Date of Award

5-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Jiro Nagatomi

Committee Member

Vyavahare , Naren

Committee Member

Ken Webb

Committee Member

Todd J Purves

Abstract

Current surgical treatments for urinary bladder disorders rely on the use of autologous intestinal segments and xenografts such as small intestinal submucosa, which suffer from various complications including mechanical mismatch and graft shrinkage. Despite early promises of bladder tissue engineering, a recent report of unsuccessful clinical trials suggests that the technology needs further improvement and evaluation through animal models of bladder dysfunction. Therefore, the objective of this doctoral dissertation was to characterize a viable bladder tissue scaffold (patch) which mimics the mechanical properties of the bladder, maintains the phenotype of the BSMC seeded in it and finally, tested in vivo in a dysfunctional bladder model to evaluate its true efficacy. In pursuit of this goal, firstly we explored the use of composite hydrogel blends composed of Tetronic (BASF) 1107-acrylate in combination with extracellular matrix (ECM) moieties collagen and hyaluronic acid seeded with bladder smooth muscle cells (BSMC). The results of in vitro experiments demonstrated that the composite hydrogel system provided an environment for bladder smooth muscle cells to adhere, migrate and secrete ECM, thereby increasing the construct's overall strength and stiffness. However, the mechanical properties of our cell-seeded composite hydrogels were limited after two weeks of culture and hence, we characterized various biodegradable elastomers as scaffolds for bladder tissue engineering. Our studies indicated that poly (carbonate urethane) urea (PCUU) scaffolds exhibit relatively high compliance under low forces and are able to withstand stress corresponding to super physiological peak stress experienced by urinary bladders in vivo and thus, possess the strength and stiffness necessary to be used as a urinary bladder tissue engineering scaffold. Finally, we attempted at implanting the PCUU scaffolds onto a bladder outlet obstruction (BOO) rat model to create a clinically informative study. The PCUU augmentation led to the enhanced survival of the rats and increased bladder capacity and voiding volume with time, indicating that the high-pressure bladder symptom was alleviated. The histological analysis of the explanted scaffold indicated smooth muscle cell and connective tissue infiltration. The knowledge gained in the present study will work towards future improvement of bladder tissue engineering technology to ultimately aide in the treatment of bladder disorders.

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