Injured Tendons Research Articles

Drill Penetration Injury to Extensor Tendons: A Biomechanical Analysis.

Little is known about extensor tendon failure following drill injury at the time of volar plate fixation. Our goals were to analyze extensor tendon injury following simulated drill penetration, and change in tendon displacement during cyclic loading following simulated drill penetration injury. Extensor pollicis longus (EPL) and extensor carpi radialis brevis (ECRB) tendons were harvested from 9 fresh frozen cadaveric arms. Eighteen EPL and 18 ECRB samples were created from harvested tendons. Drill penetration injury was performed in either a continuous or an oscillating mode. Injured tendons were subjected to 1200 cycles at 1- to 15-kg cyclic load at a frequency of 1 Hz, and analyzed for failure at drill sites and change in displacement throughout the testing cycle. Ten EPL samples and 16 ECRB samples completed testing without failure. Tendon type (ECRB, EPL), mode of injury (continuous, oscillating), and location (proximal, distal) did not affect tendon displacement during loading. A single EPL tendon failed following continuous drill penetration injury. Extensor carpi radialis brevis samples had a mean change in displacement of 2.8 (standard deviation [SD]: 1.5 mm) and 5.9 mm (SD: 4.7 mm) for oscillating and continuous modes, respectively. Six EPL samples had a mean change in displacement of 4.7 (SD: 2.7 mm) and 4.3 mm (SD: 1.8 mm) for oscillating and continuous modes, respectively. Complete extensor tendon failure due to drill penetration was rare. Drill mode did not affect the degree of elongation. Increasing cyclic loading of extensor tendons after drill injury caused modest extensor tendon elongation.

Adeno-Associated Virus-2–Mediated VEGF Gene Transfer to the Tendon Improves the Healing Strength of the Digital Flexor Tendons

Purpose: A major challenge in repairing injured digital flexor tendon is the weak intrinsic healing capacity of tendon, which is responsible for rerupture of repaired tendon after primary repair. In an experimental model of transection and surgical repair of the digital flexor tendon in chicken toes, we aim to test the effectiveness of introducing the vascular endothelial growth factor (VEGF) gene through an adeno-associated virus (AAV) vector to enhance tendon healing strength. Materials and Methods: One hundred and eighteen flexor digitorum profundus (FDP) tendons in the long chicken toes were completely transected the in zone 2 and surgically repaired using 2-strand modified Kessler method. These toes were divided into two groups: 58 FDP tendons (group 1) were injected with 2 × 109 particles of AAV2-VEGF per tendon and 62 tendons (group 2) after injection with saline. The toes were immobilized in semiflexed position for the first 3 weeks and then released for free toe motion. At postoperative 1, 2, 3, 4, 6, and 8 weeks, the ultimate strengths of the healing tendons were tested in an Instron tensile testing machine. At weeks 4, 6, and 8, the work of digital flexion (WOF) was also recorded and adhesions around the repair site scored. We also supplemented a group (20 toes) in which only empty AAV2 vector was injected to the tendon, and tendon strength and adhesions were recorded at weeks 2 and 4. Results: Delivery of AAV2-VEGF significantly increased ultimate strength of the healing tendons at postoperative weeks 3, 4, 6, and 8 ( P < .05 or P < .01). At week 4, the tendon strength was 12.4 ± 8.6 N after AAV2-VEGF injection, but 5.7 ± 1.1 N after saline injection. At week 6, the strength was 46.4 ± 19.2 N after AAV2-VEGF injection, but 27.1 ± 8.9 N after saline injection. At week 6 and 8, the adhesion scores and WOF of the toes after AAV2-VEGF injected were not increased. We found no significant increases in the strength of the tendon after injection of sham vector compared with that in saline control group. Conclusions: The results of this study show the therapeutic efficacy of AAV2-VEGF for improvement of tendon healing strength without aggravating adhesion formation after surgical tendon repair. AAV2-VEGF therapy appears to be a promising method of biological modulation of healing of the digital flexor tendons.

Tanshinone IIA Prevent Tendon Adhesion in the Rat Achilles Tendon Model

Background: Tendon adhesion between the sheath and tendon surface is a common clinical problem. Orthopedist makes the improvement of repair techniques and rehabilitation to treat tendon adhesion, but it fails to cure completely. TSA was one of the major active phytochemicals because of its anti-inflammatory activity. We used tanshinone IIA (TSA) for the prevention of tendon adhesion in the rat Achilles tendon model and investigated the possible mechanisms, including microRNAs (miRNAs) and protein expression via TGF-β/Smad signaling pathway. Method: Sprague-Dawley (SD) rat Achilles tendons were half partial lacerated and sutured by a modified Kessler's technique, with TSA and normal saline for control. Macroscopic and histological evaluations were applied to examine the injured tendon six weeks after surgery. We evaluated the degree of adhesion in Gross observation and the remodeling of collagen fibers by observing microscopically and determining the amount of scar formation. The expression of microRNAs (miRNAs) was quantified by real-time PCR detection and protein expression were quantified by western blotting detection. Results: In gross evaluation of tendon adhesion, the TSA group had less adhesion appeared. No evidences of tendon rupture or local infection were observed. The content of collagen fibers in tendon tissue was decreased in TSA group compared with the control group, it indicated a significant difference from the control group, P = 0.0004. The expression of miRNAs including miR-155, miR-29b, miR21, miR-133b and let7 were detected in the repaired tendon tissue, and only miR-29b treated with TSA was observed significantly higher than control group, P <0.0001. The protein expression of TGF-β1 and p-Smad3 treated with TSA was lower than control group. Conclusions: The usage of TSA may be an efficient approach for preventing tendon adhesion.

Nonconventional Tendon Advance for Injuries in Zones 1 and 2

Objective: Two techniques for reconstruction of tendon flexor injuries in zones 1 and 2 of Verdan in which primary suture cannot take place are presented. These techniques consists in carrying out a zetaplasty of the injured tendon in zone 5 to slide the proximal stump of the original rupture toward the distal stump of the tendon, suture both stump, and then perform the suture of the zetaplasty with the required tension. Another option, in case the end to end suture is unable, is to suture the lengthened tendon to an uninjured superficial flexor tendon. Methods: Thirteen patients with an average of 29 years of age were operated on with these two techniques. Diagnoses included 3 failures in primary suture of profundus flexor tendon, 7 tendon injuries treated 4 weeks after the trauma, and 3 injuries with shortening of the distal stump greater than 3 cm. In 7 cases, zetaplasty was performed with an end to end suture of the same flexor tendon, and in the remaining 6 zetaplasty was carried out with a suture of the proximal stump to an uninjured flexor tendon. Results: Average follow-up was 17.23 months. Assessment with the Strickand’s evaluation system yielded the following results: 8 excellent, 4 good, and 1 poor. Conclusions: The encouraging results in the short term with these techniques of shorter operating time and less surgical requirement motivate further development. A larger number of cases are necessary to obtain more reliable conclusions about their advantages and side effects.

Ex vivo Tendon Repair Augmented with Bone Marrow Derived Mesenchymal Stem Cells Stimulated with Myostatin for Tenogenesis: N/A - Not a clinical study

Consulting Fee: Arthrex (Yao) We performed an ex vivo study to investigate the effect of bone marrow derived mesenchymal stem cells (BMSC) stimulated with myostatin on tenogenesis in the setting of tendon repair. We hypothesized that BMSC that were delivered to a tendon repair site after being seeded onto sutures would improve tenogenesis if they were stimulated with myostatin. Cadaveric upper limb flexor tendons were harvested, decellularized, and divided into 1cm segments. Sutures seeded with BMSC were passed through 2 tendon segments to simulate repair. The repaired tendons were then cultured either with or without myostatin for 3, 5, and 7 days. The experiment was also repeated with non-decellularized tendons to make a total of 4 groups. The presence of tenomodulin and scleraxis using immunofluorescence analysis was measured at 3, 5, and 7 days for all 4 groups. Viable BMSC were found at all 3 time points in all 4 groups. Myostatin stimulation lead to expression of tenomodulin and scleraxis at 5 and 7 days in both the decellularized and non-decellularized tendons. In the tendons that were not treated with myostatin, tenomodulin and scleraxis were detected only at day 7 for the decellularized tendons and at days 5 and 7 for the non-decellularized tendons. There were also more cells expressing tenomodulin and scleraxis for the groups treated with myostatin at days 5 and 7. For all 4 groups, no tenomodulin or scleraxis was detected at 3 days. •BMSC delivered to tendon repair sites with sutures can survive for at least 7 days.•There is at least a 3 day delay before the markers of tenogenesis are detectable after BMSC delivery to the tendon repair site.•Myostatin results in an earlier, more robust and sustained expression of tenomodulin and scleraxis in this tendon repair model, implying that it facilitated earlier and increased differentiation of BMSC into tenocytes and/or upregulation of tenomodulin and scleraxis production by the tenocytes present.•Treatment of BMSC with myostatin following their delivery using coated sutures to a tendon repair site may result in improved tenogenesis, implying earlier and better healing of the injured tendon.

Assessment of elasticity by ARFI sonography of ruptured achilles tendons – long-term results

Purpose: Rupture of the Achilles tendon is a common injury. Only a few studies have investigated the biomechanical properties of injured tendons compared to healthy tendons in the long-term results. Our objective was to compare the elasticity of injured tendons vs. non-traumatized tendons by ultrasound elastography in the long-term outcome. Our secondary objective was to investigate differences of operatively vs. non-operatively treated tendons.

An in vitro scratch tendon tissue injury model: effects of high frequency low magnitude loading

ABSTRACTThe healing process of ruptured tendons is suboptimal, taking months to achieve tissue with inferior properties to healthy tendon. Mechanical loading has been shown to positively influence tendon healing. However, high frequency low magnitude (HFLM) loads, which have shown promise in maintaining healthy tendon properties, have not been studied with in vitro injury models. Here, we present and validate an in vitro scratch tendon tissue injury model to investigate effects of HFLM loading on the properties of injured rat tail tendon fascicles (RTTFs). A longitudinal tendon tear was simulated using a needle aseptically to scratch a defined length along individual RTTFs. Tissue viability, biomechanical, and biochemical parameters were investigated before and 7 days after culture . The effects of static, HFLM (20 Hz), and low frequency (1 Hz) cyclic loading or no load were also investigated. Tendon viability was confirmed in damaged RTTFs after 7 days of culture, and the effects of a 0.77 ± 0.06 cm scratch on the mechanical property (tangent modulus) and tissue metabolism in damaged tendons were consistent, showing significant damage severity compared with intact tendons. Damaged tendon fascicles receiving HFLM (20 Hz) loads displayed significantly higher mean tangent modulus than unloaded damaged tendons (212.7 ± 14.94 v 92.7 ± 15.59 MPa), and damaged tendons receiving static loading (117.9 ± 10.65 MPa). HFLM stimulation maintained metabolic activity in 7-day cultured damaged tendons at similar levels to fresh tendons immediately following damage. Only damaged tendons receiving HFLM loads showed significantly higher metabolism than unloaded damaged tendons (relative fluorescence units —7021 ± 635.9 v 3745.1 ± 641.7). These validation data support the use of the custom-made in vitro injury model for investigating the potential of HFLM loading interventions in treating damaged tendons.

The Properties of 3 Different Plasma Formulations and Their Effects on Tendinopathic Cells

Background: Tendinopathies are attributed to failure of the healing process and inadequate tissue remodeling. Plasma injections can trigger regenerative responses by modifying the molecular microenvironment. Purpose: To examine the differences in the mitotic, chemotactic, anabolic, and inflammatory effects between leukocyte- and platelet-rich plasma (L-PRP), platelet-rich plasma (PRP), and platelet-poor plasma (PPP). Study Design: Controlled laboratory study. Methods: Tendinopathic cells were cultured in 3-dimensional (3D) hydrogels formed using PPP, PRP, and L-PRP. Cell migration was evaluated using a μ-Slide chemotaxis chamber with video microscopy. Proliferation was assessed using XTT assays. Expression of genes associated with matrix turnover, including type 1 collagen (COL1A1), COL3A1, aggrecan, decorin, fibronectin, matrix metalloproteinase 1 (MMP-1), MMP-3, A Disintegrin-Like And Metalloprotease With Thrombospondin Type 1 Motif proteins 4 (ADAMTS-4), and ADAMTS-5, was assessed using real-time reverse-transcription polymerase chain reaction. Secreted inflammatory proteins, including interleukin (IL)–1β, IL-6, IL-8, monocyte chemotactic protein 1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES), as well as vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF), were quantified using enzyme-linked immunosorbent assay. Results: Tendinopathic cells migrate at a higher velocity along L-PRP and PRP than along PPP gradients. PRP and L-PRP promote hypercellularity. PPP and PRP showed more pronounced anabolic properties, as demonstrated by enhanced COL1A1 and COL3A1 and reduced MMP-1 expression. Decorin, fibronectin, and aggrecan were downregulated in L-PRP compared with PPP and PRP. L-PRP and PRP were shown to be more proinflammatory than PPP in terms of IL-6 secretion, but cells in PPP showed MCP-1high phenotype. CTGF secretion was significantly reduced in L-PRP compared with PPP and PRP. Conclusion: The main advantages of L-PRP and PRP use, compared with PPP, include their stronger chemotactic and proliferative properties. While PPP and PRP stimulate matrix anabolism, L-PRP is more proinflammatory. Emphasis should be placed on the temporal needs and biological characteristics of injured tendons, and plasma formulations need to be tailored accordingly. Clinical Relevance: Versatile systems allowing the preparation of different plasma formulations, such as PPP, PRP, or L-PRP, can help refine clinical applications by taking advantage of their different biological properties.

Harmful Effects of Leukocyte-Rich Platelet-Rich Plasma on Rabbit Tendon Stem Cells In Vitro

Background: Platelet-rich plasma (PRP) is now widely used as a promising treatment for patients with tendinopathy. However, the efficacy of PRP treatment for tendinopathy is controversial mainly because of inconsistent results from human clinical trials and particularly because the concentration and effect of leukocytes in PRP remain largely unknown. Hypothesis: Leukocyte-rich PRP (L-PRP) inhibits growth factor release, decreases proliferation, and induces nontenocyte differentiation of tendon stem cells (TSCs); increases catabolic cytokine concentrations; and causes inflammation and apoptosis. Thus, L-PRP has a detrimental effect on tendon stem/progenitor cells, which impairs injured tendon healing. Study Design: Controlled laboratory study. Methods: Pure PRP (P-PRP) and L-PRP were prepared from the same individual rabbit blood, and platelet numbers in each PRP product were adjusted to reach the same level. The leukocyte level in L-PRP was 4 and 8 times higher than those in whole blood and P-PRP, respectively. The growth factors in both P-PRP and L-PRP were measured by enzyme-linked immunosorbent assay kits. The morphology, stemness, proliferation, and differentiation of TSCs grown in L-PRP and P-PRP were examined by microscopy, immunocytochemistry, population doubling time, quantitative real-time polymerase chain reaction, and histological analysis. Results: L-PRP produced lower levels of growth factors, such as vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming growth factor (TGF)–β1, and platelet-derived growth factor (PDGF), than did P-PRP. TSC proliferation was significantly decreased in L-PRP in a concentration-dependent manner. Furthermore, TSCs cultured in P-PRP produced more collagen and formed tendon-like tissue; however, TSCs grown in L-PRP differentiated into nontenocytes and produced more inflammatory factors such as membrane-associated prostaglandin synthase (mPGES) and interleukin (IL)–1β. Moreover, L-PRP was associated with increased apoptosis. Conclusion: L-PRP has harmful effects on TSCs. Clinical Relevance: This study revealed the direct effects of different compositions of PRP on TSCs and provided basic scientific data to help understand the cellular and molecular mechanisms of the efficacy of PRP treatment in clinical use.

A new strategy for the decellularisation of large equine tendons as biocompatible tendon substitutes.

Tendon ruptures and/or large losses remain to be a great clinical challenge and often require full replacement of the damaged tissue. The use of auto- and allografts or engineered scaffolds is an established approach to restore severe tendon injuries. However, these grafts are commonly related to scarce biocompatibility, site morbidity, chronic inflammation and poor biomechanical properties. Recently, the decellularisation techniques of allo- or xenografts using specific detergents have been studied and have been found to generate biocompatible substitutes that resemble the native tissue. This study aims to identify a novel decellularisation protocol for large equine tendons that would produce an extracellular matrix scaffold suitable for the regeneration of injured tendons in humans. Specifically, equine tendons were treated either with tri (n-butyl) phosphate alone, or associated to multiple concentrations of peracetic acid (1, 3 and 5%), which has never before been tested in vitro.Samples were then analysed by histology and with biochemical, biomechanical, and cytotoxicity tests. The best decellularisation protocol, resulting from these examinations, was selected and the chosen scaffold was re-seeded with murine fibroblasts. Resulting grafts were tested for cell viability, histologic analysis, DNA and collagen content. The results identified 1% tri (n-butyl) phosphate combined with 3% peracetic acid as the most suitable decellularised matrix in terms of biochemical and biomechanical properties. Moreover, the non-cytotoxic nature of the decellularised matrix allowed for good fibroblast reseeding, thus demonstrating a biocompatible matrix that will be suitable for tendon tissue engineering and hopefully as substitutes in severe tendon damages.

Mechano-growth factor E peptide promotes healing of rat injured tendon

To determine the possible beneficial effects of a synthetic mechano-growth factor E peptide (MGF-C25E) on the healing of rat Achilles tendon. A significantly increased Achilles functional index was found in the MGF-C25E-treated tendons relative to the saline-treated tendons. Macroscopic observation showed that the repair of MGF-C25E-treated (1000ng/ml) tendons was superior to that of the saline-treated tendons. The mean value of the stiffness of the repaired tendons was significantly increased in the MGF-C25E-treated (1000ng/ml) tendons relative to the saline-treated tendons. Moreover, histological analysis provided evidence of tissue remodeling and cell alignment. MGF-C25E plays an important role in promoting healing of injured rat tendon and could be used as a potential therapeutic factor for tendon repair.

Scaffold-free Scleraxis-programmed tendon progenitors aid in significantly enhanced repair of full-size Achilles tendon rupture.

Currently there is no effective approach to enhance tendon repair, hence we aimed to identify a suitable cell source for tendon engineering utilizing an established clinically relevant animal model for tendon injury. We compared, by in-depth histomorphometric evaluation, the regenerative potential of uncommitted human mesenchymal stem cells (hMSC) and Scleraxis (Scx)-programmed tendon progenitors (hMSC-Scx) in the healing of a full-size of rat Achilles tendon defect. Our analyses clearly demonstrated that implantation of hMSC-Scx, in contrast to hMSC and empty defect, results in smaller diameters, negligible ectopic calcification and advanced cellular organization and matrix maturation in the injured tendons. Scaffold-free delivery of hMSC-Scx aids in enhanced repair in a clinically translatable Achilles tendon injury model.

Hypoxia enhances tenocyte differentiation of adipose-derived mesenchymal stem cells by inducing hypoxia-inducible factor-1α in a co-culture system.

Tissue engineering is a promising approach for repair of tendon injuries. Adipose-derived mesenchymal stem cells (ADMSCs) have gained increasing research interest for their potential in improving healing and regeneration of injured tendons. The present study aimed to investigate effects of O2 tension and potential signalling pathways on AMDSC differentiation into tenocytes, in an indirect co-culture system. Human ADMSCs were co-cultured under normoxia (20% O2 ) and also under hypoxia (2% O2 ). Tenocyte differentiation of AMDSCs and expression of hypoxia-inducible factor-1 (HIF-1α) were analysed by reverse transcription-PCR, Western blotting and immunohistochemistry. Furthermore, HIF-1α inhibitor and inducer (FG-4592) effects on differentiation of AMDSCs were studied using qPCR, immunofluorescence and Western blotting. Indirect co-culture with tenocytes increased differentiation of ADMSCs into tenocytes; furthermore, hypoxia further enhanced tenocyte differentiation of AMDSCs, accompanied by increased expression of HIF-1α. HIF-1α inhibitor attenuated effects of hypoxia on differentiation of ADMSCs; in contrast, FG-4592 increased differentiation of ADMSCs under both hypoxia and normoxia. Taken together, we found that growing ADMSCs under hypoxia, or activating expression of HIF-1α to be important in differentiation of ADMSCs, which provides a foundation for application of ADMSCs in vivo for tendon regeneration.

Low-level laser therapy modulates pro-inflammatory cytokines after partial tenotomy.

Tendon injuries give rise to substantial morbidity, and current understanding of the mechanisms involved in tendon injury and repair is limited. This lesion remains a clinical issue because the injury site becomes a region with a high incidence of recurrent rupture and has drawn the attention of researchers. We already demonstrated that low-level laser therapy (LLLT) stimulates the synthesis and organization of collagen I, MMP-9, and MMP-2 and improved the gait recovery of the treated animals. The aim of this study was to evaluate the effects of LLLT in the nitric oxide and cytokines profile during the inflammatory and remodeling phases. Adult male rats were divided into the following groups: G1--intact, G2-- injured, G3--injured + LLLT (4 J/cm(2) continuous), G4--injured + LLLT (4 J/cm(2)-20 Hz--pulsed laser). According to the analysis, the animals were euthanized on different dates (1, 4, 8, or 15 days after injury). ELISA assay of TNF-α, IL-1β, IL-10, and TGF-β was performed. Western blotting of isoform of nitric oxide synthase (i-NOS) and nitric oxide dosage experiments was conducted. Our results showed that the pulsed LLLT seems to exert an anti-inflammatory effect over injured tendons, with reduction of the release of proinflammatory cytokines, such as TNF-α and the decrease in the i-NOS activity. Thanks to the pain reduction and the facilitation of movement, there was a stimulation in the TGF-β and IL-1β release. In conclusion, we believe that pulsed LLLT worked effectively as a therapy to reestablish the tendon integrity after rupture.

Multilayered polycaprolactone/gelatin fiber-hydrogel composite for tendon tissue engineering

Regeneration of injured tendon and ligament (T&L) remains a clinical challenge due to their poor intrinsic healing capacity. Tissue engineering provides a promising alternative treatment approach to facilitate T&L healing and regeneration. Successful tendon tissue engineering requires the use of three-dimensional (3D) biomimetic scaffolds that possess the physical and biochemical features of native tendon tissue. We report here the development and characterization of a novel composite scaffold fabricated by co-electrospinning of poly-ε-caprolactone (PCL) and methacrylated gelatin (mGLT). We found that photocrosslinking retained mGLT, resulted in a uniform distribution of mGLT throughout the depth of scaffold and also preserved scaffold mechanical strength. Moreover, photocrosslinking was able to integrate stacked scaffold sheets to form multilayered constructs that mimic the structure of native tendon tissues. Importantly, cells impregnated into the constructs remained responsive to topographical cues and exogenous tenogenic factors, such as TGF-β3. The excellent biocompatibility and highly integrated structure of the scaffold developed in this study will allow the creation of a more advanced tendon graft that possesses the architecture and cell phenotype of native tendon tissues. Statement of SignificanceThe clinical challenges in tendon repair have spurred the development of tendon tissue engineering approaches to create functional tissue replacements. In this study, we have developed a novel composite scaffold as a tendon graft consisting of aligned poly-ε-caprolactone (PCL) microfibers and methacrylated gelatin (mGLT). Cell seeding and photocrosslinking between scaffold layers can be performed simultaneously to create cell impregnated multilayered constructs. This cell-scaffold construct combines the advantages of PCL nanofibrous scaffolds and photocrosslinked gelatin hydrogels to mimic the structure, mechanical anisotropy, and cell phenotype of native tendon tissue. The scaffold engineered here as a building block for multilayer constructs should have applications beyond tendon tissue engineering in the fabrication of tissue grafts that consist of both fibrous and hydrogel components.

Effect of transforming growth factor-β3 on the expression of Smad3 and Smad7 in tenocytes.

Tendon adhesion is a common problem in the healing of injured tendons. The molecular mechanisms of the TGF-β/Smad signaling pathway have been determined, and the role of TGF-β has been well characterized in wound healing. However, the intracellular mechanism or downstream signals by which TGF-β3 modulates its effects on tendon healing have not been well elucidated. The aim of this study was to determine the effect of TGF‑β3 on the TGF-β/Smad signaling pathway in tenocytes. Quantitative polymerase chain reaction and western blot analysis were used to analyze the effect of TGF‑β3 on the regulation of the expression of Smad proteins in tenocytes. The results demonstrated that TGF‑β3 has no significant effect on the proliferation of tendon cells. The addition of TGF‑β3 to tenocytes can significantly downregulate the expression of Smad3 and upregulate the expression of Smad7 at the gene and protein levels. The results demonstrate that TGF‑β3 may regulate Smad3 and Smad7 proteins through the TGF-β/Smad signaling pathway to minimize extrinsic scarring. Thus, it may provide a novel approach to decrease tendon adhesion and promote tendon healing.

Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model

Ectopic tendon mineralization can develop following tendon rupture or trauma surgery. The pathogenesis of ectopic tendon mineralization and its clinical impact have not been fully elucidated yet. In this study, we utilized a mouse Achilles tendon injury model to determine whether ectopic tendon mineralization alters the biomechanical properties of the tendon and whether BMP signaling is involved in this condition. A complete transverse incision was made at the midpoint of the right Achilles tendon in 8-week-old CD1 mice and the gap was left open. Ectopic cartilaginous mass formation was found in the injured tendon by 4weeks post-surgery and ectopic mineralization was detected at 8 to 10weeks post-surgery. Ectopic mineralization grew over time and volume of the mineralized materials of 25-weeks samples was about 2.5 fold bigger than that of 10-weeks samples, indicating that injury-induced ectopic tendon mineralization is progressive. In vitro mechanical testing showed that max force, max stress and mid-substance modulus in the 25-weeks samples were significantly lower than the 10-weeks samples. We observed substantial increases in expression of bone morphogenetic protein family genes in injured tendons 1week post-surgery. Immunohistochemical analysis showed that phosphorylation of both Smad1 and Smad3 was highly increased in injured tendons as early as 1week post-injury and remained high in ectopic chondrogenic lesions 4-weeks post-injury. Treatment with the BMP receptor kinase inhibitor (LDN193189) significantly inhibited injury-induced tendon mineralization. These findings indicate that injury-induced ectopic tendon mineralization is progressive, involves BMP signaling and associated with deterioration of tendon biomechanical properties.

Tendon Homeostasis in Hypercholesterolemia.

Hypercholesterolemia is a serious health problem that is associated not only with heart disease, but also tendon pathology. In high cholesterol environments (e.g. familial hyperlipidemia), lipids accumulate within the tendon extracellular matrix and form deposits called xanthomas. Lipid-related changes are known to affect several tendon mechanical properties, including stiffness and modulus, in uninjured and injured tendons, alike. Mechanisms to explain these cholesterol-related changes are multiple, including alterations in tenocyte gene and protein expression, matrix turnover, tissue vascularity, and cytokine production. Clinically, rotator cuff tear and Achilles tendon rupture are clearly associated with metabolic derangements, and elevated total cholesterol is often among the specific metabolic parameters implicated. Treatment of hypercholesterolemia using statin medications has also been shown to affect tendon properties, resulting in normalization of tendon thickness and improved tendon healing. Despite current work, the pathophysiology of lipid-related tendon pathology remains incompletely understood, and additional hypothesis-generating studies, including those incorporating whole-genome and whole-transcriptome technologies, will help to point the field in new directions.

Tendon Stem Cells: Mechanobiology and Development of Tendinopathy.

Millions of people suffer from tendon injuries in both occupational and athletic settings. However, the restoration of normal structure and function to injured tendons still remains as one of the greatest challenges in orthopaedics and sports medicine. In recent years, a remarkable advancement in tendon research field has been the discovery of tendon stem/progenitor cells (TSCs). Unlike tenocytes, the predominant resident cell in tendons, TSCs have the ability to self-renew and multi-differentiate. Because of these distinct properties, TSCs may play a critical role in tendon physiology as well as pathology such as tendinopathy, which is a prevalent chronic tendon injury. Additionally, because TSCs are tendon-specific stem cells, they could potentially be used in tendon tissue engineering in vitro, and serve as a promising cell sourcefor cell-based therapy to effectively repair or even regenerate injured tendons in clinical settings.

Evidence of healing of partial-thickness rotator cuff tears following arthroscopic augmentation with a collagen implant: a 2-year MRI follow-up.

partial-thickness rotator cuff tears frequently enlarge due to increased local strain and often progress to full-thickness tears. Studies suggest the addition of new tendinous tissue to injured cuff tendons would significantly decrease peak strain, possibly protecting against tear progression. The aim of this study was to assess the ability of a highly-porous collagen implant to induce new tissue formation and limit tear progression when placed on the bursal surface of partial-thickness cuff tears. following arthroscopic subacromial decompression, the implant was attached to the bursal surface of the supraspinatus tendon in a prospective series of 13 consecutive patients with intermediate - (3-6 mm) to high-grade (>6 mm) partial - thickness cuff tears (5 articular, 3 bursal, 5 intra-substance). Tendon thickness, defect size, and tendon quality were evaluated using magnetic resonance imaging (MRI) preoperatively and at 3, 6, 12, and 24 months postoperatively. Clinical outcomes were assessed using the Constant and American Shoulder and Elbow Society scores at the same preoperative and follow-up times. All 13 patients completed all follow-up exams (mean length of follow-up 27.0 months, range 23.3-32.0); no patients were lost to follow-up. the implant induced significant new tissue formation in all patients by 3 months (mean increase in tendon thickness 2.2 ± 0.26 mm). This tissue matured over time and became radiologically indistinguishable from the underlying tendon. The partial-thickness cuff tears showed consistent filling of the defects, with complete healing in 7 patients at 12 months, and a progressive improvement in tendon quality in the remaining patients. No tear progression was observed by MRI in any of the patients at 24 months. All clinical scores improved significantly over time. At 24 months, 12 of 13 patients (92%) had satisfactory or better results. the results of this clinical study demonstrated the ability of a highly-porous collagen implant to induce new tendon-like tissue formation and create an environment conductive to the healing of partial-thickness cuff tears.