UC Irvine

The lower urinary tract, consisting of the bladder and urethra, functions to facilitate storage and voiding of urine while maintaining low intravesical pressures to prevent renal damage. A variety of congenital and acquired pathologies including spinal cord injury and urethral stricture disease can lead to anatomical or functional obstruction of the lower urinary tract which can elevate urinary storage pressures and ultimately cause renal deterioration. In addition, malignant conditions such as bladder cancer and developmental abnormalities including bladder exstrophy can also result in tissue loss or malformed urogenital tissues which can compromise organ continuity, disrupt normal micturition, and in some cases negatively impact patient fertility. Surgical correction of urogenital defects is conventionally accomplished with autologous tissue grafts derived from extragenital sources, however this strategy is encumbered by donor site morbidity, limited tissue availability, and failure to restore native tissue functionality. Tissue engineering approaches utilizing acellular biomaterials composed of decellularized tissue grafts or synthetic polymers either alone or seeded with ex vivo expanded primary or progenitor cell sources have been previously explored as alternatives to autologous tissue grafts for urogenital reconstruction in both preclinical studies and clinical trials. Despite the successful performance of these constructs in non diseased animal models, none of these technologies have been adopted into widespread clinical practice due to poor functional outcomes, abnormal tissue formation, and serious adverse events encountered in human studies. Clinically viable biomaterial configurations must possess optimal structural, mechanical and degradative characteristics sufficient to provide for initial defect reinforcement, but allow for gradual scaffold dissipation and subsequent formation of site-appropriate functional tissue (constructive remodeling). Moreover, validation of prospective tissue engineered implant designs in diseased animal models which mimic underlying patient pathology is necessary to accurately evaluate graft potential prior to clinical translation. Alterations in the regenerative capacity of host tissues can occur as a function of disease or past injury and can ultimately influence implant functional performance. Therefore, advancements in urinary tract reconstruction are dependent on new scaffold designs which can promote host regenerative responses in diseased settings and overcome deficiencies related to autologous tissue deployment.The focus of my thesis is centered on 2 main areas of investigation: (1) creation of novel preclinical models of urinary tract disease for medical device testing and (2) evaluation of bi-layer silk fibroin (BLSF) grafts for urogenital tissue reconstruction. My first goal will be accomplished by developing and characterizing new rabbit and swine models which respectively recapitulate clinical phenotypes of Peyronie’s disease and urethral stricture disease. My second goal will involve testing the efficacy of protein-based, BLSF grafts to serve as urinary conduits for management of bladder cancer following radical cystectomy as well as biological substitutes for repair of focal vaginal defects and long urethra stricture defects in male and female porcine models.