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Joint diseases greatly impact the daily lives and occupational functioning of patients globally. However, conventional treatments for joint diseases have several limitations, such as unsatisfatory efficacy and side effects, necessitating the exploration of more efficacious therapeutic strategies. Mesenchymal stem cell (MSC)-derived EVs (MSC-EVs) have demonstrated high therapeutic efficacyin tissue repair and regeneration, with low immunogenicity and tumorigenicity. Recent studies have reported that EVs-based therapy has considerable therapeutic effects against joint diseases, including osteoarthritis, tendon and ligament injuries, femoral head osteonecrosis, and rheumatoid arthritis. Herein, we review the therapeutic potential of various types of MSC-EVs in the aforementioned joint diseases, summarise the mechanisms underlying specific biological effects of MSC-EVs, and discuss future prospects for basic research on MSC-EV-based therapeutic modalities and their clinical translation. In general, this review provides an in-depth understanding of the therapeutic effects of MSC-EVs in joint diseases, as well as the underlying mechanisms, which may be beneficial to the clinical translation of MSC-EV-based treatment. The translational potential of this article: MSC-EV-based cell-free therapy can effectively promote regeneration and tissue repair. When used to treat joint diseases, MSC-EVs have demonstrated desirable therapeutic effects in preclinical research. This review may supplement further research on MSC-EV-based treatment of joint diseases and its clinical translation.

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Tendons and ligaments, crucial components of the musculoskeletal system, connect muscles to bones. In the realm of sports, tendons and ligaments are vulnerable tissues with injuries such as Achilles tendon rupture and anterior cruciate ligament tears directly impacting an athlete's career. Furthermore, repetitive trauma and tissue degeneration can lead to conditions like secondary osteoarthritis, ultimately affecting the overall quality of life. Recent research highlights the pivotal role of mechanical stress in maintaining homeostasis within tendons and ligaments. This review delves into the latest insights on the structure of tendons and ligaments and the plasticity of tendon tissue in response to mechanical loads.

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INTRODUCTION: Tendon and ligament injuries are a frequent and debilitating issue that affects many patients worldwide. The predominant solution is the suture thread, which is not without potential side effects and limitations. Implantable medical devices have gained more attention as an alternative approach. However, due to the many challenges of the inner body environment (limited available space, chemically aggressive environment, etc), the development of suitable devices is not exempt from practical and technical difficulties. AREAS COVERED: Here, implantable medical devices for tendon and ligaments injuries are reviewed and discussed. Commercially-available products and registered patents are all considered as long as they fit the standard definitions of 'implantable medical devices' (reported in the Introduction). The research was then narrowed down to five commercial products, deemed as the most representative of the whole market. Their effectiveness and performance are analysed, as well as the possible areas of improvement and development. EXPERT OPINION: Commercially available products present overall superior mechanical performances than suture techniques. Nevertheless, these latter ones might be still preferred for their wider range of customization. This aspect, and many others, could represent an area of improvement for implantable medical devices, to further explore their potential for tendon and ligament repair.

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Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) have shown potential for the treatment of tendon and ligament injuries. This approach can eliminate the need to transplant live cells to the human body, thereby reducing issues related to the maintenance of cell viability and stability and potential erroneous differentiation of transplanted cells to bone or tumor. Despite these advantages, there are practical issues that need to be considered for successful clinical application of MSC-EV-based products in the treatment of tendon and ligament injuries. This review aims to discuss the general and tissue-specific considerations for manufacturing MSC-EVs for clinical translation. Specifically, we will discuss Good Manufacturing Practice (GMP)-compliant manufacturing and quality control (parent cell source, culture conditions, concentration method, quantity, identity, purity and impurities, sterility, potency, reproducibility, storage and formulation), as well as safety and efficacy issues. Special considerations for applying MSC-EVs, such as their compatibility with arthroscopy for the treatment of tendon and ligament injuries, are also highlighted.

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Human Microphysiological Systems (hMPS), otherwise known as organ- and tissue-on-a-chip models, are an emerging technology with the potential to replace in vivo animal studies with in vitro models that emulate human physiology at basic levels. hMPS platforms are designed to overcome limitations of two-dimensional (2D) cell culture systems by mimicking 3D tissue organization and microenvironmental cues that are physiologically and clinically relevant. Unlike animal studies, hMPS models can be configured for high content or high throughput screening in preclinical drug development. Applications in modeling acute and chronic injuries in the musculoskeletal system are slowly developing. However, the complexity and load bearing nature of musculoskeletal tissues and joints present unique challenges related to our limited understanding of disease mechanisms and the lack of consensus biomarkers to guide biological therapy development. With emphasis on examples of modeling musculoskeletal tissues, joints on chips, and organoids, this review highlights current trends of microphysiological systems technology. The review surveys state-of-the-art design and fabrication considerations inspired by lessons from bioreactors and biological variables emphasizing the role of induced pluripotent stem cells and genetic engineering in creating isogenic, patient-specific multicellular hMPS. The major challenges in modeling musculoskeletal tissues using hMPS chips are identified, including incorporating biological barriers, simulating joint compartments and heterogenous tissue interfaces, simulating immune interactions and inflammatory factors, simulating effects of in vivo loading, recording nociceptors responses as surrogates for pain outcomes, modeling the dynamic injury and healing responses by monitoring secreted proteins in real time, and creating arrayed formats for robotic high throughput screens. Overcoming these barriers will revolutionize musculoskeletal research by enabling physiologically relevant, predictive models of human tissues and joint diseases to accelerate and de-risk therapeutic discovery and translation to the clinic.

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Tendon and ligament tissues provide stability and mobility crucial for musculoskeletal function, but are particularly prone to injury. Owing to poor innate healing capacity, the regeneration of mature and functional tendon/ligament (T/L) poses a formidable clinical challenge. Advanced bioengineering strategies to develop biomimetic tissue implants are highly desired for the treatment of T/L injuries. Here, we presented a cell-based tissue engineering strategy to generate cell-laden tissue constructs comprising stem cells and tissue-specific bioinks using 3D cell-printing technology. We implemented anin vitropreconditioning approach to guide semi-organized T/L-like formation before thein vivoapplication of cell-printed implants. Duringin vitromaturation, tissue-specific decellularized extracellular matrix-based cellular constructs facilitated long-termin vitroculture with high cell viability and promoted tenogenesis with enhanced cellular/structural anisotropy. Moreover, we demonstrated improved cell survival/retention uponin vivoimplantation of pre-matured constructs in nude mice with de novo tendon formation and improved mechanical strength. Althoughin vivomechanical properties of the cell-printed implants were lower than those of human T/L tissues, the results of this study may have significant implications for future cell-based therapies in tendon and ligament regeneration and translational medicine.

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Many disorders affect the equine foot, and many hoof problems have multiple predisposing causes. Surgery may be necessary after conservative management has failed. Diseases of the hoof capsule may seem simple, but their effect on performance can be long-lasting and healing is often prolonged. Diagnosis of problems within the hoof capsule is enhanced with the use of computed tomography and MRI. The prognosis of fractures has improved with strategic placement of lag screws across fracture planes using aiming devices and advanced intraoperative imaging techniques. Collaboration between the clinician and a skilled farrier is important for successful management of hoof disorders.

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The problem of tendon and ligament (T/L) regeneration in musculoskeletal diseases has long constituted a major challenge. In situ injection of formable biodegradable hydrogels, however, has been demonstrated to treat T/L injury and reduce patient suffering in a minimally invasive manner. An injectable hydrogel is more suitable than other biological materials due to the special physiological structure of T/L. Most other materials utilized to repair T/L are cell-based, growth factor-based materials, with few material properties. In addition, the mechanical property of the gel cannot reach the normal T/L level. This review summarizes advances in natural and synthetic polymeric injectable hydrogels for tissue engineering in T/L and presents prospects for injectable and biodegradable hydrogels for its treatment. In future T/L applications, it is necessary develop an injectable hydrogel with mechanics, tissue damage-specific binding, and disease response. Simultaneously, the advantages of various biological materials must be combined in order to achieve personalized precision therapy.

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INTRODUCTION: Sport injuries, most of the time affect muscles, tendons, ligaments, cartilage and bones and range from very mild to severe, prompting different therapeutic approaches. Overuse is the most common cause of sports injuries and half of those injuries affect tendon, tendon sheet and tendon insertion to the bone. The number of ligament injuries, particularly anterior cruciate ligament (ACL) increasing. AIM: We were searching PubMed, Google Scholar and Medline focusing on human clinical studies related to stem cell therapy for tendinopathies and ligament injuries. Considering small number of published articles, we accepted papers with all level of evidence without following strict PRISMA guidelines. RESULTS: The number of studies related to ligament injuries is very low compared to tendon injuries. In human clinical trials there have been only a few studies published so far. In double blind randomized control trial (RCT) Wang and coauthors combined allogenic precursor mesenchymal stem cells (MPC) with hyaluronic acid (HA) and compared with hyaluronic acid alone in 17 patients underwent ACL reconstruction. Intensity of pain and quality of life were assessed by Knee Injury and Osteoarthritis Outcome Score (KOOS) and SF-36v2 scores. A width of joint space, volume of cartilage and bone were recorded by magnetic resonance imaging (MRI). Moderate arthralgia and swelling were detected within 24 hours after the injection in 4 out of 11 patients in the group receiving MSC+HA. In the group receiving only HA, there were no adverse reactions. The signs of slowing down of regenerative process were presented on MRI by preserving joint space and reducing degradation of cartilage volume. CONCLUSION: Clinical application of MSCs for treatment of tendon and ligament injuries might be good alternative option for athletes. Published clinical studies confirmed clinical improvement and integrity of impaired tissues. However, RTCs are needed to confirm real potential of cell therapy and their advantages comparing to other treatment options.

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Repair of ligaments and tendons requires scaffolds mimicking the spatial organisation of collagen in the natural tissue. Electrospinning is a promising technique to produce nanofibres of both resorbable and biostable polymers with desired structural and morphological features. The aim of this study was to perform high-resolution x-ray tomography (XCT) scans of bundles of Nylon6.6, pure PLLA and PLLA-Collagen blends, where the nanofibres were meant to have a predominant direction. Characterisation was carried out via a dedicated methodology to firmly hold the specimen during the scan and a workflow to quantify the directionality of the nanofibres in the bundle. XCT scans with 0.4 and 1.0 µm voxel size were successfully collected for all bundle compositions. Better image quality was achieved for those bundles formed by thicker nanofibres (i.e. 0.59 µm for pure PLLA), whereas partial volume effect was more pronounced for thinner nanofibres (i.e. 0.26 µm for Nylon6.6). As expected, the nanofibres had a predominant orientation along the axis of the bundles (more than 20% of the nanofibres within 3° and more than 60% within 18° from the bundle axis), with a Gaussian-like dispersion in the other directions. The directionality assessment was validated by comparison against a similar analysis performed on SEM images: the XCT analysis overestimated the amount of nanofibres very close to the bundle axis, especially for the materials with thinnest nanofibres, but adequately identified the amount of nanofibres within 12°. LAY DESCRIPTION: Repair of ligaments and tendons requires dedicated materials (scaffolds) mimicking the spatial organisation of the collagen (the main material composing such natural tissue). Electrospinning is a promising technique that allows production of fibres with nanometric dimension using high voltage to stretch very tiny drops of polymeric solutions. Electrospinning allows processing both polymers that can be resorbed by the host tissue, and nonresorbable ones, to obtain the desired structural and morphological features by arranging the nanofibres in bundles. The aim of this study was to perform high-resolution x-ray computed tomography (XCT) scans of bundles, where the nanofibres were meant to have a predominant direction. The investigation included bundles of different compositions: a biostable polymer (Nylon) and bioresorbable ones (pure Poly-L-lactic acid (PLLA) and PLLA-Collagen blends). The electrospun bundles were produced using a validated method (Sensini et al 2017: https://doi.org/10.1088/1758-5090/aa6204). To this end, we developed a dedicated methodology to scan such small specimens, and a workflow to quantify the directionality of the nanofibres in the bundle. For all the compositions, XCT scans with extremely high resolution (i.e. down to 0.4 µm) were successfully collected. As expected, better images were obtained for those bundles where the nanofibres were thicker than the scanning resolution (i.e. 0.59 µm for pure PLLA). The images of the thinnest nanofibres (i.e. 0.26 µm for Nylon) were poorer because the fibre diameter was smaller than the resolution (partial volume effect). The nanofibres had a predominant orientation along the axis of the bundles (more than 60% of the nanofibres were within 18° from the bundle axis). The nanofibres had a Gaussian-like dispersion in the other directions. As this is the first time that XCT is used to quantify the directionality of this kind of bundles, the directionality assessment was further validated by comparison against a similar analysis performed on SEM images. Overall, this study has demonstrated the usefulness and reliability of using high-resolution x-ray computed tomography (XCT) scans to investigate the morphology of polymeric scaffolds made of electrospun nanofibres.

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Tendons and ligaments play essential roles in connecting muscle and bone and stabilizing the connections between bones. The damage to tendons and ligaments caused by aging, injury, and arthritis induces the dysfunction of the musculoskeletal system and reduces the quality of life. Current therapy for damaged tendons and ligaments depends on self-repair; however, it is difficult to reconstruct normal tissue. Regeneration therapy for tendons and ligaments has not been achieved, partly because the mechanism, cell biology, and pathophysiology of tendon and ligament development remain unclear. This review summarizes the role of the transcription factor, Mohawk, which controls tendon and ligament cell differentiation, in the maintenance of cell homeostasis, as well as its function in disease and the possibility of new therapeutic approaches.

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The rs12722 polymorphism in COL5A1 gene has been implicated in the etiology of musculoskeletal soft tissue injuries in several association studies with limited sample size and conflicting results. The purpose of the present systematic review and meta-analysis was to evaluate and synthesize the currently available data on the association between rs12722 and musculoskeletal soft tissue injuries. Five electronic databases including Pubmed, EMBASE, ISI Web of Science, CNKI and Wanfang were searched to identify relevant studies published before 15 May, 2017. Summary odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were estimated using the RevMan 5.3 software. Nine studies comprising 1140 cases and 1410 healthy controls met the eligibility criteria. Recessive model was confirmed to be the optimum model (TT vs TC + CC). The results indicated that rs12722 SNP was significantly associated with musculoskeletal soft tissue injuries (OR 1.58, 95% CI 1.33, 1.89; P < 0.00001). When stratified by injury sites, modest but statistically significant association was found in Achilles tendon pathology (ATP), anterior cruciate ligament injuries (ACLI) and tennis elbow (TE). Subgroup-analysis by ethnicity suggested that TT genotype of rs12722 was associated with tendon and ligament injuries in Caucasians (OR 1.59, 95% CI 1.33, 1.90; P < 0.00001) but not in Asians (OR 1.46, 95% CI 0.46, 4.60; P = 0.52). Our findings indicated that rs12722 of COL5A1 was positively associated with tendon and ligament injuries, especially in Caucasian subjects. Individuals with TT genotype were predisposed to higher risk of ATP, ACLI and TE.

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It has been reported that the single nucleotide polymorphism (SNP) rs1800012 in COL1A1 might be associated with the susceptibility to sports-related tendon and ligament injuries such as ACL injuries, Achilles tendon injuries, shoulder dislocations and tennis elbow. But the data from different studies have been conflicting. Here we attempted to systematically summarize and clarify the association between the SNP and sports-related tendon and ligament injuries risk. Six eligible studies including 933 cases and 1,381 controls were acquired from PubMed, Web Of Science and Cochrane library databases. Significant association was identified in homozygote model (TT versus GG: OR=0.17, 95%CI 0.08-0.35, PH=0.00) and recessive model (TT versus GT/GG: OR=0.21, 95%CI 0.10-0.44, PH=0.00). Our results indicated that COL1A1 rs1800012 polymorphism may be associated with the reduced risk of sports-related tendon or ligament injuries, especially in ACL injuries, and that rare TT may played as a protective role.

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This review describes the normal healing process for bone, ligaments, and tendons, including primary and secondary healing as well as bone-to-bone fusion. It depicts the important mediators and cell types involved in the inflammatory, reparative, and remodeling stages of each healing process. It also describes the main challenges for clinicians when trying to repair bone, ligaments, and tendons with a specific emphasis on Charcot neuropathy, fifth metatarsal fractures, arthrodesis, and tendon sheath and adhesions. Current treatment options and research areas are also reviewed.

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Tendon and ligament injuries and degenerative conditions of these soft tissues have poor healing potential and healing is often incomplete. Biocellular and orthobiologic approaches including PRP and stem cell therapies are reviewed. A review of some of the regenerative medicine science and difficulties facing physicians exploring these methods is presented. A series of cases are reviewed demonstrating the application of these principles. Clinical experience with many of these biocellular interventions is outpacing validation in basic science studies. Clinical experience dictates the need for repeated clinical and imaging evaluation and the need for repeated intervention or change in strategies when needed.

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Economic and societal pressures influence modern medical practice to develop and implement prevention strategies. Anterior cruciate ligament (ACL) injury devastates the knee joint leading to short term disability and long term sequelae. Due to the high risk of long term osteoarthritis in all treatment populations following ACL injury, prevention is the only effective intervention for this life-altering disruption in knee health. The "Sequence of Prevention" Model provides a framework to monitor progress towards the ultimate goal of preventing ACL injuries. Utilizing this model, our multidisciplinary collaborative research team has spent the last decade working to delineate injury mechanisms, identify injury risk factors, predict which athletes are at-risk for injury, and develop ACL injury prevention programs. Within this model of injury prevention, modifiable factors (biomechanical and neuromuscular) related to injury mechanisms likely provide the best opportunity for intervention strategies aimed to decrease the risk of ACL injury, particularly in female athletes. Knowledge advancements have led to the development of potential solutions that allow athletes to compete with lowered risk of ACL injury. Design and integration of personalized clinical assessment tools and targeted prevention strategies for athletes at high risk for ACL injury may transform current prevention practices and ultimately significantly reduce ACL injury incidence. This 2016 OREF Clinical Research Award focuses on the authors' work and contributions to the field. The author's acknowledge the many research groups who have contributed to the current state of knowledge in the fields of ACL injury mechanisms, injury risk screening and injury prevention strategies. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1843-1855, 2016.

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Generalized arterial calcification of infancy (GACI), an autosomal recessive disorder caused by mutations in the ENPP1 gene, manifests with extensive mineralization of the cardiovascular system. A spontaneous asj-2J mutant mouse has been characterized as a model for GACI. Previous studies focused on phenotypic characterization of skin and vascular tissues. This study further examined the ectopic mineralization phenotype of cartilage, collagen-rich tendons and ligaments in this mouse model. The mice were placed on either control diet or the "acceleration diet" for up to 12 weeks of age. Soft connective tissues, such as ear (elastic cartilage) and trachea (hyaline cartilage), were processed for standard histology. Assessment of ectopic mineralization in articular cartilage and fibrocartilage as well as tendons and ligaments which are attached to long bones were performed using a novel cryo-histological method without decalcification. These analyses demonstrated ectopic mineralization in cartilages as well as tendons and ligaments in the homozygous asj-2J mice at 12 weeks of age, with the presence of immature osteophytes displaying alkaline phosphatase and tartrate-resistant acid phosphatase activities as early as at 6 weeks of age. Alkaline phosphatase activity was significantly increased in asj-2J mouse serum as compared to wild type mice, indicating increased bone formation rate in these mice. Together, these data highlight the key role of ENPP1 in regulating calcification of both soft and skeletal tissues.

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Tendon and ligament injuries (TLI) commonly occur in athletes and non-athletes alike, and remarkably debilitate patients' athletic and personal abilities. Current clinical treatments, such as reconstruction surgeries, do not adequately heal these injuries and often result in the formation of scar tissue that is prone to re-injury. Platelet-rich plasma (PRP) is a widely used alternative option that is also safe because of its autologous nature. PRP contains a number of growth factors that are responsible for its potential to heal TLIs effectively. In this review, we provide a comprehensive report on PRP. While basic science studies in general indicate the potential of PRP to treat TLIs effectively, a review of existing literature on the clinical use of PRP for the treatment of TLIs indicates a lack of consensus due to varied treatment outcomes. This suggests that current PRP treatment protocols for TLIs may not be optimal, and that not all TLIs may be effectively treated with PRP. Certainly, additional basic science studies are needed to develop optimal treatment protocols and determine those TLI conditions that can be treated effectively.

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BACKGROUND: Weightlessness is one of the important reasons to cause lower limb muscle atrophy of the astronauts, which is serious harm to the health of astronauts. OBJECTIVE: To explore the progress of weightlessness that cause lower limb muscle atrophy. METHODS: A computer-based online search of PubMed database and CNKI database was performed to search related articles between May 1981 and March 2013 with the key words of “weightless, weightlessness, muscle, atrophy, space” in English and Chinese, respectively. Literatures related to progress of weightlessness that cause lower limb muscle atrophy were selected; in the same field, the literatures published lately in authoritative journals were preferred. RESULTS AND CONCLUSION: A total of 409 literatures were primarily selected, and 47 documents were involved for summary according to the inclusion criteria. The progress of weightlessness that cause muscle atrophy is the hot topic among the space medical research. The main reasons that cause weightlessness muscular atrophy include the reduced muscle spindle neurotrophic factor synthesis caused by reduced information transmission of peripheral sensory nerve, damage of muscle cel ultrastructure, substantial decline in mitochondrial myofibrils, troponin decreasing, decreased intracel ular calcium content, and decreased antigravity muscle blood flow in lower limbs.