Immune Modulatory Nanofibers for Skeletal Muscle Reconstruction

摘要/项目摘要 缺血性损伤、神经横断损伤或体积性损伤导致的严重骨骼肌创伤 缺陷是一个棘手的问题。后者造成的功能障碍和残疾日益严重， 临床负担为了应对这一挑战，该提案寻求开发生物材料递送系统， 调节微环境因素，利用募集血液的促再生功能 单核细胞，以增强体积肌肉愈合结果。在体积肌肉损失的临床前模型中， 我们已经表明，靶向生物活性脂质受体的免疫调节小分子的递送 增加损伤小生境内的伤口修复巨噬细胞，并增强修复机制， 血管生成、基质沉积和肌纤维再生。拟议研究的总体假设 1-磷酸鞘氨醇（S1 P）受体的局部药理学靶向独特地募集Ly 6Clo 单核细胞直接从血液到损伤小生境，在那里它们作为伤口愈合的偏向祖细胞 受伤肌肉内的巨噬细胞。我们的具体目标如下：目标1： 浸润到鼠脊髓背角肌体积损失模型中以及免疫细胞与肌肉的相互作用 目的2：评估S1 P受体靶向小分子的局部递送对卫星细胞的影响， 聚合物支架对骨骼肌损伤后骨髓细胞聚集和行为的影响;目的3：评估 小鼠股四头肌临界大小体积缺损对局部免疫反应的功能结果 S1 P受体靶向小分子的递送。随着肌肉损伤后遗症的增加， 随着年龄的增长，肌肉损伤对国内老龄人口的负担将是不成比例的。 越来越严重。砰，周围的机制体积肌肉缺损的愈合必须是 为了推进转化疗法而阐明。

Abstract/Project Summary Severe skeletal muscle trauma resulting from ischemic damage, nerve transection injuries, or volumetric defects is an intractable problem. Dysfunction and disability owing to the latter are an increasingly significant clinical burden. To address this challenge, this proposal seeks to develop biomaterial delivery systems that regulate the micro-environmental factors that harness the pro-regenerative functions of recruited blood monocytes to enhance volumetric muscle healing outcomes. In a pre-clinical model of volumetric muscle loss, we have shown that delivery of immune modulatory small molecules targeted to bioactive lipid receptors increases wound repair macrophages within the injury niche and enhances repair mechanisms such as angiogenesis, matrix deposition, and muscle fiber regrowth. The overall hypothesis for the proposed research is that local pharmacological targeting of sphingosine 1-phosphate (S1P) receptors uniquely recruits Ly6Clo monocytes directly from blood to the injury niche where they serve as biased progenitors of wound healing macrophages within injured muscle. Our specific aims are as follows: Aim 1: To characterize inflammatory infiltrate into the murine spinotrapezius volumetric muscle loss model and immune cell interactions with muscle satellite cells; Aim 2: To assess the impact of local delivery of S1P receptor targeted small molecules from polymer scaffolds on myeloid cell accumulation and behavior after skeletal muscle injury; Aim 3: To evaluate functional outcomes within a critical-sized volumetric defect in the murine quadriceps in response to local delivery of S1P receptor targeted small molecules. As the sequelae of muscle injuries increases at a disproportionate rate with advancing age, the burden of muscle injury on an aging domestic population will be increasingly severe. Thud, mechanisms surrounding the healing of volumetric muscle defects must be elucidated in order to advance translational therapeutics.