Development of Silk Fibroin Grafts for Reconstruction of Pathological Bladders

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 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.