Modulating Inflammation and Fibrosis to Control Scarring in Muscle Wounds

描述（由申请人提供）：在美国，休闲以及工作场所和家庭中发生的肌肉损伤是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，但对于较大的缺陷，愈合缓慢和成纤维细胞过度增殖经常导致纤维化和疤痕，从而导致肌肉损伤。 可以形成机械屏障，延迟或限制肌纤维弥合损伤间隙。最近的研究结果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稳态的炎症过程之间的差异。鉴于预防纤维化疤痕所需的多种需求，我们组建了一个多学科团队，采用主动策略，以特定部位和时间安排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 将开发并表征一种机械灵活的控释系统，用于局部递送抗炎、抗氧化、促消退和抗纤维化生物分子。就这一目标而言，假设这些设备可以定制，以提供抗炎、抗氧化、促消退和抗纤维化分子，其离散分布大致遵循伤口愈合过程的动力学。目标 2 将确定抗​​炎、抗氧化、促消退和抗纤维化成分的受控、局部、顺序释放的功效，以增强啮齿动物骨骼肌缺陷模型体内的结构/组织学、生化和功能特性。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，不仅会增强肌肉再生，而且这些薄膜比那些只释放一种成分或不考虑伤口愈合过程中事件顺序而递送它们的薄膜更有效。此外，这些方法不仅可应用于修复骨骼肌缺陷，还可用于治疗许多其他需要控制炎症和随后的伤口愈合过程的疾病。

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.