Tendon Response to In Vivo Fatigue Damage

描述（由申请人提供）：肌腱病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，磨损和撕裂造成的累积疲劳损伤是肌腱病中肌腱变性的基础，这种损伤有助于肌腱弱化，导致断裂。尽管如此，人们对肌腱疲劳损伤累积的力学和微观结构机制知之甚少，肌腱对这种损伤的反应的生物学过程也不清楚。肌腱疾病的动物模型通常是急性撕裂模型，其不模拟在明显断裂之前在肌腱中观察到的慢性变性，或具有不明确的机械损伤（例如跑步机过度使用）的运动过度使用模型，其不允许梳理肌腱对精确剂量的基质损伤的机械和生物反应。拟议的研究将使用我们最近开发的大鼠髌腱模型，该模型允许在活腱中产生亚失效疲劳损伤，以测试疲劳损伤的肌腱随着时间的推移恢复正常的结构和机械性能的假设。在第一系列的研究中，我们将表征疲劳过程中的力学和形态学在活肌腱在不同的应力和不同的损伤端点加载。在实验2中，我们将在活体肌腱中引入不同程度的疲劳，并从机械和微观结构上研究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.