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-? 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.
The results of this proposal are anticipated to produce new tissue repair modalities that will overcome current limitations in enterocystoplasty by creating novel ?off-the-shelf? silk fibroin grafts capable of intravesical delivery of anti-fibrotic therapeutics for reconstruction of chronically obstructed, diseased bladders. We also seek to uncover how acute versus chronic urinary tract obstruction impacts scaffold mediated, bladder regenerative mechanisms. We anticipate the results of this study will provide new information that is wider in scope than our specific goals and which may be applicable for repair of other urinary tract organs (ureter, urethra) in general.
