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

Abstract

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.

A Review on Bladder Wound Healing after Mechanical Injury

“…Most studies on the urinary bladder have focused on VEGF as some propose that vascularization is the limiting step for a functional bladder. Incorporating VEGF has been shown to increase angiogenesis, increase muscle regeneration and affect urothelial ingrowth [115][116][117][118][119]. However, its effect on the urothelium per se in these tissue engineering studies is still not fully understood [115,116,118,120].…”

Functionalizing PLGA and PLGA Derivatives for Drug Delivery and Tissue Regeneration Applications

“…[112] Xiong et al also showed a successful action of VEGF-loaded PLGA nanoparticles in the promotion of blood vessels and smooth muscle fibers regeneration, in the bladder of a swine model, and that the nanoparticles were able to release VEGF for at least 3 months. [113] Despite all the advantages concerning PLGA-based DDSs, there are still some issues to be overcome when nanoparticles are administered, especially into bloodstream. The main problem during PLGA nanoparticles administration is their interaction with the circulating proteins, producing different protein corona profiles.…”

Experimental bladder regeneration using a poly-L-lactide/silk fibroin scaffold seeded with nanoparticle-labeled allogenic bone marrow stromal cells

“…Another possible approach to stimulate bladder regeneration in vivo could be based on application of various agents (eg, cytokines, growth factors) that promote cellular ingrowth from the native bladder wall. [44][45][46] Thus, in the recently published study by Xiong et al the authors introduced vascular endothelial growth factor-loaded poly(lactic-co-glycolic acid) nanoparticles for long-term sustained release in bladder acellular matrix allografts in a swine model. 44 Implantation of this scaffold resulted in increased angiogenesis that reduced contracture during bladder regeneration.…”

“…44 Implantation of this scaffold resulted in increased angiogenesis that reduced contracture during bladder regeneration. 44 …”