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. 2018 Aug 15;100(16):1-7. doi: 10.2106/JBJS.18.00200

Enthesis Repair

Challenges and Opportunities for Effective Tendon-to-Bone Healing

Kathleen A Derwin 1,a, Leesa M Galatz 2, Anthony Ratcliffe 3, Stavros Thomopoulos 4
PMCID: PMC6133216  PMID: 30106830

Abstract:

On May 22, 2017, the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) hosted a roundtable on “Innovative Treatments for Enthesis Repair.” A summary of the roundtable discussion, as well as a list of the extramural participants, can be found at https://www.niams.nih.gov/about/meetings-events/roundtables/roundtable-innovative-treatments-enthesis-repair. This paper reviews the challenges and opportunities for developing effective treatment strategies for enthesis repair that were identified at the roundtable discussion.

Tendon attaches to bone across a specialized fibrocartilaginous tissue termed the enthesis, which is a frequent site of injury due to a variety of factors1. Injury may occur to a healthy tendon after acute trauma or to a degenerated tendon after normal activity or minor trauma. Common anatomic sites of injury include intra-articular entheses (e.g., the rotator cuff, the flexor tendon, the anterior cruciate ligament, and the meniscal root) and extra-articular entheses (e.g., the Achilles tendon, the patellar tendon, and the medial collateral ligament). Although certain factors may be common to all injuries (e.g., inflammation and paucity of cells), there are also factors (e.g., etiology, biology, and mechanical load) that are unique to the particular injury mechanism or the anatomic location. Regardless of the injury mechanism or the anatomic location, if surgical repair is required, the torn tendon is reattached to its osseous anatomic footprint, and healing relies on reincorporation of the tendon into the bone at the enthesis.

Clinically, enthesis-related pathologies include rotator cuff disease, tennis elbow (the medial epicondyle), jumper’s knee (the inferior pole of the patella and the quadriceps insertion of the patella), and Achilles tendinosis. The most common, and perhaps the most challenging, pathology is rotator cuff disease. The rotator cuff is susceptible to degenerative changes related to its relative avascularity. There is a 30% prevalence of rotator cuff tears in asymptomatic shoulders in patients >60 years of age2, as well as a high percentage of asymptomatic tears in patients with a painful tear in the opposite shoulder3. Many tears respond to nonoperative treatment, while others are treated operatively when nonoperative treatment is unsuccessful. The difference between the rotator cuff and the many other sites of enthesis degeneration is its intra-articular environment and its exposure to synovial fluid. Intra-articular soft tissues (i.e., the rotator cuff, the glenoid labrum, the anterior cruciate ligament, and the meniscus) do not heal as reliably as extra-articular structures (i.e., the distal biceps, the lateral collateral ligament of the knee, and the Achilles tendons). The roundtable group focused its discussion on the rotator cuff, with the understanding that many of the challenges and opportunities for developing effective treatment strategies for rotator cuff repair would be more broadly applicable to other enthesis sites.

Clinical Research

The Need to Better Understand the Disease

Rotator cuff degeneration (tendinosis) is understood to commence in the early decades of life, with partial and full-thickness cuff tears increasing in frequency in the later decades. Occasionally, rotator cuff tears are truly traumatic in nature; however, they usually occur in the presence of some degree of degeneration. Historically, extrinsic damage related to acromial spurring was considered the primary etiology; however, current opinion places greater emphasis on the intrinsic nature of rotator cuff degeneration4, including the inherent avascularity of the rotator cuff. Unfortunately, the fundamental pathoetiology of intrinsic tendinosis is not well-understood, which limits our ability to intervene early or rigorously inform research efforts.

The histologic and molecular characteristics of human rotator cuff disease were recently summarized in a systematic review5. Rotator cuff disease is associated with changes to cells, vascularity, extracellular matrix (ECM) components, enzymes, cytokines, growth factors, neuronal factors, and apoptosis/cell-cycle-related factors. Relatively few studies have reported on the pathology that is specifically associated with increasing levels of severity of rotator cuff disease. The current literature on biomarkers of disease severity in human subjects is summarized in a recent review6, and points toward inflammatory markers (e.g., interleukin [IL]-1β, IL-1ra [receptor antagonist], tumor necrosis factor [TNF]-α, cyclooxygenase [COX]-2, inducible nitric oxide synthase [iNOS])7,8 and matrix remodeling markers (in particular, members of the collagen and matrix metalloproteinase [MMP] families)7,9-12 as possible biomarkers of rotator cuff disease progression. Future work should seek to identify prognostic biomarkers of rotator cuff disease and its progression, which would allow improved diagnosis and management of patients and help to identify possible targets for disease-modifying interventions (which may include drugs, growth factors, cells, matrices, etc.) aimed to reduce progression and induce repair. Ideally, these efforts would utilize a large, multicenter longitudinal cohort and adopt a systematic and standardized approach that focuses on a few relevant tissue targets and common analytical methods. The Multicenter Orthopaedic Outcomes Network (MOON), which to date has enrolled over 3,500 anterior cruciate ligament reconstruction patients from 7 centers (https://www.vumc.org/orthopaedics/moon-knee-project), offers a successful and highly productive approach for performing multicenter longitudinal studies in orthopaedics13.

The Need for Better Outcome Measures

A recent meta-analysis of Level-I and II studies investigating outcomes after full-thickness rotator cuff repair concluded that “there is not a clinically important difference in validated functional outcome scores or pain for patients who have undergone rotator cuff repair regardless of the structural integrity of the repair.”14 The current weak correlation between patient-reported outcome measures (PROMs) and structural outcomes following rotator cuff repair indicates a need for more precise imaging techniques to measure and define structural outcomes, as well as an opportunity to develop more discriminating PROMs. One possible area for improvement is to explore which subsections or individual questions in current PROMs most closely correlate or associate with structural integrity. There also is a need to better understand and differentiate the sources of shoulder pain other than that from rotator cuff pathology, and the influence of these sources of pain on the clinical outcome of rotator cuff surgery, regardless of the healing status of the rotator cuff after repair. In addition, enhanced and well-defined outcomes and consistent methods to measure shoulder range of motion and strength (including intrarater and interrater agreement and validation) should be adopted. Newer approaches for measuring shoulder range of motion using smartphone digital clinometer applications15 or wearable technologies with remote monitoring capability16 are attractive alternatives to traditional manual goniometer methods, but their reliability and validity need to be demonstrated in large patient cohorts. There also is a need to develop and validate a functional active shoulder test or assessment that provides a better measure of rotator cuff function than isometric strength testing. For example, an assessment of shoulder fatigue strength using repetitive, low-weight movements commensurate with activities of daily living, or development and validation of return-to-work or return-to-sport functional performance testing following rotator cuff repair, may better assess rotator cuff integrity and function.

Magnetic resonance imaging (MRI)17-19, MR arthrography20,21, and ultrasound22-24 are routinely used for diagnosing rotator cuff tears or retears. Excellent sensitivities and specificities have been reported for each technique25, yet none offers perfect reliability or the ability to discern tissue type or quality; thus, each has challenges of clinical interpretation. The Sugaya classification system is currently the most commonly used method for the evaluation of healing quality following rotator cuff repair26, but it provides only an indirect, subjective assessment. Hence, another avenue of investigation should include understanding the relationship between objective mechanical properties and imaging characteristics of healed tendon repairs compared with those that have failed in continuity (tendon retraction and attenuation without a recurrent defect)27 because the intervening scar tissue may not withstand load to the same degree that a healed tendon would. This would enhance existing forms of imaging assessment, like the Sugaya classification, and may elucidate why patients who are considered healed by imaging still report weakness. Improved imaging modalities and discriminating imaging outcomes (including intrarater and interrater agreement and validation) must be developed and adopted.

Demonstrating efficacy of repair augmentation strategies (scaffolds, growth factors, platelet-rich plasma, etc.) in clinical trials may prove elusive without patient-reported, clinical, and imaging outcomes that are sensitive to the spectrum of repair healing and function. Once the methods of evaluating these outcomes have improved, well-designed clinical trials can rigorously test the efficacy of strategies to improve the healing of debilitating rotator cuff tears. These trials should employ sample sizes that are large enough to allow for adequate power and multivariate analyses, likely requiring a multicenter approach as described above.

Defining Which Factors Influence Healing

Patient factors such as age, tear size and chronicity, muscle atrophy and degeneration, tendon quality, repair technique, occupation, smoking status, and Workers’ Compensation status have been shown to influence healing following rotator cuff repair28. However, these factors alone do not explain all of the variation in healing that is observed. It is unclear, for example, whether sex influences rotator cuff healing. Furthermore, postoperative rehabilitation is assumed to influence healing, yet there remains insufficient evidence to define the optimal protocol. While physical therapy protocols have been developed based on rigorous systematic review of the literature29, clinical evidence for improved tendon healing with a particular approach has not been definitively reported. For example, 1 randomized controlled trial in patients <60 years of age with smaller tears showed no difference between early and late range-of-motion protocols in ultimate healing30. The value of postoperative cold therapy, the optimal method for postoperative bracing, and the efficacy of home-based exercise programs versus facility-based rehabilitation after rotator cuff surgery also are not firmly established4. The optimal rehabilitation program for rotator cuff healing may depend on patient factors and should be a focus of future investigation.

Variable healing rates after rotator cuff repair also may be influenced by differences in the intrinsic healing potential of the patient, yet relatively few studies have investigated biomarkers that are specifically associated with varying levels of rotator cuff healing6. Inflammatory markers (COX-2)31 and matrix remodeling markers (in particular, members of the collagen and MMP families)31,32 have been shown to be associated with rotator cuff healing in human subjects. One recent study identified a significantly increased risk for a rare allele involving the single-nucleotide polymorphism (SNP) rs17583842 in the ESRRB (estrogen-related receptor beta) gene in patients who experienced lateral rotator cuff retears compared with healed patients33, while to our knowledge no studies have directly investigated cellular metrics as biomarkers of healing. Future work should seek to identify intrinsic biomarkers that predict healing after rotator cuff repair, adopting a multicenter, systematic, and standardized approach as described above. Identifying biomarkers as prognostic factors of healing after rotator cuff repair would inform current practice and possibly identify modifiable predictors of outcome, as well as provide a scientific premise for future research into modifiable variables or interventions in the treatment of rotator cuff tears.

Basic and Translational Research

Challenges of Enthesis Repair

The fundamental difficulty with repairing a tendon back to bone is the mechanical challenge of attaching a compliant material (tendon) with a modulus on the order of 200 MPa to a stiff material (bone) with a modulus on the order of 20 GPa1. In the uninjured state, the tendon-bone enthesis has a fibrocartilage transitional region that exhibits gradations in cell phenotype, matrix composition, tissue organization, and mechanical properties1,34,35. These natural gradations facilitate the effective transfer of load between the 2 materials by reducing the potentially damaging stress concentrations that would otherwise arise at their interface. There are a number of mechanical mechanisms that are conserved across species36 at various hierarchical levels that allow for effective stress transfer between tendon and bone. On the millimeter scale, stresses can be reduced by optimization of the shape of the attachment36,37. On the micrometer scale, interdigitation, fiber orientation, and a compliant band increase the toughness of the interface34,38. On the nanometer scale, spatial gradients in mineralization stiffen the matrix39. None of these mechanisms are recreated after tendon-to-bone healing40-42. These multiscale features are consistent across fibrocartilaginous entheses, including the rotator cuff, the Achilles tendon, the patellar tendon, the flexor tendon, and the meniscal root. At the rotator cuff, repair techniques focus on secure attachment of tendon to bone using sutures and bone anchors, but have not been effective in promoting regeneration of the native enthesis structure. Therefore, the mechanical properties of the fibrovascular scar tissue that forms at the interface do not approximate those of the normal tendon enthesis. Failure to recreate the structure and mechanics of the healthy enthesis may predispose the repair site to failure in continuity, gapping, or frank rupture.

The Need to Better Understand the Mechanisms of Enthesis Development

Understanding how a complex enthesis is formed by a pool of progenitor cells during development may inform strategies for enhanced healing at the surgically repaired enthesis. The tendon enthesis initially organizes as an unmineralized cartilaginous attachment unit in utero, and then mineralizes via endochondral ossification postnatally43-45. A number of key factors have been defined as necessary for chondrogenesis (e.g., Sox9) and tenogenesis (e.g., Mohawk [Mkx]46 and Scleraxis [Scx]47). Growth factors in the transforming growth factor-beta (TGF-β) and bone morphogenetic protein (BMP) families likely regulate early enthesis formation43,44, and molecules such as Indian hedgehog (Ihh) and parathyroid hormone-related protein (PTHrP) likely regulate late mineralization events48,49. A synergy between these growth factor cues and mechanical cues then gives rise to the complex structure and composition of the mature tendon enthesis. The mature enthesis maintains a gradient of cell phenotypes, from tendon fibroblast to chondrocyte to mineralizing chondrocyte to osteoblast/osteocyte. It is unclear how this gradient in cell phenotypes develops and how it is regulated by the local environment (e.g., ECM, muscle loading, and growth factors). Understanding the molecular mechanisms that control the formation of an interface with a gradient of cellular phenotypes and ECM will allow us to develop regenerative strategies for enhanced tendon-to-bone healing in the adult setting.

The Need to Better Understand the Mechanisms of Enthesis Pathology

Although the histologic and molecular characteristics of human rotator cuff disease have been described, the molecular events leading to tendinopathy and subsequent enthesis rupture are poorly understood. Rodent models have been particularly valuable for the study of tendinopathy, particularly related to the rotator cuff. Previous work established the similarity of the rodent rotator cuff anatomy to the human anatomy50. Rotator cuff tendinopathy has been induced in rodent models by overuse, disuse, surgery, chemical insult, and genetic manipulation51-53. Each of these models simulates aspects of tendon pathology and allows for exploration of disease mechanisms. Basic and clinical studies have implicated inflammatory processes in tendinopathy and crosstalk between tendon, bone, and muscle54. Although not yet fully elucidated, the immunobiology of tendinopathy involves infiltrating cells such as macrophages, resident responding cells such as mast cells, and resident tenocytes. Inflammatory mechanisms typically involve cytokines such as IL-1, IL-6, IL-17, and IL-21. For example, IL-17 and IL-21 were shown to be elevated in human tendinopathic samples, and IL-17 regulated proinflammatory cytokines in tendon fibroblasts in vitro55,56. Much work remains, however, to determine the mechanistic roles of inflammation and crosstalk in rotator cuff tendinopathy and how treatment strategies can target these processes. Animal studies in rodents also have explored outcomes after a rotator cuff enthesis repair, including the effect of tear chronicity on tendon, muscle, and bone health, and the roles of inflammation and bone loss during tendon-to-bone healing. Further exploration of enthesis pathogenesis and repair is needed to drive new treatment approaches, not only for the rotator cuff, which has been the focus of most of the translational animal model work, but also for other clinically relevant entheses, such as the Achilles tendon57, the patellar tendon58, the flexor tendon41, and the meniscal root59.

Developing Novel Strategies for Enthesis Repair

Mouse models are useful to study the fundamental mechanisms of tendon and enthesis development, growth, and pathology; however, the small size of the mouse precludes the use of clinically relevant repair techniques, making it difficult to test translational treatment strategies. However, the rat is large enough to examine tendon-to-bone healing using clinically relevant repairs40. In the rat rotator cuff, multiple studies have examined novel strategies for improving tendon-to-bone healing. For example, treatment strategies have targeted bone loss during healing60, examined the role of loading after repair40, and tested various cellular and growth factor approaches61-64. Compared with large animal models, the cost of rat studies is relatively low, and there are fewer ethical concerns. Although the rat is an excellent model for the initial testing of novel strategies for rotator cuff repair, its small size still limits its potential for translation directly to human trials. Furthermore, to date, researchers have largely focused injury models, treatment strategies, and outcomes on tendon-to-bone healing, and have not considered the complete rotator cuff muscle-tendon-enthesis-bone unit. There is a need to develop models and repair strategies aimed to treat and restore function to the entire connective tissue unit (i.e., muscle-tendon-enthesis-bone).

Establishing Relevant Animal Models for Translation of Novel Treatments

Large animals (e.g., sheep, dogs, goats, and rabbits) have been used for translational research investigations, bridging rodent models and human patients. Because of their size, many standard-of-care surgical techniques can be reasonably reproduced in large animals. As such, large animal models have been used to study surgical techniques65 and regenerative strategies for rotator cuff repair, including growth factors66, scaffold interposition67, and scaffold augmentation68. However, reports have shown that rotator cuff repairs, at least in sheep and canines, uniformly undergo retearing in the very early postoperative period, yet form robust gap scar tissue that is grossly and histologically similar in appearance to a tendon69-71. The instability of the initial repair construct combined with robust gap tissue formation in spite of repair failure confounds the interpretation of studies investigating repair strategies. Future work should carefully explore the extent to which this limitation (ubiquitous retearing with robust gap tissue formation) occurs in the rabbit model since this has not been previously reported and might lend support for using the rabbit model instead of the sheep or canine models for translational research studies of rotator cuff repair.

Arguably, there are fundamental differences in intra-articular anatomy, pathogenesis, chronicity, biomechanical loading, and age between all animal models and the human rotator cuff. These differences limit the translational value of even large animal models for studying the etiology, pathology, or repair of the rotator cuff. It may be that a particular animal model may provide clinically relevant translational information on only a portion of the factors that need to be considered. The field as a whole, including researchers, providers, and regulatory agencies, should develop a consensus on which, if any, standardized animal models and outcomes are relevant for translational investigations.

Conclusions

This paper reviews the challenges and opportunities for developing effective treatment strategies for enthesis repair. The paper focuses particularly on the rotator cuff, with the understanding that many of the challenges and opportunities for developing these strategies will be more broadly applicable to other enthesis sites. Advances in both clinical and basic/translational research are needed. Some key areas for future research include:

Clinical Research

The Need to Better Understand the Disease

  • Define the fundamental pathoetiology of intrinsic tendinosis.

  • Identify prognostic biomarkers of rotator cuff disease and its progression.

The Need for Better Outcome Measures

  • Explore which subsections or individual questions in current PROMs most closely correlate with structural integrity following rotator cuff repair.

  • Better understand and differentiate the sources of shoulder pain, other than that from rotator cuff pathology, and the influence of pain on the clinical outcome of rotator cuff surgery.

  • Develop enhanced and well-defined outcomes and consistent methods to measure shoulder function (e.g., range of motion, strength, and functional activity).

  • Develop improved imaging modalities and discriminating imaging outcomes.

  • Understand the mechanical properties and imaging characteristics of healed tendon repairs compared with those that have failed in continuity.

  • Once the methods of evaluating outcomes have improved, design clinical trials to rigorously test the efficacy of strategies to improve the healing of rotator cuff tears.

Defining Which Factors Influence Healing

  • Define optimal rehabilitation programs for rotator cuff healing.

  • Identify intrinsic biomarkers that predict healing after rotator cuff repair.

  • Determine the role of sex on healing after rotator cuff repair.

Basic and Translational Research

The Need to Better Understand the Mechanisms of Enthesis Development

  • Understand the cellular, molecular, and biophysical mechanisms that control enthesis formation.

The Need to Better Understand the Mechanisms of Enthesis Pathology

  • Determine the roles of inflammation and crosstalk between muscle, tendon, and bone in rotator cuff tendinopathy.

Developing Novel Strategies for Enthesis Repair

  • Develop models and repair strategies aimed to treat and restore function to the entire connective tissue unit (i.e., muscle-tendon-enthesis-bone).

Establishing Relevant Animal Models for Translation of Novel Treatments

  • Explore the extent to which ubiquitous retearing with robust gap tissue formation occurs in the rabbit rotator cuff repair model.

  • Develop a consensus on which, if any, standardized animal models and outcomes are appropriate for translational investigations of rotator cuff repair and the repair of other clinically relevant entheses.

  • Include sex as a variable in animal model study designs.

Acknowledgments

Note: We acknowledge NIH/NIAMS for initiating and hosting the roundtable on “Innovative Treatments for Enthesis Repair” on May 22, 2017. The following individuals were extramural participants in the roundtable discussion, from which this manuscript was derived: Benjamin A. Alman, MD, Duke University; Nelly Andarawis-Puri, PhD, Cornell University; Constance R. Chu, MD, Stanford University; Kathleen A. Derwin, PhD, Cleveland Clinic; Leesa M. Galatz, MD, Icahn School of Medicine at Mount Sinai (co-chair); Alice Huang, PhD, Icahn School of Medicine at Mount Sinai; Helen H. Lu, PhD, Columbia University; Christopher Mendias, PhD, ATC, University of Michigan Medical School; Anthony Ratcliffe, PhD, Synthasome (co-chair); Ronen Schweitzer, PhD, Oregon Health & Science University; Kurt Spindler, MD, Cleveland Clinic Sports Health Center; Johnna S. Temenoff, PhD, Georgia Institute of Technology and Emory University; and Stavros Thomopoulos, PhD, Columbia University.

Footnotes

Disclosure: On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work (Dr. Anthony Ratcliffe is an employee of Synthasome, Inc.) and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work (http://links.lww.com/JBJS/E821).

References

  • 1.Lu HH, Thomopoulos S. Functional attachment of soft tissues to bone: development, healing, and tissue engineering. Annu Rev Biomed Eng. 2013;15:201-26. Epub 2013 Apr 29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Sher JS, Uribe JW, Posada A, Murphy BJ, Zlatkin MB. Abnormal findings on magnetic resonance images of asymptomatic shoulders. J Bone Joint Surg Am. 1995. January;77(1):10-5. [DOI] [PubMed] [Google Scholar]
  • 3.Yamaguchi K, Ditsios K, Middleton WD, Hildebolt CF, Galatz LM, Teefey SA. The demographic and morphological features of rotator cuff disease. A comparison of asymptomatic and symptomatic shoulders. J Bone Joint Surg Am. 2006. August;88(8):1699-704. [DOI] [PubMed] [Google Scholar]
  • 4.American Academy of Orthopaedic Surgeons. The diagnosis and treatment of osteochondritis dissecans: guideline and evidence report. 2010. https://www.aaos.org/research/guidelines/ocd_guideline.pdf. Accessed 2018 Apr 26.
  • 5.Dean BJ, Franklin SL, Carr AJ. A systematic review of the histological and molecular changes in rotator cuff disease. Bone Joint Res. 2012. July 1;1(7):158-66. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ma J, Piuzzi NS, Muschler GF, Iannotti JP, Ricchetti ET, Derwin KA. Biomarkers of rotator cuff disease severity and repair healing. JBJS Rev. 2018. [In press]. [DOI] [PubMed] [Google Scholar]
  • 7.Shindle MK, Chen CC, Robertson C, DiTullio AE, Paulus MC, Clinton CM, Cordasco FA, Rodeo SA, Warren RF. Full-thickness supraspinatus tears are associated with more synovial inflammation and tissue degeneration than partial-thickness tears. J Shoulder Elbow Surg. 2011. September;20(6):917-27. Epub 2011 May 25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Gotoh M, Hamada K, Yamakawa H, Yanagisawa K, Nakamura M, Yamazaki H, Inoue A, Fukuda H. Interleukin-1-induced glenohumeral synovitis and shoulder pain in rotator cuff diseases. J Orthop Res. 2002. November;20(6):1365-71. [DOI] [PubMed] [Google Scholar]
  • 9.Chaudhury S, Xia Z, Thakkar D, Hakimi O, Carr AJ. Gene expression profiles of changes underlying different-sized human rotator cuff tendon tears. J Shoulder Elbow Surg. 2016. October;25(10):1561-70. Epub 2016 Apr 27. [DOI] [PubMed] [Google Scholar]
  • 10.Yoshihara Y, Hamada K, Nakajima T, Fujikawa K, Fukuda H. Biochemical markers in the synovial fluid of glenohumeral joints from patients with rotator cuff tear. J Orthop Res. 2001. July;19(4):573-9. [DOI] [PubMed] [Google Scholar]
  • 11.Lakemeier S, Schwuchow SA, Peterlein CD, Foelsch C, Fuchs-Winkelmann S, Archontidou-Aprin E, Paletta JR, Schofer MD. Expression of matrix metalloproteinases 1, 3, and 9 in degenerated long head biceps tendon in the presence of rotator cuff tears: an immunohistological study. BMC Musculoskelet Disord. 2010. November 25;11:271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Shirachi I, Gotoh M, Mitsui Y, Yamada T, Nakama K, Kojima K, Okawa T, Higuchi F, Nagata K. Collagen production at the edge of ruptured rotator cuff tendon is correlated with postoperative cuff integrity. Arthroscopy. 2011. September;27(9):1173-9. Epub 2011 Jul 12. [DOI] [PubMed] [Google Scholar]
  • 13.Spindler KP, Huston LJ, Chagin KM, Kattan MW, Reinke EK, Amendola A, Andrish JT, Brophy RH, Cox CL, Dunn WR, Flanigan DC, Jones MH, Kaeding CC, Magnussen RA, Marx RG, Matava MJ, McCarty EC, Parker RD, Pedroza AD, Vidal AF, Wolcott ML, Wolf BR, Wright RW; MOON Knee Group. Ten-year outcomes and risk factors after anterior cruciate ligament reconstruction: a MOON longitudinal prospective cohort study. Am J Sports Med. 2018. March;46(4):815-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Russell RD, Knight JR, Mulligan E, Khazzam MS. Structural integrity after rotator cuff repair does not correlate with patient function and pain: a meta-analysis. J Bone Joint Surg Am. 2014. February 19;96(4):265-71. [DOI] [PubMed] [Google Scholar]
  • 15.Werner BC, Holzgrefe RE, Griffin JW, Lyons ML, Cosgrove CT, Hart JM, Brockmeier SF. Validation of an innovative method of shoulder range-of-motion measurement using a smartphone clinometer application. J Shoulder Elbow Surg. 2014. November;23(11):e275-82. Epub 2014 Jun 9. [DOI] [PubMed] [Google Scholar]
  • 16.Ramkumar PN, Haeberle HS, Navarro SM, Sultan AA, Mont MA, Ricchetti ET, Schickendantz MS, Iannotti JP. Mobile technology and telemedicine for shoulder range of motion: validation of a motion-based machine-learning software development kit. J Shoulder Elbow Surg. 2018. March 7:S1058–2746(18)30059-4. Epub 2018 Mar 7. [DOI] [PubMed] [Google Scholar]
  • 17.Sugaya H, Maeda K, Matsuki K, Moriishi J. Repair integrity and functional outcome after arthroscopic double-row rotator cuff repair. A prospective outcome study. J Bone Joint Surg Am. 2007. May;89(5):953-60. [DOI] [PubMed] [Google Scholar]
  • 18.Koh KH, Kang KC, Lim TK, Shon MS, Yoo JC. Prospective randomized clinical trial of single- versus double-row suture anchor repair in 2- to 4-cm rotator cuff tears: clinical and magnetic resonance imaging results. Arthroscopy. 2011. April;27(4):453-62. [DOI] [PubMed] [Google Scholar]
  • 19.Iannotti JP, Deutsch A, Green A, Rudicel S, Christensen J, Marraffino S, Rodeo S. Time to failure after rotator cuff repair: a prospective imaging study. J Bone Joint Surg Am. 2013. June 5;95(11):965-71. [DOI] [PubMed] [Google Scholar]
  • 20.Barber FA, Hrnack SA, Snyder SJ, Hapa O. Rotator cuff repair healing influenced by platelet-rich plasma construct augmentation. Arthroscopy. 2011. August;27(8):1029-35. [DOI] [PubMed] [Google Scholar]
  • 21.Iannotti JP, Codsi MJ, Kwon YW, Derwin K, Ciccone J, Brems JJ. Porcine small intestine submucosa augmentation of surgical repair of chronic two-tendon rotator cuff tears. A randomized, controlled trial. J Bone Joint Surg Am. 2006. June;88(6):1238-44. [DOI] [PubMed] [Google Scholar]
  • 22.Rodeo SA, Delos D, Williams RJ, Adler RS, Pearle A, Warren RF. The effect of platelet-rich fibrin matrix on rotator cuff tendon healing: a prospective, randomized clinical study. Am J Sports Med. 2012. June;40(6):1234-41. Epub 2012 Apr 10. [DOI] [PubMed] [Google Scholar]
  • 23.Kluger R, Bock P, Mittlböck M, Krampla W, Engel A. Long-term survivorship of rotator cuff repairs using ultrasound and magnetic resonance imaging analysis. Am J Sports Med. 2011. October;39(10):2071-81. Epub 2011 May 24. [DOI] [PubMed] [Google Scholar]
  • 24.Park JY, Lhee SH, Oh KS, Moon SG, Hwang JT. Clinical and ultrasonographic outcomes of arthroscopic suture bridge repair for massive rotator cuff tear. Arthroscopy. 2013. February;29(2):280-9. [DOI] [PubMed] [Google Scholar]
  • 25.de Jesus JO, Parker L, Frangos AJ, Nazarian LN. Accuracy of MRI, MR arthrography, and ultrasound in the diagnosis of rotator cuff tears: a meta-analysis. AJR Am J Roentgenol. 2009. June;192(6):1701-7. [DOI] [PubMed] [Google Scholar]
  • 26.Sugaya H, Maeda K, Matsuki K, Moriishi J. Functional and structural outcome after arthroscopic full-thickness rotator cuff repair: single-row versus dual-row fixation. Arthroscopy. 2005. November;21(11):1307-16. [DOI] [PubMed] [Google Scholar]
  • 27.McCarron JA, Derwin KA, Bey MJ, Polster JM, Schils JP, Ricchetti ET, Iannotti JP. Failure with continuity in rotator cuff repair “healing”. Am J Sports Med. 2013. January;41(1):134-41. Epub 2012 Sep 27. [DOI] [PubMed] [Google Scholar]
  • 28.Abtahi AM, Granger EK, Tashjian RZ. Factors affecting healing after arthroscopic rotator cuff repair. World J Orthop. 2015. March 18;6(2):211-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kuhn JE. Exercise in the treatment of rotator cuff impingement: a systematic review and a synthesized evidence-based rehabilitation protocol. J Shoulder Elbow Surg. 2009. Jan-Feb;18(1):138-60. Epub 2008 Oct 2. [DOI] [PubMed] [Google Scholar]
  • 30.Keener JD, Galatz LM, Stobbs-Cucchi G, Patton R, Yamaguchi K. Rehabilitation following arthroscopic rotator cuff repair: a prospective randomized trial of immobilization compared with early motion. J Bone Joint Surg Am. 2014. January 1;96(1):11-9. [DOI] [PubMed] [Google Scholar]
  • 31.Robertson CM, Chen CT, Shindle MK, Cordasco FA, Rodeo SA, Warren RF. Failed healing of rotator cuff repair correlates with altered collagenase and gelatinase in supraspinatus and subscapularis tendons. Am J Sports Med. 2012. September;40(9):1993-2001. Epub 2012 Aug 15. [DOI] [PubMed] [Google Scholar]
  • 32.Gotoh M, Mitsui Y, Shibata H, Yamada T, Shirachi I, Nakama K, Okawa T, Higuchi F, Nagata K. Increased matrix metalloprotease-3 gene expression in ruptured rotator cuff tendons is associated with postoperative tendon retear. Knee Surg Sports Traumatol Arthrosc. 2013. August;21(8):1807-12. Epub 2012 Sep 22. [DOI] [PubMed] [Google Scholar]
  • 33.Tashjian RZ, Granger EK, Zhang Y, Teerlink CC, Cannon-Albright LA. Identification of a genetic variant associated with rotator cuff repair healing. J Shoulder Elbow Surg. 2016. June;25(6):865-72. Epub 2016 Apr 8. [DOI] [PubMed] [Google Scholar]
  • 34.Rossetti L, Kuntz LA, Kunold E, Schock J, Müller KW, Grabmayr H, Stolberg-Stolberg J, Pfeiffer F, Sieber SA, Burgkart R, Bausch AR. The microstructure and micromechanics of the tendon-bone insertion. Nat Mater. 2017. June;16(6):664-70. Epub 2017 Feb 27. [DOI] [PubMed] [Google Scholar]
  • 35.Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. 2003. May;21(3):413-9. [DOI] [PubMed] [Google Scholar]
  • 36.Deymier-Black AC, Pasteris JD, Genin GM, Thomopoulos S. Allometry of the tendon enthesis: mechanisms of load transfer between tendon and bone. J Biomech Eng. 2015. November;137(11):111005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Liu Y, Birman V, Chen C, Thomopoulos S, Genin GM. Mechanisms of bimaterial attachment at the interface of tendon to bone. J Eng Mater Technol. 2011. January 1;133(1):281-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Hu Y, Birman V, Deymier-Black A, Schwartz AG, Thomopoulos S, Genin GM. Stochastic interdigitation as a toughening mechanism at the interface between tendon and bone. Biophys J. 2015. January 20;108(2):431-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Genin GM, Kent A, Birman V, Wopenka B, Pasteris JD, Marquez PJ, Thomopoulos S. Functional grading of mineral and collagen in the attachment of tendon to bone. Biophys J. 2009. August 19;97(4):976-85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Thomopoulos S, Williams GR, Soslowsky LJ. Tendon to bone healing: differences in biomechanical, structural, and compositional properties due to a range of activity levels. J Biomech Eng. 2003. February;125(1):106-13. [DOI] [PubMed] [Google Scholar]
  • 41.Silva MJ, Thomopoulos S, Kusano N, Zaegel MA, Harwood FL, Matsuzaki H, Havlioglu N, Dovan TT, Amiel D, Gelberman RH. Early healing of flexor tendon insertion site injuries: tunnel repair is mechanically and histologically inferior to surface repair in a canine model. J Orthop Res. 2006. May;24(5):990-1000. [DOI] [PubMed] [Google Scholar]
  • 42.Rodeo SA, Arnoczky SP, Torzilli PA, Hidaka C, Warren RF. Tendon-healing in a bone tunnel. A biomechanical and histological study in the dog. J Bone Joint Surg Am. 1993. December;75(12):1795-803. [DOI] [PubMed] [Google Scholar]
  • 43.Blitz E, Viukov S, Sharir A, Shwartz Y, Galloway JL, Pryce BA, Johnson RL, Tabin CJ, Schweitzer R, Zelzer E. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev Cell. 2009. December;17(6):861-73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Blitz E, Sharir A, Akiyama H, Zelzer E. Tendon-bone attachment unit is formed modularly by a distinct pool of Scx- and Sox9-positive progenitors. Development. 2013. July;140(13):2680-90. Epub 2013 May 29. [DOI] [PubMed] [Google Scholar]
  • 45.Galatz L, Rothermich S, VanderPloeg K, Petersen B, Sandell L, Thomopoulos S. Development of the supraspinatus tendon-to-bone insertion: localized expression of extracellular matrix and growth factor genes. J Orthop Res. 2007. December;25(12):1621-8. [DOI] [PubMed] [Google Scholar]
  • 46.Ito Y, Toriuchi N, Yoshitaka T, Ueno-Kudoh H, Sato T, Yokoyama S, Nishida K, Akimoto T, Takahashi M, Miyaki S, Asahara H. The Mohawk homeobox gene is a critical regulator of tendon differentiation. Proc Natl Acad Sci USA. 2010. June 8;107(23):10538-42. Epub 2010 May 24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Schweitzer R, Chyung JH, Murtaugh LC, Brent AE, Rosen V, Olson EN, Lassar A, Tabin CJ. Analysis of the tendon cell fate using Scleraxis, a specific marker for tendons and ligaments. Development. 2001. October;128(19):3855-66. [DOI] [PubMed] [Google Scholar]
  • 48.Schwartz AG, Long F, Thomopoulos S. Enthesis fibrocartilage cells originate from a population of Hedgehog-responsive cells modulated by the loading environment. Development. 2015. January 1;142(1):196-206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Dyment NA, Breidenbach AP, Schwartz AG, Russell RP, Aschbacher-Smith L, Liu H, Hagiwara Y, Jiang R, Thomopoulos S, Butler DL, Rowe DW. Gdf5 progenitors give rise to fibrocartilage cells that mineralize via hedgehog signaling to form the zonal enthesis. Dev Biol. 2015. September 1;405(1):96-107. Epub 2015 Jun 30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Soslowsky LJ, Carpenter JE, DeBano CM, Banerji I, Moalli MR. Development and use of an animal model for investigations on rotator cuff disease. J Shoulder Elbow Surg. 1996. Sep-Oct;5(5):383-92. [DOI] [PubMed] [Google Scholar]
  • 51.Soslowsky LJ, Thomopoulos S, Tun S, Flanagan CL, Keefer CC, Mastaw J, Carpenter JE. Neer Award 1999. Overuse activity injures the supraspinatus tendon in an animal model: a histologic and biomechanical study. J Shoulder Elbow Surg. 2000. Mar-Apr;9(2):79-84. [PubMed] [Google Scholar]
  • 52.Kim HM, Galatz LM, Lim C, Havlioglu N, Thomopoulos S. The effect of tear size and nerve injury on rotator cuff muscle fatty degeneration in a rodent animal model. J Shoulder Elbow Surg. 2012. July;21(7):847-58. Epub 2011 Aug 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Liu X, Laron D, Natsuhara K, Manzano G, Kim HT, Feeley BT. A mouse model of massive rotator cuff tears. J Bone Joint Surg Am. 2012. April 4;94(7):e41. [DOI] [PubMed] [Google Scholar]
  • 54.Millar NL, Murrell GA, McInnes IB. Inflammatory mechanisms in tendinopathy - towards translation. Nat Rev Rheumatol. 2017. January 25;13(2):110-22. [DOI] [PubMed] [Google Scholar]
  • 55.Millar NL, Akbar M, Campbell AL, Reilly JH, Kerr SC, McLean M, Frleta-Gilchrist M, Fazzi UG, Leach WJ, Rooney BP, Crowe LA, Murrell GA, McInnes IB. IL-17A mediates inflammatory and tissue remodelling events in early human tendinopathy. Sci Rep. 2016. June 6;6:27149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Jelinsky SA, Rodeo SA, Li J, Gulotta LV, Archambault JM, Seeherman HJ. Regulation of gene expression in human tendinopathy. BMC Musculoskelet Disord. 2011. May 3;12:86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Leung KS, Chong WS, Chow DH, Zhang P, Cheung WH, Wong MW, Qin L. A comparative study on the biomechanical and histological properties of bone-to-bone, bone-to-tendon, and tendon-to-tendon healing: an Achilles tendon-calcaneus model in goats. Am J Sports Med. 2015. June;43(6):1413-21. Epub 2015 Mar 30. [DOI] [PubMed] [Google Scholar]
  • 58.Hettrich CM, Gasinu S, Beamer BS, Stasiak M, Fox A, Birmingham P, Ying O, Deng XH, Rodeo SA. The effect of mechanical load on tendon-to-bone healing in a rat model. Am J Sports Med. 2014. May;42(5):1233-41. Epub 2014 Apr 1. [DOI] [PubMed] [Google Scholar]
  • 59.Horie M, Driscoll MD, Sampson HW, Sekiya I, Caroom CT, Prockop DJ, Thomas DB. Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model. J Bone Joint Surg Am. 2012. April 18;94(8):701-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Shah SA, Kormpakis I, Havlioglu N, Ominsky MS, Galatz LM, Thomopoulos S. Sclerostin antibody treatment enhances rotator cuff tendon-to-bone healing in an animal model. J Bone Joint Surg Am. 2017. May 17;99(10):855-64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Gulotta LV, Kovacevic D, Montgomery S, Ehteshami JR, Packer JD, Rodeo SA. Stem cells genetically modified with the developmental gene MT1-MMP improve regeneration of the supraspinatus tendon-to-bone insertion site. Am J Sports Med. 2010. July;38(7):1429-37. Epub 2010 Apr 16. [DOI] [PubMed] [Google Scholar]
  • 62.Manning CN, Kim HM, Sakiyama-Elbert S, Galatz LM, Havlioglu N, Thomopoulos S. Sustained delivery of transforming growth factor beta three enhances tendon-to-bone healing in a rat model. J Orthop Res. 2011. July;29(7):1099-105. Epub 2011 Jan 18. [DOI] [PubMed] [Google Scholar]
  • 63.Kovacevic D, Fox AJ, Bedi A, Ying L, Deng XH, Warren RF, Rodeo SA. Calcium-phosphate matrix with or without TGF-β3 improves tendon-bone healing after rotator cuff repair. Am J Sports Med. 2011. April;39(4):811-9. Epub 2011 Mar 15. [DOI] [PubMed] [Google Scholar]
  • 64.Oak NR, Gumucio JP, Flood MD, Saripalli AL, Davis ME, Harning JA, Lynch EB, Roche SM, Bedi A, Mendias CL. Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair. Am J Sports Med. 2014. December;42(12):2860-8. Epub 2014 Sep 22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Klinger HM, Buchhorn GH, Heidrich G, Kahl E, Baums MH. Biomechanical evaluation of rotator cuff repairs in a sheep model: suture anchors using arthroscopic Mason-Allen stitches compared with transosseous sutures using traditional modified Mason-Allen stitches. Clin Biomech (Bristol, Avon). 2008. March;23(3):291-8. Epub 2007 Dec 3. [DOI] [PubMed] [Google Scholar]
  • 66.Seeherman HJ, Archambault JM, Rodeo SA, Turner AS, Zekas L, D’Augusta D, Li XJ, Smith E, Wozney JM. rhBMP-12 accelerates healing of rotator cuff repairs in a sheep model. J Bone Joint Surg Am. 2008. October;90(10):2206-19. [DOI] [PubMed] [Google Scholar]
  • 67.Adams JE, Zobitz ME, Reach JS, Jr, An KN, Steinmann SP. Rotator cuff repair using an acellular dermal matrix graft: an in vivo study in a canine model. Arthroscopy. 2006. July;22(7):700-9. [DOI] [PubMed] [Google Scholar]
  • 68.Derwin KA, Codsi MJ, Milks RA, Baker AR, McCarron JA, Iannotti JP. Rotator cuff repair augmentation in a canine model with use of a woven poly-L-lactide device. J Bone Joint Surg Am. 2009. May;91(5):1159-71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Derwin KA, Baker AR, Codsi MJ, Iannotti JP. Assessment of the canine model of rotator cuff injury and repair. J Shoulder Elbow Surg. 2007. Sep-Oct;16(5)(Suppl):S140-8. Epub 2007 Jun 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Rodeo SA, Potter HG, Kawamura S, Turner AS, Kim HJ, Atkinson BL. Biologic augmentation of rotator cuff tendon-healing with use of a mixture of osteoinductive growth factors. J Bone Joint Surg Am. 2007. November;89(11):2485-97. [DOI] [PubMed] [Google Scholar]
  • 71.Schlegel TF, Hawkins RJ, Lewis CW, Turner AS. An in vivo comparison of the modified Mason-Allen suture technique versus an inclined horizontal mattress suture technique with regard to tendon-to-bone healing: a biomechanical and histologic study in sheep. J Shoulder Elbow Surg. 2007. Jan-Feb;16(1):115-21. Epub 2006 Nov 16. [DOI] [PubMed] [Google Scholar]

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