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• W2185815723 abstract "Advances in surgical technique and rehabilitation have transformed zone II flexor tendon injuries from an inoperable no-man’s land to a standard surgical procedure. Despite these advances, many patients develop substantial range of motion–limiting adhesions after primary flexor tendon repair. These suboptimal outcomes may benefit from biologic augmentation or intervention during the flexor tendon healing process. However, there is no consensus biological approach to promote satisfactory flexor tendon healing; we propose that insufficient understanding of the complex cellular milieu in the healing tendon has hindered the development of successful therapies. This article reviews recent advances in our understanding of the cellular components of flexor tendon healing and adhesion formation, including resident tendon cells, synovial sheath, macrophages, and bone marrow–derived cells. In addition, it examines molecular approaches that have been used in translational animal models to improve flexor tendon healing and gliding function, with a specific focus on progress made using murine models of healing. This information highlights the importance of understanding and potentially exploiting the heterogeneity of the cellular environment during flexor tendon healing, to define rational therapeutic approaches to improve healing outcomes. Advances in surgical technique and rehabilitation have transformed zone II flexor tendon injuries from an inoperable no-man’s land to a standard surgical procedure. Despite these advances, many patients develop substantial range of motion–limiting adhesions after primary flexor tendon repair. These suboptimal outcomes may benefit from biologic augmentation or intervention during the flexor tendon healing process. However, there is no consensus biological approach to promote satisfactory flexor tendon healing; we propose that insufficient understanding of the complex cellular milieu in the healing tendon has hindered the development of successful therapies. This article reviews recent advances in our understanding of the cellular components of flexor tendon healing and adhesion formation, including resident tendon cells, synovial sheath, macrophages, and bone marrow–derived cells. In addition, it examines molecular approaches that have been used in translational animal models to improve flexor tendon healing and gliding function, with a specific focus on progress made using murine models of healing. This information highlights the importance of understanding and potentially exploiting the heterogeneity of the cellular environment during flexor tendon healing, to define rational therapeutic approaches to improve healing outcomes. CME Information and DisclosuresThe Review Section of JHS will contain at least 2 clinically relevant articles selected by the editor to be offered for CME in each issue. For CME credit, the participant must read the articles in print or online and correctly answer all related questions through an online examination. The questions on the test are designed to make the reader think and will occasionally require the reader to go back and scrutinize the article for details.The JHS CME Activity fee of $15.00 includes the exam questions/answers only and does not include access to the JHS articles referenced.Statement of Need: This CME activity was developed by the JHS review section editors and review article authors as a convenient education tool to help increase or affirm reader’s knowledge. The overall goal of the activity is for participants to evaluate the appropriateness of clinical data and apply it to their practice and the provision of patient care.Accreditation: The ASSH is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.AMA PRA Credit Designation: The American Society for Surgery of the Hand designates this Journal-Based CME activity for a maximum of 1.00 “AMA PRA Category 1 Credits™”. Physicians should claim only the credit commensurate with the extent of their participation in the activity.ASSH Disclaimer: The material presented in this CME activity is made available by the ASSH for educational purposes only. This material is not intended to represent the only methods or the best procedures appropriate for the medical situation(s) discussed, but rather it is intended to present an approach, view, statement, or opinion of the authors that may be helpful, or of interest, to other practitioners. Examinees agree to participate in this medical education activity, sponsored by the ASSH, with full knowledge and awareness that they waive any claim they may have against the ASSH for reliance on any information presented. The approval of the US Food and Drug Administration is required for procedures and drugs that are considered experimental. Instrumentation systems discussed or reviewed during this educational activity may not yet have received FDA approval.Provider Information can be found at http://www.assh.org/Pages/ContactUs.aspx.Technical Requirements for the Online Examination can be found at http://jhandsurg.org/cme/home.Privacy Policy can be found at http://www.assh.org/pages/ASSHPrivacyPolicy.aspx.ASSH Disclosure Policy: As a provider accredited by the ACCME, the ASSH must ensure balance, independence, objectivity, and scientific rigor in all its activities.Disclosures for this ArticleEditorsGhazi M. Rayan, MD, has no relevant conflicts of interest to disclose.AuthorsAll authors of this journal-based CME activity have no relevant conflicts of interest to disclose. In the printed or PDF version of this article, author affiliations can be found at the bottom of the first page.PlannersGhazi M. Rayan, MD, has no relevant conflicts of interest to disclose. The editorial and education staff involved with this journal-based CME activity has no relevant conflicts of interest to disclose.Learning Objectives•Discuss the epidemiology of flexor tendon injuries•Review the detailed anatomy of flexor tendons and the clinical presentations of flexor tendon injuries•Detail the cellular environment of flexor tendons and their healing mechanism•Evaluate cell and molecular modulation of flexor tendon healing•Assess pharmacologic treatment methods of flexor tendon injuriesDeadline: Each examination purchased in 2016 must be completed by January 31, 2017, to be eligible for CME. A certificate will be issued upon completion of the activity. Estimated time to complete each JHS CME activity is up to one hour.Copyright © 2016 by the American Society for Surgery of the Hand. All rights reserved. The Review Section of JHS will contain at least 2 clinically relevant articles selected by the editor to be offered for CME in each issue. For CME credit, the participant must read the articles in print or online and correctly answer all related questions through an online examination. The questions on the test are designed to make the reader think and will occasionally require the reader to go back and scrutinize the article for details. The JHS CME Activity fee of $15.00 includes the exam questions/answers only and does not include access to the JHS articles referenced. Statement of Need: This CME activity was developed by the JHS review section editors and review article authors as a convenient education tool to help increase or affirm reader’s knowledge. The overall goal of the activity is for participants to evaluate the appropriateness of clinical data and apply it to their practice and the provision of patient care. Accreditation: The ASSH is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation: The American Society for Surgery of the Hand designates this Journal-Based CME activity for a maximum of 1.00 “AMA PRA Category 1 Credits™”. Physicians should claim only the credit commensurate with the extent of their participation in the activity. ASSH Disclaimer: The material presented in this CME activity is made available by the ASSH for educational purposes only. This material is not intended to represent the only methods or the best procedures appropriate for the medical situation(s) discussed, but rather it is intended to present an approach, view, statement, or opinion of the authors that may be helpful, or of interest, to other practitioners. Examinees agree to participate in this medical education activity, sponsored by the ASSH, with full knowledge and awareness that they waive any claim they may have against the ASSH for reliance on any information presented. The approval of the US Food and Drug Administration is required for procedures and drugs that are considered experimental. Instrumentation systems discussed or reviewed during this educational activity may not yet have received FDA approval. Provider Information can be found at http://www.assh.org/Pages/ContactUs.aspx. Technical Requirements for the Online Examination can be found at http://jhandsurg.org/cme/home. Privacy Policy can be found at http://www.assh.org/pages/ASSHPrivacyPolicy.aspx. ASSH Disclosure Policy: As a provider accredited by the ACCME, the ASSH must ensure balance, independence, objectivity, and scientific rigor in all its activities. Ghazi M. Rayan, MD, has no relevant conflicts of interest to disclose. All authors of this journal-based CME activity have no relevant conflicts of interest to disclose. In the printed or PDF version of this article, author affiliations can be found at the bottom of the first page. Ghazi M. Rayan, MD, has no relevant conflicts of interest to disclose. The editorial and education staff involved with this journal-based CME activity has no relevant conflicts of interest to disclose. •Discuss the epidemiology of flexor tendon injuries•Review the detailed anatomy of flexor tendons and the clinical presentations of flexor tendon injuries•Detail the cellular environment of flexor tendons and their healing mechanism•Evaluate cell and molecular modulation of flexor tendon healing•Assess pharmacologic treatment methods of flexor tendon injuries Deadline: Each examination purchased in 2016 must be completed by January 31, 2017, to be eligible for CME. A certificate will be issued upon completion of the activity. Estimated time to complete each JHS CME activity is up to one hour. Copyright © 2016 by the American Society for Surgery of the Hand. All rights reserved. Approximately 3.5 million injuries to the upper extremity occur annually in the United States, with an incidence of 1,130 injuries per person-years.1Ootes D. Lambers K.T. Ring D.C. The epidemiology of upper extremity injuries presenting to the emergency department in the United States.Hand (N Y). 2012; 7: 18-22Crossref PubMed Scopus (124) Google Scholar Of these injuries, 38.4% involve one or more fingers, with the most common mechanism being a laceration. Furthermore, with an incidence of 221/100,000 people per-year, a laceration to the finger or thumb is the most common overall mechanism of injury in the upper extremity encountered in the emergency room setting.1Ootes D. Lambers K.T. Ring D.C. The epidemiology of upper extremity injuries presenting to the emergency department in the United States.Hand (N Y). 2012; 7: 18-22Crossref PubMed Scopus (124) Google Scholar Studies have attempted to determine the severity and concomitant injuries to tendons and neurovascular structures. Tuncali et al2Tuncali D. Yavuz N. Terzioglu A. Aslan G. The rate of upper-extremity deep-structure injuries through small penetrating lacerations.Ann Plast Surg. 2005; 55: 146-148Crossref PubMed Scopus (46) Google Scholar found that 54.8% of patients with a small laceration (less than 2 to 3 cm) to the hand, wrist, or forearm also had an associated tendon injury, and tendon injuries are more likely to occur with deep lacerations, with 92.5% of deep lacerations resulting in a tendon injury. Of these injuries, a flexor tendon was injured 38.7% of the time (vs extensor tendons 61% of the time) and of those with any tendon injury, the artery and/or nerve was damaged 14.9% of the time. In addition, a 10-year (2001 to 2010) population-based study attempted to describe these injuries by location and injuries to a specific tendon.3de Jong J.P. Nguyen J.T. Sonnema A.J. Nguyen E.C. Amadio P.C. Moran S.L. The incidence of acute traumatic tendon injuries in the hand and wrist: a 10-year population-based study.Clin Orthop Surg. 2014; 6: 196-202Crossref PubMed Scopus (132) Google Scholar The authors found 692 tendon injuries over this period, or an incidence of 33.2 per 100,000 person-years. The vast majority of injuries occurred in men (84%), mean age 35.9 years.3de Jong J.P. Nguyen J.T. Sonnema A.J. Nguyen E.C. Amadio P.C. Moran S.L. The incidence of acute traumatic tendon injuries in the hand and wrist: a 10-year population-based study.Clin Orthop Surg. 2014; 6: 196-202Crossref PubMed Scopus (132) Google Scholar In agreement with prior studies, flexor tendon injuries were less common than extensor injuries (65% vs 85%, respectively). Flexor tendon injuries occurred most often in zone II (P < .006) and the most common injured tendon was the flexor digitorum profundus (FDP) to the index and little fingers (9.1% and 8.5%, respectively); however, this was not significantly different compared with the FDP in other fingers, or relative to the flexor digitorum superficialis (FDS) or the flexor pollicis longus.3de Jong J.P. Nguyen J.T. Sonnema A.J. Nguyen E.C. Amadio P.C. Moran S.L. The incidence of acute traumatic tendon injuries in the hand and wrist: a 10-year population-based study.Clin Orthop Surg. 2014; 6: 196-202Crossref PubMed Scopus (132) Google Scholar Thus, although extensor tendon injuries occur more often, injuries to the flexor tendons often occur in zone II, which leads to important implications in their treatment and prognosis. Flexor tendon anatomy has been well defined and is beyond the scope of this article. Much of the basic research addressed injuries in zone II, which encompasses the area from the distal palmar crease to the FDS tendon insertion onto the middle phalanx. The annular pulleys are critical to prevent bowstringing of the tendon during flexion, with the A2 and A4 pulleys considered the most critical. Also, emerging evidence suggests that zone II injuries can be further broken down by the tendon location in the distal stump relative to the pulley system, but this may be more for academic purposes because there is no evidence that it has prognostic value. Zone IIA injury occurs under the A4 pulley, zone IIB under the C1 pulley, zone IIC under the A2 pulley, and zone IID under the A1 pulley. These pulleys are thickening of the flexor tendon sheath, a double-walled synovial lined canal that serves as a source of lubrication for less friction movement of the tendon and a source of nutrients to maintain tendon viability. In addition to the synovial fluid, the tendons are also directly supplied with nutrients via the vinculum, a vascular mesentery that originates from the digital arteries. The FDS and FDP tendons each have 2 vincula that contain vessels for blood supply. The unique relationship between the FDS and FDP tendons within the flexor sheath and the scarring and adhesions that inevitably occur after repair create a challenge to obtaining predictable outcomes, which makes this an area of consistent interest for both basic science and clinical research. Lacerations of the hand commonly present to the emergency department and a majority of even small lacerations have an associated tendon injury. The crux of a flexor tendon injury diagnosis is the physical examination, which should include careful neurovascular assessment. Active range of motion of the affected and surrounding digits should be assessed to aid in the classification of injury. The proximal interphalangeal and distal interphalangeal joints should be isolated to determine the involvement of the FDS or FDP tendons, or both. Furthermore, the patient’s history, including timing of presentation in relation to the injury and mechanism of injury, has implications regarding treatment and prognosis. Starnes et al4Starnes T. Saunders R.J. Means Jr., K.R. Clinical outcomes of zone II flexor tendon repair depending on mechanism of injury.J Hand Surg Am. 2012; 37: 2532-2540Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar demonstrated that zone II tendon injuries resulting from a tearing mechanism such as a saw have a higher rate of reoperation and reduced passive and active range of digital joint motion compared with injuries of patients who sustained a sharp injury such as that inflicted with a knife. Thus, the mechanism of injury, especially in dealing with zone II injuries, can influence outcomes and mechanisms and strategy for repair. Whereas recent improvements in surgical technique, suture patterns, and rehabilitation have dramatically improved outcomes of primary flexor tendon repairs,5Kim H.M. Nelson G. Thomopoulos S. Silva M.J. Das R. Gelberman R.H. Technical and biological modifications for enhanced flexor tendon repair.J Hand Surg Am. 2010; 35 (quiz 1038): 1031-1037Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 6Strickland J.W. The scientific basis for advances in flexor tendon surgery.J Hand Ther. 2005; 18 (quiz 111): 94-110Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar unsatisfactory outcomes are still often observed; up to 30% to 40% of primary flexor tendon repairs result in adhesion formation sufficient to limit digital range of motion.7Aydin A. Topalan M. Mezdegi A. et al.[Single-stage flexor tendoplasty in the treatment of flexor tendon injuries].Acta Orthop Traumatol Turc. 2004; 38: 54-59PubMed Google Scholar As such, there is an unmet need to minimize adhesions and promote tendon gliding, with biological intervention representing a potentially practical approach. To design rationale therapies, a clear understanding of the temporal and spatial cellular environment of the healing tendon is required. Currently, there is no consensus on the biological approach to promote satisfactory flexor tendon healing. We propose that insufficient understanding of the complex cellular milieu in the healing tendon has hindered the development of successful therapies. The flexor tendon repair site is a complex, dynamic environment composed of numerous cell types. The relative contributions of intrinsic and extrinsic tendon healing and extratendinous cells involved in the process are a source of much debate; here, we aim to highlight the diverse origin and functions of cells involved in the healing process with a specific focus on recent advances using murine models of flexor tendon healing. Flexor tendons heal through 3 sequential and partially overlapping phases: inflammation, granulation tissue, and remodeling.8Beredjiklian P.K. Biologic aspects of flexor tendon laceration and repair.J Bone Joint Surg Am. 2003; 85: 539-550PubMed Google Scholar Immediately after injury, an acute inflammatory response is initiated, resulting in recruitment of circulating inflammatory cells including macrophages. Because of the strong association between inflammation and adhesion formation, macrophages represent an important cellular component of healing and a potential therapeutic target. Macrophages are subdivided into 2 broad categories: classically activated M1 and alternatively activated M2. M1 macrophages promote inflammation and extracellular matrix deposition, likely leading to scar formation. In contrast, M2 macrophages promote cell proliferation, suppress inflammation, and contribute to reparative tissue remodeling. Despite these opposing functions and the potential dichotomous effects on flexor tendon healing, little is known about macrophage polarization during tendon healing. However, Wong et al9Wong J.K. Lui Y.H. Kapacee Z. Kadler K.E. Ferguson M.W. McGrouther D.A. The cellular biology of flexor tendon adhesion formation: an old problem in a new paradigm.Am J Pathol. 2009; 175: 1938-1951Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar demonstrated an influx of inflammatory cells into the flexor tendon repair site during early healing, including elevated levels of F4/80-positive macrophages in the repair site. In terms of polarization, Dakin et al10Dakin S.G. Werling D. Hibbert A. et al.Macrophage sub-populations and the lipoxin A4 receptor implicate active inflammation during equine tendon repair.PloS One. 2012; 7: e32333Crossref PubMed Scopus (63) Google Scholar demonstrated that macrophages are absent from normal equine tendons whereas M1 macrophages are predominant during the initial response to injury, with subsequent transition to an M2 phenotype during the long-term response to injury. In addition to circulating inflammatory cells, bone marrow–derived cells (BMDCs) migrate specifically to the flexor tendon repair site within 3 days of injury in a murine model, with no evidence of BMDCs in uninjured tendons,11Loiselle A.E. Frisch B.J. Wolenski M. et al.Bone marrow-derived matrix metalloproteinase-9 is associated with fibrous adhesion formation after murine flexor tendon injury.PloS One. 2012; 7: e40602Crossref PubMed Scopus (36) Google Scholar which suggests local production of a chemotactic signal from the repair site. Although the precise functions of BMDCs in flexor tendon healing are not clear, they have been identified as a source of matrix metalloproteinase-9, which is associated with adhesion formation during flexor tendon healing.11Loiselle A.E. Frisch B.J. Wolenski M. et al.Bone marrow-derived matrix metalloproteinase-9 is associated with fibrous adhesion formation after murine flexor tendon injury.PloS One. 2012; 7: e40602Crossref PubMed Scopus (36) Google Scholar During the granulation tissue phase, extensive proliferation of fibroblast-like cells is observed, with resident tenocytes being a major source of these cells. Elegant work by Hasslund et al12Hasslund S. Jacobson J.A. Dadali T. et al.Adhesions in a murine flexor tendon graft model: autograft versus allograft reconstruction.J Orthop Res. 2008; 26: 824-833Crossref PubMed Scopus (63) Google Scholar demonstrated that devitalized acellular flexor tendon allografts heal with improved gliding function and a concomitant decrease in granulation at the repair site relative to live autografts, which suggests that activation and proliferation of resident cells in the live autograft contribute to the granulation tissue response and adhesion formation. Defining the function of resident tendon cells is further complicated because there are differences between tenocytes within the tendon and those on the periphery, or epitenon cells. Progress in the murine model has been hampered by technical challenges associated with the small size of the murine hind paw and a paucity of appropriate genetic reporter models that can delineate these 2 populations. However, recent work by Cadby et al13Cadby J.A. Buehler E. Godbout C. van Weeren P.R. Snedeker J.G. Differences between the cell populations from the peritenon and the tendon core with regard to their potential implication in tendon repair.PloS One. 2014; 9: e92474Crossref PubMed Scopus (47) Google Scholar has begun to define the function of peritenon versus tendon core cells during flexor tendon healing. Peritenon-derived cells have a higher proliferation capacity and are more likely to modulate into myofibroblasts relative to resident tendon cells, which suggests an important role for epitenon-derived cells in adhesion formation. In addition, Taylor et al14Taylor S.H. Al-Youha S. Van Agtmael T. et al.Tendon is covered by a basement membrane epithelium that is required for cell retention and the prevention of adhesion formation.PloS One. 2011; 6: e16337Crossref PubMed Scopus (59) Google Scholar identified a flexor tendon basement membrane composed of type IV collagen and laminin over a keratinized epithelium, which is required for tendon gliding. Disruption of basement membrane organization and integrity via a mutation in the Col4a1 protein results in spontaneous adhesion formation between the tendon and surrounding tissues. Importantly, this work also demonstrated that basement membrane–derived cells were detected in adhesions, which highlights the complicated function of the flexor tendon basement membrane: maintaining tendon integrity during homeostasis while stabilizing adhesions during healing. Finally, the contribution of the synovial sheath cannot be overlooked in the pathogenesis of flexor tendon adhesions. Wong et al9Wong J.K. Lui Y.H. Kapacee Z. Kadler K.E. Ferguson M.W. McGrouther D.A. The cellular biology of flexor tendon adhesion formation: an old problem in a new paradigm.Am J Pathol. 2009; 175: 1938-1951Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar demonstrated proliferation of the synovial sheath cells in response to injury, resulting in adhesions between the tendon and sheath in a zone II partial transection model in the mouse. Recent development of a murine model that targets the synovial sheath15Kozhemyakina E. Zhang M. Ionescu A. et al.Identification of a prg4-expressing articular cartilage progenitor cell population in mice.Arthritis Rheumatol. 2015; 67: 1261-1273Crossref Scopus (152) Google Scholar identified this as a feasible approach to intervene in adhesion formation. The remodeling phase of flexor tendon healing restores tendon morphology and organization, leading to functional improvements. The identity of the cells involved in this process is not entirely clear. However, Farhat et al16Farhat Y.M. Al-Maliki A.A. Chen T. et al.Gene expression analysis of the pleiotropic effects of TGF-beta1 in an in vitro model of flexor tendon healing.PloS One. 2012; 7: e51411Crossref PubMed Scopus (65) Google Scholar demonstrated that tenocytes produce matrix metalloproteinase-2, which is associated with matrix remodeling, in response to transforming growth factor-β (TGF-β) using an in vitro model of flexor tendon healing. Because of its important role in inflammation and fibrosis, TGF-β has served as a common target for inhibition to improve flexor tendon healing. Recently, several small molecules have been used to inhibit TGF-β directly or by modulating downstream signaling, with some promising results. Zhou et al17Zhou Y. Zhang L. Zhao W. Wu Y. Zhu C. Yang Y. Nanoparticle-mediated delivery of TGF-beta1 miRNA plasmid for preventing flexor tendon adhesion formation.Biomaterials. 2013; 34: 8269-8278Crossref PubMed Scopus (74) Google Scholar used nanoparticle-encapsulated TGF-β micro-ribonucleic acid to suppress TGF-β, which resulted in decreased adhesions in a chicken model, although the strength of the repaired tendons was diminished. Consistent with this, we recently used an antisense oligonucleotide (ASO) approach to suppress Tgf-β and several components of TGF-β signaling including Smad3. Inhibition of Tgf-β, and Ctgf substantially enhanced gliding function relative to control ASO; however no improvement in strength was observed. Importantly, treatment with a Smad3 ASO achieved improved gliding function and strength,18Loiselle A.E. Yukata K. Geary M.B. et al.Development of antisense oligonucleotide (ASO) technology against Tgf-beta signaling to prevent scarring during flexor tendon repair.J Orthop Res. 2015; 33: 859-866Crossref PubMed Scopus (32) Google Scholar which suggesting Smad3 as a potential therapeutic target. Recent work by Wong et al19Wong J.K. Metcalfe A.D. Wong R. et al.Reduction of tendon adhesions following administration of Adaprev, a hypertonic solution of mannose-6-phosphate: mechanism of action studies.PloS One. 2014; 9: e112672Crossref PubMed Scopus (12) Google Scholar demonstrated that mannose-6-phosphate, a TGF-β inhibitor, reduces adhesions during murine flexor tendon healing, with in vitro studies demonstrating that it decreases cell migration and proliferation, consistent with decreased granulation tissue and adhesions in vivo. In addition to modulating inflammation, a proanabolic approach has recently been used to augment the healing process via administration of parathyroid hormone. Parathyroid hormone 1 to 34 resulted in a notable increase in matrix deposition and improvements in the strength of the healing tendon; however, impaired gliding function was also observed.20Lee D. Southgate R. Farhat Y. et al.PTH 1-34 treatment increases matrix synthesis and adhesion formation during flexor tendon repair.J Orthop Res. 2014; 33: 17-24Crossref PubMed Scopus (17) Google Scholar Taken together, these in vivo studies of pharmacological modification of flexor tendon healing suggest that a combination therapy involving modulation of both inflammation and collagen catabolism may hold some promise in restoring gliding function while maintaining or improving the strength of the tendon. As the molecular changes associated with each phase of healing have become better understood, investigators have used gene deletion approaches to determine or confirm the function of a specific gene during the healing process. Although this approach does not have direct clinical translation, defining the molecular mechanisms of adhesion formation will allow for rationale design of more translational studies using pharmacological approaches. Consistent with systemic inhibition of TGF-β, deletion of the TGF-β inducible early gene (Tieg1) resulted in decreased collagen I deposition in an in vitro model of flexor tendon healing.21Tsubone T. Moran S.L. Subramaniam M. Amadio P.C. Spelsberg T.C. An K.N. Effect of TGF-beta inducible early gene deficiency on flexor tendon healing.J Orthop Res. 2006; 24: 569-575Crossref PubMed Scopus (48) Google Scholar In addition, complete loss of Smad3 resulted in decreased adhesion formation, suppressed collagen matrix deposition, and impaired strength of the healing tendon, relative to wild-type mice,22Katzel E.B. Wolenski M. Loiselle A.E. et al.Impact of Smad3 loss of function on scarring and adhesion formation during tendon healing.J Orthop Res. 2011; 29: 684-693Crossref PubMed Scopus (84) Google Scholar which suggests that modulation rather than complete ablation of Smad3 may result in more desirable effects. The murine model can be challenging for studying flexor tendon healing because of the small size of the mouse paw; thus, a large animal model is more commonly used.23Galvez M.G. Crowe C. Farnebo S. Chang J. Tissue engineering in flexor tendon surgery: current state and future advances.J Hand Surg Eur Vol. 2014; 39: 71-78Crossref PubMed Scopus (16) Google Scholar At the convergence of molecular and tissue engineering approaches, Basile et al24Basile P. Dadali T. Jacobson J. et al.Freeze-dried tendon allografts as tissue-engineering scaffolds for Gdf5 gene delivery.Mol Ther. 2008; 16: 466-473Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar used a devitalized, acellular allograft tendon loaded with recombinant adeno-associated virus expressing growth and differentiation factor-5 as a delivery model. They were able to repopulate the graft, decrease scar tissue, and enhance the gliding property relative to the adeno-associated virus control, which demonstrates the feasibility of a gene therapy approach to regenerate tendon using cadaveric or tissue-engineered tendons. In large animal models, translational progress has been made with synthetic membranes25Chen S.H. Chen C.H. Fong Y.T. Chen J.P. Prevention of peritendinous adhesions with electrospun chitosan-grafted polycaprolactone nanofibrous membranes.Acta Biomater. 2014; 10: 4971-4982Crossref PubMed Scopus (62) Google Scholar and tissue-engineered synovial membranes26Baymurat A.C. Ozturk A.M. Yetkin H. et al.Bio-engineered synovial membrane to prevent tendon adhesions in rabbit flexor tendon model.J Biomed Mater Res A. 2015; 103: 84-90Crossref PubMed Scopus (12) Google Scholar to decrease peritendinous adhesions. Perhaps the most promising and advanced tissue engineering strategies to improve flexor tendon healing have been conducted in the canine model using a combination of cell, molecular, and tissue engineering approaches to modify the tendon gliding surface. Zhao et al27Zhao C. Ozasa Y. Reisdorf R.L. et al.CORR(R) ORS Richard A. Brand Award for Outstanding Orthopaedic Research: engineering flexor tendon repair with lubricant, cells, and cytokines in a canine model.Clin Orthop Relat Res. 2014; 472: 2569-2578Crossref PubMed Scopus (25) Google Scholar demonstrated that lubricin combined with hyaluronic acid and bone marrow stromal cells stimulated with growth and differentiation factor-5 can significantly improve gliding function in canine flexor digitorum profundus tendons; however, substantial decrements in strength were also observed relative to untreated controls. In conclusion, this review serves to highlight the importance of understanding and potentially exploiting the heterogeneity of the cellular environment during flexor tendon healing to develop successful biologic therapies. In this review, we have focused almost entirely on murine models of flexor tendon healing. Although this model system has certain limitations in terms of clinical translation, including the use of a quadruped animal model and inherent technical challenges owing to the small size of the murine paw, there are several strengths of this model. The feasibility of murine models of complete flexor tendon transection,11Loiselle A.E. Frisch B.J. Wolenski M. et al.Bone marrow-derived matrix metalloproteinase-9 is associated with fibrous adhesion formation after murine flexor tendon injury.PloS One. 2012; 7: e40602Crossref PubMed Scopus (36) Google Scholar partial transection in zone II,28Wong J. Bennett W. Ferguson M.W. McGrouther D.A. Microscopic and histological examination of the mouse hindpaw digit and flexor tendon arrangement with 3D reconstruction.J Anat. 2006; 209: 533-545Crossref PubMed Scopus (27) Google Scholar and flexor tendon allograft reconstruction12Hasslund S. Jacobson J.A. Dadali T. et al.Adhesions in a murine flexor tendon graft model: autograft versus allograft reconstruction.J Orthop Res. 2008; 26: 824-833Crossref PubMed Scopus (63) Google Scholar combined with sophisticated genetic models of targeted gene deletion that have recently been developed support this as a cost-effective and efficient approach to identify candidate cells and molecules that can then be tested in more translational models of healing. Journal CME QuestionsJournal of Hand SurgeryVol. 41Issue 1Preview Full-Text PDF" @default.
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• W2185815723 date "2016-01-01" @default.
• W2185815723 modified "2023-10-17" @default.
• W2185815723 title "Biological Augmentation of Flexor Tendon Repair: A Challenging Cellular Landscape" @default.
• W2185815723 cites W1490723350 @default.
• W2185815723 cites W1548284287 @default.
• W2185815723 cites W1554566492 @default.
• W2185815723 cites W1739548996 @default.
• W2185815723 cites W1823248622 @default.
• W2185815723 cites W1965942838 @default.
• W2185815723 cites W1966156677 @default.
• W2185815723 cites W1969607456 @default.
• W2185815723 cites W1970091519 @default.
• W2185815723 cites W1973400450 @default.
• W2185815723 cites W1974045101 @default.
• W2185815723 cites W1975703884 @default.
• W2185815723 cites W1989035148 @default.
• W2185815723 cites W2027926373 @default.
• W2185815723 cites W2048878988 @default.
• W2185815723 cites W2055355559 @default.
• W2185815723 cites W2060220242 @default.
• W2185815723 cites W2068148908 @default.
• W2185815723 cites W2080923020 @default.
• W2185815723 cites W2087895599 @default.
• W2185815723 cites W2092268652 @default.
• W2185815723 cites W2118177865 @default.
• W2185815723 cites W2125942838 @default.
• W2185815723 cites W2128805615 @default.
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