Development of Silk Fibroin Grafts for Reconstruction of Pathological Bladders

 描述（由申请人提供）：先天性和获得性泌尿系统异常，包括继发于脊柱裂或脊髓损伤的神经源性膀胱、后尿道瓣膜和良性前列腺增生，经常导致尿路梗阻，最终导致膀胱容量减少和顺应性差。尿失禁、复发性尿路感染和肾功能衰竭是梗阻性膀胱疾病的严重后果。肠膀胱成形术被用作增加膀胱容量和降低高膀胱内压的主要方法，以保护患有病理性膀胱梗阻的患者的肾功能。然而，这种技术的长期疗效受到频繁和严重并发症的阻碍，这些并发症对患者的生活质量产生负面影响。基于丝素蛋白（SF）的植入物提供了非常适合支持膀胱功能的物理特性的特殊组合。因此，这些支架可以克服与肠膀胱成形术相关的有害副作用，并作为用于膀胱重建的“现成”移植物。鉴于M2巨噬细胞激活在协调再生反应中的作用，我们预计可以在缺陷巩固期间促进M2表型的SF支架将有利于改善病理性膀胱性能。在本提案中，我们将检验以下总体假设：与肠膀胱成形术相比，使用能够递送pro-M2巨噬细胞活化因子（IL-4、IL-13）的SF生物材料进行膀胱扩张术将作为改善病理性膀胱功能的上级方法。本申请的具体目的是：具体目的1：在部分膀胱出口梗阻的猪模型中确定SF支架特性对膀胱扩大术后结构性重塑和器官功能的影响。具体目标二：评价基于SF的IL-4/IL-13递送系统诱导M2巨噬细胞活化、增强建设性重塑和改善梗阻性膀胱功能的效用。

 DESCRIPTION (provided by applicant): Congenital and acquired urologic abnormalities including neurogenic bladder secondary to spinia bifida or spinal cord injury, posterior urethral valves, and benign prostatic hyperplasia frequently result in urinary tract obstruction which ultimately leads to diminished bladder capacity and poor compliance. Urinary incontinence, recurrent urinary tract infections, and renal failure are debilitating consequences of obstructive bladder diseases. Enterocystoplasty is utilized as the primary approach to increase bladder capacity and decrease high intravesical pressures in order to preserve renal function in patients afflicted with pathological bladder obstruction. However, the long term efficacy of this technique is hampered by frequent and severe complications which negatively impact patient quality of life. Silk fibroin (SF)-based implants provide an exceptional combination of physical characteristics that are well suited to support bladder function. Therefore, these scaffolds may overcome the deleterious side-effects associated with enterocystoplasty and serve as an "off the shelf" graft for bladder reconstruction. Given the role of M2 macrophage activation in orchestrating regenerative responses, we anticipate that SF scaffolds which can promote an M2 phenotype during defect consolidation will be beneficial in improving pathological bladder performance. In this proposal, we will test the overall hypothesis that: bladder augmentation with SF biomaterials capable of delivering pro-M2 macrophage activation factors (IL-4, IL-13) will serve as a superior approach for improving pathological bladder function in comparison to enterocystoplasty. The specific aims of the application are: Specific Aim 1: Determine the impact of SF scaffold properties on constructive remodeling and organ function following augmentation cystoplasty in a porcine model of partial bladder outlet obstruction. Specific Aim 2: Evaluate the utility of SF-based, IL-4/IL-13-delivery systems to induce M2 macrophage activation, enhance constructive remodeling, and improve obstructed bladder function.