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Background: The inhibition of IKKβ by the inhibitor 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-(4-piperidinyl)-3-pyridine carbonitrile (ACHP) is a promising strategy for the treatment of Achilles tendinopathy. However, the poor water solubility of ACHP severely hinders its in vivo application. Moreover, the effective local delivery of ACHP to the tendon and its therapeutic effects have not been reported., Purpose: To investigate the therapeutic effects of IKKβ inhibition via injection of ACHP incorporated into a DNA supramolecular hydrogel in a collagenase-induced tendinopathy rat model., Study Design: Controlled laboratory study., Methods: Dendritic DNA, a Y-shaped monomer, and a crosslinking monomer were mixed with ACHP and self-assembled into an ACHP-DNA supramolecular hydrogel (ACHP-Gel). The effects of ACHP-Gel in tendon stem/progenitor cells were investigated via RNA sequencing and validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A total of 120 collagenase-induced rats were randomly assigned to 5 groups: blank, phosphate-buffered saline (PBS), DNA-Gel, ACHP, and ACHP-Gel. Healing outcomes were evaluated using biomechanic and histologic evaluations at 4 and 8 weeks., Results: ACHP-Gel enhanced the solubility of ACHP and sustained its release for ≥21 days in vivo, which significantly increased the retention time of ACHP and markedly reduced the frequency of administration. RNA sequencing and qRT-PCR showed that ACHP effectively downregulated genes related to inflammation and extracellular matrix remodeling and upregulated genes related to tenogenic differentiation. The cross-sectional area ( P = .024), load to failure ( P = .002), stiffness ( P = .039), and elastic modulus ( P = .048) significantly differed between the ACHP-Gel and PBS groups at 8 weeks. The ACHP-Gel group had better histologic scores than the ACHP group at 4 ( P = .042) and 8 weeks ( P = .009). Type I collagen expression (COL-I; P = .034) and the COL-I/collagen type III ratio ( P = .015) increased while interleukin 6 expression decreased ( P < .001) in the ACHP-Gel group compared with the ACHP group at 8 weeks., Conclusion: DNA supramolecular hydrogel significantly enhanced the aqueous solubility of ACHP and increased its release-retention time. Injection frequency was markedly reduced. ACHP-Gel suppressed inflammation in Achilles tendinopathy and promoted tendon healing in a rat model., Clinical Relevance: ACHP-Gel injection is a promising strategy for the treatment of Achilles tendinopathy in clinical practice., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: This study was supported by the China Postdoctoral Science Foundation (2021TQ0225, 2021M702370); the Post-Doctor Research Project, West China Hospital of Sichuan University (2021HXBH065, 2019HXBH027, 2023HXBH106); and Program of Natural Science Foundation of Sichuan (2022NSFSC1559, 2022NSFSC1569, 2023NSFSC1835). AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto.

Tendinopathy is a common musculoskeletal system disorder in sports medicine, but regeneration ability of injury tendon is limited. Tendon stem cells (TSCs) have shown the definitive treatment evidence for tendinopathy and tendon injuries due to their tenogenesis capacity. Aspirin, as the representative of nonsteroidal anti-inflammatory drugs for its anti-inflammatory and analgestic actions, has been commonly used in treating tendinopathy in clinical, but the effect of aspirin on tenogenesis of TSCs is unclear. We hypothesized that aspirin could promote injury tendon healing through inducing TSCs tenogenesis. The aim of the present study is to make clear the effect of aspirin on TSC tenogenesis and tendon healing in tendinopathy, and thus provide new treatment evidence and strategy of aspirin for clinical practice. First, TSCs were treated with aspirin under tenogenic medium for 3, 7, and 14 days. Sirius Red staining was performed to observe the TSC differentiation. Furthermore, RNA sequencing was utilized to screen out different genes between the induction group and aspirin treatment group. Then, we identified the filtrated molecules and compared their effect on tenogenesis and related signaling pathway. At last, we constructed the tendinopathy model and compared biomechanical changes after aspirin intake. From the results, we found that aspirin promoted tenogenesis of TSCs. RNA sequencing showed that growth differentiation factor 6 (GDF6), GDF7, and GDF11 were upregulated in induction medium with the aspirin group compared with the induction medium group. GDF7 increased tenogenesis and activated Smad1/5 signaling. In addition, aspirin increased the expression of TNC, TNMD, and Scx and biomechanical properties of the injured tendon. In conclusion, aspirin promoted TSC tenogenesis and tendinopathy healing through GDF7/Smad1/5 signaling, and this provided new treatment evidence of aspirin for tendinopathy and tendon injuries., (© 2019 Wiley Periodicals, Inc.)

Achilles tendon injury is one of the challenges of sports medicine, the aetiology of which remains unknown. For a long time, estrogen receptor β (ERβ) has been known as a regulating factor of the metabolism in many connective tissues, such as bone, muscle and cartilage, but little is known about its role in tendon. Recent studies have implicated ERβ as involved in the process of tendon healing. Tendon-derived stem cells (TDSCs) are getting more and more attention in tendon physiological and pathological process. In this study, we investigated how ERβ played a role in Achilles tendon healing. Achilles tendon injury model was established to analyse how ERβ affected on healing process in vivo. Cell proliferation assay, Western blots, qRT-PCR and immunocytochemistry were performed to investigate the effect of ERβ on TDSCs. Here, we showed that ERβ deletion in mice resulted in inferior gross appearance, histological scores and, most importantly, increased accumulation of adipocytes during the early tendon healing which involved activation of peroxisome proliferator-activated receptor γ (PPARγ) signalling. Furthermore, in vitro results of ours confirmed that the abnormity might be the result of abnormal TDSC adipogenic differentiation which could be partially reversed by the treatment of ERβ agonist LY3201. These data revealed a role of ERβ in Achilles tendon healing for the first time, thereby providing a new target for clinical treatment of Achilles tendon injury., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Tendon injuries are common musculoskeletal system disorders in clinical, but the regeneration ability of tendon is limited. Tendon stem cells (TSCs) have shown promising effect on tissue engineering and been used for the treatment of tendon injury. Exosomes that serve as genetic information carriers have been implicated in many diseases and physiological processes, but effect of exosomes from TSCs on tendon injury repair is unclear. The aim of this study is to make clear that the effect of exosomes from TSCs on tendon injury healing. Exosomes were harvested from conditioned culture media of TSCs by a sequential centrifugation process. Rat Achilles tendon tendinopathy model was established by collagenase-I injection. This was followed by intra-Achilles-tendon injection with TSCs or exosomes. Tendon healing and matrix degradation were evaluated by histology analysis and biomechanical test at the post-injury 5 weeks. In vitro, TSCs treated with interleukin 1 beta were added by conditioned medium including exosomes or not, or by exosomes or not. Tendon matrix related markers and tenogenesis related markers were measured by immunostaining and western blot. We found that TSCs injection and exosomes injection significantly decreased matrix metalloproteinases (MMP)-3 expression, increased expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) and Col-1a1, and increased biomechanical properties of the ultimate stress and maximum loading. In vitro, conditioned medium with exosomes and exosomes also significantly decreased MMP-3, and increased expression of tenomodulin, Col-1a1 and TIMP-3. Exosomes from TSCs could be an ideal therapeutic strategy in tendon injury healing for its balancing tendon extracellular matrix and promoting the tenogenesis of TSCs., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

BACKGROUND The aim of this study was to determine whether the local application of tendon stem cells (TSCs) with chitosan/β-glycerophosphate/collagen(C/GP/Co) hydrogel promotes healing after an acute Achilles tendon injury in a rat model. MATERIAL AND METHODS Ninety-six Sprague-Dawley (SD) rats were used to make an Achilles tendon defect model, then the animals were randomly divided into 4 groups consisting of 8 rats each: control group, hydrogel group, TSCs group, and TSCs with hydrogel group. At 2, 4, and 6 weeks after treatment, tendon samples were harvested, and the quality of tendon repair was evaluated based on histology, immunohistochemistry, and biomechanical properties. RESULTS Combining TSCs with C/GP/Co hydrogel significantly enhances tendon healing compared with the control, hydrogel, and TSCs groups. The improved healing was indicated by the improvement in histological and immunohistochemistry outcomes and the increase in the biomechanical properties of the regenerated tissue at both 4 and 6 weeks post-injury. CONCLUSIONS This study demonstrates that the transplantation of TSCs combined with C/GP/Co hydrogel significantly improved the histological, immunohistochemistry, and biomechanical outcomes of the regenerated tissue at 4 and 6 weeks after implantation. TSCs with C/GP/Co hydrogel is a potentially effective treatment for tendon injury.

Objective: To explore the effect of different intensity treadmill training on the repair of micro-injured Achilles tendon induced by collagenase in rats., Methods: Seventy-two 8-week-old male Sprague Dawley rats (weighing, 200-250 g) were selected. After adaptive treadmill training for 1 week, rats were injected with 30 μL type I collagenase solution (10 mg/mL) into both Achilles tendons to make micro-injured Achilles tendon models. After 1 week of cage feeding, the rats were randomly divided into 3 groups: the control group, the low-intensity group, and the high-intensity group, 24 rats each group. The rats in control group could move freely, and the rats underwent daily treadmill training at the intensity of 13 m/min and 20 min/d in the low-intensity group and at the intensity of 17 m/min and 60 min/d in the high-intensity group. At immediate, 1 week, and 4 weeks after training, bilateral Achilles tendons were collected from 8 rats of each group for gross observation, histological analysis, and mechanical testing., Results: At immediate after training, there was no significant difference in the gross observation, histological observation, and biomechanical properties of the Achilles tendon between groups ( P >0.05). The gross observation showed connective tissue hyperplasia near Achilles tendon and lackluster tendon in each group at 1 week; hyperplasia significantly reduced in the low-intensity group when compared with the control group, and there were more connective tissue and a large number of neovascularization in the high-intensity group at 4 weeks. At 1 week, there was no significant difference in the semi-quantitative histological total score between groups ( P >0.05), but there were significant differences in vascularity between low-intensity group or high-intensity group and control group ( P <0.05). At 4 weeks, the semi-quantitative histological total score was significantly higher in high-intensity group than control group and low-intensity group ( P <0.05), and in control group than low-intensity group ( P <0.05). There were significant differences in collagen arrangement, cell morphology, abnormal cells, and vascularity between low-intensity group and high-intensity group or control group ( P <0.05). And there was significant difference in abnormal cells between high-intensity group and control group ( P <0.05). The mechanical testing showed that there was no significant difference in cross-sectional area of the Achilles tendon, the ultimate force, tensile strength, and elastic modulus between groups at 1 week ( P >0.05); the low-intensity group was significantly higher than the control group in the ultimate force and the tensile strength ( P <0.05), and than high-intensity group in the ultimate force and elastic modulus ( P <0.05), but no significant difference was found in the other indexes between groups ( P >0.05) at 4 weeks., Conclusion: Low-intensity treadmill training can promote the repair of rat micro-injured Achilles tendon induced by collagenase.

Purpose. Tendon injuries are common musculoskeletal system disorders, but the ability for tendon regeneration is limited. Silk fibroin (SF) film may be suitable for tendon regeneration due to its excellent biocompatibility and physical properties. This study is aimed at evaluating the application value of bionic SF film in tendon regeneration. Methods. Tendon stem/progenitor cells (TSPCs) were isolated from rat Achilles tendon and characterized based on their surface marker expression and multilineage differentiation potential. SF films with smooth or bionic microstructure surfaces (5, 10, 15, 20 μm) were prepared. The morphology and mechanical properties of natural tendons and SF films were characterized. TSPCs were used as the seed cells, and the cell viability and cell adhesion morphology were analyzed. The tendongenesis-related gene expression of TSPCs was also evaluated using quantitative polymerase chain reaction. Results. Compared to the native tendon, only the 10, 15, and 20 μm SF film groups had comparable maximum loading and ultimate stress, with the exception of the breaking elongation rate. The 10 μm SF film group had the highest percentage of oriented cells and the most significant changes in cell morphology. The most significant upregulations in the expression of COL1A1, TNC, TNMD, and SCX were also observed in the 10 μm SF film group. Conclusion. SF film with a bionic microstructure can serve as a tissue engineering scaffold and provide biophysical cues for the use of TSPCs to achieve proper cellular adherence arrangement and morphology as well as promote the tenogenic differentiation of TSPCs, making it a valuable customizable biomaterial for future applications in tendon repair. [ABSTRACT FROM AUTHOR]

Achilles tendon healing (ATH) remains an unanswered question in the field of sports medicine because it does not produce tissue with homology to the previously uninjured tissue. Oestrogen receptor β (ERβ) is involved in the injury and repair processes of tendons. Our previous study confirmed that ERβ plays a role in the early stage of ATH by affecting adipogenesis, but its role in extracellular matrix (ECM) remodelling is unknown. We established a 4‐week Achilles tendon repair model to investigate the mechanism through which ERβ affects ATH at the very beginning of ECM remodelling phase. In vitro studies were performed using tendon‐derived stem cells (TDSCs) due to their promising role in tendon healing. Behavioural and biomechanical tests revealed that ERβ‐deficient mice exhibit weaker mobility and inferior biomechanical properties, and immunofluorescence staining and qRT‐PCR showed that these mice exhibited an erroneous ECM composition, as mainly characterized by decreased collagen type I (Col I) deposition. The changes in gene expression profiles between ERβ‐knockout and WT mice at 1 week were analysed by RNA sequencing to identify factors affecting Col I deposition. The results highlighted the IRF5‐CCL3 axis, and this finding was verified with CCL3‐treated TDSCs. These findings revealed that ERβ regulates Col I deposition during ATH via the IRF5‐CCL3 axis. [ABSTRACT FROM AUTHOR]