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.