Drug Eluting Silk Fibroin Grafts for Repair of Long Urethral Strictures

PROJECT SUMMARY/ABSTRACT Pediatric and adult disorders of the urethra including hypospadias, trauma, and stricture disease represent significant health care burdens which require surgical intervention to replace developmentally absent or damaged tissue to preserve urinary tract function. Autologous tissue grafts derived from extragenital skin flaps or buccal mucosa are primarily utilized to restore urethral continuity in cases where end-to-end anastomosis is not feasible. However, these approaches have been associated with adverse side effects including stricture recurrence, diverticulae and fistula formation. Silk fibroin (SF) biomaterials provide an exceptional combination of physical characteristics including high tensile strength and elasticity, diverse processing flexibility, controllable degradability, and low immunogenicity to create “off-the-shelf” scaffolds for treatment of urethral stricture disease. Novel urethral reconstructive strategies employing bi-layer (BL) SF scaffolds impregnated with SF hydrogels capable of targeted urethral delivery of stem cell homing factors, MCP1/CCL2 or SDF1α/CXCL12, will be developed and investigated for their ability to restore normal micturition and promote superior constructive remodeling in newly developed, large animal models of long urethral strictures in males and females. In this proposal, we will challenge the overall hypothesis that: composite BLSF matrices loaded with SF hydrogels capable of controlled release of MCP1/CCL2 or SDF1α/CXCL12 will provide a superior approach for restoring function of long urethral strictures in comparison to buccal mucosal grafts. The specific aims of the proposal are: Specific Aim 1: Determine the impact of CXCR4-SDF1α/CXCL12 and CCR2-MCP1/CCL2 signaling axes on scaffold-mediated, urethral tissue regeneration in a rabbit model of urethral stricture repair. Specific Aim 2: Create MCP-1/CCL2 and SDF1α/CXCL12 releasing, composite BLSF grafts with the capacity to promote superior functional urethral regeneration in novel male and female porcine models of long urethral strictures.