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性运动引起，可导致严重疼痛和长期残疾。肌腱病变的一个标志是细胞外基质（ECM）的破坏，特别是胶原蛋白，导致组织力学特性和功能的丧失。尽管各种类型的ECM蛋白酶与肌腱病变的组织变性有关，但它们的相对数量和表达时间尚不清楚。这种知识的缺乏严重阻碍了为这些酶提供抑制剂以减少病理进展和改善肌腱病变愈合的治疗方法的发展。我们的长期目标是发展改进的再生医学策略，以帮助修复肌腱病变组织。该提案的中心假设是，与注射没有载体的抑制剂相比，使用可注射的生物材料支持蛋白酶抑制剂的持续递送，对肌腱病变中的蛋白酶活性进行长期调节，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验证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体内与ECM降解相关的蛋白酶和抑制剂。2)评价蛋白酶抑制剂缓释对大鼠冈上肌腱过度使用性损伤发展的影响。这项工作是创新的，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，以防止肌腱病变进一步的组织变性。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治疗肌腱病，以及其他蛋白酶介导的退行性疾病在整个身体的一系列组织。

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.