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    [Clinical management of rotator cuff tears. Current concepts in cell-based therapy strategies]. Ficklscherer A,Pietschmann M F,Bendiks M,Roßbach B P,Müller P E Der Orthopade Due to the increasing demand for functionality in an aging yet physically active society, the treatment of rotator cuff tears is of ever-growing importance. Despite intensive research efforts, the treatment of degenerative rotator cuff tears, in particular their long-term outcome, is still a challenge. While in recent years the focus was on biomechanics and the technical aspects of rotator cuff reconstruction, attention has now turned to the biological considerations of tendon regeneration. This article highlights the current state of biological rotator cuff augmentation in a clinical setting and provides an insight into and an outlook on the experimental procedures. 10.1007/s00132-015-3213-x
    The biology of rotator cuff healing. Zumstein M-A,Lädermann A,Raniga S,Schär M-O Orthopaedics & traumatology, surgery & research : OTSR Despite advances in surgical reconstruction of chronic rotator cuff (RC) tears leading to improved clinical outcomes, failure rates of 13-94% have been reported. Reasons for this rather high failure rate include compromised healing at the bone-tendon interface, as well as the musculo-tendinous changes that occur after RC tears, namely retraction and muscle atrophy, as well as fatty infiltration. Significant research efforts have focused on gaining a better understanding of these pathological changes in order to design effective therapeutic solutions. Biological augmentation, including the application of different growth factors, platelet concentrates, cells, scaffolds and various drugs, or a combination of the above have been studied. It is important to note that instead of a physiological enthesis, an abundance of scar tissue is formed. Even though cytokines have demonstrated the potential to improve rotator cuff healing in animal models, there is little information about the correct concentration and timing of the more than 1500 cytokines that interact during the healing process. There is only minimal evidence that platelet concentrates may lead to improvement in radiographic, but not clinical outcome. Using stem cells to biologically augment the reconstruction of the tears might have a great potential since these cells can differentiate into various cell types that are integral for healing. However, further studies are necessary to understand how to enhance the potential of these stem cells in a safe and efficient way. This article intends to give an overview of the biological augmentation options found in the literature. 10.1016/j.otsr.2016.11.003
    Orthobiologics in Pediatric Sports Medicine. Bray Christopher C,Walker Clark M,Spence David D The Orthopedic clinics of North America Orthobiologics are biological substances that allow injured muscles, tendons, ligaments, and bone to heal more quickly. They are found naturally in the body; at higher concentrations they can aid in the healing process. These substances include autograft bone, allograft bone, demineralized bone matrix, bone morphogenic proteins, growth factors, stem cells, plasma-rich protein, and ceramic grafts. Their use in sports medicine has exploded in efforts to increase graft incorporation, stimulate healing, and get athletes back to sport with problems including anterior cruciate ligament ruptures, tendon ruptures, cartilage injuries, and fractures. This article reviews orthobiologics and their applications in pediatric sports medicine. 10.1016/j.ocl.2017.03.006
    Biological Therapies in Regenerative Sports Medicine. Andia Isabel,Maffulli Nicola Sports medicine (Auckland, N.Z.) Regenerative medicine seeks to harness the potential of cell biology for tissue replacement therapies, which will restore lost tissue functionality. Controlling and enhancing tissue healing is not just a matter of cells, but also of molecules and mechanical forces. We first describe the main biological technologies to boost musculoskeletal healing, including bone marrow and subcutaneous fat-derived regenerative products, as well as platelet-rich plasma and conditioned media. We provide some information describing possible mechanisms of action. We performed a literature search up to January 2016 searching for clinical outcomes following the use of cell therapies for sports conditions, tendons, and joints. The safety and efficacy of cell therapies for tendon conditions was examined in nine studies involving undifferentiated and differentiated (skin fibroblasts, tenocytes) cells. A total of 54 studies investigated the effects of mesenchymal stem-cell (MSC) products for joint conditions including anterior cruciate ligament, meniscus, and chondral lesions as well as osteoarthritis. In 22 studies, cellular products were injected intra-articularly, whereas in 32 studies MSC products were implanted during surgical/arthroscopic procedures. The heterogeneity of clinical conditions, cellular products, and approaches for delivery/implantation make comparability difficult. MSC products appear safe in the short- and mid-term, but studies with a long follow-up are scarce. Although the current number of randomized clinical studies is low, stem-cell products may have therapeutic potential. However, these regenerative technologies still need to be optimized. 10.1007/s40279-016-0620-z
    The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration. Gibbons Michael C,Singh Anshuman,Engler Adam J,Ward Samuel R Journal of orthopaedic research : official publication of the Orthopaedic Research Society Rotator cuff (RC) muscles undergo several detrimental changes following mechanical unloading resulting from RC tendon tear. In this review, we highlight the pathological causes and consequences of mechanical alterations at the whole muscle, muscle fiber, and muscle resident cell level as they relate to RC disease progression. In brief, the altered mechanical loads associated with RC tear lead to architectural, structural, and compositional changes at the whole-muscle and muscle fiber level. At the cellular level, these changes equate to direct disruption of mechanobiological signaling, which is exacerbated by mechanically regulated biophysical and biochemical changes to the cellular and extra-cellular environment (also known as the stem cell "niche"). Together, these data have important implications for both pre-clinical models and clinical practice. In pre-clinical models, it is important to recapitulate both the atrophic and degenerative muscle loss found in humans using clinically relevant modes of injury. Clinically, understanding the mechanics and underlying biology of the muscle will impact both surgical decision-making and rehabilitation protocols, as interventions that may be good for atrophic muscle will have a detrimental effect on degenerating muscle, and vice versa. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:546-556, 2018. 10.1002/jor.23662
    Technologies to Augment Rotator Cuff Repair. Murthi Anand M,Lankachandra Manesha The Orthopedic clinics of North America Healing rates after rotator cuff repair vary widely. New technologies seek to improve tendon to bone healing with the addition of platelet-rich plasma, stem cells, and biological and synthetic grafts. Platelet-rich plasma and mesenchymal stem cells are used to help create a favorable environment for tendon to bone healing, and grafts and scaffolds provide structural support for repair. The efficacy of platelet-rich plasma and stem cell products seems to be variable, with different products offering different levels of cytokine and growth factors. Scaffold material is also variable with a wide range of synthetic and biological grafts. 10.1016/j.ocl.2018.08.005
    Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications. Pak Jaewoo,Lee Jung Hun,Park Kwang Seung,Park Moonhee,Kang Lin-Woo,Lee Sang Hee Journal of biomedical science Autologous adipose stromal vascular fractions (SVFs) containing adipose tissue-derived stem cells (ASCs) are currently being used in clinical settings for various orthopedic applications for human patients. Due to its potential capability of regenerating cartilage, bone, and tendons, autologous adipose SVFs are being tried in treating patients with osteoarthritis (OA), chondromalacia, meniscus tear, osteonecrosis of the femoral head, and tendon injuries. Here, we have reviewed available human clinical studies with regard to patient applications of autologous adipose SVF containing ASCs, specifically assessing effectiveness and safety in the field of orthopedic disorders. All studies reviewed in this article presents potential benefits of autologous adipose SVF in various orthopedic applications without any serious side effects. 10.1186/s12929-017-0318-z
    Advances with platelet rich plasma therapies for tendon regeneration. Andia Isabel,Martin Jose Ignacio,Maffulli Nicola Expert opinion on biological therapy INTRODUCTION:PRPs can be used in the management of tendinopathy if we improve our understanding of pathophysiology and to integrate molecular knowledge about PRP participation in healing mechanisms. AREAS COVERED:We provide new insights into the pathophysiology of tendinopathy, PRP therapies, and the potential links between both. We discuss the place of PRP in promoting tendon repair within what is currently understood regarding the role of PRP molecules in promoting tendon regeneration. EXPERT OPINION:Development of PRP treatments is challenging because a typical group of patients with tendinopathy does not exist, as it affects multiple segments of the population. Moreover, the pathophysiology and origin of pain are not elucidated yet. Although some degree of success has been achieved, PRP is not considered standard medical treatment, and it is largely not paid nor reimbursed by insurance companies. However, the arguments for using PRP in tendinopathy are increasing, and its potential to rebalance inflammation merits further research. Moreover, PRP contains tendoinductive factors that can drive the fate of stem cells. Tailoring PRPs to the specific needs of the host tendon has not been possible to date, because unanswered questions remain about the characteristics of tendinopathy within the different stages of progression. 10.1080/14712598.2018.1424626
    Platelet-Rich Fibrin Scaffolds for Cartilage and Tendon Regenerative Medicine: From Bench to Bedside. Barbon Silvia,Stocco Elena,Macchi Veronica,Contran Martina,Grandi Francesca,Borean Alessio,Parnigotto Pier Paolo,Porzionato Andrea,De Caro Raffaele International journal of molecular sciences Nowadays, research in Tissue Engineering and Regenerative Medicine is focusing on the identification of instructive scaffolds to address the requirements of both clinicians and patients to achieve prompt and adequate healing in case of injury. Among biomaterials, hemocomponents, and in particular Platelet-rich Fibrin matrices, have aroused widespread interest, acting as delivery platforms for growth factors, cytokines and immune/stem-like cells for immunomodulation; their autologous origin and ready availability are also noteworthy aspects, as safety- and cost-related factors and practical aspects make it possible to shorten surgical interventions. In fact, several authors have focused on the use of Platelet-rich Fibrin in cartilage and tendon tissue engineering, reporting an increasing number of in vitro, pre-clinical and clinical studies. This narrative review attempts to compare the relevant advances in the field, with particular reference being made to the regenerative role of platelet-derived growth factors, as well as the main pre-clinical and clinical research on Platelet-rich Fibrin in chondrogenesis and tenogenesis, thereby providing a basis for critical revision of the topic. 10.3390/ijms20071701
    Therapeutic potential of exosomes in rotator cuff tendon healing. Connor Denton E,Paulus Jordan A,Dabestani Parinaz Jila,Thankam Finosh K,Dilisio Matthew F,Gross R Michael,Agrawal Devendra K Journal of bone and mineral metabolism Rotator cuff tears are common musculoskeletal injuries that can cause significant pain and disability. While the clinical results of rotator cuff repair can be good, failure of tendon healing remains a significant problem. Molecular mechanisms underlying structural failure following surgical repair remain unclear. Histologically, enhanced inflammation, disorganization of the collagen fibers, calcification, apoptosis and tissue necrosis affect the normal healing process. Mesenchymal stem cells (MSCs) have the ability to provide improved healing following rotator cuff repair via the release of mediators from secreted 30-100 nm extracellular vesicles called exosomes. They carry regulatory proteins, mRNA and miRNA and have the ability to increase collagen synthesis and angiogenesis through increased expression of mRNA and release of proangiogenic factors and regulatory proteins that play a major role in proper tissue remodeling and preventing extracellular matrix degradation. Various studies have shown the effect of exosomes on improving outcome of cutaneous wound healing, scar tissue formation, degenerative bone disease and Duchenne Muscular Dystrophy. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and propose the novel use of exosomes alone or seeded onto biomaterial matrices to stimulate secretion of favorable cellular factors in accelerating the healing response following rotator cuff repair. 10.1007/s00774-019-01013-z
    No evidence for the use of stem cell therapy for tendon disorders: a systematic review. Pas Haiko I M F L,Moen Maarten H,Haisma Hidde J,Winters Marinus British journal of sports medicine INTRODUCTION:Stem cells have emerged as a new treatment option for tendon disorders. We systematically reviewed the current evidence for stem cell therapy in tendon disorders. METHODS:Randomised and non-randomised controlled trials, cohort studies and case series with a minimum of 5 cases were searched in MEDLINE, CENTRAL, EMBASE, CINAHL, PEDro and SPORTDiscus. In addition, we searched grey literature databases and trial registers. Only human studies were included and no time or language restrictions were applied to our search. All references of included trials were checked for possibly eligible trials. Risk of bias assessment was performed using the Cochrane risk of bias tool for controlled trials and the Newcastle-Ottawa scale for case series. Levels of evidence were assigned according to the Oxford levels of evidence. RESULTS:4 published and three unpublished/pending trials were found with a total of 79 patients. No unpublished data were available. Two trials evaluated bone marrow-derived stem cells in rotator cuff repair surgery and found lower retear rates compared with historical controls or the literature. One trial used allogenic adipose-derived stem cells to treat lateral epicondylar tendinopathy. Improved Mayo Elbow Performance Index, Visual Analogue Pain scale and ultrasound findings after 1-year follow-up compared with baseline were found. Bone marrow-derived stem cell-treated patellar tendinopathy showed improved International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score subscales and Tegner scores after 5-year follow-up. One trial reported adverse events and found them to be mild (eg, swelling, effusion). All trials were at high risk of bias and only level 4 evidence was available. CONCLUSIONS:No evidence (level 4) was found for the therapeutic use of stem cells for tendon disorders. The use of stem cell therapy for tendon disorders in clinical practice is currently not advised. 10.1136/bjsports-2016-096794
    Clinical use of stem cells in orthopaedics Im G-I European cells & materials Stem cell research arose from the need to explore new therapeutic possibilities for intractable and lethal diseases. Although musculoskeletal disorders are basically nonlethal, their high prevalence and relative ease of performing clinical trials have facilitated the clinical application of stem cells in this field. However, few reliable clinical studies have been published, despite the plethora of in vitro and preclinical studies in stem cell research for regenerative medicine in the musculoskeletal system. Stem cell therapy can be applied locally for bone, cartilage and tendon regeneration. Candidate disease modalities in bone regeneration include large bone defects, nonunion of fractures, and osteonecrosis. Focal osteochondral defect and osteoarthritis are current targets for cartilage regeneration. For tendon regeneration, bone-tendon junction problems such as rotator cuff tears are hot topics in clinical research. To date, the literature supporting stem cell-based therapies comprises mostly case reports or case series. Therefore, high-quality evidence, including from randomised clinical trials, is necessary to define the role of cell-based therapies in the treatment of musculoskeletal disorders. It is imperative that clinicians who adopt stem cell treatment into their practices possess a good understanding of the natural course of the disease. It is also highly recommended that treating physicians do not thrust aside the concomitant use of established measures until stem cell therapy is evidently proved worthy in terms of efficacy and cost. The purpose of this review is to summarise on the current status of stem cell application in the orthopaedic field along with the author's view of future prospects. 10.22203/eCM.v033a14
    Boosting tendon repair: interplay of cells, growth factors and scaffold-free and gel-based carriers. Yan Zexing,Yin Heyong,Nerlich Michael,Pfeifer Christian G,Docheva Denitsa Journal of experimental orthopaedics BACKGROUND:Tendons are dense connective tissues and critical components for the integrity and function of the musculoskeletal system. Tendons connect bone to muscle and transmit forces on which locomotion entirely depends. Due to trauma, overuse and age-related degeneration, many people suffer from acute or chronic tendon injuries. Owing to their hypovascularity and hypocellularity, tendinopathies remain a substantial challenge for both clinicians and researchers. Surgical treatment includes suture or transplantation of autograft, allograft or xenograft, and these serve as the most common technique for rescuing tendon injuries. However, the therapeutic efficacies are limited by drawbacks including inevitable donor site morbidity, poor graft integration, adhesion formations and high rates of recurrent tearing. This review summarizes the literature of the past 10 y concerning scaffold-free and gel-based approaches for treating tendon injuries, with emphasis on specific advantages of such modes of application, as well as the obtained results regarding in vitro and in vivo tenogenesis. RESULTS:The search was focused on publications released after 2006 and 83 articles have been analysed. The main results are summarizing and discussing the clear advantages of scaffold-free and hydrogels carriers that can be functionalized with cells alone or in combination with growth factors. CONCLUSION:The improved understanding of tissue resident adult stem cells has made a significant progress in recent years as well as strategies to steer their fate toward tendon lineage, with the help of growth factors, have been identified. The field of tendon tissue engineering is exploring diverse models spanning from hard scaffolds to gel-based and scaffold-free approaches seeking easier cell delivery and integration in the site of injury. Still, the field needs to consider a multifactorial approach that is based on the combination and fine-tuning of chemical and biomechanical stimuli. Taken together, tendon tissue engineering has now excellent foundations and enters the period of precision and translation to models with clinical relevance on which better treatment options of tendon injuries can be shaped up. 10.1186/s40634-017-0117-1
    Use of stem cells and growth factors in rotator cuff tendon repair. Tsekes Dimitrios,Konstantopoulos Georgios,Khan Wasim S,Rossouw Daniel,Elvey Mike,Singh Jagwant European journal of orthopaedic surgery & traumatology : orthopedie traumatologie The management of rotator cuff tears continues to prove challenging for orthopaedic surgeons. Such tears affect most age groups and can lead to significant morbidity in patients. The aetiology of these tears is likely to be multifactorial; however, an understanding of the mechanisms involved is still under review. Despite advancements in surgical operative techniques and the materials used, post-operative recurrence rates after surgical repair remain high. A growing area of research surrounds biological adjuncts used to improve the healing potential of the repaired tissues. This review of recent publications focuses on the strengths and limitations of using stem cells and growth factors in rotator cuff repair. 10.1007/s00590-019-02366-x
    Adipose-Derived Mesenchymal Stem Cells: A Promising Tool in the Treatment of Musculoskeletal Diseases. Torres-Torrillas Marta,Rubio Monica,Damia Elena,Cuervo Belen,Del Romero Ayla,Peláez Pau,Chicharro Deborah,Miguel Laura,Sopena Joaquin J International journal of molecular sciences Chronic musculoskeletal (MSK) pain is one of the most common medical complaints worldwide and musculoskeletal injuries have an enormous social and economical impact. Current pharmacological and surgical treatments aim to relief pain and restore function; however, unsatiscactory outcomes are commonly reported. In order to find an accurate treatment to such pathologies, over the last years, there has been a significantly increasing interest in cellular therapies, such as adipose-derived mesenchymal stem cells (AMSCs). These cells represent a relatively new strategy in regenerative medicine, with many potential applications, especially regarding MSK disorders, and preclinical and clinical studies have demonstrated their efficacy in muscle, tendon, bone and cartilage regeneration. Nevertheless, several worries about their safety and side effects at long-term remain unsolved. This article aims to review the current state of AMSCs therapy in the treatment of several MSK diseases and their clinical applications in veterinary and human medicine. 10.3390/ijms20123105
    Tendon Stem/Progenitor Cells and Their Interactions with Extracellular Matrix and Mechanical Loading. Zhang Chuanxin,Zhu Jun,Zhou Yiqin,Thampatty Bhavani P,Wang James H-C Stem cells international Tendons are unique connective tissues in the sense that their biological properties are largely determined by their tendon-specific stem cells, extracellular matrix (ECM) surrounding the stem cells, mechanical loading conditions placed on the tendon, and the complex interactions among them. This review is aimed at providing an overview of recent advances in the identification and characterization of tendon stem/progenitor cells (TSPCs) and their interactions with ECM and mechanical loading. In addition, the effects of such interactions on the maintenance of tendon homeostasis and the initiation of tendon pathological conditions are discussed. Moreover, the challenges in further investigations of TSPC mechanobiology and are outlined. Finally, future research efforts are suggested, which include using specific gene knockout models and single-cell transcription profiling to enable a broad and deep understanding of the physiology and pathophysiology of tendons. 10.1155/2019/3674647
    Tendon Stem Cells: Mechanobiology and Development of Tendinopathy. Wang James H-C,Komatsu Issei Advances in experimental medicine and biology 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 source for cell-based therapy to effectively repair or even regenerate injured tendons in clinical settings. 10.1007/978-3-319-33943-6_5
    Directed Differentiation and Paracrine Mechanisms of Mesenchymal Stem Cells: Potential Implications for Tendon Repair and Regeneration. Zhang Bingyu,Luo Qing,Halim Alexander,Ju Yang,Morita Yasuyuki,Song Guanbin Current stem cell research & therapy BACKGROUND:Tendon is composed of connective tissue, is able to retract with high tensile force, and plays a significant role in musculoskeletal motion. However, inappropriate physical training or accidents often result in tendon injuries. So far, the functional healing of injured tendon is still a great challenge in orthopedics. Mesenchymal stem cells (MSCs) are multilineage cells with the ability to self-renew and differentiate into a variety of cell types, including tenocytes. The plasticity of MSCs gives rise to the chance of improved healing of injured tendons and even tissue-engineered tendons. Recently, more and more works have shown that the paracrine mechanisms of MSCs also play a critical role in driving the tendon repair process. OBJECTIVE:The purpose of this review is to summarize the current knowledge of the induction of tenogenic differentiation of MSCs by mechanical, chemical and mechanochemical stimulations. The role of paracrine mechanisms of MSCs during the repair of injured tendons is also discussed. CONCLUSION:The multilineage potential and the paracrine effects of MSCs create the chance for improved healing of injured tendons and even tissue-engineered tendons. The understanding of the regulation of the two different repair mechanisms (directed differentiation and paracrine) of MSCs has important implications for tendon repair and regeneration. 10.2174/1574888X12666170502102423
    Exploring Stem Cells and Inflammation in Tendon Repair and Regeneration. Vinhas A,Rodrigues M T,Gomes M E Advances in experimental medicine and biology Tendon injuries are frequent and are responsible for substantial morbidity both in sports and in the workplace. Despite the endogenous mechanisms of tendon repair and regeneration, tendon healing upon injury is slow and often insufficient to restore complete biomechanics functionality.Inflammation has a pivotal role in tendon healing and failed healing responses contribute to the progression of tendinopathies. However, the molecular and cellular mechanisms involved are poorly understood requiring further insights.During inflammation, bioactive molecules such as cytokines secreted locally at the injury site, influence resident stem cells that contribute as modulatory agents over the niche towards homeostasis, holding great promise as therapeutic agents for tendon pathological conditions associated to unresolved inflammation and failed healing.This review overviews the role of cytokines and resident cells, focusing on the participation of tendon stem cell population in inflammation and tendon healing upon injury and their potential action in resolution of pathological conditions. 10.1007/5584_2018_258
    The Potential Roles of Tendon Stem/Progenitor Cells in Tendon Aging. Li Yingjuan,Dai Guangchun,Shi Liu,Lin Yucheng,Chen Minhao,Li Gang,Rui Yunfeng Current stem cell research & therapy Aging is a key dangerous factor for the occurrence and severity of tendon injury, but the exact cognition of the relationship is elusive at present. More previous studies suggest age-related changes occur at tendon mechanical properties, structure and composition, but the pathological alternations may be overlooked, which might be a cause for the structure and function variations, and even speed up the progress of age-related disorders. Recently, the presence of tendon stem/progenitor cells (TSPCs) would provide new insights for the pathogenesis of tendon aging. In this review, the tendon mechanical properties, structure and composition are presented in brief, then, the pathological changes of the aging tendon are described firstly, and the latest researches on alterations of TSPCs in the pathogenesis of tendon aging have also been analyzed. At a cellular level, the hypothetical model of altered TSPCs fate for tendon aging is also proposed. Moreover, the regulation of TSPCs as a potential way of the therapies for age-related tendon diseases is discussed. Therefore, reversing the impaired function of TSPCs and promoting the tenogenic differentiation of TSPCs could become hot spots for further study and give the opportunity to establish new treatment strategies for age-related tendon injuries. 10.2174/1574888X13666181017112233
    Biomechanical evaluation of tendon regeneration with adipose-derived stem cell. de Lima Santos Alex,Silva Camila Gonzaga da,de Sá Barretto Leticia Siqueira,Franciozi Carlos Eduardo da Silveira,Tamaoki Marcel Jun Sugawara,de Almeida Fernando Gonçalves,Faloppa Flavio Journal of orthopaedic research : official publication of the Orthopaedic Research Society The use of Adipose-Derived Stem Cells (ADSC) has been presented as a new alternative for tendon reconstruction. Have been admitted that ADSCs are related to better outcomes when used in tendon healing. This research was designed to apply the potential of ADSCs in tendon healing. Flexor digitorum superficialis tendon lesion was performed on both legs of eleven New Zealand rabbits and them, at the same time, treated as follows: Suture alone (Group III - Suture, n:10), suture associated with ADSC (Group IV - Suture + ADSC, n:10) or without suture (Group II - SHAN, n:2). At four weeks after the tendon surgery, the animal was euthanized, and the tendon evaluated (biomechanically and macroscopically). We used 5 additional New Zealand rabbits in the control group "Group I - Control, n:10". In the macroscopic evaluation, the group with ADSC presented a more homogeneous gross morphology compared with the group III. Biomechanical testing showed a lower ultimate tensile load, stiffness and a higher cross-sectional area in the group III and IV compared with the control group. The group with ADSC showed a greater ultimate tensile load, a larger cross-sectional area and bigger deformation at the ultimate tensile load when compared to the group without ADSC. In general terms, the use of ADSCs in tendon healing have biomechanical advantages compared to the non-use of ADSCs at 4 weeks after surgery. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1281-1286, 2019. 10.1002/jor.24182
    Mesenchymal Stem Cells Empowering Tendon Regenerative Therapies. Costa-Almeida Raquel,Calejo Isabel,Gomes Manuela E International journal of molecular sciences Tendon tissues have limited healing capacity. The incidence of tendon injuries and the unsatisfactory functional outcomes of tendon repair are driving the search for alternative therapeutic approaches envisioning tendon regeneration. Cellular therapies aim at delivering adequate, regeneration-competent cell types to the injured tendon and toward ultimately promoting its reconstruction and recovery of functionality. Mesenchymal stem cells (MSCs) either obtained from tendons or from non-tendon sources, like bone marrow (BM-MSCs) or adipose tissue (ASCs), have been receiving increasing attention over the years toward enhancing tendon healing. Evidences from in vitro and in vivo studies suggest MSCs can contribute to accelerate and improve the quality of tendon healing. Nonetheless, the exact mechanisms underlying these repair events are yet to be fully elucidated. This review provides an overview of the main challenges in the field of cell-based regenerative therapies, discussing the role of MSCs in boosting tendon regeneration, particularly through their capacity to enhance the tenogenic properties of tendon resident cells. 10.3390/ijms20123002
    Current Progress in Tendon and Ligament Tissue Engineering. Lim Wei Lee,Liau Ling Ling,Ng Min Hwei,Chowdhury Shiplu Roy,Law Jia Xian Tissue engineering and regenerative medicine Background:Tendon and ligament injuries accounted for 30% of all musculoskeletal consultations with 4 million new incidences worldwide each year and thus imposed a significant burden to the society and the economy. Damaged tendon and ligament can severely affect the normal body movement and might lead to many complications if not treated promptly and adequately. Current conventional treatment through surgical repair and tissue graft are ineffective with a high rate of recurrence. Methods:In this review, we first discussed the anatomy, physiology and pathophysiology of tendon and ligament injuries and its current treatment. Secondly, we explored the current role of tendon and ligament tissue engineering, describing its recent advances. After that, we also described stem cell and cell secreted product approaches in tendon and ligament injuries. Lastly, we examined the role of the bioreactor and mechanical loading in in vitro maturation of engineered tendon and ligament. Results:Tissue engineering offers various alternative ways of treatment from biological tissue constructs to stem cell therapy and cell secreted products. Bioreactor with mechanical stimulation is instrumental in preparing mature engineered tendon and ligament substitutes in vitro. Conclusions:Tissue engineering showed great promise in replacing the damaged tendon and ligament. However, more study is needed to develop ideal engineered tendon and ligament. 10.1007/s13770-019-00196-w
    Biology of Tendon Stem Cells and Tendon in Aging. Lui Pauline Po Yee,Wong Chi Ming Frontiers in genetics Both tendon injuries and tendinopathies, particularly rotator cuff tears, increase with tendon aging. Tendon stem cells play important roles in promoting tendon growth, maintenance, and repair. Aged tendons show a decline in regenerative potential coupled with a loss of stem cell function. Recent studies draw attention to aging primarily a disorder of stem cells. The micro-environment ("niche") where stem cells resided provides signals that direct them to metabolize, self-renew, differentiate, or remain quiescent. These signals include receptors and secreted soluble factors for cell-cell communication, extracellular matrix, oxidative stress, and vascularity. Both intrinsic cellular deficits and aged niche, coupled with age-associated systemic changes of hormonal and metabolic signals can inhibit or alter the functions of tendon stem cells, resulting in reduced fitness of these primitive cells and hence more frequent injuries and poor outcomes of tendon repair. This review aims to summarize the biological changes of aged tendons. The biological changes of tendon stem cells in aging are reviewed after a systematic search of the PubMed. Relevant factors of stem cell aging including cell-intrinsic factors, changes of microenvironment, and age-associated systemic changes of hormonal and metabolic signals are examined, with findings related to tendon stem cells highlighted when literature is available. Future research directions on the aging mechanisms of tendon stem cells are discussed. Better understanding of the molecular mechanisms underlying the functional decline of aged tendon stem cells would provide insight for the rational design of rejuvenating therapies. 10.3389/fgene.2019.01338
    Extracellular Vesicles of Adipose-Derived Stem Cells Promote the Healing of Traumatized Achilles Tendons. Chen Shih-Heng,Chen Zhi-Yu,Lin Ya-Hsuan,Chen Shih-Hsien,Chou Pang-Yun,Kao Huang-Kai,Lin Feng-Huei International journal of molecular sciences Healing of ruptured tendons remains a clinical challenge because of its slow progress and relatively weak mechanical force at an early stage. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have therapeutic potential for tissue regeneration. In this study, we isolated EVs from adipose-derived stem cells (ADSCs) and evaluated their ability to promote tendon regeneration. Our results indicated that ADSC-EVs significantly enhanced the proliferation and migration of tenocytes in vitro. To further study the roles of ADSC-EVs in tendon regeneration, ADSC-EVs were used in Achilles tendon repair in rabbits. The mechanical strength, histology, and protein expression in the injured tendon tissues significantly improved 4 weeks after ADSC-EV treatment. Decorin and biglycan were significantly upregulated in comparison to the untreated controls. In summary, ADSC-EVs stimulated the proliferation and migration of tenocytes and improved the mechanical strength of repaired tendons, suggesting that ADSC-EV treatment is a potential highly potent therapeutic strategy for tendon injuries. 10.3390/ijms222212373
    Conditioned medium of human bone marrow-derived stem cells promotes tendon-bone healing of the rotator cuff in a rat model. Chen Wenbo,Sun Yaying,Gu Xueping,Cai Jiangyu,Liu Xingwang,Zhang Xingyu,Chen Jiwu,Hao Yuefeng,Chen Shiyi Biomaterials Rotator cuff repair is a common surgery in sports medicine. During the surgery, torn tendon was re-fixed onto the bony surface. The majority of patients gain good results. However, re-tear occurs in some patients. The reason under this phenomenon is that the normal tendon-bone enthesis cannot be reconstructed. In order to strengthen the tendon-bone healing and promote enthesis regeneration, numerous manners are tested, among which stem cell related therapies are preferred. Stem cells, due to the ability of multi-lineage differentiation, are widely used in regenerative medicine. However, safety and ethics concerns limit its clinical use. Recent studies found that it is the secretome of stem cells that is biologically effective. On ground of this, we, in the current study, collected the conditioned medium of human bone marrow-derived stem cells (hBMSC-CM) and tested whether this acellular method could promote tendon-bone healing in a rat model of rotator cuff repair. By using histological, radiological, and biomechanical methods, we found that hBMSC-CM promoted tendon-bone healing of the rat rotator cuff. Then, we noticed that hBMSC-CM exerted an impact on macrophage polarization both in vivo and in vitro by inhibiting M1 phenotype and promoting M2 phenotype. Further, we proved that the benefit of hBMSC-CM on tendon-bone healing was related to its regulation on macrophage. Finally, we proved that, hBMSC-CM influenced macrophage polarization, which was, at least partially, related to Smad2/3 signaling pathway. Based on the experiments above, we confirmed the benefit of hBMSC-CM on tendon-bone healing, which relied on its immune-regulative property. Considering the accessibility and safety of acellular hBMSC-CM, we believe it is a promising candidate clinically for tendon-bone healing. 10.1016/j.biomaterials.2021.120714