Promoting Healing of Tendinopathies Using Therapeutic Mechanobiologic Stimulation

描述(申请人提供)：肌腱的功能障碍，例如那些控制脚跟、肘部和肩膀的运动的肌腱功能障碍是一个主要的医疗保健问题。现在人们普遍认为，在运动(网球肘)或工作相关(腕管)活动中出现的肌腱过度使用是肌腱病发生的始动因素。这似乎是真的，至少对于30-50岁弱势群体中不断扩大的患者数量来说是如此。该领域大多数人支持的一种致病途径是，过度使用会导致肌腱胶原纤维的持续性微损伤，这种损伤会引发一系列细胞反应，导致组织材料特性的进一步丧失和慢性疼痛。我们的 长期目标是确定伴随肌腱病的异常细胞反应是否可以通过应用量身定制的生物和/或生物力学疗法从退化重定向到愈合。我们对研究的成功结果持乐观态度，因为我们相信我们已经发现了一条导致肌腱病的中枢致病途径，我们预计这条途径将适用于这种治疗控制。致病途径涉及肌腱基质中的沉积，我们称之为ARDS，或“富含蛋白聚糖的沉积”。这一途径是从对一种易感马匹的肌腱病的研究中得出的。我们正在对野生型和ADAMTS5缺陷小鼠进行机制研究，这些小鼠表现出模拟人类病理的肌腱变化(生物力学和生化)。研究中的机制途径表明，机械负荷(运动)和ADAMTS5途径激活都需要消除ARDS(细胞周围聚集蛋白聚糖)。我们正在研究治疗方法，通过不同的机械负荷模式(偏心运动和向心运动)以及直接注射抗血管溶解剂来消除这些沉积。此外，我们将直接应用从这些小鼠研究中获得的知识，以检验机械生物学策略治疗人类肌腱病变组织的有效性。

DESCRIPTION (provided by applicant): Functional impairment in tendons, such as those which control movement in the heel, elbow and shoulder represents a major health care problem. It is now widely believed that tendon overuse, as seen in sports (tennis elbow) or work related (carpal tunnel) activities, is the initiating factor for development of tendinopathy. This appears to be true, at least for the expanding number of patients in the vulnerable 30-50 year age group. A pathogenic pathway, favored by most in the field, is that overuse results in persistent micro- injury of tendon collagen fibers and that this "wounding" precipitates a series o cellular responses which result in further loss of tissue material properties and chronic pain. Our long-term goal is to determine whether the aberrant cell responses which accompany tendinopathies, can be redirected from degeneration to healing by the application of tailored biologic and/or biomechanical therapies. We are optimistic about a successful outcome of our studies since we believe that we have uncovered a central pathogenic pathway to tendinopathy which we anticipate will be amenable to such therapeutic control. The pathogenic pathway involves the accumulation of deposits we term ARDs, or "aggrecan-rich deposits" in the tendon matrix. This pathway has emerged from studies on equine tendinopathy in a susceptible breed of horses. We are pursuing mechanistic studies in wild type and ADAMTS5-deficient mice which exhibit tendon changes (biomechanical and biochemical) that mimic the human pathology. The mechanistic pathway under study suggests that both mechanical loading (exercise) and ADAMTS5 pathway activation are required to eliminate the ARDs (pericellular aggrecan accumulation). We are working on therapeutic approaches to eliminate these deposits via different mechanical loading modes (eccentric versus concentric exercise) as well as by direct injection of aggrecanolytic agents. Furthermore, we will directly apply the knowledge gained from these murine studies in order to examine the efficacy of mechanobiologic strategies to treat human tendinopathic tissues.