Development of Silk Fibroin Grafts for Reconstruction of Pathological Bladders

 描述(申请人提供)：先天性和获得性泌尿系异常，包括继发于脊柱裂或脊髓损伤的神经原性膀胱，后尿道瓣，以及良性前列腺增生，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、反复的尿路感染和肾功能衰竭是梗阻性膀胱病的严重后果。对于患有病理性膀胱梗阻的患者，肠膀胱成形术被用作增加膀胱容量和降低高膀胱内压以保护肾功能的主要方法。然而，这种技术的长期疗效受到频繁和严重的并发症的阻碍，这些并发症对患者的生活质量产生了负面影响。以丝素蛋白(SF)为基础的植入物提供了非常适合支持膀胱功能的特殊物理特征组合。因此，这些支架可以克服与小肠膀胱成形术相关的不良副作用，并作为一种现成的膀胱重建移植物。鉴于M2巨噬细胞激活在协调再生反应中的作用，我们预计在缺陷巩固过程中能够促进M2表型的SF支架将有益于改善病理膀胱的表现。在这项提议中，我们将检验这样的总体假设：与肠膀胱成形术相比，能够传递前M2巨噬细胞激活因子(IL-4、IL-13)的SF生物材料将是改善病理膀胱功能的更好的方法。该应用的具体目的是：具体目标1：在猪部分膀胱出口梗阻模型中，确定SF支架的性质对膀胱成形术后结构性重塑和器官功能的影响。具体目的2：评价以SF为基础的IL-4/IL-13递送系统在诱导M2巨噬细胞活化、增强结构性重塑和改善梗阻膀胱功能方面的作用。

 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.