Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside.

Tendon is composed of dense fibrous connective tissues, connecting muscle at the myotendinous junction (MTJ) to bone at the enthesis and allowing mechanical force to transmit from muscle to bone. Tendon diseases occur at different zones of the tendon, including enthesis, MTJ and midsubstance of the tendon, due to a variety of environmental and genetic factors which consequently result in different frequencies and recovery rates. Self-healing properties of tendons are limited, and cell therapeutic approaches in which injured tendon tissues are renewed by cell replenishment are highly sought after. Homologous use of individual's tendon-derived cells, predominantly differentiated tenocytes and tendon-derived stem cells, is emerging as a treatment for tendinopathy through achieving minimal cell manipulation for clinical use. This is the first review summarizing the progress of tendon-derived cell therapy in clinical use and its challenges due to the structural complexity of tendons, heterogeneous composition of extracellular cell matrix and cells and unsuitable cell sources. Further to that, novel future perspectives to improve therapeutic effect in tendon-derived cell therapy based on current basic knowledge are discussed.

Fabrication of a silver nanoparticle-coated collagen membrane with anti-bacterial and anti-inflammatory activities for guided bone regeneration.

Alveolar bone loss is a common problem that affects dental implant placement. A barrier between the bone substitute and gingiva that can prevent fibro-tissue ingrowth, bacterial infection and induce bone formation is a key factor in improving the success of alveolar ridge reconstruction. This study aims to develop a bioactive collagen barrier material for guided bone regeneration, that is coupled with anti-bacterial and anti-inflammatory properties. We have evaluated two silver coating methods and found controllable and precise coating achieved by sonication compared with sputtering. The optimized AgNP-coated collagen membrane exhibited excellent anti-bacterial effects against Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with limited cellular toxicity. It also displayed effective anti-inflammatory effects by reducing the expression and release of inflammatory cytokines including IL-6 and TNF-alpha. Additionally, AgNP-coated collagen membranes were able to induce osteogenic differentiation of mesenchymal stem cells that guide bone regeneration. These findings demonstrate the potential application of AgNP-coated collagen membranes to prevent infection after bone graft introduction in alveolar ridge reconstruction.

Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Bradycardiac Effects Caused by Co-Administration of Sofosbuvir and Amiodarone.

Co-administration of sofosbuvir, an anti-hepatitis C virus medication, and antiarrhythmic amiodarone causes symptomatic severe bradycardia in patients and animal models. However, in a few in vitro studies, the combination of sofosbuvir and amiodarone resulted in tachycardiac effects in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). This discrepancy may be attributable to the use of immature hiPSC-CMs in the in vitro studies. To address this, we evaluated the ability of our in-house hiPSC-CMs to assess the interactions between sofosbuvir and amiodarone in vitro. We performed whole-cell patch recordings on hiPSC-CMs to examine the cardiac effect of sofosbuvir and amiodarone, alone or in combination. We found that sofosbuvir and amiodarone caused bradycardiac effects (the beating rate decreased to 75% of the vehicle control, P < 0.001) on our hiPSC-CMs when applied in combination, but they had no significant effect when applied alone. Furthermore, the bradycardiac effect was membrane potential dependent: it increased with depolarization. This raised the possibility that the bradycardiac effects in vivo may originate in nodal cells, which have a more depolarized resting membrane potential compared with ventricular cells. The bradycardiac effects of sofosbuvir plus amiodarone in vitro are consistent with the clinical phenotype and suggest that our hiPSC-CMs may serve as a useful tool in assessing cardiac safety during drug discovery and development process.

In vitro loading models for tendon mechanobiology.

Tendons are the connective tissue responsible for transferring force from muscles to bones. A key factor in tendon development, maturation, repair, and degradation is its biomechanical environment. Understanding tendon mechanobiology is essential for the development of injury prevention strategies, rehabilitation protocols and potentially novel treatments in tendon injury and degeneration. Despite the simple overall loading on tendon tissue, cells within the tissue in vivo experience a much more complex mechanical environment including tension, compression and shear forces. This creates a substantial challenge in the establishment of in vitro loading models of the tendon. This article reviews multiple loading models used for the study of tendon mechanobiology and summarizes the main findings. Although impressive progress has been achieved in the functionality and mimicry of in vitro loading models, an ideal platform is yet to be developed. Multidisciplinary approaches and collaborations will be the key to unveiling the tendon mechanobiology. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:566-575, 2018.

Lateral Elbow Tendinopathy: Development of a Pathophysiology-Based Treatment Algorithm.

Lateral elbow tendinopathy, commonly known as tennis elbow, is a condition that can cause significant functional impairment in working-age patients. The term tendinopathy is used to describe chronic overuse tendon disorders encompassing a group of pathologies, a spectrum of disease. This review details the pathophysiology of tendinopathy and tendon healing as an introduction for a system grading the severity of tendinopathy, with each of the 4 grades displaying distinct histopathological features. Currently, there are a large number of nonoperative treatments available for lateral elbow tendinopathy, with little guidance as to when and how to use them. In fact, an appraisal of the clinical trials, systematic reviews, and meta-analyses studying these treatment modalities reveals that no single treatment reliably achieves outstanding results. This may be due in part to the majority of clinical studies to date including all patients with chronic tendinopathy rather than attempting to categorize patients according to the severity of disease. We relate the pathophysiology of the different grades of tendinopathy to the basic science principles that underpin the mechanisms of action of the nonoperative treatments available to propose a treatment algorithm guiding the management of lateral elbow tendinopathy depending on severity. We believe that this system will be useful both in clinical practice and for the future investigation of the efficacy of treatments.