Injectable Biomaterials to Modulate Protease Activity in Tendinopathy

描述(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，可导致剧烈疼痛和长期残疾。肌腱病的一个特征是细胞外基质(ECM)的破坏，特别是胶原，这会导致组织机械性能和功能的丧失。尽管各种类型的ECM蛋白与肌腱病的组织退行性变有关，但它们的相对数量和表达的时间尚不清楚。这种知识的缺乏大大阻碍了为这些酶提供抑制剂以减缓肌腱病的病理进展和改善愈合的治疗方法的发展。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。这一建议的中心假设是，与注射无载体的抑制剂相比，使用支持持续传递的可注射生物材料来长期调节肌腱病中的蛋白酶活性将导致更大的肌腱组织结构和力学性能。我们的总体目标将通过以下两个具体目标来检验我们的中心假设：1)在大鼠冈上肌腱过度使用的模型中，研究与ECM降解相关的酶和抑制剂。2)评价蛋白水解酶抑制剂缓释对大鼠冈上肌腱过度运动性损伤的影响。这项拟议的工作具有创新性，因为它使用了一种控制良好的可注射载体来实现局部、持续的蛋白酶抑制剂释放，以防止肌腱病中进一步的组织退化。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来治疗肌腱病，以及全身一系列组织中由蛋白酶介导的其他退行性疾病。

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.