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

基本信息

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
项目类别：
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

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

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项目摘要

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/摘要尿道的儿科和成人疾病，包括催生，创伤和严格疾病代表大量的医疗保健伯恩根（Burnens），需要手术干预才能取代发展中国家或损坏的组织以保留尿路功能。自体组织移植物衍生出经外皮肤在端到端吻合的情况下，襟翼或颊粘膜主要用于恢复尿道连续性不可行。但是，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。丝纤维蛋白（SF）生物材料提供了特殊的组合物理特征，包括高拉伸强度和弹性，潜水员处理的灵活性，受控可降解性和低免疫原性，以创建“现成”脚手架来治疗尿道狭窄疾病。新型尿道重建策略采用双层（BL）SF脚手架的SF浸渍能够靶向干细胞归因因子的水凝胶MCP1/CCL2或SDF1α/CXCL12将被开发和研究，以恢复正常排尿和促进优越的建设性的能力在新开发的大型动物模型中，男性和女性的长尿道狭窄。在这个提案，我们将挑战总体假设：加载带有SF水凝胶的复合BLSF矩阵能够控制MCP1/CCL2或SDF1α/CXCL12的释放将为恢复提供超级方法与颊粘膜移植物相比，长尿道狭窄的功能。提案的具体目的是：特定目标1：确定CXCR4-SDF1α/CXCL12和CCR2-MCP1/CCL2信号轴的影响在支架介导的尿道组织再生中，尿道狭窄修复模型。具体目标2：创建MCP-1/CCL2和SDF1α/CXCL12释放，复合BLSF移植物，具有促进的能力长尿道狭窄的新型男性和雌性猪模型中的优质尿道再生。