Drug Eluting Silk Fibroin Grafts for Repair of Long Urethral Strictures

药物洗脱丝素蛋白移植物修复长尿道狭窄

• 批准号: 10587176
• 负责人: Joshua Robert Mauney
• 金额: $ 65.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587176
• 关键词: Adipose tissue; Adopted; Adult; Anastomosis - action; Animal Model; Anti-Inflammatory Agents; Autologous; Biocompatible Materials; Bladder; Bombyx; Bombyx mori; Bone Marrow; CCL2 gene; CXCR4 Receptors; CXCR4 gene; Cell Count; Cells; Characteristics; Childhood; Chronic; Clinical; Complex; Congenital Abnormality; Defect; Development; Devices; Disease; Elasticity; End stage renal failure; Epispadias; Excision; Family suidae; Female; Fibroins; Fibrosis; Fistula; Functional disorder; Genital; Genitalia; Goals; Growth; Healthcare; Homing; Human; Hydrogels; Hypospadias; Implant; In Vitro; Incontinence; Infertility; Injury; Laboratories; Length; Mediating; Mesenchymal Stem Cells; Modality; Modeling; Morbidity - disease rate; Natural regeneration; Obstruction; Operative Surgical Procedures; Oral mucous membrane structure; Organ; Oryctolagus cuniculus; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Play; Polyesters; Publishing; Recurrence; Reporting; Research; Resources; Role; Seed Implantation; Serious Adverse Event; Signal Pathway; Signal Transduction; Silk; Site; Skin; Source; Stromal Cell-Derived Factor 1; Surgical Management; Techniques; Tensile Strength; Testing; Tissue Engineering; Tissue Grafts; Tissues; Trauma; Ureter; Urethra; Urethral Diseases; Urethral Diverticulum; Urethral Meatus Stenosis; Urethral Stricture; Urinary tract; Urinary tract infection; Urination; Urothelial Cell; Validation; biodegradable scaffold; care burden; chemokine; clinical practice; controlled release; experimental study; flexibility; functional restoration; high risk; immunogenicity; improved; innovation; male; mechanical properties; monocyte chemoattractant protein 1 receptor; novel; paracrine; patient population; porcine model; pre-clinical; preservation; receptor-mediated signaling; reconstruction; recruit; repaired; replacement tissue; scaffold; side effect; stem cell delivery; stem cells; tissue regeneration; tissue repair; transdifferentiation; wound care; wound healing

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.

项目摘要/摘要 儿童和成人的尿路疾病，包括尿道下裂、创伤和狭窄疾病 代表着巨大的医疗负担，需要手术干预来取代发育缺失 或受损的组织以保护尿路功能。来源于生殖器外皮肤的自体组织移植 在端端吻合的情况下，瓣或颊粘膜主要用于恢复尿路的连续性 是不可行的。然而，这些方法都与包括狭窄在内的不良副作用有关。 复发、憩室和瘘管形成。丝素(SF)生物材料提供了一种特殊的组合 具有高抗拉强度和弹性、多种加工灵活性、可控性等物理特性 可降解性和低免疫原性制造用于治疗尿路狭窄的现成支架 疾病。应用浸渍SF的双层SF支架重建尿路的新策略 能够靶向通过尿路传递干细胞归巢因子的水凝胶，MCP1/CCL2或SDF1α/CXCL12，将 被开发和调查他们恢复正常排尿的能力和促进更好的建设性 新开发的男性和女性长尿道狭窄大型动物模型的重塑。在这 提案中，我们将挑战以下总体假设：加载SF水凝胶的复合BLSF基质 能够控制释放mcp1/ccl2或sdf1α/cxcl12将提供一种更好的修复方法 长段尿路狭窄与口腔黏膜移植物的功能比较。该提案的具体目的 具体目标1：确定CXCR4-SDF1α/CXCL12和CCR2-MCP1/CCL2信号轴的影响 支架介导的兔尿道狭窄修复模型中的尿道组织再生。具体目标2： 创建mcp-1/ccl2和sdf1α/cxcl12释放，具有促进能力的复合BLSF移植物 新的雄性和雌性猪长尿道狭窄模型的优势功能再生。