Development of Silk Fibroin Grafts for Reconstruction of Esophageal Defects

项目摘要/摘要 先天性和获得性畸形所致的食道组织丢失通常通过外科手术治疗 自体胃肠间置移植以恢复器官连续性。不幸的是，这些 入路与严重的不良并发症有关，如食道动力障碍、吞咽困难和 供体部位发病率。丝素(SF)生物材料提供了一种特殊的物理特性组合 包括高抗拉强度和弹性、多样化的加工灵活性和可调的降解性 适合支持食道功能。因此，这些支架可能会克服有害的副作用 与传统的重建技术相关联，可作为食道组织的现成移植物 修理。通过了解先天免疫反应在促进心脏建设性重塑中的作用 对于食道缺陷，我们将设计具有选择性微环境线索的SF植入物 巨噬细胞激活表型走向最大再生结果。在本提案中，我们将测试 总体假设：无细胞SF基质通过CD206+促进食道缺损的功能恢复 M2a依赖巨噬细胞的建设性重塑。申请的具体目的是：具体目的 1：在临床前动物模型中，开发用于功能修复长间隙食道缺损的SF移植物。特定的 目的2：确定CD206+M2a巨噬细胞对支架介导的、结构性重塑的影响。 食道缺陷。具体目标3：确定免疫调节性SF移植物的有效性，以最大限度地 食道狭窄病的结构性重塑和器官功能恢复。

PROJECT SUMMARY/ABSTRACT Loss of esophageal tissue from congenital and acquired abnormalities is often surgically managed with autologous gastrointestinal interposition grafts in order to restore organ continuity. Unfortunately, these approaches are associated with severe adverse complications such as esophageal dysmotility, dysphagia, and donor site morbidity. Silk fibroin (SF) biomaterials provide an exceptional combination of physical characteristics including high tensile strength and elasticity, diverse processing flexibility, and tunable degradability that are well suited to support esophageal function. Therefore, these scaffolds may overcome the deleterious side-effects associated with conventional reconstructive techniques and serve as “off-the-shelf” grafts for esophageal tissue repair. By understanding the role of the innate immune response in facilitating constructive remodeling of esophageal defects, we will design SF implants with selective microenvironmental cues sufficient to modulate macrophage activation phenotypes toward maximal regenerative outcomes. In this proposal, we will test the overall hypothesis that: acellular SF matrices promote functional restoration of esophageal defects via CD206+ M2a macrophage-dependent constructive remodeling. The specific aims of the application are: Specific Aim 1: Develop SF grafts for functional repair of long-gap esophageal defects in a preclinical animal model. Specific Aim 2: Determine the impact of CD206+ M2a macrophages on scaffold mediated, constructive remodeling of esophageal defects. Specific Aim 3: Determine the efficacy of immunomodulatory SF grafts to maximize constructive remodeling and restore organ function in esophageal stricture disease.