibitors of factor Xa biotic prophylaxis is usually not required. Visits should be
− rivaroxaban, apixaban and edoxaban, and direct thrombin short and carried out in the early afternoon. The patient
inhibitor dabigatran. They are used in deep vein thrombosis, should be in a comfortable sitting position. If the patient
pulmonary embolism, embolism due to non-valvular atrial complains of retrosternal pain, the procedure should be
fibrillation, following orthopedic surgery as well as in acute discontinued, and oxygen and nitrates should be admini-
coronary syndrome and venous thromboembolism. There stered. If there is no improvement, a re-infarction should
are no unambiguous guidelines of how to proceed with be suspected and an ambulance should be called imme-
the use of these drugs in planned surgical procedures. The diately. In the vast majority of cases, antiplatelet drugs
manufacturers of these drugs recommend a break of 1 day and anticoagulants should not be discontinued prior to
in pharmacotherapy, extended to 2 days in cases of impaired planned surgery, since there is a significantly higher risk
renal function with glomerular filtration rate (GFR) lowering of thromboembolism than of increased bleeding in these
to 30 mL/min/1.73 m2. It is recommended that the proce- patients. In case of any doubts as to the patient’s health
dure should be performed when the drug concentration is and the possibility of dental treatment, the patient should
the lowest, i.e., 12 h or 24 h after the last dose, depending on be referred to a specialist to establish an individualized
whether the drugs are taken once or twice daily. If procedures treatment plan.
of a high risk of bleeding are planned and the medications
are taken in the morning, the dose of the drug used once ORCID iDs
a day (edoxaban) should be delayed until after the procedure, Renata Samulak-Zielińska  https://orcid.org/0000-0003-0145-9131
whereas in the case of the drugs taken twice daily (apixaban, Elżbieta Dembowska  https://orcid.org/0000-0002-3646-1314
dabigatran and rivaroxaban), the evening dose should be Piotr Lizakowski  https://orcid.org/0000-0001-5648-2027
skipped. If edoxaban is taken in the evening, there is no need
to skip the dose. If complete hemostasis is obtained during References
the procedure, the dose that was previously skipped can be 1. Bhateja S. High prevalence of cardiovascular diseases among other
taken after 6–8 h.37 In patients taking medications affect- medically compromised conditions in dental patients: A retrospec-
tive study. J Cardiovasc Dis Res. 2012;3(2):113–116.
ing hemostasis, it is recommended that dental procedures 2. Włosowicz M, Wozakowska-Kapłon B, Górska R. Periodontitis in
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antibiotics
Review
Is Antibiotic Prophylaxis Necessary before Dental Implant
Procedures in Patients with Orthopaedic Prostheses?
A Systematic Review
Angel-Orión Salgado-Peralvo 1,2 , Juan-Francisco Peña-Cardelles 2,3,4, * , Naresh Kewalramani 2,5 ,
Alvaro Garcia-Sanchez 6 , María-Victoria Mateos-Moreno 7 , Eugenio Velasco-Ortega 1,2 , Iván Ortiz-García 1,2 ,
Álvaro Jiménez-Guerra 1,2 , Dániel Végh 8,9 , Ignacio Pedrinaci 10,11 and Loreto Monsalve-Guil 1,2
1 Department of Stomatology, University of Seville, 41009 Seville, Spain;

orionsalgado@hotmail.com (A.-O.S.-P.); evelasco@us.es (E.V.-O.); ivanortizgarcia1000@hotmail.com (I.O.-G.);
alopajanosas@hotmail.com (Á.J.-G.); lomonsalve@hotmail.es (L.M.-G.)
2 Science Committee for Antibiotic Research of Spanish Society of Implants (SEI—Sociedad Española
de Implantes), 28020 Madrid, Spain; k93.naresh@gmail.com
3 Department of Basic Health Sciences, Rey Juan Carlos University, 28922 Madrid, Spain
4 Fellow Oral and Maxillofacial Surgery Department and Prosthodontics Department,
School of Dental Medicine, University of Connecticut Health, Farmington, CT 06030, USA
5 Department of Nursery and Stomatology, Rey Juan Carlos University, 28922 Madrid, Spain
6 Department of Oral Health and Diagnostic Sciences, School of Dental Medicine,
University of Connecticut Health, Farmington, CT 06030, USA; ags.odon@gmail.com
7 Department of Clinical Specialties, Faculty of Dentistry, Complutense University of Madrid,
!"#!$%&'(!
!"#$%&' 28040 Madrid, Spain; mateosmoreno80@hotmail.com
8 Department of Prosthodontics, Semmelweis University, 1085 Budapest, Hungary;
Citation: Salgado-Peralvo, A.-O.;
vegh.daniel.official@gmail.com
Peña-Cardelles, J.-F.; Kewalramani, 9 Department of Dentistry and Oral Health, Division of Oral Surgery and Orthodontics,
N.; Garcia-Sanchez, A.; Mateos-
Medical University of Graz, 8010 Graz, Austria
Moreno, M.-V.; Velasco-Ortega, E.; 10 Section of Graduate Periodontology, Faculty of Dentistry, Complutense University of Madrid,
Ortiz-García, I.; Jiménez-Guerra, Á.; 28040 Madrid, Spain; ignpedri@ucm.es
Végh, D.; Pedrinaci, I.; et al. Is 11 Department of Restorative Dentistry and Biomaterials Science, Harvard School of Dental Medicine,
Antibiotic Prophylaxis Necessary Harvard University, Boston, MA 02115, USA
before Dental Implant Procedures in * Correspondence: juanfranciscopenacardelles@gmail.com
Patients with Orthopaedic
Prostheses? A Systematic Review. Abstract: As the population ages, more and more patients with orthopaedic prostheses (OPs) require
Antibiotics 2022, 11, 93. https:// dental implant treatment. Surveys of dentists and orthopaedic surgeons show that prophylactic
doi.org/10.3390/antibiotics11010093 antibiotics (PAs) are routinely prescribed with a very high frequency in patients with OPs who are
about to undergo dental procedures. The present study aims to determine the need to prescribe
Academic Editor: Marc Maresca
prophylactic antibiotic therapy in patients with OPs treated with dental implants to promote their
Received: 8 December 2021 responsible use and reduce the risk of antimicrobial resistance. An electronic search of the MEDLINE
Accepted: 10 January 2022 database (via PubMed), Web of Science, LILACS, Google Scholar, and OpenGrey was carried out.
Published: 12 January 2022
The criteria used were those described by the PRISMA® Statement. No study investigated the need
Publisher’s Note: MDPI stays neutral to prescribe PAs in patients with OPs, so four studies were included on the risk of infections of
with regard to jurisdictional claims in OPs after dental treatments with varying degrees of invasiveness. There is no evidence to suggest
published maps and institutional affil- a relationship between dental implant surgeries and an increased risk of OP infection; therefore,
iations. PAs in these patients are not justified. However, the recommended doses of PAs in dental implant
procedures in healthy patients are the same as those recommended to avoid infections of OPs.
Keywords: antibiotic prophylaxis; antibiotics; joint replacement; prosthetic joint infection; oral
Copyright: © 2022 by the authors.
implantology; dental implants
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
1. Introduction
creativecommons.org/licenses/by/ Today, life expectancy is higher than ever before due to the declining mortality rate of
4.0/). young people in developing countries [1], while “developed” countries are experiencing
Antibiotics 2022, 11, 93. https://doi.org/10.3390/antibiotics11010093 https://www.mdpi.com/journal/antibiotics

Antibiotics 2022, 11, 93 2 of 11
a large decline in mortality at older ages, with an average life expectancy of 91 years for
women and 86 years for men [2]. This increases the number of people in need of orthopaedic
prostheses (OPs) of any kind [3]. In 2006, around 800,000 joint replacements (hip and knee,
as well as elbow, wrist, ankle, metacarpophalangeal, and interphalangeal joints) were
placed in the USA [4] and it is estimated that by 2030 these numbers will increase to
4 million for hip and knee replacements alone [5]. Globally, the age group with the highest
prevalence of tooth loss is 79-year-olds. Future figures may be even higher, as between 1990
and 2015, there was a 40% increase in the number of people with oral conditions such as
untreated caries and/or tooth loss [6]. For these reasons, it is expected that more and more
professionals will be faced with patients with OPs requiring the replacement of missing
teeth with dental implants.
Infection of orthopaedic prostheses (OPIs) occurs in 0.3 to 2% of patients with OPs [7],
requiring additional orthopaedic surgery, as well as the use of antibiotics for a long pe-
riod [5]. Depending on the timing of their occurrence concerning orthopaedic surgery, OPIs
are classified as “early”, “delayed”, or “late”. The first two occur before three months, and
between 3 and 24 months post-surgery, respectively, and are related to orthopaedic surgery.
On the other hand, late OPIs often result from the late growth of bacteria accidentally
inoculated during bleeding procedures or from a distant septic focus [8,9] (“hematoge-
nous orthopaedic prosthetic infections” (HOPIs)). It is estimated that around 10% of these
infections are caused by bacteria present in the oral cavity [3]. However, the frequency,
duration, and intensity of bacteraemia will influence the cumulative risk [8]. In this regard,
classic animal model studies have shown that high bacterial counts (>1000 colony-forming
units (CFU)/mL) are required for HOPIs to occur, which is often a consequence of systemic
sepsis [10,11].
Various surveys have shown that 63.4% [12] to 71.5% [13] of orthopaedic surgeons
consider the prescription of prophylactic antibiotics (PAs) to be necessary indefinitely
in patients with hip prostheses who are going to undergo dental treatment. A survey
conducted in Canada in 2014 revealed that around 70.7% of dentists routinely prescribe
Pas and 21.7% consider it essential for the rest of the patient’s life [12]. Despite that,
currently, antibiotic prophylaxis for patients with prosthetic joints who are undergoing
dental treatment is not routinely recommended in several countries, such as Australia [14],
the United Kingdom [15], Canada [16], and New Zealand [17]. Namely, a recent survey of
professionals dedicated to oral implantology studied for the first time their prescription
habits for PAs in patients with hip prostheses, showing that 74.3% prescribe them, as they
consider these patients to be at risk [18].
Considering the current context, these data should be considered where antimicro-
bial resistance causes around 33,000 deaths each year in the European Union [19]. The
associated healthcare costs and lost productivity are estimated to be 1.5 billion euros per
year [20]. It is a naturally occurring phenomenon, and this process is being accelerated
by the inappropriate and indiscriminate use of antibiotics in humans, food-producing
animals, and the environment. Immediate changes in the way antibiotics are prescribed
and used are urgently needed. Even if new methods are developed, resistance will continue
to pose a severe threat if current prescribing patterns are not modified [21]. In this sense, a
recent meta-analysis revealed that the average prescribed dose of PAs in implant surgery
is approximately 5 times higher than the one recommended to healthy patients without
anatomical constraints [22]. Furthermore, there is only clear scientific proof on the recom-
mended PA dose in the clinical situation mentioned above [23] and in bone augmentation
with the implant placement done in one or two phases [21], that is, 2–3 g of amoxicillin
an hour before the intervention [21,23], while in allergic patients, 500 mg of azithromycin,
1 h before surgery, has recently been suggested. [24]. Regarding the remaining clinical
situations, the type of antibiotic prescribed and its posology is up to the professional, who
in many cases tends to over-prescribe them.
Therefore, given the data described above, it is considered necessary to carry out a
literature review to determine the need for PAs in patients with OPs who are going to be
treated with dental implants to promote their responsible use.
2. Materials and Methods

The criteria used are the ones described in the PRISMA® (Preferred Reporting Items
for Systematic Reviews and Meta-Analyses) Declaration [25].
2.1. Focused Question

The main objective was to answer the following “PICO” (P = patient/problem/population;
I = intervention; C = comparison; O = outcome) question (Table 1).
Table 1. Breakdown of the “PICO” question.
Component Description
P (problem/population) 1
Patients with OPs that have had a dental implant treatment
I (intervention) PAs 2 on the day of surgery and/or extended postoperatively
Not prescribing PAsPrescribing a placeboOther antibiotics or
C (comparison) antibiotic regimensSame antibiotic with different
dosage/duration
Risk of infection from OPsSafety (for example, benefits for the
O (outcome)
patient, OPIs 3 prevention, resistance to antimicrobials)
In patients with OPs who are about to undergo an implant
PICO question procedure, does the prescription of PAs decrease the risk of
infection of OPs versus not taking them?
1 OPs, orthopaedic prostheses; 2 PAs, prophylactic antibiotics; 3 OPIs, orthopaedic prostheses infection.
In patients with OPs who are about to undergo an implant procedure, does the
prescription of PAs decrease the risk of infection of OPs versus not taking them?
2.2. Eligibility Criteria

Before proceeding, inclusion and exclusion criteria were defined and applied to the
resulting articles.
2.2.1. Inclusion Criteria

The included studies comprised (a) human studies; (b) articles published in English
or Spanish (c); meta-analysis; (d) systematic reviews; (e) randomized clinical trials (RCTs);
(f) clinical trials; (g) clinical studies; (h) comparative studies; (i) multicentre studies; (j) ob-
servational studies; and (k) grey literature.
2.2.2. Exclusion Criteria

The exclusion criteria determined the exclusion of the following: (a) experimental lab-
oratory studies; (b) animal studies; (c) studies whose main topic was not the prescription of
PAs before the dental procedure in patients with joint replacements; (d) duplicated articles;
(e) books or chapters of books; (f) letters to the Editor; (g) commentaries; (h) literature
reviews; and (i) surveys.
2.3. Information Sources and Search Strategy

A comprehensive search of the literature was conducted in the following databases:
MEDLINE (via PubMed), Web of Science, Google Scholar, and LILACS. A search for
unpublished studies (grey literature) was conducted on the OpenGrey database. Moreover,
we examined the bibliographic references of the selected articles for publications that did
not appear in the initial search and might be of interest.
The search was performed by two independent researchers (A.-O.S.-P. and J.-F.P.-C.).
The search was temporarily restricted from 2 February 2011 to 2 February 2021, and was
later updated on 16 February 2021.
MeSH (Medical Subject Headings) terms, keywords and other free terms were used
with Boolean operators (OR, AND) to combine searches: (hip prosthesis OR hip replacement
OR prosthesis joint OR joint replacement OR knee prosthesis OR knee replacement OR
ankle prosthesis OR ankle replacement OR shoulder prosthesis OR shoulder replacement
OR elbow prosthesis OR elbow replacement) AND (dental implant OR dental implants OR
dental implantology OR oral implantology OR oral surgery OR dental OR dental treatment)
AND (antibiotics OR preventive antibiotics OR antibiotic prophylaxis OR clindamycin OR
amoxicillin OR erythromycin OR azithromycin OR metronidazole). The same keywords
were used for all search platforms following the syntax rules for each database.
2.4. Study Records

Two researchers (A.-O.S.-P. and J.-F.P.-C.) independently compared the results to
ensure completeness and removed duplicates. Then, the full title and abstracts of the
remaining papers were screened individually. Finally, full-text articles included in this
systematic review were selected according to the criteria described above. Disagreements
over eligible studies to be included were discussed with a third reviewer (N.K.), and a
consensus was reached. The reference list of the included studies was also reviewed for
possible inclusion.
2.5. Risk of Bias

Data collection was conducted using a predetermined table to assess the resulting
articles. Two independent reviewers (J.-F.P.-C. and A.G.-S.) evaluated the methodological
quality of eligible studies following the Joanna Briggs Institute Checklist for Systematic
Reviews and Research Syntheses [26], which incorporates 11 domains. The studies were
classified as low-quality assessment studies (0–6) or as high-quality assessment studies
(7–11).
3. Results
3.1. Study Selection
The search strategy resulted in 106 results, of which 99 remained after removing the
duplicates. Then, two independent researchers (A.-O.S.-P. and J.-F.P.-C.) reviewed all the
titles and abstracts and excluded 86 that were outside the scope of this review. Thus, we
obtained 13 potential references. After reading the full text of those 13 papers, it was found
that none answered the PICO question as they did not investigate the need to prescribe
PAs in implant treatments to reduce the risk of OPIs. Six articles were included that
investigated the risk of bacteraemia secondary to dental procedures with varying degrees
of invasiveness, so extrapolations were made to establish clear guidelines on the need to
administer PAs in implant procedures in these patients. The same situation occurred after
the search in Google Scholar and the analysis of the references of the selected articles. Three
articles were included in this way so that a total of four papers were analysed [5,7,27,28]
(Figure 1).
3.2. Study Characteristics

Most of these studies focused on the appropriateness of the prescription of PAs in hip
and/or knee prostheses [5,27] and joints in general. The main findings were described as
follows.
The American Dental Association (ADA) and the American Academy of Orthopaedic
Surgeons (AAOS) have collaborated on the development of Clinical Practice Guidelines
(CPGs) in patients with OPs. The first collaboration was in 2013 [5], where it was determined
that it was not necessary to routinely prescribe PAs for dental procedures in patients with
hip or knee replacements because, although PAs have been shown to reduce bacteria associ-
ated with dental procedures, no evidence links these bacteraemias to HOPIs. Nevertheless,
the authors expressed that this decision should be left to the discretion of the professional
and the patient after weighing the benefits/risks. This workgroup concluded that PAs
would be “rare” or “perhaps appropriate” for non-invasive treatments, meaning those
that do not require gingival/mucosa manipulation/perforation, as well as for invasive
treatments in healthy patients. Among severely immunocompromised patients, patients
with non-controlled diabetes (with levels of glycosylated haemoglobin (HbA1c) 8 or
blood glucose level 200 mg/dL) and/or patients with a history of OPI, the prescription of
PAs would be considered “appropriate”. Patients with severely immunosuppressed states
can be classified into the following groups, according to the Center for Disease Control and
Prevention (CDC) guidelines [29]: (1) patients with stage III HIV/AIDS, i.e., patients with
a CD4 T-lymphocyte count < 200 or opportunistic infections; (2) patients on chemother-
apy with fever (absolute neutrophil count (ANC) < 2000) (39 C) or severe neutropenia
(ANC < 500) with or without fever; (3) patients with rheumatoid arthritis (RA) on treatment
with disease-modifying biologic agents, including tumour necrosis factor-alpha (TNF-↵) or
prednisone > 10 mg/day (4) patients who have received a solid organ transplant and are
on immunosuppressants; (5) patients with hereditary immunosuppressive diseases;
Antibiotics 2022, 11, x FOR PEER REVIEW 5 and
of 12
(6) patients with a bone marrow transplant from the pre-transplant period until the end of
immunosuppressive treatment (usually about 36 months after surgery).
Figure 1. PRISMA® flow diagram of the search processes and results. 1 1PAs, prophylactic antibiotics;
Figure 1. PRISMA flow diagram of the search processes and results. PAs, prophylactic antibiot-
2 OPIs, orthopaedic prostheses infection.
ics; 2 OPIs, orthopaedic prostheses infection.
3.2. Study Characteristics

Most of these studies focused on the appropriateness of the prescription of PAs in
hip and/or knee prostheses [5,27] and joints in general. The main findings were described
as follows.
Subsequently, the ADA [27] (2015) carried out a CPG with their workgroup following
previous guidelines, not systematically recommending the PAs. Despite this, they suggest
assessing the administration in diabetic or immunocompromised patients, including in
the immunocompromised group those with antibiotic resistance or under treatment with
systemic steroids/immunosuppressive drugs, the presence of some type of cancer, and/or
with a history of chronic renal disease. The odd ratios (OR) related to the mentioned
systemic alterations varied between 1.8 and 2.2 [30], although the magnitude of these
values lacks clinical relevance [27]. Thus, this recommendation should be treated carefully.
Also, they suggest assessing PAs on patients with a history of complications associated
with joint replacement surgeries that will go through an invasive dental procedure and
having an interview with the patient and a consultation with the orthopaedic surgeon. If it
is favourable, the latter should recommend the adequate antibiotic prescription and, ideally,
issue the pharmacological recipe.
Subsequently, the Canadian Agency for Drugs and Technologies in Health [28] (CADTH)
(2016) conducted a CPG updating a previous consensus document [31] where they con-
cluded that, although there were some cases of HOPIs after dental procedures, most of
these infections were not caused by microorganisms present at the oral level and there
was insufficient evidence to claim that taking PAs before a dental procedure could prevent
HOPIs. Therefore, they do not recommend its prescription in patients with total joint
replacements or with orthopaedic pins, plates, or screws.
Antibiotics 2022, 11, x FOR PEER REVIEW In 2017, the Dutch Orthopaedic and Dental Societies [7] conducted a systematic 7review, of 12
concluding that there was no convincing evidence in the literature to justify PAs to avoid
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tous techniques (16% vs. 50% vs. 97%, respectively)—the level of basal bacteraemia is
8% [40]. Lockhart [41] suggested that using local anaesthesia with epinephrine could
decrease the transit of bacteria to the bloodstream by reducing the flow. Furthermore, the
rate of secondary bacteraemia to implant surgery is very low, which was only described
by Piñeiro et al. [39] The authors analysed secondary bacteraemia with the placement of
implants in patients that rinsed with chlorhexidine digluconate (CLX) at 0.2% (10 mL for
1 min) (test group) before the anaesthetic injection versus a control group that did not use
any type of antimicrobial. The level of bacteraemia in the control group was 2% versus
6.7% in the test group. They only observed differences between patients with positive and
negative cultures concerning the intervention time (92.5 ± 24.7 min vs. 64.8 ± 20.2 min,
respectively), but not so for the history of periodontal disease, the level of oral health, or
the number of placed implants. These surgeries were carried out with general anaesthesia,
as well as a local one, which has been related to a higher risk of bacteraemia compared to
just administering local anaesthesia at 30 s (89% vs. 53%; OR = 5.04), 15 min (64% vs. 24%;
OR = 5.37), and 60 min (21% vs. 4%; OR = 6.5) [42].
On the other hand, Watters et al. [5] identified bacteria associated with a higher risk of
OPIs, such as Staphylococcus spp. (31.5%), specifically, S. aureus (26.0%) and S. epidermidis
(6.5%), Gram-positives species (9.0%), and Streptococcus spp. (6.5%). The isolated species
after secondary bacteraemia of implant placement were Streptococcus viridans and Neisse-
ria [39], which are not directly related to OPs complications. Also, certain oral hygiene
procedures carried out daily by patients have a risk of associated bacteraemia that is not in-
considerable, with higher proportions of OPI-causing bacteria than in invasive procedures
related to oral implantology [5].
Noori et al. [43] (2019) established for the first time some recommendations in patients
treated with foot and ankle surgeries, including total ankle arthroplasty. The bacteria
implicated in post-surgery infections in hip and/or knee joint prosthesis infections are
similar to those responsible for foot and ankle surgeries, so they determined that the
recommendations should be the same.
If it is decided to prescribe PAs, the first-choice antibiotic would be 2 g of amoxicillin,
30–60 min before the procedure and, to those allergic to penicillin, 500 mg of azithromycin
or clarithromycin [7,39]. Currently, there are only recommendations based on evidence
regarding the placement of unitary implants in ordinary conditions [23] and bone regener-
ation with the placement of implants in one or two phases [21]. In both procedures, the
recommended guideline is 2 or 3 g of amoxicillin, one hour before the intervention [21,23]
and, in allergic patients, 500 mg of azithromycin one hour before surgery [24], which would
be equivalent to what is recommended to prevent OPIs.
The current guidelines recommend assessing PAs in non-controlled diabetic patients,
those immunocompromised, and/or in patients with a history of OPI. For a long time,
it has been presumed that immunocompromised patients have a higher risk of HOPIs.
Nonetheless, it has not been proved after dental procedures, since they develop comparable
bacteraemia to the ones developed by healthy individuals, and with the latter, there is
no evidence that there is a higher risk [7]. On the other hand, the European Association
of Endodontics [44] recommends prescribing PAs in patients with OPs during the three
months following orthopaedic joint surgery. Dental implants entail an elective surgery,
so it does seem prudent to postpone the intervention during this time. Also, dental im-
plant surgery is not indicated for the described systemic states until the disease has been
controlled. The only scenario where the treatment could be assessed in these patients
would be in those with AR being treated with biological agents modifying the disease, and
despite this, different authors associated it with a higher risk of early placement failure and
peri-implantitis [45,46].
The relationship between the periodontal state, or the level of hygiene, and the level of
bacteraemia was not established [9,39]. Nonetheless, any implant procedure must be done
in an oral cavity without any pathology. Another preventive measure is using perioperative
antiseptics, such as CLX. Although ADA/AAOS was not able to conclude that rinsing
with different topical antimicrobials before a dental procedure prevents HOPIs [5], further
studies found that CLX rinses reduce the incidence of secondary bacteraemia in dental
extractions by 12% [47–49], possibly due to a reduction of the quantity of inoculated bacteria.
This is a simple preventive measure without evidence of adverse reactions. Thus, its use is
recommendable despite its low efficacy [47]. Furthermore, as a chemo-preventive measure
against the accumulation of biofilm, its use is recommended in the immediate post-surgery
period, a time when oral hygiene procedures could experience difficulties [50].
Given that the placement of dental implants currently involves the prescription of
PAs in healthy patients, future lines of research should focus on establishing the incidence
of infections following implant procedures in those patients with OPs. It would also be
interesting to study topical antiseptics, such as CLX, to reduce secondary bacteraemia in
implant procedures.
Strengths and Limitations

This systematic review presents several strengths, such as a previous record of protocol,
free search in the literature (including grey literature), the searching process of studies,
data extraction, and the risk analysis bias performed in duplicate, which determined a high
overall quality of the included studies.
Nonetheless, with the low number of studies available in the literature, the present
systematic review has limitations, so the external validity of the results of this review
should be confirmed with future studies.
5. Conclusions
No evidence suggests a relationship between dental implant surgery and a higher
risk of infection of OPs. Therefore, the prescription of PAs in these patients is not justified.
Nonetheless, the recommended PA dose in a dental implant procedure in healthy patients
is comparable to the dose recommended to avoid infections in OPs. We should evaluate
the prescription of PAs in patients with a history of infections in their OPs in second-stage
implant surgeries. Furthermore, it would be wise to avoid surgeries three months after
orthopaedic surgery.
Author Contributions: Conzand E.V.-O.; methodology, A.-O.S.-P. and E.V.-O.; software, A.G.-S.;
validation, Á.J.-G., I.O.-G., A.G.-S. and L.M.-G.; formal analysis, M.-V.M.-M., E.V.-O., N.K. and
M.-V.M.-M.; investigation, A.-O.S.-P. and J.-F.P.-C.; resources, L.M.-G. and E.V.-O.; data curation,
A.-O.S.-P., J.-F.P.-C. and N.K.; writing—original draft preparation, A.-O.S.-P., J.-F.P.-C., A.G.-S., I.P.
and D.V; writing—review and editing, A.-O.S.-P., E.V.-O., J.-F.P.-C., I.P. and D.V.; visualization, M.-
V.M.-M., Á.J.-G. and I.O.-G.; supervision, E.V.-O.; project administration, E.V.-O. and A.G.-S. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Data are available in a publicly accessible repository.
Conflicts of Interest: The authors declare no conflict of interest.
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Iwata et al. BMC Oral Health (2020) 20:331
https://doi.org/10.1186/s12903-020-01326-w
RESEARCH ARTICLE Open Access
Does prophylactic antibiotic administration

for tooth extraction affect PT-INR in patients
taking warfarin?
Eiji Iwata1,2*, Akira Tachibana1, Junya Kusumoto2, Naoki Takata1, Takumi Hasegawa2 and Masaya Akashi2
Abstract
Background: Various antibiotics and analgesics have been reported to interact with warfarin. Reports that investi-
gate the effects of medication taken for just a few days during tooth extraction on the prothrombin time-international
normalized ratio are rare.
Methods: A total of 110 patients receiving long-term stable warfarin therapy underwent tooth extraction without
interruption of warfarin treatment. INR values were measured 1 month before the tooth extraction, the day of the
extraction, and 1 week after the extraction. We investigated the changes in INR values between the day of extraction
and 1 week after extraction, as well as the various risk factors for increases in INR values.
Results: Before and after tooth extraction, the number of patients taking cefcapene pivoxil, amoxicillin, and azithro-
mycin was 57, 36, and 8, respectively. Nine patients were administered ampicillin before tooth extraction and received
amoxicillin after their tooth extraction. One week after tooth extraction, the INR values increased beyond the thera-
peutic range in 3 out of 110 patients (2.7%). The INR values before tooth extraction in these three patients were close
to 3.0. The INR value increased by more than twice as much in 1 out of 110 patients (0.9%).
Conclusion: Our results suggest that prophylactic antibiotic administration has little effect on INR values when
patients on stable warfarin therapy undergo tooth extraction. Surgeons have to take attention if the patients whose
INR values are close to 3.0 before their extraction.
Keywords: Antibiotics, Analgesics, Warfarin, Tooth extraction, International normalized ratio
Background cases and cases where oral intake was not possible [1–5].
Various antibiotics and analgesics have been reported To our knowledge, there is only one report that investi-
to interact with warfarin [1–5]. When tooth extraction gated the effects of medication that was administered for
is performed, patients are usually prescribed antibiotics just a few days for tooth extraction on the prothrombin
to prevent surgical site infection (SSI) or infective endo- time-international normalized ratio (PT-INR) [6]. This
carditis (IE) and analgesics to decrease pain. These drugs study investigated the effect of azithromycin (AZM) on
may also interact with warfarin and produce a clinically INR values in patients taking warfarin [6].
significant alteration in anticoagulation status. However, In the present study, we retrospectively investigated the
most previous reports were on long-term treatment effects of various antibiotics administered during tooth
extraction on the INR values in patients who were on sta-
ble warfarin therapy.
*Correspondence: eiwata@med.kobe-u.ac.jp
1
Department of Oral and Maxillofacial Surgery, Kakogawa Central City
Hospital, 439 Hon-machi, Kakogawa-cho, Kakogawa 675-8611, Japan
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea-
tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo-
main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Iwata et al. BMC Oral Health (2020) 20:331 Page 2 of 6
Methods patients, the presence of hemorrhage was checked by

Patients surgeons a few hours after tooth extraction. If the hemor-
In this study, inclusion criteria were set as patients above rhage required additional treatment, such as re-suturing,
18 years old, and exclusion criteria were set as patients we defined it as a post-extraction hemorrhage.
who hoped non-participate after the publication of this
study. From January 2014 to December 2019, 110 patients Variables
taking warfarin underwent tooth extraction at Kakogawa We investigated the rates of the changes in the INR values
Central City Hospital. Before tooth extraction, all beyond the therapeutic range 1 week after tooth extrac-
patients consulted with their primary physicians regard- tion. Additionally, the following variables from medical
ing their general medical status and whether their war- records were retrospectively reviewed: (1) medication—
farin therapies had been stable. If their INR values were types; (2) patient details in terms of—sex, age, warfarin
over 3.0, they were advised to postpone the extraction, dose, hypertension, cerebral infarction, antiplatelet ther-
according to the Guidelines for Patients on Antithrom- apy status (single or dual), preoperative non-steroidal
botic Therapy Requiring Dental Extraction’15 and the anti-inflammatory drugs (NSAIDs) being taken, serum
Guidelines for Pharmacotherapy of Atrial Fibrillation [7, creatinine levels, estimated glomerular filtration rates
8]. In the past, several studies reported that INR values (eGFR), and alanine transaminase (ALT) levels; and (3)
increased beyond the therapeutic range 1 week after oral surgical details including the—number of extracted teeth
administration of antibiotics [9]. Based on these reports, and whether they had a post-extraction hemorrhage.
at Kakogawa Central City Hospital, patients taking warfa-
rin routinely had their INR values measured on the day of Results
their tooth extraction and remeasured those them again All patients
1 week later. In this study, patients whose warfarin ther- Before and after tooth extraction, the number of patients
apy was unstable or patients whose PT-INR values were taking cefcapene pivoxil, amoxicillin, and azithromycin
above 3.0 on the day of extraction were excluded. was 57, 36, and 8, respectively. Nine patients received
ampicillin before—tooth extraction and received amoxi-
Medication cillin after—tooth extraction.
The types (e.g., cefcapene pivoxil [CFPN-PI], amoxicil-
lin [AMPC], AZM), and dose of antibiotics were chosen Patients who took CFPN-PI and APAP
at the discretion of the physicians; these were taken 1 h From January 2014 to June 2016, CFPN-PI was the pri-
before tooth extraction and for a few days after extraction mary antibiotic used to prevent SSI. All 57 patients
to prevent SSI. If the patients had valvular disease, ampi- received 300 mg of CFPN-PI per day for 3 days before
cillin (ABPC) was administered 30 min before extraction and after tooth extraction, followed by 1200–1800 mg of
to prevent IE. This was in accordance with the Guidelines APAP per day for 3 days after tooth extraction. Seven out
for Prevention and Treatment of Infective Endocarditis of the 57 patients underwent additional treatments due
(Japanese Circulation Society 2008, 2017) [10]. For anal- to post-extraction hemorrhages on the day of extraction.
gesics, only acetaminophen (APAP) was prescribed for The INR values increased beyond the therapeutic range
several days. in 1 out of 57 patients (Fig. 1). We present this patient
as Case A. Case A was a 76-year-old female taking war-
Surgical procedures farin 1.75 mg per day. A preoperative blood test showed
All patients continued taking warfarin and were hospi- an ALT value of 11. The patient took 300 mg of CFPN-
talized from the day of their tooth extraction to the fol- PI per day for 3 days, followed by 1800 mg per day for
lowing day. Tooth extraction was performed under local 3 days, similar to other patients, and had 12 teeth (the
anesthesia, administered as 1.8–3.6 mL of 2% lidocaine greatest number of teeth of the 57 patients) extracted.
containing 1/80,000 units of epinephrine. The teeth were The patient’s INR value was within the therapeutic range,
extracted by a rotation and traction movement with but was the highest out of all 57 patients, with a value of
forceps or elevators. If immediate hemostasis was not nearly 3.0 1 month before tooth extraction and on the
achieved with dry gauze compression for 5 min, then a day of the extraction (2.93 and 2.81, respectively) (Fig. 1).
hemostat composed of oxidized cellulose (surgical; Ethi-
con, Somerville, NJ, USA), sutures with 3-0 absorbent Patients who took AMPC and APAP
thread, or a surgical splint was used at the surgeon’s dis- From July 2016 to December 2019, AMPC was the main
cretion. After confirming hemostasis during the tooth antibiotic prescribed, as opposed to CFPN-PI. Most of
extraction, all patients were instructed to bite down on the 36 patients took AMPC at a dose of 750 mg/day for
the gauze for a few hours in the hospital room. In all 2 days (two patients took if for 3 days) before and after
7 7
6 CFPN-PI 6 AMPC
5 5
4 4
INR value
INR value
Case A
3 3
2 2
1 1
0 0
1 month The day of 1 week later 1 month The day of 1 week later
before extraction before extraction
Mean SD 2.04 0.36 2.04 0.39 2.05 0.42 Mean SD 1.81 0.38 1.89 0.38 1.97 0.41
7 7
6 ABPC+AMPC Case B
6 AZM
5 5
4 4
INR value
INR value
Case C
3 3
2 2
1 1
0 0
Mean SD 2.26 0.46 2.12 0.35 2.62 1.43 Mean SD 2.12 0.39 2.15 0.44 2.51 0.56
Fig. 1 Change of INR value with time. The changes in INR throughout the study were not statistically significant. (2-factor analysis of variance, NS)
tooth extraction, and APAP at a dose of 1200 mg/day for blood test showed an ALT value of 10. The patient had
3–7 days after tooth extraction. One patient underwent two teeth extracted and was treated with a single 2-g
additional treatments due to post-extraction hemor- dose of ABPC the day before tooth extraction, and then
rhages on the day of extraction. took AMPC at a dose of 750 mg/day for 2 days like the
other patients. The patient had a post-extraction hemor-
Patients who took ABPC, AMPC and APAP rhage on the day of the extraction and visited our hos-
Most of the nine patients were treated with a single 2-g pital due to re-post-extraction hemorrhage 2 days after
dose of ABPC the day before tooth extraction, and then tooth extraction as well. After the patient’s hemostasis
took AMPC at a dose of 750 mg/day for 2 days (just was treated, she was prescribed AMPC for 2 days and
one patient took it for 4 days), and 1200–1500 mg/day APAP for 3 days. In addition, the patient’s INR value was
of APAP for 3–7 days after tooth extraction. Two out of within the therapeutic range, but had a value close to 3.0
the nine patients underwent additional treatments due both 1 month before tooth extraction and on the day of
to post-extraction hemorrhages on the day of extraction, the extraction (2.73 and 2.73, respectively) (Fig. 1).
and one out of two patients had a post-extraction hemor-
rhage after discharge. Patients who took AZM and APAP
One week after tooth extraction, the INR value in one AZM was mainly used for patients with impaired renal
patient increased by more than twice as much (Fig. 1). function or penicillin allergy. All eight patients took
We present this patient as Case B. Case B was a 66-year- AZM at a dose of 500 mg/day for 3 days before and after
old female taking warfarin 4.0 mg per day. A preoperative tooth extraction, and 1200–1500 mg/day for 3–7 days
after tooth extraction. None of the patients had post- Table 1 Patient data
extraction hemorrhages. Variables
One week after tooth extraction, a patient’s INR value
increased beyond the therapeutic range (Fig. 1). We pre- Types of antibiotics CFPN-PI 57 (51.8)
sent this patient as Case C. Case C was a 78-year-old AMPC 36 (32.7)
male taking warfarin 2.25 mg per day. A preoperative ABPC + AMPC 9 (8.2)
blood test showed an ALT value of 12. The patient had AZM 8 (7.3)
one tooth extracted and took AZM at a dose of 500 mg/ Sex Male 73 (66.4)
day for 3 days, followed by 1200 mg/day of APAP for Female 37 (33.6)
7 days. However, while Case C’s INR was within the ther- Age Mean ± SD 72.5 ± 9.1
apeutic range, it was the highest of all eight patients in < 75 59 (53.6)
this group, with a value close to 3.0 both 1 month before ≥ 75 51 (46.4)
tooth extraction and on the day of the extraction (2.70 Warfarin dose (mg) Mean ± SD 2.72 ± 1.10
and 2.90, respectively) (Fig. 1). Diabetes mellitus No 85 (77.3)
Yes 25 (22.7)
Hypertension No 57 (51.8)
Discussion
Yes 53 (48.2)
In the present study, we investigated the effects that vari-
Cerebral infarction No 93 (84.5)
ous antibiotics and analgesics taken during tooth extrac-
Yes 17 (15.5)
tion had on the INR values of patients taking warfarin.
With antiplatelet therapy No 82 (74.5)
Initially, we classified the patients into two groups (INR
Single 27 (24.5)
value increasing group and decreasing group after tooth
Dual 1 (1.0)
extraction) and compared these two groups. However,
Preoperative NSAIDs No 106 (96.4)
there were no significantly different factors (e.g., warfa-
Yes 4 (0.6)
rin dose, number of extracted teeth and type or dose of
Serum creatinine (mg/dl) Mean ± SD 0.93 ± 0.30
antibiotics) between the two groups (Additional file 1:
eGFR (mL/min/1.73 m2) Mean ± SD 60.0 ± 16.9
Table S1). In addition, the increase/decrease values were
mostly within 20% of the INR before extraction, which is ALT (IU/L) Mean ± SD 21.2 ± 13.8
within the range of error. Therefore, we focused on the Number of extracted teeth Mean ± SD 2.3 ± 2.2
fact that the medication before and after tooth extraction Single tooth 54 (49.1)
hardly raised the INR value sharply and we presented Multiple teeth 56 (50.9)
three patients in which the value increased beyond the Post-extraction hemorrhage (having No 103 (93.6)
additional treatment) Yes 7 (6.4)
therapeutic range. The INR values before tooth extrac-
tion in these three patients were close to 3.0. The INR Values are expressed as absolute numbers, with the corresponding
percentage of the total in parentheses. Some variables are expressed as the
value increased by more than twice as much in 1 of 110 mean ± standard deviation in a parametric ratio scale
patients (0.9%).
According to the Guidelines for Patients on Antithrom-
botic Therapy Requiring Dental Extraction 15, tooth or liver failure, diarrhea, and drug interactions can all
extraction can be safely performed without interrupt- cause increases in INR values [16, 17]. Regarding the
ing warfarin when the INR value is below 3.0 [7]. In interaction between antibiotics and warfarin, Rice et al.
the present study, when the INR values were below 3.0 [1] conducted a review of many reports and reported
in all patients, there were no cases of hemorrhages that that many antibiotics increased INR values, although
required systemic treatment (e.g., vitamin K or clotting the duration of administration varied. The mechanism
factor), and no thromboses (e.g., cerebral embolisms). by which antibiotics increase the action of warfarin is
Post-extraction hemorrhage that required additional known to alter the intestinal flora and decrease the pro-
treatment such as re-suturing, was observed in seven duction of vitamin K, thereby enhancing the action of
out of 110 patients (6.4%) (Table 1). In the past, many warfarin. This mechanism was applicable to cephalo-
reports have investigated post-extraction hemorrhages sporins (e.g., CFPN-PI) and penicillin antibiotics (e.g.,
in patients taking anticoagulants, and reported that the AMPC). Antibiotics also inhibit cytochrome P-450
incidence of post-extraction hemorrhages was 0–26% (CYP) in the liver, increasing the concentration of war-
[11–15]. Our results were similar to those of other farin in the blood [1]. This mechanism was applicable to
reports [11–15]. macrolide antibiotics (e.g., AZM). No reports have inves-
Some reports have shown that an increased age tigated the effect of surgical invasion by tooth extraction
(> 75 years old), male, high doses of warfarin, renal failure on the INR. Several studies have shown that infection
and inflammation decrease the expression and activ- retrospective nature of this study. Second, the num-
ity of CYP, resulting in decreased drug clearance [1, 3]. ber of patients was small depending on the antibiotics
Other studies have reported that infection itself affects prescribed. Third, frequent PT-INR measurements are
the metabolism of warfarin [3, 4]. These reports may highly invasive for patients, so we have to set criteria for
suggest that tooth extraction affects the INR values. In measurements based on patients. In the present study,
the present study, Case B, whose INR value more than the INR value increased beyond the therapeutic range in
doubled 1 week after tooth extraction, was the only one 3 out of 110 patients (2.7%). The INR values were close to
patient who underwent additional treatments for two 3.0 before tooth extraction in these three patients. Our
post-extraction hemorrhages. Case B might have been results suggest that surgeons have to take precautions
the most invasive case and had evidence of an infection before performing tooth extraction when INR values are
accompanied by necrotic tissue and delayed wound heal- close to 3.0. In addition, in those cases, measuring INR
ing 1 week after tooth extraction. values 1 week later may be useful. Finally, in our hospital,
Several reports have investigated the relationship the patients have been routinely prophylactically admin-
between various antibiotics and INR values [6, 9, 18]. istered antibiotics for a few days after tooth extraction.
Ghaswalla et al. [18] reported that there was a significant However, in recent years, we have been trying to reduce
interaction between time and antibiotics on the INR val- the administration of unnecessary antibiotic prophylaxis
ues of elderly (> 65 years old) patients who were on stable to prevent antimicrobial resistance.
warfarin therapy (CFPN-PI, AMPC, AZM, levofloxacin
[LVFX]). AZM in particular, which has a significantly Conclusion
long half-life, has been widely discussed in this context [6, Our results suggest that prophylactic antibiotic adminis-
9]. Glasheen et al. reported that the INR value increased tration has little effect on INR values when patients on
beyond the therapeutic range in 31% of AZM cases stable warfarin therapy undergo tooth extraction. Sur-
and 33% of levofloxacin LVFX cases 1 week after oral geons have to take attention if the patients whose INR
administration. This was seen in patients on stable war- values are close to 3.0 before their extraction.
farin therapy [9]. On the other hand, Kusafuka et al. [6]
reported that changes in INR values 1 week before and Supplementary information
after tooth extraction were not statistically significant Supplementary information accompanies this paper at https://doi.
(2-factor analysis of variance, not significant [NS]) when org/10.1186/s12903-020-01326-w.
18 patients taking warfarin were administered AZM. In
the present study, the changes in INR values throughout Additional file 1: Table S1. Comparison of the patients whose INR
value increased and those whose INR value decreased after one week
the study were not statistically significant (2-factor anal- after extraction. Values are expressed as absolute numbers, with the
ysis of variance, NS) for all antibiotics, including AZM. corresponding percentage of the total in parentheses. Some variables are
However, in 3 patients whose INR values were close to expressed as the mean ± standard deviation in a parametric ratio scale.
3.0 before tooth extraction, the INR values increased
beyond the therapeutic range. This result indicates that Abbreviations
surgeons have to pay attention to medications when the PT-INR: Prothrombin time-international normalized ratio; SSI: Surgical site
infection; IE: Infective endocarditis; AZM: Azithromycin; CFPN-PI: Cefcapene
INR value is close to 3.0 before the tooth extraction. pivoxil; AMPC: Amoxicillin; ABPC: Ampicillin; APAP: Acetaminophen; NJ: State
Although most NSAIDs are known to enhance the of New Jersey; USA: United States of America; NSAIDs: Non-steroidal anti-
action of warfarin [5], APAP also requires discussion [19]. inflammatory drugs; eGFR: Estimated glomerular filtration rates; ALT: Alanine
transaminase; CYP: Cytochrome P-450; LVFX: Levofloxacin; NS: Not significant.
Cardeira et al. [19] conducted a review of many reports
and reported that taking APAP was associated with a Acknowledgements
mean INR increase of 0.62 compared to placebo, for The authors thank Yui Enomoto and Ryo Kadoya for supporting data
collection.
patients taking warfarin. However, in all reports used in
this review, the duration of APAP treatment was longer Authors’ contributions
than 4 weeks. In the present study the APAP treatment EI designed the study, performed the data analyses, and drafted the manu-
script. AT contributed to study design and data analysis. JK, NT, and TH con-
was just for 3–7 days after tooth extraction, so there may tributed to data collection and analysis. MA revised the article for important
have been no significant association between APAP and intellectual content. All authors read and approved the final manuscript.
the increase in the INR values 1 week after extraction.
Funding
Surgeons need to be wary about prescribing APAP long No funding was obtained for this study.
term.
This study has some limitations. First, there is a pos- Availability of data and materials
The datasets generated and analyzed during the current study are not pub-
sibility of unknown confounding factors and factors licly available because it contains personal information but are available from
not studied (e.g., the presence of diarrhea) due to the the corresponding author on reasonable request.
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102621
Contents lists available at ScienceDirect
Diabetes & Metabolic Syndrome: Clinical Research & Reviews
journal homepage: www.elsevier.com/locate/dsx
The necessity of administrating antibiotic prophylaxis to patients with

diabetes mellitus prior to oral surgical procedures-a systematic review
Maria Sykara a, Panagiotis Maniatakos b, Anastasios Tentolouris c, *, Ioannis K. Karoussis a,
Nikolaos Tentolouris c
a
Department of Periodontology, Faculty of Dentistry, National and Kapodistrian University of Athens, Athens, Greece
b
Faculty of Dentistry, National and Kapodistrian University of Athens, Athens, Greece
c
First Department of Propaedeutic Internal Medicine and Diabetes Center, Laiko General Hospital, Athens, Greece
a r t i c l e i n f o a b s t r a c t
Article history: Background and aims: Мany studies suggest the use of antibiotic prophylaxis (AP) as an appropriate
Received 1 May 2022 preventive measure for patients with diabetes mellitus (DM) due to the increased possibility of an
Received in revised form impaired wound healing and infections after surgical procedures in the oral cavity. Existing recom-
10 September 2022
mendations regarding antibiotic prophylaxis before surgical procedures are not definitive and are based
Accepted 13 September 2022
on expert opinions. The purpose of this study was to review the available scientific data about the ne-
cessity of administrating AP as a preventive measure prior to oral surgical procedures.
Keywords:
Method: PubMed®, Scopus® kai Cochrane Central Register of Controlled Trials (CENTRAL) were used as
Diabetes mellitus
Antibiotic prophylaxis
databases to search for published research. All articles were initially identified and classified based on the
Oral surgery title and subsequently on their abstract. For the next level the full scientific paper was read and
Extraction evaluated.
Infection Results: Overall, 22 articles were included in the study, of which 2 were systematic reviews, 2 cohort
studies, 2 case-control studies, 1 case series, 8 case reports and 7 professional association publications.
Conclusions: In the scientific literature, there is a wide range of recommendations and inconsistency
regarding the need to administer AP prior to surgical dental operations in patients with DM, while there
is no scientific evidence demonstrating its’ effectiveness as a precautionary measure. Both blood glucose
level measurements and recent HbA1c measurement should be evaluated before any dental procedure.
Poor regulation may result to life-threatening infections after tooth extraction. AP is recommended prior
to the placement of dental implant. Randomized, controlled, clinical trials with large number of par-
ticipants and greater variety of surgical dental procedures are needed.
© 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.
1. Introduction been recommended historically for two groups of patients: those

with heart conditions that may develop infective endocarditis and
Antimicrobial prophylaxis (AP) can be used effectively to pre- those who have a prosthetic joint who may be at risk for developing
vent infection, but its use should be limited to specific indications prosthetic joint infections secondary to bacteremia introduced
to avoid excess cost, toxicity, and antimicrobial resistance [1]. AP is during dental care [3,4].
classified to primary when it is used for the prevention of an initial Diabetes mellitus [DM] is a disease of epidemic proportions,
infection and to secondary when it is used for the prevention of the estimated to affect 1 out of 11 people worldwide, while its preva-
recurrence or reactivation of an infection [1]. lence may reach 10% by 2040 [5]. Infections provide a significant
Dentists are among the top specialty prescribers of antibiotics in issue for people with DM, who are more likely to develop severe,
the United States, prescribing one out of every ten antibiotic pre- complicated infections in comparison with the general population
scriptions [2]. The use of AP prior to certain dental procedures has [6]. Although the pathogenesis is complicated and multifaceted,
hyperglycemia appears to be the universal denominator [7].
Data regarding whether there is need for AP in people with DM
* Corresponding author. 17 Agiou Thoma St, 11527, Athens, Greece.
prior to certain dental procedures are scarce. A wide range of rec-
E-mail address: antentol@med.uoa.gr (A. Tentolouris). ommendations can be found regarding the need for AP prior to
https://doi.org/10.1016/j.dsx.2022.102621
1871-4021/© 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.
M. Sykara, P. Maniatakos, A. Tentolouris et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 16 (2022) 102621
dental and surgical procedures in patients with DM, especially 3. Results

when the glycemic control is poor [8e12]. Nevertheless, the level of
evidence supporting such practice is questionable. Initial search produced 10,224 articles. After the removal of
The aim of this systematic review was to answer the following duplicate studies, 6844 articles remained, and 207 abstracts were
question: should AP be prescribed to patients with DM as a pre- selected based on the title of the articles. Of these, 82 articles were
ventive measure prior to surgical procedures in the oral cavity to selected based on the abstract and the entire scientific text was
reduce the incidence of wound healing problems and post-surgical then meticulously evaluated. In total, 22 articles were included in
infections? the study (Fig. 1), including 2 systematic reviews, 2 cohort studies, 2
case-control studies, 1 case series study and 8 case reports, as well
2. Material and methods as and 7 scientific association publications and official recom-
mendations [8e12,14e30]. Search results could not be analyzed
This systematic review was carried out in accordance with the with statistical methods to determine the strength of the evidence
guidelines proposed by Lockhart et al. [4]. due to the lack of RCTs. The main features of clinical studies are
summarized in Table 1.
2.1. Search strategy
3.1. Systematic reviews
Two researchers (M.S and P.M), searched independently the
literature through the databases PubMed®, Scopus® and the Two systematic reviews focused on the potential benefit of AP to
Cochrane Central Register of Controlled Trials (CENTRAL). Τhe DM patients in terms of survival of dental implants and inhibition
systematic search included articles published in English language of post-operative complications [14,15]. In the systematic review of
until December of 2021. Disagreements between the two re- 22 studies by Naujokat al., authors aimed to answer the question, if
searchers in final selection of studies to be included in qualitative dental implants placed in patients with DM have a higher
analysis were resolved by the intervention of a third researcher complication rate. Secondly, they evaluated the influence of pre-
(І.Κ). Additional searches were done on web sites of scientific or- operative administration of antibiotics. Based on one prospective
ganizations for official recommendations and scientific/advisory study, they found that preoperative antibiotics offer clear benefit in
recommendations. Search terms were “antibiotic prophylaxis implant success,which is even greater in patients with DM.Ther-
dental”, “antibiotic prophylaxis diabetes”, “complications after efore, they should be used in combination with chlorhexidine
dental extraction”, “dental management of diabetes”, “diabetes mouth rinse as supportive treatment [14]. Nevertheless, they do not
infection after dental”, “diabetes oral wound healing”, “guidelines describe which antibiotic should be used. Similarly, in the sys-
for antibiotic prophylaxis dental”, “guidelines for antibiotic pro- tematic review of 7 studies, including 1142 implants, by Annibali
phylaxis diabetes”, “dental implants diabetes”. et al. [15], authors reported that implant failure during osseointe-
All articles were identified and sorted first by title and subse- gration and the first year of loading is increased in patients with
quently by abstract. The criterion for the first step of selection was a DM. Although no separate analysis was performed the authors
clear reference to the necessity of antibiotic administration to pa- recommend that in order to minimize the risk of implant failure
tients with DM prior to surgical dental procedures. At the next step, over time preoperative or peri-operative antibiotic prophylaxis is
extensive evaluation of the full text of the selected papers was recommended.
performed.
3.2. Cohort studies
2.2. Inclusion/exclusion criteria
Huang et al. [16] conducted a prospective cohort study to
The exclusion criteria at this step were: evaluate differences in the quality of healing after simple extrac-
tions between patients with type 2 DM (T2DM) treated with oral
- Animal studies hypoglycemic medication and people without DM. Antibiotics were
- Articles not written in English language prescribed only in the event of tooth infection. The sample included
- Definition of chemoprophylaxis as antibiotic coverage after 224 subjects with T2DM with an average blood glucose level (BGL)
surgery of 7.5 mmol/L (136 mg/dL), range 4.1e17.4 mmol/L (74.0e313.2 mg/
- Clinical trials without control group dL) and 232 without DM with mean blood glucose level (BGL)
- Incomplete identification of antibiotic administration 5.2 mmol/L (94 mg/dL), range 1.9e9.2 mmol/L (34.2e166 mg/dL). A
- Narrative review total of 12 (5%) patients in the T2DM group and 16 (7%) in the
- Questionnaire studies examining patient management without control group presented a delayed healing beyond one week.
reference to results or complications. Evaluation of the association between DM and adverse outcomes
defined as delayed healing showed that while odds was 30.9%
The available studies were then classified and analyzed based on higher in the control group, the difference between groups [16 (7%)
their evidence-based value in one of the following categories, in vs 12 (5%)] was not statistical significance (p ¼ 0.49). All patients
descending order [13]: fully healed within four weeks. No correlation was found between
BGL and healing in patients with DM (p ¼ 0.93). Estimation of the
! Systematic reviews or meta-analysis of all relevant randomized effect of other factors on adverse outcomes also showed that there
controlled trials (RCTs) was no effect of age (p ¼ 0.78), sex (p ¼ 0.98), or smoking (p ¼ 0.24).
! RCTs Authors conclude that prophylactic antibiotic administration for
! Cohort studies routine dental extractions is not required for patients with DM on
! Case control studies oral hypoglycemic agents [16].
! Cross-sectional studies Power et al. [17] conducted a prospective controlled study to
! Case series, case reports determine whether there was a difference in post-extraction
! Professional association publications, official recommendations, healing in patients with either type 1 DM or insulin-dependent
and scientific/advisory statements T2DM and healthy controls, matched for age and sex. Fifty-six
2
Fig. 1. Process of article selection.
Table 1
Main features of clinical studies.
Authors Study type DM Control Number НbA1c BGL (mg/dL) Medication Medical Мonitoring Conclusions
type group of (%) Act period
patients
Morris Retrospective T2DM Non- n ¼ 663 NR NR NR Dental 3 years Patients with DM tend to have more failures
et al. case- control diabetics implant than non-diabetic patients. Administration of
[19] study surgery AP resulted in a small improvement in the
(2005) 2, 632 in survival of the implants in non-diabetic
non- patients and a greater improvement in
diabetics patients with Τ2DM.
255 in
T2DM
Нuang Prospective T2DM Non- n ¼ 456 NR m ¼ 136 mg/ Per os tablets Extractions 4 weeks There was no difference in healing between
et al. cohort study diabetics 224 dL (r:74 patients with Τ2DM in hypoglycemic tablets
[16] T2DM e314) and non-diabetic patients. Antibiotics as a
(2013) 232 precautionary measure for simple
non- extractions are not necessary.
diabetics
Fernandes Prospective T2DM Non- n ¼ 82 m ¼ 7, m ¼ 186 mg/ 60% per os Extractions 60 days Τ2DM patients who are going to undergo
et al. case- control diabetics 53 6% dL (r:75 antidiabetic tablets, simple tooth extraction, not associated with
[18] study T2DM e412) 17% insulin, 23% dental infection, do not need to be covered by
(2015) 29 non- insulin & AP. It is possible that they have delayed
diabetics antidiabetic tablets epithelialization of the wound without this
being associated with an increased risk of
wound infection or other post-operative
complications.
Power Prospective T1DM Non- n ¼ 105 NR m ¼ 180 mg/ Insulin Extractions Since full The study found a slight but not statistically
et al. cohort study & diabetics 56 DM dL (r:88 healing significant increase in the number of
[17] T2DM 49 non- e378) achieved complications and the possibility of wound
(2019) diabetics infection in patients with DM treated with
insulin. The level of control of insulin-
dependent diabetics should be evaluated
preoperatively, as the possibility of
complications was higher in patients with
poor control.
BGL: preoperative blood glucose, NR: no reference, N: number, m: mean value, r: range, DM: diabetes mellitus, T1DM: type 1 diabetes mellitus, T2DM: type 2 diabetes mellitus.
patients had insulin-dependent DM with mean BGL 10.03 mmol/L acute dental infection in the presence of pus or swelling of the
(180 mg/dL), range 4.9e26 mmol/L (88e468 mg/dL), mean age 58 adjacent anatomical structures. In all patients with DM, BGL was
years; the other group consisted of 49 healthy controls with mean measured just before the extraction. Healing delay was defined as
age 65 years. Dental students performed the extraction of fully the presence of dry socket, necrotic bone, excessive granulation
erupted teeth, under the supervision of Oral and Maxillofacial tissue, or infection in re-appointment, according to standard clin-
Surgery staff (OMFS). Antibiotics were prescribed only if there was ical criteria, or the requirement of multiple re-evaluation
3
Table 2
Serious and life-threatening infections after tooth extraction in patients with diabetes.
Authors Year of Referred Control level Age Other Preoperative

publication complications (years) comorbidities AP
Мοntejo 1998 Bacterial On arrival at the hospital glucose: 218 mg/dL 48 e NR

et al. meningitis
[20]
Tung-Yiu 2000 Cervical Not reported, two of the four patients were undiagnosed diabetics m ¼ 60,5 e NR
et al. Necrotizing
[21] Fasciitis
Nakamura 2001 Clostridial deep On arrival at the OMFS clinic: glucose: 305 mg/dL 63 e NR
et al. cervical infection
[23]
Kim et al. 2001 Rhino Cerebral Insulin-dependent DM in chloropropamide treatment by patient selection, non- 57 e NR
[22] Mucormycosis regular control of glucose levels, upon entry into ED glucose: 428 mg/dL, HbA1c 13.8%
Tryfon 2002 Rhino Cerebral Undiagnosed DM, Diabetic ketoacidosis found upon entry into ED 57 e NR
et al. Mucormycosis
[24]
Bakathir 2006 Rhino Cerebral Newly diagnosed T2DM in treatment with metformin, glipizide, upon hospitalization 49 Acute NR
et al. Mucormycosis glucose: 21 mmol/L (378 mg/dL), HbA1c 19% lymphoblastic
[25] leukemia
Maurer 2009 Bacterial Undiagnosed DM 36 e No
et al. meningitis
[26]
Аntunes 2013 Cervical Known uncontrolled DM 45 Obesity NR
et al. Necrotizing
[28] Fasciitis
Lin et al. 2016 Cervical Known uncontrolled T2DM 56 e NR
[27] Necrotizing
Fasciitis
AP: antibiotic prophylaxis, OMFS: Oral and Maxillofacial Surgery, NR: No Reference, m ¼ mean value, ED ¼ Emergency department, DM: diabetes mellitus, T1DM: type 1
diabetes mellitus, T2DM: type 2 diabetes mellitus.
appointments [17]. Authors found a 35% higher risk of complica- without AP by the same experienced dentist and they were then
tions in the participants with DM in comparison with people evaluated for signs and symptoms on day 3, 7, 21, and 60 following
without DM, nevertheless the difference was not statistically sig- extraction. Characteristics of tooth extraction, as well as the dura-
nificant (p ¼ 0.25). The study also showed that people with type 1 tion and technique followed were similar between the two groups.
DM or insulin-dependent T2DM tend to heal up adequate following Glycemic control and immunological profile were evaluated on the
dental extractions if they have good diabetes control. They, also, day of extraction. On day 21 postoperatively 9/53 (17%) patients
state that discomfort and swelling caused by tooth extraction may with DM, but none in the control group showed insufficient
predispose patients with DM to fluctuations in glucose levels and epithelialization of the alveolar socket; the difference was statisti-
possibly to reduced compliance with medication. This supports the cally significant (p ¼ 0.023). However, on day 60, complete
opinion that patients with poor glycemic control and insulin- epithelialization was seen in both groups and the alveolar socket
dependent DM need closer postoperative follow-up. showed no signs of infection. The delay in epithelialization was not
associated with HbA1c levels or BGL. The mean preoperative
3.3. Case-control studies plasma glucose for patients with T2DM was 186 mg/dL (range,
75e412 mg/dL), while the mean HbA1c was 7.6% (range:
Fernandes et al. [18] carried out a prospective case-control study 5.4e12.4%), with 40% of patients having HbA1c levels >6.5%. There
to evaluate the association between metabolic control and immune was also no significant association between delayed healing and
function with post-operative complications and the healing ability reduced neutrophil function. Authors conclude that patients with
after tooth extractions in individuals with T2DM and in healthy T2DM who undergo a simple tooth extraction not associated with
subjects. All participants had an extraction of a fully erupted tooth dental infection, should not be given antibiotic prophylaxis based
Table 3
Professional association publications, official recommendations, and scientific/advisory statements regarding administrating of antibiotic prophylaxis to patients with diabetes
mellitus prior to oral surgical procedures.
Professional association Publication Controlled Uncontrolled No information on level of

year DM DM control
European Academy of Pediatric Dentistry [8] 2002 e þ

Canadian Dental Association [12] 2005 e þ
Consensus document on the use of antibiotic prophylaxis in dental surgery and 2006 þ
procedures [10]
Аmerican Academy of Pediatric Dentistry [9] 2014 þ
College of dental hygienists of Ontario [29] 2015 e þ
Аmerican Association of Endodontists [11] 2017 e þ
American Dental Association [30] 2018 NR NR NR
þ: administrating of antibiotic prophylaxis.

-: no administrating of antibiotic prophylaxis.
NR: Not Reported.
4
on DM status or level of glycemic control. Patients with T2DM are (extractions, biopsies, implants, apicectomy, pre-prosthetic sur-
likely to develop delayed epithelialization of the post extraction gery, surgery on salivary glands) mucogingival surgery, and peri-
wound, without being associated with an increased risk of wound odontal surgery [10].
infection or other post-operative complications.
Morris et al. [19] carried out a retrospective case-control study 4. Discussion
to determine whether the presence of T2DM is a risk factor for
long-term clinical performance of dental implants, using the DICRG There is a wide range of recommendations and inconsistency
(Dental Implant Clinical Research Group) comprehensive database. regarding the need to administer AP prior to surgical dental oper-
Type 1 DM was considered an important risk factor, so it was an ations in patients with DM, while there is no scientific evidence
exclusion criterion. In total, 2887 implants (663 patients) were demonstrating its’ effectiveness as a precautionary measure.
surgically placed, restored, and monitored for a period of 36 Despite the fact that there is a large variety of recommendations
months. Of these, 2632 (91%) implants were placed in patients on the need for antibiotic coverage of patients with DM in dentistry,
without DM and 255 (8.8%) in patients with T2DM. In the multiple no effort has ever been made to systematically analyze the existing
logistic regression analysis T2DM was a significant risk factor for literature. Most authors base their recommendations on other re-
long-term clinical performance of dental implants (p ¼ 0.020). AP views, books, or publications of scientific associations. Therefore,
was among the several variables examined. The administration of this study is the first attempting to determine the level of evidence
antibiotics preoperatively improved the survival of implants in both that supports such a precautionary measure.
T2DM and patients without DM. The survival of the implants in the Many reviews argue that there is no evidence for AP in a patient
group without DM receiving AP was 4.5% higher in comparison with DM, regardless of glycemic control level [4,11,31e40]. Ac-
with those without DM who did not receive AP preoperatively. cording to the results of our review, there are two main recom-
Improvement in implant survival was even greater (10.5%) in the mendations suggesting AP before surgical dental procedures in DM
T2DM group. Authors suggest that these findings need to be patients: (i) a well-controlled DM patient does not need AP and can
confirmed by other clinical studies with a larger number of people be treated as a patient without DM [33,41e46], while a DM patient
with DM. with poor glycemic control should be administered AP if urgent
surgery is needed and/or glycemic control cannot be accomplished
3.4. Case series and case reports [31,33,45e50]; and (ii) a DM patient requires AP regardless
whether the diabetes is under control or not [51,52]. Additional
Table 2 summarizes data from single case reports and a case factors for the decision to administer AP include insulin-dependent
series on the occurrence of infections following tooth extraction in DM [45,49,52], active infection [41,53,54], and the severity of sur-
patients with DM [20e28]. gery [44].
Tong et al. [45] classified DM in the category of diseases that
3.5. Professional association publications, official needs AP administration to prevent systemic spread of infection.
recommendations, and scientific/advisory statements Patients with weakened immune system are at greater risk of
bacteremia, which may in short term lead to septicemia. People
Guidelines for the management of patients with DM are sum- with DM and especially those who are insulin dependent have
marized in Table 3. some degree of leukocyte dysfunction [55]. Particularly those with
According to the European Academy of Pediatric Dentistry, poor regulation are more prone to infections [56]. For this reason,
although there are no clear guidelines for children with DM, AP is AP is recommended for patients who have uncontrolled DM, but
usually recommended before invasive dental procedures, when not necessary for those whose disease is well controlled and are not
glucose blood levels are poorly regulated or completely uncon- insulin dependent. Ramaraj PN and Cariappa KM. consider
trolled, as children with DM often present some degree of leukocyte administering AP to a patient with DM because of the potential risk
dysfunction [8]. of postoperative infection after simple extraction as a practice in
These are in accordance with the guidelines of the American dispute [40]. They suggested that providing AP for simple extrac-
Academy of Pediatric Dentistry which state that diseases, such as tions to people with DM with good glycemic control is a non-
DM, associated with an immune disorder increase patients’ risk of documented practice as it is for people without DM [40]. In
infection following dental procedures, which involve manipulation accordance with this, McKenna SJ in his article suggests that people
of gingival tissues or the periapical region of teeth or a perforation with DM and HbA1c <8% are not at greater risk for infection
of the oral mucosa. In these cases, AP is required in order to prevent following routine surgery; however, when it comes to poorly
infectious endocarditis or distant-site infection [9]. The adminis- regulated patients with DM, AP administration should be consid-
trating of antibiotic prophylaxis is suggested regardless the glyce- ered [43].
mic status (controlled DM or uncontrolled DM). Interestingly, despite of the international guidelines, practi-
In the consensus document on the use of antibiotics in Dentistry tioners do not always adopt of and adhere to them. According to the
issued by an expert conference in 2006, comprising the presidents study by Lockhart et al. [35] 99% of the 477 Infectious Disease
of the most representative scientific societies in Spain (Spanish Consultants who completed the questionnaire, were opposed to
Society for Mouth Surgery, Editor of the “Revista Medicina Oral, administering AP in the case of uncontrolled DM patients who
Patología Oral, Cirugía Bucal” Journal, Spanish Society for Oral would undergo oral surgery. Ellerval et al. [37] evaluated the
Medicine, Spanish Society for Conservative Odontology, Spanish Swedish company guidelines for various diseases, including well-
Society for Dental Prosthetics, Spanish Society for Implantology, regulated and non-regulated DM and concluded that there are no
Spanish Society for Periodontics, Spanish Society for Paediatric studies that justify the administration of AP in either well-
Odontology, Spanish Society for Chemotherapy and Spanish Society controlled or poorly-controlled patients with DM.
for Oral and Maxillofacial Surgery), the existing literature on the Table 2 which presents cases of complications in patients with
biological principles of AP and its application on medical situations DM, shows that the occurrence of serious and life-threatening
was analyzed [10]. AP is recommended for patients with DM, as complications after invasive dental procedures in these patients is
they are classified in a high-risk group for local or systemic infec- a reality. Delayed healing in conjunction with wound infection can
tion. AP is recommended more specifically in oral surgery quickly lead to systemic infection extension. However, based on the
5
data presented in Table 2, it was observed that none of these pa- Declaration of competing interest
tients were reported to be well-controlled, and on contrary most
had either a known uncontrolled or undiagnosed DM [22e26,57]. The authors declare no conflict of interest.
From the above it is understood that more scientific documen-
tation is required for both type 1 DM and T2DM patients, as existing References
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6
Iwata et al. BMC Oral Health (2020) 20:331
https://doi.org/10.1186/s12903-020-01326-w
RESEARCH ARTICLE Open Access
Does prophylactic antibiotic administration

for tooth extraction affect PT-INR in patients
taking warfarin?
Eiji Iwata1,2*, Akira Tachibana1, Junya Kusumoto2, Naoki Takata1, Takumi Hasegawa2 and Masaya Akashi2
Abstract
Background: Various antibiotics and analgesics have been reported to interact with warfarin. Reports that investi-
gate the effects of medication taken for just a few days during tooth extraction on the prothrombin time-international
normalized ratio are rare.
Methods: A total of 110 patients receiving long-term stable warfarin therapy underwent tooth extraction without
interruption of warfarin treatment. INR values were measured 1 month before the tooth extraction, the day of the
extraction, and 1 week after the extraction. We investigated the changes in INR values between the day of extraction
and 1 week after extraction, as well as the various risk factors for increases in INR values.
Results: Before and after tooth extraction, the number of patients taking cefcapene pivoxil, amoxicillin, and azithro-
mycin was 57, 36, and 8, respectively. Nine patients were administered ampicillin before tooth extraction and received
amoxicillin after their tooth extraction. One week after tooth extraction, the INR values increased beyond the thera-
peutic range in 3 out of 110 patients (2.7%). The INR values before tooth extraction in these three patients were close
to 3.0. The INR value increased by more than twice as much in 1 out of 110 patients (0.9%).
Conclusion: Our results suggest that prophylactic antibiotic administration has little effect on INR values when
patients on stable warfarin therapy undergo tooth extraction. Surgeons have to take attention if the patients whose
INR values are close to 3.0 before their extraction.
Keywords: Antibiotics, Analgesics, Warfarin, Tooth extraction, International normalized ratio
Background cases and cases where oral intake was not possible [1–5].
Various antibiotics and analgesics have been reported To our knowledge, there is only one report that investi-
to interact with warfarin [1–5]. When tooth extraction gated the effects of medication that was administered for
is performed, patients are usually prescribed antibiotics just a few days for tooth extraction on the prothrombin
to prevent surgical site infection (SSI) or infective endo- time-international normalized ratio (PT-INR) [6]. This
carditis (IE) and analgesics to decrease pain. These drugs study investigated the effect of azithromycin (AZM) on
may also interact with warfarin and produce a clinically INR values in patients taking warfarin [6].
significant alteration in anticoagulation status. However, In the present study, we retrospectively investigated the
most previous reports were on long-term treatment effects of various antibiotics administered during tooth
extraction on the INR values in patients who were on sta-
ble warfarin therapy.
*Correspondence: eiwata@med.kobe-u.ac.jp
1
Department of Oral and Maxillofacial Surgery, Kakogawa Central City
Hospital, 439 Hon-machi, Kakogawa-cho, Kakogawa 675-8611, Japan
© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and
the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material
in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material
is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds
the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea-
tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo-
main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Methods patients, the presence of hemorrhage was checked by

Patients surgeons a few hours after tooth extraction. If the hemor-
In this study, inclusion criteria were set as patients above rhage required additional treatment, such as re-suturing,
18 years old, and exclusion criteria were set as patients we defined it as a post-extraction hemorrhage.
who hoped non-participate after the publication of this
study. From January 2014 to December 2019, 110 patients Variables
taking warfarin underwent tooth extraction at Kakogawa We investigated the rates of the changes in the INR values
Central City Hospital. Before tooth extraction, all beyond the therapeutic range 1 week after tooth extrac-
patients consulted with their primary physicians regard- tion. Additionally, the following variables from medical
ing their general medical status and whether their war- records were retrospectively reviewed: (1) medication—
farin therapies had been stable. If their INR values were types; (2) patient details in terms of—sex, age, warfarin
over 3.0, they were advised to postpone the extraction, dose, hypertension, cerebral infarction, antiplatelet ther-
according to the Guidelines for Patients on Antithrom- apy status (single or dual), preoperative non-steroidal
botic Therapy Requiring Dental Extraction’15 and the anti-inflammatory drugs (NSAIDs) being taken, serum
Guidelines for Pharmacotherapy of Atrial Fibrillation [7, creatinine levels, estimated glomerular filtration rates
8]. In the past, several studies reported that INR values (eGFR), and alanine transaminase (ALT) levels; and (3)
increased beyond the therapeutic range 1 week after oral surgical details including the—number of extracted teeth
administration of antibiotics [9]. Based on these reports, and whether they had a post-extraction hemorrhage.
at Kakogawa Central City Hospital, patients taking warfa-
rin routinely had their INR values measured on the day of Results
their tooth extraction and remeasured those them again All patients
1 week later. In this study, patients whose warfarin ther- Before and after tooth extraction, the number of patients
apy was unstable or patients whose PT-INR values were taking cefcapene pivoxil, amoxicillin, and azithromycin
above 3.0 on the day of extraction were excluded. was 57, 36, and 8, respectively. Nine patients received
ampicillin before—tooth extraction and received amoxi-
Medication cillin after—tooth extraction.
The types (e.g., cefcapene pivoxil [CFPN-PI], amoxicil-
lin [AMPC], AZM), and dose of antibiotics were chosen Patients who took CFPN-PI and APAP
at the discretion of the physicians; these were taken 1 h From January 2014 to June 2016, CFPN-PI was the pri-
before tooth extraction and for a few days after extraction mary antibiotic used to prevent SSI. All 57 patients
to prevent SSI. If the patients had valvular disease, ampi- received 300 mg of CFPN-PI per day for 3 days before
cillin (ABPC) was administered 30 min before extraction and after tooth extraction, followed by 1200–1800 mg of
to prevent IE. This was in accordance with the Guidelines APAP per day for 3 days after tooth extraction. Seven out
for Prevention and Treatment of Infective Endocarditis of the 57 patients underwent additional treatments due
(Japanese Circulation Society 2008, 2017) [10]. For anal- to post-extraction hemorrhages on the day of extraction.
gesics, only acetaminophen (APAP) was prescribed for The INR values increased beyond the therapeutic range
several days. in 1 out of 57 patients (Fig. 1). We present this patient
as Case A. Case A was a 76-year-old female taking war-
Surgical procedures farin 1.75 mg per day. A preoperative blood test showed
All patients continued taking warfarin and were hospi- an ALT value of 11. The patient took 300 mg of CFPN-
talized from the day of their tooth extraction to the fol- PI per day for 3 days, followed by 1800 mg per day for
lowing day. Tooth extraction was performed under local 3 days, similar to other patients, and had 12 teeth (the
anesthesia, administered as 1.8–3.6 mL of 2% lidocaine greatest number of teeth of the 57 patients) extracted.
containing 1/80,000 units of epinephrine. The teeth were The patient’s INR value was within the therapeutic range,
extracted by a rotation and traction movement with but was the highest out of all 57 patients, with a value of
forceps or elevators. If immediate hemostasis was not nearly 3.0 1 month before tooth extraction and on the
achieved with dry gauze compression for 5 min, then a day of the extraction (2.93 and 2.81, respectively) (Fig. 1).
hemostat composed of oxidized cellulose (surgical; Ethi-
con, Somerville, NJ, USA), sutures with 3-0 absorbent Patients who took AMPC and APAP
thread, or a surgical splint was used at the surgeon’s dis- From July 2016 to December 2019, AMPC was the main
cretion. After confirming hemostasis during the tooth antibiotic prescribed, as opposed to CFPN-PI. Most of
extraction, all patients were instructed to bite down on the 36 patients took AMPC at a dose of 750 mg/day for
the gauze for a few hours in the hospital room. In all 2 days (two patients took if for 3 days) before and after
7 7
6 CFPN-PI 6 AMPC
5 5
4 4
INR value
INR value
Case A
3 3
2 2
1 1
0 0
Mean SD 2.04 0.36 2.04 0.39 2.05 0.42 Mean SD 1.81 0.38 1.89 0.38 1.97 0.41
7 7
6 ABPC+AMPC Case B
6 AZM
5 5
4 4
INR value
INR value
Case C
3 3
2 2
1 1
0 0
Mean SD 2.26 0.46 2.12 0.35 2.62 1.43 Mean SD 2.12 0.39 2.15 0.44 2.51 0.56
Fig. 1 Change of INR value with time. The changes in INR throughout the study were not statistically significant. (2-factor analysis of variance, NS)
tooth extraction, and APAP at a dose of 1200 mg/day for blood test showed an ALT value of 10. The patient had
3–7 days after tooth extraction. One patient underwent two teeth extracted and was treated with a single 2-g
additional treatments due to post-extraction hemor- dose of ABPC the day before tooth extraction, and then
rhages on the day of extraction. took AMPC at a dose of 750 mg/day for 2 days like the
other patients. The patient had a post-extraction hemor-
Patients who took ABPC, AMPC and APAP rhage on the day of the extraction and visited our hos-
Most of the nine patients were treated with a single 2-g pital due to re-post-extraction hemorrhage 2 days after
dose of ABPC the day before tooth extraction, and then tooth extraction as well. After the patient’s hemostasis
took AMPC at a dose of 750 mg/day for 2 days (just was treated, she was prescribed AMPC for 2 days and
one patient took it for 4 days), and 1200–1500 mg/day APAP for 3 days. In addition, the patient’s INR value was
of APAP for 3–7 days after tooth extraction. Two out of within the therapeutic range, but had a value close to 3.0
the nine patients underwent additional treatments due both 1 month before tooth extraction and on the day of
to post-extraction hemorrhages on the day of extraction, the extraction (2.73 and 2.73, respectively) (Fig. 1).
and one out of two patients had a post-extraction hemor-
rhage after discharge. Patients who took AZM and APAP
One week after tooth extraction, the INR value in one AZM was mainly used for patients with impaired renal
patient increased by more than twice as much (Fig. 1). function or penicillin allergy. All eight patients took
We present this patient as Case B. Case B was a 66-year- AZM at a dose of 500 mg/day for 3 days before and after
old female taking warfarin 4.0 mg per day. A preoperative tooth extraction, and 1200–1500 mg/day for 3–7 days
after tooth extraction. None of the patients had post- Table 1 Patient data
extraction hemorrhages. Variables
One week after tooth extraction, a patient’s INR value
increased beyond the therapeutic range (Fig. 1). We pre- Types of antibiotics CFPN-PI 57 (51.8)
sent this patient as Case C. Case C was a 78-year-old AMPC 36 (32.7)
male taking warfarin 2.25 mg per day. A preoperative ABPC + AMPC 9 (8.2)
blood test showed an ALT value of 12. The patient had AZM 8 (7.3)
one tooth extracted and took AZM at a dose of 500 mg/ Sex Male 73 (66.4)
day for 3 days, followed by 1200 mg/day of APAP for Female 37 (33.6)
7 days. However, while Case C’s INR was within the ther- Age Mean ± SD 72.5 ± 9.1
apeutic range, it was the highest of all eight patients in < 75 59 (53.6)
this group, with a value close to 3.0 both 1 month before ≥ 75 51 (46.4)
tooth extraction and on the day of the extraction (2.70 Warfarin dose (mg) Mean ± SD 2.72 ± 1.10
and 2.90, respectively) (Fig. 1). Diabetes mellitus No 85 (77.3)
Yes 25 (22.7)
Hypertension No 57 (51.8)
Discussion
Yes 53 (48.2)
In the present study, we investigated the effects that vari-
Cerebral infarction No 93 (84.5)
ous antibiotics and analgesics taken during tooth extrac-
Yes 17 (15.5)
tion had on the INR values of patients taking warfarin.
With antiplatelet therapy No 82 (74.5)
Initially, we classified the patients into two groups (INR
Single 27 (24.5)
value increasing group and decreasing group after tooth
Dual 1 (1.0)
extraction) and compared these two groups. However,
Preoperative NSAIDs No 106 (96.4)
there were no significantly different factors (e.g., warfa-
Yes 4 (0.6)
rin dose, number of extracted teeth and type or dose of
Serum creatinine (mg/dl) Mean ± SD 0.93 ± 0.30
antibiotics) between the two groups (Additional file 1:
eGFR (mL/min/1.73 m2) Mean ± SD 60.0 ± 16.9
Table S1). In addition, the increase/decrease values were
mostly within 20% of the INR before extraction, which is ALT (IU/L) Mean ± SD 21.2 ± 13.8
within the range of error. Therefore, we focused on the Number of extracted teeth Mean ± SD 2.3 ± 2.2
fact that the medication before and after tooth extraction Single tooth 54 (49.1)
hardly raised the INR value sharply and we presented Multiple teeth 56 (50.9)
three patients in which the value increased beyond the Post-extraction hemorrhage (having No 103 (93.6)
additional treatment) Yes 7 (6.4)
therapeutic range. The INR values before tooth extrac-
tion in these three patients were close to 3.0. The INR Values are expressed as absolute numbers, with the corresponding
percentage of the total in parentheses. Some variables are expressed as the
value increased by more than twice as much in 1 of 110 mean ± standard deviation in a parametric ratio scale
patients (0.9%).
According to the Guidelines for Patients on Antithrom-
botic Therapy Requiring Dental Extraction 15, tooth or liver failure, diarrhea, and drug interactions can all
extraction can be safely performed without interrupt- cause increases in INR values [16, 17]. Regarding the
ing warfarin when the INR value is below 3.0 [7]. In interaction between antibiotics and warfarin, Rice et al.
the present study, when the INR values were below 3.0 [1] conducted a review of many reports and reported
in all patients, there were no cases of hemorrhages that that many antibiotics increased INR values, although
required systemic treatment (e.g., vitamin K or clotting the duration of administration varied. The mechanism
factor), and no thromboses (e.g., cerebral embolisms). by which antibiotics increase the action of warfarin is
Post-extraction hemorrhage that required additional known to alter the intestinal flora and decrease the pro-
treatment such as re-suturing, was observed in seven duction of vitamin K, thereby enhancing the action of
out of 110 patients (6.4%) (Table 1). In the past, many warfarin. This mechanism was applicable to cephalo-
reports have investigated post-extraction hemorrhages sporins (e.g., CFPN-PI) and penicillin antibiotics (e.g.,
in patients taking anticoagulants, and reported that the AMPC). Antibiotics also inhibit cytochrome P-450
incidence of post-extraction hemorrhages was 0–26% (CYP) in the liver, increasing the concentration of war-
[11–15]. Our results were similar to those of other farin in the blood [1]. This mechanism was applicable to
reports [11–15]. macrolide antibiotics (e.g., AZM). No reports have inves-
Some reports have shown that an increased age tigated the effect of surgical invasion by tooth extraction
(> 75 years old), male, high doses of warfarin, renal failure on the INR. Several studies have shown that infection
and inflammation decrease the expression and activ- retrospective nature of this study. Second, the num-
ity of CYP, resulting in decreased drug clearance [1, 3]. ber of patients was small depending on the antibiotics
Other studies have reported that infection itself affects prescribed. Third, frequent PT-INR measurements are
the metabolism of warfarin [3, 4]. These reports may highly invasive for patients, so we have to set criteria for
suggest that tooth extraction affects the INR values. In measurements based on patients. In the present study,
the present study, Case B, whose INR value more than the INR value increased beyond the therapeutic range in
doubled 1 week after tooth extraction, was the only one 3 out of 110 patients (2.7%). The INR values were close to
patient who underwent additional treatments for two 3.0 before tooth extraction in these three patients. Our
post-extraction hemorrhages. Case B might have been results suggest that surgeons have to take precautions
the most invasive case and had evidence of an infection before performing tooth extraction when INR values are
accompanied by necrotic tissue and delayed wound heal- close to 3.0. In addition, in those cases, measuring INR
ing 1 week after tooth extraction. values 1 week later may be useful. Finally, in our hospital,
Several reports have investigated the relationship the patients have been routinely prophylactically admin-
between various antibiotics and INR values [6, 9, 18]. istered antibiotics for a few days after tooth extraction.
Ghaswalla et al. [18] reported that there was a significant However, in recent years, we have been trying to reduce
interaction between time and antibiotics on the INR val- the administration of unnecessary antibiotic prophylaxis
ues of elderly (> 65 years old) patients who were on stable to prevent antimicrobial resistance.
warfarin therapy (CFPN-PI, AMPC, AZM, levofloxacin
[LVFX]). AZM in particular, which has a significantly Conclusion
long half-life, has been widely discussed in this context [6, Our results suggest that prophylactic antibiotic adminis-
9]. Glasheen et al. reported that the INR value increased tration has little effect on INR values when patients on
beyond the therapeutic range in 31% of AZM cases stable warfarin therapy undergo tooth extraction. Sur-
and 33% of levofloxacin LVFX cases 1 week after oral geons have to take attention if the patients whose INR
administration. This was seen in patients on stable war- values are close to 3.0 before their extraction.
farin therapy [9]. On the other hand, Kusafuka et al. [6]
reported that changes in INR values 1 week before and Supplementary information
after tooth extraction were not statistically significant Supplementary information accompanies this paper at https://doi.
(2-factor analysis of variance, not significant [NS]) when org/10.1186/s12903-020-01326-w.
18 patients taking warfarin were administered AZM. In
the present study, the changes in INR values throughout Additional file 1: Table S1. Comparison of the patients whose INR
value increased and those whose INR value decreased after one week
the study were not statistically significant (2-factor anal- after extraction. Values are expressed as absolute numbers, with the
ysis of variance, NS) for all antibiotics, including AZM. corresponding percentage of the total in parentheses. Some variables are
However, in 3 patients whose INR values were close to expressed as the mean ± standard deviation in a parametric ratio scale.
3.0 before tooth extraction, the INR values increased
beyond the therapeutic range. This result indicates that Abbreviations
surgeons have to pay attention to medications when the PT-INR: Prothrombin time-international normalized ratio; SSI: Surgical site
infection; IE: Infective endocarditis; AZM: Azithromycin; CFPN-PI: Cefcapene
INR value is close to 3.0 before the tooth extraction. pivoxil; AMPC: Amoxicillin; ABPC: Ampicillin; APAP: Acetaminophen; NJ: State
Although most NSAIDs are known to enhance the of New Jersey; USA: United States of America; NSAIDs: Non-steroidal anti-
action of warfarin [5], APAP also requires discussion [19]. inflammatory drugs; eGFR: Estimated glomerular filtration rates; ALT: Alanine
transaminase; CYP: Cytochrome P-450; LVFX: Levofloxacin; NS: Not significant.
Cardeira et al. [19] conducted a review of many reports
and reported that taking APAP was associated with a Acknowledgements
mean INR increase of 0.62 compared to placebo, for The authors thank Yui Enomoto and Ryo Kadoya for supporting data
collection.
patients taking warfarin. However, in all reports used in
this review, the duration of APAP treatment was longer Authors’ contributions
than 4 weeks. In the present study the APAP treatment EI designed the study, performed the data analyses, and drafted the manu-
script. AT contributed to study design and data analysis. JK, NT, and TH con-
was just for 3–7 days after tooth extraction, so there may tributed to data collection and analysis. MA revised the article for important
have been no significant association between APAP and intellectual content. All authors read and approved the final manuscript.
the increase in the INR values 1 week after extraction.
Funding
Surgeons need to be wary about prescribing APAP long No funding was obtained for this study.
term.
This study has some limitations. First, there is a pos- Availability of data and materials
The datasets generated and analyzed during the current study are not pub-
sibility of unknown confounding factors and factors licly available because it contains personal information but are available from
not studied (e.g., the presence of diarrhea) due to the the corresponding author on reasonable request.
Ethics approval and consent to participate compromised patient. guidelines for patients on antithrombotic therapy
The INR measurement before and after tooth extraction were performed at requiring dental extraction: Tokyo: Gakujutsush Corporation; 2015.
Kakogawa Central City Hospital as a clinically necessary action, and is not 8. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrilla-
for research. Since this study is a retrospective study, patients did not give tion (JCS 2013)—digest version. Circ J. 2014;78:1997–2021.
informed consent. This study has been conducted in full accordance with the 9. Glasheen JJ, Fugit RV, Prochazka AV. The risk of overanticoagulation with
World Medical Association Declaration of Helsinki and was approved by the antibiotic use in outpatients on stable warfarin regimens. J Gen Intern
institutional review board of Kakogawa Central City Hospital (authorization Med. 2005;20:653–6.
number: 2019-84). The ethics committee approved the procedure of this study 10. Nakatani S, Ohara T, Ashihara K, Izumi C, Iwanaga S, Eishi K, Okita Y,
and gave us administrative permissions to access the data used in this study. Daimon M, Kimura T, Toyoda K, Nakase H, Nakano K, Higashi M, Mitsutake
K, Murakami T, Yasukochi S, Fujiu K, Mirura T, Morizane T, on behalf
Consent for publication of the Japanese Circulation Society Joint Working Group. JCS 2017
Not applicable. guideline on prevention and treatment of infective endocarditis. Circ J.
2019;83:1767–809.
Competing interests 11. Zanon E, Martinelli F, Bacci C, Cordioli G, Girolami A. Safety of dental
The authors declare that they have no competing interest. extraction among consecutive patients on oral anticoagulant treatment
managed using a specific dental management protocol. Blood Coagul
Author details Fibrinolysis. 2003;14:27–30.
1
Department of Oral and Maxillofacial Surgery, Kakogawa Central City Hospi- 12. Cannon PD, Dharmar VT. Minor oral surgical procedures in patients on
tal, 439 Hon-machi, Kakogawa-cho, Kakogawa 675-8611, Japan. 2 Department oral anticoagulants—a controlled study. Aust Dent J. 2003;48:115–8.
of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medi- 13. Sacco R, Sacco M, Carpenedo M, Mannucci PM. Oral surgery in patients
cine, Kobe, Japan. on oral anticoagulant therapy: a randomized comparison of different
intensity targets. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol.
Received: 30 June 2020 Accepted: 12 November 2020 2007;104:e18-21.
14. Morimoto Y, Niwa H, Minematsu K. Hemostatic management of tooth
extractions in patients on oral antithrombotic therapy. J Oral Maxillofac
Surg. 2008;66:51–7.
15. Morimoto Y, Niwa H, Yoneda T, Kimura K, Yasaka M, Minematsu K.
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What is th e O p t i mu m for
Alveolar Ridge
P re s e r v a t i o n ?
Firas Al Yafi, DDSa,*, Basem Alchawaf, DMD, DrMedDent
b
,
Katja Nelson, DMD, DrMedDentc
KEYWORDS
! Alveolar ridge preservation ! Ridge augmentation ! Socket preservation
! Socket grafting ! Extraction socket classification
KEY POINTS
! Bone resorption after tooth extraction is inevitable.
! Alveolar ridge preservation is effective in reducing ridge volume alteration.
! Many factors may affect the healing pattern and the treatment outcomes of the alveolar
ridge preservation.
! A clinical classification of extraction sockets and treatment guidelines is proposed.
INTRODUCTION
The alveolar ridge is a tooth-dependent structure that develops in conjunction with

tooth eruption and undergoes volume and morphologic alteration subsequent to tooth
loss.1 Early and recent studies have shown that unassisted natural healing of the alve-
olar process postextraction leads to substantial loss of the ridge volume.2–4 Volume
and morphologic alteration of alveolar ridge occur rapidly within the first 3 months
to 6 months of tooth extraction and continue gradually at a slower rate thereafter.
At 6 months, the ridge may lose up to 63% of its width and up to 22% of its original
height.4 In addition, an estimated mean bone loss of 3.87 mm horizontally and
1.25 mm to 1.67 mm vertically can be expected.4–6 Alveolar bone resorption usually
is more pronounced on the facial side, which leads to relocation of the ridge to an
Disclosure: The authors have nothing to disclose.

a
Arab Board of Oral Surgery, Division of Periodontology, Department of Oral Health Practice,
College of Dentistry, University of Kentucky, 800 Rose Street, 4th floor, Room D436, Dental
Science Bldg, Lexington, KY 40536-0297, USA; b Department of Oral and Maxillofacial Surgery,
College of Dentistry, King Saud University, PO Box 60169, Riyadh 11545, Saudi Arabia;
c
Department of Dental and Craniofacial Sciences, Clinic of Oral and Maxillofacial Surgery,
Freiburg University Hospital, Hugstetter Street 55, Freiburg im. Breisgau D-79106, Germany
* Corresponding author.
E-mail address: firasyafi@uky.edu
Dent Clin N Am 63 (2019) 399–418

https://doi.org/10.1016/j.cden.2019.02.007 dental.theclinics.com
0011-8532/19/ª 2019 Elsevier Inc. All rights reserved.
400 Al Yafi et al
unfavorable position (the bone is located in a more lingual and apical position).7
Changes of the alveolar ridge after tooth extraction could have an impact on prosthet-
ically driven dental implant placement and may necessitate augmentation procedures
(Table 1).
RATIONALE FOR ALVEOLAR RIDGE PRESERVATION
The alveolar ridge assisted healing concept was proposed to minimize postextraction
alveolar ridge alterations. Additionally, preservation of the ridge volume and contour
facilitates de novo bone formation within the socket.8,9 In the literature, different terms
have been used to describe the procedure: socket preservation, socket grafting, ridge
preservation, and site preservation. The term, alveolar ridge preservation (ARP), was
coined due to the rationale of minimizing dimensional changes of the alveolar ridge af-
ter tooth extraction.10 ARP involves the use of bone graft material, a membrane, and
biological products either alone or in combination with one another. If the objective is
to increase the width or the height of the ridge beyond its boundaries, however, the
term, ridge augmentation, should be used.9
A plethora of literature (Table 2) suggests that ARP procedures might decrease the
physiologic bone loss, facilitating delayed implant placement.8,10–16 ARP techniques
may limit but not prevent ridge resorption.17 The quality of the newly formed bone
also is not predictably improved.10 ARP is effective, however, in reducing ridge width
loss and ridge height loss after tooth extraction by 1.25 mm to 1.86 mm and 1.36 mm
to 1.62 mm, respectively, compared with unassisted ridge healing.17,18 Moreover,
ridges with damaged extraction socket walls benefit more from ARP than ridges
with intact extraction socket.17
Table 1
Systematic reviews on alveolar ridge dimensional changes after tooth extraction in humans
Type of Follow-
Study Review up Results Conclusions
Tan et al,4 Systematic 1–12 m 32% of horizontal Rapid reductions of
2012 review dimensional change alveolar ridge occur in
20 studies occurred at 3 mo. the first 3–6 mo,
3.79 mm or approximately followed by gradual
29%–63% of horizontal dimensional reductions
bone loss appeared at thereafter.
6 mo. Bone reduction is more
1.24 mm or approximately pronounced at buccal
11%–22% of vertical side.
bone loss appeared at
6 mo.
Soft tissue gains 0.4–
0.5 mm of thickness at
6 mo
Van der Weijden Systematic 3–12 m 3.87-mm reduction in Alveolar ridge undergoes
et al,5 2009 review width of the alveolar significant dimensional
12 studies ridges is expected. changes during the
1.67-mm midbuccal postextraction healing
height resorption is period.
apparent. Amount of ridge width
1.53 mm of vertical loss reduction is greater
assessed on the than the height
radiographs. reduction.
Table 2
Summary of literature review on the efficacy of alveolar ridge preservation in maintaining the tissues of the alveolar ridge after tooth extraction and the
pattern of bone healing
F
Follow-
2
A
Study Type of Review up Results Conclusions

AB
Bassir et al,17 Meta-analysis 2–9 mo 1.86 mm decrease of horizontal ridge resorption ARP is effective method in minimizing the
A(
2 DB
2018 21 studies in comparison to natural healing dimensional changes after extraction.

1.36-mm decrease of vertical ridge resorption ARP outcomes are improved by the use of barrier
membrane.
DB 1B A 2 2C )2B C 1 E AB C
Less favorable outcome with alloplasts

0 C A DB B F C DC A BB
APR is beneficial more in ridges with damaged

extraction sockets compared with ridges with
intact socket walls.
Troiano et al,11 Meta-analysis 3–9 mo 2.19-mm decrease of horizontal ridge resorption ARP using bone graft and restorable membrane
2017 7 studies in comparison to natural healing can decrease the rate of alveolar ridge
1.72-mm decrease of vertical ridge resorption horizontal and vertical resorption after tooth
extraction in comparison with spontaneous
healing.
Corbella et al,56 Quantitative 3–9 mo Bovine bone was related to a lower new bone No superiority of biomaterial over the others in
A
2017 synthesis formation compared with naturally healed terms of new bone formation; calcium sulfate
40 studies sites. and b-tricalcium phosphate show fastest
A
Meta-analysis Porcine bone and magnesium-enriched resorption rate.

C
11 studies hydroxyapatite were related to higher new Xenografts shows lower resorption rate and
2/
Alveolar Ridge Preservation

bone formation. might be better in preserving bone size
Allograft was not related to higher new bone overtime than allograft.
,B E A. ( A
formation than naturally healed sites.

3 ,B E A
Mardas et al,8 Quantitative 3–8 mo There are no difference of survival, success, and ARP might lessen the need of bone augmentation
2015 synthesis marginal bone levels of implants placed in during implant placement.
40 studies natural healed alveolar ridges or in ridges No superiority of biomaterial or a treatment
Meta-analysis undergone ARP procedures. protocol to others
27 studies
3AD2A
CB A B AE
(continued on next page)
401
402
Table 2
(continued )
Al Yafi et al
F
Follow-
2
A
De Risi et al,13 Systematic 3–7 mo Xenografts and alloplasts presented the highest No histologic and histomorphometrical
AB
2015 review rate of residual particles after 7 mo of healing differences among different ARP protocols or
A(
2 DB
38 whereas allografts had the lowest amount. in comparison to natural healing

Allografts presented best amount of new bone ARP is not effective in improving tissue quality.
formation at 3 mo. Unnecessary to wait more than 3–4 mo to insert
No differences between various ARP and natural implant in preserved sites from histologic stand
healing in terms of percentage of bone and point

connective tissue
Tomlin et al,30 Review of 4–6 mo No treatment: ridge width "2.51, ridge height All ARP procedures are effective in reducing
2014 the literature "2.07, percentage of vital bone 42.2%. dimensional changes.
14 studies Bone graft only: ridge width "1.18, ridge height Some bone graft interferes with healing inside
"1.31, percentage of vital bone 46.2%. the socket.
Membrane only: ridge width "0.08, ridge height No preference of some material over others
10.14, percentage of vital bone N/A.
Bone graft and membrane: ridge width 10.47,
ridge height "0.15, percentage of vital bone
A
31.7%.
A
Avila-Ortiz et al,12 Quantitative >3 mo 1.89-mm reduction of horizontal ridge resorption ARP using bone graft can be effective in reducing
C
2014 synthesis 2.07-mm and 1.18-mm reductions of midbuccal vertical and horizontal volume changes in
2/
8 studies and midlingual vertical resorption, respectively comparison to natural healing.

Meta-analysis 0.48-mm and 0.24-mm reductions of mesial and Flap elevation, usage of a membrane may
,B E A. ( A
6 studies distal ridge resorption, respectively. enhance the outcomes.

3 ,B E A
Xenograft or an allograft can be more effective

than alloplastic materials.
Vittorini Orgeas et al,14 Quantitative 4–12 mo Grafting materials and membranes together or ARP using bone graft can be effective in reducing
2013 synthesis alone may reduce resorption process. vertical and horizontal volume changes in
13 studies comparison to natural healing
3AD2A
CB A B AE
Meta-analysis Use of barrier membranes alone might improve

6 studies healing of extraction sockets.
Flap elevation and soft tissue primary closure
seem to have little effect on dimensional
changes.
Horváth et al,10 Systematic 1.1–9 mo ("1.0-mm and "3.5-mm # 2.7-mm) horizontal Natural remodeling led to dimensional changes
2013 review ridge resorption in ARP group and ("2.5-mm of extraction socket, more pronounced
14 Studies and "4.6-mm # 0.3-mm) in natural healing horizontally.
F
group ARP may limit but not prevent resorption rate

2
(between 11.3-mm # 2.0-mm and with no superiority of specific method.

A
"0.7-mm # 1.4-mm) vertical ridge changes in ARP might lessen the need of bone augmentation
AB
ARP group and ("0.8-mm # 1.6-mm and "3.6- procedure at implant placement
A(
2 DB
mm # 1.5-mm) changes in natural healing Some grafts interfered with the healing.
group The presence of intact socket walls and primary flap
closure is often associated with favorable results.
Vignoletti et al,15 Systemic >3 mo 1.83-mm decrease of horizontal ridge resorption ARP can be effective in reducing vertical and
2012 review in comparison to natural healing horizontal volume changes in comparison to
14 studies 1.47-mm decrease of vertical ridge resorption natural healing.
Meta-analysis No superior surgical procedure or material or
9 studies membrane
A flap and primary closure may enhance the
outcome.
Hammerle et al,9 Osteology — 3.8-mm alveolar ridge width reduction occurred ARP using biomaterial and/or membrane is
2012 consensus within 6 mo. recommended.
report after 1.24-mm vertical reduction expected within 6 mo Raising flap and primary closure is preferable.
A
discussion of No superiority of specific biomaterial or

4 comprehensive membrane on the outcome, except collagen
A
systematic reviews plug revealed negative results.

C
No comparison is available between primary

2/

closure methods (soft tissue punch, connective
tissue graft, barrier membrane, and soft tissue
,B E A. ( A
replacement matrix).
3 ,B E A
Weng,18 Literature review 3–12 mo 1.25-mm reduction of horizontal ridge resorption ARP seems effective in maintaining ridge
2011 10 studies in comparison to natural healing dimensions.
DGI conference 1.62-mm reduction of vertical ridge resorption ARP might lessen the need of bone augmentation
consensus at implant placement by 5 times.
No superiority of specific surgical procedure or
3AD2A
CB A B AE
material is evident.
Primary closure of the socket might not be
essential.
403
404
Al Yafi et al
2 F
A
AB
A(
2 DB
Table 2
(continued )
Follow-
Darby et al,31 Literature review 1 mo Grafting materials and membranes together or ARP can be effective in reducing vertical and
2009 37 studies up to alone may reduce resorption process. horizontal volume changes in comparison to
15 y natural healing.
No superiority of specific surgical procedure
No evidence that ridge preservation procedures
A
reduce the need for augmentation at implant

placement
A
Bone material may interfere with bone formation

C
2/
in the socket.
Primary closure is not always necessary; however,
the use of membranes requires soft tissue
,B E A. ( A
coverage.
3 ,B E A
Abbreviation: DGI, The German Association of Oral Implantology.

3AD2A
CB A B AE
Alveolar Ridge Preservation 405
Immediate implant placement with or without socket shielding (keeping a root remnant
at the facial wall of extraction socket) is suggested to serve the same purpose of pro-
tecting alveolar ridge structures.19–21 Immediate implant placement by itself may not
prevent the remodeling of the alveolar ridge after extraction.22 Careful selection
criteria for immediate implant cases should be followed to avoid unfavorable out-
comes.23 Although the socket shield technique has promising potential in maintaining
the alveolar ridge dimension, the presence of infection, root fracture, or decay is a lim-
itation of this technique. Furthermore, long-term prognosis of implant installation in
proximity to tooth-root fragment has yet to be proved.24
PRETREATMENT ASSESSMENT AND SURGICAL CONSIDERATIONS
The rate of volumetric changes, healing pattern, and quality and quantity of newly
formed bone may be affected by several factors; these should be considered when
choosing the appropriate treatment approach.
Soft Tissue and Hard Tissue Configuration

Interproximal bone
After tooth extraction, dimensional changes usually affect the central part of the facial
wall, whereas the proximal aspect is preserved by the healthy periodontal ligament of
the neighboring teeth.25
Thickness of buccal bone wall

Buccal bone with a thickness less than 2 mm is prone to a higher resorption rate after
tooth extraction because it is composed solely of bundle bone.15,26,27 It seems, how-
ever, that ARP can limit the reduction in the ridge dimension regardless of the thick-
ness of the buccal bone.28 Two millimeters of buccal bone thickness should be a
prerequisite for immediate implant placement. This thickness allows for predictable
remodeling of the alveolar ridge29 (Fig. 1).
Socket walls
In intact socket walls, containment and vascularity of the bone graft material are
improved.
Bone fenestration or dehiscence

A socket with no fenestration or dehiscence is reported to be associated with more
favorable clinical outcomes.10,30,31
The gingival phenotype

Thick gingival tissue is associated with better healing, along with decreased bone
resorption and gingival recession.32,33 This could be attributed to increased vascularity
and a greater presence of extracellular matrix and collagen.34 Phenotype conversion is
believed to increase the overall peri-implant health state and reduce bone loss35 (Fig. 2).
Surgical Technique
Atraumatic extraction
Performing an atraumatic extraction results in minimal trauma to soft tissue and hard
tissue and may play an important role in ridge preservation.36,37
Primary closure versus open barrier technique

Different techniques have been used for ARP, including primary wound closure,38,39
partial wound closure,40 no primary closure,41 and soft tissue graft to seal the
socket.42 ARP can be effective regardless of the closure technique.14,18
406 Al Yafi et al
Fig. 1. (A) Thin buccal bone. (B) Thick buccal bone.
Flapless procedure
According to Fickl and colleagues,43 reflection of the flap results in pronounced bone
resorption compared with flapless procedures. Other researchers have disputed this
finding and have demonstrated no significant difference between flapped and flapless
extractions.44 Vignoletti and colleagues15 found a flap procedure in combination with
ARP has a positive impact on the horizontal dimension of the ridge. These studies indi-
cate a continued controversy in the literature with regard to flap design and its impact
on the result of the ARP.
Location in the Mouth

The anterior maxilla frequently has a thin buccal bone phenotype ($1 mm) causing
pronounced facial bone remodeling.45–47 Soft tissue and hard tissue grafting in
conjunction with immediate implant placement or ARP to improve the esthetic
outcome may be needed.48
Periodontal Status
If a tooth is extracted due to advanced periodontal disease, the postextraction healing
process has been described as more complicated and less predictable compared to
non-periodontally involved sites. Furthermore, slower bone regeneration is expected
in infected sockets in comparison to disease-free sites.49
Fig. 2. (A) Thick gingival phenotype. (B) Thin gingival phenotype.
Biomaterial
Bone graft materials
Bone grafting materials are categorized into autogenous, allografts, xenografts, and
alloplasts (Table 3). Each of these materials has shown its efficacy in reducing dimen-
sional shrinkage after tooth extraction.10,11 Current literature does not provide evi-
dence for superiority of 1 material over another.7–9,15,29,50 Nevertheless, some graft
materials, such as xenografts and alloplasts, may resorb at a slower rate, with their
remnant particles existing 7 months or more after the grafting procedure; thus, they
Table 3
Bone graft types
Material Source Examples

Autogenous The patient ! Intraoral: symphysis, ramus, and tuberosity
! Extraoral: hip, rib, fibula, and tibia
Allografts Same species, ! Demineralized freeze-dried bone allograft
different individual ! Freeze-dried bone allograft
Xenografts Different species ! Bovine
! Equine
! Porcine
Alloplasts Synthetic ! Hydroxyapatite
! Calcium sulfate
! Calcium phosphate
! Bioglass
408 Al Yafi et al
may be more suitable for long-term ARP.10,13,50 On the other hand, allograft tends to
resorb more rapidly with fewer residual particles and induces more newly formed bone
after 3 months of healing.13 These properties may be more favorable for short-term
ARP. The long-term effect of residual grafting material on implant survival and success
has not been reported.
Membranes types
Resorbable membranes and nonresorbable membranes with or without bone graft
were effective on decreasing the alveolar ridge resorption after tooth extraction
(Table 4).10 ARP, however, has a more favorable outcome when a barrier membrane
is used.12,15,17
Combination of bone graft and membrane
ARP usually includes using a bone graft with a membrane. Either one, however, could
be used alone.30 Nevertheless, Troiano and colleagues11 stated that using a resorb-
able membrane with bone graft (the most common procedure used for ARP) can
decrease both horizontal and vertical ridge shrinkage.
Biologics
Platelet concentrate products51–53 and recombinant growth factors50,54,55 have
been used in ARP procedures. Their use may lead to accelerated bone regenera-
tion and enhanced soft tissue healing, reducing the reentry time for implant
placement.
CLASSIFICATION AND TREATMENT MODALITIES

Classification
An algorithm was developed by the authors to guide clinicians in an evidence-
based approach for ARP. The algorithm classifies the single extraction socket
according to the most critical factors that affect the predictability, esthetic out-
comes, and functional results of the implant. Both hard tissue and soft tissue
factors should be considered. Hard tissue examination should include the height
of the interproximal bone, thickness and integrity of the buccal bone plate, and
remaining extraction socket walls. The soft tissue contour and its relationship to
underlying bone, gingival phenotype, and esthetics also should be considered
(Fig. 3).
Using the classification decision tree (Fig. 4), a dentist is able to classify the extrac-
tion socket depending on the clinical examination, bone sounding, and periapical or
bitewing radiographs. Based on the classification of the extraction socket, the appro-
priate treatment modality can be determined for each site.
Table 4
Membrane type
Membrane
Type Examples
Resorbable ! Collagen (non–cross-linked and cross-linked)
! Amnion chorion
! Acellular dermal matrix grafts
! Synthetic: organic aliphatic polymers and modifications
Nonresorbable ! Polytetrafluoroethylene
! Titanium mesh
Fig. 3. Assessment of extraction socket. The red line represents soft tissue contour, whereas
the brown line represents the bone contour. CEJ, Cemento Enamel Junction.
410 Al Yafi et al
Fig. 4. Ridge preservation classification decision tree.
Treatment Modalities
The appropriate treatment plan can be selected based on these classifications, taking
into consideration the cost, complexity, and time needed for each procedure
(Table 5).
The treatment modalities were suggested in the order of the most favorable
choice to the least favorable. Immediate implant placement at the time of
tooth extraction is preferred in ideal situations (class I A). When suboptimal
conditions with normal gingival contour are present (class I B or II A), however,
implant installation may need to be supplemented with soft tissue and/or hard
tissue grafting. On the other hand, the presence of any midfacial recession
or big bony defect (class II A or II B) would compromise an immediate
implant outcome; ARP or delayed implant placement (at 4–8 weeks) may become
better options. A 3-stage approach includes ARP, implant site development,
and implant placement after proper healing. This approach is recommended
when esthetics are of concern in a site with a major tissue defect, especially
locations lacking vertical bone height (class IV B). Moreover, recombinant
growth factors and blood concentrate products are suggested in these challenging
cases.
Esthetics play a major role in determining the preferred treatment approach. In a pa-
tient with a low smile line with minimal esthetic concerns, anterior implant placement
may be considered as a nonesthetic site. In contrast, a posterior upper tooth, in a high-
ly esthetically concerned patient with a wide smile, may be evaluated as an esthetic
site (class IV A vs class IV B). A thorough patient assessment should be completed
to determine the esthetic desires of a patient.
Table 5
Treatment decisions
F
Treatment Option 1 Treatment Option 2 Treatment Option 3 Comments

2
Class I A Immediate implant (Fig. 5) Two-stage approach Two-stage approach Flapless approach is
A
1 ARP: bone graft 1 collagen plug 1 ARP: high-density recommended.

AB
or tissue punch (Fig. 6) polytetrafluoroethylene

A(
2 DB
2 Implant placement after proper without bone graft

healing time 2 Implant placement after proper
healing time (Fig. 7)
Class I B Immediate implant Two-stage approach Delayed implant placement with The bony defect has to be
Hard tissue and/or soft tissue 1 ARP: bone graft 1 membrane simultaneous GBR if needed completely included by the
graft is recommended (resorbable/nonresorbable) membrane.
2 Implant placement after proper Flapless approach is
healing time recommended.
Class II A Delayed implant placement with Two-stage approach Immediate implant Immediate implant has less
simultaneous GBR. 1 ARP: bone graft 1 membrane Hard tissue and/or soft tissue predictable esthetic outcomes.
(resorbable/nonresorbable) graft as needed A flap might be needed to deal
2 Implant placement with with the defect.
simultaneous GBR and soft
A
tissue grafting as needed.

Class II B Delayed implant placement with Two-stage approach Three-stage approach Immediate implant is not
A
simultaneous GBR and soft 1 ARP: bone graft 1 membrane 1 ARP: bone graft 1 membrane recommended.
C
2/
tissue grafting (resorbable/nonresorbable) (resorbable/nonresorbable) It is the clinician choice to do soft

2 Implant placement with 2 Implant site development tissue grafting at the second
simultaneous GBR and soft 3 Implant placement after the phase or third phase of the
,B E A. ( A
tissue grafting as needed proper healing time 3-stage approach.

3 ,B E A
Class III A Immediate implant Two-stage approach Enamel matrix derivative can be
Hard tissue and/or soft tissue 1 ARP: bone graft 1 membrane considered.
graft as needed (resorbable/nonresorbable) The first treatment option is
2 Implant placement after the favorable in thick phenotype
proper healing time white; the second option is
3AD2A
CB A B AE
favorable in thin phenotype.
411
412
Al Yafi et al
2 F
A
AB
Table 5
A(
2 DB
(continued )
Treatment Option 1 Treatment Option 2 Treatment Option 3 Comments
Class III B Two-stage approach Three-stage approach Enamel matrix derivative is

1 ARP: bone graft 1 membrane 1 ARP: bone graft 1 membrane recommended.

(resorbable/nonresorbable) (resorbable/nonresorbable) Immediate implant is not
2 implant placement with 2 Implant site development recommended.
simultaneous GBR and soft 3 Implant placement after the It is the clinician choice to do soft
tissue grafting as needed proper healing time. tissue grafting at the second
phase or third phase of the
3-stage approach.
Class IV A Two-stage approach Delayed implant placement with Immediate implant hard tissue Immediate implant placement is
1 ARP: bone graft 1 membrane simultaneous GBR and soft and/or soft tissue graft as not favorable and should be a
(resorbable/nonresorbable). tissue graft as needed needed case-by-case decision.
A
2 Implant placement with

A
simultaneous GBR and soft

C
tissue grafting as needed.

2/
Class IV B Three-stage approach Immediate implant is not

1 ARP: bone graft 1 membrane recommended.
,B E A. ( A
(resorbable/nonresorbable) It is the clinician choice to do soft

3 ,B E A
2 Implant site development tissue grafting at the second

3 Implant placement after the phase or third phase of the
proper healing time 3-stage approach.
The use of bone enhancing
products might be considered.
3AD2A
CB A B AE
Abbreviation: GBR, Guided Bone Regeneration.

Fig. 5. (A) The patient smile shows the remaining root of tooth #9. (B) Preoperative periap-
ical radiograph of tooth #9 showing intact interpoximal bone and (C) clinical frontal (upper)
and occlusal (lower) views showing thick biotype. (D) Post-extraction frontal (upper) and
occlusal (lower) views showing thick intact buccal bone. (E) The implant was installed
(lower) and the metal screw retained provisional abutment was placed (upper). (F) The
jumping space between the implant and the buccal bone was grafted with deproteinized
bovine bone minerals. (G) The patient’s failed crown was used to pick up the metal provi-
sional abutment. (H) Frontal (upper) and lateral (lower) views of a screw retained implant
provisional. (I) Postoperative radiograph of implant and the provisional crown. (J) The pa-
tient’s smile. (K) Three-month follow-up showing the preservation of gingival architecture.
A flapless approach is recommended when possible to minimize the patient post-

operative discomfort, unless a large defect exists and has to be visualized and con-
tained with the membrane. The treatment options for each class are not limited to
the suggested options. It is a clinician’s choice to decide bone graft material and
type of membrane to be used.
Fig. 6. (A) Preoperative radiograph of tooth #8 showing periapical lesion and intact interprox-
imal bone. (B) Clinical frontal (lower) and occlusal (upper) views showing thin gingival pheno-
type. (C) Occlusal view before extraction (lower) and after extraction (upper) showing thin
buccal bone. (D) The extraction socket was filled with a mixture of demineralized freeze-dried
bone allograft and Deproteinized bovine bone (upper). Collagen plug was used to seal the orifice
of the socket (lower). (E) An occlusal (upper) and frontal (lower) views of a PRF membrane which
was used to cover the collagen plug and secured with a criss-cross suture. (F) Occlusal (upper) and
frontal (lower) views, 2 days post operative. (G) Occlusal (upper) and frontal (lower) views, 8 days
post operative. (H) Occlusal (upper) and frontal (lower) views, 30 days post operative.
414 Al Yafi et al
Fig. 7. (A) Preoperative periapical radiograph of tooth # 3 showing failed endodontic treat-
ment. (B) Clinical occlusal photograph before extraction showing. (C) Occlusal view of the
socket after atraumatic extraction. (D) The socket was filled with platelet-rich fibrin plugs.
(E) Nonresorbable membrane covering the socket and secured with sutures. (F) Clinical
occlusal view at 1-week follow-up showing uneventful soft tissue healing. (G) Four weeks
follow up before membrane removal. (H) Four weeks follow up after membrane removal.
(I) Twelve-week follow-up showing complete soft tissue healing. (J) Occlusal view at
14 week. (K) Occlusal view at 14 week post implant placement. (L) Postoperative radiograph
with implant in place.
Multiple extraction sites are not considered in the proposed algorithm. They pose a
clinical challenge when restored with a dental implant–supported prosthesis. The
following, however, should be considered:
! Type of prosthesis, intraocclusal and interocclusal spaces
! The proximal bone adjacent to the remaining teeth
! The interproximal bone between the extracted teeth
! The integrity and thickness of the buccal and lingual plates
! The gingival biotype and architecture
! Patient smile line and lip support
! Patient esthetic expectations
! Full work-up, including cone beam CT and wax-up
In general, esthetic result of immediate adjacent implants is predictable only in ideal
scenarios, and a staged approach for site development yields better outcomes.
SUMMARY
! ARP is an effective method to limit the dimensional changes after tooth
extraction.
! No evidence has shown to support the superiority of a certain material or tech-
nique for ART. The chosen technique remains at the clinician discretion.
! Immediate implant placement should be done only in optimal conditions, espe-
cially in the esthetic zone.
REFERENCES
1. Schroeder HE. The periodontium. Berlin: Springer-Verlag; 1986.
T i s s u e En g i n e e r i n g
What is New?
Dolphus R. Dawson III, DMD, MS, MPHa,*,

Ahmed El-Ghannam, PhDb, Joseph E. Van Sickels, DDSc,
Noel Ye Naung, BDS, Higher Grad Dip Clin Sc (OMFS), MSc (OMFS), FIAOMSc
KEYWORDS
! Tissue engineering ! Soft tissue grafts ! Dental implants ! Bone grafts
! Regeneration ! Biologics
KEY POINTS
! Soft tissue engineering includes the use of mesenchymal stem cells to develop tissue
sheets for donor soft tissue graft and incorporate other cell types to create new vascular
structures within the graft.
! Osteoconductive scaffolds mixed with osteoinductive growth factors, including osteo-
genic stem and osteoprogenitor cells, enhance maxillofacial bone reconstruction.
! Hard tissue engineering of bone grafts, such as those with a silica-calcium phosphate
composite seeded with human adipose-derived stem cells, creates better grafts with
enhanced resorption profiles.
SOFT TISSUE ENGINEERING
Oral soft tissue engineering has long been associated with the reconstruction of
mucosal or gingival defects associated with chronic disease or trauma, as well as
congenital defects. The premise of the tissue engineering follows a requisite triad of
cells, scaffolds, and physiologically active substances, along with angiogenesis and
proper environmental factors/stimuli to induce tissue regeneration.1 This tenet holds
true for both hard and soft tissues. Soft tissue augmentation has evolved beyond con-
ventional autogenous-only grafts to a variety of donor grafts. The regeneration of soft
tissue has just begun to tap its potential through advancements in stem cell
Disclosure statement: The authors have nothing to disclose.

a
Division of Periodontology, Department of Oral Health Practice, College of Dentistry, Uni-
versity of Kentucky, 800 Rose Street, D-444 Dental Sciences Building, Lexington, KY 40536-0297,
USA; b Department of Mechanical Engineering and Engineering Science, University of North
Carolina at Charlotte, 9201 University City Boulevard, Charlotte, NC 28223-0001, USA; c Division
of Oral and Maxillofacial Surgery, College of Dentistry, University of Kentucky, 800 Rose Street,
Lexington, KY 40536-0297, USA
E-mail address: dolph.dawson@uky.edu
Dent Clin N Am 63 (2019) 433–445

434 Dawson III et al
technologies as well as cell signaling and cell trafficking. The focus here is to provide
an overview of some key areas of these advancements.
Soft Tissue Augmentation

Soft tissue augmentation around implants has, for many years, focused on autoge-
nous conventional epithelialized, free gingival grafts, or connective tissue grafts to
gain keratinized tissue or address mucosal recession.2 Studies indicate that shallow
recession defects ("2 mm) have shown success; there is no support for larger de-
fects.3 The adaptation of various tunneling techniques have led to minimal surgical ac-
cess that produce both successful root coverage and esthetics.4 These minimally
invasive procedures, such as the vestibular incision supraperiosteal tunnel access
or modified vestibular incision supraperiosteal tunnel access technique, have been
used to address defects around dental implants.5 Further studies are needed to better
address outcomes in the esthetic zone.6
Autogenous soft tissue grafts rely on donor sites, usually the hard palate, which can
have significant sequelae, such as postoperative pain or bleeding after the procedure.
A number of commercially available soft tissue grafts allow the elimination of harvest-
ing the graft from the donor as well as the grafting of multiple sites in 1 visit. Allogenic
human acellular dermal matrix is commonly used for soft tissue augmentation and has
similar results to autogenous grafts.7 A common feature of several of these allogenic
grafts is the preservation of the basement membrane. Xenografts, or those derived
from other species, such as porcine or bovine species, have also been used. One
such porcine collagen matrix studied in comparison to a free gingival graft showed
mature collagen in the tissue samples from the porcine graft, whereas a more frag-
mented collagen tissue was seen in the free gingival graft samples.8
Although enhancements of harvested donor tissues allow for a greater extent of
grafting and less patient morbidity, regeneration relies on the manipulation of cells
and tissues to maximize gain of lost tissues.
Soft Tissue Regeneration

Soft tissue regeneration blends the processes of wound healing with the enhancement
of cell types and functions present during the phase of regeneration. A number of key
cell processes, including proliferation, viability, migration, gene expression, and differ-
entiation have been studied in in vitro monolayer models and 3-dimensional (3D)
models provide insight into higher order activity, such as cell contractility in a fibroblast
model.9 A 3D model was used to generate autologous cell sheets in a rat model.10 Oral
mucosal cells, specifically fibroblasts, as well as fibrin were used to create scaffolds
for mucosal keratinocytes. In this rat model, reepithelization via cell sheets with fibro-
blasts was much faster than those without fibroblasts. The authors concluded that not
only was the overall process relatively fast, but also that the outcome included no
scarring. The 3D tissue models have also provided a platform to study various oral
infection models, such as oral candidiasis, allowing for a better understanding of cyto-
kine release and gene expression of the tissues as well as the process of invasion of
the epithelium by the candidiasis.11
Tissue models rely on selected cells for specific applications. Mesenchymal stem
cells (MSCs) give rise to various specialized cells. Recent efforts have focused on pro-
genitor cells of the periodontal ligament (PDL) because these cells can form cemento-
blasts, osteoblasts, or fibroblasts.12–15 Differentiated induced pluripotent stem cells
that turn into MSCs are generally safer than undifferentiated pluripotent stem cells,
but there are limitations on obtaining adequate quantities of cells.16,17 Further
research is needed to develop more sources of stem cells. Once an adequate source
Tissue Engineering 435
and quantity of therapeutic stem cells can be generated, the next challenge is getting
the cells where they are needed. Local delivery may suffice if the defects are large and
are accessed surgically; however, early defects may require attracting cells to the site.
Enhancing attraction of the patient’s own cells may be done through endogenous cell
homing via chemokines or scaffolds that influence the recruitment of specific cells.18
In a rat model, systemically transplanted MSCs were harvested from donor rats and
implants were placed after tooth extractions.19 The authors noted improved attach-
ment and proliferation of oral mucous epithelial cells. The PDL is known for its regen-
erative capacity to enhance the replacement of lost cementum and bone on natural
teeth. A novel concept of developing a PDL on dental implants has been investigated.
In a rat model, dental progenitor cells were used to seed and develop a PDL on tita-
nium implants.20 Advancements in obtaining and maintaining a PDL on implants would
be significant for regeneration around implant surfaces.
All augmentation procedures, both soft and hard tissue, rely on the establish-
ment of vascular and nutrient supply after augmentation. The collection, harvest-
ing, and delivery of specific cells would be of little use without an environment
that allows proliferation and maturation. Assessment of various scaffolds via
micro-computed tomography evaluation of perfusion can be done using a chorio-
allantoic membrane that allows for 3D imaging of the tissue engineered construct
while reducing extensive animal use in research.21 Vascularized connective tissue
grafts in humans, when compared with conventional subepithelial connective tis-
sue grafts, showed less shrinkage and maintained their initial volume better.22 In
another study, human adipose-derived cells and human umbilical vein endothelial
cells were used to create vessel structures for vascularization of the engineered
soft tissue flap.23
BONE ENGINEERING
Repair of bone defects, both large and small, in the maxillofacial skeleton have proved
to be a treatment challenge for many years. Although autogenous bone grafts have
been considered the mainstay and gold standard of treatment, allografts, xenografts,
and alloplastic substitutes have been used with success for resolving bony defects in
the maxilla and the mandible.24–28 The traditional autogenous bone graft often
required a donor site that added another source of morbidity to the patient. Searches
for alternative methods that eliminate a donor site have been many and led to the un-
derstanding of osteoconductive and osteoinductive materials. Autogenous bone
grafts stimulate bone regeneration through its osteogenic, osteoinductive, and osteo-
conductive properties, and avoid an immune reaction. In addition, autogenous grafts
contain live stem or osteoprogenitor cells that can migrate, proliferate, and potentiate
bone healing.29 An osteoinductive material can recruit immature cells and stimulate
them to develop into osteoblasts.26,27,30 Although well beyond the scope of this
article, several growth factors are involved in bone healing. They include vascular
endothelial growth factor, fibroblastic growth factors, insulin-like growth factors,
platelet-derived growth factor, and bone morphogenic proteins (BMP), to name a
few.31 Their concentration, interaction with other growth factors, and the timing of their
application is critical in normal bone regeneration.25
Osteoconductive materials allow bone to grow on a surface and act as a scaffold. A
scaffold should not only provide structural support, but also should be biodegradable
at a rate comparable with that of newly formed bone and should have a porous struc-
ture similar to bone to promote capillary infiltration and cell proliferation.28 Tricalcium
phosphate is an example of an osteoconductive material that will resorb with time.32
Bone Morphogenic Proteins

BMPs are widely recognized for their important role in the postnatal bone formation.
They are members of transforming growth factor-b group.33,34 Out of nearly 20
different BMPs that have been identified, BMP-2 and BMP-7 are the most extensively
studied and are considered to possess the most significant osteoinductive
properties.34–36
Recombinant human BMP-2 (rhBMP-2) with an absorbable collagen sponge carrier
is commercially available in the United States as INFUSE bone graft (Medtronic, Min-
neapolis, MN) and is approved by the US Food and Drug Administration. Current in-
dications include sinus augmentations, alveolar ridge augmentation, and socket
preservation procedures.37 A series of clinical trials have demonstrated the effective-
ness of rhBMP-2/absorbable collagen sponge for maxillary sinus augmentation and
alveolar ridge augmentation procedures.38–40 Separately, complete healing of alveolar
grafting of premaxillary clefts was demonstrated in 10 patients treated with BMP-2/
collagen sponges when compared with 2 control patients treated with conventional
autogenous cancellous bone grafts.41
Even though good evidence exists regarding the effectiveness of rhBMP-2, its
safety has been questioned based on a metaanalysis of individual participant data
by Simmonds and colleagues42 (2013). Their research was conducted in response
to the finding from a review of clinical trials conducted by of Carragee and col-
leagues43 (2011), where the risk of adverse events seemed to be significantly higher
than original estimates when study bias was taken into consideration.
Conway and associates44 (2014) compared the treatment of long bone union in 63
patients treated with BMP-2 versus 112 patients treated with BMP-7. They found that
treatment with BMP-2 showed a better healing (15 weeks vs 23 weeks average time to
weight bearing) and faster recovery (19 weeks vs 30 weeks average healing time) than
treatment with BMP-7.44 In contrast, another comparison study discovered that
rhBMP-7, especially in higher doses, showed less inflammation and soft tissue edema
than rhBMP-2.45
To deliver rhBMP-7 into the bony defect, bovine collagen is reconstituted with saline
to form a paste or carboxymethylcellulose is added into the rhBMP-7/bovine collagen/
saline paste to form a putty as a carrier. These are available as OP-1 Putty (Skryker
Biotech, Hopkinton, MA) under limited approval from the US Food and Drug Adminis-
tration. However, its use was discontinued in the United States in 2014 because the
product failed to clearly demonstrate its efficacy in comparison with autogenous
bone grafting.46 Nevertheless, the use of rhBMP-7 has continued in other countries
with promising results. Ayoub and colleagues47 (2016) described a successful regen-
eration of alveolar cleft with the use of rhBMP-7.
One of the challenges with collagen-based carrier systems is a lack of strength to
withstand forces exerted by the muscles of mastication. With increased pressure,
the slow controlled and sustained release of BMPs can be compromised. With pres-
sure, there is also an increased risk of the release of high doses of rhBMPs.33 Thus,
BMPs and a collagen sponge have been studied in conjunction with porous solid
osteoconductive scaffolds such as hydroxyapatite, tricalcium phosphate, and chito-
san to achieve the required mechanical support.33
Herford and colleagues30 (2012) combined recombinant BMP with a compression-
resistant osteoconductive matrix in an animal model mandibular continuity defect.
They showed a significantly higher bone density and space maintenance than just re-
combinant BMP2 and an absorbable collagen sponge.30 Their compression resistant
matrix was composed of 15% hydroxyapatite and 85% b-tricalcium phosphate.
A number of studies that advocated for the use of osteoconductive scaffolds in

combination with osteoinductive materials showed successful bone healing or regen-
eration that is comparable with those with autogenous bone grafts. However, in pa-
tients with limited native viable osteoprogenitor cells (such as osteoporotic bone or
radiation-induced hypocellular bone), the addition of bone marrow aspirate may be
beneficial. Melville and colleagues26 (2017) used recombinant BMP2 with an alloge-
neic avascular bone graft combined with a bone marrow aspirate with a poly-D, L-lac-
tic acid mesh to reconstruct the maxillary alveolus in a patient following a traumatic
maxillary defect. Six months later, they were able to successfully place 3 dental
implants.
Clinical Examples
Previously, our group published a report on the use of reconstruction plates with the
use of rhBMP2 and tricalcium phosphate for patients with fractures and continuity de-
fects of the mandible.48 A successful outcome was achieved for 2 patients with no sig-
nificant medical comorbidities, thus avoiding a secondary donor site. In 1 case, the
defect was 4 cm.48 We present an additional case using a similar technique.
Six months after maxillary and mandibular osteotomies, a 40-year-old patient pre-
sented with an infection and shifting of the occlusion. After the resolution of the infec-
tion and loss of bone, a diagnosis of a nonunion on the left side of the mandible was
made (Fig. 1). A cone beam computerized tomogram was obtained that allowed for
the fabrication of a 3D model with the patient in the proper occlusion. Intraoperatively,
a 2-mm reconstruction plate was contoured to stabilize the segments (Fig. 2). This pa-
tient is still under active treatment.
Bone Grafts: The Next Generation

Annually, more than 4 million bone grafting surgeries are performed worldwide, at an
estimated cost of US$10 billion.49–52 In 2016, the global market for craniomaxillofacial
implants was US$1.79 billion and is expected to reach US$2.49 billion by 2021.53
Despite the huge advances of the state-of-the-art bone graft technology, the recon-
struction of large craniofacial and maxillofacial bone defects remains a major chal-
lenge. The use of autografts is currently the gold standard technique despite the
associated mortality and morbidity problems.54 Cadaver bone grafts from bone banks
is second in popularity after autografts; however, it carries risks of decreases in
Fig. 1. Nonunion of the left mandible with significant loss of bone.
Fig. 2. Reconstruction plate and restoration of bone volume using rhBMP2, tricalcium phos-
phate, and demineralized bone.
mineral density owing to osteoclastic resorption and immune reaction because of ge-
netic differences.55–57 Synthetic grafts made of metals or polymers are not bioactive
because they do not bond to bone or support bone cell function. The formation of
discontinuous fibrous tissue at the interfaces with polymeric and metal implants has
been reported in preclinical and clinical studies.58–63 Several studies have shown
that excessive fibrous capsule formation at the bone–implant interface can prevent tis-
sue integration, and lead to bone resorption and fracture and implant failure.64–67 Cal-
cium phosphate ceramics such as hydroxyapatite and tricalcium phosphate are
bioactive because they are able to enhance bone cell function and tissue formation.
Nevertheless, a main concern in the application of hydroxyapatite bone grafts is the
poor resorption. Several studies have reported fibrous encapsulation around hydroxy-
apatite ceramic particles inside alveolar bone.68–70 These limitations create a signifi-
cant need for improvements in bone graft technology.
Tissue engineering approaches for bone reconstruction use porous implant mate-
rials, like calcium phosphate ceramics, as a carrier for bone cells and/or osteoinduc-
tive molecules. MSCs have been widely studied for bone tissue engineering because
they are able to differentiate to bone-forming cells (osteoblasts) and participate in frac-
ture healing. Animal models have indicated that harvesting cells from bone marrow
and delivering high numbers of cells into a graft site is inadequate to ensure appro-
priate healing and bon regenration.71 Ideally, a bioactive ceramic carrier releases
ions that signal the stem cells and induce their osteogenic differentiation. Culturing
bone marrow MSCs onto osteoconductive or osteoinductive carrier matrix until they
attach, spread, differentiate, and/or generate a specific amount of extracellular matrix
in vitro before implantation has resulted in a significant improvement in outcomes.72,73
The repair of a critical-sized femoral segmental defect using MSCs was accomplished
without adverse immune responses and without the use of immunosuppressive ther-
apy.74 Other studies have shown the feasibility of treating children with osteogenesis
imperfecta using isolated allogeneic bone marrow-derived mesenchymal cells without
significant toxicity.75–78
The successful use of stem cells in bone reconstruction depends on the use of a
suitable carrier. In a comparative study, the bone healing effect of MSCs seeded on
2 matrices, bovine bone hydroxyapatite and a-tricalcium phosphate, was compared

with that of an autologous bone transfer.79 Histomorphometric analyses showed
that the bone volume in defects treated with tricalcium phosphate seeded with mesen-
chymal cells was comparable with that of defects treated with autogenous bone.
However, although defects treated with autogenous bone showed uniform platforms
of bone formation, bone formation in defects treated with tricalcium phosphate was
associated with the ceramic particles. Defects treated with bovine bone hydroxyapa-
tite (Bio-Oss) seeded with or without mesenchymal cells scored the lowest value of
bone formation and highest value of fibrosis around the ceramic particles.
Human adipose-derived stem cells showed the ability to expand in vitro and to differ-
entiate into osteogenic, chondrogenic, adipogenic, and myogenic mesenchymal cell
lineage, in addition to others.77 Adipose-derived stem cells are more favorable for
bone regeneration than other multipotent stem cells such as bone marrow MSCs owing
to the relative ease of collection, abundance, high proliferation, and fast robust miner-
alization.80 The ability of silica-calcium phosphate composite (SCPC) scaffold seeded
with human adipose-derived stem cells to regenerate bone in a critical size canine cal-
varial defect was evaluated (Ahmed El-Ghannam, Unpublished data, 2019). Bone tissue
regeneration and graft material resorption was evaluated ay 3 and 6 months postoper-
ative using computed tomography scanning and histology. Calvarial defects grafted
with SCPC alone or SCPC-cell construct were grossly repaired, whereas a control
ungrafted defect did not repair. Microscopically, the newly formed bone in the grafted
defects was compact and integrated with the surrounding host tissues. Histomorpho-
metric analysis demonstrated higher bone surface area and near complete graft mate-
rial resorption in defects grafted with SCPC-cell hybrid compared with SCPC alone.
Resorption of the graft material takes place by 2 mechanisms, solution mediated or
cell mediated. These 2 mechanisms are intertwined; the dissolution of ions from bioac-
tive ceramic into tissue fluids stimulates bone cell function and tissue formation.
The enhanced resorbability of SCPC preseeded with differentiated osteoblasts points
to the significant role played by these cells in the resorption of the graft material.
Vascularization of the newly formed bone is essential for tissue viability and func-
tionality. The composition and porosity of the bone graft can facilitate vascularization
and perfect the quality of the bone. Silicon ion release from the bioactive ceramic fa-
cilitates endothelization. Histologic analysis done on critical size saddle-type bone de-
fects grafted with SCPC were noticeably vascularized.81 In addition, in vivo and in vitro
studies showed that silica plays an important role in bone cell differentiation and
mineralized tissue formation.82–86 A systematic increase of silica in calcium phosphate
ceramic showed a significant increase in alkaline phosphatase activity and collage-
nous protein synthesis.87 Other studies have showed that silica plays important role
in the synthesis and stabilization of collagen I.88 Calcium ions facilitate osteogenic
gene expression and many cell functions, including mineralization of the collagenous
bone matrix. Mineralization of the collagenous matrix is further enhanced by the alka-
line pH created when the bioactive ceramic releases sodium ions into the surrounding
tissue fluids.89
The efficacy of MSCs matrix graft in promoting healing is attributed to multiple
mechanisms including osteoconduction, osteoinduction, and osteogenesis. The 3D
porous scaffold provides guided bone growth in 3 dimensions, similar to natural
bone. In addition, protein adsorption and surface characteristics enhance cell adhe-
sion and osteoblastic differentiation. The high number of differentiated cells pre-
seeded on the porous matrix provides more bone-forming cells necessary to
expedite abundant bone formation. Nevertheless, barriers to the application of this
bone engineering technology in bone grafting is related to the absence of a therapeutic
strategy for the sterilization, packaging, and preservation of an MSC matrix hybrid to
make it readily available for grafting applications. Culture and expansion of cells
in vitro before seeding on the matrix is a lengthy process with complicated logistics;
therefore, it presents operational hurdles at the clinical stage.90,91 Moreover, the con-
centration of osteogenic cells from fresh bone marrow by selective adhesion is recom-
mended to eliminate the remnant of the animal protein added to the tissue culture
medium during cell expansion.91,92 Cryopreservation has been used for the long-
term storage of MSCs, enabling cells to be expanded in culture when needed, with
full retention of functionality after thawing.92,93 These studies clearly indicate that
seeding porous biomaterial matrix with cryopreserved MSCs and using the MSC ma-
trix construct as a bone graft is a promising approach that can enable enhanced bone
reconstruction. Therefore, cryopreservation and storage of cell material constructs
can maintain the osteogenic activities of stem cells and provide a strategy for unlim-
ited supply of off-the-shelf tissue engineered bone graft for immediate use in cranio-
facial and maxillofacial surgeries.
SUMMARY AND FUTURE DIRECTIONS
Current soft and hard tissue engineering advancements, as discussed in this article,
involve enhancements of the graft, that is, increased vascularization, the addition of
stem cells for cellular proliferation, bone graft composite ratios, or improvements to
the donor site (via scaffolds).Future directions include inducing human MSCs to pro-
liferate into either soft or hard tissues via selective microRNA expression from mecha-
notransduction.94 Nanotechnology presents exciting potential through developments
in electrospun poly-L-lactic nanofiber meshes for stem cell culturing as well as nano-
fiber yarns that provide strong 3D scaffolds for interwoven cell lines.95,96
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deficiency around an implant-supported restoration in the esthetic zone: modified
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8. Menceva Z, Dimitrovski O, Popovska M, et al. Free gingival graft versus mucog-
raft: histological evaluation. Open Access Maced J Med Sci 2018;6(4):675–9.
9. Weinreb M, Nemcovsky CE. In vitro models for evaluation of periodontal wound
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surgical wound healing. Head Neck 2018;40(2):394–401.
R e s o r b a b l e Ver s u s
N o n re s o r b a b l e M e m b r a n e s
When and Why?
Noel Ye Naung, BDS, Higher Grad Dip Clin Sc (OMFS), MSc (OMFS), FIAOMSa,*,
Ehab Shehata, DDS, MD, MSc (GS), PhDa,b, Joseph E. Van Sickels, DDSa
KEYWORDS
! Resorbable membrane ! Nonresorbable membrane ! Guided tissue regeneration
! Guided bone regeneration ! Barrier membrane
KEY POINTS
! Guided tissue engineering has been proved successful for alveolar ridge augmentation,
maxillary sinus implant site development, periodontal furcation defects, and treatment
of intrabony pockets and socket preservation.
! Numerous factors play a role in the success of guided bone regeneration, such as the
choice of resorbable or nonresorbable membranes and the timing of membrane removal.
! The type of membrane chosen depends on the requirements needed for space creation.
! Nonresorbable membranes are required at load-bearing regions, such as in vertical ridge
augmentation.
! Resorbable membranes are recommended to be used in non–load-bearing regions, such
as in maxillary sinus augmentation.
INTRODUCTION
It is difficult to study resorbable versus nonresorbable membranes because the use of

these 2 types of membrane are intimately tied to the site of augmentation and the ma-
terial used. Aghaloo and Moy,1 in their 2007 meta-analysis of literature on hard-tissue
augmentation techniques, noted that implant survival rate was the highest for guided
bone regenerations (95.5%) versus the other techniques used.
The use of guided membranes in an attempt to improve the quality of bone grafting
is not a new concept. In 1957, Murray and colleagues2 demonstrated new bone
Disclosure Statement: The authors have nothing to disclose.

a
Division of Oral and Maxillofacial Surgery, Chandler Medical Center, College of Dentistry,
University of Kentucky, D508, 800 Rose Street, Lexington, KY 40536-0297, USA; b Maxillofacial
and Plastic surgery department, College of Dentistry, Alexandria University, Champilion street,
Al-Azarita, Egypt
E-mail address: noel.naung@uky.edu
Dent Clin N Am 63 (2019) 419–431

420 Naung et al
growth in dog femur, ileum, and spinal column using a plastic fenestrated cage as a
barrier to soft-tissue invasion. Recognizing potential benefits of guided bone regener-
ation (GBR) in dentistry, in 1960 Linghorne3 presented the sequence of osteogenesis
events, which he described as “pathologic and physiologic phases,” after bridging a
15-mm ostectomy site in dog fibula. In 1969, Richter and Boyne4 published a paper
on new concepts in facial bone healing and grafting procedures, in which they pre-
sented the use of hematopoietic bone marrow placed in a vitallium meshwork lined
with a Millipore filter to stabilize and discourage the ingrowth of fibrous tissue.
In the intervening period, the evolution of these bone-volume growth techniques has
improved. According to Jimenez Garcia and colleagues,5 the use of a membrane tech-
nique prevents the migration of fibroblasts and soft connective tissue cells into
the intended regeneration site. In 1996, Hermann and Buser6 discussed the critical
surgical factors for adequate and predictable regeneration: use of an appropriate
membrane, attaining primary soft-tissue healing, creation and maintenance of a
membrane-protected space, close adaptation and stabilization of the membrane to
the surrounding bone, and sufficient length of healing period. In 2006 Wang and Boy-
apati7 published the PASS principles: primary wound closure without tension to
enable proper healing by means of first intention and reduction of the risk of mem-
brane exposure, angiogenesis to promote blood supply, space maintenance to create
a bed for the undifferentiated mesenchymal cells, and clot stability to allow for the
proper development of these cells.
CONCEPTS OF GUIDED TISSUE MEMBRANES AND IDEAL PROPERTIES
Current concepts to increase the outcome of successful bone regeneration are built
on those already discussed and are broken down into ideal properties anticipated
from the barrier membranes.8–10
Biocompatibility: the membrane should not trigger host immune response, sensiti-
zation, or chronic inflammatory reaction and not adversely affect healing.
Space creation and maintenance: the membrane should have adequate toughness
to create and maintain space to allow the ingrowth of nearby osteoblasts to regenerate
bone, and have adequate strength to withstand the pressures from nearby muscles of
mastication and the tongue.
Occlusivity and selective permeability: the membrane should prevent unwanted
cells such as epithelial cells, fibrous tissue, or granulation tissue from entering into
the intended bone-healing space, while permitting nearby osteoprogenitors, osteo-
blasts, and cells responsible for neovascularization as well as facilitating diffusion of
the growth factors, signaling molecules, nutrients, and bioactive substances.
Tissue integration: membrane should fully integrate with the host tissue to provide
structural integrity and provide mucosal support and stability. It should also have a
sufficient adaptability between the bone-membrane border by sealing off the cavity,
preventing fibrous tissue infiltration and encapsulation of the membrane.
Clinical manageability: the membrane should be easy to handle and should maintain
its shape and position for easy placement.
TYPES OF MEMBRANES: ADVANTAGES AND DISADVANTAGES
Various materials have been used to fabricate GBR membranes over the last decades.
The types of membrane can vary widely from titanium mesh that is very rigid to mem-
branes that are very flexible, and which may be bioresorbable or might require a sec-
ond surgery to remove it at a later stage.11
Resorbable Versus Nonresorbable Membranes 421
Nonresorbable Membranes
Cellulose acetate (Millipore) was the first material used to keep gingival connective tis-
sue away from the root surface and allow periodontal regeneration.12 Commercially
available nonresorbable guided tissue regeneration (GTR) membranes for periodontal
regeneration and GBR membranes for alveolar bone regeneration are expanded poly-
tetrafluoroethylene (e-PTFE) and high-density PTFE (d-PTFE), both of which are avail-
able with or without titanium reinforcement.13–16
Numerous studies have shown positive results with the use of e-PTFE membranes,
widely known as Gore-tex (W.L. Gore & Associates, Flagstaff, AZ, USA).17–20 How-
ever, premature exposure of e-PTFE membranes is relatively common and is reported
to be around 30% to 40%. Membrane exposure may lead to infection and lack of new
bone formation as a result of fibrous tissue ingrowth.21 Primary closure is necessary
over e-PTFE membranes, which can be challenging in larger defects.22 Another disad-
vantage of nonresorbable membranes is the need for additional surgery to remove the
membrane, increasing the risk of exposing newly regenerated bone to bacteria.
Timing of membrane removal is also important because early removal can lead to
resorption of regenerated bone, whereas late removal can increase the risks of bac-
terial contamination and infection.23
The e-PTFE membrane has been replaced with d-PTFE, marketed as Cytoplast bar-
rier membranes (Osteogenic Biomedical, Lubbock, TX, USA). This membrane has high
density and smaller pore size (0.2 mm), preventing bacterial infiltration and leading to
lower risks of infection when exposed. In addition, primary closure over the membrane
is not necessary.22,24 In a randomized controlled trial, no difference was detected in
the mean vertical bone defect fill after 6 months with either e-PTFE and d-PTFE mem-
brane; however, d-PTFE membrane was easier to remove than e-PTFE.25
Titanium mesh (eg, Ti-Micromesh; ACE, Brockton, MA, USA) is also commercially
available as nonresorbable GBR membrane. Various studies have demonstrated
that titanium mesh membranes have sufficient strength and toughness to provide
space maintenance and prevent contour collapse from mucosal compression
because of its elasticity.26 In addition, they are less susceptible to bacterial contami-
nation secondary to its smooth surface.27 However, stiffness of the material and sharp
edges caused by trimming and contouring can cause mucosal irritation and are asso-
ciated with higher risk of membrane exposure.27–29 In addition, the removal of titanium
mesh can be challenging. In a randomized clinical treatment trial of atrophic alveolar
bone in the posterior mandible, similar vertical bone gain and implant stability was
achieved by using either titanium mesh or d-PTFE membrane.30
Resorbable Membranes
Requirement for a second surgical procedure to remove a barrier membrane is the major
disadvantage of nonresorbable membranes. Since the early 1990s, bioresorbable mem-
branes have been successfully used clinically.31–33 Resorbable membranes are available
as natural and synthetic membranes. Natural membranes are manufactured using
bovine or porcine collagen or chitosan.34,35 Commercially available synthetic mem-
branes are made up of organic aliphatic polymers such as polyglycolic acid or polylactic
acid, and their modifications. These include poly-DL-lactic acid, polylactic-glycolic acid,
polyglycolic acid-trimethylene carbonate, poly-LD-lactic-glycolic acid-trimethylene car-
bonate, and poly-DL-caprolactone.23
Collagen has the ability to attract and activate gingival fibroblast cells and stimulate
fibroblast DNA synthesis.31,34,36 Biocompatible type 1 and type 3 collagen mem-
branes are commercially available with varying rates of resorption ranging from
422 Naung et al
0.5 month (CollaPlug; Zimmer Biomet, Warsaw, IN, USA) up to 10 months (Mem-Lok
RCM; BioHorizons, Birmingham, AL, USA).23 Chitosan is biodegradable and biocom-
patible, and possesses antimicrobial and osteoinductive properties.35 Synthetic mem-
branes have advantages of biocompatibility and complete hydrolysis as well as
removal by proteolytic enzymes from the body.23,37 These membranes are resorbed
by the body with variable resorption time from 1.5 to 24 months depending on the
type and properties of the materials.23,37
More recently, resorbable allograft membranes derived from natural biological ma-
terials such as human placental amnion chorion tissue (BioXclude; Snoasis Medical,
Golden, CO, USA), human pericardium (Mem-Lok Pericardium; BioHorizons), human
fascia lata (Fascia Lata Tissuenet; TissueNet, Orlando, FL, USA), and human fascia
temporalis (Tutoplast Fascia Temporalis; Biodynamics International, Milwaukee, WI,
USA) has become commercially available. As processed biological materials, they
carry minimal risk of inflammatory or foreign body reactions. In a study comparing
different types of membranes on New Zealand white rabbits, fascia lata, pericardium,
and e-PTFE membranes showed significantly better bone regeneration than fascia
temporalis.38
Because resorbable membranes do not require secondary surgery for their removal,
there is a reduced risk of infection and less tissue damage. As such, there is decreased
pain and discomfort, along with decreased costs associated with a second sur-
gery.26,39 However, the timing and degree of resorption of the membrane can be un-
predictable.40 Premature resorption can lead to gradual loss of strength, membrane
collapse, and loss of the ability to maintain space. Loss of strength can decrease
bone regeneration, allowing fibrous tissue ingrowth, and prolonged or incomplete
resorption can be associated with membrane exposure, inflammation, and bacterial
contamination. These disorders can jeopardize the healing of the newly formed
bone. In general, as resorbable membranes are not as stiff as nonresorbable mem-
branes they do not allow tenting of the tissues.
STUDIES COMPARING RESORBABLE AND NONRESORBABLE MEMBRANES
There are multiple comparative studies of resorbable versus nonresorbable mem-

branes, each with its strengths and weaknesses. To facilitate the understanding of
the topic, this section focuses firstly on a systematic review and meta-analysis and
secondly on clinical trials that address GBR in different sites.
Systematic Review and Meta-Analysis

Lim and colleagues41 retrospectively reviewed and performed a meta-analysis of 21
qualitative and 15 qualitative clinical trials to compare the wound-healing complica-
tions among resorbable and nonresorbable membranes, and found no statistically sig-
nificant difference between the types of membrane used.
Clinical Trials
Class II furcation defects
A substantial number of comparative studies of resorbable and nonresorbable mem-
branes exists regarding the treatment of class II furcation defects. Coffesse and col-
leagues42 (1997), Scott and colleagues (1997)43, Eickholz and colleagues44 (1997), and
Karapataki and colleagues45 (1999) found no significant difference in probing depth
reduction, clinical attachment gain, and vertical and horizontal bone fill between
groups. Both resorbable membrane groups and nonresorbable membrane groups
showed significant clinical and radiographic improvements. In a randomized
multicenter study of 38 patients conducted in 1995, Hugoson and colleagues46 found

a statistically significant improvement in clinical attachment level in both horizontal
and vertical direction in the resorbable membrane group. The nonresorbable mem-
brane group showed improvement in clinical attachment in the vertical direction
only. Gingival recession was significantly higher in the nonresorbable membrane
group compared with resorbable membranes. In a long-term study in 2006, Eickholz
and colleagues47 found that treatment of class II furcation defects demonstrated sta-
ble horizontal attachment gain after 10 years with no statistically significant difference
among the types of membrane used.
Class III furcation defects

Class III through-and-through furcation defects respond poorly to GTR techniques. No
significant gain in pocket depth or vertical probing attachment levels were observed in
both type of barrier membranes when used in class III furcations.48
Intrabony periodontal defects

Multiple clinical trials conducted to compare absorbable and nonresorbable barrier
membranes in the treatment of intrabony periodontal defects failed to show statisti-
cally significant differences in probing depth reduction, clinical attachment level
gain, and bone fill.44,49–52 In a 10-year follow-up study on treatment of intrabony de-
fects conducted in 2008, Pretzl and colleagues53 found no statistically significant dif-
ference in the stability of vertical attachment gain between the 2 membranes groups
after GTR therapy.
Ridge preservation procedures

In 2012, Arbab and colleagues54 found no statistically significant differences in hor-
izontal and vertical ridge dimension changes between the use of resorbable and
nonresorbable membrane for ridge preservation. In addition, the viable bone gain
in the extraction sockets was histologically found to be the same for both mem-
brane groups. The investigators concluded that the choice of barrier membrane
has no effect on the outcome of the ridge preservation both clinically and
histologically.
Implant site development

In a 2014 double-blind randomized clinical trial, Merli and colleagues55 compared the
efficacy of resorbable and nonresorbable barriers for vertical ridge augmentation pro-
cedure with simultaneous implant placement, and found no significant differences in
radiographic vertical bone gain at the 6-year follow-up visit.
Maxillary sinus augmentation

A study comparing the use of resorbable versus nonresorbable barrier membranes
for maxillary sinus augmentation revealed uneventful healing and successful
closure of the lateral sinus walls. At the microscopic level, higher amount of fibrous
connective tissue ingrowth was observed in the bone samples obtained from the
resorbable membrane group; however, the difference did not affect the clinical
outcome.56
Peri-implant bony defects

Randomized controlled trials comparing the efficacy of resorbable and nonresorbable
membrane in the treatment of bony defects around endosseous dental implants
revealed no statistically significant difference in clinical parameters between the 2
membrane types. Both membranes were proved to be successful when used in com-
bination with particulate bone grafts.57,58
424 Naung et al
CRITERIA FOR MEMBRANE SELECTION
In routine practice, the type of membrane used will vary with the choice of grafting ma-
terial and the nature of the bony defect. When a cortical or corticocancellous block
graft is used, the graft material will act as a tenting device; therefore, the use of resorb-
able membrane is recommended (Fig. 1), whereby a large anterior defect was recon-
structed with a combination of cortical and cancellous grafts augmented with a bone
morphogenetic protein (BMP) sponge and a resorbable membrane. Extensive under-
mining of mucosa of the lip was done before placement of the grafts. The cortical
grafts and autogenous marrow were obtained from the patient’s hip. The cortical
grafts were held in place with titanium screws that act as their own tenting of the graft
site. The space was created and maintained by the cortical blocks stabilized by the
titanium screws. The membrane was occlusive and did not need to be rigid, as the
grafting provided this aspect of GBR. With the necessary undermining to provide a
tension-free closure, the anterior vestibule was eliminated. At a secondary stage after
implants were placed, a maxillary vestibuloplasty was performed.
Likewise, with a sinus lifts the authors prefer a resorbable GBR because there is no
pressure on the graft after it is placed. In Fig. 2 the patient has a long-standing defect
from the loss of the upper first molar and second bicuspid. The maxillary sinus is
approached from a standard lateral window technique. Once the maxillary membrane
has been lifted and inspected for perforations, the sinus is lifted and a resorbable
membrane is placed, creating a space for the bone graft. In this case, demineralized
bone was packed against the maxillary floor and the membrane. A second membrane
was placed on the labial to provide an occlusive barrier laterally, and the flap was
closed.
Fig. 1. Augmentation of maxillary anterior region in preparation for implant placement us-
ing resorbable membrane. (A) Cortical grafts stabilized with titanium screws. (B) Cancellous
graft with autogenous marrow segment with autogenous marrow. (C) Resorbable mem-
brane placed over collagen sponge membrane with BMP-2, both placed before closure of
the wound.
Fig. 2. Maxillary sinus augmentation using resorbable membrane. (A) Exposure of bone
defect in the first M second bicuspid region. (B) Window developed, sinus lifted, and sinus
membrane visible above elevator. (C) Resorbable membrane about to be placed against the
sinus membrane. (D) Sinus packed, surgical site just before placement of a second resorbable
membrane on the labial surface.
For ridge augmentation when there is adequate interocclusal space, a nonresorb-

able membrane is preferred. Types will vary from a titanium-reinforced mesh, to a plain
titanium mesh, to a d-PTFE membrane that is tented. In Fig. 3 there is a horizontal
defect on the posterior mandibular ridge that was addressed with a nonresorbable
membrane with tenting. Because of the defect and its location, it was necessary to
have a more rigid membrane system to create space while providing an occlusive
cover. The flap was elevated and undermined, anticipating the volume of bone needed
to reconstruct the ridge. The postoperative panorex illustrates the tenting provided by
a tenting screw and the tacking down of the edges of the membrane. Two implants
were placed in the bone-grafting site and a third implant anterior to the site. The peri-
apical film was obtained 1.5 years later and illustrates the excellent bone fill that
occurred around the 2 posterior implants.
The authors consider it important to emphasize that when performing a ridge
augmentation, preparation of the bed is critical. In the authors’ experience, the flaps
must be adequately mobilized before placement of the graft material. Failure to
achieve a tension-free closure almost always results in exposure of the membrane
and loss of the graft. In some cases, as in the first one, extensive undermining will
result in loss of the vestibule, necessitating a secondary vestibuloplasty. In others,
as in the last case, the loss of vestibule is minimal and will not require a secondary
procedure.
Failure to achieve a tension-free closure, especially when a nonresorbable mem-
brane is being used, will often result in early membrane exposure. The time when a
membrane becomes exposed is important. If the membrane is exposed early—for
example, in the first few weeks after the surgical intervention—antibiotics and chlor-
hexidine may help but the membrane will have to be removed. It is the authors’ expe-
rience that when this occurs the results of the augmentation are likely to be very poor.
426 Naung et al
Fig. 3. Vertical ridge augmentation of the posterior mandibular alveolar ridge using
nonresorbable membrane. (A) Horizontal defect mandible site developed. (B) Placement
of demineralized bone and a nonresorbable membrane secured with tenting screw. (C) Post-
operative panorex of grafted site. (D) Impacts placed and restored 1 year 6 months later.
When the exposure is late—for example, after a month or two—antibiotic use and
chlorhexidine use will be required along with removal of the membrane. When expo-
sures occur late in the course of treatment, there will usually be some success with the
augmentation (Table 1).
Table 1
Criteria for the choice of membranes
Treatment Resorbable Membrane Nonresorbable Membrane

Sinus graft Underneath schneiderian Not recommended
membrane and over the
lateral window osteotomy
GTR (periodontal defects) If particulate bone is used Not generally recommended,
May be used if no particulate
bone is used
Ridge preservation U U
Alveolar ridge augmentation
Monocortical block If autogenous bone graft is Large bone defects
used If allograft is used
Vertical augmentation with
bone blocks
GBR Horizontal ridge Horizontal ridge
augmentation augmentation if only
! If xenograft or combination autograft or allograft is used
of allograft and xenograft is Vertical ridge augmentation
used
Ridge split U 7
Biologics (growth factors) With particulate bone graft Without particulate bone graft
SUMMARY
The use of guided membranes in an attempt to improve the quality of bone grafting
is not a new concept. However, the evolution of these bone-volume growth
techniques has improved and most likely will continue to improve with time.5 In
routine daily practice, both types of membranes will be used depending
on the needs of the case. Whether a nonresorbable or a resorbable membrane
is used, it should be biocompatible, allow selective permeability with good
tissue integration, and have satisfactory handling properties. Surgical techniques
to attain primary soft-tissue healing, the creation and maintenance of a
membrane-protected space with close adaptation and stabilization of the mem-
brane to the surrounding bone, and sufficient length of healing period are very
important.6
Commercially available nonresorbable GTR membranes comprise e-PTFE and
d-PTFE, both of which are available with or without titanium reinforcement.13–16 In
addition to titanium mesh membranes, these have sufficient strength and toughness
to provide space maintenance and prevent contour collapse while preventing mucosal
compression caused by its elasticity.26 The authors’ preference is to use such mem-
branes when vertical augmentation is needed. The biggest disadvantages of nonre-
sorbable membranes are early exposure, infection, and loss of graft material. Gor-
tex (e-PTFE) has a 30% to 40% risk of exposure with subsequent infection and sup-
puration. d-PTFE, marketed as Cytoplast barrier membranes, has high density and
smaller pore size (0.2 mm), eliminating bacterial infiltration, and poses a lower risk of
infection when exposed. Currently the authors use d-PTFE when we nonresorbable
membrane is required.
There are numerous resorbable membranes available as natural and synthetic
membranes. Natural membranes are manufactured using bovine or porcine
collagen or chitosan. Resorbable allograft membranes derived from natural bio-
logics are currently available. Synthetic membranes are made of organic aliphatic
polymers (polyglycolide or polylactide) and are commercially available.26 The
biggest advantage of resorbable membranes is that they do not require secondary
surgery and usually have less tissue damage with less pain and discomfort. How-
ever, the timing and degree of membrane resorption are unpredictable. Premature
resorption can lead to loss of membrane strength and space collapse. Resorbable
membranes are preferred in the authors’ practice when the graft material will func-
tion to maintain the space (eg, corticocancellous bone graft), when there is no pres-
sure on the graft after its placement (eg, as in sinus lift procedures), or when
occlusion is needed, as in socket preservation. It is clear that one type of mem-
brane will not fit all clinical needs, and further work on this valuable clinical tool
is warranted.
REFERENCES
1. Aghaloo TL, Moy PK. Which hard tissue augmentation techniques are the most
successful in furnishing bony support for implant placement? Int J Oral Maxillofac
Implants 2007;22(Suppl):49–70.
2. Murray G, Holden R, Roschlau W. Experimental and clinical study of new growth
of bone in a cavity. Am J Surg 1957;93(3):385–7.
3. Linghorne WJ. The sequence of events in osteogenesis as studied in polyeth-
ylene tubes. Ann N Y Acad Sci 1960;85:445–60.
4. Richter HE, Boyne PJ. New concepts in facial bone healing and grafting proced-
ures. J Oral Surg 1969;27(7):557–9.
Dent Clin N Am 52 (2008) 111–128
Biophosphonate-Related Osteonecrosis
of the Jaws
Salvatore L. Ruggiero, DMD, MDa,b,*,
Sook-Bin Woo, DMD, MMScc,d
a
Department of Oral and Maxillofacial Surgery, Stony Brook School of Dental Medicine,
Stony Brook, NY, USA
b
New York Center of Orthognathic and Maxillofacial Surgery,
2001 Marcus Avenue, Lake Success, NY 11042, USA
c
Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital,
75 Francis Street, Boston, MA 02115, USA
d
Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
In 2003 and 2004, the first reports of patients who developed necrosis of
the jawbones while taking bisphosphonates appeared in the literature; most
patients were on this drug for treatment of cancer and some for osteoporosis
[1–3]. Since then, more than 500 cases have been identified and the number
of these cases continues to grow. This article reviews the action of bi-
sphosphonates, the condition called bisphosphonate-associated osteonecrosis
of the jaws, strategies to minimize occurrence, and treatment of this
condition.
Nomenclature
A universally accepted term for this new condition has not been estab-
lished, which has caused some degree of confusion. This complication has
been referred to in the literature as BRONJ (bisphosphonate-related osteo-
necrosis of the jaw), BRON (bisphosphonate-related osteonecrosis), BON
(bisphosphonate osteonecrosis), BAONJ (bisphosphonate-associated osteo-
necrosis of the jaw), and simply ONJ (osteonecrosis of the jaw). Based on
the clear association between bisphosphonate therapy and jaw necrosis
that has been established in numerous retrospective studies, the American
Association of Oral and Maxillofacial Surgeons (AAOMS) has decided to
* Corresponding author. New York Center of Orthognathic and Maxillofacial Surgery,

2001 Marcus Avenue, Lake Success, NY 11042.
E-mail address: drruggiero@nycoms.com (S.L. Ruggiero).
0011-8532/08/$ - see front matter ! 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cden.2007.09.002 dental.theclinics.com
112 RUGGIERO & WOO
adopt the term BRONJ for this entity [4], and this term will be used
throughout this article.
Action of bisphosphonates
The actions and pharmacology of bisphosphonates have been well re-
viewed and only a summary is offered here [5–7]. Bisphosphonates are ana-
logs of inorganic pyrophosphates. Pyrophosphates are well-known in
dentistry, because they are a component of tartar-control toothpaste and in-
hibit calcium precipitation [8]. Unlike pyrophosphates, bisphosphonates
contain a carbon rather than oxygen molecule. This P-C-P structure allows
the molecule to bind to the hydroxyapatite crystals with high affinity, while
the presence of nitrogen in one of the side chains confers markedly increased
potency to the drug (Fig. 1). The early forms of bisphosphonate, such as
etidronate and clodronate, do not contain nitrogen and therefore are less
potent; they are available only in the oral preparation. The later forms of
bisphosphonates contain nitrogen and some are available as intravenous
preparations, making them much more bioavailable (Table 1). Pamidronate
and alendronate contain nitrogen in an alkyl chain and are 10 to 100 times
more potent than etidronate and clodronate. The most potent of the bi-
sphosphonates (such as zoledronic acid and risedronate) contain nitrogen
within a heterocyclic ring. The half-life of bisphosphonates is approximately
10 years, and therefore prolonged use of this drug causes substantial drug
accumulation within the skeleton. The drug is tightly bound to the apatite
crystals until it is released during osteoclastic-mediated bone resorption.
Antiresorptive activity
One of the most important and powerful effects of bisphosphonates is
inhibition of osteoclastic activity, and herein lies one of its most important
applications in clinical practice, both for managing osteoporosis and cancers
in the skeletal system. When bone resorption occurs, bisphosphonates are
released from the hydroxyapatite crystal and are taken up by osteoclasts.
Metabolites of non-nitrogen containing bisphosphonates (such as etidronate
and clodronate) are cytotoxic to the osteoclasts and lead to their death. Ni-
trogen-containing bisphosphonates, however, act by way of the mevalonate
Fig. 1. Structure of pyrophosphate (left) and bisphosphonate (right). For bisphosphonates, R1

acts as a ‘‘bone hook’’ for attachment of the molecule to bone, whereas R2 determines potency.
OSTEONECROSIS OF THE JAWS 113
Table 1
Bisphosphonate medications and their relative potency
Generic name Brand name/delivery Manufacturer Indication RP
Clodronate Bonefos, PO Hoffman/ Not available in 50
LaRoche the United States
Pamidronate Aredia, IV Novartis Bone cancer 100
Alendronate Fosamax, PO Merck Osteoporosis 500–1000
sodium 1000
Risedronate Actonel, PO Proctor Osteoporosis 5000
& Gamble
Ibandronate Boniva, PO/IV Roche Osteoporosis 5000–10,000
Zoledronic acid Zometa, IV Novartis Bone cancera O10,000
Abbreviations: IV, intravenous; PO, per oral; RP, relative potency.
a
Intravenous zoledronic acid also has been approved for the treatment of osteoporosis
(4–5 mg dose, once per year).
pathway (for cholesterol synthesis), inhibiting protein prenylation, a process

essential for normal functioning of vital intracellular proteins, ultimately
leading to osteoclast apoptosis (programmed cell death) [7,9]. Bisphospho-
nates also inhibit differentiation of osteoclasts and stimulates osteoblasts
to produce osteoclast-inhibiting factor [10]. Therefore, the net result is re-
duced numbers of osteoclasts and reduced bone resorption. Because bone
resorption is coupled to osteoblastic bone formation for remodeling, bone
turnover (ie, resorption and deposition) becomes severely suppressed. How-
ever, the bone continues to mineralize and could become brittle and less
elastic. In one case report, bisphosphonate taken at high doses led to an
osteopetrotic-like state [11].
Tumoricidal activity
Many studies have shown that nitrogen-containing bisphosphonates also
reduce the activity of cancer cells and control metastases [9,10,12]. This pro-
cess may be related to inhibition of protein prenylation leading to disruption
of intracellular activity within the cancer cells [9]. However, the alteration of
the microenvironment itself, caused by reduced bone resorption alone, could
also account for control of metastases [13]. Bisphosphonates also reduce ad-
hesion, invasion, and viability of cancer cells and may activate gamma delta
T cells, which have tumoricidal activity [14].
Antiangiogenic activity
In vitro, zoledronic acid inhibits angiogenesis mediated through basic fi-
broblast growth factor and may induce apoptosis of endothelial cells [15].
Antiangiogenic activity may also occur through lowering circulating levels
of vascular endothelial growth factor and platelet-derived growth factor,
both of which are proangiogenic [16,17].
114 RUGGIERO & WOO
Clinical applications
Bisphosphonates are widely used in the management of four main condi-
tions: osteoporosis, Paget’s disease of bone, multiple myeloma, and cancers
that have metastasized to the bones. This article focuses only on the onco-
logic aspects of bisphosphonate use.
Multiple myeloma is a malignancy of plasma cells that primarily affects the
skeletal system. Patients develop multiple lytic bone lesions containing malig-
nant plasma cells, and as a result may develop skeletal-related events (SRE),
such as bone pain, fractures, necessity for surgery and radiation, and hyper-
calcemia. Patients also develop hypergammaglobulinemia from secretory ac-
tivity of these cells, which can lead to renal failure. Clinical trials show that
bisphosphonates significantly reduce these SREs, and pamidronate and zole-
dronic acid are widely used for treating multiple myeloma [18,19]. Other
agents for treating this disease include thalidomide, glucocorticoids such as
dexamethasone, and proteasome inhibitors such as bortezomib, usually in
combination [20,21]. These agents also have antiangiogenic properties.
Similar SREs are noted in patients who have metastatic cancers (with
metastatic breast and prostate cancers being the most common), and bi-
sphosphonates also have been shown to significantly reduce SREs in these
patients [22,23].
Early reports of bisphosphonate-associated osteonecrosis of the jaws

The earliest reports of bona fide cases of BRONJ occurred in 2003 [1–3],
and have been followed by many more case reports and large case series [24–
27]. All cases have occurred in the maxilla or mandible except for a single
case that occurred after ear surgery [28].
Etiopathogenesis
The exact mechanism for the development of BRONJ is unclear. The cur-
rent hypothesis focuses on severe suppression of bone turnover, coupled
with the unique conditions affecting the jaws and not other bones. These
conditions include the following: (1) the jaw bones are separated from the
oral environment from a very thin mucosa (only several mm thick for the
most part) and this barrier is readily breached even with simple physiologic
activities such as mastication, (2) the oral cavity is filled with bacteria and
the jaws are often involved in infection through either the periodontal liga-
ment or the pulp, (3) dentoalveolar surgery is a common procedure (eg, ex-
tractions, periodontal surgeries, apicoectomies) in which bone is exposed to
a bacteria-rich environment, and (4) the rate of turnover of the jawbones is
higher than that for the long bones [29].
One possible mechanism of action is that after a sufficient concentration
of bisphosphonates has accumulated, the jawbones become hypodynamic
and turn over at a low rate. When infection or surgery requires increased
bone turnover for healing, this does not occur. How the bone actually be-
comes necrotic and exposed is unclear at this time. However, there is a con-
dition that mimics BRONJ that occurs spontaneously, involves only a few
millimeters of necrotic bone that heals without incident, and occurs in
healthy adults. This benign sequestration of the lingual plate is a well-recog-
nized phenomenon and its putative mechanism of action is trauma to the
lingual periosteum, loss of vascular supply of bone supplied by that area
of periosteum, death of bone with sequestration, and healing [30]. The lin-
gual plate/mylohyoid area is also a common site for spontaneously occur-
ring BRONJ.
Risk factors for bisphosphonate-associated osteonecrosis of the jaws

Not all patients who use bisphosphonates develop BRONJ. The factors
that affect its development are:
1) The use of nitrogen-containing bisphosphonates, particularly zoledronic
acid [31]. Zoledronic acid used alone produced 9.5-fold and 4.5-fold
greater risk compared with pamidronate used alone or with zoledronic
acid, respectively [32]. However, BRONJ has been seen in a patient who
had myeloma who took only oral clodronate, a first-generation non–
nitrogen-containing bisphosphonate [33].
2) The cumulative dose of bisphosphonates. This factor also indirectly re-
lates to the patient’s underlying condition, because patients who have
cancer receive much higher doses of bisphosphonates than those who
have osteoporosis. For example, a patient who has osteoporosis who re-
quires intravenous bisphosphonate therapy receives 4 to 5 mg of zole-
dronic acid per year compared with a patient who has myeloma who
receives 4 mg of zoledronic acid every 4 weeks. The median time of ex-
posure to zoledronic acid with development of BRONJ ranged from 9 to
30 months and is significantly shorter compared with other bisphosph-
onate regimens [25,31,34,35]. However, the exposure can be as little as 3
months. The risk for developing BRONJ increases over time, with a cu-
mulative hazard of 1% within the first year of treatment with zoledronic
acid, and 15% at 4 years [31].
3) Dentoalveolar surgery. Approximately 60% of all cases are associated
with either tooth extraction or other surgery (eg, periodontal and apical
surgery and implant placement) [24,25,36]. However, tooth extractions
are the most common inciting factor [26]. One study showed that the
prevalence of BRONJ in patients who had cancer who did not undergo
extractions was 1% compared with 7% to 9% in those who did [35].
BRONJ has been reported in patients after surgical endodontic proce-
dures [37,38].
4) Trauma. Many cases occur on the lingual mandible (where the mucosa
is especially fragile) and on tori [25].
116 RUGGIERO & WOO
Other factors that may contribute to the development of ONJ, but for
which the evidence is less robust, include dental infections. By the time
BRONJ develops, it is difficult to determine if the infection caused BRONJ
or was merely a consequence of BRONJ.
Other factors, such as route of administration (intravenous preparations
are more frequently associated with BRONJ) and age, are indirectly related
to the factors noted earlier. For example, patients who have cancer affecting
the skeleton (usually older patients) typically are exposed to the more potent
bisphosphonates, such as zoledronic acid and pamidronate, both of which are
only available as intravenous preparations, and are used more frequently.
Whether the antiangiogenic activity of bisphosphonates plays an impor-
tant and direct role in BRONJ is unclear. Other comorbidities have not been
entirely elucidated, but include concomitant use of antiangiogenic agents
and vascular compromise. Thalidomide, which has antiangiogenic proper-
ties, has been shown to increase the risk 2.4-fold [32], although this has
been disputed [26]. One study showed that patients who had BRONJ were
more likely to have associated diabetes mellitus, although most patients al-
ready had diabetes when their cancer was diagnosed [39]. Another study
showed that patients who developed BRONJ had hyperparathyroidism
and mild hypocalcemia compared with controls [40].
Prevalence
The prevalence varies from 4% to 7% within any one center. Most of the
studies were performed through retrospective chart reviews or telephone
interviews [41,42].
Although most patients who developed BRONJ underwent dental extrac-
tions, the number of patients who had extractions or other dento-
alveolar surgery and did not develop BRONJ is unclear.
Diagnosis and clinical presentation of bisphosphonate-associated

osteonecrosis of the jaws
Standardization of diagnostic criteria for this new clinical entity is impor-
tant to facilitate future clinical and epidemiologic research and help distin-
guish BRONJ from other intraoral osteonecrotic conditions exhibiting
delayed healing. The AAOMS established a working definition for BRONJ
that is fairly concise and specific [4]. Patients may be considered to have
BRONJ if they have all of the following characteristics: (1) current or pre-
vious treatment with a bisphosphonate, (2) exposed, necrotic bone in the
maxillofacial region that has persisted for more than 8 weeks, and (3) no his-
tory of radiation therapy to the jaws. Patients who are considered at risk ac-
cording to the AAOMS criteria have no evidence of exposed or necrotic
bone but have been exposed to either intravenous or oral nitrogen-contain-
ing bisphosphonates for long periods.
The American Society for Bone and Mineral Research (ASBMR) has
also made recommendations for a provisional case definition for confirmed
and suspected cases of bisphosphonate associated osteonecrosis [43]. A con-
firmed case is identical to the AAOMS definition for BRONJ. A suspected
case fulfills all the criteria of a confirmed case, except that the necrotic
bone has been present for less than 8 weeks. Suspected cases should be fol-
lowed up to determine if they eventually meet the criteria of a confirmed
case.
Diagnosis of BRONJ is primarily based on patient history and clinical ex-
amination. Patients present with exposed, necrotic bone varying in size from
a few millimeters to several centimeters; only 60% of cases report pain, and
some cases may remain asymptomatic for weeks, months, or years
[3,24,25]. These lesions frequently become symptomatic when surrounding
tissues become inflamed or an infection develops. Signs and symptoms that
may occur before the development of clinically detectable BRONJ include
pain, tooth mobility, mucosal swelling, erythema, ulceration, and the devel-
opment of sinus tracts. These somewhat nonspecific signs and symptoms
are similar to those of banal odontogenic infections. Some patients may
also present with complaints of altered sensation or paresthesia in the affected
area as the neurovascular bundle becomes affected by inflammation or infec-
tion around the necrotic bone. Chronic maxillary sinusitis secondary to
BRONJ with or without an oral-antral fistula may be the presenting symptom
in patients who have maxillary bone involvement [3].
Lesions have been observed more commonly in the mandible than the
maxilla (2:1 ratio) [24], and more commonly in areas with thin mucosa over-
lying bony prominences, such as tori, bony exostoses, and the mylohyoid
ridge [3,25]. Most cases occur at the site of prior dentoalveolar surgery
(Fig. 2). However, exposed bone has also been reported in patients who
have no history of trauma or in edentulous regions of the jaw (Fig. 3).
The size of the affected area can be variable, and ranges from a nonhealing
Fig. 2. BRONJ after a tooth extraction.
118 RUGGIERO & WOO
Fig. 3. BRONJ in the mylohyoid area.
extraction site to exposure and necrosis of the entire jaw (Fig. 4). The area of
exposed bone may be surrounded by inflamed erythematous soft tissue.
When infected, purulent discharge may be seen at the site of the exposed
bone and intra- and extraoral fistulae (Fig. 5). The AAOMS has proposed
a clinical staging system based on the presence of symptoms and extent of
disease (Table 2) [4,44].
Radiographic findings
Conventional radiographs will not show a change until the bone is dem-
ineralized 30% to 50%. Therefore, and also partly because of the two-
dimensional nature of these films, panoramic and periapical radiographs
may not show significant changes in the early stages of osteonecrosis.
Fig. 4. Extensive BRONJ seen in this surgical specimen of the mandible.
Fig. 5. BRONJ associated with sinus tract of anterior maxilla.
However, some studies suggest that early bone changes include diffuse os-
teosclerosis, thickening or loss of lamina dura, and widening of the peri-
odontal ligament space (Fig. 6) [44]. Little or no ossification at a previous
extraction site after the conventional 6 months of healing is also an impor-
tant radiographic sign (Fig. 7). Early or late radiographic changes may
Table 2
Staging and management of bisphosphonate-associated osteonecrosis of the jaw
Stage Clinical presentation Management
At risk No exposed bone Patient education
1 Asymptomatic exposed bone with Patient education; antibacterial
little soft tissue inflammation rinsesa; careful follow-upb
2 Exposed bone with pain, and Patient education; antibacterial
usually with associated rinsesa; antibioticsc; superficial
surrounding soft tissue debridement of bone to dislodge
inflammation or infection loose fragments and smooth
rough contours; careful follow-
upb
3 Exposed bone with pain and Patient education; antibacterial
usually with associated soft rinsesa; antibioticsc; palliative
tissue inflammation or infection; surgery; careful follow-upb
may see osteolysis extending to
the inferior border of mandible
or pathologic fracture; may see
extraoral fistula
a
Such as 0.12% chlorhexidine digluconate.
b
Follow-ups for asymptomatic patients should occur every 2 to 3 months, and every 1 to 2
weeks until the acute symptoms have resolved for stage 2 and 3 disease.
c
Commonly used antibiotics include penicillin, amoxicillin, cephalexin, clindamycin, metro-
nidazole, or first-generation fluoroquinolones.
120 RUGGIERO & WOO
Fig. 6. Radiograph showing loss of lamina dura, widening of the periodontal ligament space,
and marked osteosclerosis.
mimic classic periapical pathology, osteomyelitis, or, in cancer patients,

raise the suspicion of primary (myeloma) or metastatic bone disease. If
a strong clinical suspicion exists of metastatic disease within the jaw, and
the diagnosis of this will alter clinical treatment decisions, a bone biopsy
should be considered. Otherwise, bone biopsies in patients who have been
exposed to intravenous bisphosphonate therapy should not be performed
given the potential for creating a nonhealing bone wound.
When extensive bone involvement is present, regions of mottled bone or
sequestra formation similar to that of diffuse osteomyelitis are noted. In
more advanced stages of BRONJ, the osteolytic changes can extend to the
inferior border of the mandible and may result in a pathologic fracture
(Fig. 8).
CT scans can provide more accurate three-dimensional information
about the extent of the necrosis and is often useful for planning surgical de-
bridement procedures [45]. However, this modality has not proved helpful
Fig. 7. Panoramic radiograph showing persistence of extraction sockets in right and left
mandible.
Fig. 8. Panoramic radiograph showing extensive involvement of the mandible with pathologic
fracture of anterior portion.
for early identification of BRONJ in asymptomatic individuals. MRI can

detect marrow edema, which may be an early sign of bone ischemia and ne-
crosis, such as is seen in avascular necrosis of the hip secondary to long-term
use of steroids. However, whether this modality is helpful for detecting early
lesions of BRONJ is unclear, although established lesions are detectable as
expected [45]. Technetium 99m sestamibi is not taken up in areas of BRONJ
[18], although fluorodeoxyglucose–positron emission tomography (FDG-
PET) integrated with CT may show focal uptake [46]. All imaging modali-
ties have proved helpful in determining the extent of the existing necrotic
process, especially in advanced lesions, but have not shown any efficacy in
assessing patients at risk for BRONJ. New avenues of research include
the use of dental cone tomography, which uses only approximately 10%
of the radiation of routine CT scans [47,48].
Histopathology and microbiology

Microscopic examination of debrided specimens of exposed bone typi-
cally will show necrotic bone with associated bacterial debris and granula-
tion tissue [26,49,50]. Microbial cultures from areas of exposed bone will
usually isolate normal oral microbes and are therefore not always helpful
[26]. However, when extensive soft tissue involvement is present, microbial
culture data may help define comorbid oral infections and facilitate the se-
lection of an appropriate antibiotic regimen.
The presence of actinomycetes in the culture and within biopsy specimens
must be interpreted with caution. The presence of actinomycetes alone does
not indicate a diagnosis of actinomycosis, because they are a common en-
dogenous pathogen in dental plaque. The diagnosis of actinomycosis is
made if actinomycotic organisms are present and associated with suppura-
tion within the necrotic bone fragments, and actinomycetes was cultured
from a sterile area within the bone and not from a swab of necrotic bone
exposed to the oral cavity. The presence of pain, suppuration, and/or drain-
ing sinus tracts together with both diagnostic criteria also helps to confirm
this diagnosis [51].
122 RUGGIERO & WOO
Differential diagnosis
Several other conditions may also lead to necrosis of the bone with seques-
tration. Odontogenic infections, left untreated, may result in osteomyelitis, al-
though this does not usually present with clinical exposure of the dead bone.
Postradiation osteonecrosis of the jaws is in many ways similar to
BRONJ and occurs after a patient has received high doses of radiation to
the jawbones, usually for the treatment of primary head and neck malignan-
cies. However, these conditions have a marked difference in presentation, in
that more than 95% of osteoradionecrosis occurs in the mandible, because
one of the primary mechanisms is reduced vascularity and sclerosis of ves-
sels as a result of the high doses of radiation. The mandible has a limited
blood supply compared with the maxilla (which is supplied by many collat-
eral vessels) and is therefore more frequently involved [52].
Benign sequestration of the lingual plate differs from BRONJ in that the
lesions are much smaller (usually several millimeters only), the patients are
young to middle-aged adults who have not been exposed to bisphospho-
nates, the lesions last only a few days before the piece of bone is either spon-
taneously exfoliated or removed by a dental care provider, and no sequelae
are present [30].
Necrotizing periodontitis is usually seen in patients who have suppressed
immune systems, particularly those who have HIV infection or severe mal-
nutrition [53,54]. It is caused by a polymicrobial infection of the periodon-
tium that cannot be adequately contained by the patient’s poor immune
function, leading to destruction and exposure of bone. This condition
may spread from the bone to involve the adjacent soft tissues, a condition
known as noma or necrotizing stomatitis. It is endemic within African
nations that have high rates of malnutrition. Herpes zoster infections of
the maxilla and mandible have been reported to lead to necrosis of the
soft tissues and underlying bone. The putative mechanism is one of vascular
compromise [55,56].
Management
The goal of management for patients at risk for developing BRONJ or
who have active disease is to preserve the quality of life through controlling
pain, managing infection, and preventing the development of new areas of
necrosis. The BRONJ treatment algorithms that have been published are ei-
ther a consensus of expert opinions or based on case series data [4,25,44,57].
These management strategies have varied according to the risk for develop-
ing BRONJ or the stage of disease.
Prevention strategies (oral bisphosphonate therapy)

Low-dose oral bisphosphonate therapy is primarily used for patients who
have osteoporosis, and is rarely used for treating myeloma or metastatic
carcinoma. The incidence of BRONJ in the osteoporosis population has

been cited as 1 in 100,000 patient years [58], although a more recent study
shows that it may be as high as 1 in 2260 to 8470 patients [35]. Patients
who have myeloma are often treated with clodronate (an oral non–nitro-
gen-containing bisphosphonate) in European countries [59]; clodronate is
not approved for human use in the United States but may be associated
with a lower incidence of BRONJ.
The risk is associated with cumulative dose/number of years of use. Dif-
ferent periods deemed ‘‘safe’’, such as 3 or 5 years, are based on anecdotal
data [4]. Patients should undergo routine dental care with regular radio-
graphic examinations, be educated about the risk for developing BRONJ,
and provide informed consent for surgical procedures.
Current evidence does not contraindicate the placement of dental im-
plants. However, the studies are small and do not include the longer periods
of bisphosphonate exposure [60].
Prevention strategies (intravenous bisphosphonate therapy)

For the most part, patients who have cancer undergoing bisphosphonate
therapy should be managed with preventive measures. The main emphasis is
to minimize the risk for occurrence of BRONJ, which translates into mini-
mizing the need for dentoalveolar surgery. Therefore, optimizing dental
health is the main objective in managing these patients. The best way to op-
timize dental health is to educate all patients about their risk for developing
BRONJ and evaluate each patient fully for odontogenic infections using full
mouth intraoral and panoramic radiographs. All carious teeth should be
identified and restored. All nonvital teeth should be either endodontically
treated or extracted, especially if they have not started bisphosphonate ther-
apy. If periapical lesions are present and require apical surgery, this proce-
dure should be weighed against an outright extraction. Discussion of the
risks and benefits of all surgical procedures, including periodontal surgery,
must be undertaken and this should be reflected on the consent form.
Patients should be followed until all surgical sites are completely healed.
Routine dental care, such as restorations and scaling, and prophylaxis
should be performed regularly and patients should be encouraged to keep
routine follow-up appointments and be educated on the importance of
maintaining excellent oral hygiene.
Staging and management of bisphosphonate-associated osteonecrosis

of the jaws
The clinical staging system was developed to more accurately categorize
patients who have BRONJ, direct rational treatment guidelines, and collect
data to assess the prognosis in patients who have used either intravenous or
oral bisphosphonates (Table 2) [4,44]. Data are being collected on how dif-
ferent management strategies related to staging correlate with outcome;
124 RUGGIERO & WOO
that is, resolution of lesions, progression of lesions, or occurrence of new

lesions.
Except for patients who have stage 3 disease who require surgical resec-
tions for palliation, surgical interventions may result in an increased area of
exposed bone [3]. Patients and clinicians must realize that a cure may not
always be possible. Nevertheless, some patients show complete resolution
of BRONJ with conservative therapy [61].
Patients who have established BRONJ are likely at risk for developing it
at another site, and therefore should be educated on the benefits of prophy-
lactic dental care and avoid dentoalveolar surgery, if possible. However,
extraction of nonvital or periodontally involved teeth embedded in necrotic
bone may be necessary.
Although hyperbaric oxygen (HBO) therapy had not been found to be
useful in earlier small case series, a more recent study found that HBO
used in combination with surgery after 6 months of discontinuation of bi-
sphosphonates led to complete resolution of BRONJ [27].
Resolution of BRONJ or clinical improvement after resection and topical
application of autologous platelet-rich plasma [62,63], Nd:Yag laser biosti-
mulation [64], or systemic administration of teriparatide, a form of synthetic
parathormone [65], has been documented. Prospective randomized studies
are required to accurately assess the efficacy of these treatments.
Should bisphosphonates be discontinued?

Bisphosphonates are very efficacious in controlling bone pain and reduc-
ing the incidence of SREs in patients who have myeloma and metastatic dis-
ease. Whether discontinuation of intravenous bisphosphonates offers any
short-term benefit in the management of BRONJ is unclear. However, if sys-
temic conditions permit, long-term discontinuation may be beneficial in sta-
bilizing established sites of BRONJ, reducing the risk for new areas of
BRONJ to develop, and reducing clinical symptoms [4].
The decision to discontinue bisphosphonate therapy should be made only
by the treating oncologist in consultation with the treating dental specialist,
because discontinuation puts the patient at risk for an SRE. The benefits of
therapy must be carefully weighed against risks for fracture, cancer progres-
sion, and hypercalcemia. At some institutions, the recommendation is to use
intravenous bisphosphonates in patients who have cancer for 2 years and to
discontinue the drug if the patient is experiencing remission or a stable state,
with the option to continue or restart therapy if disease worsens or symp-
toms progress [66,67].
Monitoring of patients
The more commonly used bone markers include bone specific alkaline
phosphatase, N-telopeptide cross-linked, or C-telopeptide cross-linked
(both markers of collagen breakdown or bone resorption). Others include
osteocalcin, pyridinoline and deoxypyridinoline. Many of these have been

studied in clinical trials for osteoporosis [68].
Although no controlled studies have shown that these markers for bone
turnover are useful for monitoring the progress of BRONJ, these are being
used [69]. Alkaline phosphatase and N-telopeptide cross-linked levels are
clearly high in patients who have bone metastases and myeloma, and higher
levels clearly correlate with imminent risk for a SRE, cancer progression, or
death [70]. Disease causes the levels of these markers to rise, and the use of
bisphosphonates will cause these markers to fall. Studies are underway to
monitor levels of other markers of bone metabolism, such as receptor acti-
vator for nuclear factor kappa B ligand (RANKL) and osteoprotegerin.
Summary
Bisphosphonates are very effective drugs for treating osteoporosis, Pa-
get’s disease of bone, and other metabolic bone diseases, multiple myeloma,
and metastatic cancer to the bones. In placebo-controlled trials, the use of
bisphosphonates significantly reduced SREs in patients who had cancer. Bi-
sphosphonates also reduces vertebral and nonvertebral fractures in patients
who have osteoporosis by 25% to 77% [71,72]. The development of BRONJ
as an adverse reaction does not diminish its importance in health care.
Dental professionals should be aware of this condition and be sure to
take a careful medication and health history for all patients. Patients taking
a bisphosphonate should not be denied regular dental care, but should be
educated about this condition and encouraged to maintain an excellent level
of dental hygiene and care.
References
[1] Migliorati CA. Bisphosphonates and oral cavity avascular bone necrosis. J Clin Oncol 2003;
21(22):4253–4.
[2] Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of
the jaws: a growing epidemic. J Oral Maxillofac Surg 2003;61(9):1115–7.
[3] Ruggiero SL, Mehrotra B, Rosenberg TJ, et al. Osteonecrosis of the jaws associated with the
use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62(5):527–34.
[4] American Association of Oral and Maxillofacial Surgeons position paper on bisphospho-
nate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 2007;65(3):369–76.
[5] Fleisch H. Bisphosphonates: mechanisms of action. Endocr Rev 1998;19(1):80–100.
[6] Rogers MJ. New insights into the molecular mechanisms of action of bisphosphonates. Curr
Pharm Des 2003;9(32):2643–58.
[7] Russell RG. Bisphosphonates: mode of action and pharmacology. Pediatrics 2007;
119(Suppl 2):S150–62.
[8] Gunsolley JC. A meta-analysis of six-month studies of antiplaque and antigingivitis agents.
J Am Dent Assoc 2006;137(12):1649–57.
[9] Roelofs AJ, Thompson K, Gordon S, et al. Molecular mechanisms of action of bisphosph-
onates: current status. Clin Cancer Res 2006;12(20 Pt 2):6222s–30s.
[10] Santini D, Vespasiani Gentilucci U, Vincenzi B, et al. The antineoplastic role of bisphosph-
onates: from basic research to clinical evidence. Ann Oncol 2003;14(10):1468–76.
Oral Potentially Malignant
D i s o rd e r s
a, ,1 b,1
Stephanie L. Wetzel, DDS * , Jessica Wollenberg, DMD
KEYWORDS
! Premalignant ! Leukoplakia ! Erythroplakia ! Risk factors ! Epithelial dysplasia
KEY POINTS
! Oral potentially malignant disorders are epithelial lesions that may present clinically as
white (leukoplakia), red (erythroplakia), or red and white (erythroleukoplakia) patches.
! There are many factors that increase patients’ risk for developing a potentially malignant
lesion.
! A biopsy of the lesion is the gold standard to differentiate between a potentially malignant
lesion and other entities, and to diagnosis and grade epithelial dysplasia.
! After the diagnosis of a premalignant lesion is made, many patient-related and lesion-
related factors influence the type and extent of treatment of the lesion.
INTRODUCTION
Oral potentially malignant disorder (OPMD) is defined as an epithelial lesion or disorder

that has an increased risk for malignant transformation. The diagnosis of OMPD be-
gins with a clinical examination, and, when present, it is most commonly described
as a white lesion (leukoplakia) or less often as a red lesion (erythroplakia). These diag-
noses are only clinical, and a definitive diagnosis must be determined through biopsy
and histopathologic examination. Once the diagnosis of an OPMD is made, the pa-
tient’s risk factors must be evaluated to determine the risk for malignant transforma-
tion and appropriate treatment. This article reviews the clinical presentation of
OMPDs, including leukoplakia and erythroplakia; the risk factors, including tobacco,
alcohol, actinic damage, and human papilloma virus (HPV); the necessary microscopic
features to make the diagnosis; and the treatment and management of these lesions.
LEUKOPLAKIA
Oral leukoplakia is the most frequently seen potentially malignant disorder in the
oral cavity. Leukoplakias were first reported in the literature in 1877, when the

a
Atlanta Oral Pathology, 2701 North Decatur Road, Decatur, GA 30022, USA; b Randolph Oral
Pathology Associates, 447 Route 10, Suite 5, Randolph, NJ 07869, USA
1
Co-first author.
E-mail address: wetzeldds@gmail.com
Dent Clin N Am 64 (2020) 25–37

26 Wetzel & Wollenberg
term was applied to any white lesion occurring in the oral cavity.1 Leukoplakias are
now defined as white, irreversible, and nonscrapable plaques that carry a question-
able risk to transform into cancer.1,2 More specifically, these lesions cannot be
associated with any chemical, physical, or infectious causative agents except for
tobacco, alcohol, or betel quid. In the general population the overall prevalence
is approximately 2%, with increasing prevalence for older populations.2 Leukopla-
kia has a male predilection and is usually seen in the fifth to sixth decades of life.
One prospective study on leukoplakia found the incidence rates to be 1.1 to 2.4 per
1000 patients per year for men and 0.2 to 1.3 per 1000 patients per year for
women.1
Clinically, leukoplakias can be classified according to their surface and morphologic
features. Leukoplakias can be homogeneous in appearance and have a smooth,
white, flat surface, with well-demarcated borders (Figs. 1 and 2). Nonhomogeneous
leukoplakia is classified into 3 clinical categories:
1. Speckled leukoplakia
2. Nodular leukoplakia
3. Verrucous leukoplakia
Fig. 1. (A) Granular leukoplakia featured on the left lateral border and ventral surface
of the tongue. This lesion was diagnosed via biopsy as mild epithelial dysplasia. (B)
Flat leukoplakia of the lower lip in a 50-year-old woman. Tissue biopsy showed features
of actinic cheilitis. (C) Flat and verrucous leukoplakia of the ventral and lateral
border of the tongue in an 85-year-old woman. (D) Corrugated leukoplakia of the left
lateral border of the tongue in a 30-year-old man showing features of mild epithelial
dysplasia.
Oral Potentially Malignant Disorders 27
Fig. 2. (A) Leukoplakia with irregular borders of the floor of the mouth in a 48-year-old
woman. The lesion showed features of moderate dysplasia. (B) Flat leukoplakia of the right
ventral and lateral surfaces of the tongue in a 63-year-old man diagnosed via tissue biopsy
as moderate epithelial dysplasia. (C) Flat and verrucous leukoplakia of the lower labial mu-
cosa in a 71-year-old woman diagnosed as severe epithelial dysplasia.
Speckled leukoplakia is defined as a predominately leukoplakic lesion with areas of

erythema appearing as small, dotlike spots, or larger, irregular patches. Speckled leu-
koplakia is now termed erythroleukoplakia and is discussed in more detail later.
Nodular leukoplakia presents as an exophytic polypoid structure that is rounded
and composed of both erythematous and leukoplakic surfaces. Verrucous leukoplakia
has an elevated, proliferative, wrinkled, or corrugated surface3 Most importantly,
nonhomogeneous leukoplakia presents a higher risk for malignant transformation
than homogeneous leukoplakia. There is an overall malignant transformation rate of
1.5% to 34% for oral leukoplakic lesions. This rate can be further broken down to a
transformation rate of 3% for homogeneous lesions and 13.4% to 14.5% for nonho-
mogeneous lesions. Furthermore, 1 study showed that verrucous leukoplakia has a
transformation rate of 4.6%, with erosive lesions having a 28% risk of malignant
transformation.2
Leukoplakic lesions can occur at any site in the oral cavity. The most common sites
include the lateral border of the tongue and the floor of the mouth, followed by buccal
mucosa, hard and soft palate, and gingival/alveolar mucosa. Oral leukoplakia may be
localized to 1 site or present as diffuse and widespread oral mucosal disease.
Proliferative verrucous leukoplakia (PVL) is a rare but high-risk form of leukoplakia.
PVL most commonly presents in women more than 60 years of age who lack a clinical
history of tobacco or alcohol use. An ethnic predilection is not seen. A strong female
predilection of 4:1 has been reported with PVL. Initially, lesions of PVL present as
asymptomatic, small, well-defined white patches or plaques with or without surface
thickening. As the disease progresses, the lesions slowly enlarge and involve diffuse
surfaces along multiple sites of the oral mucosa. Lesions of PVL evolve from flat
patches to become increasingly exophytic and verrucous (Figs. 3 and 4).4,5 PVL
may involve multiple sites of the oral cavity, including the gingiva, alveolar mucosa,
tongue, palate, and buccal mucosa. The gingiva is the most commonly affected
area. Furthermore, gingival and palatal lesions are the most commonly affected sites
to undergo malignant transformation. The reported malignant transformation rate for
lesions of PVL is 63.3% to 100%.2 Even with ablative treatment, PVL has a recurrence
rate of up to 85%.6 Therefore, close surveillance of patients with PVL is of the utmost
Fig. 3. PVL in an 83-year-old woman. The gingival lesion showed features of mild epithelial
dysplasia. (Courtesy of Donna Thomas Moses, DMD, Carrollton, GA).
importance. Because of the serious nature of PVL, making the correct diagnosis is crit-
ical for the health of the patient. Criteria for the diagnosis of PVL include:
1. Existence of a verrucous area
2. Involvement of more than 2 sites
3. Lesions that have increased in size and spread to other sites during the develop-
ment of the disease over at least 5 years
4. Recurrence in a previously treated area
5. Representative biopsy samples of lesional tissue have been microscopically exam-
ined, and the presence of an invasive squamous cell carcinoma has been ruled out2,3
Fig. 4. (A) PVL featuring verrucous hyperkeratosis and hyperplasia of the basal cell layer. Li-
chenoid inflammation is also identified (hematoxylin-eosin, original magnification "10). (B)
PVL with chevron keratinization and orthokeratinization with a prominent granular cell
layer (hematoxylin-eosin, original magnification "40).
Despite these criteria, all lesions of PVL do not have a verrucous surface. A more
inclusive term for this condition, proliferative multifocal leukoplakia, has been
suggested.3
The differential diagnosis for leukoplakic lesions can be separated into the broad
categories of congenital, infectious, inflammatory, and mucosal injury. Common
congenital white lesions include leukoedema, which disappears after stretching
of the mucosa, and white sponge nevus (also known as Cannon disease or familial
white folded dysplasia), which typically affects the buccal mucosa bilaterally.
White lesions of infectious cause include pseudomembranous candidiasis and
oral hairy leukoplakia. However, pseudomembranous candidiasis presents as a
white membrane that can be physically wiped away leaving a raw erythematous
mucosal base. Oral hairy leukoplakia occurs as a secondary manifestation in pa-
tients with compromised immune systems and infected with the Epstein Barr virus
and is also known as human herpesvirus 4. Leukoplakic lesions of inflammatory
cause present with a lichenoid appearance and include lichen planus, lichenoid
mucositis as a result of medication side effects and contact hypersensitivities,
oral lesions of systemic lupus erythematosus, and graft-versus-host disease in pa-
tients with a history of bone marrow transplant. A detailed clinical history aids in dif-
ferentiation of inflammatory lesions from true leukoplakia. Chemical and thermal
mucosal burns, morsicatio, linea alba, and frictional keratoses all present as white
areas as a result of mucosal injury. The diagnosis of a mucosal injury can be
reached by determining the location of the injury and detailed questioning of the
patient.6
ERYTHROPLAKIA
Erythroplakia is defined as a potentially malignant disorder of the oral cavity that pre-
sents as a red patch of the oral mucosa that cannot be diagnosed as any other defin-
able lesion. The lesion cannot have traumatic, vascular, or inflammatory causes.
Erythroplakia occurs in middle-aged and elderly patients, most commonly in the sixth
and seventh decades of life. It occurs with equal frequency in both genders. Erythro-
plakia has a prevalence range from 0.02% to 0.83%, with a mean prevalence of 0.11%
in the general population.7,8 Although erythroplakia is rare, it has a much higher rate of
malignant transformation than other premalignant conditions, such as leukoplakia and
submucous fibrosis. The reported transformation rates range from 14% to 50%,8 4
times greater than the malignant transformation rates of leukoplakic lesions.9 System-
atic reviews have shown a range of 1.3% to 34% of malignant transformation in
erythroplakic lesions in the global population.5
Clinically, erythroplakia presents as an erythematous mucosal lesion that is often
smooth in appearance (Fig. 5). Erosive, granular, or nodular changes can be seen in
long-standing lesions.7 Rarely, lesions can be depressed below the mucosal surface,
alluding to their atrophic nature. Typically, these lesions are asymptomatic. Visually, a
well-defined margin can be appreciated between the lesional tissue and adjacent
normal mucosa. Most commonly, erythroplakia presents as a solitary lesion. However,
examples of multicentric lesions and lesions involving extensive portions of oral
mucosa have been reported.3,7 When palpated, erythroplakias are typically soft. Indu-
rated areas or lesions that are firm to palpation occur when malignant transformation
and invasion are present.2 The soft palate is the most common site for erythroplakia to
occur. Other common sites include ventral tongue, floor of mouth, and tonsillar pil-
lars.2 Other areas of the tongue are rarely affected.2 A diagnostic biopsy is required
to differentiate between a true erythroplakia and other pathologic entities of the oral
Fig. 5. (A) A 74-year-old man with erythroplakia of the left lateral border of the tongue. (B)
Erythroplakia soft palate.
cavity. Microscopic examination of affected tissue aids in distinguishing a true eryth-

roplakia from erythematous candidiasis and lichenoid lesions, including lichen planus,
lichenoid mucositis, and oral lesions of lupus erythematosus, which can have similar
clinical appearances. In addition, a biopsy can also rule out hemangiomas and other
vascular anomalies, Kaposi sarcoma, median rhomboid glossitis, lesions secondary to
local irritation, and erythema migrans. Disorders manifesting as desquamative gingi-
vitis present as erythema of the gingiva, and include lichen planus, pemphigus vulga-
ris, and mucous membrane (cicatricial) pemphigoid.7,8
Erythroleukoplakia has a mixed red and white appearance. Unlike erythroplakia,
which is well demarcated, erythroleukoplakia often has a blended or ill-defined
margin. Clinically, erythroleukoplakia, previously termed speckled leukoplakia, pre-
sents in 2 general patterns (Fig. 6): either numerous small and irregular leukoplakic
areas within a red patch, or as an erythroplakia adjacent to a leukoplakia. Unlike leu-
koplakia and erythroplakia, patients with erythroleukoplakia often present with symp-
toms such as pain or soreness. Age, gender, and commonly affected sites for
erythroleukoplakia are the same as erythroplakia.7
RISK FACTORS
Tobacco
Smoking tobacco poses the greatest increase in risk to develop precancerous le-
sions in the oral cavity. Heavy cigarette smoking is the strongest predictor, with
1 study showing that smoking more than 20 cigarettes per day led to an increased
risk of oral leukoplakia by 2.4 to 15 times that of nonsmokers. The cumulative effect
of smoking is more important than current smoking status, which suggests that
chronic long-term tobacco smoking plays a role in premalignant changes. Benzo-
pyrene, a by-product of tobacco smoking, has been shown to be both mutagenic
and carcinogenic. In addition to cigarettes, cigar and pipe smoking produce similar
risks.10
Fig. 6. (A) Erythroleukoplakia on the left lateral border of tongue in a 46-year-old man. (B)
Erythroleukoplakia of the ventral tongue in an 85-year-old woman with exophytic areas of
leukoplakia.
In some populations, the habit of placing the lit end of a cigarette into the oral cavity
is practiced, and is known as reverse smoking. The mucosal changes observed with
this practice manifest as leukoplakic plaques of the palate, mucosal nodularity, and
thickening of the mucosa surrounding salivary gland ducts. The leukoplakia associ-
ated with reverse smoking has a higher risk of malignant transformation compared
with lesions in regular cigarette smokers.3
Smokeless Tobacco
Smokeless tobacco was brought to popularity by Native Americans in North America
in the early 1900s. Smokeless tobacco saw a slight decline with the invention of cig-
arettes, but smokeless tobacco usage has continued to surge at a steady pace since.
Forms of smokeless tobacco include loose-leaf chewing tobacco, moist snuff, and dry
snuff. It is estimated that from 6 million to 22 million Americans use some form of
smokeless tobacco.
Clinically, lesions associated with smokeless tobacco use appear in the oral cavity
as inflammatory gingival and periodontal lesions, and as leukoplakia, some of which
are diagnosed as epithelial dysplasia. Squamous cell carcinoma has also been re-
ported in patients who use smokeless tobacco products. However, some studies
fail to account for risk factors such as alcohol and cigarettes. Regardless, most reports
have found clinical changes in the oral mucosa as a result of smokeless tobacco use.
The mucosal change is commonly referred to as smokeless tobacco keratosis and can
be seen at the site where the quid is placed as soon as 6 months after initial use. The
affected mucosa becomes leathery, grey-white to white, and fissured. The risk of
smokeless tobacco keratosis transforming into premalignancy or squamous cell car-
cinoma is a topic of contention. In general, most studies have found low transforma-
tion rates. High-risk sites for epithelial dysplasia seen in conjunction with smokeless
tobacco use are the buccal/vestibular mucosa and the gingiva, which are the locations
where the tobacco comes into direct contact with the mucosa. One study by Boffetta
and colleagues11 estimated that up to 4% of oral cancers in men in the United States
are associated with the use of smokeless tobacco products.
Alcohol
Approximately 65% of adults in the United States consume alcoholic beverages.12
Regardless of frequency of drinking, consuming alcohol with meals, or the type of
beverage, alcohol consumption is consistently linked to an increase risk of oral prema-
lignant lesions. One study showed that ever having alcohol increases the risk devel-
oping a leukoplakic lesion 1.5 times compared with nondrinkers.12 It has also been
shown that patients who regularly drink alcohol are at increased risk of developing
recurrent disease after an initial oral precancerous lesion has been treated. The floor
of mouth and ventral-lateral tongue are the sites most closely associated with alcohol
as a risk factor, possibly because of prolonged contact with the offending substance.
Acetaldehyde, a metabolite of ethanol produced by the liver, is carcinogenic. In addi-
tion, alcohol may increase oral mucosal permeability to other carcinogens seen in as-
sociation with tobacco use, which alters epithelial proliferation. This process
exponentially increases the risk to develop oral precancerous lesions.13
Actinic Damage
Excessive sun exposure has been shown to cause actinic cheilitis, which is an
inflammatory-associated precancerous lesion of the lower lip. It presents as a white
lesion with crusting, flaking, or dryness. Blurring of the vermillion border is a common
finding seen with this condition. People who are at risk to develop actinic cheilitis
include men, fair-skinned individuals, and patients who spend extended periods
participating in outdoor activities.14
Oral Submucous Fibrosis
Oral submucous fibrosis (OSF) is associated with the long-term use of betel quid.
Typically, the quid consists of areca nut, slaked lime, tobacco, and sometimes
other additives such as spices, wrapped in a betel leaf. The quid is then placed
in the vestibule and causes a sense of euphoria for the user. OSF is most
commonly seen in patients of southeast Asian and south Asian descent.3 OSF is
a chronic disorder of the mucosa in which fibroelasticity of the affected tissue is
lost.9 OSF is characterized by palpable fibrous bands leading to limited mouth
opening and tongue rigidity. Early in the disease process, blanching of the mucosa
is seen. Rate of malignant transformation seen in submucous fibrosis is 9.13% and
patients with OSF have a risk of developing oral cancer 29.26 times that of patients
without oral submucous fibrosis.15 A predominant male predilection is seen in OSF.
Affected sites include buccal mucosa, which is the most commonly affected, fol-
lowed by tongue, lip, palate, and gingiva.15 Areca nut contains arecoline, which
stimulates fibroblasts. The slaked lime promotes penetration of arecoline into the
mucosa, leading to fibrosis of the lamina propria. The mucosal lesion most often
associated with OSF is oral leukoplakia. Increased duration of use of areca nut is
directly proportional to an increased risk of oral leukoplakia and oral squamous
cell carcinoma associated with OSF.
Human Papilloma Virus
HPV is a well-known cause of squamous cell carcinoma. HPV has been detected in
the oral cavity at a rate of up to 12% and high-risk types have shown a prevalence
of up to 3%. Histopathologic evidence has been seen in some instances of oral

epithelial dysplasia. These lesions most commonly present as leukoplakia, but eryth-
roplakias and erythroleukoplakias have also been described. There is a male predilec-
tion, and the most common sites for HPV-associated oral epithelial dysplasia to occur
are the tongue and floor of mouth. The most common subtype of HPV seen in these
lesions is HPV-16, followed by HPV-33 and HPV-58. Immunohistochemical staining
for p16 serves as a surrogate marker for HPV infection. However, the standard to
confirm the presence of HPV in dysplastic oral lesions is through in situ
hybridization.5,16
MICROSCOPIC DESCRIPTION
Because oral epithelial dysplasias (OEDs) are a precursor to malignant transformation,

creating a grading system for these lesions is of utmost importance.17 Many attempts
have been made to produce a grading system for oral epithelial dysplasia that is both
reproducible and can serve as a reliable predictor of malignant transformation. How-
ever, assessing the degree of dysplasia in order to predict the prognosis and manage-
ment of OED remains challenging. The current 2017 World Health Organization (WHO)
3-tiered grading system remains the gold standard in classification of these le-
sions.18,19 Pathologists use this system to classify lesions into mild, moderate, and se-
vere epithelial dysplasia using diagnostic criteria for both architectural and cytologic
changes. Carcinoma in situ is considered synonymous with severe epithelial
dysplasia.18 The recent WHO update also mentions a binary system that was pro-
posed by Kujan and colleagues.20 This system uses similar diagnostic criteria to the
WHO 2017 system but classifies the lesions as either low-grade or high-grade dyspla-
sias, thus eliminating the in-between category of moderately dysplastic lesions. Binary
systems are used for precursor lesions at other sites throughout the body, including
the larynx, and are considered to be more reproducible and clinically relevant systems
compared with the 3-tiered approach.19–21 However, a binary system has yet to be
validated for use in the oral cavity.19,22 Regardless, the aim of both classification sys-
tems is to ensure standardization in reporting and therapeutic treatments of OED.21
Epithelial dysplasia is defined as an abnormal growth pattern that affects the normal
maturation sequence of the surface mucosa. It includes both architectural and cyto-
logic alterations, which can only be seen histologically. However, these changes
can manifest as a clinically visible lesion. The 2005 WHO diagnostic criteria classify
the lesion as mild dysplasia if alterations of the epithelial maturation sequence are
seen only in the lower one-third of the surface mucosa (Fig. 7). Moderate dysplastic
lesions have changes that encompass two-thirds of the epithelium (Fig. 8). Greater
Fig. 7. (A) Mild epithelial dysplasia showing atypical features confined to the lower one-
third of the epithelium (hematoxylin-eosin, original magnification "10). (B) Mild matura-
tional alterations include nuclear hyperchromatism, increased nuclear to cytoplasmic ratio,
and hyperplasia of the basal cell layer (hematoxylin-eosin, original magnification "40).
Fig. 8. (A) Moderate epithelial dysplasia in which the atypia extends beyond the lower one-
third of the surface mucosa, but does not extend the full thickness of the epithelium (hema-
toxylin-eosin, original magnification "10). (B) Dyskeratosis, increased mitotic activity, hyper-
plasia of the basal cell layer, and nuclear hyperchromatism are identified (hematoxylin-
eosin, original magnification "40).
than two-thirds of the epithelium showing atypical features is severe dysplasia and
full-thickness changes are classified as carcinoma in situ (Fig. 9).18,23 The 2005 diag-
nostic criteria are similar to the newly updated 2017 version.23
The 2017 WHO diagnostic criteria are listed as follows:
Architectural Changes
1. Irregular epithelial stratification
2. Loss of polarity of basal cells
3. Drop-shaped rete ridges
4. Increased number of mitotic figures
5. Abnormal superficial mitosis
6. Premature keratinization in single cells (dyskeratosis)
7. Keratin pearls within rete ridges
8. Loss of epithelial cohesion
Cytologic Changes
1. Abnormal variation in nuclear size
2. Abnormal variation in nuclear shape
3. Abnormal variation in cell size
4. Abnormal variation in cell shape
5. Increased nuclear-cytoplasmic ratio
6. Atypical mitotic figures
7. Increased number and size of nucleoli
Fig. 9. (A) Severe epithelial dysplasia of the oral cavity showing dysplastic features
throughout the surface mucosa (hematoxylin-eosin, original magnification "10). (B) The
dysplastic features seen in this case of severe epithelial dysplasia include increased nuclear
to cytoplasmic ratio, drop-shaped rete ridges, and abnormal variation in nuclear size and
shape. Increased mitotic activity and irregular stratification are also seen (hematoxylin-
eosin, original magnification "40).
8. Hyperchromasia
Included in the 2017 WHO Classification of Head and Neck Tumors.
Minor modifications have been made from the previously adapted 2005 WHO
classification system. These changes include elimination of basal cell hyperplasia
and the addition of loss of epithelial cohesion in the architectural change category.
Furthermore, increase in nuclear size is no longer included as a cytologic feature of
dysplasia.18,23
TREATMENT AND MANAGEMENT OF ORAL PREMALIGNANT LESIONS
Over the past 3 decades there has been little improvement in the 5-year survival rate
for patients with oral cancer.24 The current 5-year survival rate has been reported to be
approximately 57% (https://oralcancerfoundation.org/facts/). It is crucial that clini-
cians embrace the importance of early detection and treatment of premalignant
lesions.
Clinical examination and biopsy are the gold standard for the detection and diag-
nosis of oral premalignant lesions. There are many adjunctive aids available on the
market to help detect these lesions, including autofluorescence, vital staining, and
brush cytology/biopsy. These tests are minimally invasive; however, they have consid-
erable false-positive and false-negative results.24 Screening examinations for oral
cancer, as part of a comprehensive head and neck examination, are recommended
at all new patient visits, recall appointments, and emergency visits.4
The patient evaluation must begin with the collection of a detailed history from
the patient. The following information should be discussed with the patient and
documented:
! Demographic data
! History of chief complaint, including onset, progression, and symptoms
! Medical history and review of systems
! Social history, including alcohol, tobacco, and areca nut use
! Other risk factors, such as family history of cancer, and any environmental
exposures4
The clinical examination begins with an extraoral examination. Examination should
look for any head and neck asymmetry, and cutaneous lesions, followed by palpation
of the midline and lateral neck and of the major salivary glands. The intraoral examina-
tion must include visualization and palpation of all sites of the oral cavity4; this is espe-
cially important because leukoplakia is often multifocal.1 If a lesion is noted, its
characteristics, including location, size, color, surface texture, and texture and symp-
toms on palpation, must be assessed. An irritative cause of the lesion should also be
sought out. If irritation is suspected as the cause of the lesion, the cause of the irrita-
tion must be removed, and the lesion then be reevaluated in 1 to 2 months. Photo-
graphs of the lesions aid in the reevaluation process. If there is no change, or if no
irritative factor is present, a biopsy of the lesion is mandatory.1 Histopathology is
the most important factor in the diagnosis of oral premalignant lesions.4
Risk factors associated with an increased risk of malignant transformation of a pre-
malignant lesion must also be assessed. Factors that increase risk of malignant trans-
formation that are patient related include female gender, patients 45 years of age or
older, and nonsmoking status (so-called idiopathic leukoplakia).5 Factors associated
with the premalignant lesion that increase the risk of malignant transformation include
site (floor of the mouth, ventral-lateral tongue, soft palate, and retromolar pad), size
(>200 mm2), clinical appearance (nonhomogeneous lesions, presence of multiple le-

sions), and higher grade of dysplasia.4,25
Treatment and management of patients with oral precancerous lesions are deter-
mined by evaluating their risk for malignant progression. The most important factors
used to stratify patients include the clinical factors discussed earlier and histologic
grade. Treatment of low-risk lesions that show mild dysplasia on biopsy may include
habit cessation, surveillance, or surgical intervention.4 One study has shown that there
was a 44% rate of clinical improvement in lesions of mild dysplasia in smokers who
discontinued tobacco use. The decision whether to treat a lesion of mild dysplasia
should take into account the extent of the lesion, whether the lesion is multifocal,
risk factors, and the patient’s preference.1
High-risk lesions, and lesions that show moderate or severe dysplasia on biopsy,
should be treated. The goal of treatment is to remove all the epithelium affected by
the oral precancerous lesion.1 Surgical removal with cold-blade scalpel excision or
electrocautery excision significantly reduces the risk of transformation of the lesion.
The lesion may also be treated by laser ablation. Most commonly a CO2 laser is
used to vaporize the affected epithelium. Regardless of how the lesion is to be treated,
a 1-mm to 2-mm margin of normal mucosa is recommended.4
After appropriate treatment of an oral precancerous lesion, close, long-term surveil-
lance is imperative. The interval between reevaluation visits varies depending on the
patient’s risk factors. It has been recommended that a complete extraoral and intrao-
ral examination be done every 3 to 6 months. If any changes or new lesions are noted,
a biopsy is required.1 Regardless of the patient’s risk factors and previous treatments,
lifelong monitoring is suggested.4
SUMMARY
Identifying OPMDs in the oral cavity begins with thorough clinical examination of the
soft tissue in the oral cavity and assessment of the patient’s risk factors. Presence
of an OPMD is confirmed via biopsy and microscopic examination of the lesional tis-
sue. The treatment of OPMDs depends on the definitive diagnosis rendered from the
biopsy specimen. Low-risk epithelial dysplasias should be closely monitored and bio-
psied when any changes to the lesion occur. High-risk dysplastic lesions need to be
excised surgically with close and long-term follow-up of the patient. Adherence to
this protocol for OPMD remains the standard of care in prevention of transformation
to malignancy.
REFERENCES
1. Bewley AF, Farwell DG. Oral leukoplakia and oral cavity squamous cell carci-
noma. Clin Dermatol 2017;35(5):461–7.
2. Maymone MB, Greer RO, Kesecker J, et al. Premalignant and malignant mucosal
lesions: clinical and pathological findings part II. Premalignant and malignant
mucosal lesions. J Am Acad Dermatol 2018. https://doi.org/10.1016/j.jaad.
2018.09.060.
3. Warnakulasuriya S. Clinical features and presentation of oral potentially malignant
disorders. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125(6):582–90.
4. Nadeau C, Kerr AR. Evaluation and management of oral potentially malignant dis-
orders. Dent Clin North Am 2018;62(1):1–27.
5. Speight PM, Khurram SA, Kujan O. Oral potentially malignant disorders: risk of
progression to malignancy. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;
125(6):612–27.
E v aluatio n an d
Management of Oral
P o t e n t i a l l y Ma l i g n a n t D i s o rd e r s
a, b
Christine Nadeau, DMD, MSc *, Alexander Ross Kerr, DDS, MSD
KEYWORDS
! Oral potentially malignant disorders ! Leukoplakia ! Malignant transformation
! Risk assessment ! Screening ! Management
KEY POINTS
! Oral potentially malignant disorders (OPMDs) refer to epithelial lesions and conditions with
an increased risk for malignant transformation; oral leukoplakia is the most commonly
encountered.
! Overall, OPMDs have a low risk for malignant transformation, yet the challenge is the dif-
ficulty to reliably identify and predict which patients with OPMDs are at the highest risk for
malignant transformation.
! Future research is needed to elucidate the molecular aspects of OPMDs, to improve cur-
rent diagnostic strategies, leading to personalized management.
INTRODUCTION
Oral potentially malignant disorders (OMPDs) refer to all epithelial lesions and condi-
tions with an increased risk for malignant transformation (MT).1 OMPDs include
different entities; oral leukoplakia (OL) is the most common OPMD2 whereas oral
erythroplakia (OE) is relatively uncommon (Box 1).1,3 OL is defined as a “white plaque
of questionable risk having excluded (other) known diseases or disorders that carry no
increased risk for cancer.”2 It is a clinical diagnosis based on the history and exami-
nation findings and not based on specific histopathologic features. Clinically, OL is
typically unifocal and presents as 2 clinical phenotypes: homogenous and nonhomo-
geneous. The homogeneous type typically appears as a flat, thin, uniform white plaque
with or without fissuring4 (Fig. 1). The nonhomogeneous type is nonuniform in
appearance and may be subclassified into several different types, including
Disclosure Statement: No conflict.

a
Faculty of Dentistry, Université Laval, Pavillon de Médecine dentaire, 2420 rue de la Terasse,
Québec, Québec G1V 0A6, Canada; b Department of Oral and Maxillofacial Pathology, Radi-
ology and Medicine, NYU College of Dentistry, 345 East 24th Street, New York, NY 10010, USA
E-mail address: christine.nadeau@fmd.ulaval.ca
Dent Clin N Am 62 (2018) 1–27

2 Nadeau & Kerr
Box 1
Oral potentially malignant disorders
OL
Homogeneous
Nonhomogeneous
OE
PVL
OSMF
Palatal lesions in reverse smoking
Actinic keratosis
OLP
Discoid lupus erythematous
Dyskeratosis congenita
erythroleukoplakia a mixed red and white lesion but not predominantly white (Fig. 2), a
speckled leukoplakia/leukoerythroplakia a mixed red and white lesion but predomi-
nantly white (Fig. 3), and nodular or verrucous leukoplakias (Fig. 4). In addition, OL
may have a multifocal presentation, known as proliferative verrucous leukoplakia
(PVL), which can have homogeneous and nonhomogenous features1 (Fig. 5). OE is
defined as “any lesion of the oral mucosa that presents as bright red velvety plaques
which cannot be characterized clinically or pathologically as any other recognizable
condition”1,5 (Fig. 6).
Two other OPMDs that have a distinctly different pathogenesis compared with OL
and OE include oral submucous fibrosis (OSMF) and oral lichen planus (OLP).
OSMF is a chronic, insidious inflammatory disease stemming from areca nut chewing
and characterized by a loss in fibroelasticity of the oral mucosa and submucosa.6 OLP
is a chronic inflammatory disease, characterized by a T lymphocyte–mediated im-
mune response against epithelial basal cells, causing basal cell degeneration, which
may result mucosal erosion and ulceration and commensurate oral soreness.7 OPMDs
may be exhibit epithelial dysplasia or, less frequently, oral squamous cell carcinoma
Fig. 1. Leukoplakia (homogeneous). A 51-year-old Asian woman with areca nut habit
(paan). Note the extrinsic staining on teeth secondary to the habit. Definitive diagnosis
was mild epithelial dysplasia.
Management of Oral Potentially Malignant Disorders 3
Fig. 2. Erythroleukoplakia. A 71-year-old white woman with a history of heavy alcohol use.
Note the red and white colors of the lesion with ulcerated areas. The patient reported expe-
riencing soreness and there was no induration on palpation. Definitive diagnosis was squa-
mous cell carcinoma (T1N0M0).
(OSCC) at baseline presentation. Those that are not malignant are at risk for MT1,8;
therefore, early detection and management of OMPDs are critical and may reduce
the cancer-specific morbidity and mortality.8,9 There is biopsychosocial morbidity
associated with OPMDs, which can influence a patient’s quality of life (QOL).10 This
article reviews the epidemiology, evaluation, and management of OPMDs, with an
emphasis on OL, OE, PVL, OLP, and OSMF.
EPIDEMIOLOGY AND CLINICAL PRESENTATION
The worldwide reported prevalence of OPMDs (ie, number of cases identified in a

given population at any one time) ranges from 1% to 5%.11–13 This variable prevalence
is dependent on the country of origin and lifestyle differences influencing the types of
risk factors to which patients are exposed.14,15 Similar to OSCC, OMPDs are predom-
inantly associated with the use of tobacco, heavy alcohol consumption, and areca nut
chewing,16 although approximately 10% seem to have no known cause and are
Fig. 3. Leukoplakia (nonhomogeneous). A 71-year-old white man with no history of tobacco

use. Note an ulcerated area at the posterior aspect of the lesion and the thicker white area
at the superior aspect of the lesion. Definitive diagnosis was moderate with focally severe
epithelial dysplasia.
4 Nadeau & Kerr
Fig. 4. Verrucous leukoplakia. A 74 -year-old white woman with no history of tobacco or

alcohol use. Note the white lesion on the right lateral tongue harboring a verrucous appear-
ing area. Definitive diagnosis was verrucous hyperplasia with mild epithelial dysplasia.
referred to as idiopathic.14 The average age of patients with OPMDs is 50 years to

69 years,17 and male-to-female ratio is approximately 3:1.13,14 Incidence rates for
OPMDs are largely based on data obtained from the Indian subcontinent (and there-
fore are biased), with a range between 0.6/1000 and 30.2/1000 (number of new cases
per population at risk over a given time period).18,19 OPMDs have a reported MT (MTR)
of 0.13% to 36.4%20 at an annual rate of 1.36% (95% CI, 0.69%–2.03%),21 and the
male-to-female MT ratio is approximately 1:2.14
Oral Leukoplakia
OL is the most common OPMD,2,22 with an estimated worldwide prevalence of 2%13
and with a predilection for men (male-to-female ratio of 3.22:1).13 The prevalence is
less than 1% in men under 30 years of age, whereas the prevalence rates in both
men and women over the age of 70 are 8% and 2%, respectively.17 It is seen 6 times
more often among smokers than nonsmokers.2 OL may affect any part of the oral cav-
ity23; however, it most frequently involves the buccal mucosa (25%), gingiva (20%),
and the floor of the mouth and ventrolateral tongue (10%), with the remainder
dispersed among other sites (commissures, hard and soft palate, and alveolar
ridges).14 The oral site and distribution of OLs may also be influenced by the manner
in which risk factors are used; for example, reverse cigar smoking causes lesions on
the hard palate, and areca nut chewing predominantly causes buccal mucosal lesions
Fig. 5. PVL. A 68-year-old white woman with no history of tobacco or alcohol use. Note the
multifocal white lesions on right buccal mucosa (A), maxillary and mandibular mucosa (B),
and left buccal mucosa (C). Definitive diagnosis revealed 2 squamous cell carcinomas maxil-
lary alveolar mucosa with bone invasion (T4aN0M0) and right buccal mucosa (T1N0M0).
Fig. 6. Erythroplakia. A 56-year-old Asian man with a history of smoking and areca nut and
heavy alcohol use. Definitive diagnosis was squamous cell carcinoma (T1N0M0).
at the site of placement.24 The frequency of epithelial dysplasia in leukoplakia is

approximately 1% to 30%.25 Nonhomogenous OLs have a much higher chance of be-
ing dysplastic (12.63-fold) or demonstrating a focus of carcinoma (8.9-fold) compared
with homogeneous OL.26 The estimated overall MTR is 3.5% and typically occurs
within the first 5 years.16 A cross-sectional study in the United States reported the
OL sites with the highest prevalence of severe dysplasia or carcinoma in situ were
the floor of mouth (13.5%) and tongue (5%).24,25
Oral Erythroplakia
There is paucity of data on the epidemiology of OE and it is mostly based on retro-
spective analyses conducted in South Asia and Southeast Asia.27 The prevalence
ranges from 0.02% to 0.83%,27 and OE predominantly affects the middle aged and
elderly (sixth and seventh decades)27 with no significant differences between gen-
ders.28,29 The soft palate, floor of the mouth, and buccal mucosa are the most
commonly affected sites (see Fig. 5). OE is usually asymptomatic, although patients
may complain of a burning sensation associated with the lesion.30 On biopsy and his-
topathologic evaluation, OE typically presents as severe epithelial dysplasia, carci-
noma in situ, or microinvasive carcinoma. If not diagnosed as OSCC, it has the
highest potential for MT among OPMDs with an MTR, ranging from 14% to 50%.31
These data provide clinical relevance for biopsy site selection in an oral erythroleuko-
plakia because the red component of a mixed lesion is more likely to harbor the most
severe pathology.30
6 Nadeau & Kerr
Oral Lichen Planus

OLP affects 1% to 4% of the worldwide population of all races. Both genders may be
affected with a higher frequency in women with 70% of affected women between the
ages of 30 yearsto 60 years.32 Clinically, OLP presents as different subtypes: a
nonerosive-atrophic form (reticular, popular, and plaque-like) and an erosive-
atrophic form (atrophic/erythematous, erosive/ulcerative, and bullous).33 The most
common site is the buccal mucosa, followed by the lateral tongue and gingiva.34
The risk for MT of OLP is the subject of an ongoing and controversial discussion in
the literature. A recent meta-analysis for risk of MT resulted in an overall pooled pro-
portion of 1.1% (95% CI, 0.9%, 1.4%), with higher rates found among smokers (odds
ratio [OR] 2; 95% CI, 1.25, 3.22), alcoholics (OR 3.52; 95% CI, 1.54, 8.03), and HCV
infected patients (OR 5; 95% CI, 1.56, 16.07).35 The most common type of OLP to
undergo MT is the erosive form35 and most common locations for MT are the tongue
followed by buccal mucosa.34
Oral Submucous Fibrosis
OSMF is predominantly encountered in Southeast Asia, where the use of areca nut is
most prevalent, but it may also be encountered in countries like the United Kingdom,
the United states, and other developed countries with Southeast Asians immigrant
populations.36 OSMF is associated with the habitual chewing of areca nut prepara-
tions, most commonly as a betel quid or in single-use packets as pan masala or
gutkha.37 OSMF is mostly seen in young adults (ages 20–40) and affects the buccal
mucosa, retromolar area, tongue, and soft palate.37 Clinically, OSMF presents with
progressive fibrosis of the oral soft tissues, causing limited mouth opening and dimin-
ished oral function, blanching of the oral mucosa, and a burning sensation (Fig. 7).38
Fibrosis is irreversible, even after cessation of the chewing habit.39 OSMF is associ-
ated with significant morbidity and mortality. Studies have reported the presence of
dysplasia in approximately 25% of biopsied OSMF cases and the MTRs vary from
3% to 19%.36,40 OSMF associated with OL is known to increase the risk for MT.36
Proliferative Verrucous Leukoplakia

This clinical entity was first described in 1985 by Hansen and colleagues.41 PVL is
characterized by multifocal lesions with a high risk for MT42 (see Fig. 4). Patients
with PVL have a mean age of 66.8 years and are mostly women, with a female-to-
male ratio of 2.72:1.43 It has a weak association with tobacco because it may occur
Fig. 7. OSMF. A 47-year-old Indian man with history of areca nut use. Note blanching of the
(A) right and (B) left buccal mucosa and limited mouth opening due to OSMF.
in both smokers and nonsmokers.20 The most affected sites are the gingiva, followed
by buccal mucosa and alveolar ridges.43 Initially, PVL may present as a unifocal,
homogeneous white plaque and this creates difficulty in the early diagnosis of PVL
given the overlapping clinical and histopathologic features of a homogeneous leuko-
plakia.44 Early PVL lesions may also be mistaken for OLP (especially the reticular and
plaque variants) because they may share certain subtle pathologic features (such as
the presence of dense lichenoid chronic inflammation).45 PVL gradually evolves to
multifocal disease with a range of presentations, including white lesions, which often
have a verrucous appearance, or mixed red and white lesions, some with ulceration.
Over time, biopsy specimens show varying degrees of epithelial hyperplasia and
dysplasia and eventually squamous carcinoma (verrucous or conventional squamous
cell).44 Diagnosis is based on a combination of these clinical and histopathologic fea-
tures.45 PVL’s multifocal involvement makes it more difficult to manage surgically.4 It
is known for its high MTR (60%–100%), frequent recurrences after total excision
(87%–100%), and high mortality rates (30%–50%).46–48 The etiology of PVL is
unknown; few studies have suggested possible etiologies related to lifestyle habits
(tobacco use and alcohol use),41,49 infectious agents (human papillomavirus, Candida
albicans, and Epstein-Barr virus)43 but none has demonstrated an association.
NATURAL HISTORY AND MALIGNANT TRANSFORMATION OF ORAL POTENTIALLY

MALIGNANT DISORDERS
The natural history of an OPMD is variable, its evolution is not necessarily linear, and its
propensity for progression to malignancy is difficult to predict. This creates challenges
in the assessment and the management of OPMDs. Factors associated with an
increased likelihood of MT are inherent to patients (age >45 years old, female gender,
and nonsmoking status) and to clinical features such as anatomic sites (high risk sites
include floor of the mouth, ventrolateral tongue, retromolar area, and soft pal-
ate),16,50,51 size (lesions with size >200 mm2 have shown a >5-fold increase in the
risk of MT51), clinical phenotype (nonhomogeneous leukoplakia), and a higher grade
of dysplasia.16 Mehanna and colleagues52 reported that OPMDs with high-grade
dysplasia are more than twice as likely to undergo MT (mild/moderate 10.3% vs se-
vere 24.1%). Box 2 summarizes the risk factors for MT of OPMDs. A deeper under-
standing about the aberrant molecular pathways leading to carcinogenesis have led
to the identification of potential markers that can help to predict which OPMDs are
more likely to undergo MT. Loss of heterozygosity at key chromosomal loci (eg,
3p14, 9p21) and DNA ploidy are 2 examples of predictive biomarkers that have
Box 2
Risk factors for oral potentially malignant disorders malignant transformation
Female gender
Age greater than 45 years old
Leukoplakia in nonsmoker
Nonhomogeneous type
Size greater than 200 mm2
Higher grade of dysplasia
High risk site (floor of mouth, ventrolateral tongue, retromolar area, soft palate)
8 Nadeau & Kerr
been validated in longitudinal studies.53,54 Other biomarkers are under investigation

and are reviewed in Chia-Cheng Li and colleagues’ article, “Oral Cancer: Genetics
and the Role of Precision Medicine,” in this issue.
EVALUATION
Screening
Screening for and the early detection of both OPMDs and OSCC can reduce the
cancer-specific morbidity and mortality.8,9 A recent review by the Global Oral Cancer
Forum55 reported that there was insufficient research evidence that population
screening (ie, a national screening program) reduces mortality from oral cancer.
The main issues were the relative rarity of the disease, the lack of knowledge of
the natural history of the disease, and the lack of evidence on the efficacy and
cost-effectiveness of different screening methods.55 Lack of evidence regarding
the benefits and harms of screening for oral cancer in asymptomatic adults in pri-
mary care settings was also reported by the United States Preventive Service
Task Force.56 Opportunistic screening for OPMDs and oral cancer during dental
visits are recommended by the American Dental Association, Canadian Dental Asso-
ciation, and American Academy of Oral Medicine.57 Oral cancer screening is not an
isolated event but rather 1 component of the comprehensive head and neck exam-
ination58 and represents an opportunity to assess any oral abnormalities, whether
neoplastic, infectious, reactive/inflammatory, or developmental.58 Such opportu-
nistic screenings should be performed not only during a new patient examination
but also at recalls and emergency or problem-focused visits for all patients,59 partic-
ularly in those who use tobacco or who consume alcohol heavily.58 Fig. 8 summa-
rizes a possible clinical algorithm for opportunistic screening of mucosal
abnormalities including OPMDs.
Comprehensive Head and Neck Evaluation

A patient’s evaluation must include the collection of demographic data; a detailed
health history, including a patient’s chief complaint; and medical, social, and dental
histories. OPMDs are often asymptomatic, although if a patient presents with a chief
complaint (ie, pain), it is important to record all details about the onset and clinical
course. Risk assessment for OPMDs should specifically include details related to
medical conditions associated with immunosuppression, a past history of cancer (or
family history of cancer), habits (tobacco, alcohol, and areca nut use), poor diet or
nutritional deficiencies, and any environmental exposures. A comprehensive head
and neck examination consists of a visual and tactile examination. This begins with
an extraoral examination to detect any head and neck asymmetry and skin lesions
and includes palpation of midline neck structures (such as the thyroid gland), lymph
nodes, and major salivary glands. Adults with persistent neck lymphadenopathy
with no apparent explanation should be evaluated to rule out malignancy60 and should
trigger a careful intraoral examination to detect a primary OSCC if present (Fig. 9). In
the absence of an obvious primary cancer, patients must be referred for further eval-
uation (ie, imaging or a fine-needle aspiration of the involved node[s]). Signs sugges-
tive of neurologic dysfunction may include paresthesia/dysesthesia or loss of function
indicating possible nerve invasion, and this warrants a complete cranial nerve exam-
ination. The intraoral examination must include inspection and palpation of all mucosal
surfaces, and the visual detection of mucosal abnormalities warrants careful evalua-
tion of the clinical features (such as location, morphology, color, and size). Palpation
of a lesion revealing firmness/induration or pain is an ominous feature. High-risk sites
History/Risk Factor Assessmenta
Comprehensive Head and Neck Examinationb
Normal Examinationc Abnormal Examinationd
Obvious Clinical Diagnosis Uncertain Clinical Diagnosis Frank Malignancy Suspectede
Develop Differential Diagnosisf
Treat based on Diagnosis Provisional/Working Diagnosis Immediate Referral
Suspected Traumatic or No Clear Etiologyi

Infectious Etiologyg
Treat based on Possible Etiology
Resolution Persistence
Progressionh
Clinical Diagnosis of OPMDj
Fig. 8. Opportunistic screening for mucosal abnormalities including OPMDs. a History/risk

factor assessment: include patient’s chief complaint, medical/dental/social history, demo-
graphic data, and review of systems. Risk assessment specific for OPMDs includes medical
conditions associated with immunosuppression, past history or family history of cancer,
habits (tobacco, alcohol, and areca nut), poor diet/nutritional deficiencies, and environ-
mental exposure. b Comprehensive head and neck examination: extraoral examination (vi-
sual and tactile examination to detect any abnormalities: head and neck asymmetry, skin
lesion, palpation of midline and lateral structures, lymph nodes and major salivary glands,
and cranial nerve examination). Intraoral examination (inspection and palpation of all
mucosal surfaces. High risk sites: floor of mouth, ventrolateral border of the tongue, retro-
molar area, and soft palate). c Normal examination: findings are normal or within normal
limits. d Abnormal examination: Document clinical features, such as morphology, location,
color, size, and palpation of lesion revealing firmness/induration or pain. e Frank suspected
malignancy: should be immediately referred for definitive diagnosis and management.
f
Develop a differential diagnosis: with provisional/working diagnosis at the top, initiate a
diagnostic process to establish the definitive diagnosis. g Suspected traumatic or infectious
etiology: remove all sources of mechanical, thermal or chemical irritation, treat infectious
etiology. Reassess in 3 weeks to 4 weeks to confirm resolution or persistence/progression.
h
Persistence/progression: having eliminated possible etiology, if the lesion is persistent or
progressive a clinical diagnosis of an OPMD is made. i No clear etiology: a clinical diagnosis
of an OPMD is made when the clinician cannot identify the lesion or condition as otherwise
benign based on the available history and physical findings. j Clinical diagnosis of OPMD: see
Fig. 10 for potential management strategies for patients with OPMDs.
10 Nadeau & Kerr
Fig. 9. Persistent lymphadenopathy. A 69-year-old white woman with a fixed firm non-
tender right lymphadenopathy secondary metastasis from a recurrent SCC of the left lateral
tongue (the lymph drainage was directed contralaterally due to a previous history of a se-
lective neck dissection and adjuvant radiation treatment to the left side).
include the floor of mouth, ventrolateral tongue, retromolar area, and palate. Digital
photographs provide an excellent way to record any abnormalities and may be useful
to serially monitor mucosal abnormality progression.
The clinical diagnosis of an OPMD, such as an OL, is made when a clinician cannot
identify the lesion or condition as otherwise benign based on the available history and
physical findings. Clinicians should always develop a differential diagnosis when the
clinical diagnosis is uncertain. This is a list of 2 or more clinical diagnoses ordered
with the most likely, known as the working diagnosis, on top. This process initiates
a diagnostic process to establish the definitive diagnosis. As an example, Box 3 lists
different benign clinical diagnoses that might be considered in a differential diagnosis
for oral white lesions. These diagnoses must be considered or ruled out before a work-
ing diagnosis of an OPMD is made. The most common clinical diagnosis for a persis-
tent white lesion is a frictional keratosis. If a clinician suspects a traumatic etiology,
then the frictional keratosis is the working diagnosis, and leukoplakia may be consid-
ered as part of the differential. An attempt must be made to remove the source of me-
chanical, thermal, or chemical irritation and to reassess the patient in 3 weeks to
4 weeks to confirm the lesion is resolving. If a lesion persists and/or demonstrates ev-
idence of progression, a clinical diagnosis of an OPMD is made and becomes the main
working diagnosis. In all cases, a clinical diagnosis of an OPMD mandates biopsy to
establish the definitive diagnosis and rule out dysplasia or OSCC. Depending on the
clinician’s training and experience, prompt referral of patients with OPMDs to a
Box 3
White lesions of the oral cavity
Reactive/frictional
Leukoedema
Linea alba
Mordicatio
White hairy tongue
Frictional keratosis
Smokeless tobacco keratosis
Nicotinic stomatitis
Infectious
Pseudomembranous candidiasis
Hyperplastic candidiasis
Human papilloma virus infection
Hairy leukoplakia associated with Epstein-Barr virus
Immune mediated/autoimmune
OLP
Lichenoid reaction
Benign migratory glossitis
Systemic lupus erythematosus
Discoid lupus erythematosus
Graft-versus-host disease
Developmental
White sponge nevus
OPMDs/malignacy
OL
PVL
OSMF
OSCC
clinician with advanced training in the diagnosis and management of oral mucosal dis-
eases, such as an oral medicine specialist, is recommended. Patients presenting with
an OPMD with a high index of suspicion for malignancy (ie, a large mass, lymphade-
nopathy, or other ominous signs) should be immediately referred to a head and neck
oncology team. At all times, patients should be informed of all findings, proposed eval-
uation, and management. Clinicians must be certain of patient comprehension and un-
derstanding, obtain informed consent, and document all relevant information in
patient records.
Impact on Quality of Life

The biopsychosocial morbidity associated with OSCC has been established; however,
there is paucity of literature on the QOL specific to patients with OPMDs.61 Recently,
Tadakamadla and colleagues62 developed an OPMD QOL questionnaire to evaluate
the subjective perceptions of the impact of OPMDs in 150 patients with OPMDs
(n 5 50 each for OL, OSMF, or OLP with age-matched and gender-matched controls).
The study reported poorer QOL in OPMDs patients compared with controls and iden-
tified 4 main issues: (1) perceived lack of knowledge by health care professionals
about OPMDs and the diagnostic process, with most patients reporting traumatic ex-
periences (ie, multiple visits to multiple health care providers, and different kind of
treatments, often with no relief); (2) the experience of physical impairment and func-
tional limitations (ie, burning sensation while eating or performing oral hygiene, or
12 Nadeau & Kerr
limited mouth opening affecting mastication); (3) the reduction in psychological and
social well-being, notably the fear of MT, and the frustration related to the chronic na-
ture of the condition, with no specific treatment; and (4) the effects of treatment on
daily life (financial impact, difficulty in keeping appointments, treatment satisfaction,
and impact of risk factor modification/habit cessation, such as tobacco smoking). A
weakness of the study included the heterogeneity of the population: OLP and
OSMF patients are different populations in terms of QOL, especially for the physical
impairment and functional limitations (the most important issue for patients) compared
with OL/OE, which are typically asymptomatic. Nevertheless, patients’ perceptions
and the impact of OPMD diagnosis on a patient’s QOL can have an impact on psycho-
logical and social well-being and should be part of the comprehensive evaluation
process.
DIAGNOSIS OF ORAL POTENTIALLY MALIGNANT DISORDERS
The current gold standard for the definitive diagnosis of OPMDs is based on biopsy
and histopathologic examination.1,4 OPMDs may exhibit hyperplasia, hyperkeratosis,
varying degrees of dysplasia, carcinoma in situ, or OSCC.4 The diagnosis and grading
of oral epithelial dysplasia are based on a combination of architectural and cytologic
changes using a 3-tiered grading classification: mild, moderate, and severe, with
severe dysplasia and carcinoma in situ considered synonymous (2005 World Health
Organization Classification [Table 1]).63 There can be considerable interobserver
and intraobserver variations in the grading of dysplasia64,65; yet, despite these short-
comings histopathology remains the most important factor dictating management4,66
(see Fig. 8).
Diagnostic adjunctive techniques for OPMDs and OSCC are commercially available
to clinicians. Their clinical application may facilitate biopsy site selection (see Fig. 2) to
identify the most severe pathology in patients with OPMDs harboring variable histol-
ogy or for the surveillance of patients with OPMDs or history of oral cancer.67 Diag-
nostic adjunctive techniques includes optical devices, vital staining, cytopathologic
platforms, and salivary diagnostics.68–70 The role of current and emerging diagnostic
adjunctive techniques is reviewed in Michaell A. Huber’s article, “Adjunctive
Diagnostic Techniques for Oral Cancer Discovery,” in this issue.
Table 1
Grading systems of oral epithelial dysplasia
Grading Histopathologic Characteristics

Mild dysplasia The architectural disturbance is limited to the lower third of the
epithelium accompanied by cytologic atypia.
Moderate dysplasia The architectural disturbance extends into the middle third of the
epithelium; however, architectural disturbance extending into the
middle third of the epithelium with sufficient cytologic atypia is
upgraded from moderate to severe dysplasia.
Severe dysplasia The architectural disturbance involves greater than two-thirds of the
epithelium showing architectural disturbance with associated
cytologic atypia.
Carcinoma in situ Full-thickness or almost full-thickness architectural disturbance in the
viable cell layers accompanied by pronounced cytologic atypia.
Data from Barnes L, Eveson J, Reichart P, et al. World health organizations classification of tumour.
In: Pathology & genetics of head and neck tumours. IARC Press, editor. Lyon (France): IARC Press;
2005. p. 177–8.
MANAGEMENT OF ORAL POTENTIALLY MALIGNANT DISORDERS

Introduction
As stated previously, overall, OPMDs have a low risk for MT, estimated to be a rate of
approximately 1.36% per year.13 As such, it is difficult to justify interventions that are
unnecessarily aggressive or associated with potential adverse effects. Risk stratifica-
tion of patients with OPMDs seem to be the key to selecting an appropriate manage-
ment plan, each patient receiving treatment commensurate with the degree of risk for
progression and MT. Currently, the factors used to stratify risk in OL/OE include clin-
ical factors (eg, nonsmoking status, high-risk subsite, nonhomogeneous appearance,
and size of lesion >200 mm) coupled with higher histologic grade.16 Yet, such factors
are imperfect and with the advent of genomics, proteomics, and metabolomics, it is
the dawn of personalized medicine and the potential to identify biomarkers present
in patients with OPMDs that are predictive for progression and MT, the possibility to
translate this into a personalized intervention may become a reality.
A wide range of treatments has been advocated for OPMDs, ranging from habit/risk
factor control to medical and surgical interventions, surveillance/close monitoring, and
a combination of these strategies. It is critical to understand the rationale, indications,
and evidence for both the efficacy and safety of these modalities/strategies in the
management of OPMDs. Clinicians must be able to interpret the available scientific
literature, and an important question to ask is which endpoint or endpoints should
be measured to assess the efficacy of an intervention. The worst possible outcome
of not treating OPMDs is a worsening of disease; therefore, interventions that can pre-
vent progression and MT of OPMDs should provide the most meaningful benefit to pa-
tients. Multicenter randomized placebo-controlled studies with long-term follow-up
(>5 years), using the MTR as the primary endpoint or, as previously stated, surrogate
biomarkers that are predictive for MT are considered the gold standard for assessing
efficacy. Unfortunately, there is a paucity of such studies because they require larger
populations and are expensive to undertake, and only a few have used surrogate bio-
markers. As such, most of the published studies assess clinical, histologic, or molec-
ular (ie, using various biomarkers) endpoints that correlate with a resolution of OPMDs
and, therefore, are amenable to shorter follow-up intervals. In addition to efficacy, the
safety profile and the cost-effectiveness for these interventions are important. Current
strategies for the management of OPMDs are summarized, limitations of reported in-
terventions highlighted, and future research priorities recommended. The focus is on
OL/OE and PVL. The management of OSMF and OLP is not specifically covered in this
article, and readers are directed to excellent reviews.71,72
Habit Cessation
There are no specific prospective clinical RCTs with the primary aim of assessing the
efficacy of habit cessation as an intervention for patients with OPMDs. There are
data, however, from epidemiologic studies to show that a high percentage of
OPMDs in tobacco users resolve after tobacco cessation. Roosaar and colleagues73
followed a cohort of patients with OL in Sweden over 2 decades and showed that
there was a statistically significant resolution of OL in patients who had quit smoking
compared with those that had not quit. Gupta and colleagues74 explored the effect
of exposing patients to an annual tobacco cessation program on the presence of oral
lesions in a large Indian cohort of tobacco users (n 5 12,212) over a 10-year period
and showed a substantial decrease in the incidence of OL. Martin and colleagues75
showed a regression of OLs over a 6-week period after tobacco cessation in a mil-
itary population of smokeless tobacco users, although these OLs were likely reactive
14 Nadeau & Kerr
lesions rather than true OPMDs. None of these 3 studies explored histopathologic
outcomes nor did they use MT as an endpoint. Roed-Petersen and colleagues76
similarly reported an almost 30% disappearance of OLs after 3 months of absti-
nence. Nevertheless, these studies suggest that there is a subset of white lesions
in tobacco users (smoked or smokeless), classified as OPMDs, which do resolve
after tobacco cessation. Vladimirov and colleagues77 explored the effect of tobacco
cessation on a cohort of patients with OPMDs who had undergone surgical excision,
demonstrating that the patients who continued to smoke were significantly more
likely to undergo an “unfavourable outcome” (ie, recurrence of the OPMD or MT).
There are no similar studies exploring the effects of cessation of alcohol or areca
nut use on resolution of OPMDs. In summary, these studies collectively support
that it is prudent to strongly encourage cessation as a first-line intervention for pa-
tients with OPMDs who use tobacco.
Yet, the compelling and irrefutable evidence that tobacco, heavy alcohol intake, and
areca nut use are established independent causative agents for OSCC and OPMDs
abrogates the need for habit interventional studies and provides ample justification
to integrate evidenced-based guidelines for tobacco78 and alcohol cessation79 into
clinical practice. There are currently no established evidence-based guidelines for
areca nut use cessation.
Medical Interventions
Chemoprevention is defined as the use of drugs, vitamins, or other agents to try to
reduce the risk of, or delay the development or recurrence of, cancer. The rationale
is to use agents that can modulate carcinogenesis. Many topical and systemic chemo-
preventive agents have been studied on OPMDs, albeit few rigorous trials have been
conducted. A recent systematic Cochrane review published in 2016 identified 15
placebo-controlled chemopreventive RCTs for OPMDs.80 These and other trials
more recently published are summarized in Table 2, which provides a listing of the
agents, their formulation, rationale for use, and their efficacy based on primary
endpoints.
Malignant transformation as an endpoint

Only 2 RCTs, assessing 3 systemic agents (vitamin A [retinyl acetate], b-carotene, and
a b-carotene/vitamin C combination), explored MT as an endpoint.81,82 These studies
did not reveal a significant reduction in MT between those receiving the active treat-
ments versus placebo, and the small sample size and suboptimal follow-up make it
is difficult to interpret these results. MT in the active treatment groups occurred
more frequently after the discontinuation of the agents, and long-term efficacy has
not been studied in patients receiving extended courses of these or other agents
(ie, beyond 3 years).
Clinical resolution as an endpoint

Only 2 RCTs (assessing 3 systemic agents) demonstrated a statistically significant
improvement in clinical resolution of OPMDs (defined as complete clinical resolution
[CR]) compared with controls, namely vitamin A81,83 (which also prevented the devel-
opment of OPMDs at new sites), b-carotene,81 and lycopene.84 Topical bleomycin
showed a positive but not statistically significant effect.85 Many of the agents studied
demonstrated partial lesion responses, although the clinical ramifications of a partial
response are difficult to interpret. A significant proportion of patients who demon-
strated complete or partial responses relapsed after the discontinuation of many of
these agents.
Table 2
Medical interventions with randomized placebo-controlled studies
Agent Rationale Formulations Trial (Endpoint)

Retinoids Inhibiting growth and Systemic: 1(HR)
inducing cell 13-cis-retinoic acid86
differentiation Topical: 0.1% #
13-cis-retinoic acid
gel 3"/d " 4 mo115
Vitamin A Inhibiting growth Vitamin A 200,000 1(CR), 1(HR)
and inducing cell IU po/wk " 6 mo83
differentiation Vitamin A 300,000 1(CR)
IU po/wk " 12 mo81
Carotenoids Antioxidants/ b-carotene #
scavenge free 10 mg/vitamin C
reactive oxygen 500 mg po daily
species " 12 mo82
b-carotene 360 mg/wk 1(CR)
po " 12 mo81
Lycopene 4–8 mg/d 1(CR), 1(HR)
po " 3 mo84
Green tea extracts Antioxidants due Green tea capsules #
to tea polyphenols 3g 4"/d plus extract
(ie EGCG) applied to lesions
3"/d " 6 mo87
Green tea extracts
500, 750, 100 mg/m2
po tid " 3 mo116
Black raspberry Antioxidants due to Topical: black #
high anthocyanin raspberry
content bioadhesive gel
daily " 3 mo88
Chinese herbs Anti-inflammatory Zengshengping #
4 tablets po tid
" 8–12 mo117
Bowman-Birk Protease inhibitor Topical: Bowman-Birk #
inhibitor vs carcinogenesis- inhibitor
associated concentrate
proteolysis mouthwash swished
bid " 6 mo118
Nonsteroidal Cyclooxygenase Topical: 0.1% #
anti-inflammatory inhibition ketorolac rinse
drugs once/d " 3 mo119
Celecoxib 100, 200,
or 400 mg po bid
" 3 mo120
Bleomycin Chemotherapy Bleomycin in DMSO #
(1%) application
once daily " 14 d85
Erlotinib Epidermal growth Erlotinib 150 mg/d #
factor receptor po " 12 mo89
inhibition
Abbreviations: 1, positive trial; #, negative trial; CR, complete remission; DSMO, dimethyl sulf-
oxide; EGCG, epigallocatechin gallate; HR, histologic remission.
16 Nadeau & Kerr
Histopathologic improvement as an endpoint

Only 2 RCTs demonstrated a statistically significant improvement in histology of
OPMDs compared with controls: 1 assessing 13-cis-retinoic acid86 and the other lyco-
pene.84 Topical bleomycin showed a positive but not statistically significant effect.85
There are no data about changes in histopathology after discontinuation of use.
Use of predictive biomarkers

Some studies assessed biomarkers that have been established as predictive for MT.
Stich and colleagues83 performed a Feulgen staining on tissue samples before and af-
ter the course of vitamin A, and performed a crude ploidy analysis, showing a reversal
in the condensed chromatin. Li and colleagues87 demonstrated a similar reduction in
micronuclei from exfoliated cells in the active treatment group receiving green tea ex-
tracts. The black raspberry extract and erlotinib trials tested biopsied tissue for loss of
heterozygosity and showed a significant reduction in for loss of heterozygosity in the
active arms versus controls.88,89 There are no data about changes in predictive bio-
markers after discontinuation of use.
Safety
Serious adverse events were rare, and judging by the similar subject dropout rates be-
tween placebo and active treatment groups, most subjects tolerated the agents. The
systemic retinoids trial led to predictable and dose-related cutaneous adverse events
(ie, cheilitis, facial erythema, and peeling of the skin), and hypertriglyceridemia. Two
subjects experienced conjunctivitis and hypertriglyceridemia, necessitating discontin-
uation.86 Long-term b-carotene use has been linked to an increased risk for lung can-
cer in smokers.90
Quality of the studies reported

Overall, the RCTs for the medical interventions for OPMDs are deemed of poor quality,
with significant bias.80 For studies exploring similar agents, the pooling the data was
impossible due to the high degree of heterogeneity.
Surgical Removal/Ablative Interventions

Surgical excision is the first-line modality for the treatment of oral cavity squamous cell
carcinoma and is also the most common intervention for dysplastic OPMDs. The ratio-
nale is that by removing the lesion(s), the risk for MT is reduced. Yet, surgical excision
does not take into consideration the concept that not all patients presenting with
OPMDs harbor disease that is specifically localized to a discrete lesion with clinically
evident margins that are commensurate with histologic and molecular disease-free
margins. Margins can be indistinct, extending locally beyond the visible lesion or, in
some cases, widespread involving multiple mucosal sites. The concept of “field can-
cerization” was introduced by Slaughter and colleagues91 more than 60 years ago and
further elucidated in the molecular era.92 PVL exemplifies this “field effect” and as dis-
cussed previously, PVL patients have multifocal OPMDs with a high propensity for MT,
irrespective of the surgical management of the OPMDs.93 Field effects and disease-
involved margins are important factors predicting local recurrence and MT after surgi-
cal excision, not only of oral cancer but also for OPMDs. The standard of care for
OSSC excision is to take 0.5-cm to 1-cm wide margins with intraoperative (frozen sec-
tions) and postoperative histopathologic margin assessment. Given the low overall
risk for MT of OPMDs, however, it is difficult to uniformly justify similarly aggressive
oncologic excision, opting instead for 1-mm to 2-mm surgical margins with marginal
assessment not uniformly performed. The creation of a wound in patients with incom-
pletely excised lesions (ie, involved margins) might lead to an increased risk for
proliferation of neoplastic clones (ie, that harbor significant genetic and epigenetic al-
terations) during the healing process, thereby promoting disease progression and is a
subject of further discussion and investigation.94
There are no RCTs assessing surgical removal/ablative interventions, and the cur-
rent evidence is comprised of both prospective and retrospective cross-sectional or
observational cohort studies testing either a single modality or a comparison of 2 or
more surgical modalities. The primary endpoints typically include remission rates
(complete or partial remission), recurrence rates, and if there are sufficient follow-up
data, some studies have rMTRs. Secondary measures after surgical treatments may
include intraoperative and postoperative parameters (eg, bleeding, pain, swelling,
healing time, and postoperative fibrosis), and safety issues. Unfortunately, the analysis
of cost-effectiveness has not been addressed in the literature. The studies are hetero-
geneous in terms of sample size (many are small), the blend of OPMDs (often there is a
low percentage of dysplastic OPMDs or the population lacks a representative spec-
trum of histopathology), and the follow-up (most of which are <5 years). The spectrum
of surgical and ablative interventions, including traditional surgical excision, lasers,
cryotherapy, and photodynamic therapy (PDT), is discussed.
Traditional surgical excision

Traditional surgical excision includes cold blade scalpel excision or electrocautery
excision. A large systematic review conducted by Mehanna and colleagues52 included
14 studies, and the meta-analysis demonstrated a significantly reduced MT rate in pa-
tients with dysplastic OPMDs who underwent traditional surgical excision compared
with those who did not (5.4% vs 14.6%) and concluded that surgical excision seems
to decrease but does not eliminate the risk of MT. Many of the studies included in the
review were poor-quality cross-sectional and observational cohort studies and
showed significant heterogeneity. Not included in the review by Mehanna and col-
leagues was a large retrospective study conducted by Arduino and colleagues95
over a 16-year period in 207 patients with dysplastic OPMDs (135 mild-grade, 50
moderate-grade, and 22 severe-grade dysplasia). The investigators reported no sta-
tistical difference in MTRs in those who underwent surgical excision compared with
those who did not.
Lasers
Despite the purchasing costs, lasers have largely supplanted traditional surgical exci-
sion to become the workhorse surgical modality in the management of OPMDs. La-
sers may be used for excision (ie, using the laser to excise a lesion followed by
histopathologic submission) or vaporization of the lesion. The CO2 laser is the most
frequently studied, and the justifications for use seem to be based on a reduced pro-
pensity for pain, reduced postoperative edema, improved hemostasis, and reduced
scarring.96,97 Similarly, the erbium–yttrium-aluminum-garnet laser has demonstrated
reduced pain levels compared with conventional surgical excision.98
A recent review of the CO2 laser used on OPMDs was conducted by Modegas-
Vegara and colleagues99 and included 17 studies reporting recurrence rates and
MTRs of 3% to 41% and 0% to 15%, respectively, and a follow-up range of 1 year
to 5 years. Due to heterogeneity of methodology and study results, pooled data
were not available to identify factors predicting recurrence or MT. Individual studies
using multivariate analyses, however, did report such predictive factors. Thomson
and colleagues,100 in a cohort of 590 patients, showed that lesion appearance
(OE > OL), grade of dysplasia (ie, severe > mild), and the presence of a lichenoid infil-
trate (no > yes) were predictive for disease-free survival (ie, no evidence of recurrence
18 Nadeau & Kerr
of OPMD). Other studies demonstrated higher rates of recurrence in patients with

multifocal lesions,101 in those who continued to smoke,101 in those with a history of
alcohol use,102 and in those with a previous history of malignancy (oral or other types
of cancer)102 or where there was poor accessibility of the lesion margins.103 None of
the studies showed factors predicting MT, likely due to insufficient sample size and/or
inadequate follow-up.
Cryotherapy
Observational studies have explored the efficacy of cryotherapy to treat OPMDs, all
using clinical remission and recurrence rates as endpoints and reviewed by Yu and
colleagues.104 Liquid nitrogen may be applied by cotton pellet or using a topical spray
(open-system), or the freezing may be applied by a probe (closed-system). Closed
systems provided the most efficient delivery and typically led to complete clinical
remission of OLs with 1 to 6 treatments. Few of the studies included long-term
follow-up; a recurrence rate, of 24%, was reported in only 1 study105; and none of
the studies assessed MT.
Photodynamic therapy
PDT is based on the generation of cytotoxic free radicals from the activation of a
photosensitizer by an appropriate wavelength of light. The photosensitizer (eg, 5-ami-
nolevulinic acid, which is converted to protoporphyrin IX), may be administrated topi-
cally, intralesionally, or systemically, allowing time for it to be accumulated in the target
tissues. The affected tissues are then exposed to the light source (eg, a 635-nm red
light delivered by a laser) leading to a reaction releasing reactive oxygen species
and causing the cytotoxic effect.106 The clinical trials assessing the efficacy of PDT
to treat OPMDs have been systematically reviewed.107,108 In the 16 PDT studies re-
ported in the literature, 14 used topical PDT, and 4 used PDT with intralesional and
systemic photosensitizers (2 studies used 2 treatment arms comparing topical and
systemic delivery). Complete response rates ranged from 23% to 100% and recur-
rence rates from 0% to 36%, but only a few of the studies followed patients for
more than 5 years. Jerjes and colleagues109 conducted a prospective topical PDT
study on the largest and best-characterized cohort of 147 dysplastic OPMDs with a
mean follow-up of more than 7 years. The complete response rate was 81% and
correlated with grade of dysplasia (ie, complete remission 100%, 82%, 81%, and
69% for mild, moderate, severe, and carcinoma in situ, respectively). The recurrence
rate was 11.6%, and an MT was noted in 7.5% of the patients. Residual photosensi-
tization is a major adverse effect when the photosensitizer is delivered systemically;
however, the adverse effects of systemically delivered PDT are minimal and do include
postoperative pain and swelling.
Surveillance (observation)
Surveillance of patients with OPMDs means periodic follow-up at specified time inter-
vals. There are no established evidence-based guidelines for surveillance of patients
with OPMDs; however, given that the risk for MT cannot be predicted, irrespective of
past treatment, experts suggest lifelong surveillance for patients with a history of
OPMDs.94,110 The intervals between such surveillance visits vary depending on
each patient’s clinical course.
WHAT DOES THE FUTURE HOLD?
The molecular era has led to tremendous advances in understanding of the altered ge-
netic and epigenetic landscape that drive carcinogenesis. It is the authors’ hope and
19
Baseline OPMD
Unifocal Low-Risk Unifocal High-Risk

Multifocal Diseasec
Clinical Featuresa Clinical Featuresb
<2 cm >2 cm
Adjunctive technologies (optional)d
Excisional Biopsye Incisional Biopsyf
Low-Risk High-Risk
Histopathologyg Histopathologyh
Risk factor modification
Pathway 1i Pathway 3k
Pathway 2j Surgical Excision Other Modalities
Surveillance
Progression
Recurrencel
Fig. 10. Potential management strategies for patients with OPMDs. a Low-risk clinical fea-
tures: homogeneous leukoplakia. b High-risk clinical features: nonhomogeneous leukopla-
kia, erythroplakia, erythroleukoplakia, and/or ulceration. c Multifocal disease: multisite
lesions that are PVL. d Adjunctive techniques (optional, may be used if clinician has exper-
tise): may facilitate biopsy site selection/margin determination. e Excisional biopsy: lesion
<2 cm in diameter, accessible surgical site. f Incisional biopsy: lesion >2 cm, single site for ho-
mogeneous lesions(s); single or multiple sites for nonhomogeneous lesion(s). g Low-risk his-
topathology: epithelial hyperkeratosis/hyperplasia, verrucous hyperplasia, mild epithelial
dysplasia. h High-risk histopathology: moderate-severe epithelial dysplasia, carcinoma-in-
situ. Note: if OSCC, patient referred for oncologic management. i Pathway*1: initial surgical
excision (unless lesion underwent baseline excision), that is, removal of visible lesion by cold
blade, electrocautery, laser. This pathway is indicated preferably for lesions with high-risk
pathology that are amenable to surgery, or optional for lesions with low-risk pathology.
j
Pathway* 2: initial surveillance, that is, monitoring those patients who (1) underwent suc-
cessful baseline excisional biopsy with a diagnosis of either high or low-risk pathology, but
with no residual lesion; (2) have a residual lesion or lesions after baseline biopsy with a diag-
nosis of low-risk pathology; or (3) have a residual lesion or lesions after baseline biopsy with
a diagnosis of high-risk pathology that are not amenable to surgery. k Pathway* 3: other
modalities, that is, PDT, chemoprevention, or other modalities as per experience of provider.
l
Progression/recurrence: clinical progression of existing OPMD, or recurrence of OPMD after
treatment, warranting further diagnostic evaluation. If MT, patient referred for oncologic
management. * Note: there are no evidence-based management pathways. In general,
expert clinicians should manage all patients with a histopathologic finding of dysplasia
(low risk and high risk), carcinoma in situ and OSCC.
20 Nadeau & Kerr
expectation that these molecular advances will allow clinicians to improve risk strati-
fication of patients with OPMDs, linking them to interventions commensurate with their
risk profiles, particularly through the development of a genome atlas for OPMDs.54,111
There would be justification for aggressive surgical/ablative treatment or systemic
agents associated with toxicity (eg, chemotherapy, targeted therapy, or even immuno-
therapy) for patients with OPMDs at high risk for progression and MT. For those with a
moderate-risk profile, a less aggressive approach is indicated, possibly including low-
toxicity chemopreventive agents. The lowest-risk patients might be amenable to
surveillance alone with periodic assessment for markers (histopathologic, cytopatho-
logic, or other novel biomarker assessment). Translational research leading to the
identification of agents that target important pathways of carcinogenesis are under
development and in clinical trials. One drug currently under investigation is metformin,
an oral hypoglycemic agent with an excellent safety profile, which has been shown in
case-control studies to reduce the risk and prognosis of head and neck cancers,112
and in animal studies to reduce the activity of the mammalian target of rapamycin
complex 1 and lower the risk of MT.113 Another promising drug, the anticonvulsant
agent valproic acid, has been demonstrated to be a potent inhibitor of proliferation
in vivo.114
Surgical excision performed in conjunction with adjuncts that can facilitate margin
delineation (eg, optical detection methods, vital staining, or nanotechnologies with
ligands that bind specifically to neoplastic cells) are also under investigation. Finally,
surveillance of patients with a history OPMDs using emerging technologies (eg, live
biopsies using high-resolution microendoscopy, optical coherence spectroscopy
and other optical platforms, and point-of-care salivary or cytopathologic platforms
using combinations of predictive biomarkers) could conceivably replace the need
for invasive biopsy and histopathology and allow for improved monitoring. Yet, all
these advances come with a price tag, and with current health care costs, it is
hard to imagine these novel technologies will quickly move across all tiers of clinical
care.
Study design is critical to the evaluation of new interventions. Adequately powered
multicenter prospective RCTs with meaningful endpoints (ie, MTRs or validated surro-
gate markers) and sufficient follow-up are needed. Changes in habit use patterns dur-
ing studies can confound study results and must be assessed.
SUMMARY
The management of patients with OPMDs must begin with modification of avoidable
risk factors, such as tobacco use, heavy alcohol, and poor diet. Regression of OPMDs
is possible with this strategy alone; however, follow-up is critical. Risk stratification
based on the current paradigm of clinical and histopathologic factors dictates that pa-
tients with unifocal OPMDs with high-risk clinical features (ie, nonhomogeneous OLs
[eg, erythroleukoplakias], OE, or persistent ulcers with no clear explanation) undergo
incisional biopsy or biopsies to establish a baseline diagnosis. Such lesions often have
variable histopathology and those diagnosed with moderate to severe dysplasia (or
carcinoma in situ), if amenable in terms of size or accessibility, are strong candidates
for surgical excision (with submission of the specimen for histopathologic evaluation,
including margin assessment). Patients with unifocal OPMDs with low-risk features,
such as well-circumscribed, small (ie, <200 mm2), flat, homogeneous leukoplakias,
typically have a diagnosis of mild or moderate epithelial dysplasia and are amenable
to excisional biopsy at baseline. All patients with a history of dysplasia, similar to those
with a history of OSCC, require close surveillance for recurrence or MT.
The challenge in patients with OPMDs is the management of those who recur
despite baseline excision or those with multifocal disease, such as PVL with high rates
of MT. Serial excisions are often fruitless, and expert clinicians typically resort to close
surveillance to intercept early MT, followed by oncologic treatment. Fig. 10 delineates
potential management strategies for patients with OPMDs.
The role for other surgical/ablative modalities or chemopreventive agents is dictated
by the experience and preference of the treating clinician, with appropriate informed
consent to allow patients to understand the risks and benefits.
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Dent Clin N Am 52 (2008) 1–17
Multidisciplinary Approach to Cancer

Treatment: Focus on Head
and Neck Cancer
Robert Haddad, MDa,*, Donald Annino, DMD, MDb,
Roy B. Tishler, MD, PhDc
a
Department of Medical Oncology, Dana Farber Cancer Institute, 44 Binney Street,
Boston, MA, 02115, USA
b
Division of Otolaryngology and Head and Neck Surgery,
Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, USA
c
Department of Radiation Oncology, Dana Farber Cancer Institute,
Brigham and Women’s Hospital, Boston, MA, 02115, USA
Three major modalities are used in treating cancer: surgical resection, ra-
diation therapy, and chemotherapy. Depending on the type of cancer and its
stage, patients will be treated with one, two, or three modalities concurrently
or consecutively. Surgery and radiation therapy are considered local/defin-
itive therapies, but do not address the issue of distant metastasis, which
can only be achieved with chemotherapy.
Patients who have different types of cancer require different types of
treatment, and cancers can be divided into two major categories:
1. Solid tumors such as lung, breast, colorectal, head and neck, and
prostate. These cancers are typically treated with a multidisciplinary ap-
proach combining surgery, radiation, and chemotherapy.
2. Hematological malignancies such as leukemia, multiple myeloma, and
lymphoma. Treatment is primarily with chemotherapy; radiation ther-
apy plays a limited role. The exception is Hodgkin lymphoma, where ra-
diation plays a key role in tumor control.
This article focuses on squamous cell carcinoma of the head and neck
(SCCHN), the most common malignancy of the head and neck area. These
malignancies are quite important for the general dentist, who is in a unique
position to detect these tumors early. Early detection limits morbidity of
E-mail address: robert_haddad@dfci.harvard.edu (R. Haddad).
2 HADDAD et al
treatment and increases the chances of a cure. The treatment of SCCHN is

often multidisciplinary in nature and provides a model for how multimodal-
ity therapy may be applied for optimal patient management.
General principles: head and neck cancer

SCCHN affects approximately 40,000 patients each year in the United
States [1]. Most of the cancers are related to cigarette smoking, although re-
cent studies show that the human papillomavirus (HPV) is likely an impor-
tant etiologic agent in squamous cell carcinomas of the oropharynx [2].
Under the broad umbrella term of ‘‘head and neck cancer’’ are included can-
cers of the nasopharynx, oropharynx (tonsil and tongue base), oral cavity
(tongue, floor of mouth, gingiva, palate, buccal mucosa, and lips), larynx,
and hypopharynx. Management of these malignancies is complex, and
a multidisciplinary approach is often required. Many vital structures in
the head and neck area are affected by therapy, and organ preservation is
a major focus when treating a patient with SCCHN to try to preserve struc-
ture and function. Negative sequelae such as difficulty speaking, swallowing,
and breathing may be permanent and often result in significant physical and
psychologic dysfunction in surviving patients. Therefore, multiple specialties
are involved in managing these patients before, during, and after treatment.
Those include care providers in the fields of dentistry, physical therapy,
speech and swallowing therapy, nutrition, psychiatry, and social work.
Patients with SCCHN can present with a variety of symptoms depending
on the site of primary tumor involvement. For example, hoarseness is com-
mon in a laryngeal cancer, whereas dysphagia, odynophagia, and a sore
throat are more common in oropharyngeal cancer. Other symptoms include
difficulty with chewing (primary tumor in the oral cavity) and unilateral or
bilateral nasal symptoms (primary tumor in the nasopharynx). The history
and symptoms help to locate the site of the primary cancer (especially if the
tumor is not easily visualizeddsuch as, base of tongue, pharyngeal or laryn-
geal lesions). Such symptoms should also raise the index of suspicion for
cancer in a smoker. SCCHNs usually present as white or red plaques, ulcers,
or masses. Unfortunately, most of the patients will have a neck mass on pre-
sentation, representing lymph node metastasis, and often this is the reason
the patient sought medical attention in the first place.
Staging for SCCHN starts with an examination under anesthesia per-
formed by a head and neck surgeon in the operating room. This is some-
times called a triple endoscopy as it involves assessment of the larynx,
esophagus, and trachea. The goals are to establish a tissue diagnosis via a bi-
opsy, stage the cancer, and rule out the presence of a second primary, a com-
mon occurrence in patients with SCCHNs.
Once tissue diagnosis is established, imaging studies are helpful to further
delineate the extent of the tumor and its relationship with adjacent struc-
tures, and to stage it. Imaging studies such as CT scans, MRI, and PET
MULTIDISCIPLINARY APPROACH TO CANCER TREATMENT 3
scans are all useful for staging. MRIs are more helpful for evaluating soft-
tissue involvement; CT scans are more beneficial for evaluating bone
involvement. PET scanning is a nuclear medicine imaging technique that
produces a three-dimensional image or map of functional processes in the
body. To conduct the scan, a short-lived radioactive tracer isotope is in-
jected into the patient. This tracer becomes chemically incorporated into
a metabolically active molecule and decays rapidly by emitting a positron.
The molecule most commonly used for this purpose is fluorodeoxyglucose,
a sugar molecule. Cancers may use more energy and glucose than surround-
ing tissues and therefore appear brighter on the PET scan.
The role of PET scanning in the diagnosis and staging of SCCHN is not
well defined, and there is no agreement yet on when and how to use it. In the
pretherapy setting, PET scanning is used as a whole-body imaging tool to
complete the initial staging of the primary tumor and the neck and to rule
out distant metastasis. In the post-therapy setting, however, it often results
in a high false-positive rate because of inflammation that is present after sur-
gery and chemoradiotherapy [3]. In some institutions, PET scans are in-
creasingly being used as part of radiation planning, but this is still
considered investigational.
The staging system used in SCCHN is the standard T (tumor) N (nodes)
M (distal metastasis) (Table 1). The single most important determinant of 5-
year survival is the stage of disease at presentation (Table 2).
Patients who present with early stage disease (ie, stage I and II disease)
are typically treated with a single modality approach such as radiation
Table 1
Staging of squamous cell carcinoma of the oral cavity
Tumor size
– T1: Tumor 2 cm or less in greatest dimension
– T2: Tumor size between 2 and 4 cm in size
– T3: Tumor greater than 4 cm in size
– T4: Tumor invading adjacent structures such as bone, skin, deep muscle of tongue,
pterygoid plates, skull base
Lymph node involvement
– N0: No lymph nodes metastasis
– N1: One lymph node involved; 3 cm or less in size
– N2a: One lymph node involved; more than 3 cm and less than 6 cm in size
– N2b: Multiple ipsilateral lymph nodes involved; none bigger than 6 cm in size
– N2c: Multiple bilateral or contralateral lymph nodes involved none more than 6 cm in size
– N3: At least one lymph node more than 6 cm in size
Distant metastasis
– M0: No distant metastasis
– M1: Distant metastasis present
Stage I: TIN0
Stage II: T2N0
Stage III: T3N0, T3N1, T2N1, T1N1
Stage IV: All others
4 HADDAD et al
Table 2
Five-year relative survival rates by stage at diagnosis
Regionala: stage
III and IV,
All stages Local: stage no distant Distant: stage IV
Site (%) I and II (%) metastases (%) distant metastasis (%)
Larynx 64.1 83.5 50.4 13.7
Oral cavity and pharynx 58.8 81.3 51.7 26.4
a
Refers to lymph nodes involvement.
Data from American Cancer Society. Cancer facts and figures 2007. Atlanta (GA):
American Cancer Society, 2007.
therapy or surgery and typically have a favorable prognosis (see Table 2).
The choice of therapy depends on site of the primary tumor, the expected
functional outcome, and the experience of the doctors at the treating center.
On the other hand, most oral cancers are treated with surgery regardless of
the stage of the disease.
Unfortunately, approximately 75% of patients with SCCHN present
with locally advanced disease (ie, stage III and IV), and will require a multi-
disciplinary approach that incorporates chemotherapy, radiation, and
surgery. This treatment, though still potentially curative, often has serious
acute and long-term side effects (eg, mucositis, acute and chronic pain,
swallowing dysfunction, shoulder pain and dysfunction, xerostomia and
hyposalivation, dental problems, depression, and anxiety). With increasing
numbers of survivors, quality of life has become a very important outcome
measure (see related article elsewhere in this issue). Up to 40% of these
patients with stage III and IV disease will have a recurrence, either locally
or at distant sites, and often become noncurable. Management of these
patients includes salvage surgery if feasible, re-irradiation, and/or palliative
chemotherapy. In general, patients with laryngeal cancer have more poten-
tial for curative salvage surgery after chemoradiotherapy failures than
patients with cancers at other head and neck sites [4].
Treatment of locally advanced SCCHN is currently undergoing a funda-
mental change. In the past, most patients with SCCHN of any stage were
treated primarily with surgery. Today, the standard of care for patients
with previously untreated, newly diagnosed, stage III and IV disease has
been concurrent chemotherapy and radiation therapy. This is based on
multiple phase III studies that established chemoradiotherapy as the best
therapy in patients who have unresectable disease [5], laryngeal cancer [6],
and nasopharyngeal cancer [7] and in patients treated postoperatively
[8,9]. However, oral cavity cancer continues to be managed primarily with
surgery, regardless of stage. The chemotherapy agent most commonly stud-
ied and used is bolus cisplatin. The toxicity of cisplatin is significant, and
many patients are not able to tolerate the prescribed high-dose therapy dur-
ing radiation. Fortunately, identification of molecular targets within cancer
cells has led to the introduction of novel biologic agents for treating
SCHNN. Indeed, cetuximab (Erbitux, ImClone Systems Inc., Branchburg,
NJ), an epidermal growth factor receptor (EGFR) inhibitor, was recently
approved by the US Food and Drug Administration (FDA) for the treat-
ment of locally advanced and recurrent head and neck cancer, including
oral cavity tumors [10,11]. Another new approach that is being increasingly
used in the clinic is sequential chemoradiotherapy (see below), with encour-
aging results from recently reported phase III studies [12,13]. An area of ac-
tive research in head and neck cancer is the development of cytoprotective
agents and techniques that mitigate some of the effects of chemotherapy
and radiation (see the articles by Lalla and colleagues and Fischer and Ep-
stein elsewhere in this issue).
Chemotherapy in squamous cell carcinoma of the head and neck

Chemotherapy can be used in the following three settings:
1. Induction chemotherapy (also known as neoadjuvant chemotherapy or
sequential chemotherapy). This refers to using chemotherapy before
definitive therapy (radiation therapy, chemoradiotherapy, or surgery).
This is often used in patients with locally advanced disease and in pa-
tients with advanced nodal disease (ie, N2 and N3). These patients
have a high rate of distant metastases on follow-up.
2. Concurrent chemoradiotherapy. In this model, chemotherapy is given
during radiation therapy usually in an effort to achieve radiosensitiza-
tion. This is a very common modality of treatment for cancers of the
head and neck, esophagus, lung, rectum, and cervix.
3. Adjuvant chemotherapy, where chemotherapy is given after definitive ther-
apy (surgery and/or radiation). This is done in an effort to eradicate micro-
metastasis. Adjuvant chemotherapy offers a survival advantage in patients
with breast and colorectal cancer. The only setting where adjuvant chemo-
therapy is given in SCCHN is a primary tumor in the nasopharynx.
All of these delivery methods are used in SCCHN, and treatment is
usually dependent on the site and stage of the tumor. Early stage I and II dis-
ease is treated with a single modalitydeither surgery or radiation therapyd
whereas more advanced disease is treated with chemotherapy, radiation,
and surgery. Concurrent chemoradiotherapy had been the cornerstone in
treating locally advanced disease [5,6,14]. Recent data support the use of in-
duction chemotherapy, followed by concurrent chemoradiotherapy. Clinical
trials have established the superiority of TPF [13] (Taxotere [docetaxel; Sa-
nofi-aventis, Bridgewater, NJ], cisplatin, and 5-fluorouracil) as the best in-
duction regimen. Current trials are under way to compare TPF-based
induction regimens with concurrent chemoradiotherapy [15].
Table 3 provides a summary of the agents typically used in head and neck
cancer and the circumstances in which they are used. In general, the classes
Table 3
6
F
Commonly used agents and regimens in squamous cell carcinoma of the head and neck
2
Agent/regimens Mechanism of action Dosage Benefits Side effects Notes

A
AB
Cisplatin Alkylating agent 75 or 100 mg/m2 Survival benefit when Nausea, vomiting, Could be used both in
A(
2 DB
every 3 wk combined with neuropathy, ototoxicity, a curative setting with

radiation renal failure radiation or for
palliation as a single
agent for recurrent/

metastatic disease
Cisplatin (P) Alkylating agent Cisplatin: 75 or Survival advantage Nausea, vomiting, Could be used in an
100 mg/m2 when combined with neuropathy, ototoxicity, induction setting,
radiation therapy renal failure, mucositis, during radiotherapy, or
diarrhea for palliative therapy in
recurrent disease
HADDAD
5-Fluorouracil Antimetabolite 5-Fu: 1000 mg/m2/qd
(5-FU) continuous infusion
for 5 d
et al
Cisplatin (P) Alkylating agent Cisplatin: 75–100 mg/m2 Survival advantage Nausea, vomiting, Induction chemotherapy
A
compared with PF neuropathy, ototoxicity, regimen in curative

A
when used in an renal failure, mucositis, settings; FDA approved

C
induction setting diarrhea, hair loss, bone for unresectable disease

2/
marrow suppression
Docetaxel (D) D: microtubule targeting Docetaxel: 75 mg/m2
,B E A. ( A
5-FU 5-Fu: antimetabolite 5-Fu: 1000 mg/m2/

3 ,B E A
d continuous
infusion for 4 d
Carboplatin (C) Alkylating agent Carboplatin: Alternative to cisplatin Neuropathy, bone marrow Used in combination with
AUC 1.5 weekly regimens; very well suppression radiotherapy
tolerated
3AD2A
CB A B AE
Paclitaxel (P) Microtubule targeting Paclitaxel: 45 mg/m2
F
weekly
Carboplatin (C) Alkylating agent Carboplatin: AUC Alternative to cisplatin Neuropathy, bone marrow Used in induction setting
2
A
6 every 3 wk regimens suppression, hair loss with radiation for cure

AB
or in palliative setting
A(
2 DB
for recurrent disease

Paclitaxel (P) Microtubule targeting Paclitaxel: 200 mg/m2
MULTIDISCIPLINARY APPROACH TO CANCER TREATMENT

every 3 wk
40 mg/m2 weekly
Methotrexate Antimetabolite Well tolerated, palliative Mucositis, hepatitis Used for palliation
Docetaxel Microtubule targeting 30–35 mg/m2 weekly Palliative Fatigue, fluid retention, Used for palliation
or 75–100 mg/m2 bone marrow
every 3 wk suppression
Cetuximab EGFR inhibitor 250 mg/m2 weekly Survival advantage in Skin rash, Survival advantage in
curative setting and hypomagnesemia, curative setting when
can be used for infusion reaction combined with
palliation radiation. For palliation
in patients with
platinum-refractory
A
head and neck cancer

with a 10% response
A
rate.
C
2/
Abbreviation: EGFR, epidermal growth factor receptor.

,B E A. ( A
3 ,B E A
3AD2A
CB A B AE
7
8 HADDAD et al
of drugs most efficacious in treating SCCHN are alkylating agents and an-
timetabolites. The agent most commonly used is bolus cisplatin every
3 weeks during radiation, and this drug is considered to be the reference
drug in SCCHN [5,6]. The toxicity of cisplatin is significant, and many pa-
tients are not able to tolerate the prescribed high-dose therapy during radi-
ation. Toxicities include neuropathy, hearing loss, kidney failure, and bone
marrow suppression. Other drugs commonly used are carboplatin, metho-
trexate, and 5-fluorouracil.
Among the newer chemotherapy agents, taxanes such as docetaxel and
paclitaxel appear to have significant activity against SCCHN [16]. Cetuxi-
mab, an EGFR inhibitor, was recently approved by the FDA in combina-
tion with radiation [10] in the treatment of curable patients with locally
advanced disease and as a single agent for patients with cisplatin-refractory
disease [11]. Cetuximab is a monoclonal antibody that specifically targets
EGFR, which is overexpressed in the majority of squamous cell carcinoma
cell lines [17]. There is a clear synergistic activity between these new agents
and radiation and chemotherapy.
The trend in chemotherapy in SCCHN is following the advances that
have occurred in the treatment of other solid tumors such as lung, breast,
and, most notably, colorectal cancer. Results of trials performed in patients
with these cancers show that combination therapy with chemotherapy and
targeted biological therapy instead of radiation improves outcomes. Bevaci-
zumab (Avastin, Genentech, Inc., South San Francisco, CA), an anti-angio-
genesis drug that targets vascular endothelial growth factor (VEGF), for
example, is becoming a standard agent used in combination with chemo-
therapy in lung and colorectal cancer. There is synergistic activity when
these biologic agents are combined with standard chemotherapy. In recur-
rent, refractory, and metastatic SCCHN, current studies are investigating
these new targeted agentsdespecially VEGF inhibitorsdused both as single
agents and in combination with standard chemotherapy. No VEGF inhibi-
tors are currently approved for treatment of head and neck cancer.
Radiation therapy in squamous cell carcinoma of the head and neck

Radiation therapy is an intensive local-regional treatment, directed at
a limited volume of tissue, typically including the primary tumor site and
draining lymphatics. In addition to the curative potential of radiation, it
can have a significant impact on the oral health of the cancer patient in both
the long and short term. Two main radiation modalities are used in cancer
management.
External beam radiation is delivered by an accelerator from multiple angles
and directed at targets within the patient; it is delivered as outpatient treatment
on a daily basis, 5 days a week, over the course of 6 to 7 weeks. The radiation
travels through other tissue before reaching the tumor or lymph nodes, and
this leads to toxicities associated with external beam treatment. External beam
radiation therapy is the foundation of nonsurgical, conservative management
of multiple types of solid tumors. In particular, the treatment has long played
a central role in the curative therapy of SCCHN.
Brachytherapy involves the insertion of radioactive sources or implants
directly into a tumor. This has the advantage of direct treatment of the tu-
mor, but limits the volume of tumor that can be treated. It has the disadvan-
tage of requiring a surgical procedure, typically under general anesthesia,
for implant placement.
Curative treatment of squamous cell carcinoma of the head

and neck by radiation therapy
Radiation therapy is typically delivered to a well-immobilized patient ly-
ing supine on table, using 6-MV photons emanating from a linear accelera-
tor. The basis for the efficacy of radiation is its ability to (1) physically target
tumor tissue while minimizing the dose delivered to normal structures and
(2) effect a biological differential between damage to the tumor and the toxic
effects on normal tissue. Unlike surgical treatment of a site, radiation treat-
ment will leave targeted and adjacent tissues intact (organ preservation).
The goal remains tumor cure, while maintaining a high degree of function.
In deciding on an overall treatment program for a patient with SCCHN,
radiation may be used in the following ways:
1. It can often substitute for surgery as the primary modality of treatment;
the use of nonsurgical treatment approaches is clearly increasing in
SCCHN. This is especially true for advanced, stage III and IV cancers
of the oropharynx, hypopharynx, and larynx.
2. In cases where surgery is the primary therapeutic modality, radiation can
play an adjuvant role [8]. This is especially true for cancers of the oral cav-
ity, where surgery is used first and radiation or chemoradiation is given as
adjuvant therapy. Patients who have high-risk features on the pathology
specimen should receive chemoradiation after surgery. Those features are
positive margin(s), perineural invasion, lymphovascular invasion, pres-
ence of multiple positive lymph nodes, and extra-nodal spread [8,9].
3. Radiation can be used to treat high-risk areas postoperatively such as
the lymph node regions when extra-nodal extension is present, or the
primary site if there are poor prognostic features such as positive mar-
gins or local extension.
4. Radiation may also be used in combination with chemotherapy (dis-
cussed in greater detail below).
The first step in establishing a treatment plan, and what underlies all
planning for radiation treatment of SCCHN, is to define the volumes, or
‘‘targets,’’ to be treated. The gross tumor volume will include both the pri-
mary tumor and grossly involved lymph nodes. The information used to
10 HADDAD et al
identify these volumes will be integrated from multiple sources, including

the physical examination, CT, MRI, and PET scans. These targets will
include multiple structures/volumes that require the delivery of different ra-
diation doses and are outlined on individual planning CT slices. Knowledge
of the natural history and routes of spread for all of the disease processes is
critical to establishing optimal target definition.
Gross disease is treated with the highest dose of radiation, typically 70 to
72 Gy, as this volume of gross disease contains the highest tumor burden.
The next highest dose will be given to the ‘‘high-risk’’ volume, which con-
sists of several different types of structures. The high-risk volume includes
the area adjacent to the tumor that is likely to contain microscopic disease
as a result of local extension, typically defined as a 1- to 2-cm margin around
the primary tumor and grossly involved lymph nodes. Also included in the
high-risk volume are lymph node regions that have a high likelihood of har-
boring subclinical nodal disease. For example, in a floor or mouth or oral
tongue (anterior 2/3) squamous cancer, level 1 submandibular and submen-
tal lymph nodes in the neck would always be included in this volume; for
a tonsil primary, the ipsilateral level 2 jugulo-digastric nodes are always con-
sidered high risk. Other nodal groups or anatomic regions may be consid-
ered high risk, depending on the primary site and disease distribution.
The last target defined is a ‘‘low-risk’’ region, which would often consist
of the supraclavicular lymph nodes and much of the contralateral neck.
The precise definition of each of these volumes is critically dependent on
the details of the clinical presentation of the tumor.
The radiation oncologist must also identify normal structures that need to
have dose limits respected. There are ‘‘absolute’’ limits, such as limiting expo-
sure to the spinal cord (w45 Gy) and optic chiasm (w54 Gy) dose, given the
dire consequences of a functional cord transection or visual impairment.
Other, less rigid limits to structures such as the oral cavity, mandible, larynx,
and parotid glands can play a major role in the short- and long-term quality of
life outcomes, but the radiation oncologist can exercise more latitude here.
Clearly, the proximity of the normal tissue to the targets and the differences
between the tolerance doses of the normal structures and the doses needed
to control the tumor are what make this field so challenging for the head
and neck radiation oncologist.
There is a continuing evolution within the field of radiation oncology as
to how to best achieve these differential dose distributions, and this is inti-
mately related to the technology used for treatment. The traditional ap-
proach has been to employ a series of shrinking fields or sequential ‘‘cone
downs’’ to achieve this dose differential. For example, the initial set of fields
for an oral tongue cancer would include all target volumes discussed above.
An initial cone down would block the spinal cord after it had received 45 Gy
and continue to treat the overlying lymph nodes with a more superficial type
of radiation (electrons) to respect cord tolerance. Following this, the dose to
the supraclavicular lymph nodes would be limited by stopping treatment of
this field. For the last cone down or ‘‘boost,’’ the gross tumor and a margin
around it are treated. With these techniques, a constant dose is delivered to
all sites once on a given day (1.8–2.0 Gy), and the differential dosing is
achieved by changing volumes as treatment progresses.
A current approachdand an evolving standard for treating head and
neck cancersdis intensity modulated radiation therapy (IMRT), which is
a computation-intensive technique for delivering radiation. IMRT gives
the radiation oncologist much greater control over the spatial distribution
of the radiation doses delivered [18]. With IMRT, differential dosing can
be achieved by treating different targets to a different dose each day
(‘‘dose painting’’). This clearly has the potential for improved outcomes in
patients, both by allowing minimization of the normal tissue doses and
flexibility to increase tumor doses [19]. Early data have demonstrated
both excellent local control [20] as well as clinically significant improvements
in salivary flow [21], an important positive outcome. IMRT requires a signif-
icant investment of time on the part of both the radiation oncologist, who
must contour each structure on all relevant CT slices, and the radiation
physicist to plan a multiple field treatment with constantly moving field
borders.
Current radiation-based therapy

Two major advances in radiation therapy are altered fractionation and con-
current systemic therapy. Altered fractionation refers to using different radia-
tion schedules than the standard fractionation of 2 Gy per day to a total dose of
70 Gy. There are two main approaches to altered fractionation, and both in-
volve delivering multiple treatments per day for at least part of the therapy. Hy-
perfractionation is designed to take advantage of the decrease in long-term
toxicity if smaller individual doses, or fractions, are given so that more dose
can be delivered to the tumor. This involves patients receiving two 1.2-Gy
fractions per day to doses in excess of 80 Gy. The other schedule, concomitant
boost, involves the delivery of two fractions per day for the latter portion of the
treatmentdusually 1.8 Gy daily for 3.5 weeks, followed by 1.8 Gy/1.5 Gy as
twice daily therapy for the last 2.5 weeks of treatmentdand is based on tumor
kinetics. Both approaches have been demonstrated to improve local control in
a phase III study and are considered the standard of care for patients receiving
radiation alone for advanced SCCHN [22].
The other area of improvement in radiation-based therapy has resulted
from the addition of systemic therapy to standard fractionation. Many differ-
ent agents have been employed, with bolus cisplatin every 3 weeks the most fre-
quently used. The drugs given in this way are typically delivered at lesser doses
than if they are given as ‘‘stand-alone’’ treatment and are primarily used as ra-
diation sensitizers and result in better tumor control. A compound or chemo-
therapy drug functions as a radiosensitizer if it adds to the efficacy of radiation
but could not be effective as an anticancer agent if used alone. The most recent
12 HADDAD et al
addition to the drugs for concurrent systemic therapy is the targeted therapy
cetuximab, which when added to radiation leads to improved survival [17].
Though an appealing treatment approach due to the relative ease of giving ce-
tuximab this cannot yet be considered as a standard of care. At present, both
altered fractionation radiation and systemic therapy and radiation are better
than standard daily radiation. Which is better and the best combination of
these are ongoing research issues.
A note of caution needs to be added here, as the treatment modifications
leading to improvements in tumor control are associated with increases in
acute and long-term toxicity. Broadly speaking, the ‘‘cost’’ of radiation-
based organ-sparing treatment of SCCHNs can be significant in terms of lo-
cal toxicity, particularly to structures and functions of the oral cavity and
oropharynx [23]. Interest in studying and minimizing local toxicity has
increased as the survival rates improve for patients with SCCHN. Acutely,
radiation causes mucositis, which leads to increased difficulty eating and
swallowing, as well as pain and a susceptibility to infection. Among the
long-term consequences are xerostomia and hyposalivation; increased risk
of dental caries; and difficulty with taste, eating, speaking, and swallowing
[24]. Effects on the mandible vascular supply make it more prone to the de-
velopment of postradiation osteonecrosis [25] after dental manipulations.
There are radiation-based and pharmacologic approaches to mediate these
effects, but aggressive preventive and supportive care remains an essential
component. Among the pharmacologic approaches used to modulate
toxicity is the use of amifostine [26] and pilocarpine [27], though no toxic-
ity-based treatment has achieved universal acceptance. (see the article by
Fisher and Epstein elsewhere in this issue).
Surgical therapy in squamous cell carcinoma of the head and neck

Historically, surgery played a dominant role in the management of head
and neck cancer. This is clearly changing with the widespread use of chemo-
therapy and radiation. The goal of surgical resection, when indicated, is to
remove the tumor completely while maximizing preservation of form and
function for the patient. The role of surgeon in the head and neck clinic is
evolving and can be summarized as follows:
1. Initial staging and biopsy.
2. Surgical management of oral cavity cancers. These are best managed by
surgery first regardless of disease stage.
3. Surgical management of early stage I and II oropharyngeal and laryn-
geal cancer. Chemoradiotherapy is often used to treat advanced stage
III and IV disease, and surgery for salvage therapy.
4. Neck dissection (ND) in patients who have persistent neck adenopathy
after radiation or chemoradiation and up-front as part of the surgical
management of oral cavity cancer and early-stage oropharynx cancer.
5. Follow-up after primary therapy.

6. Surgical management of other tumors such as salivary gland and
thyroid tumors.
Surgery has evolved in the management of SCCHN. Overall, there has
been a trend toward minimally invasive procedures in all aspects of surgery
as compared with en bloc resections. This is also true for surgery for
SCCHN, and this concept has played a role in the management of cancer
of the larynx, oropharynx, supraglottis, hypopharynx, the paranasal sinuses,
and anterior skull base. Many cancers are treated with chemoradiation to
offer organ preservation (eg, in advanced stage III and IV laryngeal and
hypopharyngeal cancers); surgery is now mainly for salvage purposes.
A new form of minimally invasive procedure is transoral microsurgery,
where the tumor is approached from the oral cavity. Results from Europe
indicate oncologic outcomes are not compromised with the transoral resec-
tion [28]. A multicenter study from the United States also demonstrated
good local control and excellent functional results with swallowing and
voice [29]. However, at this time there is not a clear advantage of transoral
microsurgery with respect to function compared with open-en bloc proce-
dures. The advantages of the transoral approach include the decreased
need for a tracheotomy and a shorter hospital stay. However, ND for stag-
ing, which is usually indicated in these patients, cannot be performed at the
same time as the transoral microsurgery because of the risk for laryngeal
edema and subsequent need for tracheotomy, potential for infection, and
development of a fistula to the neck [28]. Therefore, the disadvantage of
this technique is that a second operation to stage ND has to be performed
2 to 3 weeks after the primary site is resected.
With improved control rates of chemoradiation at the primary tumor
site, the role of surgery to treat metastatic disease to lymph nodes in the
neck has evolved. If the patient has a complete response (no clinically pal-
pable nodes or nodes seen on imaging), there is no clear benefit from an
ND even if the patient has initially been diagnosed with an N1 or
N2 neck. If a lymph node can still be palpated or is seen on the neck CT
or PET/CT scan after chemoradiation, a ND is recommended and is typi-
cally performed 8 to 12 weeks postradiation. However, all patients with
an initial diagnosis of an N3 neck will still need a ND even with what ap-
pears to be a complete response by imaging and examination [30]. Box 1
summarizes the six lymph node levels in the neck. Parts of or all of the nodes
at these levels are dissected depending on the clinical situation.
Surgery is also used for the treatment of complications, as chemoradia-
tion has assumed a larger role in the treatment of locally advanced laryngeal
and hypopharyngeal cancers. Hypopharyngeal stenosis has become more
prominent [31] independent of the primary site treated and may occur
even after treatment of primary oral cavity tumors. The stricture usually oc-
curs at the level of the postcricoid region and becomes evident months after
14 HADDAD et al
Box 1. Lymph node levels/nodal regions

Level I: Submental and submandibular triangles
Levels II, III, and IV: Nodes associated with internal jugular
vein within fibroadipose tissue
Level II: Upper-third jugular chain, jugulo-digastric,
and upper posterior cervical nodes
Level III: Middle jugular nodes
Level IV: Lower jugular nodes
Level V: Posterior triangle of neck
Level VI: Anterior compartment structures
completion of the treatment. Treatment is with endoscopic dilation; 93% of

patients will resume swallowing after dilation and 81% will maintain their
weight on an oral diet. However, complications include perforation, abdom-
inal wall infection, and stomach wall dehiscence [31].
Surgery and oromandibular reconstruction after chemoradiation remain
a challenge. The optimal reconstruction options for large, complex defects
of bone and soft tissue remain free-tissue transfer. It offers a single-stage re-
construction at the time of surgical resection and allows for the replacement
of what was lost by using vascularized, nonradiated tissue in a post-chemo-
radiation/radiated patient. The options of microvascular free-tissue transfer
have not changed significantly. The workhorse flaps remain the radial fore-
arm, the anterolateral thigh, and the rectus abdominus for soft-tissue recon-
struction. The most common flap for immediate bone reconstruction is the
osseocutaneous fibula free flap. The potential disadvantages of free-tissue
transfer include deficits in the donor site from both a cosmetic and func-
tional perspective. Attempts to improve these two concerns have resulted
in the emergence of free-tissue perforator flaps.
Reconstruction advancements also include a move away from larger
titanium reconstruction plates to more pliable and thinner plates. This
primarily occurs with the use of vascularized bone grafts for segmental man-
dibular reconstruction. Farwell and colleagues [32] have shown that the use
of 2.0-mm locking reconstruction plates are as effective as the more bulky,
2.4- and 2.8-mm plates.
Major functional deficits may occur after surgery that may not be ame-
nable to reconstructive surgery. In such cases, patients and surgeons alike
should work closely with a maxillofacial prosthodontist and speech and
swallowing therapist to help the patient regain as much function as possible.
Other negative sequelae include anesthesia of the skin and mucosa after
nerve resection, neuropathic pain, and poor cosmetic outcome. Patients
may become more socially isolated because of cosmetic and functional dif-
ficulties (eg, embarrassment because of eating and swallowing difficulties),
resulting in depression and an increased risk of suicide. Health care pro-

viders should remain vigilant to these complications and provide the neces-
sary support and referrals where appropriate.
The role of surgery in SCCHN is continually evolving. The surgeon’s role
in the multidisciplinary treatment of head and neck cancers has changed as
more cancers are being treated by chemoradiotherapy. Salvage surgery has
become more common, and with it the increased challenges in managing
metastatic disease to neck nodes as well as managing failure of organ pres-
ervation treatments. Surgeons continue to develop and refine reconstruction
techniques to optimize cosmetic and functional outcomes.
Summary
Future development of treatments for SCCHN will have to be based on
a more thorough and profound understanding of tumor biology. Head and
neck cancer is a biologically diverse disease, and tumors of the nasopharynx,
oral cavity, oropharynx, and larynx may be associated with different risk
factors and exhibit different responses to therapy. HPV-related oropharyn-
geal cancer is likely to be different from the ‘‘traditional’’ smoking-related
disease and might require a different treatment approach [2], and there
may be a role for the HPV vaccine in preventing oropharyngeal cancer.
Treatment options for patients with stage III and IV disease have evolved
over the last 5 years and can be summarized as follows: (1) concurrent che-
moradiotherapy, (2) cetuximab and radiation therapy, and (3) sequential
chemoradiotherapy. The nature and stage of the cancer, risk of local and
distance recurrence, and comorbidity conditions must be assessed when
designing an optimal treatment for patients. Aggressive therapy is not for
everyone, and many patients will not tolerate chemotherapy and radiation.
It is through ongoing randomized clinical trials that the most appropriate
therapies will emerge.
References
[1] Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006;56(2):
106–30.
[2] D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and
oropharyngeal cancer. N Engl J Med 2007;356(19):1944–56.
[3] McCollum A, Burrell S, Haddad R, et al. Positron emission tomography with 18-F-fluoro-
deoxyglucose to predict pathologic response after induction chemotherapy and definitive
chemoradiotherapy in head and neck cancer. Head Neck 2004;26:890–6.
[4] Weber RS, Berkey BA, Forastiere A, et al. Outcome of salvge total laryngectomy following
organ preservation therapy. Arch Otolaryngol Head Neck Surg 2003;129:44–9.
[5] Adelstein D, Li Y, Adams G, et al. An Intergroup Phase III comparison of standard radia-
tion therapy and two schedules of concurrent chemoradiotherapy in patients with unresect-
able squamous cell head and neck cancer. J Clin Oncol 2003;21:92–8.
Dent Clin N Am 52 (2008) 61–77
Management of Oral Mucositis

in Patients Who Have Cancer
Rajesh V. Lalla, BDS, PhD, CCRPa,b,1,*,
Stephen T. Sonis, DMD, DMScc,2,
Douglas E. Peterson, DMD, PhDa,b,3
a
Division of Oral Medicine, Department of Oral Health and Diagnostic Sciences, University of
Connecticut Health Center MC 1605, 263 Farmington Avenue, Farmington, CT 06030, USA
b
Head and Neck/Oral Oncology Program, Neag Comprehensive Cancer Center, University of
Connecticut Health Center MC 1605, 263 Farmington Avenue, Farmington, CT 06030, USA
c
Division of Oral Medicine, Dana Farber Cancer Institute, Brigham and Women’s Hospital,
Boston, MA 02115, USA
Oral mucositis refers to erythematous and ulcerative lesions of the oral

mucosa observed in patients with cancer being treated with chemotherapy,
and/or with radiation therapy to fields involving the oral cavity. Lesions of
oral mucositis are often very painful and compromise nutrition and oral hy-
giene as well as increase risk for local and systemic infection. Mucositis can
also involve other areas of the alimentary tract; for example, gastrointestinal
(GI) mucositis can manifest as diarrhea. Thus, mucositis is a highly signifi-
cant and sometimes dose-limiting complication of cancer therapy [1,2].
Epidemiology of mucositis
Oral mucositis is a significant problem in patients undergoing chemother-
apeutic management for solid tumors. In one study, it was reported that 303
This work was supported by Grant Number K23DE016946 from the National Institutes
of Health.
* Corresponding author. University of Connecticut Health Center MC 1605, 263
Farmington Avenue, Farmington, CT 06030-1605.
1
Dr. Lalla has served as a paid consultant for MGI Pharma.
2
Dr. Sonis has received research support from Amgen, Medimmune, and Novartis. He is
a consultant to Biomodels LLC and Clinical Assistance Programs LLC.
3
Dr. Peterson has served as a paid consultant for MGI Pharma and Nuvelo.
E-mail address: lalla@nso2.uchc.edu (R.V. Lalla).
62 LALLA et al
of 599 patients (51%) receiving chemotherapy for solid tumors or lym-

phoma developed oral and/or GI mucositis [3]. Oral mucositis developed
in 22% of 1236 cycles of chemotherapy, GI mucositis in 7% of cycles,
and both oral and GI mucositis in 8% of cycles. An even higher percentage
(approximately 75% to 80%) of patients who receive high-dose chemother-
apy before hematopoietic cell transplantation develop clinically significant
oral mucositis [4].
Patients treated with radiation therapy for head and neck cancer typically
receive an approximately 200 cGy daily dose of radiation, 5 days per week, for
5 to 7 continuous weeks. Almost all such patients will develop some degree of
oral mucositis. In recent studies, severe oral mucositis occurred in 29% to
66% of all patients receiving radiation therapy for head and neck cancer
[5,6]. The incidence of oral mucositis was especially high in (1) patients with
primary tumors in the oral cavity, oropharynx, or nasopharynx; (2) those
who also received concomitant chemotherapy; (3) those who received a total
dose over 5000 cGy; and (4) those who were treated with altered fractionation
radiation schedules (eg, more than one radiation treatment per day).
Clinical significance of oral mucositis

Oral mucositis can be very painful and can significantly affect nutritional
intake, mouth care, and quality of life [1,7]. For patients receiving high-dose
chemotherapy before hematopoietic cell transplantation, oral mucositis has
been reported to be the single most debilitating complication of transplanta-
tion [8]. Infections associated with the oral mucositis lesions can cause life-
threatening systemic sepsis during periods of profound immunosuppression
[9]. Moderate to severe oral mucositis has been correlated with systemic infec-
tion and transplant-related mortality [10]. In patients with hematologic ma-
lignancies receiving allogeneic hematopoietic cell transplantation, increased
severity of oral mucositis was found to be associated significantly with an in-
creased number of days requiring total parenteral nutrition and parenteral
narcotic therapy, increased number of days with fever, incidence of significant
infection, increased time in hospital, and increased total inpatient charges [4].
In patients receiving chemotherapy for solid tumors or lymphoma, the
rate of infection during cycles with mucositis was more than twice that dur-
ing cycles without mucositis and was directly proportional to the severity of
mucositis [3]. Infection-related deaths were also more common during cycles
with both oral and GI mucositis. In addition, the average duration of hos-
pitalization was significantly longer during chemotherapy cycles with muco-
sitis. Importantly, a reduction in the next dose of chemotherapy was twice as
common after cycles with mucositis than after cycles without mucositis [3].
Thus, mucositis can be a dose-limiting toxicity of cancer chemotherapy with
direct effects on patient survival.
The majority of patients receiving radiation therapy for head and neck
cancer are unable to continue eating by mouth because of mucositis pain
MANAGEMENT OF ORAL MUCOSITIS IN CANCER PATIENTS 63
and often receive nutrition through a gastrostomy tube or intravenous line.

It has been demonstrated that patients with oral mucositis are significantly
more likely to have severe pain and a weight loss of 5% or more [6]. In one
study, approximately 16% of patients receiving radiation therapy for head
and neck cancer were hospitalized because of mucositis [11]. Further,
11% of the patients receiving radiation therapy for head and neck cancer
had unplanned breaks in radiation therapy because of severe mucositis
[11]. Thus, oral mucositis is a major dose-limiting toxicity of radiation ther-
apy to the head and neck region.
Economic impact of mucositis

Chemotherapy patients who have significant oral mucositis require
supportive care measures such as use of total parenteral nutrition, fluid
replacement, and prophylaxis against infections. These can add substan-
tially to the total cost of care. For example, in patients receiving chemother-
apy for solid tumors or lymphoma, the estimated cost of hospitalization was
$3893 per chemotherapy cycle without mucositis, $6277 per cycle with oral
mucositis, and $9132 per cycle with both oral and GI mucositis [3]. A single-
point increase in peak mucositis scores in hematopoietic cell transplant
patients is associated with one additional day of fever, a 2.1-fold increase
in risk of significant infection, 2.7 additional days of total parenteral nutri-
tion, 2.6 additional days of injectable narcotic therapy, 2.6 additional days
in hospital, and a 3.9-fold increase in 100-day mortality risk, collectively
contributing to over $25,000 in additional hospital charges [12]. Radia-
tion-induced oral mucositis also has a significant economic impact because
of costs associated with pain management, liquid diet supplements, gastro-
stomy tube placement or total parenteral nutrition, management of second-
ary infections, and hospitalizations. In one study of patients receiving
radiation therapy for head and neck cancer, oral mucositis was associated
with an increase in costs ranging from $1700 to $6000 per patient, depending
on the grade of oral mucositis [6] (see the article by Elting elsewhere in this
issue).
Pathogenesis of mucositis
Recent studies have indicated that the fundamental mechanisms involved
in the pathogenesis of mucositis are much more complex than direct damage
to epithelium alone [2]. Mechanisms for radiation-induced and chemother-
apy-induced mucositis are believed to be similar. The following five-stage
model [13] for the pathogenesis of mucositis is based on the evidence avail-
able to date (Fig. 1):
1. Initiation of tissue injury: Radiation and/or chemotherapy induce cellu-
lar damage resulting in death of the basal epithelial cells. The generation
64 LALLA et al
Fig. 1. Current five-phase pathobiologic model of oral mucositis. (Reprinted from Sonis ST.
A biological approach to mucositis. J Support Oncol 2004;2:21–36; with permission.)
of reactive oxygen species (free radicals) by radiation or chemotherapy

is also believed to exert a role in the initiation of mucosal injury. These
small highly reactive molecules are by-products of oxygen metabolism
and can cause significant cellular damage.
2. Up-regulation of inflammation via generation of messenger signals: In
addition to causing direct cell death, free radicals activate second mes-
sengers that transmit signals from receptors on the cellular surface to
the inside of the cell. This leads to up-regulation of pro-inflammatory
cytokines, tissue injury, and cell death.
3. Signaling and amplification: Up-regulation of pro-inflammatory cyto-
kines such as tumor necrosis factor- alpha (TNF-a), produced mainly
by macrophages, causes injury to mucosal cells, and also activates
molecular pathways that amplify mucosal injury.
4. Ulceration and inflammation: There is a significant inflammatory cell
infiltrate associated with the mucosal ulcerations, based in part on
metabolic by-products of the colonizing oral microflora. Production
of pro-inflammatory cytokines is also further up-regulated as a result
of this secondary infection [14].
5. Healing: This phase is characterized by epithelial proliferation as well as
cellular and tissue differentiation [15], restoring the integrity of the
epithelium.
The degree and extent of oral mucositis that develops in any particular
patient and site appears to depend on factors such as age, gender, underly-
ing systemic disease, and race as well as tissue-specific factors (eg, epithelial
types, local microbial environment, and function). The effects of patient age
and gender on the development of oral mucositis are not clear. One study
reported increased prevalence of mucositis in children [16], while other stud-
ies reported increased prevalence and/or severity in older patients [17–19].
Similarly, there is conflicting evidence for the effects of gender on risk for
mucositis with some studies reporting increased risk for mucositis in females
[18,20], and others finding no gender effect [19].
Interactions of such factors, coupled with underlying genetic influences,
are postulated to govern the risk, course, and severity of mucositis [21]. For
example, epidermal growth factor (EGF) in luminal secretions may affect
the response of intestinal mucosa to chemotherapy although overexpres-
sion of EGF in a transgenic mouse model did not reduce intestinal
mucositis [22]. Recent studies have indicated that pathways associated
with pro-inflammatory molecules including cyclooxygenase-2, nuclear
factor-kappa B, and interleukin-6 are up-regulated in oral mucositis.
Thus, these may provide potential therapeutic targets for new therapies
[23,24].
Clinical course of oral mucositis

Oral mucositis initially presents as erythema of the oral mucosa, which
then often progresses to erosion and ulceration. The ulcerations are typi-
cally covered by a white fibrinous pseudomembrane (Figs. 2 and 3). The
lesions typically heal within approximately 2 to 4 weeks after the last
Fig. 2. Oral mucositis lesion on the lateral tongue of a patient who had received 4600 cGy of
a total planned dose of 6200 cGy, without concurrent chemotherapy, for treatment of squa-
mous cell carcinoma of the tongue.
66 LALLA et al
Fig. 3. Mucositis ulcer involving the buccal mucosa in the same patient as Fig. 2.
dose of stomatotoxic chemotherapy or radiation therapy. In immunosup-

pressed patients (eg, patients undergoing hematopoietic cell transplanta-
tion), resolution of oral mucositis usually coincides with granulocyte
recovery; however, this temporal relationship may or may not be causal.
Several factors affect the clinical course of mucositis. In chemotherapy-
induced oral mucositis, lesions are usually limited to nonkeratinized surfaces
(ie, lateral and ventral tongue, buccal mucosa, and soft palate) [1]. Ulcers
typically arise within 2 weeks after initiation of chemotherapy. Selected
agents such as antimetabolites and alkylating agents cause a higher inci-
dence and severity of oral mucositis [25]. In radiation-induced oral mucosi-
tis, lesions are limited to the tissues in the field of radiation, with
nonkeratinized tissues affected more often. The clinical severity is directly
proportional to the dose of radiation administered. Most patients who
have received more than 5000 cGy to the oral mucosa will develop severe
ulcerative oral mucositis [26].
The clinical course of oral mucositis may sometimes be complicated by
local infection, particularly in immunosuppressed patients. Viral infections
such as recrudescent herpes simplex virus (HSV) and fungal infections
such as candidiasis can sometimes be superimposed on oral mucositis.
Although HSV infections do not cause oral mucositis [27], they can compli-
cate its diagnosis and management.
Measurement of oral mucositis

A wide variety of scales have been used to record the extent and severity
of oral mucositis in clinical practice and research. The World Health Orga-
nization (WHO) scale is a simple, easy-to-use scale that is suitable for daily
use in clinical practice. This scale combines both subjective and objective
measures of oral mucositis (Box 1). The National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 3.0
includes separate subjective and objective scales for mucositis (Box 2) [28].
Box 1. World Health Organization (WHO) scale for oral mucositis

Grade 0 = No oral mucositis
Grade 1 = Erythema and soreness
Grade 2 = Ulcers, able to eat solids
Grade 3 = Ulcers, requires liquid diet (due to mucositis)
Grade 4 = Ulcers, alimentation not possible (due to mucositis)
The Oral Mucositis Assessment Scale (OMAS) is an objective scale, suitable

for research purposes, that measures erythema and ulceration at nine differ-
ent sites in the oral cavity. This scale has been validated in a multicenter trial
with high interobserver reproducibility and strong correlation of objective
mucositis scores with patient symptoms [29]. The Eastern Cooperative
Oncology Group (ECOG) common toxicity criteria are also used in oncol-
ogy trials to document severity of oral mucositis [30].
Clinical management of oral mucositis

Management of oral mucositis has been largely palliative to date,
although targeted therapeutic interventions are now being developed [31].
Based on a comprehensive systematic review of the literature, the
Box 2. National Cancer Institute (NCI) Common Terminology

Criteria for Adverse Events (CTCAE) version 3.0
Oral mucositis (clinical examination)
Grade 1 = Erythema of the mucosa
Grade 2 = Patchy ulcerations or pseudomembranes
Grade 3 = Confluent ulcerations or pseudomembranes;
bleeding with minor trauma
Grade 4 = Tissue necrosis; significant spontaneous bleeding;
life-threatening consequences
Grade 5 = Death
Oral mucositis (functional/symptomatic)
Grade 1 = Minimal symptoms, normal diet
Grade 2 = Symptomatic but can eat and swallow modified diet
Grade 3 = Symptomatic and unable to adequately aliment or
hydrate orally
Grade 4 = Symptoms associated with life-threatening
consequences
Grade 5 = Death
68 LALLA et al
Mucositis Study Group of the Multinational Association for Supportive

Care in Cancer and the International Society of Oral Oncology
(MASCC/ISOO) has developed clinical practice guidelines for the manage-
ment of mucositis [32] (see the article by Fischer and Epstein elsewhere in
this issue). Management of oral mucositis is divided into the following sec-
tions: pain control, nutritional support, oral decontamination, palliation of
dry mouth, management of oral bleeding, and therapeutic interventions for
oral mucositis.
Pain control
The primary symptom of oral mucositis is pain. This pain significantly
affects nutritional intake, mouth care, and quality of life. Thus, management
of mucositis pain is a primary component of any mucositis management
strategy. Many centers use saline mouth rinses, ice chips, and topical mouth-
rinses containing an anesthetic such as 2% viscous lidocaine. The lidocaine
may be mixed with equal volumes of diphenhydramine and a soothing cov-
ering agent such as Maalox (Novartis Consumer Health, Inc., Fremont, MI)
or Kaopectate (Chattem, Inc., Chattanooga, TN) in equal volumes. Such
topical anesthetic agents may provide short-term relief.
A number of other topical mucosal bioadherent agents are also available
that are not anesthetics but are postulated to reduce pain by forming a pro-
tective coating over ulcerated mucosa. Of these, sucralfate is the most
widely studied. The MASCC/ISOO guidelines recommend against the use
of sucralfate in radiation-induced oral mucositis due to lack of efficacy.
No recommendation has been made for the use of sucralfate in chemother-
apy-induced oral mucositis due to lack of consistent results [33–35]. In
addition to the use of topical agents, most patients with severe mucositis
require systemic analgesics, often including opioids, for satisfactory pain re-
lief. The MASCC/ISOO guidelines recommend patient-controlled analgesia
with morphine for patients undergoing hematopoietic cell transplantation
[35].
Nutritional support
Nutritional intake can be severely compromised by the pain associated
with severe oral mucositis. In addition, taste changes can also occur second-
ary to chemotherapy and/or radiation therapy [36,37]. It is essential that nu-
tritional intake and weight be monitored by a dietician or other professional
working together with family caregivers. A soft diet and liquid diet supple-
ments are more easily tolerated than a normal diet when oral mucositis is
present. In patients expected to develop severe mucositis, a gastrostomy
tube is sometimes placed prophylactically, although this varies considerably
from center to center. In patients undergoing hematopoietic cell transplan-
tation, total parenteral nutrition is usually given via an indwelling catheter
such as a Hickman line.
Oral decontamination
Oral decontamination may result in significant positive outcomes in this
population. First, it has been hypothesized that microbial colonization of
oral mucositis lesions exacerbates the severity of oral mucositis and, there-
fore, decontamination may help to reduce mucositis. Indeed, multiple stud-
ies have demonstrated that maintenance of good oral hygiene can reduce the
severity of oral mucositis [38–40]. Patients who have undergone hematopoi-
etic cell transplantation and who develop oral mucositis also have been
found to be three times more likely to develop bacteremias resulting in
increased length of hospital stays as compared with patients without muco-
sitis [10]. Therefore, oral decontamination may reduce mucositis that, in
turn, may reduce bacteremia. Furthermore, oral decontamination can
reduce infection of the oral cavity by opportunistic pathogens [41]. There-
fore, a second function of oral decontamination can be to reduce the risk
of systemic sepsis from resident oral and/or opportunistic pathogens. This
is especially true in patients who are immunosuppressed as a result of che-
motherapy. The risk of systemic sepsis from oral mucositis has not been well
studied although one study found that an intensive oral care protocol
decreased risk of oral mucositis but not the percentage of patients with
a documented septicemia [40]. Patients receiving radiation therapy alone
are less likely to develop sepsis of oral origin.
The MASCC/ISOO guidelines recommend use of a standardized oral
care protocol including brushing with a soft toothbrush, flossing, and
the use of nonmedicated rinses (eg, saline or sodium bicarbonate rinses).
Patients and caregivers should be educated regarding the importance of
effective oral hygiene [42]. Alcohol-containing chlorhexidine mouthrinse
may be difficult for patients to tolerate during clinical oral ulceration;
thus, formulations without alcohol are used at some centers. Multiple stud-
ies have examined the role of chlorhexidine mouthrinse in oral mucositis
but have not demonstrated significant efficacy in reducing severity of mu-
cositis [35]. Therefore, the MASCC/ISOO guidelines recommend against
the use of chlorhexidine mouthrinse for prevention or treatment of oral
mucositis.
Nystatin rinse has not been found to be effective in reducing the severity
of chemotherapy-induced mucositis [43]. On the other hand, a recent study
indicated that systemic fluconazole versus no treatment significantly and
dramatically reduced both candidal carriage and incidence of severe muco-
sitis induced by radiation therapy (15% versus 45%) in patients with head
and neck cancer [44]. The MASCC/ISOO guidelines recommend against
the routine use of antimicrobial lozenges or of acyclovir and its analogs
to prevent oral mucositis [35]. However, drugs such as acyclovir and valacy-
clovir have a well-established role in prophylaxis and treatment of lesions
caused by HSV in this patient population [45,46] (see the article by Lerman
and colleagues elsewhere in this issue).
70 LALLA et al
Palliation of dry mouth

Patients undergoing cancer therapy often develop transient or permanent
xerostomia (subjective symptom of dryness) and hyposalivation (objective
reduction in salivary flow). Hyposalivation can further aggravate inflamed
tissues, increase risk for local infection, and make mastication difficult.
Many patients also complain of a thickening of salivary secretions because
of a decrease in the serous component of saliva. The following measures can
be taken for palliation of a dry mouth:
! Sip water as needed to alleviate mouth dryness. Several supportive prod-
ucts including artificial saliva are available.
! Rinse with a solution of half a teaspoon of baking soda half a in 1 cup
warm water several times a day to clean and lubricate the oral tissues
and to buffer the oral environment.
! Chew sugarless gum to stimulate salivary flow.
! Use cholinergic agents as necessary.
Please also see the article by Fischer and Epstein elsewhere in this issue.
Management of bleeding
In patients who are thrombocytopenic as a result of high-dose chemo-
therapy (eg, hematopoietic cell transplant recipients), bleeding may occur
from the ulcerations of oral mucositis. Local intraoral bleeding can usually
be controlled with the use of topical hemostatic agents such as fibrin glue or
gelatin sponge [47]. Patients whose platelet counts fall below 20,000/ml may
receive platelet transfusion because of the risk for spontaneous internal
bleeding, which may have grave consequences especially in the central ner-
vous system.
Therapeutic interventions
Several agents have been tested to reduce the severity of, or prevent, mu-
cositis. These different classes of agents are discussed briefly in the context of
the MASCC/ISOO guidelines where applicable.
Cryotherapy
It has been hypothesized that topical administration of ice chips to the
oral cavity during administration of chemotherapy results in decreased de-
livery of the chemotherapeutic agent to the oral mucosa. This effect is pre-
sumably mediated through local vasoconstriction and reduced blood flow.
Several studies have demonstrated that cryotherapy reduces the severity of
oral mucositis in patients receiving bolus doses of chemotherapeutic agents
[48–50]. The MASCC/ISOO guidelines recommend the use of cryotherapy
to reduce oral mucositis in patients receiving bolus doses of 5-fluorouracil,
melphalan, and edatrexate [51]. Ice chips are placed in the mouth, beginning
5 minutes before administration of chemotherapy and replenished as needed

for up to 30 minutes. Cryotherapy is only useful for short bolus chemother-
apeutic infusions, may not be well tolerated in some subjects and does not
have a role in radiation-induced oral mucositis.
Growth factors
Reduction in the proliferative capacity of oral epithelial cells is thought to
play a role in the pathogenesis of mucositis. Therefore, various growth fac-
tors that can increase epithelial cell proliferation have been studied for the
management of oral mucositis. Recent evidence shows that intravenous
(IV) recombinant human keratinocyte growth factor-1 (Palifermin, Amgen,
Thousand Oaks, CA) significantly reduced incidence of WHO grades 3 and
4 oral mucositis in patients with hematologic malignancies (eg, lymphoma
and multiple myeloma) receiving high-dose chemotherapy and total body
irradiation before autologous hematopoietic cell transplantation [52]. On
that basis, the MASCC/ISOO guidelines recommend the use of recombinant
human keratinocyte growth factor-1 in this specific population [53]. Palifer-
min has also been approved by the US Food and Drug Administration
(FDA) for patients with hematologic malignancies receiving myelotoxic
therapies requiring hematopoietic cell support. Interestingly, a related com-
pound, human keratinocyte growth factor-2 (Repifermin, Human Genome
Sciences), was found to be ineffective in reducing the percentage of subjects
who experienced severe mucositis [54]. Intravenous human fibroblast growth
factor-20 (Velafermin, Curagen Corp., Branford, CT) is currently in clinical
development for reduction of mucositis secondary to high-dose chemother-
apy in autologous hematopoietic cell transplant patients [55].
The safety of this class of growth factors has not been established in
patients with nonhematologic malignancies. There is a theoretical concern
that these growth factors may promote growth of tumor cells, which may
have receptors for the respective growth factor. However, one recent study
found no significant difference in survival between subjects with colorectal
cancer receiving palifermin or placebo at a median follow-up duration of
14.5 months [56]. Further studies are ongoing to confirm the safety of epi-
thelial growth factors in the solid tumor setting including patients receiving
radiation therapy for head and neck cancer.
Anti-inflammatory agents
Benzydamine hydrochloride is a nonsteroidal anti-inflammatory drug
that inhibits proinflammatory cytokines including TNF-a. In one Phase
III trial, benzydamine hydrochloride mouthrinse reduced the severity of mu-
cositis in patients with head and neck cancer undergoing radiation therapy of
cumulative doses up to 50-Gy radiation therapy [57]. Based on this and pre-
vious studies, the MASCC/ISOO guidelines recommended use of this agent
in patients receiving moderate-dose radiation therapy [58]. However, this
agent has not received approval for this use from the FDA; furthermore,
72 LALLA et al
most patients with head and neck cancer receive well over 50-Gy radiation
therapy with concomitant chemotherapy. A more recent Phase III trial of
this agent in radiation-induced oral mucositis in patients with head and
neck cancer was halted based on negative results of an interim analysis.
Saforis (MGI Pharma) is a proprietary oral suspension of L-glutamine that
enhances the uptake of this amino acid into epithelial cells. Glutamine may
reduce mucosal injury by reducing the production of proinflammatory cyto-
kines and cytokine-related apoptosis [59,60] and may promote healing by
increasing fibroblast and collagen synthesis [61]. In a Phase III study, this topical
agent reduced the incidence of clinically significant chemotherapy-induced oral
mucositis as compared with placebo [62]. By comparison, the MASCC/ISOO
guidelines recommend that systemically administered glutamine not be used
for the prevention of GI mucositis [35] because of lack of efficacy [63].
Antioxidants
Amifostine (Ethylol, MedImmune, Gaithersburg, MD) is thought to act
as a scavenger for harmful reactive oxygen species that are known to poten-
tiate mucositis [64]. However, because of insufficient evidence of benefit,
a MASCC/ISOO guideline could not be established regarding the use of
this agent in oral mucositis in chemotherapy or radiation therapy patients.
The use of amifostine was recommended for the prevention of esophagitis in
patients receiving chemo-radiation for non–small-cell lung cancer [65]. RK-
0202 (RxKinetix) consists of the antioxidant N-acetylcysteine in a proprie-
tary matrix for topical application in the oral cavity. In a placebo-controlled
phase II trial in patients with head and neck cancer, this agent significantly
reduced the incidence of severe oral mucositis up to doses of 50-Gy radia-
tion therapy [66].
Low-level laser therapy

Multiple studies have indicated that low-level laser therapy can reduce
the severity of chemotherapy and radiation-induced oral mucositis [67–
69], although the mechanism of such an effect is not understood. It has
been speculated that low-level laser therapy may reduce levels of reactive
oxygen species and/or proinflammatory cytokines that contribute to the
pathogenesis of mucositis. Studies are difficult to compare because of vary-
ing laser types and parameters (such as wavelength). Nevertheless, based on
the encouraging results to date, the MASCC/ISOO guidelines suggest the
use of low-level laser therapy in chemotherapy-induced oral mucositis at
centers able to support the necessary technology and training [51].
Future directions in mucositis research

As evident from the above discussion, this is an exciting period in muco-
sitis research. One drug (Palifermin) has received FDA approval for reducing
the severity and duration of oral mucositis in patients with hematologic

malignancies receiving myelotoxic therapies requiring hematopoietic cell
support. Several other promising agents are in clinical development that
eventually may be approved for the management of this debilitating condi-
tion. Future studies should evaluate if agents that work by different mecha-
nisms can be used in combination for greater clinical effectiveness. Another
approach that warrants further investigation is the use of novel drug delivery
technologies that increase uptake of the active agent (eg, glutamine) to the
oral epithelial cells. In addition, developing improved algorithms to predict
the risk for the development of clinically significant mucositis would also be
valuable so that patients at increased risk can be targeted for therapy in
a more cost-effective manner. Reducing the morbidity of mucositis will
help to avoid unwanted dose reductions or unscheduled breaks in cancer
therapy and thus improve outcomes of cancer therapy.
Summary
Oral mucositis is a clinically important and sometimes dose-limiting
complication of cancer therapy. Mucositis lesions can be painful, affect
nutrition and quality of life, and have a significant economic impact. The
pathogenesis of oral mucositis is multifactorial and complex. The present re-
view discusses the morbidity, economic impact, pathogenesis and clinical
course of mucositis. Current clinical management of oral mucositis is largely
focused on palliative measures such as pain management, nutritional sup-
port, and maintenance of good oral hygiene. However, several promising
therapeutic agents are in various stages of clinical development for the
management of oral mucositis. These agents are discussed in the context
of recently updated evidence-based clinical management guidelines.
References
[1] Lalla RV, Peterson DE. Oral mucositis. Dent Clin North Am 2005;49(1):167–84.
[2] Treister N, Sonis S. Mucositis: biology and management. Curr Opin Otolaryngol Head Neck
Surg 2007;15(2):123–9.
[3] Elting LS, Cooksley C, Chambers M, et al. The burdens of cancer therapy. Clinical and eco-
nomic outcomes of chemotherapy-induced mucositis. Cancer 2003;98(7):1531–9.
[4] Vera-Llonch M, Oster G, Ford CM, et al. Oral mucositis and outcomes of allogeneic hema-
topoietic stem-cell transplantation in patients with hematologic malignancies. Support Care
Cancer 2007;15(5):491–6.
[5] Vera-Llonch M, Oster G, Hagiwara M, et al. Oral mucositis in patients undergoing radiation
treatment for head and neck carcinoma. Cancer 2006;106(2):329–36.
[6] Elting LS, Cooksley CD, Chambers MS, et al. Risk, outcomes, and costs of radiation-
induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol
Biol Phys 2007;68(4):1110–20.
[7] Duncan GG, Epstein JB, Tu D, et al. Quality of life, mucositis, and xerostomia from radio-
therapy for head and neck cancers: a report from the NCIC CTG HN2 randomized trial of
an antimicrobial lozenge to prevent mucositis. Head Neck 2005;27(5):421–8.
Surgical Management
of Oral Cancer
a,b, b
Rabie M. Shanti, DMD, MD *, Bert W. O’Malley Jr, MD
KEYWORDS
! Oral cancer ! Mandibulectomy ! Maxillectomy ! Glossectomy ! Neck dissection
KEY POINTS
! Primarily, surgery is the standard of care for early-stage oral cancer.
! Distant metastasis must be ruled out before proceeding with surgical management of an
oral cancer.
! Oral cavity squamous cell carcinoma (SCC) is best managed with 1- to 1.5-cm surgical
margins.
! There is a survival benefit in performing a selective neck dissection in early-stage oral cav-
ity SCC.
ROLE OF SURGERY IN HEAD AND NECK CANCER MANAGEMENT
Today, most head and neck cancer subsites, such as the larynx, hypopharynx, naso-
pharynx, and oropharynx, are treated with radiation therapy (XRT) with or without
chemotherapy as a primary treatment modality. Recent advances with transoral ro-
botic surgery (TORS) have significantly impacted the management of cancers of the
oropharynx. Surgery is reserved for the salvage of recurrent tumors that occur within
the head and neck in the absence of distant (ie, lung, liver) metastasis. The results of
the Veterans Administration Larynx Trial published in 1991 identified induction chemo-
therapy followed by XRT provided the same 2-year survival as conventional laryngec-
tomy plus adjuvant XRT.1 Furthermore, in this study, the larynx was preserved in 64%
of patients in the chemoradiotherapy (CRT) arm of the study.1 Today, roughly 30% to
40% of patients who undergo primary CRT for laryngeal squamous cell carcinoma
(SCC) will experience treatment failure with locoregional recurrence of their tumor,
and in the absence of distant metastasis, these patients will go on to require either
a partial or a total laryngectomy (Fig. 1).2,3
Disclosure Statement: The authors have no relevant disclosures.

a
Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania
School of Dental Medicine, 240 S 40th Street #122, Philadelphia, PA 19104, USA; b Department
of Otorhinolaryngology/Head and Neck Surgery, Perelman School of Medicine University of
Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
* Corresponding author. Department of Otorhinolaryngology/Head and Neck Surgery, Univer-
sity of Pennsylvania Perelman School of Medicine, 3400 Civic Center Boulevard, Philadelphia,
PA 19104.
E-mail address: rabie.shanti@uphs.upenn.edu
Dent Clin N Am 62 (2018) 77–86

78 Shanti & O’Malley Jr
Fig. 1. Total laryngectomy specimen, which includes the epiglottis, vocal cords, thyroid carti-
lage, cricoid cartilage, hyoid bone, upper tracheal rings, and neck dissection lymph node
packet.
Contrary to the larynx, the oropharynx as a subsite has been shown to benefit from
primary surgery with adjuvant therapy as needed. However, the extirpation of
advanced malignant neoplasms of the oropharynx traditionally required open ap-
proaches that required invasive transcervical surgical approaches, such as lip-split
with mandibulotomy/mandibulectomy (Fig. 2). Although transcervical approaches
such as the lip-split mandibulotomy can appear quite graphic and morbid, the benefit
from extirpation of SCC of the oropharynx results in the ability to achieve locoregional
disease control with a 20% reduction in locoregional recurrence in comparison to pri-
mary CRT.4 This benefit in locoregional disease control and overall survival provided
by primary surgery in oropharyngeal SCC served the basis for significant surgical inno-
vation in head and neck surgery. In search of less invasive surgical approaches, Hock-
stein and colleagues5 reported on the potential of the da Vinci surgical system
(Intuitive Surgical, Inc, Sunnyvale, CA, USA) system in performing extirpative opera-
tions that would have classically required a transcervical access–type approach. In
2009, the US Food and Drug Administration approved the da Vinci robotic surgery
Fig. 2. Intraoperative photograph following tumor extirpation requiring lip-split

mandibulectomy.
Surgical Management of Oral Cancer 79
for surgery of the oropharynx through the work of the senior author (B.W.O.) and Greg-
ory S. Weinstein, MD from the University of Pennsylvania. Today, TORS allows sur-
geons, through the use of special retractors (Fig. 3) and sophisticated technology,
the ability to surgically treat tumors within the oropharynx, hypopharynx, and upper
portions of the larynx that would have been otherwise treated with primary CRT
or substantially more invasive traditional access approaches, such as lip-split
mandibulotomy.
Unlike all other head and neck subsites, oral SCC ideally should be managed with
primary surgery with the possibility of adjuvant XRT with or without chemotherapy,
depending on the presence of certain high-risk pathologic features. The current evi-
dence supports that when safe to do so from a surgical and medical perspective, pri-
mary surgery should be attempted whenever possible to provide patients with the
greatest chance of cure. This issue of the Dental Clinics of North America is devoted
to oral cancer; therefore, the remainder of this article focuses on the role of surgery in
the management of oral SCC, because this neoplasm constitutes 90% of oral cavity
malignancies.
Today, it is unknown why oral SCC is so responsive to primary surgery in compar-
ison to primary XRT or primary CRT, which is not necessarily the case for other sub-
sites, such as the larynx, hypopharynx, or nasopharynx, and in certain cases,
oropharyngeal SCC. However, even though surgery is the ideal primary treatment mo-
dality for oral SCC, one must not underestimate the limitations of surgery in disease
control, such as in the case of locally (primary site) or regionally (cervical lymph nodes)
advanced neoplasms of the oral cavity or in the case of neoplasms of the oral cavity
Fig. 3. Intraoperative photograph with oral retractors in place and arms of da Vinci robot
within the surgical field.
that invade critical structures, such as the carotid artery, skull base, orbital cavity, and
the intracranial cavity, thus hindering the ability to achieve adequate disease control
through surgery. The extirpation of oral cancer can vary from minimally invasive pro-
cedures that require a short anesthetic exposure and hospitalization (Fig. 4) to pro-
cedures that can involve significant operations that encompass different body parts
and a prolonged hospitalization and recovery process (Fig. 5). Furthermore, the overall
health of the patient to withstand a major operation has to be considered when
assessing the candidacy of a patient for surgical management of their oral cancer, irre-
spective of the resectability of their tumor due to the high risk for bleeding and airway
compromise, because the surgical management of oral cancer will almost always
require general anesthesia. Furthermore, aside from the critical anatomic structures
and overall patient health, at the present time, there is no role for surgery in patients
with distant metastatic disease; therefore, distant metastatic disease must be ruled
out before proceeding with the surgical management of oral cancer. The only role of
surgery for cases of metastatic cancer is securing the airway, if necessary, for a tra-
cheostomy procedure or placement of long-term enteral nutrition access via a gastro-
stomy tube.
In this article, the authors discuss the role of surgery and techniques used today in
the extirpation of malignant neoplasms of the oral cavity. The aim is for the reader to
gain insight to the operative procedures and their indications and contraindications,
and the decision-making process that goes into identifying which surgical technique
to use in balancing optimal disease control and function/cosmesis.
SURGICAL MANAGEMENT OF THE PRIMARY TUMOR SITE

Margin Status
Of malignant neoplasms of the oral cavity, 90% are SCC. Excluding the lip, tradition-
ally a 1- to 1.5-cm (10–15 mm) resection margin is recommended (Fig. 6). Obtaining a
tumor-free surgical margin is critical from a locoregional disease control perspective
and an overall survival perspective.6 Therefore, following tumor extirpation, a critical
parameter analyzed in the final pathologic report is the “margin status.” Today, a
negative (clear) margin is a margin where the invasive tumor is at least 5 mm away
from the resected margin, and a close margin is a margin where the invasive tumor
Fig. 4. (A, B) Intraoperative photograph following excision of premalignant lesion of the

tongue, with reconstruction with an off-the-shelf porcine-derived construct.
Fig. 5. (A, B) Intraoperative photograph following left oral hemiglossectomy with recon-
struction of tongue with a fasciocutaneous radial forearm free flap.
is within 1 to 5 mm from the resected margin, and a positive (involved) margin is one
that is less than 1 mm from the resected margin to the invasive tumor.6 Controversy
exists as to what constitutes an involved (positive), close, or clear (negative) margin,
because a recent survey of head and neck surgeons found that 63% of respondents
defined a close margin as a distance of less than 5 mm between the resection margin
and invasive tumor, and a clear margin being a distance of 5 mm or greater between
the 2.7 A positive margin is considered an indication for adjuvant CTR or re-resection,
whereas a close margin is an indication for adjuvant XRT.8 Therefore, in cases of early-
stage (T1 and T2) oral SCC with negative resection margins, in the absence of any
adverse histologic features, the patient can be spared adjuvant therapy. Furthermore,
the presence of a close (1–5 mm) margin has been demonstrated in several studies in
decreasing overall survival and disease-free survival; therefore, additional adjuvant
XRT is recommended.6 Of the oral cavity subsites, lip cancers, in general, have the
most favorable prognosis.9 Lip cancer margins are the most conservative of all the
oral cavity subsites, which are 0.5 to 1 cm (5–10 mm).
Tumor Extirpation Techniques

Glossectomy (tongue resection) is defined by the extent of tissue removed and the
involved portion of the tongue (oral tongue vs base of tongue). Removal of less than
Fig. 6. Intraoperative photograph of 1.5-cm superficial (mucosal) margin marked out cir-
cumferentially using electrocautery.
one-third of the tongue is defined as a partial glossectomy; one-third to one-half is

defined as a hemiglossectomy; one-half to three-quarters is defined as a subtotal
glossectomy, and greater than three-quarters is defined as a total glossectomy
(Fig. 7).
Removal of tumors that abut or invade the mandible or maxilla will require partial or
complete removal of a small or large segment of bone in order to obtain clear surgical
margins. In the case of the mandible, marginal mandibulectomy is a technique that in-
volves removal of either a portion of the alveolar bone while maintaining the integrity of
the inferior border of the mandible, versus removal of a portion of the inferior border of
the mandible while preserving the integrity of the alveolus of the mandible. This tech-
nique is contraindicated in patients with a history of head and neck XRT where the
mandible was part of the treatment field or in cases where there is clinical or radio-
graphic invasion of the bone marrow of the mandible. This technique can weaken
the structure of the mandible, and the general rule is if the mandible has 1 cm or
less of the inferior border following tumor extirpation, then it must be reinforced with
a mandibular reconstruction plate in order to reduce the risk for a pathologic fracture.
In the case of lesions that abut or invade the maxilla, a maxillectomy procedure is per-
formed. This procedure has various classification schemas that are based on the ver-
tical and horizontal extent of the bony defect of the maxilla and the involvement of the
nasal cavity or orbit.10–13
SCC of the buccal mucosa is considered a high-risk (aggressive) oral cancer sub-
site; therefore, multimodality therapy beginning with primary surgery followed by adju-
vant therapy is the preferred recommendation for patients.14,15 Surgery will consist of
wide excision of the lesion with 1.0- to 1.5-cm mucosal and deep margins (Fig. 8).
Furthermore, in cases where the lesion is in close proximity to the maxilla or mandible,
consideration for maxillectomy (infrastructure, subtotal, or total) or mandibulectomy
(marginal or segmental) should be considered. In locally advanced cases of buccal
SCC, it is not uncommon to have to resect a portion or a segment of the maxilla
and mandible as well as overlying skin, creating a complex through-and-through oro-
facial defect.
ROLE OF NECK DISSECTION (CERVICAL LYMPHADENECTOMY)
Cervical lymphadenectomy is the process of systematic removal of groups of lymph

nodes within the neck for staging of cancer, decreasing disease burden, or guiding
Fig. 7. Oral glossectomy classification based on extent of tissue excised.

Fig. 8. (A, C) T3 SCC of the left buccal mucosa. (B, C) Marked out radial forearm free flap,
which is commonly performed to reconstruct large defects of the cheek. (D) Free flap inset
to reconstruct the postoncologic defect.
oncologic decision making. At the time of initial presentation, w40% of patients will
present with cancer metastasis to cervical lymph nodes.16,17 Neck dissection is
described as either elective or therapeutic. Elective neck dissection is performed in
the case where no clinical or radiographic lymphadenopathy is noted, and removal
of certain levels of lymph nodes is aimed at ruling out the presence of metastatic
lymph nodes, which is critical in the decision-making process for adjuvant therapy
and cancer outcome prognostication.16 Therapeutic neck dissection is performed in
the presence of either clinical or radiographic lymphadenopathy with the goal of deter-
mining the degree of disease burden and also the presence of extracapsular exten-
sion, which are indications for adjuvant XRT as well as chemotherapy.16,18 The
status of the cervical lymph nodes is considered the single most important prognos-
ticator for oral cancer, because having a single metastatic lymph node will reduce
5-year survival by 50%.16
The role of elective neck dissection, that is, a neck dissection in the absence
of clinical or radiographic evidence of cervical lymph node metastasis (also known
as “N0” neck), has been debated for several decades. In 2015, a landmark
prospective, randomized, controlled trial was published in the New England Jour-
nal of Medicine and provided evidence for the benefit of elective nodal dissection
in cases of node-negative oral cancer.19 However, at the present time, depending
on institutional preference, a 3-mm depth of invasion is used as a cutoff for recom-
mending a neck dissection in the N0 neck. Although a plethora of literature
has been devoted to determining the ideal depth of invasion threshold for recom-
mending a neck dissection in N0 patients or if all patients with invasive
SCC should undergo a neck dissection, this decision is largely left to
the patient after counseling the patient on the benefits of the elective neck dissec-
tion from an oncologic perspective versus the added morbidity from a neck
dissection.
The neck dissection of oral and head and neck cancer dates back to 1906 with its
initial description by Dr George Crile from the Cleveland Clinic in Ohio.20,21 Dr Hayes
Martin from Memorial Hospital in New York City would expand on the work of Dr Crile
with his publication in 1951 that reviewed his experience in performing 1450 neck
dissections.21–23 The seminal work by Shah and colleagues24–27 stratified the lymph
nodes of the neck into the following lymph node groups: Ia (submental), Ib (subman-
dibular), IIa and IIb (upper jugular), III (middle jugular), IV (lower jugular), Va and Vb
(posterior triangle), VI (central compartment), and VII (superior mediastinal) (refer to
fig. 4 in Mel Mupparapu and Rabie M. Shanti’s article, “Evaluation and Staging of
Oral Cancer,” in this issue). Of note, levels IIa and IIb are separated by the spinal
accessory nerve (cranial nerve XI). The neck dissection in the ensuing decades would
undergo several iterations and today is simply stratified based on the dissected
lymph node groups or excised adjacent structures.16 The modified radical neck
dissection refers to cases where dissection removes lymph node levels I–V with
removal of any of the following structures: spinal accessory nerve, internal jugular
vein, and sternocleidomastoid muscle. If levels I–V lymph nodes are removed
including all 3 of these structures, this is referred to as a radical neck dissection. If
additional nonlymphatic (ie, neurovascular, muscular, or cutaneous) structures are
excised such as the hypoglossal nerve, vagus nerve, carotid artery, paraspinal mus-
cles, or overlying skin of the neck, this is referred to as an extended radical neck
dissection.16 Today, such extensive neck dissections are infrequently performed in
the primary setting, and more commonly, a functional type of neck dissection is per-
formed. The functional types of neck dissection includes the selective neck dissec-
tion (levels I–IV) or supraomohyoid neck dissection (levels I–III) with preservation of all
the aforementioned nonlymphatic structures. This is performed through conservative
cutaneous incisions in order to reduce the morbidity and improve the cosmesis of the
overall outcome of the patient (Fig. 9).
Fig. 9. (A) Intraoperative photograph of incision line indicating the length of the incision
performed at the authors’ institution. (B) Intraoperative photograph of critical structures
that are dissected during a neck dissection.
SUMMARY
Over the past 4 decades, a plethora of advancements have been made in the manage-
ment of head and neck cancers, including advancements in diagnostic (ie, PET/
computed tomography) and nonsurgical treatment modalities, such as intensity
modulated radiation therapy, proton therapy, targeted systemic therapy (ie, Cetuxi-
mab), and most recently, immunotherapy. Furthermore, a move toward minimally
invasive surgical procedures has occurred with the reduction of the extent of a neck
dissection being performed and also ground-breaking advancements such as
TORS. Nonetheless, oral cancers are primarily managed with surgery as a primary
treatment modality; therefore, familiarity of the types of extirpative procedures and
the rationale for their use is imperative for the practitioner involved in the care of pa-
tients with oral cancer.
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6. Dillon JK, Brown CB, McDonald TM, et al. How does the close surgical margin
impact recurrence and survival when treating oral squamous cell carcinoma?
J Oral Maxillofac Surg 2015;73(6):1182–8.
7. Tasche KK, Buchakjian MR, Pagedar NA, et al. Definition of “close margin” in oral
cancer surgery and association of margin distance with local recurrence rate.
JAMA Otolaryngol Head Neck Surg 2017. [Epub ahead of print].
8. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy
and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.
N Engl J Med 2004;350(19):1937–44.
9. Biasoli ER, Valente VB, Mantovan B, et al. Lip cancer: a clinicopathological study
and treatment outcomes in a 25-year experience. J Oral Maxillofac Surg 2016;
74(7):1360–7.
10. Brown JS, Rogers SN, McNally DN, et al. A modified classification for the maxil-
lectomy defect. Head Neck 2000;22(1):17–26.
11. Okay DJ, Genden E, Buchbinder D, et al. Prosthodontic guidelines for surgical
reconstruction of the maxilla: a classification system of defects. J Prosthet Dent
2001;86(4):352–63.
12. Cordeiro PG, Chen CM. A 15-year review of midface reconstruction after total and
subtotal maxillectomy: part II. Technical modifications to maximize aesthetic and
functional outcomes. Plast Reconstr Surg 2012;129(1):139–47.
Adjunctive Diagnostic
Tec h n i q u e s f o r O r a l a n d
Orophary n g eal C an c er Di scov e ry
Michaell A. Huber, DDS
KEYWORDS
! Squamous cell carcinoma ! Conventional oral examination ! Biopsy
! Adjunctive aids
KEY POINTS
! The most important prognostic factor in predicting the outcome of oral and oropharyngeal
cancer (OPC) is the stage at diagnosis.
! The accomplishment of the conventional oral examination consists of a disciplined visual
and tactile assessment of accessible head and neck structures.
! Any suspicious or equivocal lesion should be referred for further assessment or undergo
biopsy; innocuous lesions should be reevaluated within 4 weeks and referred for further
assessment.
! Evidence supporting the use of adjunctive devices to improve the general practitioner’s
ability to screen for and identify OPCs and oral premalignant lesions remains low.
INTRODUCTION
For 2017, an estimated 49,670 individuals (35,720 men and 13,950 women) were diag-
nosed with oral and oropharyngeal cancer (OPC) in the United States.1 The most
important prognostic factor in predicting the outcome of OPC is the stage at which
it is diagnosed.2–6 The growth rates for OPC vary dramatically, with tumor volume
doubling times ranging from 26 to 256 days, with a mean of about 3 months.7,8 It
has been clearly demonstrated that the discovery of OPC by the oral health care
provider (OHP) during the accomplishment of a non–symptom-driven oral examination
is associated with an earlier stage diagnosis and improved patient outcomes, when
compared with the discovery of OPC by a physician performing a symptom-driven
examination.9 Unfortunately, only 30% of patients diagnosed with OPC in 2017 pre-
sented with localized disease.1 Although the overall 5-year survival rates for OPC
have gradually improved from 52.8% to 66.2% over the last 4 decades,10 the
Disclosure: None.
Department of Comprehensive Dentistry, UT Health San Antonio School of Dentistry, 7703
Floyd Curl Drive (Mail Code 7919), San Antonio, TX 78229, USA
E-mail address: huberm@uthscsa.edu
Dent Clin N Am 62 (2018) 59–75

60 Huber
OHP’s success in identifying OPCs at an early stage remains a challenge. The purpose
of this article is to discuss the current standard for identifying OPCs and the current
status of novel adjunctive approaches being marketed to the dental profession.
DELAYS IN DISCOVERY OF ORAL AND OROPHARYNGEAL CANCER
In addressing the delay in the discovery of OPC, 2 distinct categories that have been
traditionally discussed are patient delay and professional delay.5,6,11 Patient delay is
the time delay between the patient’s first awareness of a change and his or her pre-
sentation to a health care provider. The parameters of professional delay are variable
and represent the time delay between the first presentation to the health care provider
and a specific endpoint (eg, biopsy, referral to a specialist, initiation of therapy).5,6
Patient delay represents the single most important factor underlying the delayed
discovery of OPC.5 In a retrospective study of 646 patients over a 19-year period,
Friedrich12 reported the most commonly noted signs and symptoms driving the pa-
tient to seek evaluation were localized swelling (n 5 327), pain (n 5 200), and mucosal
changes (n 5 167). The percentages for those who sought medical care for localized
swelling, pain, or mucosal changes within 1 month were 46.4%, 43.0%, 41.4%,
respectively. More problematic was finding that 15.2% of those with a localized
swelling, 16.0% of those in pain, and 17.4% of those with a mucosal change waited
more than 6 months before seeking medical care. Peacock and associates13 prospec-
tively studied a cohort of 50 patients with oral cancer and determined the mean time
gap between the first symptom and the initial visit to a health care professional was
105 days (range, 0–730).
To date, there is no clear consensus to adequately explain the issue of patient
delay.14,15 Proposed reasons include patient psychosocial factors, health-related
behaviors, socioeconomic status, education level, and health care access or availabil-
ity.5,15,16 Regardless of the ambiguity as to why, it is well-known that the public’s inter-
action with the oral health care profession is low. In a recent Gallup report of interviews
conducted during 2008 (n 5 354,645) and 2013 (n 5 178,072), only 64.7% of partici-
pants reported visiting a dentist within the past year.17 Furthermore, patients at
increased risk for OPC (eg, age >40 years, male gender, alcohol drinkers, tobacco
smokers, low fruit and vegetable intake) are more likely to avoid routine dental care.18
Clearly, concerted efforts to improve public awareness of OPC and the importance of
early diagnosis are essential to addressing the issue of patient delay.11,12,16,19 In this
regard, the oral health care professional has a professional obligation to lead the con-
versation with his or her patient regarding the risk factors, signs, and symptoms of OPC.
The most relevant form of professional delay is the time from first encounter with the
health care system to the initiation of definitive treatment. Ideally, any patient with an
oral potentially malignant lesion (OPML) is afforded a prompt diagnosis and initiation
of therapy. In the aforementioned study by Peacock and colleagues,13 the mean pro-
fessional delay from initial encounter to initiation of treatment was 101 days. Using an
ideal goal of 30 days from first visit to the specialist to initiation of definitive treatment,
Brouha et al20 determined that the goal was met for only 41% of 134 patients with
OPC.20 Thus, although most patients diagnosed with cancer desire to initiate therapy
immediately, many experience significant delays.20,21
CURRENT STANDARD FOR IDENTIFYING AND DIAGNOSING ORAL AND

OROPHARYNGEAL CANCER
In daily practice, when the oral health care professional examines a patient, the
clinician looks for any abnormality, not just OPC.22 OPC screening does not exist as
Adjunctive Diagnostic Techniques 61
an isolated event, but as an integral component of the opportunistic comprehensive

hard and soft tissue examination afforded all patients. The conventional oral examina-
tion (COE), which entails the use of appropriate lighting to accomplish a thorough vi-
sual and tactile assessment of accessible extraoral and intraoral tissues, remains the
foundation upon which lesions are discovered.4 A recently published consensus
document identified the essential elements of such an examination for all patients,
regardless of risk, and is summarized in Table 1.2
When accomplished in a disciplined manner, the sensitivity and specificity of oral
inspection is 94% and 99%, respectively.23 However, the ability to visually discrimi-
nate whether a given discovered lesion is benign or malignant is poor and the “gold
standard” by which any equivocal lesion is diagnosed is the tissue biopsy.11,24,25
Any suspicious or equivocal lesion should be referred for further assessment or un-
dergo biopsy, whereas innocuous lesions should be reevaluated within 4 weeks and
referred for further assessment or undergo biopsy if still present. Unfortunately, there
is concern that not all OHPs accomplish a thorough COE on their patients, thus
missing opportunities to diagnose OPCs at their earliest stage.4,26,27 In a survey
assessing the efficacy of continuing education efforts to address OPC early detection,
Silverman and colleagues4 determined that OHP awareness of what steps constituted
a proper OPC screening examination improved from 82.6% at baseline to 92.7% at
6 months after training. The reported compliance in accomplishing a neck palpation
after the training only improved from 60% to 69.1%, illustrating the continual need
to improve clinician performance in accomplishing the extraoral component of the
head and neck examination.
Table 1
Elements of a proper conventional oral examination
Extraoral examination Perioral and intraoral examination

Visual inspection of the face, head, and neck Visual inspectionb and manual palpation
to detect Lips, including external commissuresc
Asymmetry Labial mucosa and vestibule
Swelling Buccal mucosa, sulcus, and internal
Discoloration commissures
Ulceration Gingiva and alveolar ridge
Skin changesa Anterior tongue (up to circumvallate)
Manual palpation of Dorsum
Nodes Lateral
Preauricular lymph nodes Ventral
Posterior auricular lymph nodes Base of the tongue (including lingual
Submandibular lymph nodes tonsils)
Anterior deep cervical lymph nodes Floor of the mouth
Posterior deep cervical lymph nodes Palate
Neck Hard palate
Soft palate
Retromolar trigone area
Visual inspectionc
Palatine tonsils
Posterior pharyngeal wall
a
Crusts, fissuring, growths.
b
Visual inspection to detect asymmetry, swelling, discoloration, ulceration, or skin changes.
c
Color, texture and surface abnormality.
Adapted from Li L, Morse DE, Katz RV. What constitutes a proper routine oral cancer examina-
tion for patients at low risk? Findings from a Delphi survey. Oral Surg Oral Med Oral Pathol Oral
Radiol 2013;116:e379–86; with permission.
62 Huber
ADJUNCTIVE DIAGNOSTIC TECHNOLOGIES
One response to address this perceived diagnostic tardiness has been the development
and marketing of numerous novel adjunctive technologies with the goal of improving the
OHP’s ability to screen for and identify OPCs and OPMLs at their earliest presen-
tation.28–42 They are all marketed as aids for the clinician to use in addition to, not in
lieu of, the accomplishment of the COE and are often aggressively promoted as
advanced and necessary products. Currently marketed adjuncts to identify OPCs and
OPMLs are listed in Tables 2 and 3. Some of the adjuncts are marketed as “discovery
or screening” enhancements to the COE, and others are marketed as case assessment
utilities to further assess a visually identified lesion. Some are marketed as both.
Lingen and colleagues25 have proposed objective criteria against which emerging
adjunctive technologies may be objectively assessed (Box 1). Given the low preva-
lence of OPC, clinicians should pay attention to an adjunctive technology’s sensitivity
and specificity when it is promoted as a discovery tool to be used as an enhancement
to the COE. None of the adjunctive test are diagnostic for oral cancer.
ROLE OF THE US FOOD AND DRUG ADMINISTRATION IN REGULATING ADJUNCTIVE

TECHNOLOGIES
The OralCDx Brush Test (CDx Diagnostics, Suffern, NY), CytID (Forward Science,
Houston, TX), and MOP cytology component (PCG Molecular, Cumming, GA) are all
essentially laboratory processes, in which a cytology specimen is submitted for final
review by a pathologist. As such, they are not devices requiring clearance by the
US Food and Drug Administration (FDA).43 Some of the adjunctive test companies
will note they are certified under the Clinical Laboratory Improvement Amendments
(CLIA) program.44 However, CLIA certification simply means the laboratory is meeting
certain performance standards to ensure their results are accurate and reliable. CLIA
certification does not address the clinical validity or predictive value of a given test.
The FDA’s Center for Devices and Radiological Health regulates medical devices sold
in the United States.45 There are 2 options the manufacturer of a medical device may take
when applying for approval to market by the FDA. The Premarket Approval application
option requires a manufacturer to submit valid clinical data to support claims made for
the submitted device.43 During 2016, the FDA approved 34 original Premarket Approval
submissions.46 The other option is the Premarket Notification 510(k) process (aka 510(k)),
which requires no such clinical data to support marketing claims.43 Here, the manufac-
turer need only show that the submitted device is at least as safe and effective, that is,
substantially equivalent to a device that was legally marketed before May 28, 1976.
The legally marketed device to which equivalence is drawn is commonly referred to as
the “predicate.” Because the evidentiary burden is less stringent for the 510(k) process
compared with Premarket Approval, most manufacturers use the 510(k) process to
obtain marketing clearance (222 devices cleared during January 2017).47
Of the adjunctive methodologies discussed herein, only vital stain-based and light-
based adjuncts have been cleared for marketing by the FDA. The predicate for the first
light-based adjunct to be used in dentistry was a similar device used to illuminate the
cervix,48 and all subsequent light-based adjuncts (Table 4) have received FDA
clearance in a similar manner.29–35,37,48–56
FDA regulation of the recently developed molecular-based adjuncts is less clearly
defined. Although the FDA acknowledges it has statutory authority to regulate
molecular-based adjuncts, it has yet to release formal regulatory guidance.57 As a
consequence, ongoing FDA oversite over these newly released adjunctive tests is
sporadic.
Table 2
Available cytology-based, vital stained-based and light-based adjunctive diagnostic
technologies
Product Contact Comments

Cytology OralCDx CDx Diagnostics, Suffern, NY CLIA certified
based Brush Test
CytID Forward Science, Houston, Liquid cytology sampling
TX assessed by contract
pathologist
MOP PCG Molecular, Cumming, No response to email inquiry
GA by author
Vital Toluidine Den-Mat Holdings, LLC, Considered a device by the
staining chloride stain Lompoc, CA FDA
based (component
of ViziLite
Plus with
TBlue)
OraBlu AdDent, Inc, Danbury, CT Considered a device by the
FDA
Light-based ViziLite TBlue Den-Mat Holdings, LLC, Chemiluminescent
Lompoc, CA generated light source
(average wavelength
490–510 nm)
Microlux DL AdDent, Inc, Danbury, CT Battery-powered light
source similar to ViziLite
light component
VELscope Vx LED Dental, White Rock, LED generated light source
British Columbia, (400–460 nm), combined
Canada with optical filtration of
the viewfinder to enhance
natural tissue fluorescence
Sapphire Plus Den-Mat Holdings, LLC, Similar to VELscope Vx
Lompoc, CA
Identafi DentalEZ, Malvern, PA White light used for COE
Amber light used to
highlight superficial
vascular architecture
Violet light used in
conjunction with Identifi
Eyewear to assess tissue
fluorescence
Bio/Screen AdDent, Inc, Danbury, CT Similar to VELscope Vx
DOE SE Kit DentLight Inc, Plano, TX White light used for COE
conjunction with
fluorescent loupe filters to
assess tissue fluorescence
OralID Forward Science, Houston, Eyewear to assess tissue
TX fluorescence.
ViziLite PRO Den-Mat Holdings, LLC, Similar to VELscope Vx
Lompoc, CA
Abbreviations: CLIA, clinical laboratory improvement amendments; COE, conventional oral exam-
ination; FDA, US Food and Drug Administration; LED, light-emitting diode.
Data from Refs.29–37
64 Huber
Table 3
Available molecular-based adjuncts to diagnose OPMLs/OPC
Product Company Biomarkers Assessed

OraRisk HPV Complete OralDNALabs HPV strains: 2a, 6, 11, 16, 18, 26,
Genotype and the Eden Prairie, MN 30, 31, 32, 33, 34, 35, 39, 40, 41,
42, 43, 44, 45, 49, 51, 52, 53, 54,
55, 56, 57, 58, 59, 60, 61, 62, 64,
66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 80, 81, 82, 83, 84, 89
OraRisk HPV 16/18/HR OralDNALabs HPV strains: 16, 18, 31, 33, 35, 39,
Eden Prairie, MN 45, 51, 52, 56, 58, 59, 66, 68
MOP PCG Molecular Cumming, GA HPV, cellular changes
No response to email inquiry by
author
SaliMark OSCC PeriRx, LLC DUSP1, SAT, and OAZ1
Broomall, PA
Abbreviations: HPV, human papilloma virus; OPC, oral and oropharyngeal cancer; OPML, oral pre-
malignant lesions.
Cytology-Based Adjuncts
Available since 1999, the Oral CDx BrushTest is specifically marketed to the dental
professional to “test common oral spots (subtle red or white spots) that may appear
in your mouth from time to time.”58 As such, it is a case assessment adjunct. This
adjunctive test is a refinement of the Pap smear technique used in gynecology, in
which a special sampling brush is used to harvest a full transepithelial specimen
that is forwarded to a centralized laboratory for assessment. The appropriate CDT
code to use is D7288, “brush biopsy – transepithelial sample collection.”22 At the lab-
oratory, a sophisticated computer protocol is used to assist the pathologist to render a
final report. Variants of this technology (WATS3D, EndoCDx TNE—Transnasal Esoph-
agoscopy, EndoCDx LP—Laryngeal) are marketed to gastroenterologists and
otolaryngologists.59
Tested lesions that receive a “positive” or “atypical” result with the BrushTest
should undergo a scalpel biopsy to determine the definitive diagnosis. Proponents
of this adjunctive technique note its favorable positive predictive value and negative
predictive value, and feel it allows the practitioner to easily and reliably assess innoc-
uous lesions for benignity, precancer, and cancer, especially for patients hesitant to
Box 1
Parameters of an ideal diagnostic adjunct
1. Simple, inexpensive, safe, and acceptable to the public

2. Detect early disease
3. Detect lesions likely to progress
4. Detect lesions which are manageable
5. Have a high positive predictive value and a low false-negative value
Adapted from Lingen MW, Kalmar JR, Karrison T, et al. Critical evaluation of diagnostic aids for
the detection of oral cancer. Oral Oncol 2008;44:10–22; with permission.
Table 4
US Food and Drug Administration premarket notification 510(k) pedigree for available light-
based adjuncts
Product Applicable 510(k) Date

Speculite (predicate gynecologic illumination device) K853257 12/27/1985
K963391 12/12/1997
ViziLite Plus with TBlue K003995 3/16/2001
K012070 11/27/2001
K033033 1/31/2005
K080043 4/04/2008
Microlux DL K041614 4/04/2005
K072309 11/19/2007
VELscope Vx K060920 4/27/2006
K070523 4/05/2007
K102083 11/18/2010
Sapphire Plus K073483 4/03/2008
Identafi K082603 12/12/2008
K090135 2/17/2009
BioScreen K082668 1/23/2009
DOE SE Kit K101140 7/15/2010
OralID K123169 1/13/2013
ViziLite PRO K082668 1/23/2009
29–35,37,48–56
Data from Refs.
undergo biopsy.11,60–63 It may also be useful to initially assess a patient with multiple
lesions throughout the mouth, where the attainment of multiple biopsies may be
impractical.25
Others contend the BrushTest represents an unnecessary intermediate step,
because all “positive” or “atypical” results must be biopsied to determine the actual
diagnosis.25,64,65 Furthermore, most sensitivity and specificity values for the
BrushTest were calculated predominantly by comparing the efficacy of the test in
assessing clinically suspicious, not innocuous, lesions to traditional biopsy.25,66
Furthermore, a “negative” BrushTest result, although reassuring, is not diagnostic
for a persistent lesion.67,68 The CytID case assessment adjunct uses a liquid cytology
sampling technique whereby the harvested cells are placed in a liquid medium for
transport to the laboratory. The recommendation for use is similar to that of the pre-
viously described Oral CDx BrushTest, for assessing lesions when biopsy is not war-
ranted or possible.38 The appropriate CDT code to use is D7287, “oral
cytologybrush.”22 The use of liquid cytology is claimed to provide a more accurate
sampling compared with the Oral CDx BrushTest.69,70 Tested lesions that receive a
“malignancy” or “atypical” result with CytID must undergo a scalpel biopsy to deter-
mine the definitive diagnosis.71
Vital Stain-Based Adjuncts

Vital staining with toluidine blue (TB) has been advocated as a method to assess sus-
picious mucosal lesions for decades.60,72,73 It is metachromatic dye of the thiazine
group that has an affinity to bind with DNA. Applied topically, TB selectively stains
rapidly dividing tissues such as neoplastic, inflammatory, and regenerative epithelial
tissues and exposed connective tissue.11,60,67 Its use has been advocated by some
as a technique to monitor OPMLs for progression, assess suspect lesion margins,
66 Huber
and accomplish follow-up on patients who have undergone cancer treatment.25,74,75

False-positive results are common and primarily associated with inflammatory lesions
and healing ulcers, which also have a high cellular metabolic rate.25,60,76
TB is currently not cleared by the FDA as a stand-alone adjunctive screening aid. It
is cleared for marketing as a case assessment marking aid to the ViziLite TBlue (Den-
Mat Holdings, LLC, Lompoc, CA), Bio/Screen (AdDent, Inc, Danbury, CT), and Micro-
Lux DL (AdDent, Inc) adjunctive aids, where it may be used to further enhance the
marking of an area initially identified via the companion light-based adjunct.29,36 The
appropriate CDT code to apply when using TB is D0431, “adjunctive pre-diagnostic
test that aids in detection of mucosal abnormalities including premalignant and malig-
nant lesions, not to include cytology or biopsy procedures.”22
Light-Based Adjuncts
The development of the light-based adjuncts represents the culmination of years of
medical research investigating the unique absorbance and reflectance characteristics
of dysplastic or malignant mucosal tissues.77–85 Advocates contend these devices are
easy to use and enhance the clinician’s ability to discover OPML and OPC by
improving lesion visualization and potentially revealing lesions missed by the
COE.86,87 Unfortunately, the majority of studies addressing their efficacy have been
limited to case reports and proof-of-concept trials, often by experienced examiners
who have a higher degree of confidence in distinguishing between suspicious and
nonsuspicious lesions.25,88 The light-based adjuncts can be categorized into 2 basic
groups according to the manner in which a specific spectra of light is used to interro-
gate the reflective properties of the tissue.
The ViziLite TBlue and Microlux DL use a blue-white light (spectral wavelength of
430 and 580 nm) to interrogate the tissues. For the ViziLite TBlue product, the blue-
white light is generated through reaction between acetylsalicylic acid and hydrogen
peroxide (chemiluminescence), whereas the blue-white light for the Microlux DL prod-
uct is produced by a battery-powered light-emitting diode.25 The protocol for both
regimens entails the use of a 60-second prerinse with a 1% acetic acid solution to
remove the surface glycoprotein layer and cause cellular dehydration, to improve
the exposure of cellular elements to the blue-white light.25,88 The examination takes
place in a darkened room or with the use of special eyewear. The premise is that
normal cells absorb the blue-white light whereas dysplastic cells with abnormal nuclei
and high nuclear/cytoplasmic ratios reflect the blue-white back to the examiner as
“aceto-white.”67,88,89
The VELscope Vx (LED Dental, White Rock, British Columbia, Canada), Sapphire
Plus (Den-Mat Holdings, LLC), Identafi (DentalEZ, Malvern, PA), BioScreen (AdDent,
Inc), DOE Oral Exam System (DentLight, Inc, Plano, TX), OralID (Forward Science,
Houston, TX), and ViziLite PRO (Den-Mat Holdings, LLC) use light spectra in the
390 to 460 nm range to interrogate the tissue autofluorescent character of the mucosal
tissues.25 All of these devices use a narrow band filter (either in the device viewfinder
or via eyewear) to emphasize the autofluorescent character of the lesion. The principle
concept is that the natural autofluorescent character of dysplastic or malignant tissues
is different from normal tissues. Dysplastic or carcinogenic tissues are associated with
increased collagen destruction, nuclear/cytoplasmic ratio, and angiogenesis.67,86,90
The net result of these phenomena is a decrease in natural fluorophore concentration
and an increased absorption and scattering of light.88 Normal or healthy tissue ap-
pears pale green using autofluorescence, whereas suspect tissues appear dark
(loss of fluorescence).91 The Identafi adds an additional green-amber light (545 nm)
to better visualize the increase in angiogenesis associated with carcinoma.92,93
Although the design parameters (eg, light source, light filtration, disposability) and
visualization characteristics vary among the light-based adjuncts, the principle under-
lying their use is similar and they are all cleared for marketing by the FDA as illumina-
tion devices.94 All are marketed to assist the practitioner in discovering new or
potentially overlooked mucosal abnormalities. Some are also marketed to assist the
surgeon in defining appropriate surgical margins for excision.60,95
Although light-based adjuncts do offer the clinician a different perspective to view a
lesion (eg, assessment utility), their value and efficacy as screening adjuncts remains
unproven.88,91,96,97 Rashid and Warnakulasuriya88 reviewed 14 published reports
addressing the effectiveness of the VELscope, ViziLite, and Microlux DL adjuncts
(Table 5) and concluded they demonstrate poor specificity and lack the ability to
discriminate between high-risk and low-risk lesions. They further noted that the Vizi-
Lite and MicroLux DL preferentially highlighted keratotic lesions over red lesions
and the VELscope revealed a lack of fluorescence in benign keratosis and inflamma-
tory lesions. They concluded there is insufficient evidence to validate their efficacy as
screening adjuncts.
OHPs choosing to use any of the available visualization adjuncts in assessing their
patients should understand their limitations and ensure an appropriate referral and/or
biopsy is accomplished for any lesion deemed suspicious. The appropriate CDT code
to apply when using one of these adjunctive aids is D0431, “adjunctive pre-diagnostic
Molecular-Based Adjuncts
Saliva has become an increasingly popular medium to assess for potential biomarkers
associated with OPML and OPC.98–100 Potential biomarkers associated with OPC
include nonorganic compounds; proteins and peptides; DNA, messenger RNA, micro-
RNA; carbohydrates; and other metabolites.98 The number of potentially useful
biomarkers has increased significantly over the past decade. Sivadasan and col-
leagues101 recently reported the human salivary proteome contains more than 3400
proteins, of which 808 have been differentially expressed in OPC.
Advancements in our ability to map the molecular mechanisms underlying the path-
ogenesis of OPC should lead to the development of improved diagnostic and thera-
peutic interventions targeting OPC.25,100 The goal of developing a reliable salivary
test or tests to assess for OPML and OPC remains a significant challenge and is
complicated by our inability to effectively compare the numerous published studies,
owing to variabilities in study design and interpretation (eg, sampling techniques,
processing techniques, cutoff points, etc).98,100,102,103 Another underappreciated
Table 5
Efficacy of 3 light-based screening adjuncts
Positive Negative
Predictive Predictive
Adjunct # Articles Sensitivity (%) Specificity (%) Value (%) Value (%)
ViziLite Plus 12 0–100 0–78 18–100 0–100
Microlux DL 1 78 71 37 94
VELscope 12 30–100 15–100 6–59 57–100
Adapted from Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as
adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic re-
view. J Oral Pathol Med 2015;44:307–28; with permission.
68 Huber
confounder is the molecular heterogeneity of OPC itself.104–106 Despite these hurdles,

various molecular-based adjunctive tests (see Table 3) have been introduced to the
dental marketplace as putative aids to assess for OPC or the risk of developing
OPC and are discussed briefly.
The OraRisk HPV Complete Genotype and the OraRisk HPV 16/18/HR (OralDNA-
Labs Eden Prairie, MN) are 2 polymerase chain reaction–based tests available for
determining the presence of human papilloma virus (HPV).39,40 The OraRisk HPV
Complete Genotype utility screens for 51 strains of HPV, whereas the OraRisk HPV
16/18/HR utility tests for 20 oncogenic HPVs, to include HPV 16 and HPV 18.
The prognostic value of current or persistent HPV detection in oral rinses to predict
the risk for oral squamous cell carcinoma is unknown.107–110 The cost–benefit value of
this test is debatable, because an estimated 10,500 individual would need to be tested
to detect 1 case of OPC.109 More problematic is the fact that high-risk HPV prevalence
is estimated to be 4.0% among adults aged 18 to 69 (men, 6.8%; women, 1.2%) and,
to date, there are no available interventions to reduce or prevent the downstream
future development of HPV associated OPC.109 Ultimately, the benefit to risk of using
this test as a screening utility may not be favorable, because it is not predictive of pro-
gression to OPC and may produce significant anxiety for those who screen positive for
a high-risk HPV.110
The MOP screening test from PCG Molecular claims to test for oral cancer risk
earlier than traditional testing methods by assessing the presence of 3 parameters:
HPV infection, cellular abnormalities, and DNA damage.111 The test essentially com-
bines cytology, HPV testing, and an unspecified form of DNA assessment. It consists
of a 30-second gargle and rinse to obtain the sample, which is sent to the company for
assessment. Patients who test positive “will need to be evaluated by an ENT or an oral
surgeon depending on the levels found.” The website also alludes to litigious risk if one
does not use the product, based on the following comment, “By offering the MOP test
both the responsibility and the liability for early detection is placed on the patient. If
patients decline the test, practitioners have their written directive on file. With cases
expected to increase dramatically over the next 20 years, practitioners are well
advised to have such safeguards in place.”112
Information on this test seems to be restricted to its promotional website and there
seems to be no published literature addressing the value or validity of this testing pro-
tocol as a screening utility. In contrast, the National Cancer Institute notes there are no
currently recommended screening methods similar to a Pap test for detecting cell
changes in the oropharyngeal tissues caused by HPV infection.113
The SaliMark OSCC adjunctive test (PeriRx, LLC, Broomall, PA) is a recently intro-
duced case assessment product intended to help the practitioner stratify the risk of
malignancy for a clinically discovered oral lesion.42 The premise is that, by determining
the levels of messenger RNAs for the genes DUSP1, SAT, and OAZ1, along with the
messenger RNAs for the housekeeping genes MTATP6 and RPL30, oral lesions at
high risk for being OPC may be discriminated from low-risk oral lesions.114 In a study
of 168 patients with oral lesions suspicious for cancer, out of which 24 had cancer, the
sensitivity and specificity of the SaliMark OSCC adjunctive test was determined to be
91.7% and 59.0%, respectively.114 The results of the study essentially establish proof
of concept, but have not been validated independently. More important, the perfor-
mance of this product to assess the variety of nonmalignant oral lesions encountered
in general practice is unknown.
The SaliMark OSCC adjunctive test is marketed as a negative predictor, whereby
patients with moderate or high test results should be referred for further evaluation
and/or biopsy, whereas patients with low-risk results should be followed up to ensure
resolution. This protocol for lesion assessment has been proposed by some as a
method to reduce unnecessary referrals and biopsies.115 Such an approach seems
to assume that the only purpose of a biopsy or referral is to determine the presence
of malignancy and conflicts with the foundational principle that a referral and/or biopsy
is indicated for any lesion for which the practitioner cannot confidently establish the
diagnosis.
SUMMARY
The most important prognostic factor in predicting the outcome of OPC continues to
be the stage at which it is diagnosed. Approximately 70% of patients with OPC are
diagnosed with late stage disease and patient-related delay is a major factor in late
stage diagnosis. Efforts to increase the patient’s ability and desire to obtain an oral ex-
amination on a regular basis should be undertaken.
The OHP often has the opportunity to identify OPC at its earliest stage. When pa-
tients present for care, OHPs should accomplish a disciplined and thorough COE to
discover any abnormalities, not just OPC. Any suspicious or equivocal lesion should
be referred for further assessment or undergo biopsy, whereas innocuous lesions
should be reevaluated within 4 weeks and referred for further assessment or undergo
biopsy if still present.
The evidence for use of adjunctive devices to screen for and/or identify OPCs and
OPMLs at their earliest stage remains low. Clinicians are cautioned to consider the
available scientific literature, objective measures of performance, and available
evidence-based guidelines in determining the value of using such devices in clinical
practice.
REFERENCES
1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2016;
67:7–30.
2. Li L, Morse DE, Katz RV. What constitutes a proper routine oral cancer examina-
tion for patients at low risk? Findings from a Delphi survey. Oral Surg Oral Med
Oral Pathol Oral Radiol 2013;116:e379–86.
3. Seoane J, Alvarez-Novoa P, Gomez I, et al. Early oral cancer diagnosis: the Aar-
hus statement perspective. A systematic review and meta-analysis. Head Neck
2016;38(Suppl 1):E2182–9.
4. Silverman S Jr, Kerr AR, Epstein JB. Oral and pharyngeal cancer control and
early detection. J Cancer Educ 2010;25:279–81.
5. Stefanuto P, Doucet JC, Robertson C. Delays in treatment of oral cancer: a re-
view of the current literature. Oral Surg Oral Med Oral Pathol Oral Radiol
2014;117:424–9.
6. Varela-Centelles P, López-Cedrún JL, Fernández-Sanromán J, et al. Key points
and time intervals for early diagnosis in symptomatic oral cancer: a systematic
review. Int J Oral Maxillofac Surg 2017;46:1–10.
7. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for
radiotherapy in head and neck cancer. Radiother Oncol 2007;84:5–10.
8. Waaijer A, Terhaard CHJ, Dehnad H, et al. Waiting times for radiotherapy: con-
sequences of volume increase for the TCP in oropharyngeal carcinoma. Radio-
ther Oncol 2003;66:271–6.
9. Holmes JD, Dierks EJ, Homer LD, et al. Is detection of oral and oropharyngeal
squamous cancer by a dental health care provider associated with a lower
stage at diagnosis? J Oral Maxillofac Surg 2003;61:285–91.
Surgical Management
of Oral Cancer
a,b, b
Rabie M. Shanti, DMD, MD *, Bert W. O’Malley Jr, MD
KEYWORDS
! Oral cancer ! Mandibulectomy ! Maxillectomy ! Glossectomy ! Neck dissection
KEY POINTS
! Primarily, surgery is the standard of care for early-stage oral cancer.
! Distant metastasis must be ruled out before proceeding with surgical management of an
oral cancer.
! Oral cavity squamous cell carcinoma (SCC) is best managed with 1- to 1.5-cm surgical
margins.
! There is a survival benefit in performing a selective neck dissection in early-stage oral cav-
ity SCC.
ROLE OF SURGERY IN HEAD AND NECK CANCER MANAGEMENT
Today, most head and neck cancer subsites, such as the larynx, hypopharynx, naso-
pharynx, and oropharynx, are treated with radiation therapy (XRT) with or without
chemotherapy as a primary treatment modality. Recent advances with transoral ro-
botic surgery (TORS) have significantly impacted the management of cancers of the
oropharynx. Surgery is reserved for the salvage of recurrent tumors that occur within
the head and neck in the absence of distant (ie, lung, liver) metastasis. The results of
the Veterans Administration Larynx Trial published in 1991 identified induction chemo-
therapy followed by XRT provided the same 2-year survival as conventional laryngec-
tomy plus adjuvant XRT.1 Furthermore, in this study, the larynx was preserved in 64%
of patients in the chemoradiotherapy (CRT) arm of the study.1 Today, roughly 30% to
40% of patients who undergo primary CRT for laryngeal squamous cell carcinoma
(SCC) will experience treatment failure with locoregional recurrence of their tumor,
and in the absence of distant metastasis, these patients will go on to require either
a partial or a total laryngectomy (Fig. 1).2,3
Disclosure Statement: The authors have no relevant disclosures.

a
Department of Oral and Maxillofacial Surgery and Pharmacology, University of Pennsylvania
School of Dental Medicine, 240 S 40th Street #122, Philadelphia, PA 19104, USA; b Department
of Otorhinolaryngology/Head and Neck Surgery, Perelman School of Medicine University of
Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, USA
* Corresponding author. Department of Otorhinolaryngology/Head and Neck Surgery, Univer-
sity of Pennsylvania Perelman School of Medicine, 3400 Civic Center Boulevard, Philadelphia,
PA 19104.
E-mail address: rabie.shanti@uphs.upenn.edu
Dent Clin N Am 62 (2018) 77–86

Fig. 1. Total laryngectomy specimen, which includes the epiglottis, vocal cords, thyroid carti-
lage, cricoid cartilage, hyoid bone, upper tracheal rings, and neck dissection lymph node
packet.
Contrary to the larynx, the oropharynx as a subsite has been shown to benefit from
primary surgery with adjuvant therapy as needed. However, the extirpation of
advanced malignant neoplasms of the oropharynx traditionally required open ap-
proaches that required invasive transcervical surgical approaches, such as lip-split
with mandibulotomy/mandibulectomy (Fig. 2). Although transcervical approaches
such as the lip-split mandibulotomy can appear quite graphic and morbid, the benefit
from extirpation of SCC of the oropharynx results in the ability to achieve locoregional
disease control with a 20% reduction in locoregional recurrence in comparison to pri-
mary CRT.4 This benefit in locoregional disease control and overall survival provided
by primary surgery in oropharyngeal SCC served the basis for significant surgical inno-
vation in head and neck surgery. In search of less invasive surgical approaches, Hock-
stein and colleagues5 reported on the potential of the da Vinci surgical system
(Intuitive Surgical, Inc, Sunnyvale, CA, USA) system in performing extirpative opera-
tions that would have classically required a transcervical access–type approach. In
2009, the US Food and Drug Administration approved the da Vinci robotic surgery
Fig. 2. Intraoperative photograph following tumor extirpation requiring lip-split

mandibulectomy.
for surgery of the oropharynx through the work of the senior author (B.W.O.) and Greg-
ory S. Weinstein, MD from the University of Pennsylvania. Today, TORS allows sur-
geons, through the use of special retractors (Fig. 3) and sophisticated technology,
the ability to surgically treat tumors within the oropharynx, hypopharynx, and upper
portions of the larynx that would have been otherwise treated with primary CRT
or substantially more invasive traditional access approaches, such as lip-split
mandibulotomy.
Unlike all other head and neck subsites, oral SCC ideally should be managed with
primary surgery with the possibility of adjuvant XRT with or without chemotherapy,
depending on the presence of certain high-risk pathologic features. The current evi-
dence supports that when safe to do so from a surgical and medical perspective, pri-
mary surgery should be attempted whenever possible to provide patients with the
greatest chance of cure. This issue of the Dental Clinics of North America is devoted
to oral cancer; therefore, the remainder of this article focuses on the role of surgery in
the management of oral SCC, because this neoplasm constitutes 90% of oral cavity
malignancies.
Today, it is unknown why oral SCC is so responsive to primary surgery in compar-
ison to primary XRT or primary CRT, which is not necessarily the case for other sub-
sites, such as the larynx, hypopharynx, or nasopharynx, and in certain cases,
oropharyngeal SCC. However, even though surgery is the ideal primary treatment mo-
dality for oral SCC, one must not underestimate the limitations of surgery in disease
control, such as in the case of locally (primary site) or regionally (cervical lymph nodes)
advanced neoplasms of the oral cavity or in the case of neoplasms of the oral cavity
Fig. 3. Intraoperative photograph with oral retractors in place and arms of da Vinci robot
within the surgical field.
that invade critical structures, such as the carotid artery, skull base, orbital cavity, and
the intracranial cavity, thus hindering the ability to achieve adequate disease control
through surgery. The extirpation of oral cancer can vary from minimally invasive pro-
cedures that require a short anesthetic exposure and hospitalization (Fig. 4) to pro-
cedures that can involve significant operations that encompass different body parts
and a prolonged hospitalization and recovery process (Fig. 5). Furthermore, the overall
health of the patient to withstand a major operation has to be considered when
assessing the candidacy of a patient for surgical management of their oral cancer, irre-
spective of the resectability of their tumor due to the high risk for bleeding and airway
compromise, because the surgical management of oral cancer will almost always
require general anesthesia. Furthermore, aside from the critical anatomic structures
and overall patient health, at the present time, there is no role for surgery in patients
with distant metastatic disease; therefore, distant metastatic disease must be ruled
out before proceeding with the surgical management of oral cancer. The only role of
surgery for cases of metastatic cancer is securing the airway, if necessary, for a tra-
cheostomy procedure or placement of long-term enteral nutrition access via a gastro-
stomy tube.
In this article, the authors discuss the role of surgery and techniques used today in
the extirpation of malignant neoplasms of the oral cavity. The aim is for the reader to
gain insight to the operative procedures and their indications and contraindications,
and the decision-making process that goes into identifying which surgical technique
to use in balancing optimal disease control and function/cosmesis.
SURGICAL MANAGEMENT OF THE PRIMARY TUMOR SITE

Margin Status
Of malignant neoplasms of the oral cavity, 90% are SCC. Excluding the lip, tradition-
ally a 1- to 1.5-cm (10–15 mm) resection margin is recommended (Fig. 6). Obtaining a
tumor-free surgical margin is critical from a locoregional disease control perspective
and an overall survival perspective.6 Therefore, following tumor extirpation, a critical
parameter analyzed in the final pathologic report is the “margin status.” Today, a
negative (clear) margin is a margin where the invasive tumor is at least 5 mm away
from the resected margin, and a close margin is a margin where the invasive tumor
Fig. 4. (A, B) Intraoperative photograph following excision of premalignant lesion of the

tongue, with reconstruction with an off-the-shelf porcine-derived construct.
Fig. 5. (A, B) Intraoperative photograph following left oral hemiglossectomy with recon-
struction of tongue with a fasciocutaneous radial forearm free flap.
is within 1 to 5 mm from the resected margin, and a positive (involved) margin is one
that is less than 1 mm from the resected margin to the invasive tumor.6 Controversy
exists as to what constitutes an involved (positive), close, or clear (negative) margin,
because a recent survey of head and neck surgeons found that 63% of respondents
defined a close margin as a distance of less than 5 mm between the resection margin
and invasive tumor, and a clear margin being a distance of 5 mm or greater between
the 2.7 A positive margin is considered an indication for adjuvant CTR or re-resection,
whereas a close margin is an indication for adjuvant XRT.8 Therefore, in cases of early-
stage (T1 and T2) oral SCC with negative resection margins, in the absence of any
adverse histologic features, the patient can be spared adjuvant therapy. Furthermore,
the presence of a close (1–5 mm) margin has been demonstrated in several studies in
decreasing overall survival and disease-free survival; therefore, additional adjuvant
XRT is recommended.6 Of the oral cavity subsites, lip cancers, in general, have the
most favorable prognosis.9 Lip cancer margins are the most conservative of all the
oral cavity subsites, which are 0.5 to 1 cm (5–10 mm).
Tumor Extirpation Techniques

Glossectomy (tongue resection) is defined by the extent of tissue removed and the
involved portion of the tongue (oral tongue vs base of tongue). Removal of less than
Fig. 6. Intraoperative photograph of 1.5-cm superficial (mucosal) margin marked out cir-
cumferentially using electrocautery.
one-third of the tongue is defined as a partial glossectomy; one-third to one-half is

defined as a hemiglossectomy; one-half to three-quarters is defined as a subtotal
glossectomy, and greater than three-quarters is defined as a total glossectomy
(Fig. 7).
Removal of tumors that abut or invade the mandible or maxilla will require partial or
complete removal of a small or large segment of bone in order to obtain clear surgical
margins. In the case of the mandible, marginal mandibulectomy is a technique that in-
volves removal of either a portion of the alveolar bone while maintaining the integrity of
the inferior border of the mandible, versus removal of a portion of the inferior border of
the mandible while preserving the integrity of the alveolus of the mandible. This tech-
nique is contraindicated in patients with a history of head and neck XRT where the
mandible was part of the treatment field or in cases where there is clinical or radio-
graphic invasion of the bone marrow of the mandible. This technique can weaken
the structure of the mandible, and the general rule is if the mandible has 1 cm or
less of the inferior border following tumor extirpation, then it must be reinforced with
a mandibular reconstruction plate in order to reduce the risk for a pathologic fracture.
In the case of lesions that abut or invade the maxilla, a maxillectomy procedure is per-
formed. This procedure has various classification schemas that are based on the ver-
tical and horizontal extent of the bony defect of the maxilla and the involvement of the
nasal cavity or orbit.10–13
SCC of the buccal mucosa is considered a high-risk (aggressive) oral cancer sub-
site; therefore, multimodality therapy beginning with primary surgery followed by adju-
vant therapy is the preferred recommendation for patients.14,15 Surgery will consist of
wide excision of the lesion with 1.0- to 1.5-cm mucosal and deep margins (Fig. 8).
Furthermore, in cases where the lesion is in close proximity to the maxilla or mandible,
consideration for maxillectomy (infrastructure, subtotal, or total) or mandibulectomy
(marginal or segmental) should be considered. In locally advanced cases of buccal
SCC, it is not uncommon to have to resect a portion or a segment of the maxilla
and mandible as well as overlying skin, creating a complex through-and-through oro-
facial defect.
ROLE OF NECK DISSECTION (CERVICAL LYMPHADENECTOMY)
Cervical lymphadenectomy is the process of systematic removal of groups of lymph

nodes within the neck for staging of cancer, decreasing disease burden, or guiding
Fig. 7. Oral glossectomy classification based on extent of tissue excised.
Fig. 8. (A, C) T3 SCC of the left buccal mucosa. (B, C) Marked out radial forearm free flap,
which is commonly performed to reconstruct large defects of the cheek. (D) Free flap inset
to reconstruct the postoncologic defect.
oncologic decision making. At the time of initial presentation, w40% of patients will
present with cancer metastasis to cervical lymph nodes.16,17 Neck dissection is
described as either elective or therapeutic. Elective neck dissection is performed in
the case where no clinical or radiographic lymphadenopathy is noted, and removal
of certain levels of lymph nodes is aimed at ruling out the presence of metastatic
lymph nodes, which is critical in the decision-making process for adjuvant therapy
and cancer outcome prognostication.16 Therapeutic neck dissection is performed in
the presence of either clinical or radiographic lymphadenopathy with the goal of deter-
mining the degree of disease burden and also the presence of extracapsular exten-
sion, which are indications for adjuvant XRT as well as chemotherapy.16,18 The
status of the cervical lymph nodes is considered the single most important prognos-
ticator for oral cancer, because having a single metastatic lymph node will reduce
5-year survival by 50%.16
The role of elective neck dissection, that is, a neck dissection in the absence
of clinical or radiographic evidence of cervical lymph node metastasis (also known
as “N0” neck), has been debated for several decades. In 2015, a landmark
prospective, randomized, controlled trial was published in the New England Jour-
nal of Medicine and provided evidence for the benefit of elective nodal dissection
in cases of node-negative oral cancer.19 However, at the present time, depending
on institutional preference, a 3-mm depth of invasion is used as a cutoff for recom-
mending a neck dissection in the N0 neck. Although a plethora of literature
has been devoted to determining the ideal depth of invasion threshold for recom-
mending a neck dissection in N0 patients or if all patients with invasive
SCC should undergo a neck dissection, this decision is largely left to
the patient after counseling the patient on the benefits of the elective neck dissec-
tion from an oncologic perspective versus the added morbidity from a neck
dissection.
The neck dissection of oral and head and neck cancer dates back to 1906 with its
initial description by Dr George Crile from the Cleveland Clinic in Ohio.20,21 Dr Hayes
Martin from Memorial Hospital in New York City would expand on the work of Dr Crile
with his publication in 1951 that reviewed his experience in performing 1450 neck
dissections.21–23 The seminal work by Shah and colleagues24–27 stratified the lymph
nodes of the neck into the following lymph node groups: Ia (submental), Ib (subman-
dibular), IIa and IIb (upper jugular), III (middle jugular), IV (lower jugular), Va and Vb
(posterior triangle), VI (central compartment), and VII (superior mediastinal) (refer to
fig. 4 in Mel Mupparapu and Rabie M. Shanti’s article, “Evaluation and Staging of
Oral Cancer,” in this issue). Of note, levels IIa and IIb are separated by the spinal
accessory nerve (cranial nerve XI). The neck dissection in the ensuing decades would
undergo several iterations and today is simply stratified based on the dissected
lymph node groups or excised adjacent structures.16 The modified radical neck
dissection refers to cases where dissection removes lymph node levels I–V with
removal of any of the following structures: spinal accessory nerve, internal jugular
vein, and sternocleidomastoid muscle. If levels I–V lymph nodes are removed
including all 3 of these structures, this is referred to as a radical neck dissection. If
additional nonlymphatic (ie, neurovascular, muscular, or cutaneous) structures are
excised such as the hypoglossal nerve, vagus nerve, carotid artery, paraspinal mus-
cles, or overlying skin of the neck, this is referred to as an extended radical neck
dissection.16 Today, such extensive neck dissections are infrequently performed in
the primary setting, and more commonly, a functional type of neck dissection is per-
formed. The functional types of neck dissection includes the selective neck dissec-
tion (levels I–IV) or supraomohyoid neck dissection (levels I–III) with preservation of all
the aforementioned nonlymphatic structures. This is performed through conservative
cutaneous incisions in order to reduce the morbidity and improve the cosmesis of the
overall outcome of the patient (Fig. 9).
Fig. 9. (A) Intraoperative photograph of incision line indicating the length of the incision
performed at the authors’ institution. (B) Intraoperative photograph of critical structures
that are dissected during a neck dissection.
SUMMARY
Over the past 4 decades, a plethora of advancements have been made in the manage-
ment of head and neck cancers, including advancements in diagnostic (ie, PET/
computed tomography) and nonsurgical treatment modalities, such as intensity
modulated radiation therapy, proton therapy, targeted systemic therapy (ie, Cetuxi-
mab), and most recently, immunotherapy. Furthermore, a move toward minimally
invasive surgical procedures has occurred with the reduction of the extent of a neck
dissection being performed and also ground-breaking advancements such as
TORS. Nonetheless, oral cancers are primarily managed with surgery as a primary
treatment modality; therefore, familiarity of the types of extirpative procedures and
the rationale for their use is imperative for the practitioner involved in the care of pa-
tients with oral cancer.
REFERENCES
1. Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT,

Fisher SG, Hong WK, et al. Induction chemotherapy plus radiation compared
with surgery plus radiation in patients with advanced laryngeal cancer. N Engl
J Med 1991;324(24):1685–90.
2. Esteller E, Vega MC, Lopez M, et al. Salvage surgery after locoregional failure in
head and neck carcinoma patients treated with chemoradiotherapy. Eur Arch
Otorhinolaryngol 2011;268(2):295–301.
3. Leon X, Quer M, Orus C, et al. Results of salvage surgery for local or regional
recurrence after larynx preservation with induction chemotherapy and radio-
therapy. Head Neck 2001;23(9):733–8.
4. Kao SS, Micklem J, Ofo E, et al. A comparison of oncological outcomes between
transoral surgical and non-surgical treatment protocols in the management of
oropharyngeal squamous cell carcinoma. J Laryngol Otol 2017;1–7 [Epub ahead
of print].
5. Hockstein NG, O’Malley BW Jr, Weinstein GS. Assessment of intraoperative
safety in transoral robotic surgery. Laryngoscope 2006;116(2):165–8.
6. Dillon JK, Brown CB, McDonald TM, et al. How does the close surgical margin
impact recurrence and survival when treating oral squamous cell carcinoma?
7. Tasche KK, Buchakjian MR, Pagedar NA, et al. Definition of “close margin” in oral
cancer surgery and association of margin distance with local recurrence rate.
JAMA Otolaryngol Head Neck Surg 2017. [Epub ahead of print].
8. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy
and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.
N Engl J Med 2004;350(19):1937–44.
9. Biasoli ER, Valente VB, Mantovan B, et al. Lip cancer: a clinicopathological study
and treatment outcomes in a 25-year experience. J Oral Maxillofac Surg 2016;
74(7):1360–7.
10. Brown JS, Rogers SN, McNally DN, et al. A modified classification for the maxil-
lectomy defect. Head Neck 2000;22(1):17–26.
11. Okay DJ, Genden E, Buchbinder D, et al. Prosthodontic guidelines for surgical
reconstruction of the maxilla: a classification system of defects. J Prosthet Dent
2001;86(4):352–63.
12. Cordeiro PG, Chen CM. A 15-year review of midface reconstruction after total and
subtotal maxillectomy: part II. Technical modifications to maximize aesthetic and
functional outcomes. Plast Reconstr Surg 2012;129(1):139–47.
Adjunctive Diagnostic
Tec h n i q u e s f o r O r a l a n d
Orophary n g eal C an c er Di scov e ry
Michaell A. Huber, DDS
KEYWORDS
! Squamous cell carcinoma ! Conventional oral examination ! Biopsy
! Adjunctive aids
KEY POINTS
! The most important prognostic factor in predicting the outcome of oral and oropharyngeal
cancer (OPC) is the stage at diagnosis.
! The accomplishment of the conventional oral examination consists of a disciplined visual
and tactile assessment of accessible head and neck structures.
! Any suspicious or equivocal lesion should be referred for further assessment or undergo
biopsy; innocuous lesions should be reevaluated within 4 weeks and referred for further
assessment.
! Evidence supporting the use of adjunctive devices to improve the general practitioner’s
ability to screen for and identify OPCs and oral premalignant lesions remains low.
INTRODUCTION
For 2017, an estimated 49,670 individuals (35,720 men and 13,950 women) were diag-
nosed with oral and oropharyngeal cancer (OPC) in the United States.1 The most
important prognostic factor in predicting the outcome of OPC is the stage at which
it is diagnosed.2–6 The growth rates for OPC vary dramatically, with tumor volume
doubling times ranging from 26 to 256 days, with a mean of about 3 months.7,8 It
has been clearly demonstrated that the discovery of OPC by the oral health care
provider (OHP) during the accomplishment of a non–symptom-driven oral examination
is associated with an earlier stage diagnosis and improved patient outcomes, when
compared with the discovery of OPC by a physician performing a symptom-driven
examination.9 Unfortunately, only 30% of patients diagnosed with OPC in 2017 pre-
sented with localized disease.1 Although the overall 5-year survival rates for OPC
have gradually improved from 52.8% to 66.2% over the last 4 decades,10 the
Disclosure: None.
Department of Comprehensive Dentistry, UT Health San Antonio School of Dentistry, 7703
Floyd Curl Drive (Mail Code 7919), San Antonio, TX 78229, USA
E-mail address: huberm@uthscsa.edu
Dent Clin N Am 62 (2018) 59–75

60 Huber
OHP’s success in identifying OPCs at an early stage remains a challenge. The purpose
of this article is to discuss the current standard for identifying OPCs and the current
status of novel adjunctive approaches being marketed to the dental profession.
DELAYS IN DISCOVERY OF ORAL AND OROPHARYNGEAL CANCER
In addressing the delay in the discovery of OPC, 2 distinct categories that have been
traditionally discussed are patient delay and professional delay.5,6,11 Patient delay is
the time delay between the patient’s first awareness of a change and his or her pre-
sentation to a health care provider. The parameters of professional delay are variable
and represent the time delay between the first presentation to the health care provider
and a specific endpoint (eg, biopsy, referral to a specialist, initiation of therapy).5,6
Patient delay represents the single most important factor underlying the delayed
discovery of OPC.5 In a retrospective study of 646 patients over a 19-year period,
Friedrich12 reported the most commonly noted signs and symptoms driving the pa-
tient to seek evaluation were localized swelling (n 5 327), pain (n 5 200), and mucosal
changes (n 5 167). The percentages for those who sought medical care for localized
swelling, pain, or mucosal changes within 1 month were 46.4%, 43.0%, 41.4%,
respectively. More problematic was finding that 15.2% of those with a localized
swelling, 16.0% of those in pain, and 17.4% of those with a mucosal change waited
more than 6 months before seeking medical care. Peacock and associates13 prospec-
tively studied a cohort of 50 patients with oral cancer and determined the mean time
gap between the first symptom and the initial visit to a health care professional was
105 days (range, 0–730).
To date, there is no clear consensus to adequately explain the issue of patient
delay.14,15 Proposed reasons include patient psychosocial factors, health-related
behaviors, socioeconomic status, education level, and health care access or availabil-
ity.5,15,16 Regardless of the ambiguity as to why, it is well-known that the public’s inter-
action with the oral health care profession is low. In a recent Gallup report of interviews
conducted during 2008 (n 5 354,645) and 2013 (n 5 178,072), only 64.7% of partici-
pants reported visiting a dentist within the past year.17 Furthermore, patients at
increased risk for OPC (eg, age >40 years, male gender, alcohol drinkers, tobacco
smokers, low fruit and vegetable intake) are more likely to avoid routine dental care.18
Clearly, concerted efforts to improve public awareness of OPC and the importance of
early diagnosis are essential to addressing the issue of patient delay.11,12,16,19 In this
regard, the oral health care professional has a professional obligation to lead the con-
versation with his or her patient regarding the risk factors, signs, and symptoms of OPC.
The most relevant form of professional delay is the time from first encounter with the
health care system to the initiation of definitive treatment. Ideally, any patient with an
oral potentially malignant lesion (OPML) is afforded a prompt diagnosis and initiation
of therapy. In the aforementioned study by Peacock and colleagues,13 the mean pro-
fessional delay from initial encounter to initiation of treatment was 101 days. Using an
ideal goal of 30 days from first visit to the specialist to initiation of definitive treatment,
Brouha et al20 determined that the goal was met for only 41% of 134 patients with
OPC.20 Thus, although most patients diagnosed with cancer desire to initiate therapy
immediately, many experience significant delays.20,21
CURRENT STANDARD FOR IDENTIFYING AND DIAGNOSING ORAL AND

OROPHARYNGEAL CANCER
In daily practice, when the oral health care professional examines a patient, the
clinician looks for any abnormality, not just OPC.22 OPC screening does not exist as
an isolated event, but as an integral component of the opportunistic comprehensive

hard and soft tissue examination afforded all patients. The conventional oral examina-
tion (COE), which entails the use of appropriate lighting to accomplish a thorough vi-
sual and tactile assessment of accessible extraoral and intraoral tissues, remains the
foundation upon which lesions are discovered.4 A recently published consensus
document identified the essential elements of such an examination for all patients,
regardless of risk, and is summarized in Table 1.2
When accomplished in a disciplined manner, the sensitivity and specificity of oral
inspection is 94% and 99%, respectively.23 However, the ability to visually discrimi-
nate whether a given discovered lesion is benign or malignant is poor and the “gold
standard” by which any equivocal lesion is diagnosed is the tissue biopsy.11,24,25
Any suspicious or equivocal lesion should be referred for further assessment or un-
dergo biopsy, whereas innocuous lesions should be reevaluated within 4 weeks and
referred for further assessment or undergo biopsy if still present. Unfortunately, there
is concern that not all OHPs accomplish a thorough COE on their patients, thus
missing opportunities to diagnose OPCs at their earliest stage.4,26,27 In a survey
assessing the efficacy of continuing education efforts to address OPC early detection,
Silverman and colleagues4 determined that OHP awareness of what steps constituted
a proper OPC screening examination improved from 82.6% at baseline to 92.7% at
6 months after training. The reported compliance in accomplishing a neck palpation
after the training only improved from 60% to 69.1%, illustrating the continual need
to improve clinician performance in accomplishing the extraoral component of the
head and neck examination.
Table 1
Elements of a proper conventional oral examination
Extraoral examination Perioral and intraoral examination

Visual inspection of the face, head, and neck Visual inspectionb and manual palpation
to detect Lips, including external commissuresc
Asymmetry Labial mucosa and vestibule
Swelling Buccal mucosa, sulcus, and internal
Discoloration commissures
Ulceration Gingiva and alveolar ridge
Skin changesa Anterior tongue (up to circumvallate)
Manual palpation of Dorsum
Nodes Lateral
Preauricular lymph nodes Ventral
Posterior auricular lymph nodes Base of the tongue (including lingual
Submandibular lymph nodes tonsils)
Anterior deep cervical lymph nodes Floor of the mouth
Posterior deep cervical lymph nodes Palate
Neck Hard palate
Soft palate
Retromolar trigone area
Visual inspectionc
Palatine tonsils
Posterior pharyngeal wall
a
Crusts, fissuring, growths.
b
Visual inspection to detect asymmetry, swelling, discoloration, ulceration, or skin changes.
c
Color, texture and surface abnormality.
Adapted from Li L, Morse DE, Katz RV. What constitutes a proper routine oral cancer examina-
tion for patients at low risk? Findings from a Delphi survey. Oral Surg Oral Med Oral Pathol Oral
Radiol 2013;116:e379–86; with permission.
62 Huber
ADJUNCTIVE DIAGNOSTIC TECHNOLOGIES
One response to address this perceived diagnostic tardiness has been the development
and marketing of numerous novel adjunctive technologies with the goal of improving the
OHP’s ability to screen for and identify OPCs and OPMLs at their earliest presen-
tation.28–42 They are all marketed as aids for the clinician to use in addition to, not in
lieu of, the accomplishment of the COE and are often aggressively promoted as
advanced and necessary products. Currently marketed adjuncts to identify OPCs and
OPMLs are listed in Tables 2 and 3. Some of the adjuncts are marketed as “discovery
or screening” enhancements to the COE, and others are marketed as case assessment
utilities to further assess a visually identified lesion. Some are marketed as both.
Lingen and colleagues25 have proposed objective criteria against which emerging
adjunctive technologies may be objectively assessed (Box 1). Given the low preva-
lence of OPC, clinicians should pay attention to an adjunctive technology’s sensitivity
and specificity when it is promoted as a discovery tool to be used as an enhancement
to the COE. None of the adjunctive test are diagnostic for oral cancer.
ROLE OF THE US FOOD AND DRUG ADMINISTRATION IN REGULATING ADJUNCTIVE

TECHNOLOGIES
The OralCDx Brush Test (CDx Diagnostics, Suffern, NY), CytID (Forward Science,
Houston, TX), and MOP cytology component (PCG Molecular, Cumming, GA) are all
essentially laboratory processes, in which a cytology specimen is submitted for final
review by a pathologist. As such, they are not devices requiring clearance by the
US Food and Drug Administration (FDA).43 Some of the adjunctive test companies
will note they are certified under the Clinical Laboratory Improvement Amendments
(CLIA) program.44 However, CLIA certification simply means the laboratory is meeting
certain performance standards to ensure their results are accurate and reliable. CLIA
certification does not address the clinical validity or predictive value of a given test.
The FDA’s Center for Devices and Radiological Health regulates medical devices sold
in the United States.45 There are 2 options the manufacturer of a medical device may take
when applying for approval to market by the FDA. The Premarket Approval application
option requires a manufacturer to submit valid clinical data to support claims made for
the submitted device.43 During 2016, the FDA approved 34 original Premarket Approval
submissions.46 The other option is the Premarket Notification 510(k) process (aka 510(k)),
which requires no such clinical data to support marketing claims.43 Here, the manufac-
turer need only show that the submitted device is at least as safe and effective, that is,
substantially equivalent to a device that was legally marketed before May 28, 1976.
The legally marketed device to which equivalence is drawn is commonly referred to as
the “predicate.” Because the evidentiary burden is less stringent for the 510(k) process
compared with Premarket Approval, most manufacturers use the 510(k) process to
obtain marketing clearance (222 devices cleared during January 2017).47
Of the adjunctive methodologies discussed herein, only vital stain-based and light-
based adjuncts have been cleared for marketing by the FDA. The predicate for the first
light-based adjunct to be used in dentistry was a similar device used to illuminate the
cervix,48 and all subsequent light-based adjuncts (Table 4) have received FDA
clearance in a similar manner.29–35,37,48–56
FDA regulation of the recently developed molecular-based adjuncts is less clearly
defined. Although the FDA acknowledges it has statutory authority to regulate
molecular-based adjuncts, it has yet to release formal regulatory guidance.57 As a
consequence, ongoing FDA oversite over these newly released adjunctive tests is
sporadic.
Table 2
Available cytology-based, vital stained-based and light-based adjunctive diagnostic
technologies
Product Contact Comments

Cytology OralCDx CDx Diagnostics, Suffern, NY CLIA certified
based Brush Test
CytID Forward Science, Houston, Liquid cytology sampling
TX assessed by contract
pathologist
MOP PCG Molecular, Cumming, No response to email inquiry
GA by author
Vital Toluidine Den-Mat Holdings, LLC, Considered a device by the
staining chloride stain Lompoc, CA FDA
based (component
of ViziLite
Plus with
TBlue)
OraBlu AdDent, Inc, Danbury, CT Considered a device by the
FDA
Light-based ViziLite TBlue Den-Mat Holdings, LLC, Chemiluminescent
Lompoc, CA generated light source
(average wavelength
490–510 nm)
Microlux DL AdDent, Inc, Danbury, CT Battery-powered light
source similar to ViziLite
light component
VELscope Vx LED Dental, White Rock, LED generated light source
British Columbia, (400–460 nm), combined
Canada with optical filtration of
the viewfinder to enhance
natural tissue fluorescence
Sapphire Plus Den-Mat Holdings, LLC, Similar to VELscope Vx
Lompoc, CA
Identafi DentalEZ, Malvern, PA White light used for COE
Amber light used to
highlight superficial
vascular architecture
conjunction with Identifi
Eyewear to assess tissue
fluorescence
Bio/Screen AdDent, Inc, Danbury, CT Similar to VELscope Vx
DOE SE Kit DentLight Inc, Plano, TX White light used for COE
conjunction with
fluorescent loupe filters to
assess tissue fluorescence
OralID Forward Science, Houston, Eyewear to assess tissue
TX fluorescence.
ViziLite PRO Den-Mat Holdings, LLC, Similar to VELscope Vx
Lompoc, CA
Abbreviations: CLIA, clinical laboratory improvement amendments; COE, conventional oral exam-
ination; FDA, US Food and Drug Administration; LED, light-emitting diode.
64 Huber
Table 3
Available molecular-based adjuncts to diagnose OPMLs/OPC
Product Company Biomarkers Assessed

OraRisk HPV Complete OralDNALabs HPV strains: 2a, 6, 11, 16, 18, 26,
Genotype and the Eden Prairie, MN 30, 31, 32, 33, 34, 35, 39, 40, 41,
42, 43, 44, 45, 49, 51, 52, 53, 54,
55, 56, 57, 58, 59, 60, 61, 62, 64,
66, 67, 68, 69, 70, 71, 72, 73, 74,
75, 76, 77, 80, 81, 82, 83, 84, 89
OraRisk HPV 16/18/HR OralDNALabs HPV strains: 16, 18, 31, 33, 35, 39,
Eden Prairie, MN 45, 51, 52, 56, 58, 59, 66, 68
MOP PCG Molecular Cumming, GA HPV, cellular changes
No response to email inquiry by
author
SaliMark OSCC PeriRx, LLC DUSP1, SAT, and OAZ1
Broomall, PA
Abbreviations: HPV, human papilloma virus; OPC, oral and oropharyngeal cancer; OPML, oral pre-
malignant lesions.
Cytology-Based Adjuncts
Available since 1999, the Oral CDx BrushTest is specifically marketed to the dental
professional to “test common oral spots (subtle red or white spots) that may appear
in your mouth from time to time.”58 As such, it is a case assessment adjunct. This
adjunctive test is a refinement of the Pap smear technique used in gynecology, in
which a special sampling brush is used to harvest a full transepithelial specimen
that is forwarded to a centralized laboratory for assessment. The appropriate CDT
code to use is D7288, “brush biopsy – transepithelial sample collection.”22 At the lab-
oratory, a sophisticated computer protocol is used to assist the pathologist to render a
final report. Variants of this technology (WATS3D, EndoCDx TNE—Transnasal Esoph-
agoscopy, EndoCDx LP—Laryngeal) are marketed to gastroenterologists and
otolaryngologists.59
Tested lesions that receive a “positive” or “atypical” result with the BrushTest
should undergo a scalpel biopsy to determine the definitive diagnosis. Proponents
of this adjunctive technique note its favorable positive predictive value and negative
predictive value, and feel it allows the practitioner to easily and reliably assess innoc-
uous lesions for benignity, precancer, and cancer, especially for patients hesitant to
Box 1
Parameters of an ideal diagnostic adjunct
1. Simple, inexpensive, safe, and acceptable to the public

2. Detect early disease
3. Detect lesions likely to progress
4. Detect lesions which are manageable
5. Have a high positive predictive value and a low false-negative value
Adapted from Lingen MW, Kalmar JR, Karrison T, et al. Critical evaluation of diagnostic aids for
the detection of oral cancer. Oral Oncol 2008;44:10–22; with permission.
Table 4
US Food and Drug Administration premarket notification 510(k) pedigree for available light-
based adjuncts
Product Applicable 510(k) Date

Speculite (predicate gynecologic illumination device) K853257 12/27/1985
K963391 12/12/1997
ViziLite Plus with TBlue K003995 3/16/2001
K012070 11/27/2001
K033033 1/31/2005
K080043 4/04/2008
Microlux DL K041614 4/04/2005
K072309 11/19/2007
VELscope Vx K060920 4/27/2006
K070523 4/05/2007
K102083 11/18/2010
Sapphire Plus K073483 4/03/2008
Identafi K082603 12/12/2008
K090135 2/17/2009
BioScreen K082668 1/23/2009
DOE SE Kit K101140 7/15/2010
OralID K123169 1/13/2013
ViziLite PRO K082668 1/23/2009
29–35,37,48–56
Data from Refs.
undergo biopsy.11,60–63 It may also be useful to initially assess a patient with multiple
lesions throughout the mouth, where the attainment of multiple biopsies may be
impractical.25
Others contend the BrushTest represents an unnecessary intermediate step,
because all “positive” or “atypical” results must be biopsied to determine the actual
diagnosis.25,64,65 Furthermore, most sensitivity and specificity values for the
BrushTest were calculated predominantly by comparing the efficacy of the test in
assessing clinically suspicious, not innocuous, lesions to traditional biopsy.25,66
Furthermore, a “negative” BrushTest result, although reassuring, is not diagnostic
for a persistent lesion.67,68 The CytID case assessment adjunct uses a liquid cytology
sampling technique whereby the harvested cells are placed in a liquid medium for
transport to the laboratory. The recommendation for use is similar to that of the pre-
viously described Oral CDx BrushTest, for assessing lesions when biopsy is not war-
ranted or possible.38 The appropriate CDT code to use is D7287, “oral
cytologybrush.”22 The use of liquid cytology is claimed to provide a more accurate
sampling compared with the Oral CDx BrushTest.69,70 Tested lesions that receive a
“malignancy” or “atypical” result with CytID must undergo a scalpel biopsy to deter-
mine the definitive diagnosis.71
Vital Stain-Based Adjuncts

Vital staining with toluidine blue (TB) has been advocated as a method to assess sus-
picious mucosal lesions for decades.60,72,73 It is metachromatic dye of the thiazine
group that has an affinity to bind with DNA. Applied topically, TB selectively stains
rapidly dividing tissues such as neoplastic, inflammatory, and regenerative epithelial
tissues and exposed connective tissue.11,60,67 Its use has been advocated by some
as a technique to monitor OPMLs for progression, assess suspect lesion margins,
66 Huber
and accomplish follow-up on patients who have undergone cancer treatment.25,74,75

False-positive results are common and primarily associated with inflammatory lesions
and healing ulcers, which also have a high cellular metabolic rate.25,60,76
TB is currently not cleared by the FDA as a stand-alone adjunctive screening aid. It
is cleared for marketing as a case assessment marking aid to the ViziLite TBlue (Den-
Mat Holdings, LLC, Lompoc, CA), Bio/Screen (AdDent, Inc, Danbury, CT), and Micro-
Lux DL (AdDent, Inc) adjunctive aids, where it may be used to further enhance the
marking of an area initially identified via the companion light-based adjunct.29,36 The
appropriate CDT code to apply when using TB is D0431, “adjunctive pre-diagnostic
Light-Based Adjuncts
The development of the light-based adjuncts represents the culmination of years of
medical research investigating the unique absorbance and reflectance characteristics
of dysplastic or malignant mucosal tissues.77–85 Advocates contend these devices are
easy to use and enhance the clinician’s ability to discover OPML and OPC by
improving lesion visualization and potentially revealing lesions missed by the
COE.86,87 Unfortunately, the majority of studies addressing their efficacy have been
limited to case reports and proof-of-concept trials, often by experienced examiners
who have a higher degree of confidence in distinguishing between suspicious and
nonsuspicious lesions.25,88 The light-based adjuncts can be categorized into 2 basic
groups according to the manner in which a specific spectra of light is used to interro-
gate the reflective properties of the tissue.
The ViziLite TBlue and Microlux DL use a blue-white light (spectral wavelength of
430 and 580 nm) to interrogate the tissues. For the ViziLite TBlue product, the blue-
white light is generated through reaction between acetylsalicylic acid and hydrogen
peroxide (chemiluminescence), whereas the blue-white light for the Microlux DL prod-
uct is produced by a battery-powered light-emitting diode.25 The protocol for both
regimens entails the use of a 60-second prerinse with a 1% acetic acid solution to
remove the surface glycoprotein layer and cause cellular dehydration, to improve
the exposure of cellular elements to the blue-white light.25,88 The examination takes
place in a darkened room or with the use of special eyewear. The premise is that
normal cells absorb the blue-white light whereas dysplastic cells with abnormal nuclei
and high nuclear/cytoplasmic ratios reflect the blue-white back to the examiner as
“aceto-white.”67,88,89
The VELscope Vx (LED Dental, White Rock, British Columbia, Canada), Sapphire
Plus (Den-Mat Holdings, LLC), Identafi (DentalEZ, Malvern, PA), BioScreen (AdDent,
Inc), DOE Oral Exam System (DentLight, Inc, Plano, TX), OralID (Forward Science,
Houston, TX), and ViziLite PRO (Den-Mat Holdings, LLC) use light spectra in the
390 to 460 nm range to interrogate the tissue autofluorescent character of the mucosal
tissues.25 All of these devices use a narrow band filter (either in the device viewfinder
or via eyewear) to emphasize the autofluorescent character of the lesion. The principle
concept is that the natural autofluorescent character of dysplastic or malignant tissues
is different from normal tissues. Dysplastic or carcinogenic tissues are associated with
increased collagen destruction, nuclear/cytoplasmic ratio, and angiogenesis.67,86,90
The net result of these phenomena is a decrease in natural fluorophore concentration
and an increased absorption and scattering of light.88 Normal or healthy tissue ap-
pears pale green using autofluorescence, whereas suspect tissues appear dark
(loss of fluorescence).91 The Identafi adds an additional green-amber light (545 nm)
to better visualize the increase in angiogenesis associated with carcinoma.92,93
Although the design parameters (eg, light source, light filtration, disposability) and
visualization characteristics vary among the light-based adjuncts, the principle under-
lying their use is similar and they are all cleared for marketing by the FDA as illumina-
tion devices.94 All are marketed to assist the practitioner in discovering new or
potentially overlooked mucosal abnormalities. Some are also marketed to assist the
surgeon in defining appropriate surgical margins for excision.60,95
Although light-based adjuncts do offer the clinician a different perspective to view a
lesion (eg, assessment utility), their value and efficacy as screening adjuncts remains
unproven.88,91,96,97 Rashid and Warnakulasuriya88 reviewed 14 published reports
addressing the effectiveness of the VELscope, ViziLite, and Microlux DL adjuncts
(Table 5) and concluded they demonstrate poor specificity and lack the ability to
discriminate between high-risk and low-risk lesions. They further noted that the Vizi-
Lite and MicroLux DL preferentially highlighted keratotic lesions over red lesions
and the VELscope revealed a lack of fluorescence in benign keratosis and inflamma-
tory lesions. They concluded there is insufficient evidence to validate their efficacy as
screening adjuncts.
OHPs choosing to use any of the available visualization adjuncts in assessing their
patients should understand their limitations and ensure an appropriate referral and/or
biopsy is accomplished for any lesion deemed suspicious. The appropriate CDT code
to apply when using one of these adjunctive aids is D0431, “adjunctive pre-diagnostic
Molecular-Based Adjuncts
Saliva has become an increasingly popular medium to assess for potential biomarkers
associated with OPML and OPC.98–100 Potential biomarkers associated with OPC
include nonorganic compounds; proteins and peptides; DNA, messenger RNA, micro-
RNA; carbohydrates; and other metabolites.98 The number of potentially useful
biomarkers has increased significantly over the past decade. Sivadasan and col-
leagues101 recently reported the human salivary proteome contains more than 3400
proteins, of which 808 have been differentially expressed in OPC.
Advancements in our ability to map the molecular mechanisms underlying the path-
ogenesis of OPC should lead to the development of improved diagnostic and thera-
peutic interventions targeting OPC.25,100 The goal of developing a reliable salivary
test or tests to assess for OPML and OPC remains a significant challenge and is
complicated by our inability to effectively compare the numerous published studies,
owing to variabilities in study design and interpretation (eg, sampling techniques,
processing techniques, cutoff points, etc).98,100,102,103 Another underappreciated
Table 5
Efficacy of 3 light-based screening adjuncts
Positive Negative
Predictive Predictive
Adjunct # Articles Sensitivity (%) Specificity (%) Value (%) Value (%)
ViziLite Plus 12 0–100 0–78 18–100 0–100
Microlux DL 1 78 71 37 94
VELscope 12 30–100 15–100 6–59 57–100
Adapted from Rashid A, Warnakulasuriya S. The use of light-based (optical) detection systems as
adjuncts in the detection of oral cancer and oral potentially malignant disorders: a systematic re-
view. J Oral Pathol Med 2015;44:307–28; with permission.
68 Huber
confounder is the molecular heterogeneity of OPC itself.104–106 Despite these hurdles,

various molecular-based adjunctive tests (see Table 3) have been introduced to the
dental marketplace as putative aids to assess for OPC or the risk of developing
OPC and are discussed briefly.
The OraRisk HPV Complete Genotype and the OraRisk HPV 16/18/HR (OralDNA-
Labs Eden Prairie, MN) are 2 polymerase chain reaction–based tests available for
determining the presence of human papilloma virus (HPV).39,40 The OraRisk HPV
Complete Genotype utility screens for 51 strains of HPV, whereas the OraRisk HPV
16/18/HR utility tests for 20 oncogenic HPVs, to include HPV 16 and HPV 18.
The prognostic value of current or persistent HPV detection in oral rinses to predict
the risk for oral squamous cell carcinoma is unknown.107–110 The cost–benefit value of
this test is debatable, because an estimated 10,500 individual would need to be tested
to detect 1 case of OPC.109 More problematic is the fact that high-risk HPV prevalence
is estimated to be 4.0% among adults aged 18 to 69 (men, 6.8%; women, 1.2%) and,
to date, there are no available interventions to reduce or prevent the downstream
future development of HPV associated OPC.109 Ultimately, the benefit to risk of using
this test as a screening utility may not be favorable, because it is not predictive of pro-
gression to OPC and may produce significant anxiety for those who screen positive for
a high-risk HPV.110
The MOP screening test from PCG Molecular claims to test for oral cancer risk
earlier than traditional testing methods by assessing the presence of 3 parameters:
HPV infection, cellular abnormalities, and DNA damage.111 The test essentially com-
bines cytology, HPV testing, and an unspecified form of DNA assessment. It consists
of a 30-second gargle and rinse to obtain the sample, which is sent to the company for
assessment. Patients who test positive “will need to be evaluated by an ENT or an oral
surgeon depending on the levels found.” The website also alludes to litigious risk if one
does not use the product, based on the following comment, “By offering the MOP test
both the responsibility and the liability for early detection is placed on the patient. If
patients decline the test, practitioners have their written directive on file. With cases
expected to increase dramatically over the next 20 years, practitioners are well
advised to have such safeguards in place.”112
Information on this test seems to be restricted to its promotional website and there
seems to be no published literature addressing the value or validity of this testing pro-
tocol as a screening utility. In contrast, the National Cancer Institute notes there are no
currently recommended screening methods similar to a Pap test for detecting cell
changes in the oropharyngeal tissues caused by HPV infection.113
The SaliMark OSCC adjunctive test (PeriRx, LLC, Broomall, PA) is a recently intro-
duced case assessment product intended to help the practitioner stratify the risk of
malignancy for a clinically discovered oral lesion.42 The premise is that, by determining
the levels of messenger RNAs for the genes DUSP1, SAT, and OAZ1, along with the
messenger RNAs for the housekeeping genes MTATP6 and RPL30, oral lesions at
high risk for being OPC may be discriminated from low-risk oral lesions.114 In a study
of 168 patients with oral lesions suspicious for cancer, out of which 24 had cancer, the
sensitivity and specificity of the SaliMark OSCC adjunctive test was determined to be
91.7% and 59.0%, respectively.114 The results of the study essentially establish proof
of concept, but have not been validated independently. More important, the perfor-
mance of this product to assess the variety of nonmalignant oral lesions encountered
in general practice is unknown.
The SaliMark OSCC adjunctive test is marketed as a negative predictor, whereby
patients with moderate or high test results should be referred for further evaluation
and/or biopsy, whereas patients with low-risk results should be followed up to ensure
resolution. This protocol for lesion assessment has been proposed by some as a
method to reduce unnecessary referrals and biopsies.115 Such an approach seems
to assume that the only purpose of a biopsy or referral is to determine the presence
of malignancy and conflicts with the foundational principle that a referral and/or biopsy
is indicated for any lesion for which the practitioner cannot confidently establish the
diagnosis.
SUMMARY
The most important prognostic factor in predicting the outcome of OPC continues to
be the stage at which it is diagnosed. Approximately 70% of patients with OPC are
diagnosed with late stage disease and patient-related delay is a major factor in late
stage diagnosis. Efforts to increase the patient’s ability and desire to obtain an oral ex-
amination on a regular basis should be undertaken.
The OHP often has the opportunity to identify OPC at its earliest stage. When pa-
tients present for care, OHPs should accomplish a disciplined and thorough COE to
discover any abnormalities, not just OPC. Any suspicious or equivocal lesion should
be referred for further assessment or undergo biopsy, whereas innocuous lesions
should be reevaluated within 4 weeks and referred for further assessment or undergo
biopsy if still present.
The evidence for use of adjunctive devices to screen for and/or identify OPCs and
OPMLs at their earliest stage remains low. Clinicians are cautioned to consider the
available scientific literature, objective measures of performance, and available
evidence-based guidelines in determining the value of using such devices in clinical
practice.
REFERENCES
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67:7–30.
2. Li L, Morse DE, Katz RV. What constitutes a proper routine oral cancer examina-
tion for patients at low risk? Findings from a Delphi survey. Oral Surg Oral Med
Oral Pathol Oral Radiol 2013;116:e379–86.
3. Seoane J, Alvarez-Novoa P, Gomez I, et al. Early oral cancer diagnosis: the Aar-
hus statement perspective. A systematic review and meta-analysis. Head Neck
2016;38(Suppl 1):E2182–9.
4. Silverman S Jr, Kerr AR, Epstein JB. Oral and pharyngeal cancer control and
early detection. J Cancer Educ 2010;25:279–81.
5. Stefanuto P, Doucet JC, Robertson C. Delays in treatment of oral cancer: a re-
view of the current literature. Oral Surg Oral Med Oral Pathol Oral Radiol
2014;117:424–9.
6. Varela-Centelles P, López-Cedrún JL, Fernández-Sanromán J, et al. Key points
and time intervals for early diagnosis in symptomatic oral cancer: a systematic
review. Int J Oral Maxillofac Surg 2017;46:1–10.
7. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for
radiotherapy in head and neck cancer. Radiother Oncol 2007;84:5–10.
8. Waaijer A, Terhaard CHJ, Dehnad H, et al. Waiting times for radiotherapy: con-
sequences of volume increase for the TCP in oropharyngeal carcinoma. Radio-
ther Oncol 2003;66:271–6.
9. Holmes JD, Dierks EJ, Homer LD, et al. Is detection of oral and oropharyngeal
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I m p l a n t Su r g e r y U p d a t e f o r
the General Practitioner
Dealing with Common Postimplant Surgery
Complications
Rinil Patel, DDS*, Earl Clarkson, DDS
KEYWORDS
! Implant complications ! Nerve injury ! Infection ! Antibiotics ! Sinusitis
! Membrane perforation ! Edema
KEY POINTS
! Postimplant surgery complications are common.
! Nerve injuries should be identified and diagnosed based on degree of injury.
! Routine implants do not need antibiotics unless patient returns with an infection.
! Sinusitis first-line antibiotic is amoxicillin with or without clavulanate.
! Ibuprofen and dexamethasone can reduce postoperative edema and discomfort.
INTRODUCTION
The introduction of implants has revolutionized restorative and surgical dentistry. With
the evolution of technology, implants have become more affordable, become smaller,
and come with different surface types and shapes. However, even with these techno-
logical advances, knowledge of the anatomy, surgical skill, and management of com-
mon complications are of upmost importance. Postimplant placement complications
can be separated into 2 categories: early failure or late failure. Early failure usually is
within the first 6 months or before osseointegration, whereas late failures are after
the first 6 months or during the restorative phase.1,2 Primary predictors of implant fail-
ure include poor bone quality, chronic periodontitis, systemic diseases, smoking,
advanced age, implant location, parafunctional habits, loss of implant integration,
and inappropriate prosthesis.3 This article discusses common postimplant surgery
failures and management of these complications.
NYC Health 1 Hospitals/Woodhull, 760 Broadway, Room 2C-320, Brooklyn, NY 11206, USA
E-mail address: rinilpateldds@gmail.com
Dent Clin N Am 65 (2021) 125–134

0011-8532/21/Published by Elsevier Inc.
126 Patel & Clarkson
NEUROSENSORY DISTURBANCES AND NERVE INJURY
Neurosensory disturbances throughout the maxillofacial region can occur because of

trauma, neoplasms, infections, or secondary to a surgical procedure. Two common
neurosensory injury classification systems are Seddon and Sunderland. The classifi-
cations systems are explained in Table 1.
A review of published literature reveals studies investigating the incidence of injury
are inconsistent.4 Published articles of nerve injury from implant placement range be-
tween 0% and 13% with some reporting incidence rates as high as 40%.5,6 These in-
consistencies are primarily due to interchangeable definitions of nerve injury and
evaluation. Neurosensory disturbances can be permanent or transient. Patients usu-
ally suffer varying degrees of the following symptoms: numbness to teeth, chin,
cheeks, and lips, speech impediments, problems with speech and mastication,
inability to control food and liquid with unintended drooling, and occasionally, chronic
pain.7
Nerve damage is more likely to occur when placing dental implants in the mandible.
As bone resorption occurs in the mandible, the distance from the alveolar crest to the
inferior alveolar nerve and mental nerve decreases, consequently increasing the
chance of accidental nerve injury. Nerve damage after implant surgery is mainly
caused by direct or indirect injury from osteotomy drilling or implant placement,
stretching of the nerve caused by excess traction of the flap, or direct needle injury.8
Postoperative edema can be another cause of paresthesia; however, this usually will
resolve once the edema subsides.9 The most common areas to be affected are the
lower lip and chin region; although unlikely, but still possible, are the tongue, palate,
and localized tissues.
In order to avoid nerve injuries, the practitioner should always refer to radiographic
imaging before implant placement. If 3-dimensional imaging is available, this is far
Table 1
Classification of nerve injuries and associated findings
Injury Type Extent of Injury Recovery Time Surgical Treatment

Sunderland 1stdegree Transient ischemia, anoxia, Fast: hours None indicated
(Seddon neuropraxia) " segmental demyelination, to weeks
intrafascicular edema
causing block of conduction
Sunderland 2nd degree Axon and myelin interruption Slow: weeks None indicated
(Seddon axonotmesis) (intact endoneurium, Regeneration
perineurium, and rate 1–3 mm/d
epineurium)
Sunderland 3rd degree Injury involves endoneurium Slow: weeks Nerve exploration
(intact perineurium to months can be
and epineurium) considered
Sunderland 4th degree Injury involves endoneurium Spontaneous Microneurosurgery
and perineurium recovery not
(intact epineurium) likely
Sunderland 5th degree Complete nerve transection, Spontaneous Microneurosurgery
(Seddon neurotmesis) continuity disruption recovery not
possible
Adapted from Miloro M, Kolokythas A. Traumatic injuries of the trigeminal nerve. In: Fonseca RJ,
Walker RV, Barber HD, et al, editors. Oral and maxillofacial trauma, 4th edition. St. Louis: Elsevier
Saunders; 2013. p. 662; with permission
Postimplant Surgery Complications 127
superior to traditional 2-dimensional imaging. If only 2-dimensional imaging is avail-

able, using a radiographic marker will help calibrate any digital measurements and
reduce the margin of error for inaccuracies. Using available software to map and high-
light the nerve will always help plan for accurate placement as well as using implant
planning software. Another important factor to consider is the length of each implant
drills. Traditionally, implant drills have measurement markings to denote the depth
within the bone. However, the start and stop point of these measurements may vary
from manufacturer to manufacturer. There can be an additional 0.5 to 2 mm at the
tip of the drill from the indicator line. It is crucial to read your implant manufacturer’s
catalog or contact the representative to understand the exact length and where the
depth measurements are taken from. Another way to ensure proper depth manage-
ment is by taking intraoperative radiographs. These radiographs will help the clinician
know where he or she is within the bone. Another way to avoid nerve damage is to
control flap retraction. Overreflection of a flap, especially in the area of the mental
nerve, can cause stretching and transient neurosensory disturbances, and always
place retractors on bone, not the soft tissue.
If a postoperative patient is noted to have a neurosensory injury, the first important
step is early identification and diagnosis of the degree of injury. Subsequently, man-
agement is based upon mechanism, location, and degree of injury. An injury from
overretraction of a flap (Seddon neuropraxia, Sunderland first degree) could
completely resolve on its own or with adjunctive pharmacologic therapy. If a crush
injury is suspected directly from an implant, similar to Fig. 1, then the implant should
be backed out immediately or removed completely.5 In addition, pharmacologic
Fig. 1. Implant-related nerve injury that can occur when the implant is in proximity to the
closed canal with possible bleeding, edema, and development of a compartment syndrome
that causes deleterious effects on the nerve, even in the short term. (From Miloro M, Kolo-
kythas A. Traumatic injuries of the trigeminal nerve. In: Fonseca RJ, Walker RV, Barber HD,
et al, editors. Oral and maxillofacial trauma, 4th edition. St. Louis: Elsevier Saunders; 2013. p.
666; with permission.)
therapy should also be initiated with close monitoring of the patient. Subjective find-
ings the patient may share should be documented, but objective findings should
also be noted. Baseline testing should include testing for touch with von Frey hairs,
2-point discrimination with a Boley gauge or similar, temperature, and taste (if involve-
ment of lingual nerve is suspected). Evaluations should be completed every 3 weeks
postoperatively to assess for changes in the patient’s condition. If the patient has
persistent anesthesia at 6 to 9 weeks, microneurosurgery should be considered,
and appropriate referrals given to the patient in a timely fashion.10
PREOPERATIVE ANTIBIOTICS AND POSTOPERATIVE INFECTIONS
The routine use of prophylactic antibiotics in implant dentistry seems to be wide-

spread. However, the use of preoperative, perioperative, and postoperative antibiotics
in dental implant surgery remains controversial. A search of the literature can show
postoperative infections as high as 5.9% to 11.5% with antibiotics and as low as
7.0% without antibiotics.11 According to Mazzocchi and colleagues,12 apart from in-
dividuals suffering from systemic diseases, most patients undergoing dental implant
surgery are healthy individuals who do need antibiotics for small surgical wounds. A
study published in the Journal of Hospital Infection reported there was some evidence
that 2 g of amoxicillin given 1 hour preoperatively reduced early failures of dental im-
plants, although further research was needed to confirm the findings.13
The 2 most common types of dental implant-associated infections are peri-implant
mucositis and peri-implantitis. Peri-implant mucositis is inflammation confined to the
soft tissues surrounding an implant without signs of bone loss following normal bone
remodeling. Peri-implantitis is an inflammatory process that affects both the soft tis-
sue and the bone surrounding an implant beyond what is biologically expected
(Fig. 2).14 Table 2 outlines the distinctions between the two.
The main problems when determining frequency of peri-implant mucositis and peri-
implantitis are the lack of a common definition, study populations, and implant struc-
tures. Presently, there is no reliable evidence for treating perimucositis and peri-
implantitis. Although some clinicians advise systemic antibiotics and oral agents to
clean the surface of implants, there has yet to be a double-blind, randomized,
Fig. 2. Peri-implantitis in the right mandible. Probing with exudate, probing depth #4 mm,
bone loss. (From Misch CE. An implant is not a tooth: a comparison of periodontal indices.
In: Misch CE, editor. Dental implant prosthetics. St. Louis: Elsevier Mosby; 2015. p. 63; with
permission.)
Table 2
Diagnostic comparison of peri-implantitis versus peri-implant mucositis
Probing
Depth Radiographic
BOP ± Exudate ‡4 mm Bone Loss
Peri-implant mucositis 1 1 $
Peri-implantitis 1 1 1
Abbreviation: BOP, bleeding on probing

From Robertson K, Shahbazian T, MacLeod S. Treatment of peri-implantitis and the failing
implant. Dent Clin North Am. 2015;59(2):331; with permission.
placebo-controlled trial to prove this.13 Because of this, treatment goals should incor-
porate preventing further bone loss, functionality of the implant, esthetics, and ulti-
mately, loss of the implant itself.4 In order to do so, the treatment modalities can
include mechanical debridement, pharmacologic treatment (ie, chlorhexidine irriga-
tion, local antibiotics, systemic antibiotics), surgical debridement, and correct
anatomic conditions that impair plaque control.13 Further treatment options are
explained in “An Update on the Treatment of Peri-Implantitis” by Raza Hussan and
Michael Miloro in this issue.
Following implant surgery, if a patient returns with tissue erythema, pain, or other
signs of an active infection, the clinician must differentiate between normal postoper-
ative symptoms versus active infection. If a patient returns with abscess formation, an
incision and drainage should be completed and the patient should be started on anti-
biotic therapy.2 During incision and drainage, any purulent drainage should be
cultured and submitted for bacterial sensitivity. If a fistula is noted and the clinician
is unsure of the infection source, a gutta percha cone can be inserted into the fistula
and along with radiographic imaging to trace the source. If an implant is removed, it is
important to understand the survival rate of subsequent implant placement decreases.
Agari and colleagues15 noted over a 7-year study with placement of 5532 implants that
the survival rate for initial implants was 95%. However, the survival rate at first reim-
plantation was 77%; survival rate at second reimplantation was 73%, and by the third
reimplantation, survival rate was 50%.
SINUSITIS AND SINUS MEMBRANE PERFORATIONS
Of the paranasal sinuses, the maxillary sinus is the largest, approximately 15 mL in vol-
ume, and tends to increase with the loss of the maxillary premolars and molars. Sinus
augmentation is indicated when a patient presents with an edentulous and atrophic
maxillary alveolus that cannot support an implant. When inserting dental implants in
the posterior maxilla, the clinician should always be aware of the location to the maxil-
lary sinus, the Schneiderian membrane, and the possible complications that can arise.
When a dental implant becomes infected, sinusitis can easily occur because of the
local spread of inflammation.16 Sinusitis is one of the most commonly diagnosed dis-
eases in the United States. It refers to inflammation within the maxillary sinus and is
characterized as acute when lasting less than 4 weeks, subacute when lasting 4 to
8 weeks, and chronic when lasting longer than 8 weeks.17 When dealing with sinusitis,
it is important to understand the bacterial species that can cause an acute infection.
The usual pathogens in an acute bacterial sinusitis include Streptococcus pneumo-
niae, Haemophilus influenzae, and Moraxella catarrhalis, while anaerobes, other Strep-
tococci, Staphylococci, and Neisseria are also frequently isolated in sinus aspirate
cultures.18,19
According to the literature, maxillary sinusitis secondary to sinus augmentation

ranges between 0% and 20%, whereas perforation of the sinus membrane ranges be-
tween 10% and 55%.20,21 In this setting, maxillary sinusitis can be explained by oblit-
eration or blockage of the ostium (because of edema, hematoma, or dislodged graft),
impaired mucus production, or impaired ciliary function (Fig. 3). Perforations are usu-
ally due to operator error, anatomic variations within the sinus, thin membranes, sinus
pathologic condition, bony septa, second sinus surgery, or excess placement of graft
material.20 It is prudent not to overpack the bone graft material, as this can also lead to
blockage of the ostium, leading to inflammation and then infection of the maxillary
sinus.
With the introduction of newer instruments to facilitate the operator during sinus
augmentation procedures, the incidence of perforations, in theory, should decrease.
Examples of these instruments include Piezosurgery (Mectron s.p.a., Italy) or Dentium
Advanced Sinus Kit (Dentium USA, Cypress, California), which use either ultrasonic
transduction or diamond-coated burs to help prevent membrane perforations when
accessing the maxillary sinus. When initially performing a lateral window, the operator
should ensure the access is large and above the alveolus, as this will facilitate lifting
the membrane in subsequent steps. Another trick that can help, if a small portion of
the membrane is noted to be “stuck” along the floor or wall, opening a wet 4 % 4 gauze
and carefully and continually feeding the gauze into an area where the membrane is
already lifted can sometimes help free the adhered segment.
Amoxicillin with or without clavulanate is considered to be the first-line antibiotic
choice of acute sinusitis. For those penicillin-allergic, either doxycycline, a respiratory
fluoroquinolone (levofloxacin or moxifloxacin), or a combination therapy of clindamy-
cin plus a third-generation oral cephalosporin (cefixime or cefpodoxime) is recommen-
ded.22 Oral cephalosporins are no longer recommended for the empiric monotherapy
as well as trimethoprim-sulfamethoxazole and macrolides (azithromycin and
Fig. 3. Maxillary sinus and drainage via ostium. If blockage occurs at the ostium due to
edema, hematoma, or dislodged graft, then the sinus would be unable to drain, leading
to sinusitis. (From Treadway AL, Bankston SA. Dental implant prosthetic rehabilitation: sinus
grafting. In: Bagheri SC, Bell RB, Khan HA, editors. Current therapy in oral and maxillofacial
surgery. 1st edition. St Louis (MO): Elsevier Saunders; 2012. p. 168; with permission.)
clarithromycin) owing to unacceptably high rates of resistance to S pneumoniae and M

catarrhalis.19 Concurrently with antibiotics, other adjunctive therapies should include
adequate hydration (6–8 glasses of water daily), sleep, nutrition, systemic or nasal de-
congestants, nasal saline sprays, and pain control, while minimizing irritants such as
smoking.5,19
Box 1
Classification of sinus perforations with options for repair: Vlassis and Fugazatto
Class I
Perforation is adjacent to the osteotomy site. Class I perforations are often “sealed off” as a
result of the membrane folding on itself following completion of elevation.
Repair Options: If membrane has folded over itself, no further treatment needed. If the
perforation is small and isolated, collage tape is placed over the area with 3-mm overlap onto
unaffected membrane and place graft material at the borders of the collagen tape. Margins
of intact membrane can be sutured over perforations or suture a medial-free margin to
periosteum lateral to osteotomy with resorbable suture.
Class II
Perforation is located in the midsuperior aspect of the osteotomy, extending mesiodistally
for two-thirds of the dimension of total osteotomy site. This occurs most with an
infrastructure design of the osteotomy, rather than removing a bony window.
Repair options: same as class I perforation. Note, suturing may be more difficult in this
scenario.
Class III
Perforation is located at the inferior border of the osteotomy at its mesial or distal sixth. This
is the most common perforation and is almost always the result of inadequacy of osteotomy
or improper execution of membrane reflection. Conversion of ostetomy design from a
square to a rounded edge will dramatically decrease instance.
Repair options: completion of membrane reflection rarely results in covering a class III
perforation. If the membrane may be elevated around the perforation, thus allowing
sufficient movement of both margins of the tear, then suturing may be an option, with
subsequent covering with a lamellar bone sheet. If margins cannot be elevated, the ostetomy
site should be extended to include the perforated area, begin elevating at a new site, and
lead toward the perforation, then suture the perforation. Last option would be to use a large
lamellar bone sheet and produce a pouch over the perforated region.
Class IV
Perforation is located in the central two-thirds of the inferior border of the osteotomy site.
Such a perforation is rare and is almost always caused by lack of care when preparing the
osteotomy site. A tear in this area is also seen with improper septal elevation. Such a tear also
enlarges dramatically as management is attempted and represents a considerable clinical
challenge.
Repair options: repair options are similar to those of class III, except rather than extending
the ostetomy site, a new ostetomy site should be prepared.
Class V
Perforation is a preexisting area of exposure of the sinus membrane, due to combination of
extensive antral pneumatization and severe ridge resorption. Prior oral-antral fistula may
also be a contributing factor.
Repair options: an ostetomy is performed, which results in the creation of 2 free-floating
semiluna areas around the class V perforation. These “islands” are positioned over each
other and sutured, and the area is covered with resorbable tape. Once such closure is
accomplished, a conventional ostetomy site is then prepared lateral to the perforation.
From Vlassis JM, Fugazzotto PA. A classification system for sinus membrane perforations during
augmentation procedures with options for repair. J Periodont. 1999;70(6):692–9; with
permission.
Sinus membrane perforations and tears are frequently caused by forceful elevation.
In 1999, Vlassis and Fugazatto23 published a classification system with options for
repair (Box 1).
POSTOPERATIVE EDEMA
Postoperative edema is characterized by accumulation of fluid in interstitial tissue. The

amount of edema is proportional to the amount of tissue injury, and more edema is
likely with more loose connective tissue at the surgical site.24 Postoperative swellings
can have a negative impact on the surgical site and a patient’s clinical condition. The
main mediators of the inflammation in the postoperative stage are cyclooxygenase
(COX) and prostaglandins. When tissue is manipulated or injured, phospholipids are
converted to arachidonic acid, which then produces prostaglandins and thromboxane
A2 (collectively known as prostanoids) via COX enzymes.25 It is important to be able to
distinguish normal postoperative edema versus an acute infection (Fig. 4).
Postoperative edema can be minimized with shorter surgical times, flapless sur-
geries, practitioner experience, elevation, ice, and pharmacologic management.
Generally, postoperative edema will begin shortly after surgery and will increase for
48 hours, peaking at about 72 hours.26 The use of nonsteroidal anti-inflammatory
drugs (NSAIDs) provides analgesia and anti-inflammatory effects by inhibiting the syn-
thesis of prostaglandins from arachidonic acid, while glucocorticoids alter the connec-
tive tissue response to injury by inhibiting phospholipase A2, thereby reducing
arachidonic acid release.25
Prescribing 600 mg ibuprofen 1 hour before surgery and 600 mg 6 hours after the
first dose or 4 mg dexamethasone 1 hour before surgery and 4 mg 6 hours after the
first dose significantly reduced pain up to 3 days after surgery, reducing discomfort
2 days after surgery.27 The author of this article supports prescribing 600 mg ibuprofen
1 hour before and every 6 hours thereafter for up to 3 to 5 days as needed for pain,
supplemented with 1000 mg acetaminophen as needed for breakthrough pain (not
to exceed 4000 mg in 24 hours), and 4 mg dexamethasone 1 hour before surgery
and 4 mg 6 hours after the first dose. Alternatively, a methylprednisolone tapering
dose pack may be prescribed. When prescribing steroids, close postoperative
Fig. 4. Pathophysiology of edema and inhibitor mechanism of glucocorticoids and NSAID

medications. (From Resnik RR. Pharmacology in implant dentistry. In: Resnik RR, editor.
Misch’s contemporary implant dentistry. 4th ed. Elsevier; 2020. p. 366; with permission.)
management is recommended, although most patients will not have any adverse
outcomes.
CLINICS CARE POINTS

! Obtaining adequate imaging before implant placements can avoid neurosensory
disturbances.
! Early identification and treatment of neurosensory disturbances are key for suc-
cessful recovery.
! Recurrent infections from peri-implantitis or perimucositis decrease chances of
implant survival.
! After removal of an infected dental implant, odds of successful osteointegration
of the subsequent implant decrease.
! The use of diamond-coated rotary instruments will help decrease membrane
perforation when creating a bony window for sinus augmentation,
! Postoperative edema can be decreased by starting the patient on preoperative
steroids.
DISCLOSURE
The authors have nothing to disclose.
REFERENCES
1. Froum SJ. Dental implant complications etiology, prevention, and treatment.

Hoboken: Wiley-Blackwell; 2010.
2. Singh P, Cranin AN. Atlas of oral implantology. Maryland Heights: Mosby; 2010.
3. Manor Y, Oubaid S, Mardinger O, et al. Characteristics of early versus late
implant failure: a retrospective study. J Oral Maxillofac Surg 2009;67(12):
2649–52.
4. Khoury F, Keeve P, Ramanauskaite A, et al. “Surgical treatment of peri-implantitis
- Consensus Report of Working Group 4.” International Dental Journal, U.S. Na-
tional Library of Medicine. 2019. Available at: www.ncbi.nlm.nih.gov/pubmed/
31478576. Accessed April 20, 2020.
5. Dym H. Implant procedures for the general dentist. Philadelphia: Elsevier; 2015.
6. Fonseca RJ. Oral & maxillofacial trauma. St. Louis: Elsevier; 2013.
7. Libersa P, Savignat M, Tonnel A. Neurosensory disturbances of the inferior alve-
olar nerve: a retrospective study of complaints in a 10-year period. J Oral Maxil-
lofac Surg 2007;65(8):1486–9.
8. Park YT, Kin SG, Moon SY. Indirect compressive injury to the inferior alveolar
nerve caused by dental implant placement. J Oral Maxillofac Surg 2012;70(4):
e258–9.
9. Garg AK. Implant dentistry a practical approach. Maryland Heights: Elsevier;
2010.
10. Park C, Indresano T. Nerve evaluation protocol 2014. Oakland: California Associ-
ation of Oral and Maxillofacial Surgeons; 2014.
11. Figueiredo R, Camps-Font O, Valmaseda-Castellon E, et al. Risk factors for post-
operative infections after dental implant placement: a case-control study. J Oral
12. Mazzocchi A, Passi L, Moretti R. Retrospective analysis of 736 implants inserted
without antibiotic therapy. J Oral Maxillofac Surg 2007;65(11):2321–3.
Ver t i c a l a n d H o r i z o n t a l
Augmentation of Deficient
M a x i l l a an d M a n d i b l e f o r I m p l a n t
P lac e me n t
a, b,c
Amanda Andre, DDS *, Orrett E. Ogle, DDS
KEYWORDS
! Alveolar bone loss ! Horizontal bone augmentation ! Vertical bone augmentation
! Bone grafting
KEY POINTS
! The ideal position of a dental implant should not be compromised in the setting of a defi-
cient maxillary or mandibular alveolar ridge. Overall, bone augmentation techniques can
be highly predictable and can provide significant horizontal and vertical gain.
! Since there is currently no true consensus in the literature on which bone grafting tech-
nique or material is strictly indicated for each clinical scenario, dental professionals can
benefit from gaining an understanding on the various methods to achieve horizontal
and vertical augmentation of the deficient alveolar ridge.
! The surgical techniques presented in this article for the augmentation of the deficient alve-
olar ridge can vary from simple to advanced and require proper training for successful out-
comes and minimizing complications.
INTRODUCTION
The loss of alveolar bone is a common phenomenon linked to various systemic and
local factors. Systemic factors include age, nutrition, osteoporosis, and other skeletal
disturbances, and local factors include the premature loss of teeth, trauma, pathology,
and periodontal disease. In the United States, partial edentulism affects the majority of
the population and the number of partially edentulous individuals is expected to in-
crease to more than 200 million in the next 8 years.1 The increased focus in preventa-
tive dental care over the past years has positively impacted tooth retention and thus a
decrease in fully edentulous individuals is expected. Interestingly, the premature loss
a
The Brooklyn Hospital Center, 121 Dekalb Avenue, Brooklyn, NY 11201, USA; b Mona Dental
Program, Faculty of Medicine, Univ. of the West Indies, Kingston 6, Jamaica; c Oral and
Maxillofacial Surgery, Woodhull Hospital, Brooklyn, NY 11206, USA
E-mail address: aafernandez@tbh.org
Dent Clin N Am 65 (2021) 103–123

104 Andre & Ogle
of permanent teeth remains correlated with an increase in age. The growth of a more
socially active and more esthetically demanding aging population in the United States
has increased the demand for more comfortable, functional, and esthetic dental pros-
thetic solutions. The placement of dental implants broadens the treatment options for
these individuals. Prosthetically driven implant restorations may not only significantly
improve the patient’s treatment outcomes by improving the esthetics, occlusion, pho-
netics, retention, and stability of the prosthesis, but also preserve the remaining alve-
olar bone. The atrophy of the maxillary and mandibular alveolar arches is a common
occurrence that can pose many challenges for the rehabilitation of these patients,
both surgically and restoratively. In contemporary implant dentistry, a practitioner
may choose between the use or augmentation of the remaining bone based on the
clinical and radiographic presentation. In this article, we discuss the various indica-
tions and techniques for the vertical and horizontal augmentation of the deficient
maxilla and mandible for endosseous implant placement. Ridge preservation and
socket augmentation procedures are beyond the scope of this article.
PATTERNS OF BONE LOSS
The classic study by Cawood and Howell2 demonstrated there are predictable pat-
terns of progressive horizontal and vertical anatomic changes following the loss of
teeth (Box 1). The loss of teeth induces the progressive loss of alveolar bone until
completely resorbed.2,3 In addition, the loss of basal bone from ill-fitting dentures or
occlusal overloading can further contribute to the atrophy of the ridge. Identifying
the various patterns of bone loss can facilitate the treatment planning and increase
the predictability of the rehabilitation of atrophic ridges.
When teeth are lost prematurely, it can lead to a decrease in the alveolar ridge’s vol-
ume owing to the lack of functional stimulus necessary to preserve its vertical and hor-
izontal dimensions. Function influences the delicate balance that exists at the cellular
level between bone resorption and bone formation.4 When permanent teeth are loss
prematurely, the loss of stimulus from the forces of mastication in the area lead to a
shift to bone resorption.
Generally, the loss of teeth in the maxilla tends to occur before the loss of teeth in the
mandible and mandibular anterior teeth are commonly the last teeth remaining in the
mouth.5 However, the rate of resorption of the alveolar crest of the mandible is 4 times
the average rate of resorption of the maxilla. The rate of resorption occurs more rapidly
within the first 6 months after the loss of teeth.3 Combination syndrome is a well-
documented condition seen in patients with a completely edentulous maxilla and a
partially edentulous mandible with preserved anterior teeth. This syndrome leads to a
classical pattern of severe resorption of the anterior maxilla and posterior mandible, over-
growth of the maxillary tuberosities, papillary hyperplasia of the hard plate, and extrusion
of the lower anterior teeth.6 The treatment for combination syndrome with dental implants
Box 1
Cawood and Howell Classification of Edentulous Jaws
I Dentate
II Immediately after extraction
III Well-rounded ridge form, adequate in height and width
IV Knife-edge ridge form, adequate in height and inadequate in width
V Flat ridge form, inadequate in height and width
VI Depressed ridge form, with some basilar loss evident
Vertical and Horizontal Augmentation 105
has made it possible for the rehabilitation of posterior occlusion, the redistribution of the
forces of mastication, and the prevention of further bone loss.
The loss of teeth can also be attributed to the body’s response to the presence of
bacterial biofilm in the oral cavity or trauma from occlusal forces. Periodontal disease
can lead to the permanent destruction of supportive periodontal structures, alveolar
bone, and ultimately the teeth involved. Without treatment, the resulting inflammatory
reaction leads to an average bone loss per year of approximately 0.2 mm for facial sur-
faces and 0.3 mm for proximal surfaces, with a radius of 1.5 to 2.5 mm from the site of
bacterial biofilm formation.4 In addition, bone destruction caused by persistent
occlusal trauma results in a widening of the periodontal ligament and resorption of
adjacent bone. These changes to the adjacent bone can lead to tooth mobility and
when paired with inflammatory reactions to the bacterial biofilm can result in vertical
bone loss or unusual bone loss patterns.4 The most prevalent form of bone loss
caused by periodontal disease is horizontal bone loss, whereas vertical or angular
bone loss tends to occur in areas of greater bone volume.
Vertical bone loss was classified by Goldman and Cohen on the basis of the number
of osseous walls present in the defect (Fig. 1). Consequently, various defect patterns
can arise after dental extractions. Furthermore, Misch and Dietsh7 classified the
resulting extraction socket defects based on the amount of remaining bony walls
and provided recommendations on the appropriate graft materials and techniques
to be used for the restoration of such defects (Fig. 2). The 5-wall defect results from
extraction sockets or cystic cavities. Bone grafting is optional in these defects owing
to the tendency of 5-wall defects to fill in with bone without additional surgical inter-
ventions. For this reason, the use of inexpensive materials is recommended when
considering socket preservation procedures. The 4-wall defect typically consists of
missing labial and occlusal walls, whereas the 2- and 3- wall defects present a larger
area for bone augmentation and require the use of autogenous bone. Moreover, the 1-
walll defect is the most challenging to augment and, thus, block grafts are usually rec-
ommended for the restoration of the ridge’s volume.
Deteriorating changes to the quality of the soft tissue architecture can also occur
owing to the loss of alveolar bone. The alveolus is typically protected by a strong layer
of keratinized attached gingiva. Upon the loss of alveolar bone, the soft tissue can be
replaced with a less keratinized oral mucosa, allowing for the area to be more easily
traumatized upon normal function.5 The loss of keratinized mucosa can add to the
challenges in placing dental implants in the esthetic zone.
HORIZONTAL AND VERTICAL REQUIREMENTS FOR IMPLANT PLACEMENT
A successful treatment outcome in relation to dental implants depends the restoration

of the patient’s function, comfort, speech, and esthetics. Alveolar bone atrophy in the
vertical or horizontal dimensions may obstruct the surgeon’s ability to place endo-
sseous implants in the desired position for the prosthetic rehabilitation of the arch.
The development of advanced techniques has allowed for the achievement of these
outcomes despite the patient’s level of maxillary or mandibular atrophy. Owing to
the predictability of bone augmentation procedures, the practitioner should avoid
compromising the ideal position of the implant when adequate bone width and height
are not available. Nonetheless, the fact remains that the greater the loss of teeth and
bone volume, the more challenging the process of achieving a functional and esthetic
outcome. Careful treatment planning must take into account the 3-dimensional posi-
tion of the implant in the bone and the horizontal and vertical requirements for implant
placement.
106
Andre & Ogle
2 F
A
AB
A(
2 DB
A
A
C
2/
,B E A. ( A
3 ,B E A
Fig. 1. Representation of vertical defects of the right lateral incisor. (A) Three-wall defect: distal, lingual, and facial. (B) Two-wall defect: distal and
lingual. (C) One-wall defect: distal. (D) Combined osseous defect with 3 walls in its apical half and 2 in the occlusal half. (From Camargo PM, Takei
HH, Carranza FA. Bone loss and patterns of bone destruction. In: Newman MG, Takei HH, Klokkevold PR, Carranza FA, editors. Newman and Carranza’s
3AD2A
CB A B AE
clinical periodontology. 13th edition. Philadelphia: Elsevier; 2019. p. 323–5; with permission.)
Fig. 2. Classification of wall defects. (A) A 5-wall defect usually results from tooth extraction
sockets or cystic cavities. (B) Four-wall defect. (C) Three-wall defect and 2-wall defect. (D) A
1-wall defect usually has the lingual/palatal wall present. RGM, resorbable graft material.
(From Resnik RR, Suzuki JB. Atraumatic tooth extraction and socket grafting. In: Resnik
RR, editor. Misch’s contemporary implant dentistry. 4th ed. Elsevier; 2020. p. 900; with
permission.)
A cone beam computed tomography scan offers the most accurate measure for the
available bone structure in the mesiodistal, buccolingual, and apicoronal planes. To
minimize damage to adjacent teeth, the ideal distance from the implant to adjacent
tooth should be at least 1.5 mm. However, to achieve soft tissue health, the distance
between the neck of the implant and the crown of the adjacent tooth should be
increased to at least 2.0 mm. In addition, if the coronal distance between the implant
and the tooth exceeds 4.0 mm, the cantilever effect would lead to bone loss, magni-
fied occlusal forces, and ultimately possible restoration and/or implant failure. After
implant placement, the width of the remaining bone should be at least 2.0 mm on
the facial aspect and 1.0 mm or more on the lingual or palatal aspect to prevent
bone recession owing to a lack of blood supply. It is widely accepted that, to deter-
mine the horizontal dimension required for implant placement, the practitioner must
follow the formula: Implant diameter 1 2.0 mm facial bone 1 1.0 mm lingual bone.8
Therefore, the horizontal dimension of the available bone should be at least
3.00 mm or greater than the diameter of the implant.
As opposed to calculated measurements, the vertical dimension requirements
depend on soft tissue height, prosthetic needs, and proximity to vital structures.
The ideal depth of placement of a dental implant is 2.0 to 4.0 mm apical to the adjacent
cemento–enamel junction or free gingival margin to allow for adequate prosthetic
crown soft tissue emergency profile. The fabrication material of the final prosthesis
should be taken into account.8 Typically, a space of 15 mm is suggested from the crest
of the alveolar ridge to the incisal edge of the prosthesis. The specific crown height
space (CHS) requirements depend on the selected material for the final restoration.
If the interocclusal space is deemed insufficient or excessive, it can be detrimental
108 Andre & Ogle
to the survival of the prosthesis and additional procedures should be considered.9 Vi-
tal structures should be identified in the treatment planning phase with the assistance
of 3-dimensional imaging studies or computer-generated models. To prevent trau-
matic injury to the nerve, implants should be positioned at least 2.0 mm away from
the inferior alveolar nerve canal or mental foramen. Moreover, bleeding and other iat-
rogenic complications can result from the penetration of the dental implant through the
inferior border of the mandible or border of the maxillary sinus and nasal cavity and,
thus, great care should be taken to avoid these structures (Box 2).8
There is no consensus in the literature in regard to strict guidelines on which tech-
nique or material is indicated for each bone deficiency or clinical scenario.8,10 Rather,
the decision should be made after careful consideration and treatment planning. The
combination of different techniques and materials is encouraged to achieve optimal
treatment outcomes.
HORIZONTAL AUGMENTATION
Advanced horizontal bone augmentation procedures are indicated when the bone vol-
ume available in the proposed implant site is deemed to be insufficient for the pros-
thetically ideal placement of the dental implant. The final decision on which bone
augmentation technique is adequate for each clinical scenario remains the responsi-
bility of the clinician because there are no clear set protocols in the literature.10 Clini-
cians should be familiar with the various options for restoring the deficient alveolar
ridge (Table 1). Some of the most predictable surgical techniques available are:
! Tunnel technique using particulate bone
Box 2
Implant Placement Considerations
Mesiodistal
Implant–tooth (apical) >1.5 mm
Implant–tooth (coronal) >2.0 mm, <4.0 mm
Implant–implant >3.0 mm
Buccolingual/faciopalatal
Facial/buccal thickness >2.0 mm
Lingual/palatal thickness >1.0 mm
Apicocoronal
Implant platform- 2–4 mm
cemento–enamel
junction/free gingival margin
Distance from vital structures
Inferior alveolar nerve canal or >2 mm
mental foramen
Inferior border of the mandible Avoid cortical bone perforation
Nasal cavity Avoid cortical bone perforation
Inferior border of maxillary sinus Without bone grafting,
can penetrate
approximately 1–2 mm
into the sinus
Interocclusal/CHS
Alveolar ridge–incisal <15 mm
edge of prosthesis
Data from Resnik RR, Misch CE. Ideal implant positioning. In: Resnik RR, editor. Misch’s contem-
porary implant dentistry. 4th ed. Elsevier; 2020. p. 670–705.
Table 1
Summary of horizontal bone augmentation techniques
Recommended
Time to
Potential Bone Implant
Technique Indication Gain Placement
Tunnel technique 2-wall defect 1–4 mm 4 mo
Satisfactory vertical height
<4 mm ridge width
A ridge that widens
as it approaches
the basal bone
GBR 2-wall defect, 3-wall defect, 3–6 mm 9–12 mo
4-wall defect
Onlay bone grafting 1-wall defect 4 mm 4–6 mo
<3 mm ridge width Ramus 3–4 mm
Symphysis 4–6 mm
Ridge Split/Expansion 3–4 mm ridge width 2–3 mm Immediate or
4 mo
Distraction Osteogenesis >5 mm horizontal deficiency Not reported 3–4 mo
! Guided bone regeneration (GBR)

! Onlay block grafting
! Ridge splitting or expansion technique
! Distraction osteogenesis
Tunnel Technique Using Particulate Bone

The placement of particulate bone under the periosteum using a tunneling technique
for space maintenance has shown to successfully increase the width of the alveolar
ridge. This technique is minimally invasive, simple, and can be more cost effective
than other augmentation procedures. In an article by Block,11 the reported indications
for the procedure are (1) satisfactory vertical height, (2) a lack of at least 4.0 mm of
bone width, and (3) widening of the ridge as it approaches the basal bone. The ideal
defect type for this procedure is the 2-wall defect.
The technique described starts with a crestal incision on the superior aspect mesial
to the site of the defect running inferior in a vertical fashion. The blunt end of a perios-
teal elevator is used to create a subperiosteal tunnel posterior to the incision site. At
the crest of the ridge, the periosteum is elevated over the ridge. Excessive lingual
dissection should be avoided. Using a TB-type syringe, the particulate material is
deposited in a posterior to anterior direction, directly against bone and removed at
an angle to create a bevel. Digital pressure is then used to mold the graft until the
desired shape is achieved. The incision is then closed using interrupted resorbable su-
tures. The recommended bone grafting particle sizes range from 350 to 500 mm and
the volume from 0.5 mL to 1.5 mL. A healing period of at least 4 months is recommen-
ded before implant placement.11 Overall, the use of allogenic or xenogeneic grafting
materials seems to result in a higher potential for horizontal gain, compared with the
use of synthetic materials.12 The potential bone gain of this technique has not been
widely reported in systematic reviews, however, case studies show a 2.0- to 4.0-
mm augmentation after 4 months of healing time.11
110 Andre & Ogle
A retrospective cohort study by Deeb and colleagues13 compared the treatment

outcomes between 21 patients treated by the tunnel technique and 31 treated with
the open technique. After a 6-month healing period, their data showed no significant
difference between the outcomes of the tunnel technique versus GBR using a
titanium-reinforced polytetrafluoroethylene membrane for the augmentation of hori-
zontal ridge augmentation. The tunnel technique provides a minimally invasive option
for patients for the rehabilitation of the deficient alveolar ridge.
Guided Bone Regeneration

GBR is one of the most common and predictable methods for the treatment of hori-
zontal bone defects. Space maintenance can be provided by nonresorbable and
resorbable membranes preventing the migration of undesired soft tissue and guiding
the growth of bone into the grafted site. There is evidence to support the use of GBR
for horizontal augmentation at the time of implant placement for ridges measuring
approximately 4 mm or as a staged procedure in preparation for implant placement
for residual crests measuring less than 3 mm.10 Nonresorbable membranes include ti-
tanium mesh, expanded polytetrafluoroethylene, and titanium-reinforced expanded
polytetrafluoroethylene membrane. Resorbable membranes include collagen, poly-
lactic acid, amniotic membrane, pericardial membrane, and dura mater.14 The barrier
material seems to have little effect on horizontal ridge augmentation and although
there are more complications reported with the use of titanium meshes (ie, dehis-
cence), the conclusion on recent systematic reviews has not shown the data to be sta-
tistically significant (Figs. 3–5).12
Karmon and colleagues15 described a novel technique combining GBR and the
tunnel technique with the use a subperiosteal bag for horizontal bone augmenta-
tion. The authors created a “bag” by perforating, folding and suturing a Bio-Gide
bilayer resorbable collagen membrane. The bag was then filled with Bio-Oss
bovine-derived xenograft bone substitute. A vertical incision was made and a sub-
periosteal tunnel created distal to the site. The bag was inserted inside the tunnel
with the perforated side facing the alveolar ridge and the nonperforated side of the
bag facing the flap. Primary closure was then achieved with resorbable sutures.
The time recommended from grafting procedure to implant placement in this study
was 6 months.
Fig. 3. Exposed severe defect of the anterior maxilla owing to mechanical trauma.
Fig. 4. Placement of reinforced polytetrafluoroethylene mesh for GBR and augmentation of

the deficient anterior maxilla, secured with membrane tent screws.
Onlay block bone grafting

Autogenous bone remains the gold standard for alveolar bone augmentation owing to
its osteogenic, osteoinductive, and osteoconductive properties. When indicated, the
donor site is typically selected depending on the size of the required bone block
and type of defect. Block grafts are the procedure of choice for the effective augmen-
tation of 1-wall defects. A recent systematic review by Milinkovic and Cordaro10 re-
ported a mean linear horizontal bone gain of 4.3 mm after an average healing period
of 5.2 months when bone block grafts were used. Correspondingly, another recent
systematic review by Troeltzsch and colleagues12 that analyzed 184 studies, reported
an overall weighted mean of a 4.5 mm increase in horizontal gain. In accordance, the
calculated mean gain of horizontal bone thickness using autogenous block grafts in a
review of 42 cases by Von Arx and Buser16 was 4.6 mm with a range between 2 and
7 mm.
Intraoral sites such as the mandibular symphysis, ramus, maxillary tuberosity, and
bony exostoses can be harvested for augmentation of small size (<5.0 mm) defects.
The harvesting of these sites can often be performed under local anesthesia and
have minimal morbidity. In contrast, when greater amounts of bone (>5.0 mm) are
required, donor sites such as the tibia, anterior iliac crest, posterior iliac crest, and
calvarium can provide substantial amounts of cancellous, corticocancellous, or
cortical bone (Fig. 6). Although the harvesting of these distal sites can be done safely,
it is recommended for the procedure to be performed under general anesthesia by
trained oral surgeons, to minimize more significant complications.17
Ridge Split or Expansion Technique

The literature supports alveolar ridge split/expansion osteotomies for the augmenta-
tion of alveolar ridges between 3.0 and 4.0 mm to gain 2.0 and 3.0 mm of alveolar
bone (Fig. 7). Milinkovic and Cordaro10 reported a mean bone gain of 2.95 mm among
6 studies with an average healing time of 4.5 months.10 A technique described by Dym
and colleagues17 recommends the use of different size osteotomes increasing in size
to force the direction of the split buccally, grafting of the site, and closure by primary
intention or by the covering of the graft with a membrane before closing with sutures.
Another described variation to this technique is the island flap osteotomy, which allow
for simultaneous vertical and horizontal augmentation. In the island flap osteotomy
112 Andre & Ogle
Fig. 5. Use of resorbable (A) and nonresorbable (B) membranes to protect the regenerative
space fill and prevent soft tissue ingrowth. Nonresorbable membranes (A) such as polytetra-
fluoroethylene (PTFE) membranes provide structural support, which prevents the collapse of
the soft tissue into the grafted site. (From Caldwell CS. Particulate membrane grafting/
guided bone regeneration. In: Resnik RR, editor. Misch’s contemporary implant dentistry.
4th ed. Elsevier; 2020. p. 962; with permission.)
technique, the buccal plate is intentionally fractured to create a segment of bone

attached to the buccal periosteum. The use of Piezo surgery as an adjunct simplifies
the technique and increases the safety of the procedure by decreasing the potential
risk for soft tissue damage and thermal necrosis.18
Fig. 6. Onlay block graft for ridge augmentation of the anterior maxilla using corticocancel-
lous onlay mandibular block graft. (A) Bone osteotomy in mandibular molar area. (B) Cor-
ticocancellous bone graft. (C) Onlay graft fixation with miniscrews. (D) Covering the graft
with a collagen membrane. (From Mansour A, Al-Hamed FS, Torres J, et al. Alveolar bone
grafting: Rationale and clinical applications. In: Alghamdi H, Jansen J, editors. Dental im-
plants and bone grafts. Cambridge, MA: Woodhead Publishing; 2020. p. 62; with
permission.)
Distraction Osteogenesis
Distraction osteogenesis is a technique used for severe defects requiring more than
5.0 mm of expansion. The general alveolar distraction timeline consists of the surgical
placement of the distractor followed by a latency period of 5 to 7 days. The distraction
period involves adjustments of 0.5 mm to 1.0 mm daily. A consolidation period of 8 to
12 weeks follows, the distractor device is removed and implant placement can take
place.19 Although distraction osteogenesis is more commonly used for vertical ridge
augmentation, it has also been reported for the augmentation of the narrow alveolar
114 Andre & Ogle
Fig. 7. Diagram showing the ridge splitting technique for the augmentation of the deficient
alveolar ridge. (A) Implant marks. (B) Sagittal osteotomy connecting marked implant sites.
(C) Use of motorized bone expander. (D) Dental implants placed. (E) Bone graft placed
into osteotomy site. (F) Flap repositioned and sutured. (From Anitua E, Alkhraisat MH. Is
alveolar ridge split a risk factor for implant survival? J Oral Maxillofac Surg.
2016;74(11):2183; with permission.)
Fig. 8. Horizontal alveolar distraction device placed on a model. (From Funaki K, Takahashi
T, Yamuchi K. Horizontal alveolar ridge augmentation using distraction osteogenesis: com-
parison with a bone-splitting method in a dog model. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod. 2009;107(3):351; with permission.)
ridge (Fig. 8).20 The surgical technique was described in a case study by Garcia-
Garcia and colleagues.20 An incision is made in the mucosa along the crest of the alve-
olar ridge without a release. A tunnel is created between the vestibular mucosa and
bone to the level of the base of the transport segment. The vestibular and lateral
osteotomies are made using a ridge-splitting osteotome. The distractor screw is
placed through the freed transport segment in a vestibular–lingual direction. The
slow tension forces between the basal bone and transport device allow for the gradual
growth of bone and soft tissue.
VERTICAL AUGMENTATION
It is generally accepted that the minimum bone height for successful placement of
dental implants in ideal bone density is 10 mm (plus a margin of 2 mm from vital land-
marks such as the inferior alveolar canal, floor of nose or maxillary sinus). Alveolar
bone height less than 10 mm will require vertical augmentation to improve functional
biomechanics and reduce excessive stresses on the implant. The consensus panel of
the International Congress of Oral Implantologists recommended that vertical bone
height for fixed prosthesis should be based on the excessive CHS9 rather than an ab-
solute number. According to the consensus panel, excessive CHS conditions relate to
a CHS that is more than 15 mm. (The definition of CHS is from the bone to the occlusal
plane.) An increased CHS of more than 15 mm is usually a result of the vertical loss of
alveolar bone from long-standing edentulism. Vertical augmentation should aim to
decrease the CHS to less than 15 mm. The ideal space for a cement-retained pros-
thesis is 9 mm to 10 mm in the posterior and 10 mm to 12 mm in a maxillary central.
This dimension allows an ideal 3 mm of soft tissue, 2 mm of occlusal or porcelain thick-
ness, and a 5-mm height for the abutment.21 Prosthesis design is, therefore, an impor-
tant consideration before surgical decisions are made. Overgrafting may produce a
very short CHS, which would be unacceptable for prosthetic rehabilitation. An
implant-retained removable prosthesis, in contrast, hand needs at least 15 mm to
17 mm of CHS. Overgrafting would also be deleterious in this reconstruction.
The issue of excessive CHS should be addressed before implant placement. Surgi-
cal augmentation of the residual ridge height will reduce the CHS and improve implant
biomechanics. Surgical techniques available to remedy the problem are:
! Onlay block bone grafts
! Interpositional bone grafts
! GBR
! Distraction osteogenesis
! Particulate bone grafts with titanium mesh or barrier membranes.
Fig. 9. Techniques for vertical ridge augmentation. (A) Interpositional graft. (B) Distraction
osteogenesis. (C) Onlay bone graft. (D) GBR. (From Sheikh Z, Sima C, Glogauer M. Bone
replacement materials and techniques used for achieving vertical alveolar bone augmenta-
tion. Materials. 2015;8(6):2953–93.)
116 Andre & Ogle
A staged approach to reconstruction of the jaws is often preferred to simultaneous

implant placement, especially when large volume gains are required (Fig. 9).9
Onlay Block Grafting

Onlay block bone grafting is when a block of transplanted bone tissue is placed
directly unto the recipient bone at the intended implant site. Most often in the outpa-
tient setting, the bone is harvested from the mandibular symphysis (which offers the
greatest bone volume), external oblique ridge (lower morbidity compared with sym-
physis grafts), and rarely from coronoid process. These sites are readily available
and will provide good bone quality and quantity with few postoperative complications.
Allogenic grafts and anorganic bovine bone are other options with predictable suc-
cess. Bone substitutes have not been shown to be reliable for vertical augmentation
of the dentoalveolar process.
A conservative corticotomy is first performed at the recipient site to encourage
blood clot formation and bone marrow osteoblast precursor migration into the graft.
The bone block is next harvested from the selected donor site, contoured, and is
laid over the prepared recipient site devoid of soft tissues, where it is fixated with
osteosynthesis titanium screws as an onlay graft to achieve the desired vertical
augmentation of the alveolar ridge. Placement of the bone graft should be guided
by an augmentation template.22 Close contact and good initial stabilization of the
block graft to the recipient bed is critical to achieving a successful clinical result.
Tension-free closure of the overlying soft tissue is required.
Interpositional Bone Grafts

The concept of interpositional or “sandwich” grafting is based on the theory that a
bone graft placed between 2 pieces of pedicled bone with internal cancellous bone
will undergo rapid and complete healing and graft incorporation.23 The main advan-
tage of this technique is the preservation of the attached gingiva. The bone pedicles
are achieved through a vascularized segmental osteotomy performed on the alveolar
bone. Success of the technique depends on maintaining the vascularization of the
bone pedicles from the overlying periosteum. The free vascularized osteoperiosteal
flap, in combination with the bone graft in the gap, raises the superior/inferior flap to
the desired position to achieve vertical ridge augmentation. The incision is made in
the free mucosa at least 10 mm lateral to the mucogingival junction to allow for
closure. A vertical releasing incision is placed about 5 mm anteriorly to the planned
graft site. If the graft site is close to the mental foramen, a mucosa-only dissection
should be performed to isolate the branches of the mental nerve. The nerve branches
may be retracted atraumatically with vessel loops.
The periosteum is incised 3 to 5 mm inferiorly to the planned osteotomy site and is
elevated inferiorly only, maintaining the periosteal attachments to the superior aspect
of the ridge. The lingual mucosa should not be elevated. The horizontal osteotomy is
made above the inferior alveolar canal. The vertical bone cuts are made with minimal
elevation of the periosteum. The osteotomy cuts should be made through the lingual
cortical plate. A finger should be placed over the lingual mucosa to feel the cutting
blade exit the bone but not the lingual mucosa. The alveolar ridge segment is mobi-
lized passively and elevated to the extent of the soft tissue attachments.
Fixation is achieved with an X-shaped miniplate (1.2-mm screws) The plate should
be attached first to the superior mobilized segment of the crest. After the plate is
secured to the mobilized segment, it is raised to the desired height, oriented to mini-
mize sharp edges on the lingual mucosa, and the final screws placed in the inferior
intact bone. The space is then grafted. Cancellous/particulate marrow, autogenous
block grafts, or a freeze-dried mineralized allograft may be used. The allograft has the
advantage in that there is no donor site surgery. After the graft is placed, the incision
should be closed without tension. Endosteal implants should be placed at 3 months
after grafting.
Guided Bone Regeneration

GBR is a surgical procedure that uses barrier membranes to direct the growth of new
bone. It may be achieved with or without particulate bone grafts and/or bone substi-
tutes. Osseous regeneration by GBR depends on the migration of pluripotential and
osteogenic cells (eg, osteoblasts derived from the periosteum and/or adjacent bone
and/or bone marrow) to the bone defect site and exclusion of cells impeding bone for-
mation (eg, epithelial cells and fibroblasts).24 To ensure successful GBR, 4 principles
need to be met: exclusion of epithelium and connective tissue, space maintenance,
stability of the fibrin clot, and primary wound closure.25 GBR is often considered to
be the preferred technique for vertical ridge augmentation because it is highly predict-
able and has a low complication rate.
The surgical procedure for GBR depends on the size of the defect and on the pros-
thetic plan. For small defects, GBR and implant placement can be done at the same
time if the osseous defect around the implant is small and good primary stabilization of
the implant can be achieved. To increase the alveolar height and improve the ridge
shape in larger defects, the GBR should be done before implant placement. For small
defects in which GBR and implant placement is being done simultaneously, the use of
an allograft material is recommended. For ridges with severe vertical bone loss, an
autogenous graft combined with a xenograft should be used.
For small defects, a trapezoid flap can be used to expose the crest, followed by
implant placement. The implant should be placed above the height of the atrophic
ridge and covered by the graft material. The membrane is placed and secured. The
wound is closed tension free.
In moderate to severe vertical edentulous bone loss, the goal is to replace the orig-
inal bone crest of the edentulous area. The same incision that is used for the interposi-
tional graft is used. If a large vertical bone loss area is to be grafted, a greater number
of releasing incisions will be needed for tension-free flap closure because failure often
occurs because of wound dehiscence. A full-thickness mucoperiosteal flap is elevated
to adequately expose the edentulous area. Small bur holes are drilled through the cor-
tex or a corticotomy is performed. The bone graft material is placed and molded to
form and covered with a membrane, which is stabilized with titanium bone tacks. In
the posterior maxillary, a vertical GBR procedure and maxillary sinus grafting using
the lateral window approach could be done simultaneously. Treatment of complex
vertical defects requires a stable and stiff membrane, usually made of titanium or
metal-reinforced polytetrafluoroethylene.26
Distraction Osteogenesis
Distraction osteogenesis is a technique used to generate new bone after an
osteotomy and gradual distraction. It is based on the biological principle of bone
callus mechanical elongation through slow and progressive separation under ten-
sion of the 2 bone fragments surrounded by the callus to achieve new bone forma-
tion at the distraction gap.27 In the edentulous alveolar ridge, small distraction
devices are used to simultaneously gradually lengthen the bone and expand the
soft tissue.
A horizontal mucoperiosteal incision is made following the mucogingival junction
extending the extent of the defect to be elevated. The mucoperiosteal flap is elevated
118 Andre & Ogle
to about 5 mm beyond the planned osteotomy site. At the ends of the defect to be
elevated, vertical tunneling is done toward the alveolar crest to facilitate vertical
osteotomies. After adequate exposure, the distraction device should be adapted to
the buccal cortex and the osteotomy line scored. In a long alveolar defect, 2 distrac-
tion devices are recommended to better control the vector of elongation at both bone
edges. The horizontal and vertical osteotomies can be performed with a 701 fissure
bur under copious irrigation with sterile water, taking care not to injure the medial mu-
cosa and to preserve the blood supply to the bone from the medial periosteum. After
completion of the osteotomies the alveolar segment is immobilized and the distractor
is replaced. The distractor should be activated and the transport segment elevated
about 5 mm to check for vertical movement without bony interferences. It is then
brought back to the original position and the wound closed in layers—periosteal
closure and mucosal closure.
The distraction phase should be started in 5 to 7 days to allow for the formation of a
callus and healing of the soft tissue. The time period for distraction depends on the
amount of augmentation that is required. The segment should be moved 0.5 mm twice
daily to achieve a rate of 1 mm/d (Fig. 10). After distraction, a consolidation period of
about 2 months should be maintained to allow the stretched callus to mature with the
support of the device. It is important to keep the callus stable in the stretched position.
We use a consolidation period of 1 week for each 1 mm of distraction and to wait for
1 month after removal of the distractor before implants are placed.
The procedure to be used for vertical augmentation is based on the amount of
elevation that is, required from the residual alveolar crest for standard length crowns.
The necessary bone elevation required can be divided as follows: small 3 to 5 mm, me-
dium 6 to 9 mm, and large 10 mm.
! Small augmentations: onlay bone grafts, staged GBR
! Medium augmentations: GBR, onlay bone grafts, interpositional grafts with or
without membranes
! Large augmentations: GBR, distraction osteogenesis, onlay graft (unpredictable)
Fig. 10. Vertical distraction of deficient alveolar bone. (From Hariri F, Chin SY, Rengarajoo J,
et al. Distraction osteogenesis in oral and craniomaxillofacial reconstructive surgery, osteo-
genesis and bone regeneration. In: Yang H, editor. Osteogenesis and bone regeneration.
https://doi.org/10.5772/intechopen.81055).
Table 2
Complications by method of augmentation
Method of
Augmentation Complications
Onlay graft More complications in the vertical than
in the horizontal bone grafts.
Wound dehiscence
Premature exposure of graft
Mobility of the graft with fibrosis of the interface
Resorption of graft before implant placement
Screw loosening or fracture
Infection
GBR Wound dehiscence
Premature exposure of the membrane
Failure of the regeneration
Additional graft needed at time of
implant placement,
to obtain sufficient implant stability
Distraction osteogenesis Flap damage
Inability to mobilize the transport fragment
Tipping of transport segment
Improper vector at one of the ends
Lingual inclination of the transport segment
in the mandible.
Interference of the distractor with occlusion
Fracture of the distractor
Perforation of the mucosa by the transport segment
Dehiscence of incision
Resorption of the transport segment
Infection
Ridge split Only for vertically sufficient but
horizontally insufficient alveolar ridges
Flap damage
Bad split
Fracture of the buccal plate
Complete loss of buccal bone
Wound dehiscence
Deficiency of the buccal volume
at time of implant placement
Buccal bone fracture at time of implant surgery
Infection
Inlay bone graft Only corrects vertical defects, not horizontal defects
Flap damage
Wound dehiscence
Necrosis of alveolar segment
Loss of graft
Inadequate vertical augmentation for crown height.
COMPLICATIONS
Complications related to ridge augmentation can occur at the time of surgery, in the
early postoperative stages, or late in the postoperative phase. Complications at the
time of surgery include hemorrhage, soft tissue flap injury, injury of nerves, bone frac-
ture, and an inability to obtain a tension-free closure (there is a relationship between
flap tension and early wound dehiscence). Early complications include hematoma,
120 Andre & Ogle
Box 3
Complications related to bone augmentation procedures
GBR
Soft tissue dehiscence 1.7%
Membrane exposure 6.6%
Infection 2%
Insufficient augmentation 2%
Onlay bone grafts
Soft tissue dehiscence
Horizontal augmentation 25.9%
Vertical augmentation 18.2%
Infection
Horizontal augmentation 11%
Vertical augmentation 9%
Insufficient augmentation
Horizontal augmentation 37%
Vertical augmentation 9%
Distraction osteogenesis
Wound dehiscence 4.7%
Displacement of the transport segment 41.6%
Lack of device activation 5.4%
Fracture of transport segment 1.8%
Infection 14.5%
Fracture of device 1.5%
Perforation of mucosa during distraction 1.7%
Ridge Split Technique
Fracture of buccal plate in a 2-step procedure 6.7%
With immediate implant placement 23%
wound dehiscence, membrane and graft exposure, and infection. Late complications
include significant graft resorption, shifting of the graft, fibrous union of the grafted
bone, bony defects, and poor esthetics.
It should be noted that ridge augmentation in the vertical dimension has a higher
complication rate and implant failure rate when compared with horizontal augmenta-
tions or sinus lift procedures (Table 2).28
An Internet literature search of articles listing bone grafting complications were
selected and analyzed. The quality of the reports was not evaluated. The only criterion
was that the article listed percentages for any complication related to alveolar ridge
Box 4
Generalizations
! The survival rates of implants placed into grafted areas are comparable with survival rates of
implants placed into pristine bone.33
! Survival rates of implants placed in horizontally and vertically augmented alveolar ridges are
high.28
! Augmentation of vertical alveolar ridge defects exhibit higher complication rates than those
for horizontal defects.34
! Complications are higher in smokers.35
augmentation. The numbers shown in Box 3 were selected from several Internet sour-
ces and averaged when more than one report was available. It must be emphasized
that this search did not meet the standards of a review article nor was meta-
analysis possible.
OUTCOMES
Advanced alveolar bone loss will always pose a problem for prosthetic rehabilitation
for the individual. Retention and function of dentures are usually not satisfactory.
The majority of these patients will not have sufficient bone in either vertical or hor-
izontal dimensions for implants placement and will require ridge reconstruction
before implant insertion. Augmentation of the residual alveolar bone will allow for
the placement of dental implants with prosthetic rehabilitation which will be comfort-
able and very functional. Ridge augmentation has proven successful over a number
of years with high implant survival rates. Implants placed in grafted maxillomandib-
ular regions, displayed a success rate of 95.17%.29 In a systematic review of 23
retrospective studies during a 5-year period, Albrektsson and Donos30 reported a
success rate of 97.7%.
In a more recent study that looked at 1222 patients with 2729 implants placed in
pure native bone compared with those placed after a separate bone graft proced-
ure from 1985 to 2012, the cumulative survival rates at 5 and 10 years were 92%
and 87% for implants placed in native bone and 90% and 79% for implants
placed in grafted bone, respectively.31 The results from multivariate analysis
(Cox regression) indicated no significant difference in survival between the 2
groups in this study. There was no difference in the dental implant survival rate
when implants were placed in native bone or bone-grafted sites. Smoking and
lack of professional maintenance were significantly related to increased implant
loss.
In a systematic review of onlay grafts by Clementini and colleagues,32 they observed
a success rate of implants in areas of autogenous graft, ranging from 72.8% to 97%, in
most of the reviewed studies (Box 4).
SUMMARY
Ridge augmentation for implant procedures has been shown to be very successful.
There are several techniques available to the dentist but they require some degree
of surgical expertise and experience. No particular technique has been shown to be
superior. This article has presented the indications, techniques, and complications
of the various procedures for alveolar ridge augmentation. This information will
educate the general dental practitioner of the techniques available and provide infor-
mation on the surgical procedures that could be used to discuss with patients when
they are being referred to a specialist.
CLINICS CARE POINTS

! The greater the loss of teeth and consequently bone volume, the more chal-
lenging the process of achieving a functional and esthetic outcome becomes.
A combination of surgical techniques may be required in order to achieve suc-
cessful outcomes.
! The horizontal dimension of the available bone for implant placement should be 3
mm or greater than the diameter of the proposed implant.
122 Andre & Ogle
! The vertical dimension requirements depend on tissue height, prosthetic needs

and the proximity of the implant to vital structures.
DISCLOSURE
REFERENCES
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2. Cawood JI, Howell RA. A classification of edentulous jaws. Int J Oral Maxillofac
Surg 1998;17:232–6.
3. Atwood DA, Coy WA. Clinical, cephalometric, and densitometric study of reduc-
tion of residual ridges. J Prosthet Dent 1971;26(3):280–95.
4. Camargo PM, Takei HH, Carranza FA. Bone Loss and Patterns of Bone Destruc-
tion. In: Newman and Carranza’s clinical periodontology. 13th edition. St. Louis:
Elsevier, Inc.; 2019. p. 316–27.
5. Carr AB, Brown DT. Partially, edentulous, epidemiology, physiology, and terminol-
ogy. In: McCracken’s removable partial Prosthodontics. 13th edition. St. Louis:
Elsevier, Inc.; 2016. p. 2–7.
6. Tolstunov L. Combination syndrome: classification and case report. J Oral Im-
plantol 2007;33(3):139–51.
7. Misch CE, Dietsh F. Bone-grafting materials in implant dentistry. Implant Dent
1993;2(3):158–67.
8. Resnik RR, Misch CE. Misch’s contemporary implant dentistry. 4th edition. Can-
ada: Elsevier; 2020.
9. Misch CE, Goodacre CJ, Finley JM, et al. Consensus conference panel report:
crown-height space guidelines for implant dentistry—Part 1. Implant Dent
2005;14(4):312–21.
10. Milinkovic I, Cordaro L. Are there specific indications for the different alveolar
bone augmentation procedures for implant placement? A systematic review. Int
11. Block MS. Horizontal ridge augmentation using particulate bone. Atlas Oral Max-
illofac Surg Clin North Am 2006;14(1):27–38.
12. Troeltzsch M, Troeltzsch M, Kauffmann P, et al. Clinical efficacy of grafting mate-
rials in alveolar ridge augmentation: a systematic review. J Craniomaxillofac Surg
2016;44(10):1618–29.
13. Deeb GR, Wilson GH, Carrico CK, et al. Is the tunnel technique more effective
than open augmentation with a titanium-reinforced polytetrafluoroethylene mem-
brane for horizontal ridge augmentation? J Oral Maxillofac Surg 2016;74(9):
1752–6.
14. Haggerty CJ, Vogel CT, Fisher GR. Simple Bone Augmentation for Alveolar Ridge
Defects. Oral Maxillofac Surg Clin North Am 2015;27(2):203–26.
15. Karmon B, Tavelli L, Rasperini G. Tunnel Technique with a Subperiosteal Bag for
Horizontal Ridge Augmentation. Int J Periodontics Restorative Dent 2020;40(2):
223–30.
16. Von Arx T, Buser D. Horizontal ridge augmentation using autogenous block grafts
and the guided bone regeneration technique with collagen membranes: a clinical
study with 42 patients. Clin Oral Implants Res 2006;17(4):359–66.
Soft Tissue Injury in
P re p a r a t i o n fo r I m p l a n t s
a b, b,
Earl Clarkson, DDS , Monica Hanna, DMD *, Guillermo Puig, DMD *
KEYWORDS
! Grafting ! Incision ! Soft tissue ! Split-thickness ! Tissue
KEY POINTS
! Proper medical and clinical evaluations of patients is imperative to avoid soft tissue com-
plications in implant planning.
! Several grafting techniques are available, and proper clinical judgment should be used to
evaluate which technique patients may benefit most from.
! Patient anatomy should be taken into consideration when planning for soft tissue grafting.
! Soft tissue grafting may be indicated before, at time of, or after implant placement in order
to reduce risk of soft tissue complications.
OVERVIEW OF GRAFTING PRINCIPLES

Soft Tissue Evaluation
Evaluation of adequate quality and quantity of soft tissue is imperative before implant
placement in order to optimize success. Attached tissue around dental implants al-
lows for increased soft tissue stability, a decreased risk of soft tissue complications,
and a favorable esthetic outcome. Evaluation begins with the gingival biotype as
described by Olsson and Lindhe1: thin scalloped versus thick flat (Fig. 1). Gingival
biotype is determined by variances in soft tissue, bone, and tooth morphology. Thin
scalloped biotype reacts to insult with recession as opposed to thick flat biotype
that reacts with pocket formation. The underlying buccal plate in thin biotype is thin
with frequent fenestration and dehiscence type of defects, whereas the underlying
bone of thick flat biotype is typically much thicker and rarely has dehiscences or fen-
estrations. The bony architecture in thin biotype tends to extensively remodel after
extraction of teeth including increased loss of height and buccal plate and socket
dimension, whereas thicker plates tend to undergo lesser remodeling. In thin biotype,
teeth tend to be more triangular in shape with narrow contact areas in the incisal one-
third, whereas in thick biotype, teeth are squarer in shape with long contact areas
a
NYC Health 1 Hospitals/Woodhull, 760 Broadway, Brooklyn, NY 11206, USA; b Oral and
Maxillofacial Surgery, NYC Health 1 Hospitals/Woodhull, 760 Broadway, Brooklyn, NY
11206, USA
* Corresponding authors.
E-mail addresses: Mhanna0113@gmail.com (M.H.); guillermo_puig@outlook.com (G.P.)
Dent Clin N Am 65 (2021) 57–66

58 Clarkson et al
Fig. 1. (A) Thin scalloped gingival biotype with triangular teeth, thin buccal plate, fenestra-
tions, and scalloping of the bony architecture. (B) Thick flat gingival biotype with square
teeth, thick buccal plate, and flat bony architecture. (From Batal H, Yavari A, Mehra P.
Soft tissue surgery for implants. Dent Clin North Am. 2015;59(2):472–3; with permission.)
extending to the cervical one-third with a more pronounced emergence profile.2 Soft
tissue grafting in patients with thin scalloped biotype results in improved esthetic out-
comes and improves long-term soft tissue stability.3
General Principles
Following the general principles in soft tissue grafting increases the chances of suc-
cess and decreases complications. These principles involve the proper creation of
recipient site, recipient site vascularity, adequate operative hemostasis, good graft
adaptation to recipient site, graft thickness, proper immobilization, and closure.
During the initial healing stages (first 24 hours), a graft receives its nutrients by plas-
matic diffusion, a process known as imbibition. This plasmatic diffusion is guided by
the hypoxic gradient between graft and recipient site, providing initial nutrition to
the graft. Following this, during days 2 to 3, the process of inosculation takes place
and vessels from the graft anastomose with vessels from the recipient site. As graft
healing proceeds during days 3 to 7, revascularization begins and ingrowth of new
vessels into the graft takes place. After vascularity is achieved, remodeling takes place
restoring normal histologic architecture.4
Early graft mobility disrupts revascularization and increases chances of necrosis.
Failure to achieve intimate adaptation of the graft to the recipient bed decreases plas-
matic diffusion and increases capillary travel distance; similarly uncontrolled hemosta-
sis can cause hematoma or blood clot formation hindering adequate nutrient support.
Graft thickness also plays an important factor in healing. Thin and intermediate-
thickness grafts tend to have higher survival rates. Thicker grafts also have less sec-
ondary contracture leading to better clinical outcomes.
Timing of soft tissue grafts can be variable, depending on several factors including
the type of graft being used. No difference has been seen in outcome between simul-
taneous and phased soft tissue augmentation in implant placement when keratinized
Soft Tissue Injury in Preparation for Implants 59
tissue width and soft tissue thickness are considered.5 They may be performed
before, during, or after bone grafting, during or after implant placement, during
second-stage abutment placement, or after crown placement. However, successful
outcomes decrease when soft tissue grafting procedures are performed after crown
placement.2
Types of Soft Tissue Grafts

There are various options for soft tissue grafting, including connective tissue auto-
grafts, vascularized interpositional periosteal connective tissue flaps, palatal roll tech-
nique, and epithelialized palatal grafts.
Connective soft tissue autografts are commonly harvested from the hard palate or
alternatively the maxillary tuberosity. The palate provides maximum volume, whereas
the maxillary tuberosity provides a greater thickness. Palatal soft tissue is composed
of 3 layers: epithelium, subepithelial connective tissue, and submucosa. Connective
tissue grafts can be categorized as either subepithelial connective tissue grafts or
epithelial connective tissue grafts.6
Subepithelial connective tissue grafts are typically harvested between the palatal
root of the first molar and the canine tooth for optimal thickness.7 Careful consider-
ation should be given to the location of the greater palatine artery in this region to avoid
injury. Reiser and coworkers reported the greater palatine artery enters the palate in
the area of the greater palatine foramen and travels anteriorly in the direction of the
incisive foramen8 (Fig. 2A). The greater palatine foramen most commonly is at the
junction of the horizontal and vertical shelf of the palatine bone corresponding with
the position between the second and third molar.2 The neurovascular bundle is
located between 7 and 17 mm from the cementoenamel junction of the teeth with
an average of 12 mm distance, with the distance being shorter in patients with a
shallow palatal vault and longer in patients with a higher palatal vault2 (Fig. 2B).
Dissection should therefore be limited to 8 mm in height to avoid injuring the greater
palatine artery.
Vascularized interpositional periosteal connective tissue flaps were initially
described by Sclar.9 The technique involves a rotation of a pedicled subepithelial
finger flap to the anterior maxilla with a random pattern blood supply.2 This technique
has several advantages as compared with free soft tissue grafts: it allows for effective
simultaneous hard and soft tissue augmentation, provides superior soft tissue
augmentation in both vertical and horizontal directions, and provides greater stability
Fig. 2. (A) Course of the greater palatine artery exiting the greater palatine foramen,
crossing the palate in the direction of the incisive canal. (B) The greater palatine artery is
located between 7 and 17 mm from the cementoenamel junction of teeth. (From Batal H,
Yavari A, Mehra P. Soft tissue surgery for implants. Dent Clin North Am. 2015;59(2):475;
with permission.)
60 Clarkson et al
with decreased secondary shrinkage. It is ideal to correct large defects, and it is an

optimal graft for compromised tissue beds.2 The main disadvantages are that this
flap cannot be used with concomitant temporization or if the implant is not
submerged.
The palatal roll technique as first described by Abrams is a split-thickness palatal
flap that is reflected separating the epithelium from the connective tissue.10 The con-
nective tissue is reflected from the palate and rolled onto the buccal to correct defi-
ciencies in the buccolingual direction.2 The palatal roll technique was modified by
Scharf and Tarnow in 1992 and is commonly indicated to correct minor buccal soft tis-
sue defects during the time of implant placement or placement of the healing
abutment.11
The epithelialized palatal graft was first described by Bjorn and coworkers12 and
was later modified by Sullivan and colleagues13 to describe full-thickness versus
split-thickness grafts. Full-thickness grafts consist of epithelium and the entire zone
of lamina propria, whereas split-thickness grafts contain epithelium and only partial
thickness of lamina propria.13 Split-thickness grafts are further divided into thick, inter-
mediate, or thin based on the width of lamina propria included. Epithelialized palatal
grafts are indicated for mucogingival defects as well as the need to increase the
zone of keratinized tissue.
SOFT TISSUE COMPLICATIONS DURING IMPLANT PREPARATION
Soft tissue injuries and complications can result without proper evaluation of soft tis-
sue sites before implant placement. An adequate preoperative medical evaluation also
plays an important role in decreasing risk of complications, especially in smokers, al-
coholics, immunocompromised patients, or those suffering from cancer, cardiovascu-
lar, or hematologic disorders. Although sometimes inevitable, surgical complications
can be minimized through ensuring adequate planning and preparation of the soft tis-
sue of the implant recipient site. Injuries and complications may occur before implant
placement, after grafting, during implant placement, or after implant placement.
Infection
Surgical site infection can arise during the initial postoperative days and present as
excessive edema, pain, erythema, and discharge. Adequate use of surgical asepsis
may decrease the risk of this complication. Additional preventive measurements
such as the use of preoperative antibiotics, appropriate oral hygiene, and the use of
chlorhexidine 0.12% rinses during the first 2 weeks has also shown benefits. A study
by Lambert and colleagues reported that there is a significant reduction in infectious
complications when chlorhexidine rinses were used perioperatively during implant
surgery. With chlorhexidine, there was a reduction of infection complications from
8.7% in the control group to 4.1% infection rate in the study group.14 Use of antibiotics
is advised; however, they are not indicated in every case.
Edema
Swelling is caused by excess plasma fluid (transudate) accumulation in the interstitial
space of tissues, defined as at least a 10% increase. It is correlated with the extent of
surgical trauma and to the duration of surgery,15 and can cause severe discomfort to
the patient and may negatively affect overall healing. Minimizing traumatic damage,
the use of postoperative cold compresses postoperatively (<48 hours) and warm
compress (after >48 hours), and corticosteroids may prevent or decrease edema after
implant surgery.
Bleeding
Bleeding can occur due to traumatic handling of soft tissue during implant placement.
This bleeding can be caused by failure to stabilize the flap, tearing of soft tissue
caused by placing too much tension on soft tissue during closure, or a sharp suture
material. Other causes of soft tissue bleeding include masticatory trauma from the
opposing dentition or failing to appropriately modify a prostheses to be used after
implant placement. Eliminating the cause of bleeding and use of local measures to
promote hemostasis are included in treatment. Continuous bleeding after local mea-
sures are used will require reevaluation of the flap and exploration, followed by reap-
proximation of the flap to fully immobilize the soft tissue in order to promote clot
formation and stabilization.
Ecchymoses and Hematomas

Ecchymoses are blood effusions infiltrating surface tissues, and hematomas are cir-
cumscribed blood collections. These can be dramatic and more prominent in elderly
patients due to their increased capillary fragility. Several factors can contribute to
these injuries such as longer and more complex surgical time, lack of surgical expe-
rience, traumatic surgical techniques, lack of postoperative patient compliance,
elderly patients, and failure to discontinue antiplatelets medications (if indicated)
before surgery. Intraoperative and postoperative ecchymoses and hematomas can
be extensive if there is poor hemostasis during the surgical procedure.
Soft tissue ecchymoses typically resolve on their own, but the use of intermittent ice
packs in the first 24 hours followed by moist heat after 48 hours can aid in resolution.15
If a hematoma is present between bone and the mucoperiosteal flap, it should be
drained and external compression applied on soft tissue to avoid relapse.
Loss of the Graft

Partial or complete loss of connective tissue grafts is possible despite their high suc-
cess rates (Fig. 3). Adequate healing of graft sites depends on vascularity, thus immo-
bilization of the graft at the time of surgery is imperative. Creating a flap at the recipient
site allowing for primary closure may also decrease the risk of graft necrosis. Immedi-
ately postoperatively, the grafted site may seem pale and may turn grayish after
Fig. 3. (A) Partial loss of subepithelial connective tissue graft. (B) Partial loss of subepithelial
connective tissue graft. (From Batal H, Yavari A, Mehra P. Soft tissue surgery for implants.
Dent Clin North Am. 2015;59(2):490; with permission.)
62 Clarkson et al
48 hours due to tissue ischemia. If adequate neovascularization is achieved by day 14,

tissue will return to normal pink color and edema will resolve.16 Observation or conser-
vative debridement is recommended depending on the extent of graft necrosis. The
use of local measures such as gentle saline irrigations may also be beneficial.
Subcutaneous Emphysema
Emphysema results from a sudden increase in intraoral pressure that may occur if a
patient sneezes, and air is forced through the mucoperiosteal flap into connective tis-
sues or fascial planes. Patients present with facial swelling and crepitus on palpation.
Massage and cold compresses will help resorb air that is trapped in the tissues, result-
ing in spontaneous resolution of the emphysema. The use of antibiotics should be
considered, as these may prevent secondary infection from oral bacteria.
Avoiding the use of high-velocity instruments for osteotomy preparation, using
copious irrigation, and ensuring adequate and proper closure of flap margins when su-
turing may contribute to minimizing the risk of developing emphysema. More severe
complications can arise with extensive emphysema, as it dissects fascial planes
into the mediastinum. Subcutaneous emphysema can be life-threatening in the pres-
ence of air embolism. Severe infections may also arise due to microbial dissemination
through emphysematous tracts.
Flap Dehiscence
Dehiscence results when surgical wound edges separate, exposing the dental implant
or bone (Fig. 4). Contributing factors include thin gingival mucosa, excessive tension
causing soft tissue necrosis, failure to adequately reapproximate flap margins, cover
screw loosening, mechanical irritation, edema or hematomas, premature use of pros-
thodontic appliances, trauma from the opposing dentition, subperiosteal debris, and
smoking due to its vasoactive and cytotoxic effects. As previously mentioned, there
are 2 distinct gingival biotypes: thin scalloped and thick flat. Thin scalloped gingival
biotype tends to react to insult with recession. The underlying buccal plate is typically
thin with frequent fenestration and dehiscence type of defects.
Fig. 4. Dehiscence of soft tissue at palatal donor site. (From Batal H, Yavari A, Mehra P. Soft
tissue surgery for implants. Dent Clin North Am. 2015;59(2):490; with permission.)
The extent of the exposure and bone health determines treatment17:

! Small exposures usually do not require correction; the presence of granulation
tissue compensates the opening and promotes healing by secondary intention.
" A small exposure within the first 24 to 48 hours can be resutured.
" If the granulation tissue formation process lasts longer than 2 weeks, and there
is no necrotic bone, the epithelial wound margins may be refreshed and re-
sutured.
! Large exposures or a time lapse greater than 48 to 72 hours and no necrotic bone
require removing sutures, refreshing epithelial wound margins, and resuturing.
! Recurring exposures in healthy, young, and nonsmoking patients may require
debridement thorough irrigation and mouthwash with chlorhexidine. Denuded
bone should also be covered with dressing, gradually reducing dressing size
and monitoring region for 3-6 weeks until healed.
! Nonresolving dehiscence with necrotic bone requires bone removal until fresh
bleeding bone is reached. Consider implant removal if there is infection present
or if the implant is mobile, as these can interfere with tissue closure. Excision of
wound margins and mobilization of a large mucoperiosteal flap buccally and
lingually are also indicated. An antibiotic regimen should also be prescribed for
7 to 10 days.
Wound dehiscence can be prevented by tension-free closure using a buccal
releasing incision and adequate preoperative assessment of the soft tissues. Assess-
ing the amount of keratinized mucosa present and planning of augmentation proced-
ures when appropriate are imperative. Minimally invasive flap elevation and reflection,
proper reapproximation and suturing of the flap, copious irrigation of subperiosteal
debris, and delaying use of prosthodontic appliances until soft tissue healing is
completed may also reduce the risk of wound dehiscence.
Deficient Attached Gingiva

When using open flap implant surgery versus the flapless technique, particular care is
given to the esthetics zone in order to enhance soft tissue appearance. Flapped pro-
cedures are indicated when the ridge is narrow in a buccal/lingual dimension or there
is limited attached gingiva that would be lost using a punch at the crest. In order to
conserve the attached gingiva, the crestal incision should be placed palatally in order
to provide greater thickness of keratinized tissue on the facial aspect of the flap. This
also enhances papilla height by allowing more interproximal tissue to be elevated.
A narrow zone of attached gingiva surrounding implant restoration is associated
with a higher risk of gingival inflammation, gingival recession, and decreased resis-
tance to plaque accumulation. Sufficient keratinized gingiva around dental implants
offers resistance to forces of mastication and external trauma and provides a barrier
to inflammatory infiltrates.
Patients with thin gingival biotypes may benefit from soft tissue grafting. The
increased thickness provides more esthetic outcomes, especially at the level of the
buccal gingival margin. Epithelialized palatal grafts are indicated for mucogingival de-
fects and to increase the zone of keratinized tissue.18
Thicker grafts are more ideal for increasing the zone of attached gingiva and provide
better outcomes as they contract less than split-thickness grafts.
Mucoperiosteal Perforation
Screw exposure is a common complication and can be associated with excessive
prosthetic pressure compromising vascularity, trauma, thin mucosal soft tissues, or
64 Clarkson et al
cover screw loosening. Exposure of implant screws can lead to plaque buildup,
inflammation, and eventually bone loss around the implant surface. Cehreli and col-
leagues19 confirmed that there is a direct relation between spontaneous early cover
screw perforations and early crestal bone loss. He also concluded that early placed
implants experienced more spontaneous perforations and associated bone loss in
comparison with conventionally placed submerged implants. Typically mucoperios-
teal perforations do not require treatment because tight closure of the soft tissue
flap is not indispensable for implant osseointegration. In some cases, in order to
decrease plaque accumulation and inflammation, areas of exposure may be extended
and the implant cover screw may be replaced by a healing abutment. In early exposure
of crestal bone, flap elevation or soft tissue grafting should be considered to cover the
defect.
Adequate preoperative evaluation can decrease the frequency of this complication.
If soft tissue thickness is deficient, a connective tissue graft should be planned along-
side implant placement. A study by Linkevicius and colleagues20 reported that initial
gingival tissue thickness at the crest of implants may have significant influence on
marginal bone stability around implants. If there is soft tissue thickness of 2.0 mm
or less, crestal bone loss up to 1.45 mm may occur, despite a supracrestal position
of the implant-abutment interface.
Maxillary Sinus Perforation

In cases where there is a severe degree of resorption that may preclude placement of
a short implant or the primary stability of the implant would be compromised, the
maxillary sinus must be augmented. Bone regenerative procedures for implant prep-
aration are encompassed by 2 main approaches: the lateral sinus window and the
transalveolar or crestal approach. Although each procedure is very different, perfora-
tion of the maxillary sinus is one of the complications that both procedures share.
Maintaining the integrity of the sinus membrane is important to decrease bacterial
contamination and infection to the grafting site. This could lead to a further decrease
in potential future complications, but in some cases it may be unavoidable despite
adequate presurgical evaluation.
Management of maxillary sinus perforations changes according to the extent of
damage to the sinus membrane21:
! Small perforations of less than 1 mm, the membrane may self-repair by folding
over or through clot formation.
! Perforations of less than 5 mm may benefit from the use of fibrin glues, collagen
tapes, bioabsorbable membranes, or suturing the membrane defect, which are
usually sufficient to allow for simultaneous implant placement.
! Perforations larger than 5 mm may require the use of bioabsorbable membranes,
lamellar bone plates, suturing alone or in combination with fibrin glue, or ulti-
mately aborting the procedure.
! Larger perforations are even more challenging to repair and may require more
specific management with the use of collagen membranes to cover all internal si-
nus walls, local flaps, or autogenous bone blocks.
Perforation of the membrane may also occur during the implant placement itself. If
this happens, implants that penetrate inside of the sinus cavity less than 2 mm do not
require further intervention, as spontaneous covering of the implants with the sinus
mucosa may occur. However, if the implant extends into the maxillary sinus more
than 2 mm, chances of spontaneous mucosal repair are diminished and accumulation
of debris around the implant surface could lead to maxillary sinusitis. In a study by
Corbella and colleagues,22–26 it was observed that there were no statistically signifi-
cant differences in implant survival between implants penetrating less than or equal
to 4 mm or greater than 4 mm with long-term survival rates of 99.5% and 98.5%,
respectively. Complications associated with maxillary sinus perforations such as
epistaxis, sinusitis, and membrane thickening are common.
SUMMARY
Several soft tissue injuries and complications may be prevented with proper presurgi-
cal evaluation. A detailed medical and clinical evaluation also play an important role in
decreasing the risk of future complications.
Soft tissue grafting may be indicated before, at the time of, or after implant place-
ment in order to minimize risks of injury. Thus, a rigorous examination of soft tissues
before implant placement is always recommended. Proper evaluation and preparation
of soft tissue sites, surgeon experience, and careful postoperative care may contribute
to reducing these soft tissue injuries and complications.
CLINICS CARE POINTS

! Most of the implant placement surgeries complications can be avoided as long
as the case has been properly diagnosed, planned and adequate surgical princi-
ples are followed.
! Failure to follow proper surgical techniques can have detrimental effects in an im-
plants sucess.
! Care during retraction and proper soft tissue management can help avoid com-
plications such as flap tearing and tissue dehiscence.
DISCLOSURE
REFERENCES
1. Olsson M, Lindhe J. Periodontal characteristics in individuals with varying form of

the upper central incisors. J Clin Periodontol 1991;18(1):78–82.
2. Dym H. Implant Procedures for the General Dentist. Dent Clin North Am 2015;
59(2). https://doi.org/10.1016/j.cden.2014.12.002.
3. Bhat V, Shetty S. Prevalence of different gingival biotypes in individuals with vary-
ing forms of maxillary central incisors: a survey. J Dent Implants 2013;3(2):
116–21.
4. Greenwood J, Amjadi M, Dearman B, et al. Real-time demonstration of split skin
graft inosculation and integra dermal matrix neovascularization using confocal
laser scanning microscopy. Eplasty 2009;9:e33.
5. Cho-Ying L, Zhaozhao C, Whei-Lin P, et al. Impact of timing on soft tissue
augmentation during implant treatment: A systematic review and meta-analysis.
Clin Oral Implants Res 2018;29(5):508–21.
6. Rees TD, Brasher WJ. A technique for obtaining thin split-thickness grafts in peri-
odontal surgery. Oral Surg Oral Med Oral Pathol 1970;29(1):148–54.
7. Dibart S, Karima M. Practical Periodontal plastic surgery. Danvers (MA): Black-
well; 2006.
8. Reiser GM, Bruno JF, Mahan PE, et al. The subepithelial connective tissue graft
palatal donor site: anatomic considerations for surgeons. Int J Periodontics
Restorative Dent 1996;16(2):130–7.
H o w to Av o i d L i f e -
T h rea t e n i n g C o m p l i c a t i o n s
A ss oc ia ted wi t h I mp l a n t Surge ry
Earl Clarkson, DDS, Eunsu Jung, DDS*, Spencer Lin, DMD
KEYWORDS
! Life-threatening implant complications ! Hematoma ! Hemorrhage ! Floor of mouth
! Aspiration ! Ingestion
KEY POINTS
! Life-threatening complications of dental implants are hematoma, hemorrhage of floor of
the mouth, aspiration, and ingestion.
! The key to preventing hemorrhagic complication is knowing anatomic structures relevant
to the implant position and proper planning.
! Aspiration and ingestion can be better prevented by understanding clinical settings and
patient risk factors.
INTRODUCTION
Ever since the discovery of dental implants, its surgery has become more prevalent
and now routinely done in a clinical setting due to its high success rate and safety.
Although many methods and technological advances have emerged in the recent de-
cades, complications still occur as described in previous chapters (periimplantitis,
mucositis, infection, nerve damage). Although unfortunate, these complications often
do not pose lethal consequences. These adverse outcomes are often preventable and
are typically able to be managed in a clinical setting. Despite being uncommon, life-
threatening complications can occur in some situations. Such emergencies include
hemorrhage/hematoma formation of the floor of mouth, aspiration, and ingestion of
foreign bodies, that is, implant parts. These complications can happen during routine
dental implant surgery and can cause lethal events such as airway obstruction, perfo-
ration of organs, and infection. Management of these life-threatening conditions can
be more challenging and have life altering consequences to the patient in addition
to both legal and financial loss to the practitioner. It is crucial for clinicians to be
able to promptly recognize life-threatening emergencies and take appropriate
Department of Dentistry, Department of Oral and Maxillofacial Surgery, NYC Health 1 Hos-
pitals/Woodhull, 760 Broadway, Brooklyn, New York 11206, USA
E-mail address: vcleaner7@gmail.com
Dent Clin N Am 65 (2021) 33–41

34 Clarkson et al
measures. With pertinent preparation, knowledge of anatomic structures, and preven-

tative protocols, these adverse events can be prevented.
HEMORRHAGE/HEMATOMA IN THE FLOOR OF THE MOUTH
One of the common complications in implant surgery is hemorrhage. Minor bleeding is

frequently encountered during and after the procedure and is relatively well managed
with local measures in a clinical setting. However, significant hemorrhage and hema-
toma formation in anterior mandible can be life threatening, as it can lead to airway
obstruction. In general, the incidence of severe implant related hemorrhage was found
to be w 24%. Reported causes included soft tissue damage, violation of arteries, and
osteotomy perforations.1 Regarding the site of injury, life-threatening consequences
via airway obstruction originated more commonly from bleeding in the anterior
mandible compared with other parts of the mouth. This is due to perforation of the
lingual cortex causing vascular injury within soft tissue.2
The lingual aspect of the anterior mandible has a rich vasculature as it is supplied by
the sublingual, submental, and incisive arteries. These arteries also supply the mus-
cles and soft tissues of the floor of the mouth. The sublingual artery originates from
the lingual artery, anastomosing with the submental artery that branches from the
facial artery. These arteries run along the lingual side of the anterior mandible parallel
to the mylohyoid muscle. In most of the cases (80%–90%) sublingual arteries run
through the lingual foramen in the midline, penetrating through the lingual cortical
plate.2–4 These vessels anastomose with the incisive arteries that are branches of
the inferior alveolar artery These vessels together form a highly vascularized network
in the lingual aspect of mandible (Fig. 1). Damaging vessels in this area during implant
surgery can cause significant hemorrhage with blood loss rate of 14 mL/min. This
bleeding can spread through the loose adipose and connective tissues of the floor
of the mouth to involve facial spaces such as sublingual, submental, and
Fig. 1. The lingual aspect of the anterior mandible, showing complex vasculature with
anastomoses.
Life-Threatening Complications 35
submandibular spaces. As this hemorrhage worsens, it can cause posterior displace-

ment of the tongue. This will apply direct pressure against the soft palate into the phar-
ynx, leading to rapid upper airway obstruction.1,5 In such circumstances, often
aggressive airway management may be necessary. Law and colleagues found that
in 25 reported cases, lingual cortex perforation was the most common cause of severe
hemorrhage, resulting in 68% of patients requiring intubation or tracheostomy due to
airway obstruction.6 Therefore, knowing key anatomic structures in the anterior
mandible combined with precise surgical planning is crucial to preventing life-
threatening consequences.
Management
The definitive procedures to control airway obstruction due to severe hemorrhage/he-
matoma in the floor of the mouth are limited in a dental office setting. Initial recognition
of such symptoms should prompt the clinician to consider transfer and immediate
airway management. Clinical findings of hemorrhage progressing to airway obstruc-
tion may present with evident bleeding in the oral cavity, severe pain, protrusion of
the tongue, bruising, and swelling of the floor of the mouth. The patient can show
symptoms of dysphagia, dyspnea, and cyanosis with inadequate oxygen saturation,
eventually resulting in respiratory arrest.
Local hemostatic measures are crucial; however, initial treatment options are limited
in an ambulatory clinic in the event of severe hemorrhage in the floor of the mouth. In
such event, one should immediately terminate the surgical procedure and apply direct
pressure. Bimanual compression inferiorly at the floor of the mouth and lingual surface
of the mandible in conjunction with upward force against the submental region is rec-
ommended. The goal is to decrease bleeding and expansion of the hematoma to ul-
timately prevent airway obstruction. In addition, compression with ice can aid in
hemostasis.7 Hemostatic agents such as resorbable gelatin sponges, oxidized cellu-
lose, or bovine collagen plugs combined with pressure can be applied to osteotomy
and/or extraction sites. If available, electrocautery can aid in hemostatic efforts. If
hemorrhage/hematoma expansion remains uncontrolled or signs of airway obstruc-
tion are present despite attempting local measures, activate 911 response and rapid
transport to the nearest hospital emergency department. Meanwhile, vital signs
should be monitored and oxygen may be supplied through nasal canula to lessen dys-
pnea stress. Moreover, efforts should be made to reduce patient anxiety to prevent
further bleeding due to hypertension.2 Endotracheal intubation or tracheostomy may
be required if the patient is unable to breath adequately, demonstrating signs of oxy-
gen desaturation.
Emergency evacuation of the hematoma can be considered if the clinician is
adequately trained to do so. However, an inexperienced practitioner attempting this
procedure can worsen the bleeding and create more soft tissue destruction.6 More-
over, experienced clinicians can attempt to ligate the damaged vessel. Studies sug-
gest that ligating the facial or sublingual artery can control floor of the mouth
hemorrhage. If unsuccessful, ligation of the lingual artery can be attempted.5 Howev-
er, without adequate anesthesia or specialized training, attempting to ligate the
damaged vessel might worsen the situation due to multiple anastomoses of nearby
arteries and a limited visual field in an office setting. Hence, prompt transport to an
emergency department is crucial as definitive treatment involves airway management
and complex operations that require the expertise of a skilled surgeon. If direct intrao-
ral approach is unsuccessful, angiographic e-embolization or ligation of the carotid ar-
tery via extraoral approach can be considered in conjunction with using vascular
angiography or computed tomographic (CT) scans.3
36 Clarkson et al
Prevention
Severe hemorrhage in the floor of the mouth can put the patient’s life at risk, requiring
invasive treatment. The importance of using preventive measures cannot be overem-
phasized. One of the simple and easy preventive methods is obtaining a preoperative
cone-beam computed tomographic (CBCT) scan. Compared with conventional 2-
dimensional radiographs, CBCT is superior, as it can reveal the position and diameter
of intrabony vascular canals that may contain significant vessels, especially in anterior
mandible. This can be advantageous to the clinician in avoiding or preparing to control
any incidental arterial hemorrhage during implant placement. In the studies of 25 re-
ported cases of hemorrhage, most of the bleeding was caused by lingual cortex perfo-
ration.6 Only one case used preop 3-dimensional imaging before implant placement.
This demonstrates the importance of obtaining preop CT. In addition, CBCT allows
one to visualize mandibular atrophy and its angulation. This encourages ideal implant
position by engaging more bone, leading to better primary stability while avoiding
perforation of the lingual plate, protecting sublingual soft tissue.
Injecting local anesthesia multiple times in anterior mandible, especially it the lingual
aspect, is suboptimal, as it can cause bleeding from nicks in vessels that do not cease
spontaneously. These local injections with a vasoconstrictor can delay the symptoms
of a hematoma of the floor of the mouth. Therefore, inferior alveolar nerve blocks are
preferred to avoid direct damage to vessels in that region.8
Favoring a narrower diameter implant in anterior mandible can be another method
to prevent hemorrhagic complications. The occlusal load of the anterior mandible is
one-third of the posterior and generally has a bone dense enough to resist occlusal
forces. The clinician can opt for narrow diameter implants that can be placed a few
millimeters away from the midline to possibly avoid a single large sublingual artery.
In patients with severely angulated and/or atrophic mandibles, there is an
increased risk of perforating the lingual cortical plate, which is in close vicinity to a
vascular plexus that has great potential to cause severe bleeding. Avoiding lingual
subperiosteal tears is of utmost importance, as its injury can lead to detrimental
bleeding, as the main vascular osseous supply of the anterior mandible is provided
by the facial artery via periosteal vasculature in the atrophic mandible. Injury of
mandibular lingual vascular canals itself is less concerning due to their small diam-
eter. CBCT and surgical stents can decrease the chance of perforating the lingual
cortical plate by encouraging correct implant positioning. In addition, digital palpa-
tion on the lingual mandible should be applied for tactile feedback to avoid perfora-
tion while gently advancing the bur. Furthermore, lingual subperiosteal flap
enhances visualization to prevent lingual perforation.5 On the contrary, some claim
that flapless implant placement in the anterior mandible may have fewer complica-
tions compared with open flap procedures.7 However, if excessive bleeding occurs
while using the flapless technique, blood can expand into the floor of the mouth and
deep neck region rather than draining into the oral cavity. Therefore, manual palpa-
tion of the lingual mandible in conjunction with proper preop planning of implant po-
sition with CBCT should be considered.
ASPIRATION AND INGESTION
Aspiration and ingestion of instruments and/or materials can occur during any stage of
implant surgery and may lead to life-threatening consequences. The foreign object
can be either aspirated or swallowed, depending on the route taken beyond the phar-
ynx. It is evident in the literature that aspiration was observed more often during im-
plantation, prosthodontics, and restorative dentistry, whereas prosthodontics and
root canal treatment was more related to ingestion.9 In general, aspiration or ingestion
is an infrequent occurrence, the latter happening more often as a direct result of the
strong coughing that occurs when there is a foreign object in the patient’s airway.
Although aspiration has lower incidence, it poses a higher risk for lethal complications,
as an aspirated object can lead to acute airway obstruction and lung infections
including abscess formation or pneumonia. Similarly, an ingested foreign object can
also be life threatening, as objects can become entrenched through its passage
through the gastrointestinal (GI) tract and lead to severe inflammation, obstruction,
and infection.10
There are various risk factors related to a patient’s medical history in addition to
modifiable clinical factors that can facilitate aspiration and ingestion of a foreign
body during implant surgery. Patients with psychological disorders, mental retarda-
tion, excessive gag reflex, alcoholism, small oral cavity, and macroglossia; those
who are obese or pregnant; and the elderly should be considered at higher risk for
complications. In a clinical setting, the patient’s risk of aspiration and ingestion of
foreign objects may also be increased by local anesthesia, supine positioning, inade-
quate lighting, ineffective assistants, and airway protection.11 Evidently, these compli-
cations can be detrimental to the patient but can also create potential for legal action
against the clinician and related economic costs. Thus, it is crucial to thoroughly eval-
uate a patient’s medical history for aspiration/ingestion risk factors and be mindful of
adjustable clinical settings to prevent complications.
Symptoms
The symptoms of aspiration and ingestion can be varied. In general, patients
commonly present with coughing, gagging, and dyspnea following aspiration of a
foreign body. If larger objects are aspirated, immediate airway obstruction is possible,
which can present as inspiratory stridor, paradoxic breathing, and cyanosis with inad-
equate oxygen saturation. On physical examination, one may notice tachypnea,
tachycardia, stridor, unilateral or bilateral decreased breath sounds, localized
wheezing, and/or crackles. It is possible for a patient to not present with any initial
discomfort or symptoms. However, even asymptomatic patients who had potentially
aspirated a foreign body, necessary protocol should be taken, because chronic reten-
tion of foreign bodies in the airway can manifest as serious consequences including
infection, pneumothorax, vocal cord paralysis chronic cough, hemoptysis, pneu-
monia, unexplained fever, and even death.
In contrast, patients with ingested foreign bodies are often asymptomatic. Never-
theless, signs and symptoms can still develop, commonly presenting as coughing,
gagging, dysphagia, odynophagia, cramps, nausea, and vomiting. In the event of an
asymptomatic patient who has ingested foreign body, adequate treatment protocol
is still necessary, as complications can progress to bowel obstruction, infection,
and perforation.
Management and Prevention

Consequences of aspiration and ingestion may lead to lethal complications that
require invasive treatment, and thus prevention is key. A simple yet important pre-
ventative technique is applying a gauze screen. Often times, the practitioner negates
this method for various reason; however, there is no superior way to prevent acci-
dents. The gauze screen should be applied posterior to the surgical site to block en-
try of a foreign body passing the oropharynx. Tying floss or sutures to small
instruments such as an implant screwdriver can prevent aspiration and ingestion,
as it provides the clinician a fast way to retrieve the fallen object. In addition,
38 Clarkson et al
controlling variables such as inadequate lighting, the lack of assistance, or proper

instrumentation such as high-speed suction should be addressed before any
implant-related procedure. This becomes crucial especially when placing implants
in posterior regions where visibility and accessibility can be compromised. Control-
ling chair position can be advantageous especially when patients have an unfavor-
able gag reflex and are unable to tolerate a gauze screen. In this circumstance,
patients seated upright with their head turned sideways is beneficial. Also, adequate
suction to evacuate excessive saliva and blood can help reduce the gag reflex, lead-
ing to unpredictable movements.12
If an object is lost beyond the oropharynx while in a supine position, the patient
should be kept supine, turned to their right side, and attempt to “cough up” the
foreign body. Slow inhalation followed by a forceful cough can minimize aspirating
the object deeper.13 Because the adult right bronchus diverges at a more acute
angle from the trachea compared with the left side and also has a greater diameter
than the left bronchus, the right side is the more common path for aspirated objects
(Fig. 2).14,15 This right-sided Trendelenburg positioning decreases the effect of grav-
ity pushing the foreign body deeper while helping keep the aspirated object to the
right mainstem bronchus. Spontaneous or endoscopic retrieval is easier in the right
mainstem bronchus, as its diameter is wider and provides a straight passage. If aspi-
ration occurs while the patient is upright, the patient should be lowered to the
favored right-sided Trendelenburg position, unless they are violently coughing.13
In contrast, there are conflicting views, as some experts believe that the patient
should be placed into reverse Trendelenburg position before being encouraged to
cough. They believe this maneuver may aid in regurgitating the foreign body.11
Regardless, if the object is visible, the clinician may use forceps or high-volume suc-
tion to retrieve the object while being careful not to dislodge it further. Immediate ac-
tion must be taken to prevent respiratory failure if the patient shows signs of airway
obstruction such as choking, dyspnea, stridor, and using accessory muscles to
breathe. In this instance, abdominal thrusts in conjunction with finger sweeps and
suction can be performed. If unsuccessful, cricothyroidotomy may be considered
by emergency personnel while the patient is being arranged for immediate transfer
to the closest emergency department. It is also important to reassure asymptomatic
Fig. 2. The lung, showing difference between right and left mainstem bronchus. Right bron-
chus branches at a more acute angle and has a wider diameter.
and stable patients who have aspirated or ingested foreign body that the situation is
manageable. At the same time, patients must seek immediate medical attention and
determine whether the object was aspirated or ingested by taking a series of radio-
graphs of the abdomen and chest. The treatment modality depends on the location
of the foreign body.
Aspiration
If radiographic examination reveals aspiration, it is a medical emergency that requires
immediate intervention. Patient will require evaluation for urgent bronchoscopy.
Retrieval of the object can be accomplished via bronchoscopy in conjunction with a
suctioning or grasping device. Intubation may be required before bronchoscopy in
the event of complex cases such as deeply dislodged foreign bodies. Literature sug-
gests that bronchoscopy has been extremely effective in foreign body removal, reach-
ing a 99% success with a complication rate ranging from 2.4% to 5%.12 In severe
cases where the retrieval has failed with bronchoscopy, thoracotomy with bronchot-
omy may be indicated.
Ingestion
Most foreign body ingestions are asymptomatic and fortunately, once an objects
reaches the stomach, there is a greater than 90% chance of the object being passed
from the GI tract without complications, usually over a 7 to 10-day period.16 If an
ingested object is radiographically confirmed to be passing, conservative monitoring
is possible as long as the foreign body is blunt and is less than 2.5 cm in diameter and
is less than 6 cm in length.17 In this case, patients must be informed about their sit-
uation in addition to instructions for examining their stools. Mandatory daily inspec-
tion of stool combined with a high-bulk, high-fiber diet may be helpful, although no
literature specifically demonstrates increased success with any specific diet. Laxa-
tives are contraindicated as excessive peristalsis can lead to mucosal perforations. If
passage of a blunt foreign object is not confirmed within 7 days or if the patient be-
comes symptomatic, additional CT scan and endoscopic removal might be
necessary.
In cases of an ingested sharp object or if acute symptoms of obstruction occur,
immediate intervention is required. Sharp objects pose the risk of organ perforation,
whereas larger object greater than 6 cm have greater risk of obstruction and perfo-
ration. In these circumstances, immediate transfer to an equipped facility and
endoscopy is indicated. The most common location for obstruction is the upper
esophagus, which can lead to esophageal perforation with subsequent mediastinitis.
Esophageal obstruction can eventually transition into aspiration, further adding to
the urgency of the situation. Although some experienced clinicians may attempt to
retrieve the foreign body via direct visualization using a laryngoscope and forceps,
this can risk dislodging the object deeper. Hence, endoscopy is considered as the
treatment of choice due to its relatively low complication rate, its high success
rate, and because it often does not require postoperative hospital admission. If
the foreign body is unable to be removed via endoscopy, does not progress along
the GI tract in 72 hours, or if severe symptoms such as vomiting, continuous abdom-
inal pain, hematemesis, or melena occur, more invasive measures such as cervical
esophagectomy might be necessary.17
CLINICS CARE POINTS

! Use caution and precise surgical planning when working near the lingual aspect
of the anterior mandible as it contains rich vasculature.
40 Clarkson et al
! Activate 911 response and rapid transport to the nearest hospital emergency
department if uncontrolled hemorrhage in the floor of the mouth.
! Thoroughly evaluate a patient’s medical history for aspiration/ingestion risk fac-
tors and be mindful of adjustable clinical settings to prevent complications.
! Radiographic examination is crucial to determine location of ingested/aspirated
foreign body, even if asymptomatic.
DISCLOSURE
REFERENCES
1. Misch K, Wang HL. Implant Surgery Complications: Etiology and Treatment.

Implant Dent 2008;17(2):159–68.
2. Schiegnitz E, Moergel M, Wagner W. Vital Life-Threatening Hematoma after
Implant Insertion in the Anterior Mandible: A Case Report and Review of the Liter-
ature. Case Rep Dent 2015;2015:531865.
3. Limongelli L, Tempesta A, Crincoli V, et al. Massive Lingual and Sublingual Hae-
matoma following Postextractive Flapless Implant Placement in the Anterior
Mandible. Case Rep Dent 2015;2015:839098.
4. Saquib Mallick M, Rauf Khan A, Al-Bassam A. Late Presentation of Tracheobron-
chial Foreign Body Aspiration in Children. J Trop Pediatr 2005;51(3):145–8.
5. Tarakji B, Nassani MZ. Factors associated with hematoma of the floor of the
mouth after placement of dental implants. Saudi Dent J 2012;24(1):11–5.
6. Law C, Alam P, Borumandi F. Floor-of-Mouth Hematoma Following Dental Implant
Placement: Literature Review and Case Presentation. J Oral Maxillofac Surg
2017;75(11):2340–6.
7. Peñarrocha-Diago M, Balaguer-Martı́ JC, Peñarrocha-Oltra D, et al. Floor of the
mouth hemorrhage subsequent to dental implant placement in the anterior
mandible. Clin Cosmet Investig Dent 2019;11:235–42.
8. Sakka S, Krenkel C. Hemorrhage Secondary to Interforaminal Implant Surgery:
Anatomical Considerations and Report of a Case. J Oral Implantol 2013;39(5):
603–7. Allen Press, Available at: meridian.allenpress.com/joi/article/39/5/603/
7243/Hemorrhage-Secondary-to-Interforaminal-Implant.
9. Hou R, Zhou H, Hu K, et al. Thorough documentation of the accidental aspiration
and ingestion of foreign objects during dental procedure is necessary: review
and analysis of 617 cases. Head Face Med 2016;12:23.
10. Santos Tde S, Antunes AA, Vajgel A, et al. Foreign Body Ingestion During Dental
Implant Procedures. J Craniofac Surg 2012;23(2):e119–23.
11. Pingarrón Martı́n L, Morán Soto MJ, Sánchez Burgos R, et al. Bronchial impaction
of an implant screwdriver after accidental aspiration: report of a case and revision
of the literature. Oral Maxillofac Surg 2010;14(1):43–7.
12. Fields RT Jr, Wolford LM. Aspiration and Ingestion of Foreign Bodies in Oral and
Maxillofacial Surgery: A Review of the Literature and Report of Five Cases. J Oral
13. Bosack R, Lieblich S. Anesthesia complications in the dental office. Hoboken:
John Wiley & Sons; 2015.
14. Lee EJ, Yang HR, Cho JM, et al. Two Cases of Colonoscopic Retrieval of a
Foreign Body in Children: A Button Battery and an Open Safety Pin. Pediatr Gas-
troenterol Hepatol Nutr 2017;20(3):204–9.
A n U p d a t e o n t h e Trea t m e n t
of Periimplantitis
a,b, c d
Raza A. Hussain, BDS, DMD *, Michael Miloro, DMD, MD , Jennifer B. Cohen, DDS
KEYWORDS
! Dental ! Implants ! Failing ! Salvage ! Periimplantitis ! Inflammation
KEY POINTS
! Increased dental implant placement equates to an increased number of long-term main-
tenance issues.
! Discussion of methods to avoid short- and long-term issues in relation to dental implants.
! Techniques for management of early, intermediate, and late stage issues that can arise
from periimplantitis.
! Algorithm for when to attempt implant repair/salvage versus removal and replacement.
INTRODUCTION
Dental implants have been used to replace natural dentition since the 1960s. Brane-
mark discovered that when titanium was implanted into a patient’s bone, it would
lead to a process termed “osseointegration.” Gosta Larsson was the recipient of
the first dental implant, placed by Branemark himself in 1965. When Larsson died in
2006, several implants were still in function. It can be assumed that he was a motivated
patient who was diligent in maintaining his newly acquired dentition for decades. Many
of the authors’ medical colleagues wonder how it is possible to implant a foreign body
in the oral cavity without the constant risk of infection and rejection. The capacity of
surgical grade titanium to promote bony fusion and acceptance is critical in the suc-
cess of dental implants. The excellent vascularity of the head and neck area and rapid
bony/oral epithelial turnover is also paramount. In addition, the constant flow of saliva,
with its protective properties, is necessary in maintaining a healthy microbiological
a
Oral and Maxillofacial Surgery, Jesse Brown VA Medical Center, 820 South Damen Avenue,
4th Floor Damen Pavilion, Chicago, IL 60612, USA; b Department of Oral and Maxillofacial
Surgery, University of Illinois at Chicago, Chicago, IL, USA; c Department of Oral and Maxillo-
facial Surgery, University of Illinois at Chicago, 801 South Paulina Street, M/C 835, Chicago, IL
60612, USA; d Jesse Brown VA Medical Center, 820 South Damen Avenue 4th Floor Damen
Pavilion, Chicago, IL 60612, USA
* Corresponding author. Jesse Brown VA Medical Center, 820 South Damen Avenue, 4th Floor
Damen Pavilion, Chicago, IL 60612.
E-mail address: raza.hussain@va.gov
Dent Clin N Am 65 (2021) 43–56

0011-8532/21/Published by Elsevier Inc.
44 Hussain et al
environment for the titanium and synthetic fixtures associated with the implant. It has
been well established, however, that a significantly smaller amount of bacteria is
needed to create inflammation, and subsequently infection, around a dental implant
compared with a natural tooth.1
Bacteria such as streptococci, lactobacilli, staphylococci, and corynebacteria along
with large numbers of anaerobes, such as the bacteroides species, which normally
make up the healthy oral flora of most humans, can turn into pathologic entities result-
ing in acute or chronic infection. The groves, threads, and irregularities, essential in
osseointegration, could begin to harbor bacteria and then spill their toxic bioproducts
into the periimplant space.2
DIAGNOSIS OF PERIIMPLANTITIS
Unlike periodontal disease, which is well defined and organized into specific cate-
gories, periimplantitis is an ambiguous, and often controversial, term. It is typically
used to describe any “less-than-ideal” condition surrounding a dental implant fixture.
A survey by J. Thakkar and colleagues from the University of Michigan Department of
Oral and Maxillofacial Surgery reported that approximately 62% of respondents
considered periimplantitis a serious issue. Furthermore, 50% thought they did not
receive sufficient training on this subject matter during residency.3 Many clinicians
believe the most important criteria for a diagnosis of periimplantitis are exposure
and gingival recession. Occasionally, a patient may present as asymptomatic with
exposed implant threads, yet inflammation is minimal to nonexistent. This is often
seen in patients who maintain excellent oral hygiene. Conversely, smokers with
poor oral hygiene and a history of periodontal disease are particularly prone to devel-
oping periimplant issues.
In a recent article, Tolstunov describes a situation of progressive buccal bone loss,
occurring in the anterior maxilla after implant placement.4 The clinical presentation is
blueish in color and with granulation tissues or purulent discharge. In the absence of
inflammation, this case does not meet the traditional definition of periimplantitis.
Rather, Tolstunov refers to this presentation as “periimplantosis,” a noninflammatory
diseased state.
The term periimplant mucositis can be used to describe a compromised implant in
its earliest stage. It is often associated with exudate, increased pocket depth, and
Fig. 1. It is obvious from the radiographic appearance of the implant that a diagnosis of
periimplantitis is warranted. Based on the clinical images, however, there is lack of inflam-
mation and the gingival tissue seems healthy and pink, even considering the visible exposed
threads. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
An Update on the Treatment of Periimplantitis 45
progressive bone loss. With early intervention, it may be possible to avoid severe bone
loss, infection, and mobility leading to implant failure (Fig. 1, Table 1).
CONTRIBUTING FACTORS
Keratinized Tissue
The role of keratinized tissue, in relation to both natural dentition and dental implants,
is a controversial topic among clinicians and the absolute necessity is still un-
known.4–22 This type of tissue tends to be more resistant to abrasion and more resilient
when considering its susceptibility to gingival recession. In many cases, its presence
results in decreased probing depths and less plaque accumulation, which limits bac-
terial penetration into the periimplant space. Additional benefits include easier cleans-
ability and increased patient comfort. Alternatively, there are several studies that
confirm implant success in regions with little to no keratinized tissue.11,12,23 Therefore,
it can be concluded that an implant with healthy keratinized tissue is preferable. Those
without are not guaranteed to become compromised but it is more likely and even
more diligent home care is required.
Table 1
Periodontal disease chart
Type Subtype
Gingival diseases Dental plaque-induced gingival diseases
Non–plaque-induced gingival lesions
Chronic periodontitis (previously adult Slight (1–2 mm CAL)
periodontitis) Moderate (3–4 mm CAL)
Severe (>5 mm CAL)
Localized (<30% of sites involved)
Generalized (>30% of sites involved)
Aggressive periodontitis11 (previously early Slight (1–2 mm CAL)
onset periodontitis) Moderate (3–4 mm CAL)
Severe (>5 mm CAL)
Localized (<30% of sites involved)
Generalized (>30% of sites involved)
Periodontitis as a manifestation of systemic Associated with hematological
diseases Disorders
Associated with genetic disorders
Not otherwise specified
Necrotizing periodontal diseases Necrotizing ulcerative gingivitis
Necrotizing ulcerative periodontitis
Abscesses of the periodontium Gingival abscess
Periodontal abscess
Pericoronal abscess
Periodontitis associated with endodontic Combined periodontic-endodontic lesions
lesions
Developmental or acquired deformities and Localized tooth-related factors that modify
conditions or predispose to plaque-induced gingival
diseases/periodontitis
Mucogingival deformities/conditions around
teeth
Mucogingival deformities/conditions on
edentulous ridges
From Nair SC, Anoop KR. Intraperiodontal pocket: An ideal route for local antimicrobial drug de-
livery. J Adv Pharm Technol Res. 2012;3(1):9–15; with permission.
46 Hussain et al
Implant Surface
A rough, hydroxyapatite-coated implant surface, combined with an absence of kerati-
nized gingiva, has been associated with periimplantitis and subsequent bone loss. An
insufficient amount of attached tissue leaves the rough surface exposed, increasing
the chances of implant failure.24,25 A meta-analysis by Esposito and colleagues26
revealed 20% fewer cases of periimplant complications among implants with smooth
surfaces compared with those with rough surfaces.
Implant Location
It has been well established that posterior implants experience greater bone loss than
their anteriorly placed counterparts. The difference amounts to 3.5 times more bone
loss in the posterior, with these implants losing approximately 0.14 mm of bone annu-
ally. Conversely, anterior implants only lose 0.04 mm of bone on average.27 In addition,
the amount of keratinized tissue more profoundly affects implants in the posterior in
terms of soft tissue health.
Restorative Factors
Prosthetic design can play a significant role in both the short- and long-term health of
an implant. Home care can prove to be challenging, even for patients with excellent
oral hygiene, if the restoration is poorly designed.28 Bulky crowns and nonhygienic
embrasures, for example, are extremely difficult to maintain. The crown-to-implant ra-
tio must also be considered when treatment planning in order to avoid excessive
occlusal and lateral forces. Clinicians should reevaluate the occlusal scheme and
consider the placement of additional implants to decrease the occlusal loading if
the fixture becomes compromised. The progression from periimplant mucositis to
periimplantitis and to eventual implant failure is more gradual in cases with these un-
favorable restorations. If recognized early, interventions to impede the periimplant dis-
ease process can be initiated (Figs. 2–4).
Alcohol
The relationship between alcohol and periimplantitis was investigated by Carr and col-
leagues.29 He concluded that mild to moderate consumption led to fewer occurrences
of periimplantitis (12% and 6%, respectively) than heavy consumption, which resulted
in 42% of cases. Based on this study, it was presumed that mild to moderate alcohol
consumption decreases inflammatory markers, leading to improved overall periim-
plant health. The investigators could not determine why heavy consumption of alcohol
led to a nearly 3-fold increase in the rate of periimplantitis. Since the data were incon-
clusive, it remains uncertain whether a topical application of alcohol would be bene-
ficial or if the improved periimplant environment was a systemic effect.
PREVENTION OF PERIIMPLANTITIS
Education and Home Care
Implant candidate selection and patient education are paramount in the long-term
success of the final restoration. Establishing realistic expectations with the patient
before initiating implant therapy is extremely important. It must be made clear that
health and maintenance of an implant is distinctly different from that of a natural tooth.
For example, removal of supragingival plaque is even more critical in maintaining an
implant. Oral hygiene instructions, including various brushing techniques, should be
emphasized and demonstrated by the clinician. Certain anatomic presentations
must also be taken into consideration. Posterior implants frequently lack adequate
Fig. 2. A crown-to-implant ratio of 1:1 and posterior maxillary position of these implants
makes them prone to periimplantitis and eventual failure. (Courtesy of Raza A. Hussain,
BDS, DMD, FACS, Chicago, IL.)
keratinized, which can make oral hygiene challenging for the patient. If this is the case,
a pulsatile oral irrigation device should be provided. The patient must be instructed to
use the lowest setting possible to removal all supragingival debris. The goal of this de-
vice is to decrease bacterial burden rather than remove intrasulcular calculus, which
can be accomplished during hygiene visits.30
In-Office Implant Maintenance

The hygiene team must understand the armamentarium and techniques necessary in
maintaining dental implants. Instruments used in routine care, such as ultrasonic and
metallic scalers, should be avoided as they have been proved to damage the delicate
implant surface.31 Any imperfections created can promote bacterial growth, which
Fig. 3. Large, overcontoured crowns with large occlusal tables. Also note the frenal attach-
ments and lack of keratinized tissue. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chi-
cago, IL.)
48 Hussain et al
Fig. 4. Close-up image of the same implants after restoration. Note the bulky crowns and
progressive bone loss. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
subsequently results in periimplantitis, bone loss, and possible implant failure. Alterna-
tively, ultrasonic scalers with plastic sleeves or nonmetallic tips are preferred for
implant maintenance. Hand instruments made of graphite, nylon, or plastic, along
with those coated in Teflon are also recommended. In addition, titanium curettes
are appropriate for scaling, and the implant can be polished with a rubber cup and
pumice.32–34 A smooth, flawless implant surface is important in the prevention of pla-
que accumulation and periimplant bacterial colonization.
In the case of the patient with clinically evident perimucositis, without associated
bone loss, a deep pseudopocket often exists. Typically, the tissue is flaccid with
poor tone, allowing food and plaque to collect along the implant surface. Unlike a
healthy implant, which requires gentle maintenance, these pockets require a deeper,
more extensive debridement, similar to scaling and root planing, with the instrumen-
tation listed earlier. Once the deposits are removed, the desired outcomes are
increased tissue tone, decreased bacterial burden, and elimination of a passage in
which bacteria can accumulate. In some instances, however, tissue redundancy re-
curs and must be treated through surgical methods, such as gingivectomy or gingivo-
plasty (Fig. 5).
Intervention
The International Congress of Oral Implantologists (ICOI) developed a table to delin-
eate and evaluate the health of a functional dental implant. It categorizes an implant
as having either (1) optimal health, (2) satisfactory health, (3) compromised health,
or (4) failure. If an implant falls into group II or III, clinical intervention may be possible
in order to decrease progression of periimplantitis and thereby salvage the ailing
implant (Table 2).
Patients with implants of satisfactory health experience no discernible pain or
tenderness on function, palpation, or percussion. There is no mobility in any direction
with loading forces of 500 g or less. Radiographs typically reveal between 2 mm and
4 mm of bone loss from the time of implant placement. The coinciding probing depths
are usually in excess of this due to the pseudopocket that often forms in these circum-
stances. Intervention for these cases include occlusal stress reduction, frequent hy-
giene visits, and possible reduction surgery.
Fig. 5. A standard ultrasonic scaler tip with and without the protective nonmetallic cover.
(Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
Table 2
Health scale for dental implantsa
Implant Quality Scale

Group Clinical Conditions
I. Success (optimum health) a. No pain or tenderness on function
b. 0 mobility
c. <2 mm radiographic bone loss from initial surgery
d. No exudates history
II. Satisfactory survival a. No pain on function
b. 0 mobility
c. 2–4 mm radiographic bone loss
d. No exudates history
III. Compromised survival a. May have sensitivity on function
b. No mobility
c. Radiographic bone loss >4 mm (<1/2 of implant body)
d. Probing depth >7 mm
e. May have exudates history
IV. Failure (clinical or Any of following:
absolute failure) a. Pain on function
b. Mobility
c. Radiographic bone loss >1/2 length of implant
d. Uncontrolled exudate
e. No longer in mouth
a
International Congress of Oral Implantologists, Pisa. Italy. Consensus Conference. 2007.
From Misch CE, Perel ML, Wang H-L, et al. Implant success, survival, and failure: the International
Congress of Oral Implantologists (ICOI) Pisa Consensus Conference. Implant Dent. 2008;17(1):8;
with permission.
50 Hussain et al
Implants classified by the quality scale as “compromised survival” often exhibit mild
to moderate periimplantitis with associated bone loss of up to 50% radiographically.
These cases are also defined by the presence of bleeding, periimplant pocketing, and
purulent drainage. Despite these conditions, the patient typically does not experience
any pain on function and may only present with slight tenderness to percussion and
palpation. Bone loss is greater than 4 mm, and probing depths are in excess of
7 mm. These circumstances can be mitigated with open debridement, implantoplasty,
chemical/antibiotic applications to the implant surface, and regrafting with primary
closure and return for reexposure. The patient must be appropriately consented and
informed that these measures are a final attempt at salvaging the compromised
implant.
The type of intervention necessary should be considered on a case-by-case basis,
with factors, such as age, taken into account. In certain situations, removal of the
failing implant with regrafting and replacement is a more predictable option. For pa-
tients who cannot tolerate invasive salvage surgery, the use of titanium tubes has
proved to be beneficial. J. Woo and colleagues35 described the technique of sliding
this smooth titanium sleeve over the exposed rough threads in an attempt to maintain
the severely compromised implant.
Based on guidelines set forth at the 2007 ICOI, the scenario discussed earlier would
fall into the category of compromised health. The patient was not in pain and no move-
ment was noted, yet the bone loss and exudate would indicate that some type of inter-
vention to prevent disease progression would be indicated. In the past, the likely
course of treatment would have involved implant removal, regrafting, and reimplanta-
tion (Figs. 6–8).
TECHNIQUE FOR IMPLANT SALVAGE
Before initiating implant salvage, the prosthetic fixture and abutment will need to be
removed. Ideally, this has been completed by the restorative dentist and only a sur-
gical cover screw will be in place. The purpose of this cover screw is to promote soft
tissue coverage over the compromised implant. The role of soft tissue coverage is
critical in obtaining primary closure over the implant after salvage has been
attempted.
Fig. 6. These images clearly depict how an implant is more prone to structural bone loss as
compared with natural dentition. The images were taken approximately 2 years apart. The
teeth show stable bone level; however the implant fixture has been preferentially affected
by the process of periimplantitis. At presentation the implant was stable and the patient
had little to no complaints from the region. The bone loss was discovered incidentally on
routine follow-up radiographs. On probing there was bleeding and exudate expressed
from the sulcus. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
Fig. 7. Radiograph depicting 3 to 4 mm of bone loss from CEJ of adjacent dentition. Implant
has no associated mobility, pain, and minimal periimplant inflammation. CEJ, cemento-
enamel junction. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
Fig. 8. Appearance 2 weeks after removal of restorative components and placement of

cover screw. Note the improved gingival health and lack of inflammation. (Courtesy of
Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
52 Hussain et al
Fig. 9. All granulation tissues should be removed before implant surface preparation. Some
noted on distal in this image. (Courtesy of Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
Once the patient presents with healed soft tissue and minimal inflammation, the
clinician can proceed with implant salvage surgery. The initial step involves wide expo-
sure of the entire surgical field. The defect is typically circumferential, and significant
reflection of both the buccal and lingual flaps is required. After the soft tissue is re-
flected and the implant can be visualized completely, all granulation tissue must be
debrided. This may be challenging, as this tissue is particularly adherent to the implant
surface and grows into every thread and porosity. Aggressive mechanical curettage
with hand instruments, and often ultrasonic scalers, should be used in order to ensure
complete removal. The high-volume irrigation from the ultrasonic assists in decreasing
the bacterial burden around the implant. Once the implant surface has been cleansed
of all visible granulation tissue, the next step is surface decontamination and biofilm
removal. The biofilm of a compromised typically consists of Bacteroides,
Fig. 10. Tension-free, primary closure achieved. Note the placement of a resorbable mem-
brane to bolster and protect against any perforations. (Courtesy of Raza A. Hussain, BDS,
DMD, FACS, Chicago, IL.)
Fig. 11. Radiograph of titanium mesh in place around attempted salvage site. (Courtesy of
Raza A. Hussain, BDS, DMD, FACS, Chicago, IL.)
Fusobacterium, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis,

and Prevotella intermedia.36 Removal can be accomplished with citric acid 40% ph1
application or an antibiotic slurry with proxy brush to prevent release of antigens and
reaction with local tissues.
In addition, the surrounding bone should be prepared in anticipation of bone graft
placement. Before insertion of the grafting material, the clinician must ensure
adequate soft tissue mobilization. Tension-free primary closure is imperative and
may require significant undermining of the flap and periosteal releasing incisions.
This must be completed in order to prevent displacement of these devices. The mem-
brane, composed of nonresorbable titanium mesh or titanium reinforced polytetra-
fluoroethylene, allows for rigid protection of the newly grafted site. Significant soft
tissue laxity is required to minimize exposure of this membrane and prevent the
salvage surgery from becoming compromised.
The type of grafting material used for implant salvage varies widely among clini-
cians. Autogenous, allogenic, bovine, and synthetic are all suitable options in cases
where periimplantitis has induced bone loss. After all granulation tissue, compromised
bone, and biofilm have been removed, the graft material is worked along and pressed
into all available spaces. The entire implant should be covered by the graft and then
the selected nonresorbable membrane is placed over top. The mobilized soft tissue
can then be reapproximated and tension-free, primary closure achieved.
Occasionally, the clinician may observe small voids or fenestrations in the soft tis-
sue, which can be remedied by laying a resorbable collagen membrane over the tita-
nium mesh, thereby decreasing the chances of propagation (Figs. 9–12).
Fig. 12. (A) Presalvage. (B) Postsalvage in function 3 years. (Courtesy of Raza A. Hussain,
BDS, DMD, FACS, Chicago, IL.)
54 Hussain et al
SUMMARY
Dental implants have become a routine solution for replacing missing teeth over the
years, yet it is important for patients to understand they are not equivalent to their nat-
ural dentition. Reasonable expectations should be established before placement and
patients should be provided with the tools they need to maintain their new teeth. Cli-
nicians must be prepared for complications, however, that may arise over time. Each
compromised implant case, whether simple or complex, requires an individualized
and well-organized plan of action to resolve the issue. Although further research is
warranted, considering the diagnosis and management of periimplantitis remains
controversial, various degrees of intervention have proved to be effective, leading to
many successful outcomes for ailing implants.
CLINICS CARE POINTS

! Periimplantitis is a complex and more commonly arising issue.
! Patient education and involvement are paramount.
! Early recognition and interceptive treatment can improve outcomes.
! In cases where implant stability is present salvage of the compromised fixture
may be attempted.
! Implant mobility requires removal and possible replacement.
DISCLOSURE
Dr M. Miloro is a consultant for Axogen. The other authors have nothing to disclose.
REFERENCES
1. Quirynen M, deSote M, Steeberghe D. Infectious risks for oral implants: a review

of the literature. Clin Oral Implants Res 2002;13:1–19.
2. Nevins M, Langer B. The successful use of osseointegrated implants for the treat-
ment of the recalcitrant periodontal patient. J Periodontol 1995;66:150.
3. Thakkar J, Oh J, Inglehart S, et al. Etiology, Diagnosis and Treatment of Peri-Im-
plantitis- a National Survery of AAOMS Members. J Oral Maxillofac Surg 2017;
75(10):e355–6.
4. Tolstunov L. Peri-implant disease: peri-implantitis versus “peri-implantosis”.
5. Lang NP, Loe H. The relationship between the width of keratinized gingiva and
gingival health. J Periodontol 1972;43:623–7.
6. Wennstrom JL. Lack of association between width of attached gingiva and devel-
opment of soft tissue recession: a 5 year longitudinal study. J Clin Periodontol
1987;14:181–4.
7. Kennedy J, Bird W, Palcanis K, et al. A longitudinal evaluation of varying widths of
attached gingiva. J Clin Periodontol 1985;12:667.
8. Miyasato M, Crigger M, Egelberg J. Gingival condition in areas of minimal and
appreciable width of keratinized gingiva. J Clin Periodontol 1977;4:200–9.
9. Stetler K, Bissada NF. Significance of the width of keratinized gingiva on the peri-
odontal status of teeth with subgingival restoration. J Periodontol 1987;58:
696–700.
10. Valderhaug J, Birkeland JM. Periodontal conditions in patients 5 years following
insertion of fixed prostheses. Pocket depth and loss of attachment. J Oral Rehab
1976;3:237–43.
A re Th e re A l t e r n a t i v e s t o
Invasive Site Development
f or D enta l I mp l an t s ? Pa rt I
a, b
Vaughan J. Hoefler, DDS, MBA *, Mohanad Al-Sabbagh, DDS, MS
KEYWORDS
! Dental implants ! Bone augmentation ! Bone grafting ! Implant site
! Short dental implants ! Narrow diameter implants
KEY POINTS
! Alternatives to invasive site development for dental implant therapy include the use of
short dental implants and narrow diameter implants.
! These alternatives have the advantages of reduced morbidity, fewer complications,
shorter treatment time, lower costs, and better patient acceptance.
! Short dental implants may provide comparable outcomes to standard length implants in
vertically augmented sites.
! Narrow diameter implants can be a valid alternative to standard diameter implants in hor-
izontally grafted bone.
INTRODUCTION
Dental implant therapy is a widely accepted, long-term treatment option to restore

edentulous sites.1–4 However, the most favorable outcomes have been reported in
sites with adequate native bone or with minor bone regenerative procedures.5,6 Place-
ment of longer and wider implants was initially preferred to improve bone-to-implant
contact, primary stability, crown-to-implant ratio,7 esthetics, hygiene, and restoration
support.8,9 However, edentulous sites are often characterized by inadequate bone
quality and quantity.10–12
Implant sites with deficient bone often have to be augmented laterally, vertically, or a
combination of both to achieve ideal 3-dimensional implant positioning that is pros-
thetically driven.13,14 However, bone grafting increases the cost, time, and morbidity

a
Department of Oral Health Practice, Division of Prosthodontics, University of Kentucky Col-
lege of Dentistry, D630 UK Chandler Hospital, 800 Rose Street, Lexington, KY 40536-0297, USA;
b
Division of Periodontology, Department of Oral Health Practice, University of Kentucky College
of Dentistry, D-438 Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0927, USA
E-mail address: vaughan.hoefler@uky.edu
Dent Clin N Am 63 (2019) 475–487

476 Hoefler & Al-Sabbagh
of treatment.15 Tooth loss and edentulism also disproportionately afflict low-income

populations, for which the cost of both bone augmentation and restoration of edentu-
lous sites with dental implants may be prohibitive.16 This finding has led to the search
for less invasive treatment options with greater patient acceptance.6,17
The broader use of 3-dimensional imaging techniques and computer-aided guided
surgery, as well as the introduction of stronger implant alloys with improved surface
structures, has led to the development of alternative treatment protocols. These alter-
natives include the use of shorter, narrower, and tilted implants to avoid bone grafting,
as well as fewer implants to restore edentulous arches.
In Part I, we investigate the following questions: (1) Are short dental implants (SDIs) a
reasonable alternative to vertically augmented bone with standard length implants? (2)
Are narrow diameter implants (NDIs) a valid alternative to laterally augmented bone
with standard diameter implants? The use of tilted and fewer implants as an alternative
to conventional treatment protocols will be discussed in Part II.
ARE SHORT DENTAL IMPLANTS A REASONABLE ALTERNATIVE TO VERTICALLY

AUGMENTED BONE WITH STANDARD LENGTH IMPLANTS?
When an implant site is completely devoid of bone, missing bone volume must be sur-
gically regained before implant placement. However, there are times when a site has
insufficient alveolar ridge height for standard length implants, but is otherwise adequate
for SDIs. The use of SDIs is controversial. Higher failure rates have been associated with
the use of SDIs in some studies,18–24 whereas other reports indicate similar outcomes
regardless of implant length.25–32 Factors that explain these conflicting outcomes
include a lack of standardized definitions for SDIs, and implant primary stability and sur-
gical protocols. The skill and experience level of the clinician, implant surface character-
istics, and bone quality are additional contributing factors that influence the predictability
of SDIs.7,33–36
Short Dental Implant Definition

The maximum length of an SDI in the published literature remains controversial, with
proposals ranging from 5 to 11 mm.26,36–40 The length of the implant has been defined
as the distance from the platform to the apex.8 However, the intrabony length (ie, the
distance from the apex to the most coronal bone-to-implant contact) has a greater
relevance. Intrabony length represents the height of the implant that is anchored in
bone and determines how external forces are transmitted to surrounding bone.35,41
The first European Association of Osseointegration consensus conference in 2006
defined SDI as an implant fixture with an intrabony length of 8 mm or less.39 This
SDI definition is used in this article because it is gaining acceptance and been adopted
in a number of recent studies and reviews.30–32,42
Surgical Protocol and Primary Stability

Some studies that reported lower survival rate of SDI used a standard surgical protocol
regardless of bone density.21,43,44 Such protocols, often using tapping and counter-
sinking, may have resulted in implants with reduced primary stability. Other publica-
tions reported favorable clinical outcomes for SDIs when modified surgical protocols
that ensured greater primary stability in sites with lower bone quality were used.45,46
Clinician Experience
The clinician’s skill and experience have been postulated to be factors affecting SDI
outcomes.7,39,47 A systematic review compared survival and complications for
Alternatives to Invasive Site Development 477
implant-supported prostheses of current studies (studies completed after 2000) with

studies published in 2000 or prior years.48 Higher implant survival rates and lower re-
ported technical, biological, and esthetic complications were found in the more cur-
rent studies. The authors concluded that the learning curve has a positive impact
on implant clinical outcomes.
As an example, a retrospective study reported an 88% implant cumulative sur-
vival rate (CSR) over 5 years for 17 patients treated with SDI-retained overdentures
from 1989 to 1993.10 The identical clinical protocol was followed by the same au-
thors via a randomized, controlled trial in 2003. They reported a 100% CSR at
12 months.41 Although there was a difference in the duration of the reporting
period between these 2 studies, the outcomes are comparable, because 7 of the
8 failures in the earlier study occurred in the initial healing period, before prosthetic
loading.
Short Dental Implant Surface Structure

Rough textured implant surfaces have been recommended by some authors because
they provide greater bone-to-implant contact and higher removal torque.49,50 A recent
systematic review reported a higher CSR for SDIs with rough surfaces.33 In contrast,
studies documenting increased numbers of SDI failures used machined surface im-
plants.19,21,24,51–53 Several studies indicated that the implant length did not influence
survival when SDIs with textured surfaces were used.54–57 This finding suggests that
SDIs with a more favorable surface topography may have greater success than im-
plants with machined surfaces.58
Bone Quality
Poor bone quality as well as low bone volume are risk factors for implant failure,
particularly with SDIs.34,43 Of the 2 factors, bone quality has a greater impact on
SDI survival than bone quantity.59 Short implants are mostly used in the posterior re-
gions,33 and the posterior maxilla in particular has the poorest quality of bone.40 A
study compared the implant survival of SDIs and standard implants in poor quality
bone. SDIs had failure rates of 78%, whereas standard length implants had a failure
rate of 0% in the most unfavorable quality and shape of bone.51 Although the differ-
ence was not significant owing to low patient enrollment, SDIs were used in dispro-
portionately high numbers in this study in sites with low volumes of poor quality
bone.
Short Dental Implant Outcomes for Fixed Dental Prostheses

A multicenter, randomized, controlled trial compared SDIs with standard length im-
plants placed in vertically augmented bone of the posterior maxilla and restored
with single crowns.60,61 At 3 years, there were no reported differences between the
2 groups with respect to implant survival or periimplant bone loss.61
Another research group compared SDIs with standard length implants placed in
vertically augmented bone in posterior sites of both arches.31,55,56,62 Significantly
more complications occurred with grafts in mandibular sites, and greater periimplant
marginal bone loss (MBL) was associated with longer implants in grafted sites in both
arches compared with SDIs.56,62 Although these reported outcomes suggest a ther-
apeutic advantage for SDIs, the weaknesses of these studies include short follow-up
periods ("5 years), small sample sizes, and procedures that were performed by a
single, highly skilled and experienced clinical research group. These limitations
should be considered before forming a generalized conclusion regarding the use
of SDIs (Fig. 1).
Fig. 1. (A) SDIs (6 mm) placed in the posterior mandible to avoid vertical augmentation and
placement of standard length implants. (B) Adequate crestal bone stability present after
5 years of function.
Short Dental Implant as Abutments for Mandibular Implant Overdentures

The 2-implant retained overdenture is the standard of care for the edentulous
mandible.63 In contrast, maxillary implant-assisted overdentures are associated
with lower rates of implant survival and a greater frequency of prosthetic complica-
tions.64,65 In a prospective cohort study, 19 functionally dependent elderly adults
with conventional dentures received 2 SDIs in the canine regions of their edentulous
mandibles.66 After 6 to 8 weeks of healing, the SDIs received Locator attachments
(Zest Dental Solutions, Carlsbad, CA) which were retrofitted to the mandibular com-
plete dentures. Implant survival was 94.7% at 5 years, with acceptable periimplant
bone loss and other soft tissue biological parameters. The limitations of this study
included a small study cohort, high levels of dropouts, and the lack of a comparison
group. However, it demonstrates that cognitive decline and the inability to provide
self-care may not be contraindications or risk factors for SDIs. A 10-year study fol-
lowed 49 patients with severely atrophic mandibles that were restored with fixed or
removable full-arch prostheses retained by 260 SDIs.67 Seventeen implants failed
over the study period with a CSR of 92.3%.
Short Dental Implants Outcomes for Full-Arch Fixed Dental Prostheses

Studies comparing SDIs with longer implants in vertically augmented bone for the sup-
port of full arch fixed dental prostheses are lacking. One retrospective study reported
outcomes for 43 patients with edentulous maxillae rehabilitated with fixed prostheses
supported by 172 short and long implants following the all-on-4 treatment concept.68
After an average observation period of 3 years, 3 short and 3 long implants were lost
with a CSR of 95.7% and 95.4% for short and all implants, respectively. MBL for short
implants at 3 years was 1.25 mm, with no significant differences in bone loss between
the groups. The limitations of this study included the use of outcomes from an individ-
ual clinical center as well as a short follow-up periods. In addition, SDIs were splinted
to standard and longer length implants in the same arch in many patients. These fac-
tors should be considered before generalizing conclusions to full arch fixed dental
prostheses supported entirely by SDIs.
ARE NARROW DIAMETER IMPLANTS A VALID ALTERNATIVE TO LATERALLY

AUGMENTED BONE WITH STANDARD DIAMETER IMPLANTS?
Owing to volumetric bone loss after tooth extraction, lateral ridge augmentation is
often performed before or simultaneously with implant placement. Although bone
grafting is a common and a predictable treatment, it is associated with higher levels of

complications and increased expense. Therefore, NDIs have been used as a less inva-
sive alternative to laterally augmented sites with standard implant diameters.
Implant diameter is the maximum cross-sectional dimension within the intrabony
length of an implant. It is measured from the peak of the widest thread to the same
point on the opposite side of the implant.8 Each implant system has its own inventory
of diameters and lengths, with most manufacturers offering narrow, standard, and
wide diameter implants.69
Implant diameter selection should be steered by site-specific surgical and pros-
thetic requirements. Surgical considerations include the location of the surgical site,
the volume of residual bone, the level of primary stability, and the proximity to adjacent
teeth and surrounding vital structures. The implant should engage as much crestal and
buccolingual cortical bone as possible,70 with at least 1 mm of residual bone adjacent
to the implant surface.9,71,72 Prosthetic factors include the planned occlusion, gingival
esthetics, emergence profile, and the prosthesis design such as the size of the tooth or
teeth to be replaced.9,73
Narrow Diameter Implant Definition

Implants with diameters of 3.75 mm and larger are widely regarded as standard or reg-
ular diameter implants.9,70,71,74 However, the definition of an NDI remains controversial.
The terms reduced diameter, narrow diameter, small diameter, microimplants, and mini-
implants are used interchangeably with overlap in their definitions across studies.72,75–80
A lower narrow diameter threshold of less than 3.0 mm has been proposed in systematic
reviews by some authors,79,81 whereas others agree with 3.5 mm or less as the upper
diameter limit.72,81,82 For this reason, implants with diameters that fall within the range
of 3.0 to 3.5 mm are gaining acceptance for meeting the NDI criteria.81
Narrow Diameter Implant Limitations

Several factors should be considered before selecting an NDI. NDIs have biome-
chanical limitations relative to implants with wider diameters.71 Although NDIs are
significantly narrower than implants with standard diameters, they are subject to
the same stresses under loading. For this reason, the material and design of
NDIs must fulfill similar demands for strength and stability.83 The thin fixture wall
around the abutment or screw, resulting from the decreased implant diameter,
can increase the risk for fixture or screw fracture.84 In addition, NDI abutments
have decreased surface areas relative to standard designs. This characteristic
may result in greater numbers of prosthetic complications such as retention loss
and screw loosening.78 Finally, NDIs purportedly are at greater risk for fatigue fail-
ure than standard and wide diameter implants, particularly in posterior areas sub-
ject to high occlusal loads.70,77,84
NDIs were originally designed for the replacement of teeth with small cervical diam-
eters, such as maxillary lateral and mandibular central and lateral incisors, as well as
for implant sites with limited interdental space78,84,85 (Fig. 2). It is recommended that
the diameter of the implant should be slightly less than that of the crown for single
tooth restorations.9 A single mandibular incisor has a cervical diameter of 3.5 mm,
which is ideally suited for an NDI.71 However, maxillary and mandibular premolars
and molars have diameters that exceed twice those of NDIs.71 The nonjudicious
use of NDIs for these situations can result in unsightly, overcontoured restorations
with large gingival embrasures that lead to plaque accumulation, food impaction, peri-
implant soft tissue inflammation, and gingival recession, all of which can contribute to
decreased implant survival.86
Fig. 2. (A) Limited mesiodistal space (5-mm interradicular distance at narrowest dimension)
after comprehensive orthodontic treatment. (B) Narrow diameter Straumann implant at site
after 1 year of function.
Narrow Diameter Implant and Anterior Full-Arch Fixed Dental Prostheses

Anterior NDI-supported fixed dental prostheses must be able to withstand the func-
tional forces of mastication and occlusion, as well as meeting esthetic requirements.
This means that the implant restoration is expected to provide appropriate protrusive
and lateral guidance for the patient without fracture or displacement.
In a prospective, single-arm study on NDIs that replaced missing maxillary lateral
and mandibular incisors with single implant crowns,87,88 a 95.9% implant survival
rate form the time of placement to the time of loading and 100% implant survival
rate from the time of loading up to a 5-year follow-up was reported. The mean change
in MBL from the day of the surgery to 5 years was #0.15 mm. Although 8.43% of the
implants lost more than 1 mm of crestal bone, there was no measurable bone loss for
50.6% of the implants after 5 years. A number of technical complications were re-
ported in this study. Seven implants in 7 patients experienced abutment fracture,
and retention loss of 6 crowns occurred for 6 patients. In some cases, patients lost
the crowns more than once.
A second prospective, single-arm study reported similar outcomes for NDIs that
replaced congenitally missing maxillary lateral and mandibular incisors.89 An overall
96.8% CSR at 36 months was reported, and none of the implants were lost after
loading. Gingival recession was negligible, and the mean change in MBL from implant
insertion to 36 months was a loss of 0.21 mm. Technical complications were also
similar, with 5 fractured abutments, 1 loose abutment screw, and 8 crowns that
needed to be recemented.
Despite these reported complications, the investigators in both previous studies
demonstrated acceptable biological outcomes and implant survival over a period of
3 to 5 years when NDIs were used to restore maxillary lateral and mandibular incisor
sites.87–89 Although prosthetic complications were reported in the 2 studies cited, a

direct comparison between NDIs and anterior single crowns supported by standard
diameter implants in similar sites was not possible owing to the lack of comparison
groups.
A longitudinal study used 20 NDIs at the maxillary lateral incisor sites of 10 patients
to support 4-unit partial fixed dental prostheses replacing numbers 7 to 10.90 After
5 years, no implants were lost and there were no reported technical or biological com-
plications. Marginal bone levels were stable over 5 years for all implants, gingival
recession was negligible, and overall patient satisfaction was 96.9%. Although the re-
sults of this study illustrate the usefulness of NDIs in multiunit fixed applications, the
expertise and clinical skills of this research group should be given consideration
before adopting this treatment concept.
Narrow Diameter Implants and Posterior Full-Arch Fixed Dental Prostheses

Posterior natural teeth have cervical diameters much greater than the diameters of
NDIs. The occlusal load from the cantilever created by the increased occlusal surface
diameter relative to the NDI diameter increases the risk for overload on abutments,
abutment screws, and fixtures.70,91
A retrospective study on 247 NDIs in posterior sites (follow-up of "11 years) re-
ported a CSR of 95.1%.83 This study did not report prosthetic complications. A sec-
ond retrospective study on 98 NDIs placed in premolar and molar sites and restored
with single crowns and short span multiunit fixed dental prostheses reported a 96.9%
implant CSR at 8 years.86 There were no implant fractures or abutment screw loos-
ening or fracture. The most common mechanical complication was ceramic veneer
chipping (18.4%) and retention loss (5 single crowns). Although 84.6% of the patients
were satisfied with restorative function, the main reason for dissatisfaction was
gingival recession and food impaction around the restorations. A third study reported
the 5- to 10-year outcomes on NDIs placed in anterior as well as posterior sites.92 An
overall CSR of 92.3% was reported at 124 months. In this study, posterior sites
demonstrated increased risk for failure and retention loss was the most common pros-
thetic complication.
Narrow Diameter Implants as Overdenture Abutments

The mandibular edentulous arch is often severely resorbed and characterized by nar-
row crestal bone. A 2-implant overdenture using standard diameter implants may
require either surgically reducing the height of the ridge to a level of adequate bucco-
lingual width, or lateral bone augmentation followed by implant surgery. In addition,
patients requesting this treatment are often elderly, under the care of a physician,
and have limited self-care capability.66 Two-implant overdentures retained by NDIs
can be the most conservative treatment alternative for these patients.
A longitudinal study reported implant and prosthesis outcomes at 3 and 5 years.92,93
The majority of implant sites showed minimal change in crestal bone and an implant
CSR of 97.8%. Complications requiring intervention included prosthesis fracture, peri-
implant inflammation and infection, and replacement of the retentive matrix.92
A second NDI study that included 24 two- and four-implant overdentures reported
an implant CSR of 92.3% at 124 months.94 Another study investigating immediate
versus delayed loading of mandibular NDI overdentures reported 98% implant CSR
and very few prosthesis complications at 12 months.95
The lack of studies using a comparison group make it difficult to directly compare
2-implant mandibular overdentures retained by NDIs to overdentures retained by
standard diameter implants. However, reported clinical outcomes for NDIs are
acceptable, and the minimally invasive treatment approach makes this option partic-
ularly suitable for patients who are at higher surgical risk with limited economic
means.
SUMMARY
Short and narrow implants have proven to be successful within certain applications.
However, they still require a minimum volume and quality of bone to succeed. Ques-
tions regarding the long-term effects of MBL and fatigue on SDIs and NDIs success
and survival remain unanswered.
There are clear indications for surgical site development, including gross bone de-
ficiencies in the esthetic zone, severe alveolar ridge resorption resulting from pro-
longed periods of edentulism, and congenital or acquired defects that prevent
proper 3-dimensional implant positioning. To this end, considerable effort has been
directed toward developing methods for ridge augmentation. Despite progress in
regenerating lost bone, augmentation procedures are expensive, invasive, technically
demanding, and accompanied by greater morbidity and longer treatment times.
Furthermore, although bone regeneration is predictable over the short term, the
long-term volumetric stability of grafted bone is not well-documented. For these rea-
sons, alternatives to invasive site development should always be considered when
planning implant care.
REFERENCES
1. Hjalmarsson L, Gheisarifar M, Jemt T. A systematic review of survival of single im-

plants as presented in longitudinal studies with a follow-up of at least 10 years.
Eur J Oral Implantol 2016;9(Suppl 1):S155–62.
2. Wyatt CC, Zarb GA. Treatment outcomes of patients with implant-supported fixed
partial prostheses. Int J Oral Maxillofac Implants 1998;13(2):204–11.
3. Chrcanovic BR, Kisch J, Albrektsson T, et al. A retrospective study on clinical and
radiological outcomes of oral implants in patients followed up for a minimum of 20
years. Clin Implant Dent Relat Res 2018;20(2):199–207.
4. Goodacre BJ, Goodacre S, Goodacre CJ. Prosthetic complications with implant
prostheses (2001-2017). Eur J Oral Implantol 2018;11(Suppl 1):S27–36.
5. Albrektsson T, Zarb G, Worthington P, et al. The long-term efficacy of currently
used dental implants: a review and proposed criteria for success. Int J Oral Max-
illofac Implants 1986;1(1):11–25.
6. Thoma DS, Cha JK, Jung UW. Treatment concepts for the posterior maxilla and
mandible: short implants versus long implants in augmented bone.
J Periodontal Implant Sci 2017;47(1):2–12.
7. Nisand D, Renouard F. Short dental implant in limited bone volume. Periodontol
2000 2014;66(1):72–96.
8. Lee JH, Frias V, Lee KW, et al. Effect of implant size and shape on implant suc-
cess rates: a literature review. J Prosthet Dent 2005;94(4):377–81.
9. Lazzara RJ. Criteria for implant selection: surgical and prosthetic considerations.
Pract Periodontics Aesthet Dent 1994;6(9):55–62.
10. Stellingsma C, Meijer HJ, Raghoebar GM. Use of short endosseous implants and
an overdenture in the extremely resorbed mandible: a five-year retrospective
study. J Oral Maxillofac Surg 2000;58(4):382–7 [discussion: 387–8].
11. Chiapasco M, Zaniboni M, Boisco M. Augmentation procedures for the rehabili-
tation of deficient edentulous ridges with oral implants. Clin Oral Implants Res
2006;17(Suppl 2):136–59.
A re Th e re A l t e r n a t i v e s t o
Invasive Site Development
for Dental Implants? Part II
a, b
Vaughan J. Hoefler, DDS, MBA *, Mohanad Al-Sabbagh, DDS, MS
KEYWORDS
! Tilted implant ! All-on-4 ! Atrophic ridge ! Site development ! Zygomatic implant
KEY POINTS
! Alternatives to invasive site development for dental implant therapy include the use of
tilted dental implants, zygomatic implants, and fewer numbers of implants. These alterna-
tives have the advantages of reduced morbidity, fewer complications, shorter treatment
time, lower costs, and better patient acceptance.
! Tilted implants often eliminate the need for bone grafting.
! Use of tilted and upright implants in combination allows clinicians to predictably rehabil-
itate edentulous arches with a fixed prosthesis supported by as few as 4 dental implants.
! Zygomatic implants, either alone or in combination with upright and tilted maxillary im-
plants, can provide a graftless solution to restore the atrophic edentulous maxilla when
there is inadequate bone for conventional or all-on-4 treatment.
INTRODUCTION
Edentulous sites are often characterized by moderate or advanced ridge resorption

and irregular crestal bone topography, which compromises proper 3-dimensional
implant positioning. If a given site cannot be functionally or esthetically restored
with a dental implant, bone grafting is often needed.1–3 Bone grafting often prolongs
treatment time and increases morbidity and expense. For these reasons, patients pre-
fer less invasive treatment alternatives.4–6
One alternative to bone grafting is the use of tilted implants that engage native bone
with adequate volume, density, and structure to support a fixed restoration. For the

a
Department of Oral Health Practice, Division of Prosthodontics, University of Kentucky,
College of Dentistry, UK Chandler Hospital, D630, 800 Rose Street, Lexington, KY 40536-0297,
USA; b Division of Periodontology, Department of Oral Health Practice, University of Kentucky
College of Dentistry, D-438 Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-
0927, USA
E-mail address: vaughan.hoefler@uky.edu
Dent Clin N Am 63 (2019) 489–498

edentulous arch, a second alternative is to use a combination of four or fewer tilted

and upright implants to support full-arch fixed dental prostheses (FAFDPs). This chap-
ter will address three questions: (1) Are tilted implants a sound alternative to axially
loaded implants placed in grafted edentulous sites? (2) Are 4 or fewer axially loaded
and tilted implants adequate to support a cross-arch fixed prosthesis? (3) Are zygo-
matic implants a viable alternative to invasive bone grafting of severely atrophic eden-
tulous maxillary ridges?
Are Tilted Implants a Sound Alternative to Axially Loaded Implants Placed in
Grafted Sites in Edentulous Arches?
Historically, the use of upright implants (implants placed perpendicular to the plane of
occlusion) was the standard procedure for the rehabilitation of completely edentulous
arches with implant-supported fixed prostheses.7,8 However, this is often not achiev-
able without extensive bone grafting and avoiding vital anatomic structures (eg, the
inferior alveolar nerve, the maxillary sinus, and the nasal cavity).8 The use of tilted im-
plants is an alternative to upright implant placement in grafted bone. Tilted implants
engage the maximum available residual bone in remote sites for enhanced anchorage
and stability.
Guidelines and history
Tilted implants allows fixtures to be placed in any direction targeting native bone.9 For
the edentulous maxilla, these sites include the anterior and posterior walls of the
maxillary sinus, the nasal floor, the nasal spine, the pterygoid process, and the maxil-
lary tuberosity.10,11 The use of tilted implants to avoid bone grafting in the edentulous
maxilla was first described by Mattson et al.10 This study utilized 86 axial and tilted
implants to treat 15 patients who needed bone grafting for conventional axial implant
placement. In the edentulous mandible, a combination of axially loaded and tilted im-
plants can be placed in the interforaminal region to avoid bone grafting in the poste-
rior region. In addition, angulated implants can optimize anchorage, minimize
cantilever length, and maximize interimplant distance.8,12 Maló et al12 restored the
edentulous mandibles of 44 patients with FAFDPs supported by 176 axially and
distally inclined Brånemark implants.12 Maló et al called this the “all-on-4” treatment
concept.12
Advantages of tilted implants
Implant angulations, lengths, and diameters are generally selected to fit within the
boundaries of available bone. A minimum angulation that defines a tilted implant
has not been established. However, a range of 15" to 45" off the vertical axis has
been used to describe tilted implants by several authors.8,12–15 Longer implants are
generally preferred to improve primary stability and engage as much residual bone
as possible.14,15 Most tilted implant diameters fall within the range of 3.3 to
5.0 mm.12,14,16
For implant rehabilitation of edentulous arches with inadequate bone volume, tilted
implants have several advantages over axially loaded implants. The use of longer fix-
tures improves primary stability by engaging more bone.15 The increased distance be-
tween the anterior and posterior restorative platforms created by tilting implants
reduces cantilever length and improves load distribution.8,9 Tilted implants are placed
in residual native bone, eliminating the need for nerve lateralization and bone grafting,
thereby reducing morbidity, expense and treatment time.8,10,11 Finally, tilted implants
with good primary stability and cross-arch distribution can generally be immediately
loaded with a fixed interim prosthesis, while allowing fewer numbers of implants to
be used (Figs. 1–4).12–14
Fig. 1. Full arch implant rehabilitation using axially loaded implants to support FAFDP. (A)
Teeth were diagnosed with severe periodontitis. (B) Bilateral maxillary sinus grafting was
performed before extraction of teeth. (C) All maxillary teeth were extracted, and 6 parallel
implants were placed perpendicular to the occlusal plane and distributed to minimize can-
tilevers and optimize load distribution. (D) Final maxillary and mandibular FAFDPs after
5 years in function.
Outcomes for tilted versus upright implants

There is a scarcity of randomized controlled trials (RCTs) comparing outcomes for pa-
tients treated with upright implants placed in grafted sites with similar groups restored
with tilted implants in nongrafted sites. One of the first forays into this area was by Wid-
mark et al., who reported that in the maxilla, implants placed in native bone had a
higher success rate after five years (87%) than implants placed in grafted sites
(74%).17 A limitation of this study is that although trial implants were positioned to
avoid bone grafting, not all were tilted.17,18
Fig. 2. Rehabilitation of the maxillary and mandibular arches with implant supported fixed
prostheses using tilted implants. The use of tilted implants allows for longer implants to
engage more native bone. This promotes primary stability and eliminates the need for on-
lay, interpositional block grafts, or maxillary sinus grafting. Additional advantages include
reduced treatment time and decreased numbers of implants to support an FAFDP.
Fig. 3. Full-arch fixed dental mandibular prosthesis with 5 implants. The mandibular arch is
square, and the interforaminal area is wide enough to accommodate 5 well-distributed,
axially loaded implants.
Another early study restored maxillary posterior quadrants of 25 partially-edentu-

lous patients with partial fixed dental prosthesis (PFDP) using 101 upright and tilted
implants in nongrafted sites.11 After five years, investigators reported a cumulative
survival rate (CSR) of 95.2% for 42 tilted implants and 91.3% for 59 axial implants.
Prosthesis survival at five years was 100%. A more recent study reported three-
year outcomes for 37 patients restored with a mandibular FAFDP supported by either
four upright implants, or two upright anterior and two tilted posterior implants.16 There
were no reported differences in outcomes between the 2 groups with respect to
implant survival, prosthesis complications, marginal bone loss (MBL), or periodontal
probing depth. Recent systematic reviews pooling data from a number of clinical
studies using tilted implants reported similar findings.9,14,15,19
In summary, tilted implants, placed in tandem or in combination with upright im-
plants, can reduce or eliminate the need for bone grafting, reduce complication risk,
and result in high levels of patient satisfaction when used to restore partially and fully
edentulous jaws.6,9,11,14
Are Four or Fewer Implants Adequate to Support a Full Arch Fixed Prosthesis?
An implant load analysis investigation concluded that as few as four implants may
be adequate for a full-arch fixed prosthesis when the implants are properly posi-
tioned.20 An early application of this finding was the introduction of the all-on-4
Fig. 4. Full-arch fixed dental mandibular prosthesis with 4 implants. The mandibular arch is
V-shaped, and the interforaminal area is narrow. Posterior implants were tilted to avoid the
mental foramina and increase the anteroposterior spread. Four implants (2 axially loaded
implants in the anterior segment of the mandible and 2 tilted implants mesial to the mental
foramina) were adequate to support full a 12-unit FAFDP.
immediate-function treatment concept for the mandible in 2003,12 and the maxilla in
2005.12,21 The all-on-4 immediate-function treatment concept consists of 3 princi-
ples: the use of a combination of upright and tilted implants to avoid bone grafting,
4 implants in each edentulous jaw to support a fixed prosthesis, and immediate
loading.
The all-on-4 treatment protocol uses four upright and tilted implants in the anterior
edentulous jaw to support an immediately loaded, cross-arch fixed prosthesis. Two
anterior implants are axially oriented and placed in the incisor region, while posterior
implants are tilted distally with the implant platform in the second premolar/first molar
area.12,13,21 The goal is to create a large inter-implant distance that minimizes canti-
lever length. To facilitate immediate loading, a modified surgical protocol can be fol-
lowed which achieves an adequate minimum insertion torque depending on the
quality and volume of available bone.12,21
All-on-4 treatment outcomes

Studies comparing the effectiveness of the all-on-4 treatment concept to 5 or more
upright implants in grafted bone are lacking. One retrospective study reported out-
comes for 380 patients restored with 482 immediately loaded FAFDPs supported by
4, 5, and 6 upright and tilted implants.22 The 7-year CSR for the 2081 implants was
97.0%. Implant survival rates for restorations supported by 4, 5, and 6 implants
were 96.5%, 96.6%, and 99.7%, respectively. However, the study protocol dictated
that if an insertion torque of #30 Ncm was achieved for 4 implants, no additional im-
plants were placed. This suggests that when five or six implants were placed they may
have been used in arches with lower bone volume or quality.
Two systematic reviews reported favorable all-on-4 treatment outcomes,13,23
although some of the included studies were of limited quality and short duration. A
long-term clinical study followed 245 patients with edentulous mandibles treated
with the all-on-4 protocol for 10 years.24 The 10-year implant CSR was 94.8%,
with a prosthesis survival rate of 99.2%. Another clinical research group treated
200 maxillary and mandibular arches with 800 implants following the all-on-4 treat-
ment protocol.25 After five-years, an, implant CSR of 97.3% was reported for both
axial and tilted implants. The prosthetic survival rate was 99.0%. Similar outcomes
were reported in another study where 111 patients were treated and followed for
up to 7 years.26 The 7-year implant CSR was 94.5%, while prosthetic survival rate
was 97.8%. The average MBL at 5 years was 1.27 mm for tilted implants and
1.34 mm for axial implants. A study that followed 12 patients for 7 years reported
100% implant and prosthetic survival rates, but documented several prosthetic com-
plications.27 These complications included tooth fracture (6.25%), loosening of pros-
thetic and abutments screws (18.75%), and replacement of denture teeth (18.75%)
Full-arch fixed dental prostheses with 2 or 3 implants

Recent preliminary investigations report 6- and 12-month outcomes for FAFDPs sup-
ported by 2 (fixed-on-2) or 3 (fixed-on-3) implants in the mandible and maxilla, respec-
tively.28,29 A 6-month cohort study placed machined surface implants as parallel as
possible using a flapless surgical approach to treat 25 patients.28 If a minimum inser-
tion torque could be achieved, an immediate, interim fixed prosthesis was placed. In-
vestigators reported 100% implant and prosthesis survival for both arches after
6 months of loading.
Another 12-month study followed a similar treatment protocol (fixed-on-2 for the
mandible, fixed-on-3 for the maxilla), with 40 patients randomly assigned to 1 of 2
treatment arms.29 Group 1 received machined surface implants, while the other
received rough surface implants. For the mandible, implants were placed in both
canine/first premolar positions, while in the maxillae, the 2 distal implants were
placed as far posteriorly on each side of the arch as bone volume allowed. The third
implant site was placed as centrally as possible, preferably in the central incisor re-
gion but, wherever bone volume allowed. Two implants were lost during the reporting
period. Only minor prosthetic complications were reported, including several func-
tional or esthetic complaints associated with the shortened dental arch prosthesis.
Otherwise, significant differences were not detected between the two treatment
groups.
Advantages of these treatment protocols include the ability to simultaneously
treat both jaws in a single, relatively short surgical session, the comparative
ease of fabricating prosthesis frameworks that precisely and passively seat on
fewer numbers of implants, and lower expense associated with fewer implants.
However, while these results suggest that an immediately loaded cross-arch fixed
prosthesis can be supported by only 2 mandibular and 3 maxillary dental implants,
it must be emphasized that this treatment approach has not been validated. For
this reason, it should be considered preliminary and highly experimental at this
time.
It remains unclear as to the optimal minimal number of implants needed to sup-
port a partial or cross-arch fixed prosthesis at this time. Two well-constructed
recent reviews independently concluded that successful outcomes after 5 years
and beyond should be expected for FAFDPs supported by 4 to 6 implants.30,31
However, the number of teeth replaced by an implant-supported FAFDP can be var-
iable, making it difficult to make direct comparisons across studies. Since FAFDPs
generally replace 10 to 12 teeth,22,29,30 the implant-to-replaced-units ratio may be a
more reliable metric for reporting implant and prosthetic survival outcomes in the
future.30
Are Zygomatic Implants a Viable Alternative to Invasive Bone Grafting Severely

Atrophic Edentulous Maxillary Ridges?
Planning the restoration of the edentulous maxilla with an implant-supported
FAFDP can sometimes require addressing profound anatomic challenges. The
combination of a severely atrophic maxillary ridge and large pneumatized maxillary
sinus can lead to inadequate bone volume for vertical or tilted implants.32 In 1998,
Branemark introduced zygomatic implants as an alternative anchorage solution for
cancer patients who had undergone maxillectomy.33 Zygomatic implants are self-
tapping, screw-shaped fixtures that engage the zygomatic buttress to gain primary
stability and anchorage.
Zygomatic implants can be used to restore the severely atrophic edentulous maxilla
without bone grafting and in reduced treatment time.34–36 Zygomatic implants can be
used independently, or in combination with vertical and tilted implants placed in the
anterior and posterior maxilla.34–36 A limitation of zygomatic implants is the surgical
parameters dictated by the anatomy of zygomatic bone.37 Zygomatic implants have
also been associated with increased sinusitis and peri-implant bleeding due to oral hy-
giene difficulties.38
Zygomatic implants are available in 8 different lengths starting from 30 mm to
52.5 mm. They have a 45" angulated head to create a restorative platform that is
accessible to the restorative dentist and parallel to the platforms of vertically placed
implants.36 The apical section, which engages the zygomatic bone, is threaded with
a diameter of 4 mm, while the head of the fixture, which engages the maxillary residual
alveolar ridge, has a diameter of 4.5 mm.
General guidelines for zygomatic implants

Patient selection is determined following a detailed prosthetic and surgical evalua-
tion.35 Bedrossian et al divided the maxilla into three zones, the anterior teeth
(zone 1), the premolars (zone 2), and the molars (zone 3).35,36 The treatment concept
is based on the volume of available bone in each of the 3 zones. If adequate bone is
available in zones 1, 2, and 3 for axially loaded implants, a traditional approach can be
followed using upright implants in the anterior and posterior maxilla.36 If adequate
bone is only available in zones 1 and 2, the all-on-4 treatment concept can be imple-
mented.36 The zygomatic implant concept was developed for patients with insufficient
bone in zones 2 and 3, or lacking bone in all 3 zones. In cases where bone is only avail-
able in zone 1, prosthesis support can be derived from a minimum of 4 implants, 2 pre-
maxillary implants and 2 zygomatic implants.36,37 The angulation of the head of the
zygomatic implant allows the restorative platform of all implants to be in the same
plane.36 Anterior and zygomatic fixtures can then be splinted to support a screw-
retained fixed prosthesis. In situations whereby bone is lacking in all 3 zones, 4 zygo-
matic implants (quad zygoma), 2 in each buttress, can be used to support an
FAFDP.36,37
In summary, when posterior bone is unilaterally or bilaterally lacking in zones 2 and 3
for proper prosthesis support, zygomatic implants can complement upright or tilted
conventional implants. It is also provides a graftless solution when all 3 zones are defi-
cient in bone.
Treatment outcomes with zygomatic implants
A recent systematic review38 investigated the survival and complications of zygomatic
implants over 12 years. The survival rate of zygomatic implants was 95.21%. Implant
failure was only detected in the first six months following surgery, with sinusitis the
main complication at a rate of 2.4%. In three additional reports, zygoma quad and
two zygoma implants coupled with maxillary anterior axial implants have been shown
to have similar survival rates.39–41
SUMMARY
At this time, the literature does not report greater risk for implant loss, MBL, and peri-
implant soft tissue complications for tilted implants compared to upright implants
placed in grafted bone. Moreover, tilted implants create several advantages when
used in combination with upright implants to support FAFDPS. Tilted implants reduce,
and in many cases eliminate, the need for vital structure navigation and complex bone
regenerative procedures. Tilted implants also allow greater spacing between their
restorative platforms relative to upright implants, optimizing load distribution and
allowing prosthesis designs with reduced distal cantilevers. Tilted implants in many
cases allow the use of fewer implants to replace missing teeth in edentulous jaws
restored with FAFDPs.
While the all-on-4 treatment concept appears to provide a predictable
long-term outcome when used to restore edentulous jaws with FAFDPs, there is
no evidence at this time that similar results should be expected with fixed-on-2
or fixed-on 3 protocols. Properly designed controlled trials comparing
different numbers and distributions of implants are needed before adopting these
protocols.
Finally, for the severely atrophic maxilla with pneumatized maxillary sinuses, the use
of zygomatic implants can be the treatment of choice as an alternative to an invasive
bony ridge augmentation and/or maxillary sinus elevation procedure. Long-term RCTs
comparing diverse populations of patients treated with zygomatic implants to similar
groups treated with upright and tilted implants placed in grafted maxillary sites are not
available at this time.
REFERENCES

2006;17(Suppl 2):136–59.
2. Aghaloo TL, Moy PK. Which hard tissue augmentation techniques are the most
successful in furnishing bony support for implant placement? Int J Oral Maxillofac
Implants 2007;22(Suppl):49–70 [Erratum in Int J Oral Maxillofac Implants
2008;23(1):56].
3. Aloy-Prósper A, Peñarrocha-Oltra D, Peñarrocha-Diago M, et al. The outcome of
intraoral onlay block bone grafts on alveolar ridge augmentations: a systematic
review. Med Oral Patol Oral Cir Bucal 2015;20(2):e251–8.
4. Thoma DS, Haas R, Tutak M, et al. Randomized controlled multicenter study
comparing short dental implants (6 mm) versus longer dental implants (11-
15 mm) in combination with sinus floor elevation procedures. Part 1: demo-
graphics and patient-oriented outcomes at 1 year of loading. J Clin Periodontol
2015;42(1):72–80.
5. Felice P, Barausse C, Pistilli V, et al. Posterior atrophic jaws rehabilitated with
prostheses supported by 6 mm long X 4 mm wide implants or by longer implants
in augmented bone. 3-year post-loading results from a randomized controlled
trial. Eur J Oral Implantol 2018;11(2):175–87.
6. Pommer B, Mailath-Pokorny G, Haas R, et al. Patients’ preferences towards mini-
mally invasive treatment alternatives for implant rehabilitation of edentulous jaws.
Eur J Oral Implantol 2014;7(Suppl 2):S91–109.
7. Block MS, Widner JS. Method for insuring parallelism of implants placed simulta-
neously with maxillary sinus bone grafts. J Oral Maxillofac Surg 1991;49(4):
435–7.
8. Krekmanov L, Kahn M, Rangert B, et al. Tilting of posterior mandibular and maxil-
lary implants for improved prosthesis support. Int J Oral Maxillofac Implants
2000;15(3):405–14.
9. Peñarrocha-Oltra D, Candel-Marti E, Ata-Ali J, et al. Rehabilitation of the atrophic
maxilla with tilted implants: review of the literature. J Oral Implantol 2013;39(5):
625–32.
10. Mattson T, Köndell PA, Gynther GW, et al. Implant treatment without bone grafting
in severely resorbed edentulous maxillae. J Oral Maxillofac Surg 1999;57(3):
281–7.
11. Aparicio C, Perales P, Rangert B. Tilted implants as an alternative to maxillary si-
nus grafting: a clinical, radiologic, and periotest study. Clin Implant Dent Relat
Res 2001;3(1):39–49.
12. Maló P, Rangert B, Nobre M. “All-on-Four”: immediate-function concept with Brå-
nemark System implants for completely edentulous mandibles: a retrospective
clinical study. Clin Implant Dent Relat Res 2003;5(Suppl 1):2–9.
13. Patzelt SB, Bahat O, Reynolds MA, et al. The all-on-four treatment concept: a sys-
tematic review. Clin Implant Dent Relat Res 2014;16(6):836–55.
14. Del Fabbro M, Bellini CM, Romeo D, et al. Tilted implants for the rehabilitation of
edentulous jaws: a systematic review. Clin Implant Dent Relat Res 2012;14(4):
612–21.
Z y g o m a Im p l a n t s o r Si n u s
L i f t f o r t h e A t ro p h i c M a x i l l a
with a Dentate Mandible
Which is the Better Option?
Enif A. Dominguez, DDSa,*, Cesar Guerrero, DDSb,c,d,

Ehab Shehata, DDS, MD, MSc (GS), PhDa,e, Joseph E. Van Sickels, DDS
a
KEYWORDS
! Tilted implants ! Immediate loading ! Delayed loading ! Maxillary sinus grafting
! Zygoma implant
KEY POINTS
! “Teeth-in-a-day” in atrophic maxilla is achieved by immediate loading of zygomatic im-
plants following the concept of cross-arch stabilization.
! Placement of zygomatic implant is technique sensitive and requires knowledge of
the local anatomy. However, it reduces the treatment time before the prosthetic
reconstruction.
! In cases of severe maxillary anatomic constraints, zygomatic implant to rehabilitate maxil-
lary atrophy is considered a valid alternative treatment to maxillary sinus graft or alveolar
ridge bone augmentation.
! Zygomatic implant is performed in atrophic maxilla with dentate mandible. Restoration
varies depending on the residual maxillary anatomy.
INTRODUCTION
Maxillary atrophy represents a challenge for surgeons and restorative providers.

Ideally, prosthetic restoration should restore mastication, comfort, and phonation,
allowing for an improved quality of life.1–4 Autogenous bone graft is considered the

a
Division of Oral and Maxillofacial Surgery, Department of Oral Health Science, University of
Kentucky, College of Dentistry, Albert B. Chandler Hospital, D508, 800 Rose Street, Lexington,
KY 40536, USA; b Private Practice, Clear Choice Dental Implant Center, 929 Gessner Road, Suite
2050, Houston, TX 77024, USA; c The Woodlands Oral & Facial Surgery Center, 10857 Kuy-
kendahl Road. Ste 150, The Woodlands, Tx 77382, USA; d Private Practice, Oral and Maxillo-
facial Surgery, 907 Bay Area Boulevard, Houston, TX 77058, USA; e Department of Maxillofacial
and Plastic Surgery, College of Dentistry, Alexandria University, Alexandria, Egypt
E-mail address: enif.dominguez@uky.edu
Dent Clin N Am 63 (2019) 499–513

500 Dominguez et al
gold standard technique because of its osteogenic, osteoconductive, and osteoin-

ductive properties.5–7 Historically, restoration of the severely atrophic maxilla involved
obtaining bone graft from the iliac crest for onlay or interpositional techniques. Such
surgical procedures required multiple surgical sites, prolonged hospital stays, and
possible donor site morbidities.4,8 Potential complications encountered include sinus-
itis, graft exposure or resorption, infection, neurosensory deficits, and insufficient
bone quantity or quality. In addition, failure and unpredictable outcome of such autog-
enous grafting techniques often reduced patient acceptance.4,8,9
To avoid the disadvantages of autogenous bone grafting, bone substitutes and bi-
ologics (bone morphogenetic proteins, membranes, platelet-rich plasma, platelet-rich
fibrin) are commonly used. However, they remain inferior to clinical outcomes
achieved by using autogenous bone grafts.5–7
Sinus Augmentation
Maxillary sinus augmentation and bone grafting has provided an alternative treatment
option to augment maxillary atrophic ridges, allowing for restoration with immediate or
delayed implant placement. Primary implant stability requires a minimum of 3 to 5 mm
of crestal bone to justify simultaneous implant placement with maxillary sinus lift and
bone grafting.10 When inadequate alveolar bone height is present, a maxillary sinus
graft and 4 to 8 months healing time is required before the implant placement. In addi-
tion, a third surgical procedure is needed to uncover the implants for the final pros-
thetic rehabilitation. Three surgical stages is still a common practice in many clinics;
however, it prolongs the time before the prosthetic reconstruction.10–12
Chin13 introduced a dental implant stabilization system for simultaneous sinus lift
and implant placement when poor primary stability is present that allows the osseoin-
tegration to occur in conjunction with bone healing. This technique is applied to single
or multiple implants and is combined with temporary implants for immediate provi-
sional prosthetic anchorage.
All-on-X
The introduction of all-on-four by Malo and coworkers14–17 has changed the clinical
protocols emphasizing the use of available bone with predictable bone maintenance
and implant success.18 He demonstrated the use of longer, wider implants with
deeper threads and newer implant surfaces. In addition, tilted implants with multiunit
abutments placed at different angulations allow the clinician to immediately deliver the
provisional prosthesis and avoid additional surgical procedures, such as maxillary
sinus and ridge augmentation. The definitive restoration may be delivered after 3 or
4 months of healing.19 To overcome anatomic limitations to atrophic maxillae, all-
on-four is modified to include placement of zygoma implants.
Zygoma Implants
The use of zygoma implants in the posterior maxilla and conventional implants in the
anterior zone offers the possibility to provide anchorage for immediate provisional
teeth in the upper arch.20
This technique eliminates donor site morbidity and reduces the treatment time.
Zygoma implants engage multiple cortical walls, allowing for adequate primary stabil-
ity for immediate loading.21 Implants are inserted through the crestal bone into the
bicortical zygoma with adequate quality and quantity of bone. Even when crestal
bone of the maxillary alveolar ridge is not adequate, the implant fixtures allow a min-
imum of 8 to 10 mm of bone contact within the body of the zygoma for primary stabil-
ity. The zygomatic implant platform is straight (0" ) or angled up to 45" to allow the
Zygoma Implants or Sinus Lift 501
platforms to be in the same plane as the conventional implants for passive prosthetic
insertion.21–25 Cross-arch distribution of the functional is essential to prevent undesir-
able forces, osseointegration failure, and prosthetic complications. The prosthesis
must be reinforced with a rigid bar for cross-arch stabilization.25–29
SURGICAL APPROACHES FOR VARIOUS ANATOMIC PRESENTATIONS
The maxillary anatomy as assessed is divided into three radiographic zones as

described by Bedrossian and colleagues.24 Zone 1 is the maxillary anterior teeth,
zone 2 is the premolar region, and zone 3 is at the molar region. We use this classifi-
cation to stratify our treatment as seen next.
Ideal Bone Morphology
Modified classical implant distribution and immediate loading
When ideal bone quantity and quality are present in all zones of the maxilla, six parallel
implants are placed in sites 3, 5, 7, 10, 12, and 14 (wide implants in sites 3 and 14, if
possible). After implants are integrated, a fixed prosthesis is installed. Bone reduction
may be required to allow room for the prosthetic suprastructure.10–12
Large Maxillary Sinus with Moderate Posterior Vertical Bone Deficiency
All-on-X concept (five or six fixtures) with immediate loading
Sinus pneumatization decreases the amount of available vertical bone in the posterior
maxilla (zone 3). Two tilted implants (up to 45" ) avoiding the sinus floor cavity can be
placed in sites 4 and 13. Three or four additional implants are placed anteriorly in sites
6, 8, 9, and 11. Bone reduction (ostectomy) may be required for insertion of a pros-
thesis. Immediate loading with provisional teeth is often predictable because of the
cross-arch stabilization concept (Fig. 1).14–17
Fig. 1. Implants avoiding the sinus. (A) Panoramic view showing angulated implants avoid-
ing the maxillary sinus. (B) Immediate temporary dental rehabilitation. (C) Verifying paral-
lelism and adjusting the need to move the implant (arrow) for passive prosthetic
Insertiton. (D) Implants placed and wounds sutured with perfect emergence profile.
502 Dominguez et al
Large Maxillary Sinus with Severe Posterior Vertical Bone Deficiency

Two- or three-stage surgery (treatment time 24–36 months)
The maxillary sinus graft is completed first, followed by 5 to 6 months of healing time.
Next, the implants are placed and an additional 4 to 6 months of healing time is
needed for osseointegration of the implants. Temporary implants are placed during
the maturation of the bone and osseointegration, allowing immediate provisional
prosthesis (Fig. 2).5–8
Large Maxillary Sinus with Severe Posterior Bone Deficiency

Two surgical stages (treatment time 6–9 months)
When less than 3 to 5 mm of crestal bone is present, simultaneous sinus lift, implant
placement and plate stabilization are used for long-term predictability as described by
Chin (Fig. 3).6,7,10–13
Fig. 2. (A–D) Lateral window approach for Schneiderian membrane elevation. Bone graft
is placed in the floor of the sinus. Membrane is placed to cover the window and avoid
mucosal invagination and flap sutured. Pre and post-op panorex showing (E) Severe maxil-
lary sinus pneumatization bilaterally with no room for implant placement (F) Long term
follow-up with implants and final restoorations in place. (14 years F/U). (G) Final restorations
radiographically and clinically after 14 years of follow-up. (Courtesy of Robert Gilbert Tri-
plett, DDS, Dallas, TX.)
Fig. 3. Martin Chin’s protocol. (A) Intraoperative view with implant stabilized with a three-
hole microplate fixed to buccal and palate and the middle hole is stabilizing the implant by
inserting a cover screw through the plate into the implant. (B) Preoperative radiograph
showing the severe alveolar crest defect with sinus pneumatization. (C) Immediate postop-
erative radiograph to confirm position of the plate and implant. The anterior implant had
enough bone for primary stability and did not require sinus lift or plate stabilization. (D)
Radiographic confirmation of adequate osseointegration of the implants and ready for
functional loading. (E, F) Intraoral views with healing abutments in place to guide soft tissue
healing and final rehabilitation.
Moderate to Severe Generalized Maxillary Atrophy

All-on-X concept with immediate loading
When generalized maxillary atrophy is present (zones 1, 2, and 3), all-on-X is accom-
plished by placing implants in sites 4, 6, 11, and 13. Long implants placed in the piri-
form rims are preferred coupled with a wide short implant in the maxillary midline. If
inadequate bone is present in sites 4 and 13, an alternative option is placement of
angled implants in the tuberosity/pterygoid plate. The stability of these implants is ob-
tained from the pterygoid plate. The wide anteroposterior distribution of implants al-
lows immediate loading (Fig. 4).14–17
Extremely Severe Generalized Maxillary Atrophy

Multiple zygoma implants with immediate loading
Patients with severe maxillary atrophy, poor alveolar bone quality, or excessive masti-
catory load have the highest failure rate of maxillary implants.20–27 Placement of
implant should take into consideration the load distribution to follow a short cantilever
principle. Three-dimensional placement of anterior and posterior zygoma implants is
considered. Other options are used and are described later in the surgical procedure
section.
SURGICAL PROTOCOLS
The pattern of implant placement varies with the anatomy present and some are dis-
cussed in more detail later in the surgical section (Fig. 5).
504 Dominguez et al
Fig. 4. This case was treated with combined techniques: Angled implants to avoid the maxil-
lary sinus on the right side and unilateral zygoma implants on the left. (A, B) Intraoral and
occlusal views showing the posterior edentulism. (C, D) Right tuberosity implant with two
conventional anterior implants. Left; two zygoma implants and one conventional anterior.
(E, F) Pre and post-op Panoramic radiographs showing right side sinus pneumatization and
final restoration with tuberosity and two anterior conventional implants and left side with
severe maxillary sinus pneumatization and the final restoration with two unilateral zygoma
and one anterior conventional implants. (G) Occlusal views showing the failed dentition and
edentulous sites and final rehabilitation.
ORIGINAL SURGICAL TECHNIQUE OF ZYGOMA IMPLANT

1. Incision and dissection: A 2.5-cm lateral maxillary vestibular incision,30 similar to
Le Fort approach, with full thickness mucoperiosteal flap is elevated, exposing
the lateral wall of the maxilla.20,21,31 A bony window is created to access the
maxillary sinus membrane. Dissection is then carried out superiorly and posteri-
orly to visualize the infraorbital nerve. The fibers of the masseter muscle are
transected as close to the periosteum as possible with Dean scissors. Piezo sur-
gery or conventional round bur are used to create the antrostomy and expose the
maxillary sinus membrane. This window is transpositioned superiorly, while still
attached to the membrane, or removed to have direct visualization of the antral
floor.1
2. Retraction of the membrane: Once the membrane has been exposed, a folded wet
gauze aids in displacing the membrane medially and superiorly. This technique al-
lows the direct visualization of the drilling protocol avoiding injury to anatomically
important structures.
3. Sequential drilling: Under copious irrigation and using the zygoma retractor, a
703-fissure bur is used to create a groove for orientation at the alveolar crest
and zygomatic buttress region. Only two twist drills (2.9 and 3.5 mm) are used
Fig. 5. Zygoma implant design. (A) Conventional design by Brånemark with two zygoma im-
plants and four conventional in anterior zone. (B) Quadrangular design zygomas with two
posterior zygoma implants on each side and two anterior conventional implants. (C)
Quadrangular design zygomas with two posterior zygoma implants on each side and one
anterior conventional implant in the midline area. (D) Quadrangular design zygomas with
two posterior zygoma implants on each side that are not parallel to avoid rotational forces.
(E) Pentagonal design with two posterior zygoma implants on each side and one anterior
zygoma implant anchored to infraorbital rim. (F) Hexagonal design; six zygoma implants
sites 3, 5, 7, 10, 12, and 14 for class III patients of severe bruxism, especially with complete
mandibular dentition. (G) Unilateral zygoma design; unilateral severe atrophy or cleft
patients.
for the zygoma implant site preparation. The zygoma drill guard protects the
commissure from injury while using the drills at insertion. Double irrigation should
be used to avoid overheating of the bone at the crestal and zygoma levels.The
path of insertion for zygomatic implants extends from the alveolar crest, through
the maxillary sinus, and enters the body of the zygoma anchored to solid bone.
The technique is sensitive and requires knowledge of the local anatomy. The
506 Dominguez et al
presence of a dentate mandible decreases the amount of space available to insert

the greater than 50-mm drill bits, making placement challenging and difficult. The
presence of mandibular teeth should not be a contraindication for the placement of
zygoma implants.The hand piece is positioned on the contralateral side at the level
of the commissure with long drills, mandating maximal opening of the mouth be
maintained. The drilling sequence starts at the alveolar crest, passing through
the maxillary sinus, and the drill is advanced to reach the body of the zygoma to
the desired emergence level. The most challenging zygoma fixtures placed are
the posterior because of soft and hard tissue constraints. General anesthesia
may be required to improve maximum opening.
4. Depth measurement: Final measurement is taken with the depth gauge to confirm
adequate implant selection.
5. Implant placement: To ensure adequate cortical anchorage and primary stability,
the tip of the zygoma implant should extend 2 mm beyond the body of the zygoma
(Fig. 6).
Fig. 6. Surgical steps and armamentarium. (A, B) Incision and flap elevation: the
lateral maxillary walls are exposed bilaterally and once the masseter fibers are visualized,
Dean scissors are used to dissect them from the inferior border of the zygomatic arch
to allow for an easier flap retraction. (C) Depth gauges, zygoma drill guard (to protect
the commissure), and onion (implant manual driver). (D) Antrostomy: with piezo
surgery or electrical Hall drill, a window in the lateral sinus wall is removed and the maxil-
lary sinus membrane is elevated superiorly and medially with curettes. Brånemark retractor
in the zygoma bone for proper visualization and initial drilling with single irrigation with
703 fissure bur at the alveolar ridge and to countersink in the zygoma body to create vector
of insertion if extrasinus approach is desired. (E) Depth gauge to confirm size of zygoma
implant and finally implant insertion with the use of double irrigation.
PROSTHETIC CONSIDERATIONS
Prosthetic restorations (teeth and infrastructure) usually require at least 15 mm of

interocclusal space. The recent development of virtual surgical planning allows fabri-
cations of a bone reduction guide before surgery to be used by the surgeon for alve-
olar crest reduction as needed.31,32 Multiple zygoma implants with wide distribution
avoiding large cantilevers are recommended to restore patients with severe posterior
maxillary bone atrophy (Fig. 7).26,31–37
A. Anteroposterior cantilever: Anterior implants should emerge within the crestal bone
at the level of incisors, whereas posterior implants should be positioned to emerge
distal to first molars.
B. Vertical cantilever: By placing the implant in the alveolar ridge, the vertical canti-
lever is less than that seen with one placed more palatal.
C. Transverse cantilever: The posterior implants should emerge in the alveolar crest
area to avoid transverse cantilever. Ideal placement of the implants should be
following the extrasinus technique. This implies covering the implant with buccal
fat pad for closure to avoid exposure to the oral cavity.
MODIFIED PROTOCOLS
1. Pentagonal design: Five maxillary-zygomatic implants are placed at distal of 4,
distal of 6, mesial of 7, distal of 11, and distal of 13. The implant stability is
based on the body of the zygoma and piriform rim (Figs. 8 and 9).26,31,32,36
2. Hexagonal design: An additional anterior zygoma implant is placed in the contralat-
eral piriform rim to increase bone anchorage, decrease interdental gap, and to
Fig. 7. Medial illustration showing the importance of short cantilevers of the prosthetic
restorations to the implants in three dimensions. (A) Anteroposterior and vertical. (B)
Transversal.
508 Dominguez et al
Fig. 8. Medial illustrations demonstrating the pentagonal design. (A) Zygoma implants
placed posteriorly and anteriorly for load distribution. (B) Dental prosthesis with ideal dis-
tribution and short transversal cantilevers. (C) Intraoperative view with the 5 zygoma im-
plants in place. (D) Medical schematic representations for anterior zygoma implant
anchored in the infraorbital rim.
Fig. 9. Pentagonal design of zygoma implant. (A, B) Panoramic radiographs showing the se-
vere maxillary atrophy with no bone for conventional implant placement and postoperative
with implants and dental prosthesis. (C) Intraoral views preoperative and postoperative.
minimize the anteroposterior cantilever. This design is recommended for patients

with class III malocclusions, poor zygoma size, and/or severe bruxism habits
(Fig. 10).32
3. Unilateral design: Zygoma implants can also be placed when severe maxillary
posterior atrophy is present unilaterally. In these cases, two posterior zygoma
implants are placed and rigidly fixated to an anterior conventional implant
(Fig. 11).32
MODIFIED SURGICAL TECHNIQUES

1. Sinus slot: To improve the emergence profile and avoid maxillary sinus window os-
teotomy, Stella and Warner modified the soft tissue approach and bony engage-
ment points. They used a mucoperiosteal elevation similar to a traditional Le Fort
I extending the palatal dissection to reach the crestal bone. Using a fissure bur,
marks are made at the crest and zygomatic buttresses, orienting the surgeon dur-
ing the sequential drilling.31,32,35,38,39,40
2. Extrasinus technique: Aparicio described implant placement outside the sinus wall
in patients with pronounced buccal concavities. Implants were placed at the level
of the alveolar crest achieving ideal emergence profile. A standard drilling
sequence was used without violating the integrity of the maxillary sinus membrane.
The buccal fat pad must be used to cover the lateral aspect of the implant to avoid
exposure to oral cavity (Fig. 12).31,32,35,38,39
Fig. 10. Hexagonal design of zygoma implant. (A,B) Hexagonal design medical illustrations
showing six zygoma implants for severely three-dimensional atrophy. Notice there is mini-
mal to no anteroposterior and transverse cantilevers transferred from the implants to the
final prosthesis. (C) Preoperative and postoperative panorex showing the hexagonal design
with six zygoma implants in place immediately after placement.
510 Dominguez et al
Fig. 11. Unilateral zygoma implants. (A–D) Post-operative views of the final dental rehabil-
itation with unilateral zygoma treatment.
Fig. 12. Buccal fat pad must be used to cover the lateral aspect of the zygoma implants to
avoid exposure to the oral cavity.
SUMMARY
This article helps clinicians evaluate different treatment options to rehabilitate maxil-
lary edentulism. The protocols described all have the goal of immediate loading. Pa-
tient variables can dictate the ideal procedure in a given situation. Patient variables
can include medical comorbidities, the degree of maxillary atrophy, presence or
absence of mandibular teeth, and the need for immediate loading. Alternatives for se-
vere atrophy include but are not limited to sinus grafting versus zygoma implants. Si-
nus grafting requires additional steps and associated bone graft–related morbidities,
whereas zygoma implants are placed in one stage but requires specialized skills. It is
difficult to tell the reader which is the best technique to use. The ideal technique should
be tailored to the individual patient and surgeon experience.
ACKNOWLEDGMENTS
The authors acknowledge the work of colleagues on the cases as shown in

the following figures: Joe Shirley, DDS (Fig. 1), Rafaelle Pisano, DDS (Figs. 4 and
9), Giancarlo Romero, DDS (Fig. 10), and Nathan Nussembaum, DDS (Fig. 11).
REFERENCES
1. Cawood J, Howell R. Reconstructive preprosthetic surgery. Anatomical consider-

ations. Int J Oral Maxillofac Surg 1991;20:75–82.
2. Brånemark PI, Breine U, Adell R, et al. Intra-osseous anchorage of dental pros-
theses, I. Experimental studies. Scand J Plast Reconstr Surg 1969;7:321–9.
3. Brånemark P-I. The Brånemark novum protocol for same-day teeth a global
perspective. Berlin (Germany): Quintessence; 2001.
4. Barros Saint-Pasteur J. Alveoplasty ridge reconstruction. Acta Odontol Venez
1970;8:168.
2006;17:136.
6. Chiapasco M, Zanibon M. Methods to treat the edentulous posterior maxilla: im-
plants with sinus grafting. J Oral Maxillofac Surg 2009;67:867–71.
7. Choukroun J, Diss A, Simonpieri A, et al. Platelet-rich fibrin (PRF): a second-
generation platelet concentrate. Part V: Histologic evaluations of PRF effects on
bone allograft maturation in sinus lift. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2006;101:299–303.
8. Brånemark P-I, Gröndahl K, Worthington P. Osseointegration and autogenous on-
lay bone grafts: reconstruction of the edentulous atrophic maxilla. Chicago: Quin-
tessence; 2001.
9. Regeev E, Smith RA, Perrot DH, et al. Maxillary sinus complications related to en-
dosseous implants. Int J Oral Maxillofac Implants 1995;10:451–61.
10. Rangert B, Sennerby L, Nilson H. Load factor analysis for implants in the posterior
maxilla. In: Jensen T, editor. The sinus bone graft. Chicago: Quintessence; 1999.
p. 167–77.
11. Brånemark PI, Svensson B, Van Steenberghe D. Ten- year survival rates of fixed
prostheses on four of six implants and modum Brånemark in full edentulism. Clin
Oral Implants Res 1995;6:227–331.
12. Schnitman P, Wohrle PS, Rubenstein J, et al. Ten years results for Brånemark im-
plants immediately loaded with fixed prostheses at implant placement. Int J Oral
Maxillofac Implants 1997;12:495–503.
A re Th e re C o n t r a i n d i c a t i o n s
f o r Pl a c i n g D e n t a l I m p l a n t s ?
Amritpal S. Kullar, BDS, Craig S. Miller, DMD, MS*
KEYWORDS
! Contraindication ! Risk factors ! Dental implants ! Implant failure ! Implant survival
KEY POINTS
! There are few absolute contraindications to dental implant placement.
! Relative contraindications include cognitive decline, American Society of Anesthesiology
Patient Status IV or higher categories, or medical conditions that may jeopardize the life or
lifespan of the patient.
! Precautions for placing dental implants should be viewed with respect to the evidence-
based exposures that can contribute to risk of failure, including but not limited to local,
behavioral, and medical factors.
! Risk for dental implant failure increases in association with (1) past history of periodontal
disease, (2) bruxism, (3) smoking, and (4) radiation therapy.
INTRODUCTION
Dental clinicians on a daily basis should be mindful of the indications, precautions, and
contraindications of treatment in order to achieve the best patient outcomes. Indica-
tions for treatment generally are considered when a patient initially presents with a
problem or complaint. After the indication,1 the precautions and contraindications
should be considered as balancing components of the decision-making and informed
consent process. Precautions and contraindications involve taking into account the
relative seriousness of a particular treatment and when specific treatment would be
inadvisable because of the harm or serious adverse outcome that may, or is likely
to, occur. A precaution indicates that there is ability to prevent or mitigate the adverse
event. In contrast, a contraindication is a more serious situation in which the likelihood
and severity of the adverse event outweighs any potential benefit to the patient (Fig. 1).
Contraindications are recognized as being either absolute or relative. An absolute
contraindication indicates that the procedure could cause a life-threatening event or
the risk of the procedure clearly outweighs any possible therapeutic benefit. A relative

Division of Oral Diagnosis, Oral Medicine, Oral Radiology, MN324 College of Dentistry, Uni-
versity of Kentucky, 800 Rose Street, Lexington, KY 40356-0297, USA
E-mail address: cmiller@uky.edu
Dent Clin N Am 63 (2019) 345–362

346 Kullar & Miller
Fig. 1. Spectrum of risk when considering placement of a dental implant.
contraindication indicates that caution should be exercised and it is likely that the
benefit of the procedure outweighs the risks involved.
Placing a dental implant is an elective procedure that requires consideration for the
desires, oral anatomy, potential trauma, and healing capacity of the patient. Hence,
indications, precautions, and contraindications are key components of the diagnostic
work-up. During the planning phase, health conditions and medical comorbidities are
to be respected, and caution should be used before engaging in a procedure or treat-
ment to ensure that the benefits are likely to outweigh the risks.
Expert opinion suggests that there are few situations or medical conditions that
create an absolute contraindication for placing a dental implant.2 Relative contraindi-
cations are those situations associated with patients who are categorized with a health
condition that may increase the risk of an adverse event, implant failure, or postoper-
ative problem. These patients include those categorized as American Society of
Anesthesiology patient status IV or higher (eg, oropharyngeal malignancies, recent ce-
rebrovascular accidents and myocardial infarction, uncontrolled or poorly controlled
epilepsy, diabetes mellitus or psychiatric illness, risk of osteoradionecrosis, bleeding
disorders, profound immunosuppression, drug and alcohol abuse, active cancer
chemotherapy and receiving intravenous antiresorptive medication, or conditions
that may jeopardize the life or lifespan of the patient). However, little evidence exists
to date to support contraindications to placing a dental implant, but there are contrast-
ing opinions that exist among practitioners.3–5 Readers are referred to other publica-
tions on this topic for additional perspectives.6–8
In the context of decision making and dental implants, evidence suggests that 90%
to 95% of dental implants are successfully maintained for 10 years9 and 51.97% to
75.8% survive at 16 to 20 years.10,11 The most common causes for failure of a dental
implant include peri-implantitis, peri-mucositis, failure of osseous integration, place-
ment error, anatomic anomalies, persistent pain, and breakage caused by force
applied during function.8,9,12–14
In as much as dental implants have a high rate of success and few contraindications
for placement,3 this article focuses on conditions associated with increased risk of
dental implant failure, generally defined as cases in which the implant is removed
because of disease, pain, or mobility. In this article, our opinions focus on systematic
reviews (SRs) of the literature because this is the highest level of evidence. Readers
are referred to primary studies on proton pump inhibitors15,16 and selective serotonin
reuptake inhibitors17 as well as case series regarding chronic pain18 and neuropathic
pain19–21 following implant placement for additional information on this topic. Readers
are cautioned that although SRs provide a high level of evidence for decision making,
SRs are not without flaws and some are better than others. Detailing the limitations of
SRs is beyond the scope of this article, and the authors do not attempt to analyze the
quality of the SR. Readers should be aware that SRs can vary at many levels, including
whether investigators of the primary studies or the SR used accurate and consistent
definitions of disease or proper inclusion/exclusion criteria; measured publication
Contraindications for Dental Implants? 347
bias, type, and frequency of treatment provided; or measured the outcome domains
(ie, success, survival, failure). For this report, risks for dental implant failure have
been categorized into local factors, behavioral factors, and medical factors.
Local
Periodontal disease
Periodontal disease is a global disease22 that is a diagnostic consideration for patients
seeking a dental implant. Both a history and the presence of periodontal disease are
well-recognized risk factors for periimplant disease and implant failure.23,24 The
increased risk may be caused by compromised bone level; reduced bone quality; im-
mune dysregulation; or concurrent exposures, such as poor oral hygiene, tobacco
use, or persistent periodontal pathogens.25 At present, there are 10 SRs on peri-
odontal disease and dental implants. Both aggressive and chronic periodontitis
have been evaluated in SRs.
There are 2 SRs on the topic of aggressive periodontitis and dental implants
(Table 1).23,26 In the Al-Zahrani26 SR, 9 primary studies involving 72 patients who
had a history of aggressive periodontitis were evaluated.27–35 These patients, in gen-
eral, received periodontal treatment for several years before implants were placed.
There were 4 case reports and 5 longitudinal studies. Patients ranging from 17 to
82 years of age received more than 260 dental implants and were followed for 2 to
36 months. More than 90% of the dental implant survived 24 to 36 months; however,
patients with a history of aggressive periodontitis showed greater periimplant crestal
bone breakdown than patients without a history of periodontal disease.35 Hazard ra-
tios were not calculated, and the primary studies were not evaluated for level of evi-
dence or publication bias.
Table 1
Summary data from systemic reviews associated with potential increased risk of dental implant failure
Number Duration
of Number Number of Odds Ratio of
Number Primary of Number of of Number of Primary Dental Implant
Condition of SRs Studies Patients Implants Cases Controls Studies Failure
Periodontal disease 10 35 975 14,332a 10,481a 385a 1.2–10 y NR
(aggressive and
23,24,26,38–43
chronic)
Smoking70–73 4 110 24,618 104,350a 19,836a 60,464a 8 mo to 2.92 (95% CI,
20 y 1.76–4.83)
(P<.001)
Bruxism80–83 3 24 2297 7043a 1356a 3924a 1 mo to 4.72, (95% CI,
15 y 2.66–8.36)
Diabetes 8 41 9519 37,782a 9606a 16,137a 4 mo- 0.62, (95% CI,
mellitus96–103 17 y 0.0225–1.705;
P 5 .354)
Osteoporosis112,113 2 18 9066 30,381a 790a 4609a 1–22 y Risk for
periimplantitis
1.89, (95% CI,
1.31–2.46;
P<.01)
Bisphosphonate117–121 5 19 1988 5927a 2039a 3888a 1 mo to 1.43, P 5 .156
11 y
Radiation140,144–147 5 58 2622 10,570a 5647a 3854a 1 mo to RR 2.63 (95% CI,
23 y 1.93–3.58;
P<.001)
Abbreviations: CI, confidence interval; NR, not reported; RR, risk ratio; SRs, systematic reviews.
a
Not all studies reported the number of implants, cases, or controls.
348 Kullar & Miller
The Monje and colleagues23 SR included 6 prospective human studies.31–34,36,37

Five of the studies were from the Mengal and colleagues author group32-34,36,37 and
4 studies had been previously evaluated by Al-Zahrani.26 The 2014 SR provides a
more rigorous study design than the Al-Zahrani26 SR, with the inclusion of meta-
analysis and assessments for heterogeneity, quality, and publication bias. Here the
survival rates for 264 dental implants in 60 patients with aggressive periodontitis
were 83.3% to 100%, with a follow-up period ranging from 12 to 120 months. A
meta-analysis yielded an overall failure rate risk ratio (RR) of 4.00 (95% confidence in-
terval [CI], 1.79–8.93; P<.001) in patients who had a history of aggressive periodontitis
compared with healthy controls. Risk was also increased in patients who had aggres-
sive periodontitis compared with chronic periodontitis (RR, 3.97; 95% CI, 1.68–9.37).
Eight SRs were published between 2008 and 2016 that considered periodontal dis-
ease and implant survival.24,38–43 The most comprehensive data sets were found in the
2014 and 2016 SRs. Here, 22 and 24 primary studies were evaluated, respectively,
and 16 primary studies appeared in both data sets. In 12 prospective studies, the in-
vestigators evaluated 2825 implants placed in 843 patients with treated periodonti-
tis.33,44–54 In the 9 retrospective studies,55–64 8102 implants were evaluated in 2086
patients. In total, more than 10,000 implants placed in persons who had periodontal
disease were compared with 3851 implants placed in 1606 healthy patients over a
period of 1.2 to 10 years.24,38 Evidence from these SRs indicate that there is increased
risk of marginal bone loss, periimplantitis, and implant failure (odds ratios [ORs]
ranging from 1.7 [CI, 1.23–2.79]; 95% CI, 1.12–8.15) with chronic periodontitis. Sur-
vival rates of implants in patients without periodontitis ranged from 91.7% to 100%
compared with 71% to 100% for patients with treated periodontitis.24,38,39 The
severity of periodontal disease also contributed to lower implant survival,24 but dura-
tion of disease generally was not assessed in the SRs. Periodic periodontal mainte-
nance program is documented to be associated with improved implant survival.24
The rationale of increased risk is not well established; however, the literature suggests
that adjacent periodontally involved teeth may contribute to the cause through the
transfer of periodontal pathogens from adjacent disease sites to the implant site.25,65
Although large-scale case-control clinical trials are lacking, the findings from these
SRs suggest that dental implants can be used in patients treated for aggressive and
chronic periodontitis. However, clinicians need to consider several factors, including
the length of time between active periodontal therapy and when an implant should
be placed, whether questionable teeth should be extracted before implant placement,
and the maintenance program that will be provided regularly to periodontally compro-
mised teeth that are adjacent to the implant. Caveats to consider in the interpretation
of these data include that periodontal disease is often associated with confounders (ie,
tobacco smoking) and comorbidities (eg, diabetes) and that these factors are not al-
ways well controlled for in the SRs published to date. Also, the SRs reviewed generally
showed variability in the definitions in periodontitis and implant failure, loading and
follow-up period, details regarding the type and frequency of periodontal treatment
provided, and outcome criteria, each of which contribute to difficulty in accurate inter-
pretation of the findings.
Behavioral Factors
Smoking
Smoking is a well-recognized risk factor for periodontal diseases that contributes to an
anaerobic environment, growth of periodontal pathogens, and detachment of the peri-
odontal ligament.66,67 Together, these factors can lead to implant failure. It is esti-
mated that 37.8 million (15.5%) adults smoke cigarettes every day,68 and about 15
of every 100 adults aged 18 years or older in the United States smoke cigarettes.69
Smoking is considerably higher among American Indians/Alaska Natives (31.8%)
and persons of color, and lowest among Asians (9.0%).68 Smoking is directly corre-
lated with educational status. Although smoking rates decreased from 42.4% in
1965 to 15.7% in 2016, the Healthy People 2020 national objective of 12% has not
yet been reached.68
There are 4 SRs on smoking and implant failure. These SRs evaluated 113 primary
studies and more than 28,000 dental implants over a 20-year period.70–73 Evidence
from these SRs indicates increased risk of implant failure among smokers. The data
support that the risk of implant failure, postoperative infections, and marginal bone
loss for smokers is at least twice that for nonsmokers.72 One SR reported 1259
(6.35%) failures of 19,836 dental implants placed in smokers and 1923 failures
(3.18%) of 60,464 dental implants placed in nonsmokers.72 Evidence from this SR in-
dicates that smokers experienced higher rates of implant failure (RR, 2.23; 95% CI,
1.96–2.53).72 The success rate of dental implants dropped considerably when patients
smoked more than 10 cigarettes per day.74 Overall, the risk of dental implant failure
seems to be at least twice as high in smokers as in nonsmokers.
Bruxism
Bruxism, a condition in which the patient clenches and grinds the teeth, is a recog-
nized risk factor for implant fracture and failure as a result of abnormal physical
force.75–79 It is important for clinicians who are planning dental implants to consider
that patients who brux often report morning stiffness or tightness in masticatory mus-
cles, and show wear of the dentition. Assessment of these clinical features is critical
for the long-term success of dental implants. There are 2 SRs and 1 meta-analysis
on bruxism and dental implants that evaluated 38 primary studies over a 15-year
period.80–82 The meta-analysis evaluated 760 implants in patients who showed
bruxism and 2989 control (nonbruxism) patients. This analysis reported 49 (6.45%)
implant failures that occurred in the patients who showed bruxism compared with
109 (3.65%) implant failures in nonbruxism patients.82 The findings support about a
2-fold higher risk for those who are bruxers versus nonbruxers.
Medical Factors
Bleeding disorders
Hemorrhage is a potential complication during or after dental implant placement. A
surgical procedure can lead to hemorrhage in patients who have a congenital (hemo-
philia A – factor VIII deficiency; hemophilia B – factor IX deficiency) or acquired
bleeding disorder; however, medical consultation with the patient’s physician and
precise treatment planning before the surgical procedure can minimize adverse out-
comes. Most patients taking antiplatelets (low-dose aspirin) or oral anticoagulants
(coumadin, Warfarin) should not have their medication discontinued before implant
placement.83–86 However, elective surgery should not be performed if hemostasis is
not possible.3 Patients with International Normalized Ratio (INR; prothrombin
ratio 5 patient prothrombin/control prothrombin) value of higher than 3.5 should be
referred to their physicians for improved control and, once controlled, considered
for treatment in a setting that will provide for good hemostasis.87 The INR value should
be current (ie, taken between 24 and 72 hours before surgery). Direct oral anticoagu-
lant (DOAC) drugs are newer agents prescribed for persons with deep vein throm-
bosis, pulmonary embolism, atrial fibrillation, myocardial infarction, and heart valve
prosthesis.88,89 Although there is some controversy regarding whether DOACs
should be temporarily discontinued during the surgical placement of a dental
350 Kullar & Miller
implant,90 accumulating data indicate that DOACs should not be discontinued for this
procedure.89,91,92
Abnormalities in platelet count and function can also contribute to abnormal
bleeding during or after implant surgery. Low platelet levels are associated with leuke-
mia, radiotherapy, idiopathic thrombocytopenia purpura, and myeloablation.3 The
reference value for platelet count is between 150,000 and 400,000 cells/mm3.
Abnormal postsurgical hemorrhage may be noticed in mild thrombocytopenia
(50,000–100,000 cells/mm3). In case of severe thrombocytopenia, platelet values
less than 50,000 cells/mm3 can complicate implant placement or lead to postopera-
tive hemorrhage. In patients with very low platelet values (<20,000 cells/mm3), hemor-
rhage of mucous membranes often occurs,93 and these patients require transfusion
before invasive dental procedures such as placement of a dental implant.
At present, there are no SRs on the topic of dental implants and failure or contrain-
dications in patients who have bleeding disorders. However, precautions are advised
and should be taken with these patients before and during the procedure to prevent
bleeding-related adverse events that may occur.
Diabetes mellitus
Diabetes is a well-recognized risk factor for poor wound healing after surgical proced-
ures caused by abnormal glucose blood levels and altered immune response, both of
which may contribute to implant failure. Diabetes can also hinder the process of
osteointegration.94 A patient is diagnosed with diabetes if the fasting blood glucose
is 126 mg/dL or higher, or the hemoglobin A1c is 6.5% or greater. In the United States,
more than 29 million people have diabetes mellitus and 25% of affected persons are
unaware of their condition.95 Approximately 86 million are prediabetic, and 90% of
these persons do not know it. Hispanic and Latino people, African Americans, Amer-
ican Indians, Pacific Islanders, and Asian Americans are at higher risk for diabetes than
white people.95
There are 8 SRs on diabetes that have analyzed 14 to 22 primary studies.96–103 These
SRs evaluated the failure rate of more than 3000 dental implants placed in more than
2000 (type I or type II) diabetic patients. In the Moraschini and colleagues101 SR, 14 pri-
mary studies published between 2000 and 2015 were evaluated. Most involved pro-
spective studies. Overall, this SR analyzed 802 diabetics and 1532 nondiabetic
patients between the ages of 15 and 89 years, with a follow-up period of 3 months
to 17 years. The investigators did not consider the glycemic control levels, and reported
that survival rates of diabetics were similar to those of healthy controls (95.1 vs 97%,
97.2 vs 95%, 92 vs 93.2%, and 97 vs 98.8%) in 4 primary studies48,104–106 that had a
follow-up of more than 1 year; however, 2 studies showed a shorter survival period,
which yielded an RR of 4.8 and 2.75 for implant failure in diabetic patients.107,108
Because of the predominance of favorable outcomes, Moraschini and colleagues101
reported there was no difference in the rate of implant failure in diabetic patients versus
nondiabetic patients. Similar findings are reported by Naujokat and colleagues,98 who
evaluated 22 primary studies in which survival was measured within the first 6 years of
placement; however, dental implant failure was observed to be increased in diabetic
patients when the observation period was 20 years.
Glycemic control has also been evaluated. Shi and colleagues99 evaluated the fail-
ure rate of 286 dental implants placed in 252 well-controlled diabetics and 301 dental
implants placed in poorly controlled patients reported in 7 primary studies. Findings
from this meta-analysis showed no difference in the dental implant failure rate among
well-controlled versus poorly controlled diabetics (RR, 0.620; 95% CI, 0.0225–1.705;
P 5 .354). In contrast, an SR by Monje and colleagues103 published in 2017 that
evaluated 12 primary studies with 2892 implants placed in 1955 subjects with a follow-
up period of up to 11 years concluded that the risk of periimplantitis in patients with
diabetes mellitus or hyperglycemia is 1.21 to 2.46 times higher than in nondiabetics
or persons with normoglycemia.
Bone diseases
The presence of bone disease may be a risk factor for implant disease and failure. The
literature to date provides little guidance on dental implant success rates in patients
with osteogenesis imperfecta, ankylosing spondylitis, and polyarthritis,8,14 although
SRs are present for osteoporosis. Osteoporosis is a medical condition characterized
by low bone mass associated with imbalances in bone metabolism causing the bone
to become brittle and fragile because of a decrease in bone volume and quantity.
Osteoporosis mainly affects older women (>50 years old).109,110 Worldwide, more
than 200 million women have osteoporosis and it affects approximately 75 million peo-
ple in the United States, Japan, and Europe according to the International Osteopo-
rosis Foundation.111 An estimated 14 million people by 2020 will have osteoporosis
in the United States.
There are 2 SRs on osteoporosis and dental implants.112,113 These systematic re-
views included 18 studies from 2001 to 2017, and examined more than 20,000 dental
implants over a period of 1 to 22 years. Evidence from these SRs indicates that there
is no difference in dental implant survival in patients with or without osteoporosis.
In these studies, the survival rate is reported to be 96% in the osteoporosis group.112
Nevertheless, increased periimplant bone loss was observed in patients with
osteoporosis.112
Antiresorptive medications
Antiresorptive medications are prescribed for several diseases (eg, osteoporosis,
Paget disease, hypercalcemia of malignancy, bone metastasis of prostate, lung and
breast cancer) that affect bone quality and metabolism.114 Antiresorptive medications
are available as bisphosphonates, receptor activator of nuclear factor kappa-B ligand
(RANKL) inhibitors, and antiangiogenic agents (Box 1). Antiresorptives are given either
orally or intravenously. These agents show various potencies. Bisphosphonates have
a high affinity for hydroxyapatite crystals115 and are used to increase bone strength
and reduce the risk for fractures.116 Bisphosphonates are generally prescribed for
osteoporosis as an oral medication or a single annual injection of zoledronic acid. In
contrast, the more potent antiresorptive medications (eg, zoledronic acid) are often
used intravenously in cancer therapy to limit bone metastases.
The relationship between dental implant survival and bisphosphonate use has been
documented in 5 SRs that evaluated more than 4500 dental implants.117–121 The most
comprehensive data sets are found in 2 recent publications.120,121 Here 14 and 15 pri-
mary studies were evaluated. Ten primary studies appeared in both data sets. Data
from the de-Freitas and colleagues121 SR included 8 retrospective studies,122–129 1
prospective study,130 and 6 case series.131–136 In total, 1330 implants were placed
in 528 bisphosphonate users and 2418 implants were placed in 811 healthy patients.
The follow-up period was up to 11 years. During this time, 113 dental implants failed in
bisphosphonate users (8.5%) and 39 in healthy patients (1.6%).121 Osteonecrosis was
reported to occur in 78 patients (53 in mandible and 23 in maxilla) who used
bisphosphonates, with the highest prevalence in those who had combined use of
oral and intravenous bisphosphonates.121
In 2 SRs, implant survival rates in individuals with a history of bisphosphonate use
ranged from 95% to 100% versus 99% in healthy individuals with a follow-up period
352 Kullar & Miller
Box 1
Antiresorptive medications
Bisphosphonates
Non–nitrogen-containing bisphosphonates:
Etidronate (Didronel)
Clodronate (Bonefos, Loron)
Tiludronate (Skelid)
Nitrogen-containing bisphosphonates:
Pamidronate (APD, Aredia)
Neridronate (Nerixia)
Olpadronate
Aledronate (Fosamax)
Ibandronate (Boniva)
Risedronate (Actonel)
Zoledronate (Zometa, Aclasta)
RANKL inhibitors
Denosumab (Prolia, Xgeva)
Angiogenesis inhibitors
Axitinib (Inlyta)
Bevacizumab (Avastin)
Cabozantinib (Cometriq)
Everolimus (Afinitor, Zortress)
Lenalidomide (Revlimid)
Pazopanib (Votrient)
Ramucirumab (Cyramza)
Regorafenib (Stivarga)
of 4 months to 7.4 years.117,118 In a meta-analysis of 8 primary studies involving 1090

implants in bisphosphonate users and 3472 implants placed in healthy controls, Ata-
Ali and colleagues120 reported only 1 study that offered statistical evidence that
bisphosphonates reduce dental implant success, with an overall OR of 1.43 (95%
CI, 0.87–2.34; P 5 .156). Together, these data indicate that patients taking
bisphosphonates are not at higher risk of implant failure.118,120 This finding is consis-
tent with a recent study published by Al-Sabbagh and colleagues137 who reported
no increased risk of implant failure among patient with osteoporosis who took oral
bisphosphonates.
There are no SRs available on RANKL inhibitors or antiangiogenic medications as of
this date. Accordingly, dental practitioners should be cognizant of the current evi-
dence and review the medical status of each patient before beginning a procedure
for dental implant placement in a patient who uses or has received antiresorptive med-
ications.121 If necessary, the patient’s medical practitioner should be consulted.
Radiation therapy
It is estimated that 51,540 new cases of oropharyngeal cancer will be diagnosed in
2018 and an estimated 10,030 lives will be lost because of this disease.138 Most
oropharyngeal cancer diagnoses occur in persons who are at least 60 years of age;
however, at least one-quarter of cases occur in persons younger than age 55 years.
Radiation therapy is a common component of the cancer treatment of many of these

patients. Radiation therapy is generally administered over a period of 5 to 7 weeks at
doses that destroy cancer cells or slow their rate of growth. The high dose of radio-
therapy is also damaging to the adjacent tissues and can result in reduced blood sup-
ply to bone, bone sclerosis, and reduced ability of osseous regeneration.139,140
Accordingly, survival of dental implants is potentially affected in the field of irradiation
because of hypovascularization and reduced regenerative ability, which can affect the
osseointegration process.141–143
There are 5 SRs on radiation and implant failure. These SRs evaluated 58 primary
studies, and more than 10,000 dental implants over a 23-year period.140,144–147
Most primary studies were retrospective and only 1 study was a randomized trial. Ev-
idence from these SRs indicate a higher rate of failure (15% to 25%) in irradiated jaw
areas compared with nonirradiated areas (5%) over a 60-month period.140,147 In an
analysis based on random effect, the RR of failure was higher (RR, 2.63; 95% CI,
1.93–3.58; P<.001) in irradiated patients versus nonirradiated patients.140 Risk seems
to increase when the radiotherapy dose is more than 50 Gy145; however, most SRs did
not analyze the dose received as a confounder.
The anatomic location is also a consideration. Evidence from a recent SR indicates
a higher survival rate of dental implants in irradiated mandible than in irradiated
maxilla (OR, 3.67; 95% CI, 2.81–4.79; P<.0001).145 This finding is also reported in
the SRs by Shugaa-Addin and colleagues147 and Schiegnitz and colleagues146; how-
ever, not all primary studies have reported this finding.148–150 Hyperbaric oxygen is a
consideration when a dental implant is planned for a region that has received greater
than 50 Gy; however, consensus is lacking on the need for this treatment.151 The
accumulated evidence from these SRs indicates that irradiated areas in the maxilla
or mandible may receive dental implants, but strict evaluation that includes informa-
tion on the radiation dose received in the site planned for the dental implant,
informed consent that includes risks involved, as well as monitoring of the area
are needed.140
SUMMARY
Although there are no absolute contraindications for placing a dental implant, the fac-
tors discussed in this article show increased risk for decreased implant survival when
certain factors or comorbidities are present. In situations in which risk is increased, the
patient should be informed of the uncertainties and risks, and the practitioner and pa-
tient need to understand the requirement for close follow-up and proper periodontal
maintenance therapy. It is possible that the factors discussed in this article are addi-
tive, thus persons who have periodontal disease, bruxism, and poorly controlled dia-
betes could be at even higher risk than patients who have only 1 of these exposures.
Thus, relative contraindications could relate to the potential additive risk and clinicians
should consider these factors carefully when more than 1 exposure is present. Future
research should include longitudinal studies and the consideration for additive risk to
help expand knowledge on this topic.
REFERENCES
1. Anesthesiologists ASo ASA Physical Status Classification System. Available

at: https://www.asahq.org/resources/clinical-information/asa-physical-status-
classification-system. Accessed September 2, 2108.
2. Sugerman PB, Barber MT. Patient selection for endosseous dental implants: oral
and systemic considerations. Int J Oral Maxillofac Implants 2002;17(2):191–201.
Is Digital Guided Implant
Surgery Accurate and
R e l ia ble?
Firas Al Yafi, DDSa,*, Brittany Camenisch, DDS, MS
b,c
,
Mohanad Al-Sabbagh, DDS, MSd
KEYWORDS
! Computer-aided surgery ! Implant-guided surgery ! Computer-assisted surgery
! Accuracy ! Dental implants ! Digital workflow ! Virtual plan
KEY POINTS
! The benefits of guided implant placement include increased predictability, and decreased
surgery time and complication rate.
! Static guides remain the most commonly used guide for computer-assisted implant
surgery.
! The digital workflow can be divided into 6 steps. Each step may produce deviations from
the virtual plan.
! The accuracy, efficacy, and complication rate of computer-guided implant treatment
remain within acceptable clinical limits.
! Proper execution of each digital workflow step must be carefully verified to reduce
inaccuracies.
INTRODUCTION
Guided implant surgery simplifies the execution of implant placement procedures and
renders optimal clinical outcomes. Digital implant planning allows the accurate diag-
nosis of an implant site and virtual visualization of the final prosthetic restoration. Addi-
tional clinical benefits include reduced surgical time and a lower complication rate
leading to increased patient acceptance and satisfaction. However, all the assumed
advantages of guided implant surgery over traditional surgeries depend on the precise
execution of the virtual implant plan.1–4
a
Arab Board of Oral Surgery, University of Kentucky, College of Dentistry, 4th floor (room
D436), Dental Science Bldg, 800 Rose street, Lexington, KY 40536-0297, USA; b Private Practice,
519 Hampton Way, Suite 10, Richmond, KY 40475, USA; c University of Kentucky, College of
Dentistry, 800 Rose Street, Lexington, KY 40536-0297, USA; d Division of Periodontology,
Advanced Education Externship Program, American Academy of Periodontology, University of
Kentucky, College of Dentistry, D-438 Chandler Medical Center, 800 Rose Street, Lexington, KY
40536-0927, USA
E-mail address: firasyafi@uky.edu
Dent Clin N Am 63 (2019) 381–397

382 Al Yafi et al
TYPES OF GUIDED SURGERY
Guided implant surgery can generally be classified as dynamic or static. Dynamic

guided surgeries involve the use of a computer-aided navigation system to
allow for real-time implant surgery. The major advantage to the dynamic design
is the ability to intraoperatively adjust the planned implant positioning.3 Although
navigated surgeries are gaining popularity, static guides remain the most
commonly used method. This article focuses on static guide–facilitated implant
surgeries.
The static guided surgery approach is based on the 3-dimensional (3D) data
obtained from cone-beam computed tomography (CBCT) and optical surface
scanning, and computer-aided design/computer-aided manufacturing (CAD/CAM)
technology for virtual implant planning and guide fabrication. The fabricated
surgical guide can be supported by tooth, mucosa, or bone. Additional
stabilization and support can be achieved using mini-implants, screws, or pins.2
Once the guide is fully seated, the planed drilling protocol beings. The drilling
protocol can include using the guide for the pilot drill only, or a partially or
fully guided drilling protocol. The implant insertion can be executed without the
surgical guide or through the guide via a fully guided approach. Proper case
selection and planning throughout the digital workflow allow for accurate
execution.
THE DIGITAL WORKFLOW
The digital workflow can generally be divided into 6 steps: (1) patient assessment,
(2) data collection, (3) data manipulation, (4) virtual implant planning, (5) guide and
prosthesis manufacture, and (6) execution of surgery and delivery of an immediate
provisional prosthesis (Fig. 1). It is worth mentioning that a combination of analog
and digital steps may be applied. In addition, different virtual planning implant soft-
ware may have some variation in the digital workflow.
Step 1: Initial Patient Assessment

During patient assessment, a comprehensive esthetic and functional evaluation
should include the following.
Dentition status
Both periodontal and restorative status for the remaining teeth must be
assessed. Evaluation of the existing denture must be performed in the case of
edentulism.
Fig. 1. Digital workflow. The 6 steps of the digital workflow guide clinicians from the initial
patient assessment to the execution of the implant surgery. CAD/CAM, computer-aided
design/computer-aided manufacturing; CBCT, cone-beam computed tomography; STL, stan-
dard tessellation language.
Digital Guided Implant Surgery 383
Initial radiographic assessment

The quantity and quality of the bone should be assessed to determine whether grafting
or a graftless approach is appropriate; this can be performed on 2-dimensional (2D)
radiographs.
Occlusion
Occlusal assessment is essential for acceptable esthetics and function. Adequate
mouth opening must be assessed because guided surgery requires extra access,
especially in posterior regions.
Aesthetic evaluation and prosthetic consideration
The prosthetic design should ensure appropriate lip support and white/pink display.
The prosthetic plan will mandate bone-reduction or augmentation procedures.
Step 2: Data Collection
Data collection includes CBCT acquisition and surface optical scanning. The process
of each is reviewed here.
CBCT acquisition
A CBCT is obtained with or without a radiographic guide in dentate patients. A dual-
scan technique is the primary method for the edentulous patient (Fig. 2); however,
direct mucosal scanning techniques are currently being explored.5
Limitations to CBCTs include poor soft-tissue contrast and distortion. Distortion can
be caused by patient movement6 and beam-hardening artifacts7,8 caused by high-
density materials such as composite filling, metal restorations, and implants. The
distortion affects the quality of the image and hence influences the accuracy of the
guided surgery.
Surface optical scanning
Soft-tissue and teeth inaccuracy depicted by CBCT can be compensated by obtaining
a surface optical scan, which represents the teeth surface and soft-tissue contour.
Hard-tissue and soft-tissue changes must be avoided after the surface scan is
captured, otherwise the fit of the surgical guide will be affected. The scan can be
created via direct or indirect methods. The patient’s impression or stone model is
Fig. 2. In the dual-scan technique, fiducial markers are attached to a well-fitting denture;
otherwise, a new denture or wax-up should be made. Two separate scans are taken, one
of the denture (A), and one of the patient with the denture inserted (B). Note the superim-
position of the 2 scans (C–F). The clinician must ensure that the denture is stable and is in the
appropriate position, as the intaglio surface of the scanned denture will represent the soft-
tissue surface.
384 Al Yafi et al
scanned using a lab scanner in the indirect method. In the direct method, an intraoral
scanner is used to scan the area of interest of the patient’s dental arch. Each arch
should be scanned individually and then together in occlusion to represent teeth
articulation.
The CBCT data are saved in Digital Imaging Communication in Medicine format
(DICOM) and the surface optical scan is saved and transferred in a standard tessel-
lation language format (STL). In addition, new CBCTs have the ability to merge
facial photographs with the CBCT to obtain an accurate representation of the dig-
ital smile.
Step 3: Data Manipulation

Data (the DICOM and STL files) are imported into the digital implant planning software.
Data manipulation consists of virtual dissection and orientation of the DICOM file,
identification of panoramic curve, tracking of inferior alveolar nerve, and merging
the CBCT and surface datasets.
Virtual dissection (segmentation)
CBCT shows both soft and hard tissue, and segmentation of the raw data allows for
the differentiation and colorization of anatomic structures and areas of interest. In
addition, segmentation reduces the image distortion caused by the metal scattering
and motion artifacts. The first step of segmentation is to obtain the appropriate density
threshold (also coined as gray-value threshold) to clearly visualize the hard tissues
(bone and teeth). Manual setup is the preferred method.9 Any portion of the scan
(known as a voxel) at a selected threshold with the same or larger density will be visible
in the selected volume (Fig. 3A–C).
CBCT gray values are often not reliable compared with multidetector-row computed
tomography.10–12 Furthermore, different CBCT machines provide variable gray
values.13,14 The selection of the threshold is subjective because it can be affected
Fig. 3. Segmentation of CBCT volume. The density threshold scale (measured in Hounsfield
units) can be adjusted. (A) Low-threshold value shows soft tissue. (B) Intermediate density
threshold between soft tissue and bone. (C) Higher-threshold value shows clear bone win-
dow. After establishing the proper threshold for bone, the areas of interest can be labeled.
(D, E) The frontal and lateral view of the segmented maxilla and mandible. (F) The
segmented 2 jaws after the default volume is turned off.
by the bone irregularities and maturation. Gray-value thresholds can also influence the
3D reconstruction and the fitting of surgical guides.15
Orientation and panoramic curve definition

The rendered reconstructed volume has to be correctly oriented into the 3 planes
(Fig. 4), after which the panoramic arch needs to be defined.
Nerve tracking
The software provides a nerve-tracking tool to detect the inferior alveolar canal by
placing dots along its path. Most software programs automatically join the dots and
provide a nerve pathway (Fig. 5).
Merging of CBCT and surface datasets

The files are merged by selecting identical anatomic landmarks of teeth surfaces or
fiducial markers (Fig. 6). Misalignment between DICOM and STL data sets can be a
possible source of error.
Step 4: Virtual Implant Planning

Once an accurate virtual patient model is obtained, the wax-up of the future prosthesis
will allow for the virtual placement of the implants. The surgical guide and prosthesis
are designed according to the virtual plan.
The wax-up
The future prosthesis is based on the scanned actual or virtual wax-up (crown-down
approach) (Fig. 7).
Virtual implant planning

The implant type and size can be chosen from the implant library in the software.
Implant position and axis are adjusted according to the available bone. A paralleling
tool may be used in the case of multiple implants. Most systems provide an option
to set a safety boundary around and between implants (see Fig. 7); accordingly, the
system will alert the user if these boundaries are violated. In addition, the possibility
of a flapless approach or any need for bone augmentation are determined at this time.
Surgical guide design

Once the virtual plan is finalized, the user can design the surgical guide including the
type of support (tooth, tissue, bone, or any combination). A minimum of 2 teeth are
Fig. 4. (A) The occlusal plane must be paralleled to the horizontal line in the sagittal view.
The patient’s midline should be reflected in the coronal view and axial view. (B) Panoramic
curve definition.
386 Al Yafi et al
Fig. 5. Nerve tracking allows 3D visualization of the nerve in the posterior mandible.
Fig. 6. Files merging. (A, B) The segmented DICOM file with selected areas that correspond
to those of the STL file in (B). (C–F) Alignment of the 2 files. Note the homogeneous align-
ment on different section and views to ensure accurate superimposition.
Fig. 7. Virtual implant positioning. The 3D virtual implant placement based on the future
prosthesis.
Fig. 8. Surgical guide design. (A) Inspection windows for tooth-supported guide are added
to allow the confirmation of the intraoperative seating of the guide. (B) The position for
fixation pins may be incorporated if needed. (C–E) Note the different sleeve heights corre-
sponding to the distance from the implant platform.
388 Al Yafi et al
recommended to support the guide.16 If additional support is needed, mini-implants

may be considered.
The sleeve size (length and diameter) and height (the distance between sleeve and
implant platform) may vary among different systems and according to the implant site
and plan requirements (Fig. 8). In general, decreasing the sleeve height and using a
shorter implant may reduce the angular deviation of guided implant placement.17,18
In addition, this will enable the clinician to perform the guide surgery in cases with
limited mouth opening.
Prosthesis design
The wax-up (actual or virtual) can be used as a blueprint to fabricate the custom-made
provisional or definitive prosthesis. The restorative space should be assessed during
the prosthesis design. Virtual abutments can be inserted to ensure a proper emer-
gence profile and access holes. The fully guided protocol will provide the appropriate
implant timing and depth for a prefabricated immediate provisional prosthesis (Fig. 9).
The concept of stackable guides was introduced to reduce surgery time and
improve the quality of the provisional full-arch prosthesis in implant-retained full-
arch cases. A foundation guide can be oriented using the occlusion, or anatomic land-
marks and may serve as a bone-reduction guide. The implant guide is stacked onto
the foundation guide to perform guided implant placement. Finally, a prefabricated,
enhanced provisional prosthesis with premade holes allows for rapid conversion of
the provisional (Fig. 10).
Surgical and prosthetic report

Following completion of the planning phase, the designed guides and prosthesis
are exported into an STL format for fabrication. A detailed report is generated,
which includes the drilling protocol with corresponding implants and prosthetic
components.
Step 5: Guide and Prosthesis Manufacturing

The fabrication of guide and prosthesis can be carried out via conventional or CAD/
CAM methods. Digital methods for the fabrication of the surgical guide, jaw models,
Fig. 9. Implant timing and depth. The orange arrows indicate precise alignment of the
implant (the dot on the mount) to the guide indicator (the groove on the guide). The red
arrow indicates that the implant is at the appropriate depth; the horizontal line on the
implant mount is at the most coronal portion of the guide sleeve.
Fig. 10. Digital fully guided surgery of full-arch, screw-retained, fixed immediate provisional
restoration. (A, B) Intraoral frontal and occlusal views of edentulous maxilla. (C, D) Actual
and scanned wax-up, which was used as the blueprint for the provisional prosthesis. (E) Vir-
tual implant planning. (F) Prefabricated monolithic polymethylmethacrylate, stackable pro-
visional prosthesis with premade holes. (G) Foundation guide on the stereolithographic
model of the jaw. (H) Foundation guide is used as a bone-reduction guide and is fixed pre-
cisely in position. (I, J) Implant guide snaps on the foundation guide. (K) Fully guided
implant placement. (L) Provisional metal abutments screwed on the multiunit abutments.
(M, N) Provisional prosthesis is seated in place on the foundation guide. Note the blue tissue
gasket that is used to isolate the implant plate forms during conversion procedure. (O) Pa-
tient’s smile. (P) Postoperative panoramic radiograph.
and the prosthesis include additive (rapid prototyping) or subtractive (milling) tech-
niques. Rapid prototyping involves the use of a 3D printer to cure photosensitive resin
in layers to generate the surgical guide and the stereolithographic models of jaws. Af-
ter the surgical guide is printed, implant system-specific metal sleeves are
incorporated.
The CAM milling systems offer many material options to produce the provisional and
final prosthesis or abutment.
Step 6: Surgical Execution

Proper fitting and seating of the surgical guide should be verified before surgery.
The surgical protocol, which includes the implant size and drilling sequence, is
followed. Each guided implant kit is specific to the implant system, and the
clinician should be familiar with the components before undertaking the surgery
(Fig. 11).
390 Al Yafi et al
Fig. 11. Fully guided, flapless surgery of a maxillary implants to retain an overdenture
with obturator. The patient has a history of cleft lip and palate. (A) Virtual implant
planning. Note the bilateral maxillary sinus graft. (B) Mucosa-supported implant
guide seated in place. (C) Flapless approach via tissue punch. (D) Osteotome correspond-
ing to the same drill size is used through the guide. (E) Fully guided implant placement.
(F) Postoperative panoramic radiograph showing proper implant position and
distribution.
Adequate irrigation throughout the surgery is crucial. The surgical guide may
prevent sufficient irrigation and therefore induce more heat. Recent in vitro
studies19,20 found that guided surgery generates more heat than the free-handed
drilling protocol. However, the additional induced heat was within the acceptable
temperature threshold. Jeong and colleagues21 have found that proper external
irrigation in an up-and-down pumping motion may reduce the risk of overheating
the bone during the guided drilling protocol. The authors recommend the use
of additional irrigation underneath the surgical guide, specifically an irrigation
syringe.
ACCURACY OF GUIDED IMPLANT SURGERY
Although guided surgery has become very predictable, deviations will always exist be-
tween the virtual plan and execution. Superimposition of preoperative and postoper-
ative CBCT is used to assess the accuracy of the guided implant surgery. The
deviation between the planned and the actual implant’s positioning in the mouth is
assessed through 4 measurements (Fig. 12). Model matching using preoperative
and postoperative models is an alternative method to assess the accuracy of the
guided surgery.22
Despite the clinically acceptable deviations of guided surgery, the current
level of accuracy does not justify the blind execution of the surgical plan. The
2018 International Team for Implantology consensus paper1 evaluated the accu-
racy of static computer-aided implant surgeries. The mean crestal point, apical
point, angular, coronal depth, and apical depth deviations were reported to be
1.2 mm, 1.4 mm, 3.5o, 0.2 mm, and 0.5 mm, respectively (Table 1). Based on
the aforementioned accuracy, a safety margin of 2 mm should always be
considered.
Fig. 12. Deviation measurements. 1, crestal point deviation: the horizontal linear distance
between the virtual and actual implants at the center of implant platform. 2, apical point
deviation: the horizontal linear distance between the virtual and actual implants at the level
of implant apex. 3, depth deviation: the vertical linear distance at between the virtual and
actual implants the center of implant platform (however, it can also be measured at the
implant apex level). 4, angular deviation: the angle between the long axis of the virtual
and actual implants.
SOURCES OF INACCURACY
Each of the aforementioned steps within the digital workflow carry a margin of inaccu-
racy. Current literature does not provide quantitative data on the deviation of each
step. However, overall guided surgery inaccuracy consists of the accumulated devia-
tions throughout. Both patient-related and surgery-related factors affect the accuracy
of the computer-aided surgery. Patient-related factors include the type of support and
location, whereas surgery-related factors include the skill of the clinician, flap design,
and drilling technique.
Patient-Related Factors
Type of support
In general, guided surgeries are more accurate in partially edentulous patients than in
fully edentulous patients.1 Tooth-supported guides are considered the most accurate,
followed by mucosa-supported guides (Box 1). Bone-supported guides are consid-
ered the least accurate.2,25 Many factors can affect the stability of each of these
guides. However, mini-implants, fixation screws, and pins are recommended to
further stabilize the guide and enhance the accuracy.2,23 Three to 4 fixation points
were recommended in different studies.1
Location
The literature regarding the accuracy of guided surgeries in the maxilla versus mandible
remains controversial. There are studies that show no difference.2,16,32–34 Some
studies indicate that guided surgeries in the mandible are more accurate,6,23,29,35
whereas others indicate greater accuracy of guided surgeries in the maxilla.36,37
392
Table 1
Recent systematic reviews on the accuracy of guided implant surgery
Al Yafi et al
F
Deviation
2
Study Title Method Crestal Point Apex Angular Depth Conclusion

A
AB
The accuracy of static SR and MA 1.2 mm 1.4 mm 3.5" (3.0" –3.96" ) At crestal point Guided surgery is
A(
computer-aided 20 CT (1.04–1.44 mm) (1.28–1.58 mm) Partially edentulous: 0.2 mm (#0.25 to significantly more
2 DB
implant surgery: a 2238 implants, 471 Partially edentulous: Partially edentulous: 3.3" (2.07–4.63) 0.57 mm) accurate in partial
systematic review patients 0.9 mm 1.2 mm Edentulous: At apex point edentulism
and meta-analysis Fully guided drilling (0.79–1.00 mm) (1.11–1.20 mm) 3.3" (2.71–3.88) 0.5 mm (#0.08 to compared with
Tahmaseb et al,1 2018 protocol Edentulous: Edentulous: 1.13 mm) fully edentulous
1883 fully guided 1.3 mm (1.09– 1.5 mm cases
implants placed 1.56 mm) (1.29–1.62 mm) The overall accuracy
is clinically
acceptable
Clinical factors SR and MA 1.25 mm (1.22– 1.57 mm 4.1" (3.97" –4.23" ) At crestal point A totally guided
affecting the 14 CT, 1513 implants 1.29 mm) (1.53–1.62 mm) (3 studies, 260 system using
accuracy of guided implants) fixation screws
implant surgery: a 0.64 mm with a flapless
systematic review (0.53–0.74 mm) protocol
A
and meta-analysis At apex point (4 demonstrated the

Zhou et al,23 2018 studies, 295 greatest accuracy.
A
implants)
C
1.24 mm
2/
(1.16–1.32 mm)
Accuracy of implant SR: 34 studies, 3033 CT CT CT Only 14 studies: Fully guided implant
,B E A. ( A
placement with implants 1.10 $ 0.09 mm 1.40 $ 0.12 mm 3.98" $ 0.33" CT placement has
3 ,B E A
computer-guided Including: CS: 1.18 $ 0.12 mm CS: 1.52 $ 0.18 mm CS: 2.82" $ 0.40" 0.74 $ 0.103 lower deviation
surgery: a 22 CT, 2244 implants IVS: 0.77 $ 0.15 mm IVS: 0.17 $ 0.85 mm IVS: 2.39" $ 0.35" CS: 0.28 $ 0.049 mm values compared
systematic review 8 IVS, 543 implants IVS: 0.61 $ 0.149 mm with half-guided
and meta-analysis 4 CS, 246 implants implant placement
comparing (only static guides)
3AD2A
CB A B AE
cadaver, clinical,
and in vitro studies
Bover-Ramos et al,24
2018
Abbreviations: CS, cadaver study; CT, clinical trial; IVS, in vitro study; MA, meta-analysis; SR, systematic review.
Box 1
Factors affecting accuracy of mucosal supported guides in edentulous patients
! Bone density
! Mucosal thickness
! Local anesthetics (because of tissue inflation)
! Smoking (because of increased mucosa thickness)
Surgery-Related Factors
Clinician experience
Current literature is inconsistent on whether experience in guided implant placement
plays a role in accuracy.38–40 Cassetta and Bellardini41 consider furthering clinicians’
experience in conventional implant placement as the gold standard before switching
to guided surgery. However, higher levels of accuracy can be obtained by expert sur-
geons when initially using computer-guided surgery,41 especially the accuracy of
implant depth.42 Nonetheless, guided surgery has a positive correlation with the
reduction of surgical complications.43
Flap versus flapless approach

There are advantages and disadvantages to each approach (Table 2). Fixation
pins16,33,49 and mucosal resilience29,32,50 affect the stability and accuracy of the
mucosa-supported guides. Fully guided implant placement using the flapless
approach with fixation screws is the most accurate approach.23 Bone-supported
guides necessitate extensive flap reflection, which may interfere with the guide posi-
tioning; this may be an explanation for the reduced accuracy.51
Drilling technique
Eccentric drilling through the sleeve has a substantial effect on accuracy, especially
with limited access to the posterior jaw or limited mouth opening. This factor may
be of clinical importance, affecting the overall accuracy.52,53
It may be concluded that fully guided surgery is more accurate than partially guided
surgery.2,23,24 Even with increased accuracy and efficacy, guided implant surgery is a
technically demanding procedure and is not complication free. Hence, the belief that
“less training is needed” is far from true.54 However, the limited scientific evidence
available suggests that guided placement has equal or greater implant and prosthesis
survival rate compared with conventional protocols with an equivalent clinical compli-
cation rate.2,55,56
Table 2
Advantages and disadvantages of flap and flapless approaches
Flapless Flap
Advantages Reduces patient postoperative discomfort, Improves intraoperative
surgical time, postoperative bleeding, and assessment47,48
healing period3,44–46
Disadvantages and Less visualization and adequate keratinized Increases patient
prerequisites tissue are necessary discomfort3,44,47
394 Al Yafi et al
SUMMARY
Current guided technology enables implant planning and placement in a prosthetically

driven manner. The digital workflow generally consists of 6 steps: (1) patient assess-
ment, (2) data collection, (3) data manipulation, (4) virtual implant planning, (5) guide
and prosthesis manufacture, and (6) execution of surgery and potential delivery of
an immediate provisional prosthesis. However, sometimes a combination of analog
and digital steps may be applied to the workflow.
Guided implant surgery is assumed to be accurate, precise, and reliable compared
with free-handed implant surgery. However, deviation between implant virtual plan-
ning and implant real position may occur because of the surgical learning curve and
the accumulated errors that may occur throughout the multiple steps of the digital
workflow.
The reliability of computer-guided surgery does not justify a blind execution. The
learning curve is undeniable and a clinician with basic surgical skills, including conven-
tional implant dentistry, will be in a better position to address any unforeseen
complications.
ACKNOWLEDGMENTS
The author would like to acknowledge Dr Ryan Rubino, who provided photos and
radiographs for Fig. 10.
REFERENCES
1. Tahmaseb A, Wu V, Wismeijer D, et al. The accuracy of static computer-aided

implant surgery: a systematic review and meta-analysis. Clin Oral Implants Res
2018;29(Suppl 16):416–35.
2. Tahmaseb A, Wismeijer D, Coucke W, et al. Computer technology applications in
surgical implant dentistry: a systematic review. Int J Oral Maxillofac Implants
2014;29(Suppl):25–42.
3. Jung RE, Schneider D, Ganeles J, et al. Computer technology applications in sur-
gical implant dentistry: a systematic review. Int J Oral Maxillofac Implants 2009;
24(Suppl):92–109.
4. D’Haese J, Van De Velde T, Komiyama A, et al. Accuracy and complications us-
ing computer-designed stereolithographic surgical guides for oral rehabilitation
by means of dental implants: a review of the literature. Clin Implant Dent Relat
Res 2012;14:321–35.
5. Oh JH, An X, Jeong SM, et al. Digital workflow for computer-guided implant sur-
gery in edentulous patients: a case report. J Oral Maxillofac Surg 2017;75:
2541–9.
6. Pettersson A, Komiyama A, Hultin M, et al. Accuracy of virtually planned and tem-
plate guided implant surgery on edentate patients. Clin Implant Dent Relat Res
2012;14:527–37.
7. Tadinada A, Jalali E, Jadhav A, et al. Artifacts in cone beam computed tomogra-
phy image volumes: an illustrative depiction. J Mass Dent Soc 2015;64:12–5.
8. Schulze RK, Berndt D, d’Hoedt B. On cone-beam computed tomography arti-
facts induced by titanium implants. Clin Oral Implants Res 2010;21:100–7.
9. Flugge T, Derksen W, Te Poel J, et al. Registration of cone beam computed to-
mography data and intraoral surface scans—a prerequisite for guided implant
surgery with CAD/CAM drilling guides. Clin Oral Implants Res 2017;28:1113–8.
Maxillofacial Bone Grafting
M a t e r i a l s 2021 Update
Nabil Moussa, DDS*, Yijiao Fan, DDS, Harry Dym, DDS
KEYWORDS
! Bone ! Tissue grafting ! Bone regeneration ! Osteoinductivity
! Regenerative materials ! Tissue engineering ! Bone morphogenetic protein
KEY POINTS
! This article provides a summary of the basic knowledge and fundamental principals of
bone grafting in the setting of Oral and Maxillofacial Surgery.
! Autogenous bone graft is currently the gold standard in regards to grafting success.
! Available grafting materials include autograft, allograft, xenograft and alloplast.
! Bone morphogenic protein is predictable method for inducing bone formation.
INTRODUCTION
Successful outcomes in the use of bone grafting and reconstructive outcomes heavily
depend on understanding the fundamentals and material properties. The purpose of
grafting is to achieve regeneration of hard tissues. The regenerated bone must have
the capacity to provide the same physiologic support as the original dentition. Such
goals can be achieved through regenerating well-vascularized bone that will undergo
normal remodeling and healing. Prosthetically, a variety of restorative options,
including fixed, hybrid, and removable restorative options, have become available.
These options restore functionality and quality of life to patients who may have both
esthetic and functional disabilities. Regenerated bone must have histologically and
physiologically identical characteristics to native bone. Implant integration and func-
tion depend on the composite characteristics and structural stability of native bone
to function. This article provides an overview of the currently available bone regener-
ative materials, their advantages, and their uses in the current literature.
BIOLOGY OF BONE
Bone is a composite structure composed of a macrostructure of type I collagen with

calcified components. Bone is a dynamic structure undergoing constant resorption
This article has been updated from a version previously published in Dental Clinics of North
America, Volume 64, Issue 2, April 2020.
Department of Dentistry, Division of Oral and Maxillofacial Surgery, Brooklyn Hospital Center,
121 Dekalb Avenue, Brooklyn, NY 11201, USA
E-mail address: moussanabil@gmail.com
Dent Clin N Am 65 (2021) 167–195

168 Moussa et al
and deposition by osteoclasts and osteoblasts. To maintain balance, the body orches-
trates cell activity by secreting parathyroid hormone (PTH), vitamin D, and calcitonin.
This dynamic system plays an important role in growth, adaptation to biomechanical
stresses, and repair of macrofractures and microfractures.
Bone deposition, resorption, and maintenance are achieved through the actions of
osteoblasts, osteoclasts, and osteocytes. Osteoblasts are derived from local differen-
tiated osteoprogenitor cells in reaction to stimuli. Such osteoprogenitor cells are pre-
sent in the periosteal and endosteal layers of the bone. These critical parenchymal
tissues serve as a vital reservoir for undifferentiated stem cells in addition to serving
as a blood supply to the native tissue. Minimizing the reflection of periosteum during
dissection preserve vascularity to the local tissues, which leads to improved outcomes
of bone regeneration. Osteoclasts are resorptive cells that, through the actions of alka-
line phosphatase, resorb bone and release calcium. Through the coordinated actions
of PTH, calcitonin, and vitamin D, bone turnover and calcium levels are maintained.
Diseases that affect this balance can be detrimental to the body. Diseases such as
Paget, rheumatoid arthritis, and osteopenia can compromise the integrity of the
bony framework. Conditions such as release of parathyroid hormone–related proteins
in squamous cell carcinoma and renal osteodystrophy can result in osteolytic lesions
defects that make bone susceptible to fracture.
Bone is composed of 2 major components: cortical and trabecular bone. Cortical
bone is a dense housing that forms the outer layers that encase the trabecular bone
marrow. Harvesting and grafting each type affects the quality of the regenerated
bone. Cortical bone is a dense structure made of haversian canal systems. Examina-
tion of cortical bone reveals bone resembling tubes with a central core containing os-
teocytes. Cortical bone is composed of multiple units of tubules, referred to as
haversian canals. Trabecular bone is formed by an aggregate of bone loosely arranged
in a meshlike fashion. Within this lattice, erythron and leukopoiesis takes place.
During bone formation, mesenchymal cells are stimulated by growth factors during
development and differentiate into osteoblasts. Osteoblasts deposit bone in their im-
mediate surrounding, encasing themselves within a mineralized matrix termed
lacunae. As the bone grows, these osteoblasts mature into osteocytes. Groups of
lacunae form into conical structures previously referred to as haversian canals. The in-
dividual osteocytes communicate with one another through the canals, which allow
resorption and deposition in response to the needs of the body. Trabecular bone
forms within the core of the developing cortical bone. A thin, fibrous tissue subse-
quently forms around the maturing bone. Periosteum is the layer that envelopes
cortical bone. In comparison, endosteum envelopes trabecular bone. The tissue sur-
rounding these bony structures provides vascular supply and nutrition (Table 1).
Bone is classified into several categories depending on the thickness and volume of
cortical and cancellous bone. The composition changes depending on the load and de-
mands on the bone. Branemark1 described and classified bone based on the compo-
sition of cortical and trabecular bone. Type 1 bone is composed mainly of cortical bone
with minimal amounts of trabecular bone. In contrast, type 4 bone is composed mainly
of trabecular bone and little cortical bone. Types 2 and 3 bridge the gap between types 1
and 4, with more trabeculae present in type 3 bone. The mandible is typically character-
ized by a composition of type 1 and 2 bone. Type 3 bone primarily makes up the maxil-
lary alveolus, with sections of type 4 bone posteriorly toward the tuberosity.
Implant placement and primary stability are affected by the type of bone in which it
is placed. Implant placed in type 2 bone is likely to have good primary stability with
good bone/implant interface, and such bone is typically found in the mandible. Type
3 bone may need an implant with a more aggressive thread design, and such bone
Maxillofacial Bone Grafting Materials 169
Table 1
Composition of bone
Type of Bone Histologic Features

Organized matrix 40% of the dry weight of bone. Composed of 90% type 1 collagen,
noncollagenous proteins, ground substance, water, proteoglycans,
cytokines, and growth factors
Cells Osteoprogenitor cells: osteoblasts osteocytes osteoclasts
Vascular and Bone receives 5%–10% of cardiac output via arterial supply through
nutrient the periosteum and endosteum.
Distribution Microcirculation, lymphatics, and venous return
Neurologic Bone is supplied by autonomic and neurosensory networks
Marrow Serves hematopoietic and osteogenic functions
Periosteum A source of osteoprogenitor cells, neurovascular distribution, and blood
supply
Endosteum A source of osteoprogenitor cells
Communication A network including haversian and Volkmann canaliculi lacunae and
systems extracellular fluid
From Moussa NT, Dym H. Maxillofacial bone grafting materials. Dental Clin North Am.
2020;64(2):474; with permission.
is typically found in the maxilla. Both types 1 and 4 bone have their own respective
disadvantages and are not favorable for implant placement. Type 1 bone is dense
with minimal trabecular bone present. Such bone has reduced vascularity and subse-
quently is more susceptible to necrosis and implant failure. Type 4 bone has minimal
cortical bone present, and implants placed in such bone, although integrated, may not
be able to support functional loads. The end result is implant failure and compromise
in the foundation of the prosthesis.
BONE HEALING BIOLOGY
The mechanism of bone healing closely follows that of other tissues. Bone must pro-
ceed through the 3 phases of healing: inflammation, proliferation, and remodeling.
Inflammation leads to blood coagulation and hematoma formation. Damage to endo-
thelial cells leads to platelet aggregation and degranulation. Critical growth factors are
released to promote angiogenesis and formation of a hematoma. Growth factors
include fibroblastic growth factor and vascular endothelial growth factors. In the pro-
liferative phase, fibroblasts are recruited and migrate into the surgical site. Fibrin
deposition and angiogenesis result in organized tissue development, referred to as
granulation tissues. The fibrin and collagen network paves the way for osteoblast
migration and collagen deposition within 48 hours.
Initial collagen meshwork in bone is composed of type I and III collagen. The fibers
are laid in a haphazard manner and the process of ossification begins. Calcification
begins in what are referred to as ossification or maturation centers. Immature
osteoid forms around these foci of calcified tissues, slowly growing in a concentric
manner. Additional osteoblasts are recruited and surround the osteoid, further
expanding the bone until ossification centers come into contact with one another
and merge. Large blocks of osteoid are referred to as a soft callus, forming 4 to
7 days following the initial insult. As the soft callus matures and bone consolidates
in the remodeling phase, osteoid begins to reorganize into organized matrices of
cortical and trabecular bone. The remodeling phase starts at 8 weeks and forms
what is known as a hard callus. The remodeling phase is orchestrated by the actions
170 Moussa et al
of osteoblasts and osteoclasts, which are responsible for bone deposition and
resorption respectively. Type III collagen is replaced by the composite structure
made of type I collagen. At the time of remodeling, the bone is most brittle and sus-
ceptible to fracture. Sixteen weeks following the insult is when bone maturation and
remodeling is completed. The bone is considered to have the structural integrity for
load-bearing forces.
EFFECTS OF BONE GRAFTING ON HEALING
The purpose of bone grafting and reconstruction is to regenerate tissues that are histo-
logically identical to the native bone tissues. Aside from autogenous tissue, grafting ma-
terials are limited to those that are acellular. The remaining types of graft material are
processed to maintain the macrostructure of bone or synthesized to mimic local scaf-
folding of bone to facilitate the movement and migration of local cells into the graft. This
property of grafting materials is referred to as being osteoconductive. Techniques have
been developed to preserve or add growth factors that add osteoinductive potential to
the graft. The ability to facilitate and recruit cells into the graft material is referred to as
being osteoinductive. Synthetic grafts such as calcium carbonate or even xenografts
have been shown to have a slower rate of resorption and can act to resist compressive
forces from wound contraction or masticator forces that may cause volume loss. Auto-
grafts have osteoinductive and osteoconductive properties. In addition, autografts
transplant live osteoclasts, osteoblasts, and the pluripotent osteoprogenitor cells.
Such tissues are considered to have osteogenic potential. The osteogenic potential
of autografts has a significant positive impact on tissue healing and bone integration.
Autografts are considered the gold standard of bone grafting materials.
IMPACTS ON BONE HEALING
Minimizing factors that can negatively affect bone healing leads to reduced risk of graft
failure and increased volume of regenerated bone. Immobility and vascular perfusion
are essential in bone healing. Micromotion in healing is considered an important
contributing factor for nonunion. For example, fractured bone segments that are not
immobilized result in micromotion and severance of the newly formed blood vessels.
Compromises in the vascular supply lead to nonunion. In a similar fashion, grafted
bone that receives pressure and is not immobilized has an increased incidence of fail-
ure, with greatly reduced bone volume regenerated. Pressure on grafted bone when
placed under function can result in graft failure during the healing period due to
compromised vascular supply.
Patients who have received radiation have drastically reduced angiogenic and
cellular capacity for healing. Free radicals formed through radiation damage cell struc-
ture and cause sclerosis of vital vessels. The result is referred to as the 3 Hs: hypocel-
lular, hypo-oxygenated, and hypovascular tissue. In such circumstances, patients must
receive treatment to improve tissue oxygen perfusion in the form of hyperbaric oxygen.
Hyperbaric oxygen treatment increases the oxygen tension of the tissues, subsequently
stimulating angiogenesis with the goal of improving the chances of bone healing.
Systemic conditions that affect the vascular supply of tissues also have a negative
effect on bone healing. Conditions such as diabetes and atherosclerosis reduce the
flow of blood to the healing bone, subsequently reducing the nutritional supply to
the healing tissues. In addition, modifiable risk factors such as smoking have devas-
tating effects on the vascular supply to healing bone. The effects of nicotine on the
vasculature last 5 hours (5 half-lives of 60 minutes) and compromise the blood flow
to tissues. In addition, smokers have reduced oxygen carrying capacity through the
formation of carboxyhemoglobin, which shifts the hemoglobin dissociation curve to

the left. The result is a reduced proportion of hemoglobin molecules available for car-
rying oxygen. Patients that have stopped smoking have been found to have impaired
macrophage and antimicrobial resistance for up to 6 months.
BASICS OF BONE GRAFTING
Clinical success in bone regeneration depends on good clinical practice and under-
standing the basics. Bone must have adequate blood supply and fixation. Several
technical basics must be kept in mind when conducting patient care. Obtaining a
good vascular supply is largely influenced by the clinician’s ability to design and
handle soft tissue gently. Mucosal and attached gingiva must be handled with care,
and crush injuries must be avoided when using the tissue forceps. When designing
a flap, the base of the flap must be wider than the free margin of the flap. Folding or
kinking flaps must be avoided to optimize blood flow and perfusion pressure to the
flap. The clinician must conduct appropriate release of the soft tissue and periosteum.
Without primary closure, blood supply is compromised and the bone is exposed to the
oral flora, giving rise to potential infections. However, it is important to maintain
tension-free closure to avoid ischemic necrosis in the soft tissue. It is prudent to
pay attention to detail in flap design and not create incisions that will result in closure
over root prominences (eg, over the canine root). Such flaps conveniently place inci-
sions over points of tension.
When grafting, primary stability of the grafted material is critical. Micromotion in
bone grafting or any pressure applied to the graft can compromise the vascular supply
to the grafted material. Often, fibrous nonunion and subsequent graft failure result.
Grafts can be fixated with the use of fixation screws or pins. A minimum of 2 screws
must be placed to prevent rotational forces. Titanium mesh is a reliable medium to
secure and house particulate grafts. The material is able to maintain its shape, resist
functional forces of deformation, and minimize motion. Materials such as polytetra-
fluoroethylene (PTFE) have been developed to provide protection in cases where pri-
mary closure is difficult or not possible. These membranes have the capacity to remain
exposed in the oral cavity and can be stabilized with the use of titanium screws or pins.
Both PTFE and titanium mesh are nonresorbable membranes and must be removed
before additional fixture placement. The PTFE membrane is typically removed 4 weeks
following placement once the soft tissue callus has formed.
BONE GRAFTING MATERIALS
Four basic types of bone grafting materials are available for use clinically to augment
and reconstruct the maxillofacial skeleton (Tables 2 and 3).
AUTOLOGOUS BONE
Autologous bone refers to bone that is harvested form the individual’s own tissue. Ex-
amples of harvest sites used in the oral surgery setting include the anterior and pos-
terior hip, calvarium, tibia, and mandibular ramus and symphysis. Use of autologous
bone and its popularity in the routine oral surgical setting has decreased because of
the predictability and availability of allogenic bone. However, autogenous bone is still
maintained as the gold standard for bone grafting.2 This particular source of bone is
the only graft material that boasts osteoconductive, osteoinductive, and osteogenic
properties. In the contemporary setting, autogenous bone is typically reserved for
large defects or situations where predictable results are hard to obtain; for example,
172 Moussa et al
Table 2
Classes of bone graft materials
Bone Type Description

Autograft (autogenous) Transplant of viable cortical or cancellous bone from one location
of the body to another within the same patient
Xenograft Cross-species transplant of tissue: the use of organic bovine bone
or porcine collagen
Alloplast Implantation of synthetic material, such as apatite or tricalcium
phosphate, bioactive glass, or polymers
From Moussa NT, Dym H. Maxillofacial bone grafting materials. Dental Clin North Am.
2020;64(2):475; with permission.
in continuity defects and alveolar clefts.3 In patients with craniofacial dysplasia and
oculoauriculovertebral spectrum disorders, rib grafts, with their respective cartilagi-
nous components, have been used in the reconstruction of temporomandibular joints.
Depending on the harvest site, different volumes and compositions of grafts can be
harvested (Table 4).
As discussed previously, adequate vascular supply to the grafted bone is critical in
the survival and integration of the graft. Defects ranging more than 6 to 8 cm are
considered the limit for nonvascularized bone grafting. Reconstruction in defects large
than 6 to 8 cm becomes challenging when using nonvascularized grafts because the
nutritional and oxygen supply is inadequate. Nonvascularized grafts obtain their nutri-
tional supply through a process known as imbibition. Subsequent inosculation of
blood vessels to the graft provides new anastomosis and vascular network for the
grafted tissues. The limitations of this process are reached when defects become
bigger than 6 to 8 cm. When reconstructing large defects as a result of resections
from ameloblastoma and squamous cell carcinoma or loss from traumatic injuries,
vascularized grafts are indicated. A vascularized graft is needed to maintain nutrition
and oxygen tension to the grafted tissue. Examples of vascularized bone grafts
include free fibula, iliac crest, and scapular tip grafts.
Table 3
Bone grafting material overview
Bone Graft Structural Strength Osteoconduction Osteoinduction Osteogenesis

Autograft — — — —
Cancellous No 111 111 111
Cortical 111 11 11 11
Allograft — — — —
Cancellous — — — —
Frozen No 11 1 No
Freeze No 11 1 No
dried
Cortical — — — —
Frozen 111 1 No No
Freeze 1 1 No No
dried
From Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury.

2005;36(Suppl3):S21; with permission.
Table 4
Typical noncompressed graft volumes available for harvest
Noncompressed Corticocancellous Cortical Block

Tibia 25–40 cm3 1 " 2 cm
Anterior Ilium 50 cm3 3 " 5 cm
Posterior Ilium 100–125 cm3 5 " 5 cm
Calvarium Variable, minimal Abundant
From Zouhary KJ. Bone graft harvesting from distant sites: concepts and technique. Oral Maxillofac
Surg Clin North Am. 2010;22(3):303; with permission.
In planning for reconstruction, it is important to consider the volume and composi-

tion of the graft that can be harvested. It is generally accepted that a 1-cm defect
require 10 cm3 of bone for reconstruction. Depending on the harvest site, large vol-
umes of cortical or trabecular bone may be harvested. For example, the symphysis
of the mandible yields primarily cortical bone, which is useful in reconstructing alveolar
defects in the area of lateral incisors or in gaining structural support (vertical and hor-
izontal). In contrast, harvesting graft from the ilium (anterior or posterior) yields a large
volume of trabecular bone, which is useful in guided tissue regeneration and recon-
struction of alveolar clefts. Cortical blocks are often used for their structural integrity
in reconstruction. Periosteum often constricts during the healing process. Cortical
grafts resist compression forces placed on the graft material during the healing pro-
cess. Such resistance is important to maintain the volume of regenerated tissue and
achieve the appropriate dimensions for fixture placement. Trabecular bone is often
favorable for filling defects. The handling characteristics make marrow bone ideal
for filling walled defects and contouring the graft sites.
Autogenous graft is advantageous for the key reason that it is the host’s own tissue.
As mentioned previously, it has osteoinductive, osteoconductive, and osteogenic
properties. Osteoconduction and osteoinduction refer to the graft’s ability to facilitate
movement of cells into the graft and induce differentiation of host monocytes into os-
teoblasts, respectively. When harvested, the graft maintains the original macrostruc-
ture and microstructure of the tissue, which includes the cytokines, growth factors,
and cells of the tissue. The transplant of vital host cells is referred to as osteogenic
grafting. Components of the graft give autograft distinct advantages of efficient
signaling and differentiation of osteoprogenitor cells present within the periosteum
and endosteum within the host site and the graft. These properties facilitate efficient
new osteoid formation and graft integration.
Because the tissue is harvested from the host, there is no risk of immune rejection
and disease transmission. Autogenous grafts eliminate risks in transmission of dis-
eases, including human immunodeficiency virus and hepatitis B and C. There are still
reported cases of disease transmission despite the manufacturers’ efforts to appropri-
ately screen, test, and process tissue in a disease-free condition.
The need for a secondary surgical site is the main disadvantage of autologous
grafts. In addition, limited volume can be harvested and the process is associated
with its own morbidity. For example, anterior and posterior iliac crest grafts have an
associated risk of gait disturbance, which can result in difficulty ambulating. Compli-
cation rates have been reported to be 8.5% to 20%.4–8 Other types of complications
include hematoma formation, gastric ileus, blood loss, neurosensory disturbances,
hernia formation, pelvic fracture, and chronic pain. Harvest sites such as the symphy-
sis can result in cosmetic defects, droopy chin, and sensory disturbances in the dis-
tribution of the mental nerve. The invasive nature and risk of morbidity restrict its
174 Moussa et al
access to those clinicians that are appropriately trained in the harvest of autogenous
graft. In addition, its use must be carefully planned so the risks of harvest are justified
by the benefits of the graft. However, with the use of trephine burs and bone scrapers,
local harvesting techniques have made obtaining grafts easier. In summary, autoge-
nous bone is a superior graft material with numerous advantages, such as improved
healing time and predictable results compared with other types of available grafting
material. However, its use must be carefully considered and the risks must be weighed
against the benefits.
Cleft lip and palate is a good example of an indication for the necessary use of
autogenous bone grafting. Carlini and colleagues9 report a case series of 16 patients
with bilateral transincisive foraminal defects of the premaxilla. Following a period of
orthodontic optimization and stabilization using a transpalatal appliance, the premax-
illary segment was surgically repositioned and secured using an acrylic splint. The sur-
gery involved invasive reflection and repositioning of soft and hard tissues (Fig. 1). Iliac
crest bone (cortical and trabecular) was harvested and the cortical plates were used to
fixate the premaxilla to the posterior alveolar segments with titanium screws to
achieve primary stability. Medullary bone was subsequently used to fill the remaining
void and contour the bone. In such cases where incisions and osteotomies compro-
mise the vascular supply to the tissues, autogenous graft provides the appropriate
stability, tissue volume, and growth potential to obtain a predictable result.9 Precious
Fig. 1. (A) Access and osteotomy to separate the premaxilla; (B) premaxilla displacement for
closure of the nasal mucosa; (C) suturing to remake the nasal fossa floor; and (D) cortical fix-
ation with screws (1.5 mm) in the maxilla and premaxilla. (From Carlini JL, Biron C. Use of the
iliac crest cortex for premaxilla fixation in patients with bilateral clefts. J Oral Maxillofac
Surg. 2020;78(7):1192.e3; with permission.)
and colleagues10 outlined repair of the cleft palate with the use of iliac crest bone graft.
Repair and excellent results were achieved with the use of careful surgical planning,
technique, and autogenous bone (Fig. 2).
Acocella and colleagues11 evaluated the clinical, histomorphic, and histologic qual-
ity of bone in transplanted mandibular ramus grafts used for the regeneration of maxil-
lary alveolar bone. The study population consisted of 15 patients with maxillary
alveolar defects planned for implant placement and prosthesis fabrication. Recon-
structive sites involved defects of both the anterior and posterior maxilla. The clinical
procedures focused on horizontal augmentation. The mean width of augmentation
was measured preoperatively and at time of reentry (Fig. 3).
The grafts were allowed to heal for a period of 3 to 9 months. Bone samples were
harvested at the time of implant site preparation. The study reported a mean augmen-
tation thickness of 4.6 mm, with a range from 3 to 6 mm. Following adequate healing,
the mean thickness of bone remaining was 4.0 mm, which showed a loss of thickness
to resorption of 0.6 mm. These findings were consistent with what is reported in the
literature, with good volumetric stability of cortical grafting and minimal resorption.
A total of 30 implants were placed with no reported failures. The histologic findings
of the study are of particular interest because the investigators paid attention to the
rate of neovascularization of bone. All of the samples collected in the study showed
signs of remodeling and were free of inflammatory tissue. In addition, the investigators
noted good neovascularized tissue present in the grafted bone, with good osseous
integration of the host site with the grafted bone. However, the investigators did
note a histologic change in the direction of lamella demarcating the margin of the
grafted bone with the native bone. The histologic observations that vital bone con-
tained osteocytes in a core of osteoid surrounded by neovascularized bone suggest
that the host tissue recolonized the grafted bone (Fig. 4).
The study noted that neovascularized bone tissue represented an area of osteo-
cytes that did not survive the transplant and required tissue reperfusion and remodel-
ing for the graft to survive.11 In comparison, Ellegaard and colleagues12 found that,
following disruption of blood vessels, many osteocytes do receive the nutrition neces-
sary for osteocyte survival. In support of these findings, Ham and colleagues13 noted
that osteocytes require less than 0.1-mm proximity to haversian systems for survival.
The literature provides evidence that, with adequate time, autogenous grafting
Fig. 2. Preoperative and postoperative results following bone grafting. Visible is the good
soft tissue perfusion and integration of the graft with the host tissue. (From Carlini JL, Biron
C. Use of the iliac crest cortex for premaxilla fixation in patients with bilateral clefts. J Oral
Maxillofac Surg. 2020;78(7):1192.e4; with permission.)
176 Moussa et al
Fig. 3. View of a maxillary narrow ridge after flap elevation (A); bone osteotomies on
mandibular buccal shelf (B); the monocortical is out-fractured (C); adaptation and fixation
of the graft to the maxillary recipient site (D); gaps around the block grafts were filled
with bone chips harvested from the donor site (E); primary flap closure without tension
(F). (From Acocella A, Bertolai R, Colafrenceschi M, et al. Clinical, histological and histomor-
phometric evaluation of the healing of mandibular ramus bone block grafts for alveolar
ridge augmentation before implant placement. J Craniomaxillofac Surg. 2010;38(3):225;
with permission.)
supports neovascularization and survival of osteocytes in grafted autogenous bone.

The regenerated bone provides a good foundation for implant placement and survival.
Harvesting bone from the hip provides large volumes of grafting material (see
Table 4): between 50 and 100 cm3 based on harvest site. Fretwurst and colleagues14
investigated the bone level changes around dental implants placed in autogenous
bone grafted from iliac crest (Figs. 5 and 6). Both maxillary and mandibular regenerative
tissues were evaluated. A total of 32 patients were recruited for the study, and 150 im-
plants were placed into the regenerated tissues. Following a mean observation period of
69 months (12–165 months of healing), implant success rates were evaluated. The study
reported a success rate of 96% in the maxilla and 92% in the mandible. The mean
crestal bone loss was 1.8 mm, which is consistent with rates reported in the literature.14
In the reconstruction of large mandibular and maxillary defects, the fibula serves as
a large source of available bone. The fibula is a non–weight-bearing bone and does not
Fig. 4. Histologic changes of grafted bone. (A) (a1) Four months following surgery with sub-
stantial amount of fibrous tissue (FT) and minimal amounts of vital bone (VB), (a2) same
specimen at a higher magnification. VB is surrounded by new vascularized bone (NVB)
with empty lacunae representing creeping substitution. (B) (b1) Six months following sur-
gery, active bone remodeling is appreciated with presence of larger amounts of VB, (b2)
same specimen at higher power, with larger composition of VB containing osteocytes
compared with 4 months. (From Acocella A, Bertolai R, Colafrenceschi M, et al. Clinical, his-
tological and histomorphometric evaluation of the healing of mandibular ramus bone block
grafts for alveolar ridge augmentation before implant placement. J Craniomaxillofac Surg.
risk the patients’ ability to ambulate when harvested. The graft can be harvested as a
vascularized or nonvascularized graft. When reconstructing defects larger than 6 to
8 cm, vascularized grafts are necessary to maintain nutritional supply to the grafted
bone. Duttenhoefer and colleagues15 provided their results with grafting of atrophic
mandibles. The investigators showed that atrophic mandibles (thickness <10 mm)
could be predictably grafted with the use of avascular fibular grafts. In addition, the
study showed long-term stability and osseointegration of implants placed in the re-
generated bone. The patients were followed up to 15 years with stable results. The
bone was sampled at the time of implant placement, which supported that autoge-
nous bone successfully revascularized and retained cortical bone structure
(Fig. 7).15 The findings of Duttenhoefer and colleagues15 were consistent with other
reports in the literature. Nelson and colleagues16 reported their results on 10 patients
augmented with avascular fibular graft in a vertical fashion. Vertical grafting is very
technique sensitive and has a significant risk of volumetric loss. However, the study
178 Moussa et al
Fig. 5. Harvested iliac crest bone graft. (From Fretwurst T, Nack C, Al-Ghrairi M, et al. Long-
term retrospective evaluation of the peri-implant bone level in onlay grafted patients with
iliac bone from the anterior superior iliac crest. J Craniomaxillofac Surg. 2015;43(6):957; with
permission.)
reported a loss of 7.2% of the gained vertical height with a mean follow-up period of
6.25 years. The bone height was then observed to stabilize with minimal vertical loss
subsequently (Fig. 8).16
ALLOGENEIC BONE
Because of increasing popularity in dental implants and the ease of placement, an

increasing number of general practitioners have incorporated implant dentistry into
their practices. In a similar fashion, the availability of allogenic graft material has
increased. The graft has shown a 15-fold increase in use. In the year 2000, it
Fig. 6. Maxillary iliac crest bone grafting. Maxillary defect shown with horizontal and ver-
tical deficiencies (A). Reconstruction of the maxillary defect with iliac bone graft (B).
(From Misch CM. Maxillary autogenous bone grafting. Oral Maxillofac Surg Clin North
Am. 2011;23(2):230; with permission.)
Fig. 7. Histologic specimen of fibular bone 10 years following grafting to the mandible and
implant loading. (From Duttenhoefer F, Nack C, Doll C, et al. Long-term peri-implant bone
level changes of non-vascularized fibula bone grafted edentulous patients. J Craniomaxillo-
fac Surg. 2015;43(5):614; with permission.)
Fig. 8. Intraoperative view showing well-vascularized avascular fibular graft 3 months

following surgery and before implant placement. (From Nelson K, Glatzer C, Hildebrand
D, et al. Clinical evaluation of endosseous implants in nonvascularized fibula bone grafts
for reconstruction of the severely atrophied mandibular bone. J Oral Maxillofac Surg.
180 Moussa et al
represented one-third of all grafting material in the medical community.17 Allogenic

bone graft refers to bone that is harvested from the same species (ie, human ca-
davers). The donated bone is screened for any transmissible diseases and processed
and prepared using several different techniques. Depending on the processing tech-
nique and degree of processing, various types of bone grafting material can be pre-
pared. The properties of the bone change based on the remaining components.
Types of available bone include fresh, fresh-frozen, freeze-dried, and demineralized
types of bone. Demineralized graft material no longer contains the calcium phosphate
mineral component of bone, leaving the collagen network of the composite material.
Following the processing, a minimal risk remains of disease transmission, and this risk
increases and is inversely related to the degree of processing the material undergoes.
If any cellular components are remaining within the graft, there is an additional risk of
the host mounting an immunologic reaction to the graft material. Fresh bone samples
have the least amount of processing and must undergo a rigorous screening process
to ensure little to no transmission disease. Freeze-dried bone, which is heavily pro-
cessed, has very little risk of disease transmission but has little to no osteoconductive
or osteoinductive potential. Fresh bone may be prepared to contain the maximum
amount of growth factors and, in some cases, viable cells. Vivigen, sold by DePuy
Synthes, is fresh bone that is advertised to contain lineage-committed bone cells
for differentiation. Freeze-dried demineralized bone grafting materials receive the
most processing and may provide only osteoconductive benefits to grafting. Growth
factors normally found in bone, such as bone morphogenetic protein (BMP), are
removed as a consequence of the processing. The growth factor BMP induces differ-
entiation of neighboring bone mesenchymal cells to differentiate into osteoblasts.
However, the remaining macrostructure continues to promote migration and angio-
genesis of bone at the graft site.
Particle size has a strong influence on the osteoconductive properties of allogenic
bone. Goldberg and colleagues18 published their work to show that a particle size
of 100 to 300 mm has the greatest osteoconductive potential. This size allows osteo-
clasts and osteoblasts to migrate into the macrostructure of the grafted bone. In com-
parison, a particle size of 1000 to 2000 mm does not promote predictable
osteoconduction. Moreover, particles of less than 100 mm have been associated
with eliciting a macrophage response that results in resorption of the graft. Using a
graft that is not optimal for osteoconduction results in resorption of the grafted mate-
rial with decreased volume of gained regenerative bone.
The major advantage of allogenic bone compared with autogenous bone is that no
harvest site is required to obtain the graft. Patient experience and acceptance of treat-
ment improved without the need for a harvest site. In addition, supply of allogenic
bone is limited by the quantity available for purchase. With regard to success and
achievable bone volume, allogenic bone yields comparable results with autogenous
bone when used for alveolar bone regeneration. Limitations may be encountered
with larger defects (eg, segmental reconstructions) when using allogenic bone alone.
Chaushu and colleagues19 conducted a split-mouth study to compare volumetric
changes after sinus augmentation of completely edentulous maxilla with autogenous
and allogenic fresh-frozen bone particles. Harvested bone from the mandibular ramus
was placed concurrently with allogenic bone to compare volumes of regenerated
bone at 1 week, 6 months, and 12 months following the graft. Allogenic bone showed
no statistically significant difference in grafted bone volume compared with autoge-
nous bone. The investigators noted that autogenous bone had a distinct disadvantage
of added donor site morbidity. The study concluded that allogenic bone was clinically
effective in providing comparative results in regenerated bone volume in the maxillary

sinus.20
Monje and colleagues21 investigated the stability and predictability of allogenic
block grafts in the edentulous maxilla. The investigators conducted a systematic re-
view of the literature and studied the results of 361 cases of allogenic block grafting
to the maxilla followed by a mean follow-up of 4 to 9 months after surgery. The study
reported that, of the 361 cases, 9 grafts failed within 1 to 2 months, representing a 2%
failure rate. The study additionally reported a mean horizontal width gain of 4.79 mm
from 119 graft sites. The study concluded that block grafting with allogenic blocks to
gain horizontal width is predictable And, furthermore, that it provides enough augmen-
tation to facilitate implant placement.21 As previously noted, the goal of grafting is to
regenerate histologically identical tissue to the native host site. Acocella and col-
leagues11 provided histologic evidence that regenerated tissue structure was consis-
tent with that of the host tissues. The investigators sampled clinical specimens of bone
regenerated through the use of allogenic bone grafted for the regeneration of atrophic
maxillary ridges. Samples were taken at 4, 6, and 9 months postoperatively. At
4 months, creeping substitution from vital host bone into the allograft was observed
with scant osteoclasts and poor neovascularization. At 6 months, cellular activity
was still poor; however, graft resorption and regeneration with native bone was
observed. After 9 months of healing, the histology showed significant progression,
showing invasion of new vital bone surrounding nonvital bone. The process seemed
to show continued regeneration and resorption at this time.2 Bone is considered clin-
ically stable for implant placement at 3 months and 6 months following grafting to the
mandible and maxilla respectively. Although clinical success is achieved and the study
shows invagination and regeneration of new bone, it suggests that bone is still actively
being regenerated after 9 months of healing. It is imperative to use good clinical judg-
ment when examining the grafted bone at the time of placement and to examine the
radiodensity of bone before conducted surgery because the site may not be stable for
implant placement even though the expected healing time has passed.
Failure rates reported with allogenic bone grafting are similar to those reported in
autogenous grafting. Chaushu and colleagues19 reported a failure rate of 7% in a sam-
ple pool of 137 graft sites. The study reported an infection rate of 13%; however, not all
infected grafts failed. This finding included both partial and full removal of the grafted
material in both the maxilla and mandible. Additional complications rates were also re-
ported in the study. Soft tissue complications, specifically soft tissue dehiscence and
membrane exposure, were reported at 30%. In their conclusions, the investigators
noted that soft tissue coverage is often difficult to achieve. Failure to achieve primary
closure is suspected to have contributed to their complication rates. The investigators
noted that maintaining good technique, careful handling of soft tissues, and mainte-
nance of blood supply are critical in preventing graft and membrane exposure and
reducing complication rates.19 Similar studies in the literature reported similar compli-
cations and rates.22,23
As mentioned earlier, processing of bone material has important impacts on their
compositions. Vivogen, a fresh-frozen bone graft, requires strict screening to prevent
possible disease transmission. However, the bone is able to maintain vital mesen-
chymal precursor cells within the grafts. Barone and colleagues24 conducted a study
to investigate the success and stability of implants in augmented ridges using fresh-
frozen bone. Twenty-four alveolar ridges were grafted with corticocancellous blocks
that were secured with screws (Figs. 9 and 10). Soft tissue compromise in the form
of dehiscence was observed in 2 of the grafted sites. The grafts necessitated removal
because of infection. The remaining grafts showed good integration with the recipient
182 Moussa et al
Fig. 9. Corticocancellous block; allogenic block allograft restored in rifamycin. (From Barone
A, Varanini P, Orlando B, et al. Deep-frozen allogeneic onlay bone grafts for reconstruction
of atrophic maxillary alveolar ridges: a preliminary study. J Oral Maxillofac Surg.
sites, and implants showed good success following prosthetic restoration. The study
followed implant stability and 2 implants were deemed failures and had to be removed.
The study concluded that fresh-frozen bone grafts provided predictable and long-term
stable regeneration of bone to augment the maxilla.
XENOGENEIC BONE
Xenograft refers to tissues transplanted between animals of different species. Typi-

cally grafts are often obtained from bovine or equine sources. The tissues are
completely devitalized and any cellular or immunogenic materials are removed. This
process is important to prevent disease transfer and rejection. Reducing risk of immu-
nologic reactions to xenografts is important because these grafts are harvested from a
different species. Similar to allografts, xenograft availability is dictated by the supply.
However, costs are often notably less than that of cadaveric bone.
Use of xenogenic bone has been extensively reported in the literature and its suc-
cess has been documented. Xenografts possess poor osteoinductive properties
because of the rigorous processing of the tissues. All of the organic constituents of
Fig. 10. Horizontal onlay augmentation. (From Barone A, Varanini P, Orlando B, et al. Deep-
frozen allogeneic onlay bone grafts for reconstruction of atrophic maxillary alveolar ridges:
a preliminary study. J Oral Maxillofac Surg. 2009;67(6):1302; with permission.)
the material must be removed to prevent immune reactions from the host. For
example, temperature deorganification is used to process and burn away organic
components of the donor tissue. Simple osteoconductive properties are maintained
because of preservation of the macrostructure of the graft. Often xenograft is mixed
with autogenous graft to augment the volume of autograft. The osteoinductive and
osteogenic properties of autogenous bone combined with the osteoconductive prop-
erties of xenograft makes for a successful regeneration of substantial volume of
bone.22 Factors such as BMP or platelet-rich plasma (PRP) must be used to supple-
ment xenografts. In addition, xenografts may have poor handling properties, requiring
placement of a membrane to ensure stability of the graft.
Split-mouth studies were used to investigate the success, predictability, and sta-
bility of xenografts used in augmentation for the purposes of implant placement.
Lima and colleagues25 compared the volumetric stability of autologous grafts
and xenografts with subsequent implant placement. The study compared
augmented anterior maxilla with autologous and xenogenic block grafts. The graft
sites were split in the midline where 1 side was grafted with each respective graft.
Particulate grafts were used to contour the irregular margins, and autogenous bone
was processed through a bone mill to harvest particular autogenous graft. Mea-
surements were conducted clinically and radiographically with the use of three-
dimensional imaging. The grafts were allowed to heal for a period of 6 months
and the radiographic thicknesses of the grafts were recorded. The grafts did not
show a statistically significant difference in the achieved thickness of the grafts.
Higher insertion torques were achieved when implants were placed in autogenous
graft, suggesting a higher density of bone in autogenous grafts. The study
concluded that graft stability and predictability in achieving horizontal augmenta-
tion were comparable.25
Histologic examination of grafted xenogenic bone was completed by Li and col-
leagues.26 The investigators examined the histology of horizontally augmented atro-
phic ramus using block grafts following 9 months of healing. The histology revealed
consistent vital bone invasion of the block xenograft following augmentation.26 Verti-
cal augmentations were investigated by Simion and colleagues.27 The investigators
vertically grafted atrophic mandible with a mixture of 1:1 xenograft with allograft.
The autograft was harvested with the use of bone trephine burs. Implants were placed
simultaneously with the graft with a PTFE membrane using a tenting technique. Histo-
logic examination of the graft sites showed formation of cortical and lamellar bone
consistent with that of the host tissues. However, the core section of the regenerated
tissue revealed speculum of residual xenogenic bone. The contact point of the graft
showed histologic continuity with the host lamellar bone. The histology additionally
revealed good vascular penetration of the graft to the core. The study concluded
that autogenous bone grafted with xenograft provides better outcomes in bone regen-
eration than xenograft alone.27
ALLOPLASTIC BONE
When grafting in the oral cavity, challenges such as handling properties, lack of struc-
tural support, and pressure from contraction of tissues during healing can make
obtaining predictable results difficult. Alloplastic grafting materials have been engi-
neered for improved handling properties and specialized use. Alloplastic bone grafts
are defined as grafting materials or bone substitutes made synthetically or derived
from coral of algae hydroxyapatite. Examples of alloplastic materials include coralline
calcium carbonate, bioceramic alloplasts (b-tricalcium phosphate), and bioactive
184 Moussa et al
glass. Alloplastic materials are often combined with allogeneic grafts when grafting the
maxillary sinus. The grafts have properties of being radiopaque and not resorbing,
which provide support to the graft against the contractile forces of the sinus mem-
brane when healing.
The grafting success of hydroxyapatite materials depends on the total surface area
that is available for the body to interact with. Porous materials allow osteoblasts and
osteoclasts to invade and allow space for vascular invasion to incorporate the material
into the host’s tissue. The biological basis of why coral-based hydroxyapatite works
lies in the material’s macromolecular structure. The structure of the material is very
similar to that of the bone’s macromolecular structure. Coral, which is composed of
calcium carbonate, is processed by manufacturers to produce calcium carbonate,
which has a similar structure to hydroxyapatite. Engineers have even developed a
subtype of calcium phosphate that allows it to be more resorbable. Resorbable hy-
droxyapatite has been synthesized at a particle size that allows the macrophages of
the body to remove the particles, essentially making the material resorbable. Biphasic
calcium phosphate is such a type of alloplast. The material is engineered from a com-
bination of hydroxyapatite and tricalcium phosphate or from pure tricalcium phos-
phate. Depending on the ratio of hydroxyl apatite to tricalcium phosphate, the
degree of resorption of the material changes.
Alloplasts can have the unique ability of allowing bone to bond to its surface. Silica-
based materials, also known as bioactive glass. have this property. BioGran and Peri-
oGlas are two such examples. The bone creates a chemical bond between the bone
and glass interface. Maintaining the particle size within a very narrow range allowed
the materials to degrade enough to allow cells to access the particulate and lay
down new bone in the material. The glass gets lost through degradation processes
over time.
Calcium sulfates were developed as bone void filler. Their excellent handling prop-
erties made them useful as a binder with other materials or as a barrier laid on top of
bone graft. First, the material is synthesized in its hemihydrate form (CaSO4 ½ H2O).
Mixing with water yields a partially hydrated solid form of plaster of Paris. In addition,
polymeric bone graft is composed of polymethyl methacrylate (PMMA) and has an in-
ner core of PMMA. This material is less than ideal in a bone graft because it is nonre-
sorbable (Table 5).
To compare the clinical effects of alloplast, Bechara and colleagues28 conducted a
study comparing the predictability of nonceramic hydroxyapatite when used as a
graft with autogenous bone graft. The investigators conducted a split-mouth study
to evaluate the stability of the grafted sites. The study used a sandwich osteotomy
technique to reconstruct the vertical height of bone by placing graft material be-
tween the osteotomized segments. Autogenous bone graft was harvested from
the ramus of the host and hydroxyapatite was placed in the contralateral mandible.
The segments were stabilized with titanium plates and screws (Fig. 11). The bone
was sampled at 6 months and histologic examination revealed residual graft material
in the experimental group (Fig. 12). In addition, bone marrow density and marrow
spaces were similar between the test and control. The study concluded that alloplas-
tic hydroxyapatite graft material is a suitable substitute for grafting the mandible us-
ing a sandwich technique. Orsini and colleagues29 also conducted a split-mouth
study to regenerate periodontal defects with calcium sulfate and autogenous bone
graft. Twelve patients were treated in this study using guided bone regeneration.
Autogenous bone graft was harvested from the mandible and coated with a collagen
membrane or calcium sulfate. The graft was exposed in 6 of 12 patients and covered
with membrane, and in 4 of 12 patients it was covered with calcium sulfate. The
2 F
A
AB
A(
2 DB
Table 5
Bone selection and properties
Type Graft Osteoconduction Osteoinduction Osteogenesis Advantages

Bone Autograft 3 2 2 Gold standard
Allograft 3 1 0 Availability in many forms
Biomaterials DBM 1 2 0 Supplies osteoinductive BMPs, bone graft
extender
Collagen 2 0 0 Good as delivery vehicle system
Ceramics TCP, hydroxyapatite 1 0 0 Biocompatible
Maxillofacial Bone Grafting Materials

Calcium phosphate cement 1 0 0 Some initial structural support
A
Composite grafts p-TCP/BMA composite 3 2 2 Ample supply

A
BMP/synthetic composite — 3 — Potentially limitless supply

C
2/
DMB, demineralized bone; TCP, tricalcium phosphate.

From Giannoudis PV, Dinopoulos H, Tsiridis E. Bone substitutes: an update. Injury. 2005;36(Suppl3):S22; with permission.
,B E A. ( A
3 ,B E A
3AD2A
CB A B AE
185
186 Moussa et al
Fig. 11. (A) Osteotomized mandible bone segments. (B) Elevated bone segment fixated with
a titanium plate for immobility. (C) Alloplast graft packed into defect. (D) Six months
following healing of the grafted segment. (E) Harvested ramus graft before delivery. (F)
Fixated elevated bone segment with titanium plate for immobility. (G) Healed segment
following ramus autogenous graft. (H) Radiograph showing comparable regenerative
height achieved with autograft (right) and alloplast (left). (Adapted from Bechara K, Dot-
tore AM, Kawakami PY, et al. A histological study of non-ceramic hydroxyapatite as a
bone graft substitute material in the vertical bone augmentation of the posterior mandible
using an interpositional inlay technique: A split mouth evaluation. Ann Anat. 2015;202:2–3;
with permission.)
grafted sites healed following the exposure by secondary intention with good tissue
coverage and quality of soft tissue. There was no statistical difference in the regen-
eration of periodontal defects. This study suggested that alloplastic materials can
act as a barrier surface to prevent soft tissue invasion.29
The current consensus for grafting with alloplastic materials is for its use as an
adjunct used in conjunction with autograft or allograft. The mechanical properties of
Fig. 12. Low-power and high-power (original magnification "100) histophotographs of hy-
droxyapatite (HA)-incorporated bone graft material. The hydroxyapatite particles are sur-
rounded by newly formed bone. (A) lower power microscopic view. (B) high power
microscopic view. MS, marrow space, NB, new bone. (From Bechara K, Dottore AM, Kawa-
kami PY, et al. A histological study of non-ceramic hydroxyapatite as a bone graft substitute
material in the vertical bone augmentation of the posterior mandible using an interposi-
tional inlay technique: A split mouth evaluation. Ann Anat. 2015;202:5; with permission.)
the alloplastic material make it ideal for handling. The predictability of the graft when
used alone is suspect.
BONE MORPHOGENETIC PROTEIN
The bulk of osseous regeneration is focused on a strategy of providing the host oste-
oblasts and osteoclasts with a scaffold for new bone construction. Biologically active
agents have been developed to bridge the gap and provide predictable and depend-
able stimulation for bone formation. BMPs, specifically BMP2 and 7, have been devel-
oped to promote osteoinduction in grafted materials. BMPs have been extensively
studied and have received US Food and Drug Administration approval for sinus
augmentation.30 The literature reports that BMP contains the capacity to stimulate
endochondral and intramembranous bone formation from mesenchymal cells in situ.31
188 Moussa et al
The osteoinductive potential of BMP was investigated by Boyne and colleagues,30

who grafted recombinant human bone morphogenic protein (rhBMP2) into sinus lift
sites without conjunctive bone grafting. Collagen sponges were soaked in rhBMP2
and placed under lifted sinus membranes in patients planned for maxillary implant
placement (Fig. 13).26 Concentrations of 0.75 mg/mL were used to soak membranes.
The study evaluated volumetric changes with the use of computed tomography pre-
operatively and at 4 and 6 months postoperatively. Results were compared with volu-
metric changes achieved in a control group receiving conventional allografting. After a
period of 4 months, 11.3 mm of bone height was noted in the test group. In compar-
ison, the control group showed a mean height gain of 10.2 mm. There were no statis-
tically significant differences between the heights gained with rhBMP2-soaked
sponges alone and allografted sinuses. The histologic examination of the study
revealed mature bone formation in the grafted sinuses with rhBMP2. Comparison of
the bone showed no histologic differences between the test and control groups
(Figs. 14 and 15). The study provides evidence to suggest that BMP carries the poten-
tial to induce bone formation without the need for a grafted scaffolding. Furthermore,
the study advocates that the induced bone can be predictably used for implant place-
ment and loading for oral rehabilitation.26
Evidence of the predictability of bone inductions has been well documented in the
literature. Triplett and colleagues31 conducted a similar study in which the maxillary
sinus was augmented with BMP2-soaked collagen sponges. The investigators con-
ducted a split-mouth study using BMP and autograft harvested from the hip. The in-
vestigators used computed tomography scans not only to measure augmented
height but to investigate the bone density (Fig. 16).31 After a healing period of
6 months, a mean of 7.8 mm of height was regenerated with BMP alone compared
with 9.4 mm with allograft material. Histologic examination revealed no significant dif-
ferences in the regenerated bone, which closely resembled native bone. The study did
not report any complications that were unique to BMP-grafted sites. In comparison,
the autograft was associated with expected complications and morbidity associated
with its harvest (pain, gait disturbance, and paresthesia). The study restored the
Fig. 13. (A) Completed Schneiderian membrane elevation. (B) Augmented Schneiderian
membrane with BMP-infused sponge. (From Boyne PJ, Lilly LC, Marx RE, et al. De novo
bone induction by recombinant human bone morphogenetic protein-2 (rhBMP-2) in maxil-
lary sinus floor augmentation. J Oral Maxillofac Surg. 2005;63(12):1695; with permission.)
Fig. 14. Histology from patient treated with 0.75 mg/mL rhBMP2. Twenty-eight weeks post-
operative (Goldner stain, original magnification "10). (From Boyne PJ, Lilly LC, Marx RE,
et al. De novo bone induction by recombinant human bone morphogenetic protein-2
(rhBMP-2) in maxillary sinus floor augmentation. J Oral Maxillofac Surg. 2005;63(12):1701;
with permission.)
arches of 160 patients, and a total of 251 and 241 implants were placed in BMP and
autografted sites, respectively. The postoperative failure rate was reported to be 42 of
241 in the BMP-regenerated bone and 50 of 251 implants in autogenous bone. No sta-
tistical differences in implant success and survivability were noted. The investigators
concluded that BMP alone achieved similar results to what can be achieved with
autogenous bone.
COLLAGEN-INFUSED BONE GRAFT MATERIALS
A newer development in bone grafting is the addition of collagen to the graft material
proper. Unlike most other developments in bone grafting material, the addition of
collagen is not designed to increase bone growth or osteointegration. Instead, embed-
ding bone material in a collagen matrix gives cohesion to the bone graft material,
providing markedly improved workability intraoperatively. This advantage is especially
applicable for xenografts, where the preparation of bone graft material and collagen
can be easily and abundantly assembled and packaged for use for immediate availabil-
ity. Traditionally, organic components are removed from a variety of xenografts to
190 Moussa et al
Fig. 15. Histology from patient treated with combination of demineralized, freeze-dried
allograft, and autograft 34 weeks postoperative (Goldner stain, original magnification
"10). High-power (A) and low-power (B) pictomicrograph of sampled bone from BMP-
augmented sinus alone. (From Boyne PJ, Lilly LC, Marx RE, et al. De novo bone induction
by recombinant human bone morphogenetic protein-2 (rhBMP-2) in maxillary sinus floor
augmentation. J Oral Maxillofac Surg. 2005;63(12):1701; with permission.)
reduce risk of triggering an immune reaction against the graft and to reduce risk of trans-
fer of potential infectious agents.32,33 The remaining graft material is brittle and granular
owing to its lack of structural framework, and is demanding to use during surgeries.
Renewed interest in reintroducing treated fibrillar collagen in small amounts allows
increased graft material workability by holding the graft together in a way that better
contours to the surgical defect. Fibrillar collagen has been shown to carry and deliver
BMP2 in a workable form; for example, in alveolar cleft reconstruction.34 Bio-Oss (Geist-
lisch Pharmaceutical) is an example of adaptation of this technology. Traditional Bio-
Oss is a product of deproteinized bovine cancellous bone used in many standard
bone grafting applications. Bio-Oss Collagen is cancellous bone granules in a matrix
of 10% collagen fibers in block form. The collagen in this case is treated with gamma
radiation to mitigate adverse immunologic effects of organic material in the graft.32 Intu-
itively, anecdotally, and through personal experience, the consistency of Bio-Oss
Collagen is vastly superior to Bio-Oss because of its ability to be adapted to osseous
defects and ease of handling. The company claims the material is indicated for a variety
of therapeutic areas, including ridge preservation, bone augmentation, and periodontal
surgeries, and it claims that the collagen is absorbed after a few weeks, allowing pre-
dictable osteointegration.35 Wong and colleagues32 evaluated Bio-Oss Collagen for
osteointegration in rabbits and found it to be a viable bone grafting material producing
Fig. 16. (A) Osteotomy site ready to receive BMP sponge. (B) Osteotomy site with delivered
BMP-soaked sponge. (From Triplett RG, Nevins M, Marx RE, et al. Pivotal, randomized, par-
allel evaluation of recombinant human bone morphogenetic protein-2/absorbable collagen
sponge and autogenous bone graft for maxillary sinus floor augmentation. J Oral Maxillofac
Surg. 2009;67(9):1951; with permission.)
339% more new bone versus collagen graft alone. Clinically, socket preservation
studies in the form of randomized controlled clinical trials in human subjects consistently
found collagen-infused bone graft to be viable. Jung and colleagues36 found that
collagen-infused demineralized bovine bone with or without a soft tissue graft outper-
formed control and a traditional mineral phosphate graft in terms of residual bony di-
mensions at the extraction site. Nart and colleagues37 showed that deproteinized
bovine bone mineral and deproteinized bovine bone material with 10% collagen per-
formed statistically indistinguishably following a socket preservation procedure. Ergo,
collagen-infused bone graft material seems promising in that it is both successful as
a bone graft material and provides the advantage of improved intraoperative handling.
Contraindications to grafting with Bio-Oss and similar materials include an infected
wound and patients with known allergy to collagen.
PLATELET RICH CONCENTRATES
Platelet-rich concentrates are autologous filtrates that are rich in growth factors such
as platelet-derived growth factor (PDGF) and transforming growth factor (TGF) beta
and are made from centrifuging a patient’s own blood, which can be added to a
bone graft material to potentially enhance its success. They contain a patient’s own
growth factors (largely from blood-borne platelets) and white blood cells. Their pro-
posed mechanism of action is supersaturating a wound with these growth factors,
thereby promoting tissue regeneration, including osteointegration. They are easily
produced chairside at the time of surgery, and there is a growing mass of literature
substantiating their use in bone grafting in dentistry. There are 2 varieties of
192 Moussa et al
platelet-rich concentrates now used. PRP is whole blood centrifuged to remove red
blood cells, leaving behind a suspension rich in white blood cells and plasma rich in
growth factors. PRP is used as a liquid that is applied over a bone grafting site and
bone graft material. There is anticoagulant in the centrifuge tubes to keep the blood
products in suspension form so that they can be separated. In contrast, platelet-
rich fibrin (PRF) omits the anticoagulation and, through controlled slow centrifugation,
produces a moldable solid composed of a fibrin matrix containing abundant growth
factors. Per unit quantity, PRP has a greater initial concentration of growth factors,
and PRF has more delayed sustained release of growth factors.38
PRF can be further subdivided into 2 forms: a solid and a liquid. Both are routinely
used and allow sustained delayed release of growth factors.38 Solid PRF is the most
common and allows upfront consolidation of the fibrin matrix. In this form, PRF can be
used as a mass to fill large defects, flattened to a wafer to produce a membrane
analogue, or divided and mixed with bone as a particulate bone substitute. Liquid
PRF, also known as injectable PRF, is produced as a liquid by using very low centri-
fuge force for a shorter period of time. The resultant liquid is used as an injection by
itself or used to wet a bone graft.38
To produce PRP/PRF, start with venipuncture.38 Collect blood in 10-mL cylinders.
Glass cylinders activate clotting more than plastic cylinders. Either can be used,
depending on the type of platelet concentrate needed. Transfer the blood to the centri-
fuge immediately. A PRF/PRP centrifuge is used to spin the blood product, typically at
preprogrammed settings.
In the setting of bone grafting in dentistry, Marx and colleagues39 showed that PRP
can be an osteoinductive force by retaining a high concentration of PDGF and TGF-
beta, which act to promote mitogenesis of stem cells nearby and to promote chemo-
taxis of inflammatory cells. This process resulted in a 2-fold increase in bone density.
Fennis and colleagues40 used PRF in reconstruction of mandibular continuity defects
in animal models. Garg and colleagues41 and Kim and colleagues42 showed that PRF
can successfully be used to bone graft around implants with good success. In ridge-
preservation procedures, a PRF graft shaped as a plug to fit into an extraction socket
showed minimal ridge width loss of 7.38% and ridge height loss of 7.13% versus
11.59% and 17.79%, respectively, in groups in which only a bone graft with a collagen
membrane was used.43 In some cases, PRF was used alone without a bone graft with
successful osseous healing of the bone graft. Dhote and colleagues44 showed that
PRF alone could be used to graft a defect after removal of a radicular cyst in a
10-year-old patient. On 2-year follow-up, the defect was healed and there was also
eruption of a nearby displaced premolar.44 Essentially, platelet-rich concentrates
are associated with promotion of wound healing and show promise as an adjunct in
all bone grafting applications.
SUMMARY
Autogenous bone has been the staple and gold standard for grafting purposes.
Recent trends in bone grafting practice have seen increased use of allograft combined
with growth factors such as PRF and BMPs. However, although clinically effective,
these methods come with risks and complications, such as harvest site morbidity
with autogenous grafts and risks of disease transmission with allografts. Recent ad-
vances in engineering have shown promise in resorbable synthetic grafting materials.
Newer materials show the promise of clinically significant volumes of bone augmenta-
tion with resorbable membranes, which would eliminate important complications and
increase patient comfort and safety. Autogenous bone grafts will most likely remain
the gold standard of grafting materials and will continue to be essential in reconstruc-
tion of the maxillofacial skeleton. New materials will most likely shift the bone grafting
philosophies of clinicians toward synthetic resorbable materials in the future.
CLINICS CARE POINTS

! Bone is a composite and dynamic structure undergoing constant resorption and
deposition by osteoclasts and osteoblasts.
! Bone deposition, resorption, and maintenance are achieved through the actions
of osteoblasts, osteoclasts, and osteocytes.
! Branemark described and classified bone based on composition of cortical and
trabecular bone.
! Autologous bone refers to bone that is harvested form the individual’s own
tissue.
! Allogenic bone graft refers to bone that is harvested from the same species (ie,
human cadavers).
! Alloplastic bone grafts are defined as grafting materials or bone substitutes made
synthetically or derived from coral of algae hydroxyapatite.
! Xenograft refers to tissues transplanted between animals of different species.
! BMP, specifically BMP2 and BMP7, have been developed to promote osteoin-
duction in grafted materials through stimulation of endochondral and intramem-
branous bone formation from mesenchymal cells.
! Platelet-rich concentrates are autologous filtrates that are rich in growth factors
such as PDGF and TGF-beta and that can be added to a bone graft material.
DISCLOSURE
REFERENCES
1. Brånemark P-I, Zarb GA, Albrektsson T. Tissue-Integrated Prostheses. In:

Brånemark P-I, Zarb GA, Albrektsson T, editors. Osseointegration in Clinical
Dentistry. 1985.
2. Acocella A, Bertolai R, Ellis E 3rd, et al. Maxillary alveolar ridge reconstruction
with monocortical fresh-frozen bone blocks: a clinical, histological and histomor-
phometric study. J Craniomaxillofac Surg 2012;40(6):525–33.
2006;17(Suppl 2):136–59.
4. Arrington ED, Smith WJ, Chambers HG, et al. Complications of iliac crest bone
graft harvesting. Clin orthop Relat Res 1996;(329):300–9.
5. Banwart JC, Asher MA, Hassanein RS. Iliac crest bone graft harvest donor site
morbidity. A statistical evaluation. Spine 1995;20(9):1055–60.
6. Ross N, Tacconi L, Miles JB. Heterotopic bone formation causing recurrent donor
site pain following iliac crest bone harvesting. Br J Neurosurg 2000;14(5):476–9.
7. Seiler JG 3rd, Johnson J. Iliac crest autogenous bone grafting: donor site com-
plications. J South Orthop Assoc 2000;9(2):91–7.
8. Skaggs DL, Samuelson MA, Hale JM, et al. Complications of posterior iliac crest
bone grafting in spine surgery in children. Spine 2000;25(18):2400–2.
9. Carlini JL, Biron C. Use of the iliac crest cortex for premaxilla fixation in patients
with bilateral clefts. J Oral Maxillofac Surg 2020;78(7):1192.e1–13.
Can Osseointegration Be
A chie ve d Wi t h o u t Pr i ma ry
Stability?
Mohanad Al-Sabbagh, DDS, MSa,*, Walied Eldomiaty, b
BDS ,
Yasser Khabbaz, DDS, MSc
KEYWORDS
! Primary stability ! Secondary stability ! Osseointegration ! Bone density
! Insertion torque ! Resonance frequency analysis ! Bone-to-implant contact (BIC)
KEY POINTS
! Factors influencing primary stability include implant design, bone density, and surgical
techniques used.
! Implant primary stability is not an absolute prerequisite to osseointegration; however, it
has an effect on the implant survival rate.
! Resonance Frequency analysis is the most frequent method used by clinician to assess
both primary and secondary stability.
INTRODUCTION
The term osseointegration was coined and first defined in 1977 as a direct structural
and functional connection between living bone and the surface of a load-carrying
implant.1 Histologically, osseointegration can be identified by the presence of regen-
erated bone at the implant-bone interface. For dental implant osseointegration to
occur, adherence of cells to the surface of the biomaterial is a critical factor. The
implant surface characteristics can modulate the adsorption of proteins, lipids, sugar,
and ions present in the tissue fluids. Accordingly, several factors2 have been deter-
mined to influence these interactions at the implant-host interface (Fig. 1).
PRIMARY STABILITY
In the Branemark paradigm, implant immobility during the first 6 months of healing is a
perquisite for osseointegration to occur. Primary stability is defined as the biometric
a
Division of Periodontology, Department of Oral Health Practice, University of Kentucky, Col-
lege of Dentistry, D-438 Chandler Medical Center, 800 Rose Street, Lexington, KY 40536-0927,
USA; b Division of Periodontology, Department of Oral Health Practice, University of Kentucky,
College of Dentistry, Lexington, KY 40536, USA; c Ambulatory healthcare services -SEHA-,
Muroor Street, Po box 111355, Abu Dhabi, United Arab Emirates
E-mail address: malsa2@email.uky.edu
Dent Clin N Am 63 (2019) 461–473

462 Al-Sabbagh et al
Fig. 1. Factors affecting implant-host interface response with foreign body.
stability immediately following the insertion of an implant and is a direct result of the
mechanical engagement of an implant with the surrounding bone. Primary stability
has been widely referenced in the literature as a requirement for the osseointegration
of dental implant and the long-term success.3,4 This “mechanical stability” gradually
decreases during the early stages of healing due to bone remodeling. As new bone
is formed along the implant surface, secondary stability is established, which is the
direct result of the osseointegration corresponding to both mechanical and biological
features5 (Fig. 2).
Micromotion of dental implants is the minimal displacement of an implant body from
the surrounding bone, which is not visible to the naked eye.6 It has been suggested
that micromotion between implant and surrounding bone must not exceed a threshold
value of 150 mm for a successful implant healing.7 Any movement even at the micro-
meter range can induce stress and strain that may hinder the recruitment of new cells
Fig. 2. Implant stability curve study. (Adapted from Raghavendra S, Wood MC, Taylor TD.
Early wound healing around endosseous implants: a review of the literature. Int J Oral Max-
illofac Implants 2005;20(3):430; with permission.)
Osseointegration and Primary Stability 463
and negatively influence osseointegration and bone remodeling leading to forming

fibrous tissues.8
FACTORS INFLUENCING PRIMARY STABILITY
Primary stability is influenced by multiple factors, including implant design (length/

diameter, microscopic/macroscopic morphology of implant), bone condition (qual-
ity/quantity), and the surgical protocol specific for each implant system (Fig. 3).
Implant Design (Macro/Microstructure)

The 3-dimensional structural design of an implant plays a vital role in attaining primary
stability.9,10 The threaded design increases the surface area of the implant in contact
with bone, thereby offering a higher percentage of bone-to-implant contact (BIC) in
comparison to implants with cylindrical design. Tapered implants were later intro-
duced to provide a degree of compression of the cortical bone in an implant site
with inadequate bone.11,12
Several implant surface modifications have been developed to modulate and
enhance biological response to improve osseointegration and primary stability
(Fig. 4). Studies have shown that surface topography and roughness increases the
surface area of the implant and allows a firmer mechanical link to the surrounding tis-
sues, thus enhancing primary stability.13
Veis and colleagues14 showed that implants with acid-etched surfaces can achieve
a significantly higher BIC and primary stability in poor bone quality sites in comparison
to implants with machined surface. Schätzle and colleagues15 compared a chemically
modified sandblasted/acid-etched titanium surface (modSLA) with a standard SLA
Fig. 3. Factors influencing implant stability.
Fig. 4. Types of implant surface treatments.
surface and found higher implant stability quotient (ISQ) values at 12 weeks in the
(modSLA) group versus SLA group.
Bone Density and Quality

Clinical studies have reported that dental implants in the mandible have higher survival
rates compared with those in the maxilla, especially the posterior region.16 The distri-
bution and percentage of both the cancellous and cortical bone in the implant site play
a crucial role in determining the insertion resistance of an implant during
placement.17–19
A balance between the cancellous and cortical part of the bone is always desired.
Type I cortical bone will lead to highly insertion torques with possible negative bone
resorption.12 On the other hand, type IV bone with no cortical bone provides minimal
or no primary stability, which in turn may result in no osseointegration due to implant
micromotion.12,20,21
Turkyilmaz and colleagues22 observed a significance correlation between mean
voxel values (gray scale) (751 " 257) and ISQ values (70.5 " 7) at implant placement.
In a similar study, Fuster-Torres and colleagues23 found a significance relationship be-
tween mean voxel values (623 " 209) and ISQ values (62.4 " 8).
Surgical Techniques
Several modalities of osteotomy preparation techniques have been proposed to opti-
mize a high degree of implant stability. Among these techniques are using undersized
drilling protocol, osteotomes to laterally condense the bone, and counter-clock wise
rotational surgical drills.
It is worth mentioning that drilling into the implant bed not only incurs mechanical
damage to the bone but also increases the temperature of the bone directly adjacent
to implant surface. Bone cell necrosis occurs when the temperature exceeds 47# C for
1 min. Mechanical and thermal damage to the surrounding tissue around the implant
surface can have a destructive effect on the initial state of the osteotomy housing the
implant.24
Even though primary stability is always desired, it may not be achievable either from
patient specific reasons, for an example bone quality, or from operator related factors,
such as overpreparing the implant osteotomy.25 However, it has been reported in the
literature that implants that lacked or had low primary stability have comparable sur-
vival rates to those with high primary stability.3,18,26–28
MEASURING PRIMARY STABILITY
Although primary stability is widely discussed in the literature, there is no simple and
clear method to quantify or measure it rather than unreliable clinicians’ hand tactile
sensation. Several investigators presented techniques and methods to quantify
implant stability in general and primary stability in particular.29
Cutting Torque Resistance Analysis

Cutting torque resistance analysis (CRA) was developed by Friberg and colleagues30
in 1995. This method measures the required current needed in an electric motor to cut
off a unit volume of bone during the low-speed threading of implant osteotomy site.
The measured energy is significantly correlated to the bone density because it iden-
tifies areas with soft, cancellous bone.30,31 The technique consists of incorporating
a torque gauge within the drilling unit to measure implant insertion torque in newton
centimeter (Ncm) to be converted to J/mm3. The major limitation of the CRA technique
is that it does not give any information on bone quality until the osteotomy site is pre-
pared. CRA also fails to provide a clear lower cutting torque threshold to indicate the
risk of implant failure.32
Insertion Torque
Clinically, insertional torque (IT) is more widely used in assessing primary stability than
CRA.33,34 However, torque measurement can only be recorded at the time of implant
placement and does not assess any changes that happens after implant placement.
Ottoni and colleagues35 investigated the relation between IT and implant survival in
single implants. The recommendation of this study to achieve osseointegration was
a minimum IT value of 20 Ncm and an optimal torque of 32 Ncm. A high IT value maybe
an indication of good primary stability; however, maximum insertion torque can be
deceiving; direct pressure of the implant on the dense cortical bone without adequate
BTI contact at the rest of implant surface can produce high IT.
IT and resonance frequency analysis (RFA) are the most widely used methods to
measure primary stability so their relationship has been extensively analyzed by
numerous researchers and yet remains controversial. Lages and colleagues,36 in a
recent systematic review, concluded that insertion torque and RFA are independent
and incomparable methods to measure primary stability.
Periotest
Periotest (Siemens A, Benshein, Germany) has been considered a reliable method to
measure primary stability.37,38 It was originally developed by Schulte to test natural
tooth mobility using a metallic rod that applies an electronically controlled tapping
force to the object (tooth or an implant). The response time to this “controlled tapping”
is measured by a sensor on the handpiece and converted into a value called periotest
value (PTV). This value represents the damping characteristics of the surrounding tis-
sues around the tooth or implant. PTV ranges from $8 (low mobility) to 150 (high
mobility). Olive and colleagues39 found that a normal PTV of an osseointegrated
implant falls in a relatively narrow zone ($5 to 15). Other studies40,41 found that
PTVs of osseointegrated implants falls within a narrower zone ($4 to $2 or $4 to 12).
Many investigators presumed that PTV precisely reflects the condition of BIC.40,42
However, the prognostic accuracy of PTV for implant stability has been criticized for
poor sensitivity, difficulty of application in posterior region, and susceptibility to oper-
ator variables.43,44
Resonance Frequency Analysis

RFA suggested by Meredith in 1998 has recently gained popularity as a noninvasive
diagnostic method to measure both primary and secondary implant stability.45 It
uses an L-shaped transducer that is inserted into the implant or abutment containing
a vibrating element and a receptor. The vibrating element applies a sinusoidal wave or
an impact force wave and the receptor measures the resonance signal from the
implant-bone component that has shown to measure implant stability.29 It represents
a measurement of the axial stiffness between implant and bone.
Currently, 2 machines are available in the market that measures implant stability via
RFA: Osstell (Integration diagnostics) and Implomates (Bio TechOne). Osstell is a more
widely used device and combines the transducer, computerized analysis, and vibra-
tion source into one device. Initially, Hertz was used as a measurement unit; then
ISQ was developed as a measurement unit by Osstell. The ISQ value ranges from
0 to 100, of which the higher value referring to more implant stability.29 The Implo-
mates device applies an impact force instead of the sinusoidal effect to trigger the
resonance of the implant and a receptor measures in range from 2 to 20 kilohertz.
More research has been conducted on the application and efficacy of the Osstell de-
vice compared with the Implomates.
IMPLANT BED PREPARATION
The goal of improving primary stability has been a constant objective ever since the
development of the early endosseous implants. The concept of placing a longer, wider
implant suitable for an implant site is the most commonly cited method to improve pri-
mary stability. However, the development of tapered implant with aggressive thread
design challenged such a concept.11,12
The quality and dimension of implant site can be assessed through cone beam
computed tomography to customize the surgical protocol in sites where softer type
III or IV bone is present.46
Summers Osteotome Technique

After using the pilot drill, a series of osteotomes can be tapped into the implant site to
laterally compact the cancellous bone, which results in better dense bone allowing for
better implant primary stability.47 Markovic and colleagues obtained significantly
higher implant stability values using lateral bone condensation versus conventional
bone drilling techniques, both immediately after implant placement surgery
(74.03 " 3.53 vs 61.2 " 1.63 ISQ) and at 6 weeks following the surgery (70.3 " 1.21
vs 65.23 " 0.43 ISQ).
Undersized Drilling Technique

Several studies48–50 have proved that when dental implants are inserted in underpre-
pared osteotomy sites using smaller diameter drills, maximum bone volume preserva-
tion and enhanced bone density are achieved. Furthermore, underpreparation of
osteotomy sites will allow translocation of osteogenic bone fragments along the
implant surface, which will contribute to bone healing and remodeling.51
In the presence of soft trabecular bone, experienced clinicians may choose to
underprepare the osteotomy by not using the last drill of the implant system surgical
protocol.50 Degidi and colleagues52 compared primary stability parameters (insertion
torque and RFA) of 3 study groups of implants placed in poor-quality fresh bovine
bone where standard osteotomy preparation (control group), 10% undersized prepa-
ration, and 25% undersized preparation were performed. They found improved pri-
mary stability with 10% undersized preparation group; however, 25% undersized
group did not provide an added benefit to stability.
Osseodensification Technique (VERSAH)

Unlike traditional drilling techniques, osseodensification does not excavate and sub-
tract bone tissue. During the drilling process, bone tissue in this technique is simulta-
neously compacted and autografted in an outward expanding direction from the
osteotomy, resembling somewhat a traditional hammered osteotome technique, but
without the trauma. When a Densah Bur is rotated at high speed in a reversed, non-
cutting direction with steady external irrigation, a strong and dense layer of bone tis-
sue is formed along the walls and the base of the osteotomy.53
Bicortical Fixation
Bicortical fixation has historically been implemented to increase the primary stabil-
ity of implants. The technique entails the use of long implant to engage 2 layers of
cortical bone: the cervical crest and the sinus or nasal floor cortex or lower border
of anterior mandibular cortex. In a study by Hsu and colleagues,54 they used a
stopper drill and self-threading implants to firmly engage the sinus floor cortex
to improve implant stability in one group, an indirect vertical sinus floor lift in a sec-
ond group, and unicortical fixation in a third group. They found that primary and
secondary implant stabilities of bicortical fixation did not differ significantly from
those of unicortical fixation and indirect sinus elevation. However, bicortical fixa-
tion technique is simpler and more economical than indirect sinus elevation. In
contrast, Ivanoff and colleagues55 found that bicortically anchored implants failed
nearly 4 times more often than the monocortical ones. Bicortical fixation is
currently not widely used. Further studies are needed to validate the outcomes
of this concept.
RESONANCE FREQUENCY ANALYSIS AND LACK OF PRIMARY STABILITY
Lack of primary stability does not have a clear definition in the literature. Rodrigo and
colleagues26 classified lack of primary stability into 4 categories according to the
perception of rotation: (1) No rotation, (2) light rotation with a feeling of resistance,
(3) rotation with no resistance, and (4) rotation and lateral oscillation. Second, third,
and fourth groups were categorized as having no primary stability. Other investigators
identified lack of primary stability as low insertion torque of less than 10 Ncm and slight
lateral mobility,56 implants without rotational primary stability,57 and implants without
apical or rotational primary stability that can be rotated or depressed with gentle
force.25,58
Multiple studies have correlated ISQ values (obtained by RFA) with primary stability
and future implant survival rates.59–61 However, most of the studies did not investigate
RFA in implants that lacked primary stability with exception of few.26,62 Rodrigo and
colleagues26 collected ISQ values from 542 implants (42 out of 542 were grouped
as unstable implants) at time of insertion and restoration. The results showed signifi-
cant association between the degree of the implant initial stability and the correspond-
ing RFA values taken at implant insertion. However, low RFA values at time of insertion
were not correlated with implant failure. Only low secondary stability RFA values (>60
ISQ) taken at the time of restoration predicted implant failure. In a similar fashion, Nedir
and colleagues62 investigated whether primary stability assessed by RFA can predict
osseointegration. They concluded that RFA is not a reliable method for assessing mo-
bile implants. However, it was a reliable method to determine implant stability at the
time of placement with a subsequent successful osseointegration if ISQ greater
than or equal to 47.
Turkyilmaz and colleagues50 investigated the difference in insertion torque and RFA
values for implants placed in the posterior region of maxilla following a modified sur-
gical protocol using thinner drills in the test implant sites. They found strong correlation
between insertion torque measurements and RFA values. This was in agreement with
other study findings.19,34,61
The clinician tactile assessment (lack of resistance to rotation and/or presence of
lateral or depressible mobility to gently hand forces) of an implant at insertion seems
to be a more reliable method identifying the implants with minimal or no primary
stability.
OSSEOINTEGRATION PREDICTABILITY OF IMPLANTS WITH NO OR LOW PRIMARY

STABILITY
Clinical studies that evaluated osseointegration of implants with no primary stability

at the time of placement are scarce and are mostly conducted on animal
model.63,64 Orenstein and colleagues58 followed 2770 implants of 6 different de-
signs for 3 years following placement, and among those, 89 implants were mobile
at placement. The implants were mainly split into 2 groups: hydroxyapatite (HA)-
coated and non-HA–coated (Titanium alloy) groups. Implants were placed in a 2-
stage protocol and were left submerged for 4 to 6 months in the mandible and 6
to 8 months in the maxilla before uncovering. The cumulative survival rate at 3 years
of mobile implants was 79.8% (71 out of 89) compared with 93.4% for the stable
implants. When the survival rate was broken down by the implant surface coating
of the mobile implant group, the difference was very significant with 91.8% in the
HA-coated group (56/61) compared with 53.6% survival (15/28) for the non-HA–
coated (Ti alloy) group. The conclusion of the study was that implant primary sta-
bility is not an absolute prerequisite to osseointegration; however, it significantly
affects the implant survival rate.
An advancement in the treatment of implant surface has been introduced to
enhance primary stability and accelerate osseointegration. Current implants have
modified macro/micro design when compared with the older machined surface and
HA-coated implants. It is thought that an improved survival rate exists when those
modified implant surfaces are inserted even when primary stability is not achieved.
In a retrospective analysis, Balshi and colleagues57 found that implants (total 88)
with apical but no rotational primary stability have a cumulative survival rate of
82%. Survival rate of implants with smooth machined surface (20 out of 44) and tita-
nium oxide rough surface (20 out of 44) is 70% and 91.7%, respectively. This is in
agreement with the Orenstein and colleagues’ study that showed implants with rough
surface may have a more predictable outcome when primary stability is not achieved
at the time of implant placemat.25,58 In a prospective study, Rodrigo and colleagues
(2010) evaluated 4114 SLA Straumann implants.26 The survival rate of implants with
primary stability was 99.1% compared with 97.2% in implants with no primary stabil-
ity. The investigators concluded that the high (97%) survival rate of nonstable implants
clearly shows that primary stability is not a prerequisite for osseointegration. This is in
agreement with a more recent report by Verardi and colleagues.56 He reported a 100%
survival rate for 11 implants that had less than 10 Ncm insertion torque and slight
mobility to lateral force of 250 g at the time of placement.
In conclusion, early literature suggested a low survival rate for machined surface im-
plants25,57,58; however, osseointegration of rough surface implants with no primary
stability at placement is predictable and is similar to implants with primary stability
at time of placement.18,26,57
RECOMMENDATIONS FOR MANAGING IMPLANTS WITH NO PRIMARY STABILITY

1. Planning and execution: the clinician should properly assess the implant site before
and during the osteotomy preparation. Osteotomy preparation protocol can be
modified with the use of osteotome, undersized implant bed preparation, or osseo-
densification to improve the quality of bone and achieve adequate primary stability.
2. Implant design: in the presence of soft trabecular bone, tapered implant with
aggressive thread design is recommended to engage bone and enhance primary
stability.
3. Rescue implant: if the planned implant used did not achieve proper primary stabil-
ity, a rescue implant (longer/wider implant) can be considered to further engage
available bone.
4. Bone graft: in case of the mobility of an implant due to overpreparation of the os-
teotomy or the presence of a jumping distance in an immediate implant following
extraction, adding bone graft particles within the osteotomy may help create a
wedging effect of the implant, thus minimizing any micromovement during healing.
5. Two-stage protocol: an implant with no primary stability should be submerged and
the flap should be repositioned with primary closure to minimize micromotions and
disturbances of the nonstable implants during the healing time until secondary sta-
bility is achieved. Caution should be followed to eliminate any forces on the nonsta-
ble implants during healing. For example, the intaglio of the denture corresponding
to implant site needs to be relieved.
6. Prolonged healing period: extra healing time is needed before loading to assure
adequate osseointegration, especially in less dense bone.
7. Abort implant placement: the golden rule of prosthetically driven implant placement
should always be applied. If the abovementioned recommendations cannot be at-
tained in nonstable implant with crown-down position, then the implant placement
should be aborted.
SUMMARY
It is essential to aim for primary stability; preoperative assessment of bone quality, an

appropriate implant size and design, and osteotomy preparation technique modifica-
tion for those sites with suspected poor bone quality need to be considered. However,
even with all measures taken, clinicians may experience cases where the implant has
no primary stability. A decision must be made to keep that implant, replace it with a
longer/wider implant, graft around the implant, or simply abort implant placement all
together. From the few studies discussing this topic along with the investigators’ per-
sonal experience, keeping the implant with no primary stability has a high chance of
integrating similar to the ones with good primary stability.
The current titanium surface treatments along with a more engaging implant geom-
etry seem to have a major role in a high survival rate of mobile implants at the time of
insertion. More studies with larger sample sizes and with different implant systems are
warranted to develop a standard management protocol for implants that have no pri-
mary stability or are mobile at the time of placement.
REFERENCES
1. Branemark PI, Hansson BO, Adell R, et al. Osseointegrated implants in the treat-
ment of the edentulous jaw. Experience from a 10-year period. Scand J Plast Re-
constr Surg Suppl 1977;16:1–132.
2. Albrektsson T, Albrektsson B. Osseointegration of bone implants. A review of an
alternative mode of fixation. Acta Orthop Scand 1987;58(5):567–77.
3. Albrektsson T. Direct bone anchorage of dental implants. J Prosthet Dent 1983;
50(2):255–61.
4. Rabel A, Kohler SG, Schmidt-Westhausen AM. Clinical study on the primary sta-
bility of two dental implant systems with resonance frequency analysis. Clin Oral
Investig 2007;11(3):257–65.
5. Raghavendra S, Wood MC, Taylor TD. Early wound healing around endosseous
implants: a review of the literature. Int J Oral Maxillofac Implants 2005;20(3):
425–31.
6. Laney WR. Glossary of oral and maxillofacial implants. Int J Oral Maxillofac Im-
plants 2017;32(4). Gi–G200.
7. Szmukler-Moncler S, Salama H, Reingewirtz Y, et al. Timing of loading and effect
of micromotion on bone-dental implant interface: review of experimental litera-
ture. J Biomed Mater Res 1998;43(2):192–203.
8. Brunski JB. Avoid pitfalls of overloading and micromotion of intraosseous im-
plants. Dent Implantol Update 1993;4(10):77–81.
9. Chong L, Khocht A, Suzuki JB, et al. Effect of implant design on initial stability of
tapered implants. J Oral Implantol 2009;35(3):130–5.
10. Romanos G, et al. Dental implant design and primary stability. A histomorphomet-
ric evaluation. in 42nd annual meeting, International Association of Dental
Research meeting Continental European Division. Thessaloniki, 2008.
11. Shapoff CA. Clinical advantages of tapered root form dental implants. Compend
Contin Educ Dent 2002;23(1):42–4, 46, 48 passim.
12. O’Sullivan D, Sennerby L, Meredith N. Influence of implant taper on the primary
and secondary stability of osseointegrated titanium implants. Clin Oral Implants
Res 2004;15(4):474–80.
13. Davies J. Mechanisms of endosseous integration. Int J Prosthodont 1998;11(5).
14. Veis AA, Papadimitriou S, Trisi P, et al. Osseointegration of Osseotite! and
machined-surfaced titanium implants in membrane-covered critical-sized de-
fects: a histologic and histometric study in dogs. Clin Oral Implants Res 2007;
18(2):153–60.
15. Schätzle M, Männchen R, Balbach U, et al. Stability change of chemically modi-
fied sandblasted/acid-etched titanium palatal implants. A randomized-controlled
clinical trial. Clin Oral Implants Res 2009;20(5):489–95.
16. Jemt T, Stenport V. Implant treatment with fixed prostheses in the edentulous
maxilla. Part 2: prosthetic technique and clinical maintenance in two patient
Update on Maxillary Sinus
Augmentation
Natasha Bhalla, DDS*, Harry Dym, DDS
KEYWORDS
! Transcrestal sinus lift ! Lateral window sinus lift ! Osseodensification
! Schneiderian membrane
KEY POINTS
! Over time, the maxillary sinus undergoes a process called pneumatization.
! Over time, the alveolar bone of the posterior maxilla will undergo resorption.
! Augmentation of the maxillary sinus can be performed by using a transcrestal sinus lift or a
lateral approach.
INTRODUCTION
A common clinical finding facing the implant surgeon when planning for implant place-
ment in the posterior maxilla is lack of adequate bone height either due to low lying
maxillary sinus or due to atrophy of the alveolous following extraction. Augmentation
of the site can be performed by using a transcrestal sinus lift or a lateral approach.
Both techniques are discussed in this chapter.
ANATOMY OF THE MAXILLARY SINUS
The maxillary sinus is an air space that occupies the maxilla bilaterally1 and is sur-
rounded by the nasal cavity mesially, the maxillary tuberosity laterally, the orbit supe-
riorly, and the alveolar bone inferiorly.1 The volume of the maxillary sinus is
approximately 20 mL1 and is usually present at birth completing its development at
18 years of age.1
The maxillary sinus is also lined with ciliated pseudostratified epithelium, and there
are cilia lining the membrane of the maxillary sinus as well,1 the purpose of which is to
clear the paranasal sinus cavity of pathogens and debris that are continually inspired
in normal respiration.1
Department of Dentistry/Oral and Maxillofacial Surgery, The Brooklyn Hospital Center, 121
DeKalb Avenue, Brooklyn, NY 11201, USA
E-mail address: natashaa95@gmail.com
Dent Clin N Am 65 (2021) 197–210

198 Bhalla & Dym
The maxillary sinus is robustly supplied by multiple arteries,1 which include the
infraorbital artery, greater palatine artery, lesser palatine artery, sphenopalatine artery,
and the posterior superior alveolar artery.1
INDICATIONS
Over time, the maxillary sinus undergoes a process called pneumatization. This pro-
cess occurs when an individual loses their posterior maxillary teeth and in response
to this loss of teeth the maxillary sinus will enlarge and encompass a larger portion of
the posterior maxillary alveolous. Pictured in Fig. 1 is a pneumatized maxillary sinus.
Over time, the alveolar bone of the posterior maxilla will undergo resorption. The
pneumatization of the maxillary sinus and resorption of the maxillary alveolar bone
results in difficulty placing dental implants in the maxillary sinus. A maxillary sinus
lift is conducted in order to facilitate the placement of dental implants in an environ-
ment with diminished vertical bone height. In order to have a successfully integrated
dental implant, the recommendation is to place at least a 10-mm long implant with a
width of 3 mm.1
WORKUP
The diagnostic and surgical workup for those patients who may require a sinus lift be-
gins as most other surgical workups do, beginning with obtaining the following needed
information: chief complaint, medical history, medications, allergies past surgical
Fig. 1. Posteroanterior radiograph demonstrating inferior portion of pneumatized maxil-

lary sinus.
Update on Maxillary Sinus Augmentation 199
history, and dental history. A patient who may require a maxillary sinus lift may indicate
that they lost their maxillary posterior teeth many years ago and have trouble eating.
Other patients with big smiles may indicate that they do not smile as much as the
missing posterior teeth are noticeable.
An important part of the medical history is for the practitioner to ascertain that the
patient does not have a history of bleeding problems.2 This is especially important
as one of the complications of a maxillary sinus lift is perforation of the maxillary sinus
intraoperatively, which can lead to bleeding, which would be worse in a patient with a
history of bleeding problems.2 A patient with a history of bleeding problems may report
a history of frequent nose bleeds, heavy menstrual bleeding (in females), easy
bruising, and a history of prolonged bleeding after a wisdom tooth extraction.2 A pa-
tient on blood thinners such as Warfarin or PO Heparin is also prone to excessive
bleeding intraoperatively.2
Another important factor relevant to the medical questionnaire is learning about a
possible history of rhinosinusitis. Rhinosinusitis is associated with nasal congestion,
postnasal drip, headaches, and sore throat,3 and evidence of rhinosinusitis may be
seen on dental imaging. Later in this text, the author will discuss the implication of
radiographic findings associated with the maxillary sinus.
Following the medical history, a physical examination must be conducted. The
author recommends starting the examination with a complete head and neck exami-
nation to rule out any gross abnormalities followed by the intraoral examination. Spe-
cifically, it is important to note the buccal/palatal width of the maxillary alveolar bone,
presence of keratinized tissue, and intraocclusal distance for the final prostheses. In
order to place an implant of 3 mm diameter the buccal palatal length of the maxillary
bone must be 4 mm.1
Following completion of the physical examination a radiographic examination is per-
formed. Generally, a panoramic imaging study is adequate; however many practi-
tioners may include a cone beam computed tomography (CBCT) study as well in
order to accurately assess a patient. The 3-dimensional CBCT allows one to obtain in-
formation necessary information about the buccal/lingual width of the maxillary alve-
olar bone, and one can also determine the exact distance from the crest of the alveolar
bone to the maxillary sinus. In addition, the CBCT study can also reveal whether there
are septa within the planned sinus surgical site. Normally, septa with low height (less
than 2 mm) do not require further attention because the membrane can usually be
elevated without difficulty.2 However, high septa with partial or complete separation
of the sinus cavity may involve the preparation of 2 windows during sinus lift surgery.2
Finally, the clinician can observe possible sinus mucosal thickening, sinus polyps, and
air fluid levels.3 This chapter, in a later section, discusses the implications of these
findings on the success of a maxillary sinus lift and ultimately, the placement of a
dental implant.
A maxillary sinus augmentation is recommended when there is less than 10 mm of
space available from the alveolar crest to the maxillary sinus,1 and the clinician and
patient wish not to use small implants to reconstruct the area. As part of the discussion
with the patient, the length of treatment time should be discussed with the under-
standing that the patient may or may not have a single stage or possible 2-stage
implant procedure.
In a 1-stage implant placement, the implant can be placed at the same appointment
as the sinus augmentation, whereas in a 2-stage implant placement, the sinus
augmentation is performed first and the dental implant is placed 4 to 6 months later.
Later in this chapter, the recommendations based on evidence-based medicine for
one procedure versus the other are discussed.
200 Bhalla & Dym
During this appointment, the risks, benefits, and alternatives to the procedure must
also be discussed with the patient, and it is recommended that a formal consent be
obtained and signed by the patient as well.
ABNORMAL RADIOGRAPHIC FINDINGS
Upon review of the imaging studies, the practitioner may notice abnormal maxillary si-
nus findings including, but not limited to, mucosal thickening, sinus polyps, mucosal
perforation, opacification of the maxillary sinus, and obstruction of the osteomeatal
complex.3 The reported rate of incidental radiologic sinus abnormalities in asymptom-
atic patients is as high as 60%.3
An air fluid level would be the most typical imaging finding of mucosal thickening
(Fig. 2).3 A sinus polyp would be viewed as a hypodensity in the maxillary sinus
(Fig. 3).3 Opacification as the name suggests would be seen as an opacified maxillary
sinus (Fig. 4).3 Lastly, the obstruction of an osteomeatal complex would be seen as
opacification of the maxillary sinus.3
If any of these pathologies are viewed on the patient’s radiograph, additional dis-
cussion with the patient is warranted. This discussion should rule out any history of
rhinosinusitis. Rhinosinusitis can be divided into acute and chronic states,3 with acute
being defined as symptoms lasting less than 4 weeks.3 These symptoms include nasal
mucopurulent drainage, facial pressure and/or feeling of fullness, nasal congestion,
and possible loss of sense of smell,3 whereas chronic rhinosinusitis is defined as
symptoms lasting greater than 4 weeks.3
If a patient denies any symptoms of rhinosinusitis, the radiographic findings can be
considered to be incidental findings and is not a contraindication to performing maxil-
lary sinus augmentation.3 The most common augmentation complication is maxillary
sinusitis and has been reported in 27% of cases.3 Incidental radiographic findings with
no clinical symptoms do not increase the risk of developing maxillary sinusitis.3 It is
important to note that patients who do have symptoms of acute or chronic sinusitis
should be referred to an ear, nose, and throat doctor for possible treatment,3 as these
patients are at possible increased risk for postaugmentation maxillary sinusitis.3
Fig. 2. Waters view radiograph demonstrating thickening of mucosa (arrow).
Fig. 3. Panoramic radiograph showing a sinus polyp on the floor of right maxillary sinus
(arrow).
BONE GRAFTING MATERIALS
During the maxillary sinus augmentation technique, bone grafting material is placed
inferior to the sinus membrane. Before this, the sinus membrane is elevated on the
medial and lateral walls. The options of bone graft materials available include the
following:
1 .Autograft—bone graft from the patient
2 .Allograft—bone graft from the same species (but not from the patient)
Fig. 4. (A) Periapical film showing opacification of the inferior portion of the left maxillary
sinus. (B) Panoramic radiograph showing opacification of the inferior portion of the left
maxillary sinus. (C) CT Maxillofacial (axial cut) showing opacification of the inferior portion
of the left maxillary sinus.
202 Bhalla & Dym
3 .Alloplast—a graft material that is engineered, it is derived from a nonanimal source

4 .Xenograft—bone graft from a different species
The graft material that is the gold standard and has the highest success rate is the
autogenous bone graft.1 In situations where large amounts of bone graft is required,
the anterior iliac crest is an option.1 From this site, one can obtain approximately
50 cc of corticocancellous bone1; however, if even more bone graft is required the op-
tions are either anterior iliac crest or the posterior iliac crest. If a small amount of bone
is needed, there are several options. These include the maxillary tuberosity, mandib-
ular ramus, or mandibular symphysis.
As an alternative to autogenous bone grafting, nonautogenous bone grafts are also
a viable option1 and are advantageous because there is no associated donor site
morbidity, they are associated with good success rates, are easily obtained, and
are easy to use.1
SURGICAL PROCEDURE
A lateral maxillary window sinus lift is generally performed on patients who require
more than 3 mm of augmentation.2 Generally, when a large amount of bone is required
to place an implant, the lateral window sinus lift is recommended2 rather than a trans-
crestal sinus lift.
An incision is made over the alveolar crest from the maxillary midline to where the
implant osteotomy site is planned. The incision should extend past the osteotomy
site so that the incision can be closed on sound bone. While making the osteotomy,
one should keep principles of surgical access and good visualization in mind. A
dental bur or a piezoelectric device is used to create an oval or rectangular osteot-
omy over the lateral maxillary sinus wall2 (Fig. 5). It is important to not perforate the
sinus membrane during this step. Once the lateral window has been made, the si-
nus membrane is teased off the floor of the sinus and from the surrounding walls
(Fig. 6). The bone graft is then placed under the sinus membrane. The practitioner
should aim for having 12 mm of bone after the sinus lift is completed,2 keeping in
mind that the length of the implant will be at least 10 mm. The few extra millimeters
of bone are in order to account for bone resorption during the healing process.
Fig. 5. An osteotomy over the lateral maxillary sinus wall.
Fig. 6. The lateral approach involves elevation of a full-thickness buccal flap and osteotomy
through the lateral wall. (A) Full thickness mucoperiosteal flap raised in order to gain access
to osteotomy site. (B) Osteotomy. (C) Augmentation. (D) Placement of implant. (From Louis
PJ. The maxillary sinus lift. In: Kademani D, Tiwana PS, editors. Atlas of oral & maxillofacial
surgery. St. Louis: Elsevier Saunders; 2016. p. 199–209; with permission.)
Once the bone graft has been placed, the incision is primarily closed with resorb-
able sutures.
The healing process for a maxillary sinus augmentation procedure is approximately
6 months. The authors usually take radiographic imaging after the sinus lift procedure
and then again 5 months later in order the evaluate the height of the alveolar crest.2
PLATELET-RICH FIBRIN
Platelet concentrates have been used in dentistry since the 1980s as a way to achieve
better clinical outcomes. In order to generate platelet-rich fibrin (PRF), the patient’s
blood is put through a centrifuge without any anticoagulant.4,5 The advantage to the
patient is better potential bone and wound healing.4,5 The disadvantage may include
discomfort to the patient during the drawing of blood, additional financial costs, and
longer length of surgery.4,5
In a systematic review conducted by Ortega-Mejia and colleagues, it was found
that the use of PRF in sinus augmentation procedures did not demonstrate any sig-
nificant increase in bone formation.4 The review proposed that perhaps the use of
PRF may improve the healing period and bone formation after a sinus augmentation
procedure.4
204 Bhalla & Dym
ONE-STAGE VERSUS TWO-STAGE IMPLANT PLACEMENT
For many decades, the recommendation has been to conduct a 2-stage implant
placement if the height of the maxillary alveolar bone is less than 4 to 5 mm. In a 2-
stage implant placement, the sinus augmentation is carried out initially and the surgi-
cal site is allowed to heal for 4 to 6 months and then the implant is placed in a second
surgical appointment. The disadvantage of a 2-stage procedure is the length of time it
takes for completion of the procedure. It can take longer than a year for a patient to
receive their implant and final prosthesis.
In the recent past, there have been a number of studies that have examined the suc-
cess rate of an implant placement when placed in alveolar bone less than 5 mm. One
study followed-up patients for up to 2 to 6 years after implant placement and found a
98% implant survival and 100% prosthesis survival in implants placed in less than
6 mm maxillary alveolar bone.6,7 In another study, patients were followed up to 9 years
after implant placement.6 Implants were placed in residual bone less than 5 mm, and
the success rate of the implants was 97.9%.6
Kim and colleagues conducted a study that compared implant survival in 1-stage
versus 2-stage implant placement in residual bone less than 4 mm,6 and they found
no statistical difference in the survival of implants in each stage,6 with the patients
followed-up for 10 years. However, if time is a consideration for a patient, the practi-
tioner may choose to conduct a 1-stage implant placement for their patients6 if clini-
cally acceptable.
COMPLICATIONS AND MANAGEMENT
It is important to review the patient’s past medical history, as it can relate directly to
postsurgical possible complications. Specific things that the practitioner is looking
to glean is whether the patient has uncontrolled diabetes mellitus and other possible
immunodeficient diseases,2 as these medical conditions can interfere with wound
healing and may decrease the chance of the dental implant ultimate osseointegration.2
If a patient has been on bisphosphonate or denosumab therapy, a medical consult
from their medical doctor is also recommended.2 Other conditions that would require
a medical consult are chronic liver disease and radiation therapy to the head and neck
region.2
Other important medical considerations include a patient’s alcohol intake and use
of cocaine.2 A patient who is a chronic alcohol drinker has a greater chance of
bleeding postoperatively,2 and a patient who uses cocaine will likely have damage
to their nasal passageways and sinuses.2 Finally, if a patient is a smoker it is recom-
mended for the patient to quit smoking 1 week before the procedure and for 8 weeks
following the procedure. If the patient is undergoing a 1-stage procedure with place-
ment of dental implant, this will possibly help increase the chance of success of
osseointegration.2
Membrane Perforation
The Schneiderian membrane is the membrane that lines the maxillary sinus.2 During
the maxillary sinus lift, it is not unusual for a small perforation of the membrane to
occur,2 with the resulting defect being covered with a resorbable membrane.2 Alter-
natively, the practitioner can choose to use bone morphogenic protein (BMP)-
infused collagen to cover the perforated membrane2 before filling the sinus with
bone graft material. Larger perforations will require using larger absorbable mem-
branes fixated to the superior bony wall of the maxillary opening with bone tacks
or screws before bone augmentation. However, it is important to keep in mind that
if not done correctly, the BMP graft can extravasate into the maxillary sinus.2 This
can lead to an increased risk of infection of the maxillary sinus and possible loss
of the bone graft.2 If the tear is exceedingly large and one is unable to stabilize a
long-lasting resorbable membrane, there may be a need to possibly abort the pro-
cedure at this time.2
Antral Septae
The presence of antral septae can sometimes complicate lateral sinus augmentation
procedures,2 the reason being that it is challenging to lift the sinus membrane from a
septa without tearing it.2 The presence of antral septae can be detected on the preop-
erative imaging,2 and the practitioner can modify the planned procedure based upon
the precise location of the septa.2 The initial lateral bony window can be made larger to
lessen the probability of perforating the membrane in this clinical situation.2 Another
alternative is to create 2 lateral window osteotomies so that the practitioner does
not have to operate over the maxillary septa.2
Bleeding
As mentioned earlier, the maxillary sinus is robustly supplied by multiple arteries,2 and
it is for this reason that an artery can be encountered and damaged during the planned
sinus surgical procedure, which can lead to profuse bleeding within the maxillary.2
This is an issue that can complicate the procedure, as it will certainly decrease the
visualization of the surgical field and may prove challenging if not impossible to control
the bleeding.2 In the author’s experience when profuse bleeding has occurred during
lateral approach to the maxillary sinus, packing the sinus with ½ inch iodoform gauze
and applying digital pressure for 5 minutes has led to cessation of bleeding in all cases
when this situation was in fact encountered.
TRANSCRESTAL OR INTRAORAL SINUS LIFT APPROACH
The previous section in this chapter dealt with the more often performed lateral win-
dow surgical approach to the maxillary sinus for the augmentation of the deficient pos-
terior maxilla before the placement of endosseous implants.
The disadvantages of this technique, however, is that it is a relatively large surgical
operation; a need for specialized instrumentation and the procedure takes time to do
well, so clinician patience is required to avoid possible Schneiderian membrane perfo-
ration. The technique is also often accompanied by postoperative symptoms and high
costs.
A less invasive procedure, often referred to as the transcrestal osteotome sinus floor
elevation technique, was first presented by Dr Summers8 in 1994 and is a viable alter-
native in certain clinical settings to the lateral window sinus lift procedure.
Alveolar bone loss that occurs in the posterior maxilla can be demarcated into 3
main categories:
1 .An alveolar ridge containing 5 to 10 mm of bone before encroaching upon the sinus
2 .An alveolar ridge equal to or less than 5 mm of bone
3 .A complete absence of alveolar bone between the sinus floor and alveolar crest
In the opinion of one of the authors (HD), the lateral maxillary sinus window
approach for categories 2 and 3 is absolutely indicated, with category 1 being more
amenable to the Summers technique for sinus lift elevation and augmentation, which
is discussed in the following section.
206 Bhalla & Dym
SUMMERS/CRESTAL SINUS LIFE TECHNIQUE
As in the traditional lateral sinus window approach, a prior imaging study of the
planned surgical posterior maxillary area with a clear view of the sinus should be avail-
able before the initiation of the procedure. The imaging study can be a panoramic view
or cone beam study or a CT scan or even a quality periapical film. The patient must be
made aware of the risks of the procedure, which can include the standard surgical
complications one sees with almost all oral surgical procedures including pain, post-
operative swelling and edema, possible infection in the sinus (maxillary sinusitis), and
possible infection of the grafted material placed. Local anesthesia is often all that is
necessary for this procedure although of course sedation, either oral, intravenous,
or via inhalation, can also be used.
One necessary piece of equipment required for this procedure is a set of surgical
osteotomes of varying incremental increasing diameter size. A set of 4 or 5 osteo-
tomes is all that is necessary and can be obtained from multiple specialized dental
and oral surgical supply houses. The osteotomes (Ace Surgical or Salvin Dental)
contain graduated markings on the side to allow you to be aware of the depth of
the insertion at all times. They are available as either straight or off-set osteotomes.
If the bone is soft in the area in which the transcrestal sinus augmentation is planned
then the entire procedure can be done with a series of osteotomes. The osteotomes
have a concave tip and are introduced into the maxillary soft bone. By controlled up-
ward pressure they cause the soft bone to be retained and displaced and compacted
laterally and also moved apically toward the antral floor. The antral floor can be flexed
upward and elevated with repeated pressure from the osteotome tip as the trapped
bone particles and fluids are pushed upward. Summers writes9 that adding hydrated
bone into the osteotomy site, the combined bone plus trapped fluids will act as a hy-
draulic plug to push up the sinus membrane with less likelihood of membrane tear.
However, if the bone is a bit more dense, the first osteotomy will require using a stan-
dard pilot drill. In the technique described by Dr Summers,8 after having determined
the height of the residual crest the first length of the 2 mm initial drill bit is drilled to
a depth that is 1 mm beneath the sinus floor. Then, sequentially a 2.8 mm and a
3.3 mm diameter osteotomes are introduced and malleted into place. Before inserting
the final osteotome, the grafting material that is planned to be used to augment the
sinus floor is inserted in a slurry form into the osteotomy site. The last osteotome
should always be 0.7 to 1.0 mm less in diameter than the planned implant diameter
for better implant stability.
A novel technique using osteotomes, as described by Summers, followed by hy-
draulic pressure from saline syringe to elevate the sinus membrane has also been
described in the literature.10
OSSEODENSIFICATION-ASSISTED TRANSCRESTAL SINUS LIFT
Osseodensification is a technique that involves plastic deformation of bone that is

created by rolling and sliding contact using a densifying bur that is fluted in such a
manner that it densifies and compacts the bone with minimal heat elevation.
A rather new implant site/osteotomy preparation technique was developed in
2013, which densifies the bone as it prepares the implant site by means of a nonsub-
stractive drilling technique referred to as by its innovator Dr Huwais11 as osseoden-
sification. This is a surgical technique that uses specialized designed fluted burs
(DENSAH burs) that help densify the bone as they prepare the osteotomy site. Stan-
dard drills excavate bone during site preparation, whereas the DENSAH burs allow
for bone preservation and condensation through compaction that occur during the
preparation, thus increasing the bone density in the periimplant area and improving
mechanical stability.12,13 The drills are used at high speed (1200 RPM) in a counter
clockwise direction with a steady external irrigation referred to as the densifying
mode.
Increasing bone density is a critical factor in ensuring primary implant stability. Trisi
and colleagues13 found a statistically significant correlation between periimplant bone
density, insertion torque, and micromotion. Increasing bone density was directly
related to significant increase in implant insertion torque and a concomitant reduction
in micromotion. This technique was introduced for horizontal augmentation in narrow
alveolar ridges but can also be used to gain vertical height with an internal sinus lift via
a transcrestal approach described in Boxes 1 and 2.
According to the inventor’s DENSAH protocol,11 if additional lift beyond the 3 mm is
needed, an allograft material can be added and gently pushed into the sinus to achieve
additional 2 mm increase in height. Well-hydrated cancellous bone is used to fill the
osteotomy of the final diameter drilled site and then the last diameter DENSAH drill
used is run at 150 to 200 REM with no irrigation in a counter clockwise direction to pro-
pel the allograft into the sinus. The final drill diameter should be 7 mm to 1 mm less
than the planned implant diameter.
Following the lift, the implant is placed into the site with the appropriate torque
wrench.
The osseodensification procedure can, according to the published literature, not
only expand osteotomy sites both horizontally and vertically but also help to improve
maxillary bone density leading to an increase in bone-to-implant contact, thereby
improving implant stability.12
ALTERNATIVE METHOD FOR TRANSCRESTAL APPROACH

Dentium-Advanced Sinus Kit System
The senior author (HD) has written14 about this system in the past, and it is a viable
alternative with a click learning curve for augmenting the maxillary sinus via a trans-
crestal approach. Similar to the other techniques, a series of varying size of drill bits
are used to achieve the desired osteotomy diameter, leaving a 1 mm ceiling of bone
between final drill and sinus floor. Then the specialized (DASK System) DASK drill is
introduced into the osteotomy, which due to its unique dome shape and diamond fin-
ish will thin out the antral floor bone without causing a perforation in the Schneiderian
Box 1
Technique for vertical augmentation of 3 mm or more
Step 1: measure the bone height to the sinus floor

Step 2: flap the soft tissue using instruments and techniques as usual
Step 3: begin with DENSAH bur 2.0 diameter in osseodensification (OD) mode
(counterclockwise drill speed 800 to 1500 RPM with copious irrigation). Continue running bur
until you are at the sinus floor but not further and confirm position with a radiograph.
Step 4: use the next drill diameter 3.0 at the same drill speed with a pumping motion and
advance past the sinus floor 1 mm in increments up to 3 mm. Bone will be pushed toward the
apical end and will begin to gently lift the membrane. Confirm the drill position with a
radiograph.
Step 5: depending on the diameter of the implant you wish to place, continue with the next
size diameter drill bit.
208 Bhalla & Dym
Box 2
Osseodensification technique for transcrestal sinus lift
Step 1: measure height of maxillary sinus

Step 2: rotate pilot drill in standard clockwise direction to 1 mm short of sinus floor
Step 3: next DENSAH drill bits at 800 to 1220 RPM in counterclockwise direction
Step 4: final drill is advanced past sinus floor at maximum of 3 mm
Step 5: if posterior bone height is 4 to 5 mm add slurry of bone to osteotomy site and advance
drill (maximum of 3 mm) running at 150 to 200 RPM
NOTE: always undersize the osteotomy site by 0.7 mm to 1.0 mm drill bits to planned implant
diameter.
membrane. The membrane is then elevated and bone graft is then introduced
(Fig. 7).
Transcrestal Sinus Lift Complications

The most common complications related to the transcrestal sinus flaps elevation pro-
cedure are similar to the lateral window surgical approach: sinus membrane perfora-
tion and maxillary sinusitis. However, unlike the lateral maxillary approach, the sinus
Fig. 7. DASK system transcrestal sinus augmentation technique with simultaneous implant
placement. (Courtesy of Dentium.)
membrane perforations in the transcrestal approach can sometimes go unnoticed due

to the lack adequate visibility. The most reliable method for identifying sinus mem-
brane perforation during transcortical sinus lift procedures would be flexible endo-
scope examination. This technique is unlikely to ever become the standard of care
due to the expensive nature of the equipment and its infrequent use. Most clinicians
rely on using the Valsalva maneuver (which involved moderate forceful exhalation
against a closed airway) as a reliable clinical method for detecting sinus membrane
perforation. The patient’s nostrils are gently squeeze shut while advising patient to
breathe out. A positive result will be recognized by bubbling seen at the perforated si-
nus membranes at the prepared implant site or viewing the membrane flutter through
the prepared implant site. Perforations via the transcortical approach can occur while
infracturing the floor or while inserting the implant or while placing the graft material.
If a small sinus membrane perforation occurs the clinician is faced with a few clinical
options. Number one would be to proceed with the planned procedure: placing a
collagen sponge into the socket followed by the bone graft material and the implant.
However, the patient will require frequent follow-up to monitor for possible develop-
ment of sinusitis. If the perforation is rather large, equal to more than half the size of
the osteotomy, the other option would be to perform a lateral window in the usual
manner and lift the sinus membrane into position and then seal the perforation with
a large collagen membrane. The other option would be to place the implant 2 mm
into the sinus with no grafting, thus engaging the cortical floor of the sinus. The liter-
ature15 has shown that in canine studies, implants protruding 2 mm or less in the
maxillary sinus will lead to complete healing of the sinus membrane and bone forma-
tion with no sinusitis developing. The literature has also shown in human studies that
implants protruding an average of 4 mm (some were 6 mm) did not lead to a clinical
maxillary sinusitis and bone and implant failure or loss of osseous integration, but
the likelihood of being covered by the maxillary Schneiderman membrane would be
lessened.
SUMMARY
Augmenting the posterior alveolous before implant placement is often required to

obtain solid implant stability. Two time-tested techniques—lateral and transcrestal si-
nus lifts—are presented in this chapter above with the most common complications.
Sinus augmentation of the atrophic posterior maxilla via either the transalveolar or
lateral window approach is a highly predictable procedure associated with a success
rate of 90% or better.16,17
DISCLOSURE
REFERENCES
1. Carrao V, DeMatteis I. Maxillary sinus bone augmentation techniques. Oral Maxil-

lofacial Surg Clin N Am 2015;27(2):245–53.
2. Kao DW. Clinical maxillary sinus elevation surgery. Ames (IA): John Wiley & Sons;
2014. Accessed May 23, 2020.
3. Ritter A, Rozendorn N, Avishai G, et al. Preoperative maxillary sinus imaging and
the outcome of sinus floor augmentation and dental implants in asymptomatic pa-
tients. Ann Otol Rhinol Laryngol 2020;129(3):209–15.

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A n a t o m y o f th e

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298 © 2014 Australian Dental Association

Emergency surgery in the absence of tissue factor.25 In a rat-tail model,

Table 4. Summary of management of oral surgical patients taking dabigatran

300 © 2014 Australian Dental Association

© 2014 Australian Dental Association 301

Available online at www.sciencedirect.com

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Address for correspondence