Drug Eluting Silk Fibroin Grafts for Repair of Long Urethral Strictures

项目总结/摘要 儿童和成人尿道疾病，包括尿道下裂、创伤和狭窄疾病 代表需要手术干预以替代发育缺失的显著卫生保健负担， 或受损组织来保护尿道功能生殖器外皮肤自体组织移植 皮瓣或颊粘膜主要用于在端端吻合的情况下恢复尿道连续性 是不可行的。然而，这些方法与不良副作用有关，包括狭窄 复发、憩室和瘘管形成。丝素蛋白（SF）生物材料提供了一个特殊的组合 物理特性，包括高拉伸强度和弹性，多种加工柔性，可控性， 可降解性和低免疫原性，以创建用于治疗尿道狭窄的“现成”支架 疾病采用SF浸渍的双层（BL）SF支架的新型尿道重建策略 能够靶向尿道递送干细胞归巢因子MCP 1/CCL 2或SDF 1 α/CXCL 12的水凝胶将 开发和研究其恢复正常排尿和促进上级建设性的能力 在新开发的雄性和雌性长尿道狭窄的大型动物模型中进行重塑。在这 我们的建议，我们将挑战的整体假设，即：复合BLSF矩阵载有SF水凝胶 能够控制释放MCP 1/CCL 2或SDF 1 α/CXCL 12将提供一种上级的恢复方法， 与颊粘膜移植物相比，长尿道狭窄的功能。提案的具体目标 具体目标1：确定CXCR 4-SDF 1 α/CXCL 12和CCR 2-MCP 1/CCL 2信号轴的影响 支架介导的尿道组织再生在兔尿道狭窄修复模型中的作用。具体目标二： 产生MCP-1/CCL 2和SDF 1 α/CXCL 12释放的复合BLSF移植物，其具有促进 新型雄性和雌性猪长尿道狭窄模型中的上级功能性尿道再生。

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.