A Nanomedicine Approach to Effectively Inhibit Contracture During Bladder Acellular Matrix Allograft-Induced Bladder Regeneration by Sustained Delivery of Vascular Endothelial Growth Factor

Macroscopic evidence of contracture has been identified as a major issue during the regeneration process. We hypothesize that lack of angiogenesis is the primary cause of contracture and explore a nanomedicine approach to achieve sustained release of vascular endothelial growth factor (VEGF) to stimulate angiogenesis. We evaluate the efficacy of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for long-term (3 months) sustained release of VEGF in bladder acellular matrix allografts (BAMA) in a swine model. We anticipate that the sustained release of VEGF could stimulate angiogenesis along the regeneration process and thereby inhibit contracture. Bladder was replaced with BAMA (5×5 cm), modified with PLGA NPs encapsulated with VEGF in a pig model. The time points chosen for sampling were 1, 2, 4, and 12 weeks. The regenerated areas were then measured to obtain the contracture rate, and the extent of revascularization was calculated using histological and morphological features. In the control group of animals, the bladder was replaced with only BAMA. The in vivo release of VEGF was evident for ∼3 months, achieving the goal of long-acting sustained release, and successfully promoted the regeneration of blood vessels and smooth muscle fibers. In addition, less collagen deposition was observed in the experimental group compared with control. Most importantly, the inhibition of contracture was highly significant, and the ultimate contracture rate decreased by ∼57% in the experimental group compared with control. In isolated strips analysis, there were no significant differences between BAMA-regenerated (either VEGF added or not) and autogenous bladder. BAMA modified with VEGF-loaded PLGA-NPs can sustainably release VEGF in vivo (>3 months) to stimulate angiogenesis leading to the inhibition of contracture. This is the first study to report a viable nanomedicine-based strategy to overcome contracture during bladder regeneration induced by BAMA. Furthermore, this study also confirms that insufficient angiogenesis plays a crucial role in the onset of contracture.