Partial Bladder Outlet Obstruction: Mechanisms of Injury and Novel Repair Strategies

项目摘要/摘要 先天性和获得性泌尿系功能性和解剖性膀胱梗阻 异常导致膀胱容量减少，顺应性降低，尿路上皮功能障碍，以及 大小便失禁。肠膀胱成形术被用作增加膀胱容量和减少膀胱体积的主要策略 高膀胱内压对梗阻性膀胱病患者肾功能的保护作用然而， 自体胃肠道移植物中可吸收的肠上皮的存在常常导致 慢性尿路感染、粘液产生和代谢异常等并发症 整合到尿路中。丝素(SF)生物材料提供了一种特殊的物理组合 特点：抗拉强度和弹性高，加工灵活性多样，可控 可降解性和低免疫原性制造用于治疗梗阻性膀胱的现成支架 疾病。应用浸渍SF的双层SF支架重建膀胱的新策略 水凝胶能够靶向膀胱内输送抗纤维化治疗药物、常青藤酮、ABT-263和PAN-2。 将开发转化生长因子-β中和抗体，并研究其恢复正常尿动力学的能力 参数并促进新开发的部分节段性脑缺血大动物模型的优越结构重构 膀胱出口梗阻(PBOO)。在这项提案中，我们将挑战总体假设：复合 加载了能够在膀胱内释放抗纤维化化合物的SF水凝胶的BLSF基质将提供 一种恢复慢性梗阻膀胱正常膀胱功能的更好方法 肠膀胱成形术。申请的具体目标是：具体目标1：评估慢性疾病的影响 PBOO对BLSF支架膀胱成形术后膀胱再生过程的影响。特定目标 2：开发浸渍SF水凝胶的复合BLSF移植物，具有膀胱内释放的能力 抗纤维化药物及对慢性梗阻性膀胱重建的疗效比较 肠膀胱成形术。

PROJECT SUMMARY/ABSTRACT Functional and anatomical obstruction of the urinary bladder from congenital and acquired urologic abnormalities results in reduced bladder capacity, diminished compliance, urothelial dysfunction, and incontinence. Enterocystoplasty is utilized as the primary strategy to increase bladder capacity and decrease high intravesical pressures to preserve renal function in patients with obstructive bladder disease. However, the presence of absorptive intestinal epithelium in autologous gastrointestinal grafts frequently leads to serve complications such as chronic urinary tract infection, mucus production, and metabolic abnormalities once integrated into the urinary tract. 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 obstructive bladder disease. Novel bladder reconstructive strategies employing bi-layer (BL) SF scaffolds impregnated with SF hydrogels capable of targeted intravesical delivery of anti-fibrotic therapeutics, halofuginone, ABT-263, and pan- TGF-β neutralizing antibodies will be developed and investigated for their ability to restore normal urodynamic parameters and promote superior constructive remodeling in a newly developed, large animal model of partial bladder outlet obstruction (pBOO). In this proposal, we will challenge the overall hypothesis that: composite BLSF matrices loaded with SF hydrogels capable of intravesical release of anti-fibrotic compounds will provide a superior approach for restoring normal bladder function in chronically obstructed bladders in comparison to enterocystoplasty. The specific aims of the application are: Specific Aim 1: Evaluate the impact of chronic pBOO on bladder regenerative processes following augmentation cystoplasty with BLSF scaffolds. Specific Aim 2: Develop composite BLSF grafts impregnated with SF hydrogels with the capacity for intravesical delivery of anti-fibrotic agents and compare their efficacy for reconstruction of chronically obstructed bladders to enterocystoplasty.