Project Summary: Bladder cancer patients with locally advanced disease often need their bladder removed to effectively treat their cancer. Additionally, there are a number of benign disease conditions, including congenital abnormalities, spinal cord injury, and neurogenic bladders that need tissue and organ replacement. An acute shortage of organ donation, challenges associated with the immune-suppression, and short and long-term health complications encountered in applications of non-native tissues, make the problem worse. With the current gold-standard surgical procedure that utilizes gastrointestinal (GI) tract, namely the ileum to create a urinary diversion or neo-bladder, patients are prone to many health complications, including chronic infections and kidney disease, due to the inherent absorptive and secretory properties of GI tract. In order to reduce the significant morbidity that results from utilization of the alimentary tract, tissue-engineered urinary diversions are highly desirable. Despite the proven feasibility and promises in pre-clinical models, clinical translations of tissue engineered neo-urinary organs to patients have been critically limited and largely unsuccessful due to urine leakage and contracture of the implant. To overcome this major limitation, we, therefore, propose to create a new collagen-based urinary diversion that is uniquely compliant yet strong and suturable, which has a urine-leakage resistive polymer coated engineered urothelium substitute. Since, the composition of urinary tissue directly dictates its urodynamic response, we hypothesize that by increasing the entropy of the collagen network by creating sliding crosslinking sites we can account for both the tissue-compliance and tensile strength of the biomaterial construct. We further hypothesize that an engineered urine-protecting layer of negatively charged polysaccharides on an urothelium substitute will protect the regenerating stroma from urine that is otherwise known to cause many undesirable clinical conditions, including urinary infections, stone formation, failure of the graft, and even deaths in some cases. The findings of the proposed study will advance our understanding of the influence of material composition, compliance and urine-leakage on the functional ability of regenerated urinary tissues. We anticipate our research findings can be translated into clinical applications in 3-5 years and it will have a huge impact on patient’s post-operative quality of life and recovery from the bladder removal surgery.