Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds

描述(申请人提供)：肌肉损伤，发生在娱乐场所以及工作场所和家庭，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的潜力，但对于较大的缺陷，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。 可以产生一种机械屏障，延迟或限制肌纤维弥合损伤间隙。最近的发现已经开始阐明促进损伤后肌肉修复和再生的炎症过程与破坏肌肉内稳的炎症过程之间的差异。鉴于预防纤维性瘢痕形成所需的多种需求，已经组建了一个多学科团队来应用一种积极的策略，即以特定部位和临时协调的方式输送多种生物分子，以治疗炎症和伤口愈合过程的不同方面。目的1将开发和表征一种机械灵活的控制释放系统，用于局部递送抗炎、抗氧化、促拆分和抗纤维化的生物分子。关于这一目标，假设这些设备可以量身定做，以提供抗炎、抗氧化剂、促分解和抗纤维化分子，其离散的轮廓大致遵循伤口愈合过程的动力学。目的2在啮齿动物骨骼肌缺陷模型中，确定受控、局部、顺序释放抗炎、抗氧化、促拆分和抗纤维化成分以增强体内结构/组织学、生化和功能特性的有效性。工作假说是，顺序治疗设备，即化解炎症并防止纤维化的材料，不仅将促进肌肉再生，而且这些薄膜将比那些只释放其中一种成分或提供它们的薄膜更有效，而不考虑伤口愈合过程中的顺序。此外，这些方法不仅适用于骨骼肌缺损的修复，而且还适用于许多其他需要控制炎症和随后的伤口愈合过程的疾病的治疗。

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.