Promoting Healing of Tendinopathies Using Therapeutic Mechanobiologic Stimulation

描述（由申请人提供）：肌腱的功能障碍，例如控制脚跟、肘部和肩部运动的肌腱，代表了一个主要的医疗保健问题。现在人们普遍认为，运动（网球肘）或工作相关（腕管）活动中肌腱的过度使用是肌腱病发生的起始因素。这似乎是真的，至少对于数量不断增加的 30-50 岁弱势群体患者来说是这样。该领域大多数人所青睐的致病途径是，过度使用会导致肌腱胶原纤维的持续微损伤，并且这种“损伤”会引发一系列细胞反应，从而导致组织材料特性的进一步丧失和慢性疼痛。我们的 长期目标是确定是否可以通过应用定制的生物和/或生物力学疗法将肌腱病伴随的异常细胞反应从退化转向愈合。我们对研究的成功结果感到乐观，因为我们相信我们已经发现了肌腱病的主要致病途径，我们预计该途径将适合这种治疗控制。 致病途径涉及肌腱基质中沉积物的积累，我们称之为 ARD，或“富含聚集蛋白聚糖的沉积物”。这条途径是从对易感马种的马肌腱病的研究中得出的。我们正在对野生型和 ADAMTS5 缺陷型小鼠进行机制研究，这些小鼠表现出模仿人类病理学的肌腱变化（生物力学和生物化学）。正在研究的机制途径表明，机械负荷（运动）和 ADAMTS5 途径激活都是消除 ARD（细胞周围聚集蛋白聚糖积累）所必需的。我们正在研究治疗方法，通过不同的机械负荷模式（偏心运动与同心运动）以及直接注射骨蛋白分解剂来消除这些沉积物。此外，我们将直接应用从这些小鼠研究中获得的知识来检查机械生物学策略治疗人类肌腱病组织的功效。

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.