SUMMARY Each year in the United States there are 14,000 bladder augmentation enterocystoplasty surgeries to address trauma, urological cancers, severe cases of spina bifida, and interstitial cystitis. Although enterocystoplasty is the standard of care for patients with end-stage pathologic bladder, 33% of patients have complications due to anatomical and physiological differences between bladder and bowel tissue used to augment bladder capacity. Complications include bladder perforations, renal failure, and malignant transformation. There is currently no viable alternative to augmentation enterocystoplasty. Several strategies have been reported to replace enterocystoplasty and regenerate bladder tissue, but these have failed clinically. Reasons for the failure include the common use of phylogenetically dissimilar pre-clinical animal models that do not accurately represent the human bladder or its disease condition, the use of inadequate materials to serve as scaffolds for cells to grow on and regenerate bladder tissue, the use of often diseased autologous bladder cells that have lost the capacity to regenerate functional bladder tissue, and an inability to continuously monitor the tissue regeneration process to identify potential problems at an early stage. The overall goal of this proposal is to accelerate bladder tissue formation and enable wireless, real-time monitoring of bladder function. Toward this goal, we have demonstrated that: 1) we can restore normal bladder function at 6 months through 24 months post-surgery in a clinically relevant baboon bladder augmentation model using a new mechanically compatible biodegradable elastomer scaffold, poly(1,8 octamethylene citrate-co-octanol) (POCO) seeded with autologous baboon bone marrow-derived mesenchymal stromal cells (MSCs) and hematopoietic stem/progenitor cells (CD34+ HSPCs). At 24 months, peripheral nerve regeneration was adequate and functional in the regenerated area; 2) engineering scaffold microtopography with parallel microgrooves can improve anatomical features of the regenerated bladder. Specifically, in a nude rat bladder augmentation model, microgrooved POCO scaffolds seeded with human bone marrow-derived MSCs and CD34+ HSPCs, blood vessel density, muscle to collagen ratio, and urothelium thickness were increased relative to cells seeded on scaffolds with smooth surface; 3) bladder contraction events in rats and baboons can be wirelessly detected in real time via a biointegrated electronic strain gauge; 4) stretchable electronics can be integrated into citrate-based elastomers; and 5) electrically conductive POCO scaffolds enable bladder tissue regeneration in a rat bladder augmentation model without the need for seeded cells, simplifying clinical translation of this approach. The specific aims of this proposal are to: 1) investigate electrically conductive and non-conductive microgrooved POCO scaffolds for accelerated bladder tissue regeneration, and 2) investigate wireless bioelectronic strategies to monitor real time bladder dynamics.

PROJECT NARRATIVE Bladder enterocystoplasty causes many severe complications due to anatomical and physiological differences between bladder tissue and the bowel tissue used to augment the bladder's capacity. Several strategies have been reported to replace enterocystoplasty and regenerate bladder tissue but these have mostly failed clinically. This proposal will develop unprecedented regenerative engineering tools and technologies via the integration of advanced biomaterials, and bio-integrated electronics to enable the regeneration of functional bladder tissue and the non-invasive, real-time assessment thereof to better predict outcome.