A Biomechanocompatible Small Molecule Releasing Scaffold for Bladder Augmentation

PROJECT SUMMARY/ABSTRACT Patients with a pathologic bladder have chronic medical problems with urinary incontinence, infections, and potential renal failure. Conventional surgical management of the end-stage pathologic bladder uses detubularized bowel as a patch (enterocystoplasty) to enlarge the bladder to limit increases in intravesical pressure. Although enterocystoplasty provides functional improvement, it is associated with significant short- and long-term complications. Thus, alternative methods to enterocystoplasty have been explored through tissue engineering approaches. One approach utilized seeding autologous, patient-cultured bladder cells on synthetic scaffolds as an augmentation patch. With these techniques, poor to marginal results were described but regeneration of fully functional normal bladder tissue was not achieved. Several obstacles currently limit the advancement in this research field including: 1) a cell-free approach to drive native bladder tissue regeneration without the use of suspect, exogenous cells; 2) the lack of a truly translational bladder tissue regeneration animal model; 3) poor graft peripheral nerve regeneration and vascularization; and 4) primitive bioscaffold design. Thus, an alternative to these barriers are desperately needed to address unmet clinical needs. Bone marrow stem/progenitor cells (BMSPCs) represent a highly-defined population of cells and our group has shown its effectiveness in regenerating bladder tissue. However, there are numerous obstacles that effect the utility of these cells. These include the quality, low frequency and heterogeneity of stem cells found in the bone marrow especially in patients with increasing age and those likely to be suffering from bladder disease. As an alternative, we propose the use of a small molecule that can drive bladder tissue regeneration in vivo and can either perform similarly to or out-perform analogous BMSPC cell-seeded grafts. This would eliminate the need of exogenous cell sources for bladder tissue regeneration or bowel for bladder augmentation enterocystoplasty, where applicable. We have demonstrated that our team can reproducibly synthesize elastomeric scaffolds that possess anti-inflammatory properties and can mimic the mechanical properties of the bladder. Lastly, we have established a unique nonhuman primate animal model that is phylogenetically similar to humans with regards to bladder anatomy and physiology. This proposal will demonstrate that our small molecule directed platform will promote bladder tissue regeneration that is anatomically correct and physiologically functional.