Tendon Response to In Vivo Fatigue Damage

描述（申请人提供）：肌腱病变和肌腱断裂是导致疼痛和残疾的主要临床问题。许多研究表明，由磨损和撕裂引起的累积疲劳损伤是肌腱病变中所见的肌腱变性的基础，这种损伤导致肌腱变弱导致断裂。尽管如此，人们对肌腱疲劳损伤积累的力学和微观结构机制知之甚少，肌腱对这种损伤作出反应的生物学过程也不清楚。肌腱疾病的动物模型通常要么是急性撕裂伤模型，不能模拟肌腱在明显断裂之前的慢性变性，要么是运动过度使用模型，机械损伤定义不清（例如，跑步机过度使用），不能戏弄肌腱对精确剂量的基质损伤的机械和生物反应。我们提出的研究将使用我们最近开发的大鼠髌骨肌腱模型，该模型允许生产亚失效疲劳损伤的活肌腱，以测试疲劳损伤的肌腱随着时间的推移恢复正常结构和机械性能的假设。在第一个系列的研究中，我们将描述活肌腱在不同应力和不同损伤端点载荷下的机械和形态学疲劳过程。在实验2中，我们将在活肌腱中引入不同程度的疲劳，并从机械和微观结构上检查这些肌腱如何随着时间的推移对这种损伤做出反应。在第三系列研究中，我们将在细胞和分子水平上确定肌腱对疲劳损伤的反应是否反映了正常愈合，以及是否利用了不同的机制。

DESCRIPTION (provided by applicant): Tendinopathy and tendon rupture are major clinical problems causing pain and disability. Many studies have suggested that accumulated fatigue damage from wear and tear underlies the tendon degeneration seen in tendinopathy and that this damage contributes to tendon weakening leading to rupture. Despite this, little is known about the mechanical and microstructural mechanisms of fatigue damage accumulation in tendons, and the biologic processes by which tendons respond to such damage are not understood. Animal models of tendon disease have generally been either acute laceration models which do not model the chronic degeneration seen in tendons prior to overt rupture, or exercise-overuse models with poorly defined mechanical insults (e.g. treadmill overuse) which do not allow teasing apart the tendon's mechanical and biologic response to precise doses of matrix injury. The proposed studies will use our recently developed rat patellar tendon model, which allows the production in living tendons of subfailure fatigue damage, to test the hypothesis that fatigue damaged tendons restore normal architecture and mechanical properties over time. In the first series of studies, we will characterize the fatigue process mechanically and and morphologically in living tendons at loaded at different stresses and to different damage endpoints. In experiment 2, we will introduce different levels of fatigue into living tendons, and examine mechanically and microstructurally how these tendon respond to this damage over time. In the third series of studies, we will determine at cellular and molecular levels whether tendon response to fatigue damage mirrors normal healing and whether it utilizes different mechanisms.