Tendon Biology Research Articles

Tendon injury: from biology to tendon repair.

Tendon is a crucial component of the musculoskeletal system. Tendons connect muscle to bone and transmit forces to produce motion. Chronic and acute tendon injuries are very common and result in considerable pain and disability. The management of tendon injuries remains a challenge for clinicians. Effective treatments for tendon injuries are lacking because the understanding of tendon biology lags behind that of the other components of the musculoskeletal system. Animal and cellular models have been developed to study tendon-cell differentiation and tendon repair following injury. These studies have highlighted specific growth factors and transcription factors involved in tenogenesis during developmental and repair processes. Mechanical factors also seem to be essential for tendon development, homeostasis and repair. Mechanical signals are transduced via molecular signalling pathways that trigger adaptive responses in the tendon. Understanding the links between the mechanical and biological parameters involved in tendon development, homeostasis and repair is prerequisite for the identification of effective treatments for chronic and acute tendon injuries.

Rotator cuff biology and biomechanics: a review of normal and pathological conditions.

The glenohumeral joint is a complex anatomic structure commonly affected by injury such as tendinopathy and rotator cuff tears. This review presents an up-to-date overview of research on tendon biology and structure, shoulder joint motion and stability, tendon healing, and current and potential future repair strategies. Recent studies have provided information demonstrating the serious impact on uninjured tissues after a rotator cuff tear or other cause of altered shoulder joint mechanics. Another major focus of recent research is biological augmentation of rotator cuff repair with the goal of successfully reinstating normal tendon-to-bone structure. To effectively treat shoulder pathologies, clinicians need to understand normal tendon biology, the healing process and environment, and whole shoulder stability and function.

Improving results of flexor tendon repair and rehabilitation.

The global time and effort attributed to improving outcomes in the management of flexor tendon injury are large, but the degree of advancement made over the past 50 years is relatively small. This review examines the current perceived wisdom in this field and aims to explore the limitations to the authors' understanding of the tendon healing process, examining how this may be a factor that has contributed to the authors' modest progress in the field. The authors critically evaluate the sum of laboratory and clinical literature on the topic of zone II flexor tendon management that has guided their practice and provide evidence to support their methods. The review highlights some of the key developments over the years and assesses their influence on changing current practice. It also highlights recent innovations, which have the potential to influence flexor tendon outcomes by altering the surgical approach, techniques, and rehabilitation regimens. Future innovations in the field will also be discussed to examine their potential in expanding the development in the management of flexor tendon injury. A better understanding of flexor tendon biology will allow progress in developing new therapies for flexor tendon injuries; however, there are as yet few real breakthroughs that will dramatically change current practice.

Réparation primitive des tendons fléchisseurs en zone 2

Primary flexor tendon repair is still challenging even in the most experienced hands. With atraumatic surgery, the goal is to suture the tendon in a way that it will be strong enough to allow for tendon gliding without the risk of rupture or adhesions during the 12 weeks needed for the tendon to heal. After reviewing the zone 2 anatomy, the authors describe the state of art for flexor tendon repair along with their personal preferences. Although suture methods and postoperative rehabilitation programs are not universal, most specialized teams now use multistrand suturing techniques with at least 4 stands along with protected and controlled early active mobilization. Although the published rates of failure of the repair or postoperative adhesions with stiffness have decreased, these complications are still a concern. They will continue to pose a challenge for scientists performing research into the mechanics and biology of flexor tendon repairs, especially in zone 2.

Periostin secreted by mesenchymal stem cells supports tendon formation in an ectopic mouse model.

True tendon regeneration in human patients remains a vision of musculoskeletal therapies. In comparison to other mesenchymal lineages the biology of tenogenic differentiation is barely understood. Specifically, easy and efficient protocols are lacking that might enable tendon cell and tissue differentiation based on adult (stem) cell sources. In the murine mesenchymal progenitor cell line C3H10T½, overexpression of the growth factor bone morphogenetic protein 2 (BMP2) and a constitutively active transcription factor, Smad8 L+MH2, mediates tendon cell differentiation in vitro and the formation of tendon-like tissue in vivo. We hypothesized that during this differentiation secreted factors involved in extracellular matrix formation exert a major impact on tendon development. Gene expression analyses revealed four genes encoding secreted factors that are notably upregulated: periostin, C-type lectin domain family 3 (member b), RNase A4, and follistatin-like 1. These factors have not previously been implicated in tendon biology. Among these, periostin showed a specific expression in tenocytes of adult mouse Achilles tendon and in chondrocytes within the nonmineralized fibrocartilage zone of the enthesis with the calcaneus. Overexpression of periostin alone or in combination with constitutively active BMP receptor type in human mesenchymal stem cells and subsequent implantation into ectopic sites in mice demonstrated a reproducible moderate tenogenic capacity that has not been described before. Therefore, periostin may belong to the factors contributing to the development of tenogenic tissue.

The development of zebrafish tendon and ligament progenitors.

Despite the importance of tendons and ligaments for transmitting movement and providing stability to the musculoskeletal system, their development is considerably less well understood than that of the tissues they serve to connect. Zebrafish have been widely used to address questions in muscle and skeletal development, yet few studies describe their tendon and ligament tissues. We have analyzed in zebrafish the expression of several genes known to be enriched in mammalian tendons and ligaments, including scleraxis (scx), collagen 1a2 (col1a2) and tenomodulin (tnmd), or in the tendon-like myosepta of the zebrafish (xirp2a). Co-expression studies with muscle and cartilage markers demonstrate the presence of scxa, col1a2 and tnmd at sites between the developing muscle and cartilage, and xirp2a at the myotendinous junctions. We determined that the zebrafish craniofacial tendon and ligament progenitors are neural crest derived, as in mammals. Cranial and fin tendon progenitors can be induced in the absence of differentiated muscle or cartilage, although neighboring muscle and cartilage are required for tendon cell maintenance and organization, respectively. By contrast, myoseptal scxa expression requires muscle for its initiation. Together, these data suggest a conserved role for muscle in tendon development. Based on the similarities in gene expression, morphology, collagen ultrastructural arrangement and developmental regulation with that of mammalian tendons, we conclude that the zebrafish tendon populations are homologous to their force-transmitting counterparts in higher vertebrates. Within this context, the zebrafish model can be used to provide new avenues for studying tendon biology in a vertebrate genetic system.

Crucial transcription factors in tendon development and differentiation: their potential for tendon regeneration

Tendons that connect muscles to bone are often the targets of sports injuries. The currently unsatisfactory state of tendon repair is largely attributable to the limited understanding of basic tendon biology. A number of tendon lineage-related transcription factors have recently been uncovered and provide clues for the better understanding of tendon development. Scleraxis and Mohawk have been identified as critical transcription factors in tendon development and differentiation. Other transcription factors, such as Sox9 and Egr1/2, have also been recently reported to be involved in tendon development. However, the molecular mechanisms and application of these transcription factors remain largely unclear and this prohibits their use in tendon therapy. Here, we systematically review and analyze recent findings and our own data concerning tendon transcription factors and tendon regeneration. Based on these findings, we provide interaction and temporal programming maps of transcription factors, as a basis for future tendon therapy. Finally, we discuss future directions for tendon regeneration with differentiation and trans-differentiation approaches based on transcription factors.

Functional tissue engineering of tendon: Establishing biological success criteria for improving tendon repair

Improving tendon repair using Functional Tissue Engineering (FTE) principles has been the focus of our laboratory over the last decade. Although our primary goals were initially focused only on mechanical outcomes, we are now carefully assessing the biological properties of our tissue-engineered tendon repairs so as to link biological influences with mechanics. However, given the complexities of tendon development and healing, it remains challenging to determine which aspects of tendon biology are the most important to focus on in the context of tissue engineering. To address this problem, we have formalized a strategy to identify, prioritize, and evaluate potential biological success criteria for tendon repair. We have defined numerous biological properties of normal tendon relative to cellular phenotype, extracellular matrix and tissue ultra-structure that we would like to reproduce in our tissue-engineered repairs and prioritized these biological criteria by examining their relative importance during both normal development and natural tendon healing. Here, we propose three specific biological criteria which we believe are essential for normal tendon function: (1) scleraxis-expressing cells; (2) well-organized and axially-aligned collagen fibrils having bimodal diameter distribution; and (3) a specialized tendon-to-bone insertion site. Moving forward, these biological success criteria will be used in conjunction with our already established mechanical success criteria to evaluate the effectiveness of our tissue-engineered tendon repairs.

Musculoskeletal regeneration and its implications for the treatment of tendinopathy

Tendinopathies are common muskoloskeletal injuries that lead to pain and disability. Development and pathogenesis of tendinopathy is attributed to progressive pathological changes to the structure, function, and biology of tendon. The nature of this disease state, whether acquired by acute or chronic injury, is being actively investigated. Scarring, disorganized tissue, and loss of function characterize adult tendon healing. Recent work from animal models has begun to reveal the potential for adult mammalian tendon regeneration, the replacement of diseased with innate tissue. This review discusses what is known about musculoskeletal regeneration from a molecular perspective and how these findings can be applied to tendinopathy. Non-mammalian and mammalian models are discussed with emphasis on the potential of Murphy Roths Large mice to serve as a model of adult tendon regeneration. Comparison of regeneration in non-mammals, foetal mammals and adult mammals emphasizes distinctly different contributing factors to effective regeneration.

COMPARISON OF THE ACUTE INFLAMMATORY RESPONSE AND PROLIFERATION OF DRY NEEDLING AND ELECTROLYSIS PERCUTANEOUS INTRATISSUE (EPI) IN HEALTHY RAT ACHILLES TENDONS

IntroductionElectrolysis Percutaneous Intratissue (EPI) is a new technique that involves the application of a galvanic current with an acupuncture needle that causes a theoretical local inflammatory process and subsequent tissue...

Regional Differences in Stem Cell/Progenitor Cell Populations from the Mouse Achilles Tendon

Specific niches may affect how cells from different regions contribute to tendon biology, particularly in regard to the healing of certain tendinopathies. The objectives of this study are to determine whether distinct subpopulations of stem/progenitor cells are found within the tendon proper and the epi- and paratenon, the peritenon, as well as to characterize these stem/progenitor cell populations. In this study, we hypothesized that tendon stem/progenitor cells exist in each region, that these populations possess distinct features, and that these populations while multipotent could have differing potentials. To test this hypothesis, stem/progenitor cells were isolated and characterized from the peritenon and tendon proper of mouse Achilles tendons. Colony-forming unit and multipotency assays, as well as flow cytometry, and real-time quantitative polymerase chain reaction analyses of stem cell markers were performed. Significantly, more stem/progenitor cell colonies were observed from cells derived from the tendon proper relative to the peritenon. Analysis of surface markers for stem/progenitor cells from both regions indicated that they were Sca1(+) (stem cell marker), Cd90(+) and Cd44(+) (fibroblast markers), Cd18(-) (leukocyte marker), Cd34(-) (hematopoietic and vascular marker), and Cd133(-) (perivascular marker). Tendon proper stem/progenitor cells had increased expression levels for tenomodulin (Tnmd) and scleraxis (Scx), indicative of enrichment of stem/progenitor cells of a tendon origin. In contrast, cells of the peritenon demonstrated relative increases in the vascular (endomucin) and pericyte (Cd133) markers relative to cells from the tendon proper. Stem/progenitor cells from both regions were multipotent (adipogenic, chondrogenic, osteogenic, and tenogenic). These findings demonstrated that different progenitor populations exist within discrete niches of the Achilles tendon-tendon proper versus peritenon. Overall, these data support the hypothesis that the progenitor pools from both regions have distinct properties and contain enriched progenitor subpopulations of different origins. Moreover, in considering their roles in tendon healing more broadly, they are potential cell sources that may differentially contribute to intrinsic and extrinsic tendon repair mechanisms. That is, intrinsic repair may require a progenitor class with predominant tendon marker expression, while extrinsic repair may involve a progenitor class recruited from perivascular cells of the peritenon.

A novel in vitro loading system for high frequency loading of cultured tendon fascicles

Tendons are known to adapt to their mechanical environment, however high frequency low magnitude (HFLM) loading regimes (10–50Hz), which are effective in promoting bone anabolic effects, have not been investigated in controlled conditions in tendon. In vitro loading systems (IVLS) enable precise characterisation of the link between their controlled mechanical environment and cultured tissue biological response.We report a novel IVLS design using an applied magnetic field to produce time varying loading in cultured rat tail tendon fascicles (RTTF). The design was validated through magnetic flux, load cell and viability measurements, and we report the results of preliminary experiments testing the hypothesis that an HFLM loading regime will maintain the biochemical and mechanical properties of fresh RTTF in culture over 7 days.Tissue viability was maintained for 7 days under all loading conditions, and the average peak load applied to RTTFs using the IVLS at 20Hz was 0.125N. RTTFs cultured for 7 days with HFLM loading showed a trend for a higher tangent modulus than fresh tissue, and significantly higher modulus than unloaded RTTFs. GAG content of HFLM cultured RTTFs was not significantly changed from that of fresh RTTFs.This novel, validated IVLS will provide new knowledge of tendon mechanobiology and has already shown the potential of clinically relevant HFLM loading for influencing tendon biology.

Biological Solutions in Rotator Cuff Healing

One of the most common causes of shoulder pain and dysfunction is rotator cuff tears, and the extent of this problem is increasing with an aging population. High retear rates after rotator cuff repairs suggest that simple repairs lack the mechanical integrity to promote effective tendon healing. Greater insight into the biology underlying tendon healing processes have suggested a number of target pathways that could be modulated to encourage tendon healing after rotator cuff repairs. This review evaluates the evidence to support commonly used biological therapies and also novel and future therapeutics. The scope of this review encompasses biological therapies, modulation of systemic factors that contribute to tendinopathies and healing, as well as cellular and structural repair solutions. The role for mechanical modulation of tendon biology is also considered.

2012 Annual Meeting of the Orthopaedic Research Society: tendon and ligament biology and development

2012 Annual Meeting of the Orthopaedic Research Society: tendon and ligament biology and development

The Effect of Platelet-Rich Fibrin Matrix on Rotator Cuff Tendon Healing

Background: There is a strong need for methods to improve the biological potential of rotator cuff tendon healing. Platelet-rich fibrin matrix (PRFM) allows delivery of autologous cytokines to healing tissue, and limited evidence suggests a positive effect of platelet-rich plasma on tendon biology. Purpose: To evaluate the effect of platelet-rich fibrin matrix on rotator cuff tendon healing. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Seventy-nine patients undergoing arthroscopic rotator cuff tendon repair were randomized intraoperatively to either receive PRFM at the tendon-bone interface (n = 40) or standard repair with no PRFM (n = 39). Standardized repair techniques were used for all patients. The postoperative rehabilitation protocol was the same in both groups. The primary outcome was tendon healing evaluated by ultrasound (intact vs defect at repair site) at 6 and 12 weeks. Power Doppler ultrasound was also used to evaluate vascularity in the peribursal, peritendinous, and musculotendinous and insertion site areas of the tendon and bone anchor site. Secondary outcomes included standardized shoulder outcome scales (American Shoulder and Elbow Surgeons [ASES] and L’Insalata) and strength measurements using a handheld dynamometer. Patients and the evaluator were blinded to treatment group. All patients were evaluated at minimum 1-year follow-up. A logistic regression model was used to predict outcome (healed vs defect) based on tear severity, repair type, treatment type (PRFM or control), and platelet count. Results: Overall, there were no differences in tendon-to-bone healing between the PRFM and control groups. Complete tendon-to-bone healing (intact repair) was found in 24 of 36 (67%) in the PRFM group and 25 of 31 (81%) in the control group (P = .20). There were no significant differences in healing by ultrasound between 6 and 12 weeks. There were gradual increases in ASES and L’Insalata scores over time in both groups, but there were no differences in scores between the groups. We also found no difference in vascularity in the peribursal, peritendinous, and musculotendinous areas of the tendon between groups. There were no differences in strength between groups. Platelet count had no effect on healing. Logistic regression analysis demonstrated that PRFM was a significant predictor (P = .037) for a tendon defect at 12 weeks, with an odds ratio of 5.8. Conclusion: Platelet-rich fibrin matrix applied to the tendon-bone interface at the time of rotator cuff repair had no demonstrable effect on tendon healing, tendon vascularity, manual muscle strength, or clinical rating scales. In fact, the regression analysis suggests that PRFM may have a negative effect on healing. Further study is required to evaluate the role of PRFM in rotator cuff repair.

Studies in Flexor Tendon Reconstruction: Biomolecular Modulation of Tendon Repair and Tissue Engineering

The Andrew J. Weiland Medal is presented each year by the American Society for Surgery of the Hand and the American Foundation for Surgery of the Hand for a body of work related to hand surgery research. This essay, awarded the Weiland Medal in 2011, focuses on the clinical need for flexor tendon reconstruction and on investigations into flexor tendon biology. Reconstruction of the upper extremity is limited by 2 major problems after injury or degeneration of the flexor tendons. First, adhesions formed after flexor tendon repair can cause decreased postoperative range of motion and hand function. Second, tendon losses can result from trauma and degenerative diseases, necessitating additional tendon graft material. Tendon adhesions are even more prevalent after tendon grafting; therefore these 2 problems are interrelated and lead to considerable disability. The total costs in terms of disability and inability to return to work are enormous. In this essay, published work from the past 12 years in our basic science laboratory is summarized and presented with the common theme of using molecular techniques to understand the cellular process of flexor tendon wound healing and to create substances and materials to improve tendon repair and regeneration. These are efforts to address 2 interrelated and clinically relevant problems that all hand surgeons face in their practice.

Tendinosis-like Histologic and Molecular Changes of the Achilles Tendon to Repetitive Stress: A Pilot Study in Rats

Tendinopathy (pain and tendon degeneration) is associated with repetitive use and mechanical overload. However, the etiology of tendinopathy remains unclear. Clarification of histologic and molecular changes of tendon to repetitive stress could provide better understanding of Achilles tendon disorders related to repetitive stress. We asked whether repetitive stress simulating overuse of the Achilles tendon induced (1) histologic changes in rats similar to tendinosis (increased cellularity of fibrocytes, increased disorganization of collagen fiber, and increased roundness of the nucleus of the fibrocyte), (2) increased collagen Type III occurrence, and (3) increased inducible nitric oxide synthase (iNOS) expression. We used an exercise protocol simulating repetitive, jerky, eccentric contraction of the triceps surae in 15 rats. We conducted the exercise for 2 hours per day, three times per week using the right rear legs only and the left legs as internal controls. We harvested Achilles tendons after either 2, 4, or 6 weeks of exercise, and evaluated changes in tendon thickness, fibrocyte count, collagen fiber arrangement, collagen fiber type, and occurrence of iNOS. Exercised Achilles tendons showed increased cellularity of fibrocytes at 4 and 6 weeks of exercise, and disorganized collagen fiber arrangement at 6 weeks of exercise. There was a trend for Type III collagen occurrence being greater in experimental groups. Expression of iNOS increased after 2 and 4 weeks of exercise when compared with that of the controls, but decreased after 6 weeks. These observations suggest repetitive, synchronized, passive, and jerky exercise induced by electrical stimulation can lead to the tendinosis-like changes in the Achilles tendons in rats with imbalance between synthesis and degeneration after 4 weeks of exercise. This newly designed exercise protocol may be used to design an animal model of Achilles tendon overuse. With this model, therapeutic interventions of tendinopathy could be analyzed by investigation of tendon biology and response in terms of histologic and molecular changes.

The mechanics of healing

This chapter discusses research and engineering programs undertaken to study knees and machines to help ligament-graft patients get on their feet. At the Hospital for Special Surgery in New York, researchers are investigating the biological mechanisms of how tendon heals to bone to ultimately influence rehabilitative protocols for the anterior fibula. The lab has been focusing on how mechanical loads placed on tendons affect the healing process by initiating biological signals. The current model involves studying rodents that have undergone anterior cruciate ligament (ACL) reconstruction to examine the effect of mechanical loading on tendon biology. The team will develop empirical evidence that is expected to lead to future protocols for therapy—in short, to have people heal and return to their normal lives.. One therapy that has demonstrated some success in patients recovering from ACL surgery has been continuous passive motion (CPM). The clinical CPM design has been rendered in Solidworks. The lab built a device and is now testing it on cadaver rats before moving on to live subjects.

Rotator Cuff Repair Should Be Done Arthroscopically: Body of Evidence—Opposes

The surgical management of rotator cuff tears has seen a rapid evolution from open surgical techniques to arthroscopic techniques as the perceived treatment of choice. But like most things in medicine— always is never appropriate. Many surgeons believe that all cuff tears can and should be treated arthroscopically regardless of tear size, tear configuration, and other patient specific considerations. There remains a very critical role for the maintenance of surgical skills in the treatment of rotator cuff tears with open surgical technique, as this specific clinical case will review. Recent publications suggest a much greater failure rate in 2 tendon tears when treated arthroscopically when compared with the open technique. Despite the near-daily marketing of newer suture, newer anchors, newer materials, newer knotless anchors, etc., tendon biology and physiology have not changed. Although certain smaller tears can be very appropriately repaired arthroscopically, many larger tears should be treated with open surgery.

회전근 개의 생물학적 특성

Purpose: Rotator cuff disease is the most common shoulder disease. Rotator cuff tear, which is related to cuff tendon degeneration, is commonly encountered in clinical practice. Materials and Methods: Knowledge about the biology of the normal rotator cuff is fundamental to understanding the pathophysiology of and degenerative processes in rotator cuff tendon tears. Furthermore, such basic knowledge provides a rationale for and facilitates the development of treatment modalities. Results and Conclusion: Therefore, we reviewed the biology of the normal rotator cuff tendon, theories to explain the pathophysiology of rotator cuff tendon tear, and current research on apoptosis of rotator cuff tenofibroblasts.