Urethra-inspired biomimetic scaffold: A therapeutic strategy to promote angiogenesis for urethral regeneration in a rabbit model.

Limited angiogenesis and epithelialization make urethral regeneration using conventional tissue-engineered grafts a great challenge. Consequently, inspired from the native urethra, bacterial cellulose (BC) and bladder acellular matrix (BAM) were combined to design a three dimensional (3D) biomimetic scaffold. The developed BC/BAM scaffold was engineered for accelerating urethral regeneration by enhancing angiogenesis and epithelialization. The BC/BAM scaffold reveals the closest mimic of native urethra in terms of the 3D porous nanofibrous structure and component including collagen, glycosaminoglycans, and intrinsic vascular endothelial growth factor (VEGF). In vitro studies showed that the bioinspired BC/BAM scaffold promoted in vitro angiogenesis by facilitating human umbilical vein endothelial cells (HUVECs) growth, expression of endothelial function related proteins and capillary-like tube formation. Effect of the BC/BAM scaffold on angiogenesis and epithelialization was studied by its implantation in a rabbit urethral defect model for 1 and 3 months. Results demonstrated that the improved blood vessels formation in the urethra-inspired BC/BAM scaffold significantly promoted epithelialization and accelerated urethral regeneration. The urethra-inspired BC/BAM scaffold provides us a new design approach to construct grafts for urethral regeneration. STATEMENT OF SIGNIFICANCE: Findings in urethral regeneration demonstrate that an ideal tissue-engineered urethra should have adequate angiogenesis to support epithelialization for urethral regeneration in vivo. In this study, inspired from the native urethra, a bioinspired bacterial cellulose/bladder acellular matrix (BC/BAM) scaffold was developed to promote angiogenesis and epithelialization. The designed scaffold showed the closest physical structure and component to natural urethra, which is beneficial to angiogenesis and regeneration of urethral epithelium. This is the first time to utilize BC and dissolved BAM to develop biomimetic scaffold in urethral tissue engineering. Our biomimetic strategy on urethra graft design provided enhanced angiogenesis and epithelialization to achieve an accelerated and successful rabbit urethral repair. We believe that our urethra-inspired biomimetic scaffold would provide new insights into the design of urethral tissue engineering grafts.