Stem Cell-Derived Extracellular Vesicles for Enhanced Tendon Healing

项目总结/摘要 肌腱和韧带损伤占美国每年所有肌肉骨骼损伤的近一半 States.即使有相当大的改善，手术修复也不能始终如一地恢复患者的身体功能。 受伤的组织因此，有很长的延迟或未能恢复到受伤前的活动，从而构成了一个 严重的临床、经济和社会负担。手术结果不佳主要是由于过度 炎症和修复组织再生不足。因此，本研究的长期目标是 开发生物疗法以增强肌腱修复。随着再生医学的最新进展， 细胞外囊泡（EV）的研究，拟议的项目已被设计为调查的机制作用 以及干细胞EV在肌腱修复中的临床相关应用。EV是膜封闭的纳米颗粒 通过将生物活性分子（蛋白质、RNA等）从细胞到 cell.虽然已经发现来自脂肪源性干细胞（ASC）的EV调节组织炎症， 反应并促进一些软组织的再生，但它们在肌腱修复中的作用尚未直接研究 探讨了目的1将使用共培养模型来确定ASC的作用和潜在的分子机制 EV在调节巨噬细胞炎症反应和肌腱细胞活性和功能中的作用 肌腱损伤与修复目标2将使用临床相关的小鼠跟腱损伤和修复模型， 确定ASC EV在减轻炎症、增加肌腱基质再生、 并恢复受损肌腱的结构和强度。目标1的结果将揭示对 探讨ASC EV调控肌腱愈合过程的机制，为进一步工程化 在ASC EV中定义组件，以提供改善的治疗效果和安全性。积极成果 目的2将证明基于ASC EV治疗肌腱损伤以及其他相关疾病的概念 并进行临床研究，从而有助于改善肌肉骨骼健康。

PROJECT SUMMARY/ABSTRACT Tendon and ligament injuries account for nearly half of all musculoskeletal injuries each year in the United States. Even with considerable improvements, surgical repairs do not consistently restore physical function of injured tissues. As a result, there are lengthy delays or failures to return to pre-injury activities, thus posing a substantial clinical, economic and social burden. Poor surgical outcomes primarily result from excessive inflammation and insufficient regeneration of repaired tissues. Therefore, the long-term goal of this study is to develop biologic therapies to enhance tendon repair. With recent advances in regenerative medicine and extracellular vesicle (EV) research, the proposed project has been designed to investigate the mechanistic role and clinically relevant application of stem cell EVs in tendon repair. EVs are membrane-enclosed nanoparticles that mediate intercellular communication by transferring bioactive molecules (proteins, RNAs, etc.) from cell to cell. Although EVs from adipose-derived stem cells (ASCs) have been found to modulate tissue inflammatory response and to promote regeneration of some soft tissues, their role in tendon repairs has not been directly explored. Aim 1 will use co-culture models to determine the role and underlying molecular mechanism of ASC EVs in regulating macrophage inflammatory response and tenocyte activity and function in the context of tendon injury and repair. Aim 2 will use a clinically relevant mouse Achilles tendon injury and repair model to determine the therapeutic efficacy of ASC EVs in reducing inflammation, increasing tendon matrix regeneration and restoring structure and strength of injured tendons. Results from Aim 1 will reveal new insights into the mechanism of ASC EVs in regulating tendon healing process and provide guidance for further engineering of defined components within ASC EVs to provide improved therapeutic efficacy and safety. Positive outcomes from Aim 2 will prove the concept of ASC EV-based therapy for tendon injury as well as other related disorders and lead to clinical studies, thus contributing to the improvement of musculoskeletal health.