Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds

描述（由申请人提供）：肌肉损伤，发生在娱乐以及工作场所和家庭中，是美国最常见的肌肉骨骼疾病之一。卫星细胞为肌肉提供再生潜力，但对于大的缺陷，成纤维细胞的缓慢愈合和过度增殖经常导致纤维化和瘢痕形成， 可以产生延迟或限制肌纤维桥接损伤间隙的机械屏障。最近的研究结果已经开始阐明损伤后促进肌肉修复和再生的炎症过程与破坏肌肉稳态的炎症过程之间的差异。鉴于预防纤维化瘢痕形成所需的多种需求，已经组建了一个多学科团队，以应用主动策略，其中以位点特异性和时间协调的方式递送多种生物分子，以治疗炎症和伤口愈合过程的不同方面。目标1将开发和表征用于抗炎、抗氧化、促分解和抗纤维化生物分子的局部递送的机械柔性控释系统。关于这一目标，假设可以定制该装置以递送具有大致遵循伤口愈合过程的动力学的离散分布的抗炎、抗氧化剂促消退和抗纤维化分子。目的2将确定抗炎、抗氧化、促消退和抗纤维化组分的受控、局部、顺序释放在啮齿动物骨骼肌缺损模型中体内增强结构/组织学、生物化学和功能特性的功效。工作假设是，顺序治疗装置，即，解决炎症然后防止纤维化的材料将不仅增强肌肉再生，而且这些膜将比仅释放一种组分或在伤口愈合期间不考虑事件顺序而递送它们的那些膜更有效。此外，所述方法不仅可适用于修复骨骼肌缺陷，而且可适用于治疗其中需要控制炎症和随后的伤口愈合过程的许多其它疾病。

DESCRIPTION (provided by applicant): Muscle injuries, occurring recreationally as well as in the workplace and home, are among the most common musculoskeletal conditions in the U.S. Satellite cells provide muscle with the potential for regeneration, but for large defects, slow healing and excessive proliferation of fibroblasts frequently results in fibrosis and scarring that can create a mechanical barrier that delays or restricts myofibers from bridging the injury gap. Recent findings have begun to elucidate differences between inflammatory processes that promote muscle repair and regeneration following injury and those that disrupt muscle homeostasis. In light of the multiple demands needed for preventing fibrotic scarring, a multidisciplinary team has been assembled to apply a proactive strategy in which multiple biomolecules are delivered in a site-specific and temporally orchestrated manner to treat different aspects of the inflammatory and wound healing processes. Aim 1 will develop and characterize a mechanically flexible controlled release system for localized delivery of anti- inflammatory, anti-oxidant, pro-resolution, and anti-fibrotic biomolecules. With respect to this Aim, it is hypothesized that the devices can be tailored to deliver anti-inflammatory, anti-oxidant pro-resolution, and anti-fibrotic molecules with discrete profiles that roughly follow the kineticsof the wound healing process. Aim 2 will determine the efficacy of controlled, localized, sequential release of anti-inflammatory, anti- oxidant, pro-resolution, and anti-fibrotic components to enhance structural/histological, biochemical, and functional properties in vivo in a rodent skeletal muscle defect model. The working hypothesis is that sequential treatment devices, i.e., materials that resolve inflammation and then prevent fibrosis, will not only enhance muscle regeneration, but these films will be more effective than those releasing only one of the components or that deliver them without regard to the sequence of events during wound healing. Furthermore, the methods may be applicable not only to repair of skeletal muscle defects but also for treatment of many other diseases in which control of inflammation and subsequent wound healing processes is needed.