The bladder is exposed to a variety of possible injuries from the time the fetus develops. Aside from congenital abnormalities, individuals may also suffer from other disorders such as cancer, trauma, infection, inflammation, iatrogenic injuries r other conditions which may lead to painful bladder damage or loss, requiring eventual bladder replacement or repair. Currently, gastrointestinal segments are commonly used as tissues for bladder replacement or repair. However, when gastrointestinal tissues are in contact with the urinary tract, multiple complications may ensure, such as infection, metabolic disturbances, urolithiasis perforation, increased mucous production, and malignancy. Even though the use of bowel for bladder tissue replacement was first proposed over 100 years ago, it still remains the gold standard today, despite its known associated problems and due to a lack of a better alternative. It is evident that urothelial to urothelial anastomoses are preferable functionally. However, the limited amount of autologous urologic associated tissues fro reconstruction generally precludes this option. There is a critical need for tissues to replace lost and functionally- deficient bladder tissues. Bioengineering bladder tissues using selective cell transplantation may provide a means to create functional new genitourinary tissues. The approach which we have followed to bioengineer tissues in our laboratory involves the eventual use of autologous cells, thus avoid rejection, wherein a biopsy of tissue is obtained from the host, the cells are dissociated and expanded in vitro, reattached to a biodegradable matrix, and implanted into the same host. The proposed application is based on several proven concepts derived from our previous work, performed over the last 9 years, which have lead to the development of large portions of bioengineered bladder tissue for augmentation and subtotal replacement. However, before patients who require complete bladder replacement can benefit from this technology, further studies need to be performed wherein total bladder cystectomies are performed. This would not entail the partial replacement of bladder tissue, as had been demonstrated experimentally, but rather, complete bladder replacement with ureteral reimplantation. Therefore, the overall goal of this proposal is to achieve complete bladder replacement using bioengineered tissues in an experimental model, thus avoiding the problems associated with the currently used gastrointestinal segments. Like other types of orthotopic bladders created with gastrointestinal segments, it is expected that the neobladders created with bioengineered tissues could empty mostly by intermittent catheterization, but these should be able to provide low pressure and high compliance reservoirs with native autologous tissues.
The specific aims of this proposal:
Specific Aim 1 : To determine the feasibility of reimplanting ureters long term in tissue engineered bladders. In these experiments we will test the hypotheses that ureters can be hyper-implanted into engineered bladder tissue, that the ureters will not obstruct, and the ureters will not reflux.
Specific Aim 2 : To determine the feasibility of attaining complete bladder replacement using tissue engineering techniques. In these experiments we will test to the hypothesis that bioengineered bladder tissues can be anastomosed to native urethras, that complete bladder replacement is feasible using bioengineered bladder tissues that ureteral replacement in a model of total bladder replacement is feasible, without ureteral obstruction or vesicoureteral reflux, and that bioengineered bladders can be emptied efficiently in an intermittent fashion.
Specific Aim 3 : To determine the short term and long term phenotypic and functional characteristics of bladder tissues engineered for subtotal and complete replacement. In this aim we will attempt to determine the phenotypic and functional characteristics, over time, of the bioengineered bladder tissues, as compared to controls.
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