In - A Randomized Split Face Histomorphologic Study Comparing A Volumetric Calcium Hydroxylapatite and A Hyaluronic Acid Based Dermal Filler
In - A Randomized Split Face Histomorphologic Study Comparing A Volumetric Calcium Hydroxylapatite and A Hyaluronic Acid Based Dermal Filler
In - A Randomized Split Face Histomorphologic Study Comparing A Volumetric Calcium Hydroxylapatite and A Hyaluronic Acid Based Dermal Filler
ABSTRACT
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Background: Soft-tissue augmentation with fillers is an aesthetic procedure for restoring age-related volume loss.
Objective: To compare neocollagenesis and elastin production stimulated by Radiesse® (calcium hydroxylapatite; CaHA, Merz Pharma-
ceuticals GmbH) and a hyaluronic acid-based filler (HA; Juvéderm® VOLUMA®).
Methods: Twenty-four women, aged 35–45, participated in this split-face, comparative study. Punch biopsies were taken 4 and 9
months after supraperiostal injection of each filler into the ipsilateral or contralateral postauricular area. Samples were analyzed for
collagens type I and III, elastin, Ki-67, and inflammatory and angiogenic markers.
Results: At month 4, collagen type III was greater with CaHA vs HA (P=0.0052). By month 9, type I staining was higher with CaHA vs
HA (P=0.0135), whereas type III was lower with CaHA than HA (P=0.0019). Staining for elastin, Ki-67 and angiogenesis was greatest
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with CaHA at both timepoints. Inflammatory markers increased most with HA treatment.
Conclusions: CaHA resulted in more active, physiologic remodeling of the extracellular matrix than HA by stimulating a two-step
process whereby collagen type I gradually replaced type III. Increased elastin stimulated by CaHA also indicates active remodeling.
The results of this study suggest that, in the first 9 months after treatment, by reconstituting tissue homeostasis without inducing
inflammation suggests CaHA has more desirable characteristics for a dermal filler than HA.
INTRODUCTION
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oft-tissue augmentation with dermal fillers is a popu- Studies have shown that the HA gel, which is a combination
lar, minimally invasive aesthetic procedure.1 In 2012, in of a low (<1 mDa) and high (>1 mDa) molecular weight HA
the USA, most non-surgical augmentation treatments (20 mg/mL), is effective and well-tolerated in restoration of
performed with a dermal filler used a product based on facial volume loss.4,7 Similarly, the porous CaHA gel matrix
hyaluronic acid (HA), with the second most popular type be- has well-established tolerability,8 having been used in re-
ing the calcium hydroxylapatite (CaHA)-based filler, Radiesse® constructive and orthopedic surgery and dentistry for over 20
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(Merz Pharmaceuticals GmbH, Frankfurt, Germany), hereafter years.9 The CaHA gel matrix has been studied in many clini-
referred to as CaHA gel matrix.2 cal trials for volume augmentation in facial aesthetics and has
demonstrated efficacy, safety, and good tolerability in the cor-
Several HA-based fillers are available, including the product rection of NLF,10-12 as well as the volume loss associated with
Juvéderm® VOLUMA® (Allergan Inc., Irvine, CA), hereafter HIV infection.13 In one direct comparison study of CaHA gel
referred to as ‘HA gel’, an injectable cross-linked gel implant matrix and another HA gel product (Juvéderm® 24; HA 24; 24
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intended to restore the volume of the face. It is a member of mg/mL HA; Allergan Inc.) for the improvement of NLF, CaHA gel
a family of HA-based fillers that differ with respect to their matrix was more efficacious and longer-lasting than HA 24.14
degree of cross-linking and HA concentration.3,4 The CaHA gel
matrix is formulated to immediately augment volume and, The CaHA gel matrix has also been shown to stimulate an
subsequently, to stimulate collagen production.5 As a sub- increase in the production of collagen within the injected re-
dermal implant, CaHA gel matrix is indicated for plastic and gion.15 Collagen and elastin are components of the extracellular
reconstructive surgery of the facial area, including the correc- matrix (ECM) that confer important biomechanic properties to
tion of moderate-to-severe facial wrinkles and folds, such as the skin.16 Dermal collagen in adult skin accounts for 77% of the
nasolabial folds (NLF) and restoration and/or correction of the fat-free dry weight of the skin, and is primarily composed of col-
signs of facial fat loss (lipoatrophy) in people with human im- lagen types I and III. These collagen subtypes provide the skin
munodeficiency virus (HIV) infection.6 with its tensile strength and structural support, and are known
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Journal of Drugs in Dermatology Y.Yutskovskaya, E. Kogan, E. Leshunov
September 2014 • Volume 13 • Issue 9
Safety FIGURE 1. Mean scores for collagen type I staining intensity (stain-
Safety and tolerability were monitored throughout the study ing index; weak=2, hyperexpression=8) 9 months after treatment
and for a further month after study completion. Safety infor- with CaHA gel matrix or HA gel.
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mation was gathered from questionnaires given to participants
and from face-to-face interviews prior to treatment. At each vis-
it, subjects were asked about adverse events (AEs) and serious
AEs, and details of concomitant medications were recorded.
RESULTS
Participant Demographics
A total of 24 healthy women (age range, 35–45 years) took part
in this study.
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Analysis of Collagen Expression at Month 4
At month 4, collagen type I formation was found to be higher
with CaHA (mean staining intensity: 4.0±1.44) than with HA gel
(mean staining intensity: 3.65±1.65), nearing a level of statisti-
cal significance (P=0.0679). At this timepoint, the mean staining
intensity of collagen type III was significantly greater with
CaHA gel matrix than HA gel (5.2±1.67 vs 4.2±1.44, respectively;
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P=0.0052).
FIGURE 3. Mean score for elastin staining intensity (staining index; weak=2, hyperexpression=8) at a) month 4 and b) month 9 after treatment
with CaHA gel matrix and HA gel; c) elastin expression, indicated by the brown staining at month 9 after injection of CaHA gel matrix, showing
preserved perivascular elastin fibers in dermal tissue and d) expression of elastin at month 9 after injection of HA gel, showing fragmentation of
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elastin fibers in dermal tissue. Magnification x600.
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c)
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d)
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deeper layers were organized linearly but sparsely. After treat- duction of collagen type III and then collagen type I, which
ment with CaHA gel matrix, a more homogeneous epidermal replaces the former. This was demonstrated by the reversal in
structure was seen, with clear separation from the dermis. A the differential levels of staining for the two collagen types at
more uniform dermal structure was also seen, with a more lin- the timepoints investigated here.
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ear and dense arrangement of superficial and deep-layer fibers.
At month 4 after injection of HA gel, the filler was visualized in Collagen types I and III play independent roles in the neocol-
the dermis with fixed-area hyperechogenicity and edema of the lagenesis associated with ECM remodeling after tissue injury.
papillary dermis, though the epidermis and hypodermis were Neocollagenesis under physiologic conditions is dependent
unchanged. At month 9 there was no swelling of the dermis; on collagen type I gradually replacing the collagen type III
dilated dermal vessels could be seen, and the collagen fibers of that is formed as part of the early response to tissue injury.17
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the dermis were linear, not compact. This results in tissue with a high tensile strength.17 Our results
indicate that, relative to HA gel, the CaHA gel matrix may
Safety evoke ECM remodeling more consistent with this two-step
There were no AEs reported during the study. process whereby collagen type III is gradually replaced by col-
lagen type I. At the initial assessment (4 months), the staining
DISCUSSION for collagen type III was significantly greater with CaHA gel
This study evaluated collagen production following a single- matrix than with HA gel. By month 9, collagen type I staining
dose administration of a CaHA gel matrix and a HA gel-based was higher following CaHA gel matrix treatment than HA gel
dermal filler. The results indicate that at the timepoints evalu- treatment, whereas collagen type III was significantly lower
ated here, CaHA stimulates a process more consistent with following CaHA gel matrix treatment than HA gel treatment
the two-step physiologic neocollagenesis than HA ie, pro- at this timepoint. Our findings are consistent with a previous
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Journal of Drugs in Dermatology Y.Yutskovskaya, E. Kogan, E. Leshunov
September 2014 • Volume 13 • Issue 9
FIGURE 4. Histomorphologic characteristics at (a) month 4 and (b) and, therefore, nutrient delivery to the skin was improved
month 9 after treatment with CaHA gel matrix and HA gel. with CaHA gel matrix compared with HA gel. Moreover, the
increase in angiogenesis correlates with, and may result in,
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the early synthesis of collagen type III.
This study was the first known examination of the effect of der-
mal fillers on elastin levels. It found that CaHA gel matrix also
stimulated remodeling of the ECM by increasing elastin levels
to a significantly greater extent than HA gel. Elastin provides
skin with the ability to recoil after deforming stresses have been
applied. Therefore, unlike HA gel, the CaHA gel matrix appears
to have the potential to improve not only the structural strength
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of skin via collagen remodeling, but also its elasticity, proper-
ties that are known to decline in ageing skin in parallel with the
loss of both collagen and elastin fibers.19,20
CaHA gel matrix also stimulated cell proliferation signifi- In conclusion, CaHA gel matrix produced an instant volume
cantly more than HA gel, as reflected by a relative increase in enhancement, but with a longer reconstructive process
Ki-67 staining with the former at month 9, which may support brought about through collagen neogenesis. At the timepoints
the observed increase in collagen production by stimulating evaluated here, CaHA gel matrix treatment resulted in a pro-
proliferation of collagen-producing cells. This is consistent cess indicative of more active, physiologic remodeling of the
with previous work showing the presence of fibroblasts and ECM in comparison with HA gel. The CaHA gel matrix stimu-
macrophages 6 months after injection of CaHA gel matrix.5,15 lated the production of collagen type III and type I in a two-step
Treatment with CaHA gel matrix also stimulated neoangio- process whereby collagen type I gradually replaced collagen
genesis at both 4 and 9 months, suggesting that blood flow type III, consistent with the process of remodeling and collagen
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Journal of Drugs in Dermatology Y.Yutskovskaya, E. Kogan, E. Leshunov
September 2014 • Volume 13 • Issue 9
REFERENCES
1. Carruthers J, Cohen SR, Joseph JH, et al. The science and art of dermal fill-
ers for soft-tissue augmentation. J Drugs Dermatol. 2009;8:335–50.
2. ASAPS. The American Society for Aesthetic Plastic Surgery Statistics 2012. Avail-
able at: http://www.surgery.org/media/statistics. Accessed February 10, 2014.
3. Bogdan Allemann I, Baumann L. Hyaluronic acid gel (Juvéderm) preparations
in the treatment of facial wrinkles and folds. Clin Interv Aging. 2008;3:629–34.
4. Hoffmann K, Juvéderm Voluma Study Investigators Group. Volumizing ef-
fects of a smooth, highly cohesive, viscous 20-mg/mL hyaluronic acid volu-
O
mizing filler: prospective European study. BMC Dermatol. 2009;9:9.
5. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic and electron micro-
scopic findings after injection of a calcium hydroxylapatite filler. J Cosmet
Laser Ther. 2004;6:223–6.
6. Jacovella PF. Use of calcium hydroxylapatite (Radiesse) for facial augmenta-
tion. Clin Interv Aging. 2008;3:161–74.
7. Callan P, Goodman GJ, Carlisle I, et al. Efficacy and safety of a hyaluronic acid
filler in subjects treated for correction of midface volume deficiency: a 24
O
month study. Clin Cosmet Investig Dermatol. 2013;6:81–9.
8. Pavicic T. Calcium hydroxylapatite filler: an overview of safety and tolerability.
J Drugs Dermatol. 2013;12:996–1002.
9. Berlin A, Cohen JL, Goldberg DJ. Calcium hydroxylapatite for facial rejuvena-
tion. Semin Cutan Med Surg. 2006;25:132–37.
10. Smith S, Busso M, McClaren M, Bass LS. A randomized, bilateral, prospective
comparison of calcium hydroxylapatite microspheres versus human-based col-
lagen for the correction of nasolabial folds. Dermatol Surg. 2007;33:S112–21.
FS
11. Bass LS, Smith S, Busso M, McClaren M. Calcium hydroxylapatite (Radiesse)
for treatment of nasolabial folds: long-term safety and efficacy results. Aes-
thet Surg J. 2010;30:235–8.
12. Graivier MH, Bass LS, Busso M, et al. Calcium hydroxylapatite (Radiesse) for
correction of the mid- and lower face: consensus recommendations. Plast
Reconstr Surg. 2007;120:55S–66S.
13. Silvers SL, Eviatar JA, Echavez MI, Pappas AL. Prospective, open-label,
18-month trial of calcium hydroxylapatite (Radiesse) for facial soft-tissue
augmentation in patients with human immunodeficiency virus-associated
lipoatrophy: one-year durability. Plast Reconstr Surg. 2006;118:34S–45S.
14. Moers-Carpi M, Vogt S, Santos BM, et al. A multicenter, randomized trial
comparing calcium hydroxylapatite to two hyaluronic acids for treatment of
nasolabial folds. Dermatol Surg. 2007;33:S144–51.
15. Berlin AL, Hussain M, Goldberg DJ. Calcium hydroxylapatite filler for facial
rejuvenation: a histologic and immunohistochemical analysis. Dermatol