Enhance Tendon Healing Research Articles

Difference between early versus delayed postoperative physical rehabilitation protocol following arthroscopic rotator cuff repair

Early passive motion exercise has been the standard rehabilitation protocol following rotator cuff repair. However, recent research studies show that longer immobilization may enhance tendon healing. The aim of this study was to compare early passive range of motion (ROM) exercise with a delayed rehabilitation protocol with regard to the effectiveness of stiffness reduction and functional improvements and rates of tendon healing in patients undergoing arthroscopic repair for torn rotator cuffs. This study was performed on 164 patients having a full-thickness tear of the supraspinatus muscle that was repaired using the arthroscopic single-row suture anchor technique along with subacromial decompression. The patients were divided into two groups, early (group 1) and delayed ROM (group 2). In group 1, 78 patients were started on passive elevation and rotation exercises on the second day after surgery. In group 2, 86 patients had their shoulder immobilized for 6 weeks, after which passive motion exercise was started. Patients were followed-up clinically for a minimum of 12 months, and rotator cuff healing was assessed using MRI. Both groups had a statistically significant difference between preoperative and postoperative results. As regards American Shoulder and Elbow Surgeon scores, the early group improved from 45.4 preoperatively to 90.9 postoperatively (P<0.0001) and the delayed group improved from 44.59 preoperatively to 91.6 postoperatively (P<0.0001). As regards Constant score, the early group improved from 35.7 preoperatively to 86.5 postoperatively (P<0.0001) and the delayed group improved from 37.8 preoperatively to 88.1 postoperatively (P<0.0001). However, there were no statistically significant differences in rotator cuff healing between the two groups. The follow-up mean of visual analog scale was significantly better in group 2 compared with group 1 at 6 weeks postoperatively but no difference was found after 3 months. In contrast, ROM was better in group 1 compared with group 2 at 6 months postoperatively but no difference was found after 1 year. Significant improvement in pain, ROM, and function after arthroscopic rotator cuff repair was seen at 1 year postoperatively, regardless of early or delayed postoperative rehabilitation protocols. However, early motion increases pain scores and may increase the possibility of rotator cuff retear but with early regain of ROM. A delayed rehabilitation protocol with immobilization for 6 weeks would be better for tendon healing without risk for retear or joint stiffness and easily convalescence with less postoperative pain.

Moderate treadmill running exercise prior to tendon injury enhances wound healing in aging rats.

The effect of exercise on wound healing in aging tendon was tested using a rat moderate treadmill running (MTR) model. The rats were divided into an MTR group that ran on a treadmill for 4 weeks and a control group that remained in cages. After MTR, a window defect was created in the patellar tendons of all rats and wound healing was analyzed. We found that MTR accelerated wound healing by promoting quicker closure of wounds, improving the organization of collagen fibers, and decreasing senescent cells in the wounded tendons when compared to the cage control. MTR also lowered vascularization, increased the numbers of tendon stem/progenitor cells (TSCs) and TSC proliferation than the control. Besides, MTR significantly increased the expression of stem cell markers, OCT-4 and Nanog, and tenocyte genes, Collagen I, Collagen III and tenomodulin, and down-regulated PPAR-γ, Collagen II and Runx-2 (non-tenocyte genes). These findings indicated that moderate exercise enhances healing of injuries in aging tendons through TSC based mechanisms, through which exercise regulates beneficial effects in tendons. This study reveals that appropriate exercise may be used in clinics to enhance tendon healing in aging patients.

History of rotator cuff surgery.

Rotator cuff surgery is a rapidly evolving branch in orthopaedics, which has raised from a minor niche to a fully recognized subspecialty. This article summarizes its history, examining the development of its key principles and the technical advancements. Literature was thoroughly searched, and few senior surgeons were interviewed in order to identify the significant steps in the evolution of rotator cuff surgery. A wide variety of surgical options is available to reduce pain and restore function after rotator cuff tears. Rotator cuff repair surgical techniques evolved from open to arthroscopic and are still in development, with new fixation techniques and biological solutions to enhance tendon healing being proposed, tested in laboratory and in clinical trials. Although good or excellent results are often obtained, there is little evidence that the results of rotator cuff repair are improving with the decades. An overall high re-tear rate remains, but patients with failed rotator cuff repairs can experience outcomes comparable with those after successful repairs. Rotator cuff repair techniques evolve at a fast pace, with new solutions often being used without solid clinical evidence of superiority. It is necessary to conduct high-level clinical studies, in which data relating to anatomical integrity, patient self-assessed comfort and function, together with precise description of patient's condition and surgical technique, are collected. IV.

Parathyroid hormone 1-34 enhances extracellular matrix deposition and organization during flexor tendon repair.

Parathyroid hormone (PTH) 1-34 is known to enhance fracture healing. Tendon repair is analogous to bone healing in its dependence on the proliferation and differentiation of mesenchymal stem cells, matrix formation, and tissue remodeling.(1,2,3) We hypothesized that PTH 1-34 enhances tendon healing in a flexor digitorum longus (FDL) tendon repair model. C57Bl/6J mice were treated with either intraperitoneal PTH 1-34 or vehicle-control (PBS). Tendons were harvested at 3-28 days for histology, gene expression, and biomechanical testing. The metatarsophalangeal joint range of motion was reduced 1.5-2-fold in PTH 1-34 mice compared to control mice. The gliding coefficient, a measure of adhesion formation, was 2-3.5-fold higher in PTH 1-34 mice. At 14 days post-repair, the tensile strength was twofold higher in PTH 1-34 specimens, but at 28 days there were no differences. PTH 1-34 mice had increased fibrous tissue deposition that correlated with elevated expression of collagens and fibronectin as seen on quantitative PCR. PTH 1-34 accelerated the deposition of reparative tissue but increased adhesion formation.

Distinct Effects of Platelet-Rich Plasma and BMP13 on Rotator Cuff Tendon Injury Healing in a Rat Model

Background: Although platelet-rich plasma (PRP) is used clinically to augment tendon healing, bone morphogenetic protein–13 (BMP13) may provide a better therapeutic avenue to improve early tendon healing and repair. Hypothesis: Exogenous expression of BMP13 in tenocytes will up-regulate genes involved in tendon healing. Direct delivery of adenovirus-mediated BMP13 (AdBMP13) into the injured rat supraspinatus tendon will increase biomechanical properties. Study Design: Controlled laboratory study. Methods: Exogenous expression of BMP13 and the major growth factors in PRP (transforming growth factor–β1 [TGF-β1], vascular endothelial growth factor–A [VEGF-A], and platelet-derived growth factor–BB [PDGF-BB]) was accomplished by using recombinant adenoviral vectors. The expression of tendon- and matrix-associated genes in growth factor–treated tenocytes was analyzed by use of semiquantitative reverse-transcription polymerase chain reaction. A total of 32 rats with supraspinatus defect were divided into 4 groups and injected with adenovirus-containing green fluorescent protein (AdGFP; negative control), PRP, AdBMP13, or PRP+AdBMP13. All rats were sacrificed at 2 weeks after surgery, and tendons were harvested for biomechanical testing and histologic analysis. Results: BMP13 up-regulated type III collagen expression compared with AdGFP control and PRP growth factors (P < .01). BMP13 and PRP growth factors each up-regulated fibronectin expression (P < .01). There was an increase in stress to failure in each of the 3 treatment groups (P < .05 for PRP; P < .01 for AdBMP13 or PRP+AdBMP13) compared with AdGFP control. AdBMP13 demonstrated higher stress to failure than did the PRPs (P < .01). The addition of PRP did not increase the BMP13-enhanced stress to failure or stiffness. The biomechanical results were further supported by histologic analysis of the retrieved samples. Conclusion: Exogenous expression of BMP13 enhances tendon healing more effectively than PRP as assessed by tendon- and matrix-associated gene expression, biomechanical testing, and histologic analysis. Clinical Relevance: While PRP is used in the clinical setting, BMP13 may be explored as a superior biofactor to improve rotator cuff tendon healing and reduce the incidence of retears.

Statins Enhance Rotator Cuff Healing by Stimulating the COX2/PGE2/EP4 Pathway

Background: Statins are lipid-lowering drugs with many beneficial pleiotropic effects. Cyclooxygenase (COX2) selective inhibitors that are commonly prescribed in orthopaedic patients may effect healing. Evidence indicates that statins stimulate COX2 activity. Hypothesis: Atorvastatin (ATV) administration will enhance tendon healing by stimulating the acute inflammatory phase via increasing the production of prostaglandin E2 (PGE2). Study Design: Controlled laboratory study. Methods: After experimental rotator cuff (RC) tearing and suturing, 48 Wistar rats were randomly allocated into 4 groups: (1) ATV (20 mg/kg), (2) celecoxib (CEL; COX2 inhibitor) (10 mg/kg), (3) ATV + CEL (20 mg/kg + 10 mg/kg), and (4) saline alone. Animals were sacrificed 3 weeks after RC tears and repair, and tendon integrity was tested biomechanically in tension. To further evaluate the underlying mechanism of action, human and rat primary tenocytes were obtained from the supraspinatus tendon. Cultures were treated with a therapeutic dosage of 5 commonly used statins: CEL, ATV + CEL, PGE2, and a selective antagonist of PGE2 receptor 4 (EP4). Cell proliferation (thymidine incorporation), migration (wound healing assay), and adhesion (iCELLigence) were evaluated. The expression of all PGE2 receptors (EPs) was determined by quantitative reverse transcription polymerase chain reaction. Results: Tension testing of healed tendons demonstrated significantly higher maximal loading and stiffness in the ATV group as compared with the saline (+30% and +20%, respectively; P < .001) and CEL groups (+33% and +50%, respectively; P < .005). Celecoxib alone did not affect tendon healing (P = .88). In line with these in vivo results, tenocytes treated with statins demonstrated significantly higher proliferation rates; CEL abrogated this effect, and PGE2 treatment stimulated tenocyte proliferation even in the presence of CEL. Also, ATV stimulated the migration (wound healing) and adhesion of tenocytes. Among all PGE2 receptors, tenocytes mainly express EP4, and an EP4 selective antagonist blocked the effect of ATV. Conclusion: Results indicate that ATV enhances tendon healing by stimulating tenocyte proliferation, migration, and adhesion via increased COX2 activity and autocrine/paracrine PGE2 signaling. Findings also demonstrate that this effect is mediated by EP4 signaling. Clinical Relevance: Although chronic inflammation contributes to the development of tendinopathy, study results advocate for a positive role of PGE2 in tendon healing during the acute inflammatory phase that follows tendon surgical repair. It is therefore suggested that ATV should be further investigated as a possible modality to improve tendon healing.

A Comparative Study of the Effects of Growth and Differentiation Factor 5 on Muscle-Derived Stem Cells and Bone Marrow Stromal Cells in an In Vitro Tendon Healing Model

To investigate the ability of muscle-derived stem cells (MDSCs) supplemented with growth and differentiation factor-5 (GDF-5) to improve tendon healing compared with bone marrow stromal cells (BMSCs) in an in vitro tendon culture model. Eighty canine flexor digitorum profundus tendons were assigned into 5 groups: repaired tendon (1) without gel patch interposition (no cell group), (2) with BMSC-seeded gel patch interposition (BMSC group), (3) with MDSC-seeded gel patch interposition (MDSC group), (4) with GDF-5-treated BMSC-seeded gel patch interposition (BMSC+GDF-5 group), and (5) with GDF-5-treated MDSC-seeded gel patch interposition (MDSC+GDF-5 group). After culturing for 2 or 4 weeks, the failure strength of the healing tendons was measured. The tendons were also evaluated histologically. The failure strength of the repaired tendon in the MDSC+GDF-5 group was significantly higher than that of the non-cell and BMSC groups. The stiffness of the repaired tendons in the MDSC+GDF-5 group was significantly higher than that of the non-cell group. Histologically, the implanted cells became incorporated into the original tendon in all 4 cell-seeded groups. Interposition of a multilayered GDF-5 and MDSC-seeded collagen gel patch at the repair site enhanced tendon healing compared with a similar patch using BMSC. However, this increase in vitro was relatively small. In the clinical setting, differences between MDSC and BMSC may not be substantially different, and it remains to be shown that such methods might enhance the results of an uncomplicated tendon repair clinically. Muscle-derived stem cell implantation and administration of GDF-5 may improve the outcome of tendon repair.

Exuberant Inflammatory Reaction as a Side Effect of Platelet-Rich Plasma Injection in Treating One Case of Tendinopathy

Platelet-rich plasma (PRP) contains a large number of growth factors, which may enhance tendon healing processes. Local injection of PRP represents a relatively new treatment for tendinopathies. To date, no side effects have been reported after injection of PRP to treat tendinopathy. We report a case of exuberant inflammatory reaction after 1 injection of PRP to treat jumper's knee in a 35-year-old male type 1 diabetic patient. Injections of PRP should be proposed only after careful consideration in cases of patients with morbidity risks linked to insulin-dependent diabetes.

Regenerative medicine in rotator cuff injuries.

Rotator cuff injuries are a common source of shoulder pathology and result in an important decrease in quality of patient life. Given the frequency of these injuries, as well as the relatively poor result of surgical intervention, it is not surprising that new and innovative strategies like tissue engineering have become more appealing. Tissue-engineering strategies involve the use of cells and/or bioactive factors to promote tendon regeneration via natural processes. The ability of numerous growth factors to affect tendon healing has been extensively analyzed in vitro and in animal models, showing promising results. Platelet-rich plasma (PRP) is a whole blood fraction which contains several growth factors. Controlled clinical studies using different autologous PRP formulations have provided controversial results. However, favourable structural healing rates have been observed for surgical repair of small and medium rotator cuff tears. Cell-based approaches have also been suggested to enhance tendon healing. Bone marrow is a well known source of mesenchymal stem cells (MSCs). Recently, ex vivo human studies have isolated and cultured distinct populations of MSCs from rotator cuff tendons, long head of the biceps tendon, subacromial bursa, and glenohumeral synovia. Stem cells therapies represent a novel frontier in the management of rotator cuff disease that required further basic and clinical research.

The injury response of aged tendons in the absence of biglycan and decorin

Recent studies have demonstrated that the small leucine-rich proteoglycans (SLRPs) biglycan and decorin impact tendon development, aging and healing in mature mice. However, despite the increased risk of tendon injury in the elderly, the role of SLRPs in tendon repair has not been investigated in aged animals. Therefore, our objective was to elucidate the influences of bigylcan and decorin on tendon healing in aged mice to relate our findings to previous work in mature mice. Since the processes of aging and healing are known to interact, our hypothesis was that aging mediates the role of biglycan and decorin on tendon healing. Patellar tendons from wild-type, biglycan-null and decorin-null mice were injured at 270days using an established model. At 3 and 6weeks post-surgery, structural, mechanical and biochemical analyses were performed and compared to uninjured controls. Early stage healing was inferior in biglycan-null and decorin-null mice as compared to wild type. However, tendons of all genotypes failed to exhibit improved mechanical properties between 3 and 6weeks post-injury. In contrast, in a previous investigation of tendon healing in mature (i.e., 120day-old) mice, only biglycan-null mice were deficient in early stage healing while decorin-null mice were deficient in late-stage healing. These results confirm that the impact of SLRPs on tendon healing is mediated by age and could inform future age-specific therapies for enhancing tendon healing.

Biological Strategies to Enhance Rotator Cuff Healing.

Rotator cuff tear causes a high rate of morbidity. After surgical repair, the presence of a scar tissue reduces tendon biomechanical properties. Emerging strategies for enhancing tendon healing are growth factors, cytokines, gene therapy and tissue engineering. However their efficacy has to be proved. Growth factors help the process of tendon healing by aiding cells chemotaxis, differentiation and proliferation. Numerous growth factors, including the bone morphogenetic proteins and platelet-derived growth factor can be found during the early healing process of a rotator cuff repair. Growth factors are delivered to the repair site using tissue-engineered scaffolding, coated sutures, or dissolved in a fibrin sealant. Platelet-rich plasma is an autologous concentration of platelets and contains an high density of growth factors. There is some evidence that platelet-rich plasma may improve pain and recovery of function in a short time period, but it does not improve healing rates in rotator cuff. Thus the routine use of platelet-rich plasma in rotator cuff repair is not recommended. The addition of mesenchymal stem cells to scaffolds can lead to the production of a better quality healing tissue. Gene therapy is a gene transfer from a cell into another, in order to over-express the gene required. In this way, cultures of stem cells can over-express growth factors. Better understanding of the mechanisms of physiological tendon healing can promote the correct use of these new biological therapies for a better healing tissue.

Human iPSC-Derived Neural Crest Stem Cells Promote Tendon Repair in a Rat Patellar Tendon Window Defect Model

Induced pluripotent stem cells (iPSCs) hold great potential for cell therapy and tissue engineering. Neural crest stem cells (NCSCs) are multipotent that are capable of differentiating into mesenchymal lineages. In this study, we investigated whether iPSC-derived NCSCs (iPSC-NCSCs) have potential for tendon repair. Human iPSC-NCSCs were suspended in fibrin gel and transplanted into a rat patellar tendon window defect. At 4 weeks post-transplantation, macroscopical observation showed that the repair of iPSC-NCSC-treated tendons was superior to that of non-iPSC-NCSC-treated tendons. Histological and mechanical examinations revealed that iPSC-NCSCs treatment significantly enhanced tendon healing as indicated by the improvement in matrix synthesis and mechanical properties. Furthermore, transplanted iPSC-NCSCs produced fetal tendon-related matrix proteins, stem cell recruitment factors, and tenogenic differentiation factors, and accelerated the host endogenous repair process. This study demonstrates a potential strategy of employing iPSC-derived NCSCs for tendon tissue engineering.

Nanoparticle-mediated delivery of TGF-β1 miRNA plasmid for preventing flexor tendon adhesion formation

Treatment of the disrupted digital flexor tendon is troublesome because of the lack of sufficient healing capacity and the formation of adhesions. Sustained gene delivery may be a promising approach of modulating gene expression in enhancing tendon healing and decreasing adhesions. In this study, a microRNA-based RNAi plasmid was used to specifically silence the expression of TGF-β1 gene associated with scar and adhesion formation in the flexor tendons. The miRNA plasmids were complexed with polylactic-co-glycolic acid (PLGA) nanoparticles to form nanoparticle/TGF-β1 miRNA plasmid (nanoparticle/plasmid) complexes. In vitro and in vivo transfection efficiencies experiments against tenocytes revealed that nanoparticle/plasmid complexes have significantly superior transfection efficiency over the lipofectamine/plasmid complexes. The gene and protein expression associated with adhesion of tendon treated with nanoparticle/plasmid complexes were evaluated by real-time PCR and immunoblotting. The grading of adhesions for tendons treated with nanoparticle/plasmid complexes was less severe than that treated with the nanoparticle/mock plasmid complexes. However, the ultimate strength of repaired tendons treated with nanoparticle/plasmid complexes was significantly lower than that of tendons treated with the nanoparticle/mock plasmid complexes.

Clinical and biological aspects of rotator cuff tears

Rotator cuff tears are common and are a frequent source of shoulder pain and disability. A wide variation in the prevalence of rotator cuff tears has been reported. The etiology of rotator cuff tear remains multifactorial and attempts to unify intrinsic and extrinsic theories tried to explain the etiopathogenesis of rotator cuff tears. Knowledge of the etiopathogenesis of rotator cuff tears is important to improve our therapies, surgical techniques and promote tendon repair. Several strategies have been proposed to enhance tendon healing and recently research has focused on regenerative therapies, such as Growth Factors (GFs) and Plasma Rich Platelet (PRP), with high expectations of success.

The Effect of Suture Coated With Mesenchymal Stem Cells and Bioactive Substrate on Tendon Repair Strength in a Rat Model

Exogenously administered mesenchymal stem cells and bioactive molecules are known to enhance tendon healing. Biomolecules have been successfully delivered using sutures that elute growth factors over time. We sought to evaluate the histologic and biomechanical effect of delivering both cells and bioactive substrates on a suture delivery vehicle in comparison with sutures coated with bioactive substrates alone. Bone marrow-derived stem cells were harvested from Sprague-Dawley rat femurs. Experimental cell and substrate-coated, coated suture (CS) group sutures were precoated with intercellular cell adhesion molecule 1 and poly-L-lysine and seeded with labeled bone marrow-derived stem cells. Control (substrate-only [SO] coated) group sutures were coated with intercellular cell adhesion molecule 1 and poly-L-lysine only. Using a matched-paired design, bilateral Sprague-Dawley rat Achilles tendons (n = 105 rats) were transected and randomized to CS or SO repairs. Tendons were harvested at 4, 7, 10, 14, and 28 days and subjected to histologic and mechanical assessment. Labeled cells were present at repair sites at all time points. The CS suture repairs displayed statistically greater strength compared to SO repairs at 7 days (12.6 ± 5.0 N vs 8.6 ± 3.7 N, respectively) and 10 days (21.2 ± 4.9 N vs 16.4 ± 4.8 N, respectively). There was no significant difference between the strength of CS suture repairs compared with SO repairs at 4 days (8.1 ± 5.1 N vs 6.6 ± 2.3 N, respectively), 14 days (22.8 ± 7.3 N vs 25.1 ± 9.7 N, respectively), and 28 days (40.9 ± 12.4 N vs 34.6 ± 15.0 N, respectively). Bioactive CS sutures enhanced repair strength at 7 to 10 days. There was no significant effect at later stages. The strength nadir of a tendon repair occurs in the first 2 weeks after surgery. Bioactive suture repair might provide a clinical advantage by jump-starting the repair process during this strength nadir. Improved early strength might, in turn allow earlier unprotected mobilization.

Is Early Passive Motion Exercise Necessary After Arthroscopic Rotator Cuff Repair?

Background: Early passive motion exercise has been the standard rehabilitation protocol after rotator cuff repair for preventing postoperative stiffness. However, recent approaches show that longer immobilization may enhance tendon healing and quality. Purpose: To elucidate whether early passive motion exercise affects functional outcome and tendon healing after arthroscopic rotator cuff repair. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: One hundred five consecutive patients who underwent arthroscopic repair for small to medium-sized full-thickness rotator cuff tears were included. Patients with large to massive tears and concomitant stiffness or labral lesions were excluded. Patients were instructed to wear an abduction brace for 4 to 5 weeks after surgery and to start active-assisted shoulder exercise after brace weaning. Fifty-six patients were randomly allocated into group 1: early passive motion exercises were conducted 3 to 4 times per day during the abduction brace-wearing period. Forty-nine patients were allocated into group 2: no passive motion was allowed during the same period. Range of motion (ROM) and visual analog scale (VAS) for pain were measured preoperatively and 3, 6, and 12 months postoperatively. Functional evaluations, including Constant score, Simple Shoulder Test (SST), and American Shoulder and Elbow Surgeons (ASES) score, were also evaluated at 6 and 12 months postoperatively. Ultrasonography, magnetic resonance imaging, or computed tomography arthrography was utilized to evaluate postoperative cuff healing. Results: There were no statistical differences between the 2 groups in ROM or VAS for pain at each time point. Functional evaluations were not statistically different between the 2 groups either. The final functional scores assessed at 12 months for groups 1 and 2 were as follows: Constant score, 69.81 ± 3.43 versus 69.83 ± 6.24 (P = .854); SST, 9.00 ± 2.12 versus 9.00 ± 2.59 (P = .631); and ASES score, 73.29 ± 18.48 versus 82.90 ± 12.35 (P = .216). Detachment of the repaired cuff was identified in 12% of group 1 and 18% of group 2 (P = .429). Conclusion: Early passive motion exercise after arthroscopic cuff repair did not guarantee early gain of ROM or pain relief but also did not negatively affect cuff healing. We suggest that early passive motion exercise is not mandatory after arthroscopic repair of small to medium-sized full-thickness rotator cuff tears, and postoperative rehabilitation can be modified to ensure patient compliance.

The role of nitric oxide in tendon healing

Nitric oxide (NO) is a small free radical that is generated by a family of enzymes called the nitric oxide synthases (NOS). There are 3 isoforms of NOS: endothelial NOS (eNOS), brain or neuronal NOS (bNOS), and inducible NOS (iNOS). In experiments performed during the last 20 years, we have shown that NO is induced by all 3 isoforms of NOS after tendon injury and that NOS activity is upregulated in tendinopathy. In normal uninjured tendons, there is very little NOS activity. In injured rat and human tendons, NOS activity was found in healing fibroblasts in a temporal fashion. In animal models, competitive inhibition of NOS resulted in reduced tendon healing, whereas the addition of NO resulted in enhanced tendon healing. In cultured human cells, the addition of NO via chemical means and adenovirus transfection resulted in enhanced collagen synthesis. We performed 3 randomized, double-blinded clinical trials that demonstrated a significant positive beneficial effect of NO treatment on clinical symptoms and function in patients with Achilles tendinopathy, tennis elbow, and supraspinatus tendonitis. NO was delivered via glyceryl trinitrate (GTN) patches. We also conducted a 3-year prospective follow-up that demonstrated significant long-term efficacy of GTN patches in treating noninsertional Achilles tendinopathy. In a 5-year prospective comparison treating lateral epicondylitis, we found no additional benefits of GTN vs placebo at 5 years. The use of a new GTN patch, OrthoDerm, demonstrated no evidence for efficacy in treating chronic lateral epicondylitis.

Effect of Therapeutic Ultrasound on Tendons

Ultrasound is a therapeutic agent commonly used to treat sports-related musculoskeletal conditions, including tendon injuries or tendinopathy. Despite the widespread popularity of therapeutic ultrasound, few clinical studies have proved its efficacy. Several animal studies have been conducted to explore its effectiveness. In addition, a number of in vitro studies investigating the mechanisms underlying the ability of this physical modality to enhance tendon healing or to treat tendinopathy are in progress. There is strong supporting evidence from animal studies about the positive effects of ultrasound on tendon healing. In vitro studies have also demonstrated that ultrasound can stimulate cell migration, proliferation, and collagen synthesis of tendon cells that may benefit tendon healing. These positive effects of therapeutic ultrasound on tendon healing revealed by in vivo and in vitro studies help explain the physiologic responses to this physical modality and could serve as the foundation for clinical practice.

Tendon Biomechanics and Mechanobiology—A Minireview of Basic Concepts and Recent Advancements

Due to their unique hierarchical structure and composition, tendons possess characteristic biomechanical properties, including high mechanical strength and viscoelasticity, which enable them to carry and transmit mechanical loads (muscular forces) effectively. Tendons are also mechanoresponsive by adaptively changing their structure and function in response to altered mechanical loading conditions. In general, mechanical loading at physiological levels is beneficial to tendons, but excessive loading or disuse of tendons is detrimental. This mechanoadaptability is due to the cells present in tendons. Tendon fibroblasts (tenocytes) are the dominant tendon cells responsible for tendon homeostasis and repair. Tendon stem cells (TSCs), which were recently discovered, also play a vital role in tendon maintenance and repair by virtue of their ability to self-renew and differentiate into tenocytes. TSCs may also be responsible for chronic tendon injury, or tendinopathy, by undergoing aberrant differentiation into nontenocytes in response to excessive mechanical loading. Thus, it is necessary to devise optimal rehabilitation protocols to enhance tendon healing while reducing scar tissue formation and tendon adhesions. Moreover, along with scaffolds that can mimic tendon matrix environments and platelet-rich plasma, which serves as a source of growth factors, TSCs may be the optimal cell type for enhancing repair of injured tendons.

Tendon‐derived stem cells (TDSCs) promote tendon repair in a rat patellar tendon window defect model

Injured tendons heal slowly and often result in the formation of mechanically and functionally inferior fibrotic scar tissue or fibrous adhesions. This study investigated the use of tendon-derived stem cells (TDSCs) for tendon repair in a rat patellar tendon window defect model. Fibrin glue constructs with or without GFP-TDSCs were transplanted into the window defect. The patellar tendons were harvested for histology, ex vivo fluorescent imaging and biomechanical test at various time points up to week 4. Our results showed that TDSCs significantly enhanced tendon healing as indicated by the increase in collagen production as shown by hematolxylin stain-ability of the tissue, improvement of cell alignment, collagen fiber alignment and collagen birefringence typical of tendon. The labeled cells were observed at weeks 1 and 2 and became almost undetectable at week 4. Both the ultimate stress and Young's modulus were significantly higher in the TDSCs group compared to those in the fibrin glue group at week 4. In conclusion, TDSCs promoted earlier and better repair in a rat patellar tendon window defect model.