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

项目总结/摘要 先天性和后天性泌尿系膀胱功能性和解剖性梗阻 异常导致膀胱容量减少、顺应性降低、尿路上皮功能障碍， 失禁肠膀胱成形术被用作增加膀胱容量和减少 高膀胱内压以保护梗阻性膀胱疾病患者的肾功能。但 在自体胃肠道移植物中存在吸收性肠上皮常常导致 并发症，如慢性尿路感染，粘液生产，代谢异常，一旦 整合到泌尿道中。丝素蛋白（SF）生物材料提供了一种特殊的物理组合， 具有高拉伸强度和弹性，加工灵活性多样， 可降解性和低免疫原性，以创建用于治疗梗阻性膀胱的“现成”支架 疾病采用SF浸渍的双层（BL）SF支架的新型膀胱重建策略 能够靶向膀胱内递送抗纤维化治疗剂、常山酮、ABT-263和泛- 将开发TGF-β中和抗体并研究其恢复正常尿动力学的能力 参数，并促进上级建设性重塑，在一个新开发的，大型动物模型的部分 膀胱出口梗阻（pBOO）。在本提案中，我们将挑战以下总体假设： 载有能够膀胱内释放抗纤维化化合物的SF水凝胶的BLSF基质将提供 与以下方法相比， 肠膀胱成形术具体目标1：评估慢性病的影响 pBOO对使用BLSF支架进行膀胱扩大成形术后的膀胱再生过程的影响。具体目标 2：开发浸渍有SF水凝胶的复合BLSF移植物，其具有膀胱内递送 抗纤维化药物，并比较其重建慢性梗阻膀胱的疗效， 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.