Development of Silk Fibroin Grafts for Reconstruction of Esophageal Defects

项目总结/摘要 先天性和后天性异常引起的食管组织丢失通常通过手术治疗， 自体胃肠间置移植物，以恢复器官连续性。可惜这些 入路与严重的不良并发症相关，如食管动力障碍、吞咽困难， 供区发病率。丝素蛋白（SF）生物材料提供了一种特殊的物理特性组合 包括高拉伸强度和弹性、多种加工柔性和可调降解性， 适合支持食管功能。因此，这些支架可以克服有害的副作用 与传统的重建技术相关，并作为食管组织的“现成”移植物 修复.通过了解先天性免疫反应在促进组织结构重建中的作用， 食管缺损，我们将设计具有选择性微环境线索的SF植入物，足以调节 巨噬细胞活化表型对最大的再生结果。在本提案中，我们将测试 总体假设：脱细胞SF基质通过CD 206+促进食管缺损的功能恢复 M2 a巨噬细胞依赖性结构重建。申请的具体目的是：具体目的 1：在临床前动物模型中开发SF移植物用于长间隙食管缺损的功能性修复。具体 目的2：确定CD 206 + M2 a巨噬细胞对支架介导的， 食管缺损具体目标3：确定免疫调节SF移植物的功效，以最大限度地 食管狭窄性疾病的结构性重建和器官功能恢复。

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.