Mechanisms of Sub-rupture Local Tendon Damage and Repair

描述（由申请人提供）：肌腱病和肌腱断裂是常见的疼痛和衰弱的临床问题，与经常经历的高拉伸载荷、结构和材料不均匀性以及对损伤的愈合反应不足有关。因此，研究评估了韧带和肌腱在过度使用和循环负荷下的机械和结构退化，以研究肌腱病变的发生和进展机制。已经量化了钢筋束中的表面应变，以推断其承载能力和损伤开始或进展的可能性。总体分子表达也已评估，以应对肌腱负荷，使肌腱损伤和修复的机制的结论。尽管从这些研究中获得了一些见解，但局部肌腱应变、结构损伤和局部分子对亚断裂疲劳损伤的反应之间的关系尚未建立。建立分子和结构变化与肌腱承载能力之间的直接关系将有助于深入了解肌腱损伤和修复的机制。体内应变测量方法和分子分析的局限性排除了随时间推移体内局部肌腱应变的分子响应与幅度和方向之间的关系的评价。因此，本提案的总体目标是量化大鼠髌腱中的局部应变与体内疲劳损伤模型中肌腱内的局部分子反应之间的关系。将在疲劳加载后测量肌腱的局部分子反应，并随着时间的推移确定对损伤和修复的反应。将开发技术来测量高分辨率的体内肌腱应变和结构损伤，这将与空间分子反应。这将提供缺失的力学和结构背景来解释肌腱对损伤和愈合的分子反应。 评价局部而非大块组织力学和分子响应将提供对大块组织分析中与亚破裂疲劳损伤修复相关的任何分子变化是否源于承载或机械缺陷区域的深入了解。虽然肌腱的整体分子反应可能表明修复或重塑，但拟议研究的数据将显示受损的机械缺陷区域是否可以愈合或仅进一步受损。随着时间的推移，评估这些关系将探索肌腱修复的机制，这可能会影响有效治疗的发展。 公共卫生相关性：肌腱病是一种常见的和使人衰弱的临床问题。该提案的目标是量化疲劳加载后体内肌腱内应变、分子反应和结构变化之间的局部关系，并随着时间的推移确定对损伤和修复的反应。这将提供缺失的力学和结构背景，以解释肌腱对损伤和修复的分子反应。

DESCRIPTION (provided by applicant): Tendinopathy and tendon rupture are common painful and debilitating clinical problems associated with frequently experienced high tensile loads, structural and material inhomogeneity, and inadequate healing responses to injury. Studies have therefore evaluated mechanical and structural degeneration of ligaments and tendons in response to overuse and cyclic loading to investigate mechanism of initiation and progression of tendinopathy. Surface strain in the tendon has been quantified to extrapolate its load bearing capacity and likelihood of damage initiation or progression. Overall molecular expression has also been evaluated in response to tendon loading to make conclusions regarding mechanisms of tendon damage and repair. Despite insight gained from these studies, the relationship between local tendon strain, structural damage, and the local molecular response to sub-rupture fatigue damage has not been established. Establishing the direct relationship between the molecular and structural changes and the load bearing capacity of the tendon will lend insight into the mechanisms of tendon damage and repair. Limitations of in-vivo strain measurement methods and molecular analyses preclude evaluation of the relationship between the molecular response and the magnitude and direction of the local tendon strain in-vivo over time. Therefore the general objective of this proposal is to quantify the relationship between the local strain in rat patellar tendons and the local molecular response within the tendon in an in-vivo fatigue damage model. The local molecular response of the tendon will be measured after fatigue loading, and over time to determine the response to damage and repair. Techniques will be developed to measure high resolution in-vivo tendon strain and structural damage which will be related to the spatial molecular response. This will provide the missing mechanical and structural context to interpret the molecular response of tendon to damage and healing. Evaluating the local instead of bulk tissue mechanics and molecular response will provide insight into whether any molecular changes associated with sub-rupture fatigue damage repair in bulk tissue analysis stem from load bearing or mechanically deficient regions. While the bulk molecular response of the tendon may be indicative of repair or remodeling, data from the proposed study will show whether a damaged mechanically deficient region can heal or only be further damaged. Evaluating these relationships over time will explore mechanisms of tendon repair which could influence development of effective treatment. PUBLIC HEALTH RELEVANCE: Tendinopathy is a common and debilitating clinical problem. The goal of this proposal is to quantify the local relationship between strain, molecular response, and structural changes within the tendon in-vivo after fatigue loading and over time to determine the response to damage and repair. This will provide the missing mechanical and structural context to interpret the molecular response of the tendon to damage and repair.