Injectable Biomaterials to Modulate Protease Activity in Tendinopathy

描述（由申请人提供）：肌腱病是一种常见的肌腱疾病，由工作场所或体育活动中的重复运动引起，可导致严重疼痛和长期残疾。肌腱病的一个标志是细胞外基质（ECM），特别是胶原蛋白的破坏，这导致组织机械性能和功能的丧失。虽然各种类型的ECM蛋白酶已被牵连在肌腱病变的组织变性，其相对量和其表达的时间仍然不清楚。这种知识的缺乏显著阻碍了治疗的发展，以提供这些酶的抑制剂，以减少病理进展和改善肌腱病的愈合。 我们的长期目标是开发改进的再生医学策略，以帮助修复肌腱病变组织。该提议的中心假设是，与注射无载体的抑制剂相比，使用支持蛋白酶抑制剂持续递送的可注射生物材料长期调节肌腱病变中的蛋白酶活性将导致更大的肌腱组织结构和机械性能。我们的总体目标将通过在以下两个具体目标中测试我们的中心假设来实现：1）在大鼠冈上肌腱过度使用模型中研究与ECM体内降解相关的蛋白酶和抑制剂。2)评价蛋白酶抑制剂缓释剂对大鼠冈上肌腱过度使用损伤的影响。 这项研究是创新性的，因为它采用了一种控制良好的可注射载体来实现蛋白酶抑制剂的局部持续释放，以防止肌腱病变中的进一步组织变性。这些研究的结果预计将产生重大影响，因为它们将导致更有效的再生医学疗法用于肌腱病，以及全身一系列组织中的其他蛋白酶介导的退行性疾病。

DESCRIPTION (provided by applicant): Tendinopathy is a common tendon disorder resulting from repetitive motion in the workplace or during athletic activity that can cause severe pain and long-term disability. A hallmark of tendinopathy is disruption of extracellular matrix (ECM), particularly collagen, which leads to loss of tissue mechanical properties and function. Although various classes of ECM proteases have been implicated in tissue degeneration in tendinopathy, their relative amounts and the timing of their expression remains unclear. This lack of knowledge has significantly hampered development of treatments to deliver inhibitory agents for these enzymes to reduce pathology progression and improve healing in tendinopathy. Our long-term goal is to develop improved regenerative medicine strategies to aid repair of tendinopathic tissues. The central hypothesis of this proposal is that long-term regulation of protease activity in tendinopathy using injectable biomaterials supporting sustained delivery of a protease inhibitor will result in greater tendon tissue structure and mechanical properties compared with injection of inhibitor without the carrier. Our overall objective will be accomplished by testing our central hypothesis in the following two specific aims: 1) Investigate proteases and inhibitors related to ECM degradation in vivo in a rat supraspinatus tendon overuse model. 2) Evaluate the effects of sustained release of a protease inhibitor on the development of overuse injury in rat supraspinatus tendons. The proposed work is innovative because it employs a well-controlled, injectable carrier to achieve local, sustained release of protease inhibitors to protect against further tissue degeneration in tendinopathy. Results from these studies are expected to have a significant impact because they will lead to more efficacious regenerative medicine therapies for tendinopathy, as well as other protease- mediated degenerative conditions in a range of tissues throughout the body.