Rotator Cuff Tears: What Have We Learned From Animal Models?
Rotator Cuff Tears: What Have We Learned From Animal Models?
Rotator Cuff Tears: What Have We Learned From Animal Models?
ReviewArticle Hylonome
Abstract
Rotator cuff tendon tears are among the most common soft tissue injuries that occur at the shoulder. Despite advancements in
surgical repair techniques, rotator cuff repairs experience a high rate of failure. The common occurrence of tears and the frequency
of re-tears require a further understanding of the mechanisms associated with injuries, healing, and regeneration of the rotator
cuff. This paper reviews in vivo studies using the various animal shoulder models of the rat, rabbit, sheep, canine, and primate.
These animal models have been used to study intrinsic and extrinsic factors leading to shoulder degeneration, various suture tech-
niques, effects of post-surgical treatment, numerous biologic and synthetic scaffolds, and an assortment of biologic augmentations
used to accelerate healing. These effects can be examined in a controlled manner using animal models without other confounding
factors that sometimes limit clinical studies. The clinically impactful results will be explained to highlight the specific knowledge
gained from using animal models in rotator cuff research.
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has only been used in one recent in vivo study of rotator cuff
tears and healing18. This is most likely due to the large cost,
complexities, facilities, and management difficulties required
to maintain primates in sufficient numbers for such purposes.
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L. Edelstein et al.: Rotator Cuff Tears and animal models
Figure 2. A theoretical paradigm linking mechanical stress to tendon degeneration via cytokines, protein kinases, oxygen free radicals, and apoptotic
mediators which can be studied in animal models. (Reprinted with kind permission of Springer Science and Business Media from Millar NL, Wei AQ,
Molloy TJ, Bonar F,Murrell GA. Heat shock protein and apoptosis in supraspinatus tendinopathy. Clin Orthop Relat Res 2008;466-7:1569-76).
152
L. Edelstein et al.: Rotator Cuff Tears and animal models
Figure 4. Magnetic resonance images depicting pennation angles of uninjured control rotator cuff, successful, and failed surgical repair of
chronic infraspinatus tears in a sheep model. (Reprinted from, J Shoulder Elbow Surg, 18-2, Gerber C, Meyer DC, Frey E, von Rechenberg B,
Hoppeler H, Frigg R, Jost B, Zumstein MA. Neer Award 2007: Reversion of structural muscle changes caused by chronic rotator cuff tears
using continuous musculotendinous traction. An experimental study in sheep, 163-71, 2009, with permission from Elsevier).
Alterations associated with rotator cuff tears MMP-3, and TIMP-2)38, representing a continual degradation
of the remaining tendon. When attempting to repair the chronic
A rotator cuff tear that goes untreated commonly leads to as- rotator cuff tear, the mechanical properties were found to
sociated alterations or injuries of the surrounding tissues. This is slightly improve but remained inferior to controls14,39-41.
commonly observed in the long head of the biceps tendon for In addition to studying the torn tendon, research has exam-
example, which develops a variety of lesions ranging from ten- ined the remaining intact rotator cuff tendons after a tear. It
donitis to complete tears. Alterations to the biceps have been ob- was found that they had decreased mechanical properties and
served in the rat model, mimicking the clinical observations seen increased cross sectional area after a variety of tear situations42.
in human rotator cuff tears. Specifically, biceps mechanical prop- This demonstrates that after a rotator cuff tear, the stabilizing
erties decreased with both rotator cuff tear size and time34. Re- loads of the shoulder are distributed to the remaining tendons
gional decreases in the mechanical properties along the length of resulting in increased stress to the otherwise healthy tendons.
the biceps after a combination of rotator cuff tears and increased The rotator cuff muscles also go through several adaptations
loading were also noted35. These results demonstrate the specific after rotator cuff tears and repairs. One observed alteration,
tissue changes that occur in the biceps after rotator cuff tears and muscle atrophy, is also observed in the rat and sheep model,
may lead to more effective treatment options for patients. which is potentially caused by the muscle’s inability to pro-
When the rotator cuff is not surgically repaired after a com- duce tension14,39,43,44. In conjunction with muscle atrophy, func-
plete tear, it loses its ability to function and transfer force cre- tional characteristics such as reduced force, power, and fatigue
ated in the muscle to the humerus. This inability to transfer have been seen in both a rabbit and sheep model after cuff
force alters the structure and composition of the tendon result- tears39,45,46. Structural changes of the muscle have also been
ing in potential difficulties for tendon healing. The rabbit, rat, identified in rabbits, rats, and sheep including decreased sar-
and sheep animal models have been used to examine the al- comere length, pennation angle, fiber length, and fiber diam-
terations to the rotator cuff tendon after a chronic detachment. eter44,47,48. The structural changes of the muscle likely dictate
Specifically, the mechanical properties of the torn tendons ini- the decreased functional characteristics after cuff tears.
tially decrease and then increase at later healing times36. Sim- Fatty infiltration of the rotator cuff muscle is a common
ilar findings were observed in massive rotator cuff tears, clinical occurrence with chronic tears which has been repro-
defined as detachment of both the supraspinatus and infra- duced in animal models including the sheep, rabbit, and
spinatus tendons37. When examining the composition and bio- rat14,39,48-51. The models determined that fatty infiltration wors-
chemistry of the torn tendon, alterations were found in the ens over time52 and progresses proximal to distal within the
expressions of several extracellular matrix (ECM) proteins muscle53. When repairing a chronically torn rotator cuff, the
(collagen I, II, III, XII, aggrecan, and sulfated GAGs) and progression of fatty infiltration did stop but did not reverse or
genes (IL-1β, cyclooxygenase-2, prostaglandin E2, MMP-13, return to control levels after repair39,50,54.
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L. Edelstein et al.: Rotator Cuff Tears and animal models
Since the tension required to repair a chronically torn tendon of rotator cuff injuries. It is designed to optimize the body’s
back to the greater tuberosity can reach high levels55 and rapid natural healing ability. Overuse is a common mechanism of
stretching of shortened muscle can cause fibrosis56,57, a traction injury, however little scientific evidence exists evaluating treat-
device was developed to progressively lengthen the tendon in ments. Supraspinatus tendons in rats recovered from the mo-
a chronic sheep model. Muscle atrophy decreased and the pen- lecular and biological effects of 4 weeks of overuse activity in
nation angle improved after successful traction and tendon re- as little as 2 weeks70. This demonstrates that rest can heal tissue
pair (Figure 4). Similar to previous research, fatty infiltration damage caused by overuse activity, at least in the case of a
of the muscle remained unchanged after traction and repair; short period of overuse.
however, it did stop progressing44. Joint immobilization is commonly used after surgical repair
A complete rotator cuff tendon injury has many character- to protect the repaired structures until adequate strength is ob-
istics similar to that of an isolated neural injury12. The rabbit tained. Longer durations of immobilization (16 weeks) in the
model has been extensively used to study the relationship be- rat improve the strength, organization, and composition of in-
tween nerve injury and cuff pathology. An experimentally in- sertion site healing71,72. Conversely, shorter durations of immo-
duced acute inflammation had an excitatory and sensitizing bilization (4 and 6 weeks) in rat and sheep rotator cuff repair
effect on the mechanosensitive afferent units in the rotator models do not result in improvements in insertion site healing71-
cuff58. Electrophysiologic experiments found a high density of 73
. Although long periods of joint immobilization benefit rotator
nociceptors in the infraspinatus insertion site and muscle59. A cuff insertion site healing, immobilization has also been linked
study using the rabbit subscapularis muscle found that a com- to increased joint stiffness and a decreased range of motion.
plete tenotomy resulted in muscular changes similar to those However, increased joint stiffness and decreased range of mo-
seen with denervation of the muscle, suggesting that chronic tion resolves 8 weeks after remobilization74. In addition, exer-
rotator cuff tears may induce neurologic damage13. cise following 2 weeks of immobilization decreases range of
motion, but does not improve collagen organization or tendon
Tendon to bone healing mechanical properties 12 weeks post-surgery75. This further
demonstrates the need for a period of protection for the healing
insertion site. Surprisingly, complete removal of load, which
The high re-tear rate seen clinically following cuff repair is
differs from immobilization due to the absence of muscular ten-
due to lack of a strong tendon to bone integration. In a reat-
sion, has been found to be detrimental to tendon healing76.
tached rabbit supraspinatus tendon, formation of a new enthesis
Therefore, a low, balanced and controlled load may be neces-
was accompanied by extensive non-chondrocytic proliferation,
sary to optimize rotator cuff insertion site healing and provide
followed by the appearance of chondrocytes and eventual im-
successful functional outcome following repair.
provements in ECM reformation, correct spatial alignment of
collagen fibers, and recovery of the surgical construct strength60
over extended time which may prohibit early rehabilitation61. Surgical repair
Additionally, delaying repair of the supraspinatus by up to 12
weeks did not impair this enthesis reformation62. Without optimal suture configuration, the injured tendon
Cells in surrounding tissues can be important in the repair will not remain approximated to the bone insertion during
process. In the rabbit supraspinatus tendon repair, increased healing, contributing to high failure rates in cuff repairs. The
cellularity was observed in the underlying bone, and the thick- suture configuration must initially provide superior strength
ness of the subacromial bursa was also increased compared to without impeding blood flow or damaging the tendon.
control. Meanwhile, the cellularity of the tendon stump was The sheep model has been used to study suture configura-
significantly decreased. In the clinical setting, the cell source tion based on the loads that the rotator cuff experiences. Ten-
of the subacromial bursa could be important in the healing don repairs were first studied in the sheep comparing bone
process63. Similarly, the epitenon has been noted to be a source tunnels and anchors. Differences were only found at time zero
of healing64 and this should be considered clinically. demonstrating that bone tunnels had higher failure loads77. Fur-
The normal characteristics of rotator cuff healing are required ther studies demonstrated the modified mason-allen suture
to examine surgical and rehabilitation techniques that are devel- technique is superior compared to other simple suture config-
oped to improve tendon to bone healing. A primate model was urations, but both techniques caused similar tissue damage
used to examine the properties of tendon healing. Histology was within the distal tendon15. Variations in the modified mason-
examined at 12 weeks post repair and demonstrated an integra- allen did not demonstrate differences in mechanical proper-
tion of collagen fibers into the bone18. When examining the bi- ties78,79, but did show increased expression of collagen II and
ology of the healing rotator cuff tendon in both the rabbit and improved fibrocartilage at the insertion site for the modified
rat model, several ECM proteins, growth factors, and degrada- mason-allen80. In a rabbit model, no clear differences in me-
tion factors are temporally expressed (col1, col3, TGFβ1, chanical properties and histology were observed between sin-
TGFβ3, bFGF, bmp-12, bmp-13, bmp-14, COMP, CTGF, gle and double row repairs; however, the double row had less
PDGF-bb, MMP-2, and TIMPS) demonstrating the complex in- failures over the course of healing81.
teractions that are required to heal the tendon back to bone65-69. One of the challenges of chronic rotator cuff repair is over-
Rehabilitation is commonly used to augment the treatment coming the large tension required to re-approximate the re-
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L. Edelstein et al.: Rotator Cuff Tears and animal models
Augmentations
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L. Edelstein et al.: Rotator Cuff Tears and animal models
Figure 6. Sections stained with hematoxylin and eosin illustrating: a) well-aligned collagen fibers and trabecular bone ingrowths after repair
with use of a chitin fabric scaffold and b) unaugmented control repair in a rabbit rotator cuff model. (Reprinted from Funakoshi T, Majima T,
Suenaga N, Iwasaki N, Yamane S, Minami A. Rotator cuff regeneration using chitin fabric as an acellular matrix. J Shoulder Elbow Surg
2006;15:112-8, with permission from Elsevier).
Other synthetic scaffolds have also been examined for ef- the rabbit to evaluate the impact of tenocyte addition in over-
fectiveness in augmenting cuff repairs. Non-woven chitin fab- coming the inflammatory response induced by the scaffolds.
ric, an acellular matrix, was tested in rabbit infraspinatus Bioscaffolds seeded with tenocytes did display an inflamma-
tendons. Use of this fabric increased cellularity and improved tory reaction, but to a lesser degree than the bioscaffolds alone,
collagen fiber alignment (Figure 6), resulting in regenerated and produced a histological appearance more similar to control
tissues consisting of type III collagen along with improved tendon. The addition of autologous tenocytes led to better ten-
structural properties96. don healing and remodeling than unseeded scaffold101.
Tissue engineered scaffolds have also been presented as Mesenchymal stem cells (MSCs) are a third type of cell ap-
possible materials to augment cuff repairs. One such material, plied in attempt to improve rotator cuff healing. Their effec-
a polyglycolic acid sheet, was used to repair a resected infra- tiveness was tested in the rat by the application of MSCs in a
spinatus tendon in the rabbit model. The material allowed for fibrin carrier to the repair site at the time of surgery. No dif-
the tendon insertion to be regenerated with a fibrocartilaginous ferences were determined in structure, composition, or strength
layer consisting mainly of type III collagen; however, the ma- of the healing tendon after MSC application, suggesting cell
terial properties remained inferior to those of uninjured ten- based strategies may require combination with growth and/or
don97. Due to the potential of adverse tissue reactions, the differentiation factors to be effective102. For example, adenovi-
biologic response to an implant is commonly examined. A ral membrane type 1 matrix metalloproteinase (Ad-MT1-
polycarbonate polyurethane patch was tested in rat supraspina- MMP)-transduced MSCs in a fibrin glue carrier was added to
tus tendon defects with no inflammatory reactions and excel- the repair site, which attempted to evade scar tissue formations
lent integration of tissue into the patch98. Using an ovine at the repair interface and drive a regenerative process. Al-
chronic cuff repair model, a polyurethane scaffold mesh patch though no differences were detected between Ad-MT1-MMP
was tested and found to significantly improve the force at fail- transduced MSCs and unadultered MSCs at 2 weeks, the Ad-
ure compared to nonaugmented controls, thus use of the ma- MT1-MMP MSC treated group generated more fibrocartilage,
terial provides greater mechanical strength during healing than higher ultimate load to failure, ultimate stress to failure, and
the traditional suture anchor repair alone99. stiffness values. This encourages the exploration of biologic
The addition of cells or biologic additives to the rotator cuff augmentation to improve regeneration of the tendon-to-bone
is another approach to enhance repair. A chitosan-based interface103.
hyaluron hybrid scaffold seeded with fibroblasts has been However, future studies are required to optimize which
shown to increase production of type I collagen and the regen- growth factors are most advantageous for tendon-to-bone re-
erated tissue in a large defect created in a rabbit infraspinatus. generation after repair. For example, modulating MMP activity
The fibroblast seeded scaffold significantly improved tensile results in distinct changes in histologic observations and is one
strength and tangent modulus compared to a non-fibroblast potential avenue for altering tendon-to-bone healing104. Mean-
seeded scaffold100. while, MSCs transduced with adenoviral-mediated gene trans-
Tenocytes are another cell type being explored to improve fer of human BMP-13 applied at time of surgical repair in the
massive rotator cuff tendon defects. Porcine small intestine rat model did not result in improved properties105.
submucosa and a type I/III collagen bioscaffold were used in The application of FGF-2 in conjunction with a dermal matrix
156
L. Edelstein et al.: Rotator Cuff Tears and animal models
graft improved ultimate failure loads and histology scores with Translational applications
time106. Ultimate failure loads were also comparable to controls,
providing evidence for the use of FGF-2 during cuff repair. An- The goal of animal model research is to systematically test
other approach coated sutures with PDGF-bb found no differ- emerging theories and treatments in a controlled and consistent
ences in ultimate failure load, but improved histology scores107. environment with the intention of improving patient care. As
In addition to enhancing tendon healing, attempts have been a consequence of animal studies related to the rotator cuff, sev-
made to enhance bone healing. A variety of bone growth fac- eral advances in clinical medicine have been made and a few
tors (osteoinductive bone protein extract, rhBMP-12 paste, and examples are provided here. Animal models have been used
marrow supplementation, cartilage derived BMP-2) were used to identify that overuse activity can cause rotator cuff tendon
to enhance insertion site healing. An enhanced fibrocartilage degeneration and rest is an effective treatment to restore nor-
zone, higher ultimate failure loads, and higher stiffness were mal tendon properties70,120. The successful repair of chronically
observed108-110. This approach demonstrates the feasibility to torn rotator cuff tears has been shown to be dependent on the
enhance cuff repairs with the implementation of both tendon amount of force required to reapproximate the tendon to the
and bone growth factors. rotator cuff footprint82, and that the reapproximation force also
It is common for nonsteroidal anti-inflammatory drugs increases with time55. This information has led to, and sup-
(NSAIDs) to be prescribed after surgical repair of the rotator ported, the timely repair of rotator cuff tears, decreasing the
cuff. The effect of celecoxib, a cyclooxygenase-2-specific likelihood of a failed repair. Although the outcomes of many
NSAID, and indomethacin, a nonselective NSAID were eval- animal studies have yet to be clinically implemented, it is clear
uated. Both of these drugs resulted in worsened repair condi- that an avenue exists for them to influence future clinical treat-
tions, including complete failure to heal, lower failure loads, ments. Work done on joint immobilization and remobilization
and poor collagen organization and maturation providing con- has the potential to influence post-operative treatment and re-
cern about administration of NSAIDs clinically111. habilitation protocols. Similarly, experimentation in the clinic
Controversy also surrounds the use of anabolic steroids for is avoided by the rigorous evaluation provided by animal re-
cuff repair. The effect of nandrolone decanoate was examined search on treatments involving synthetic scaffolds and biologic
in a surgical repair in a rat model which resulted in poorer heal- additives. This improves the introduction of new treatments to
ing and weaker tendon strength. It also led to focal fibroblastic the clinic.
reaction and inflammation compared to the extensive fibrob-
lastic activity observed in groups without steroids112. Conclusion
Another approach for cuff repairs is through the use of bipo-
lar radiofrequency energy, which is used to trigger healing In conclusion, animal models have been instrumental in
through controlled inflammatory and angiogenic responses by identifying mechanisms of rotator cuff injury, evaluating re-
disrupting the molecular bonds of collagen. However, this habilitation, and assessing surgical alternatives. Unlike clinical
treatment had no definitive effect in improving acute research, animal model research has the ability to conduct well
supraspinatus repairs in the rat model113. controlled experiments on a consistent population, with the ca-
pacity to run a large number of assays, and without the inter-
Systemic risk factors ference of confounding factors. The ability to experiment with
new synthetic devices, scaffolds, and growth factors to exam-
Systemic factors can also have an effect on tendon degen- ine the biologic response prior to implementation in patients
eration and healing. In a rat cuff repair model, diabetes caused further enhances the appeal of animal models. Although ani-
a decrease in ultimate failure load, stiffness, fibrocartilage and mal models can be used to address many clinically relevant
organized collagen at the tendon insertion site. There was also questions, they can never replace the human in research; how-
an increased deposition of advanced glycation end-products ever, it does provide a starting point to investigate novel ideas
(AGE)114, produced by a chemical reaction between collagen and theories.
and hyperglycemia115. AGEs are thought to be one of the cul-
prits of diabetic related heart and renal disease116,117.
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