A biomimetic urethral scaffold with spatiotemporally coordinated functions promotes scar-free urethral healing through barrier protection and regenerative microenvironment remodeling.

Abstract

The integrity of the urethral epithelium is critical for functional urethral reconstruction. Once disrupted, persistent exposure of the injured wound to the harsh urinary microenvironment triggers inflammatory responses, hampers re-epithelialization, and leads to fibrosis and urethral dysfunction. In this study, we developed a biomimetic urethral scaffold with a spatiotemporally coordinated design that enables early-stage barrier protection and late-stage scar-free urethral reconstruction (termed PTAA scaffold). The luminal layer of the scaffold is constructed by covalent crosslinking of thioctic acid and allicin to mimic the barrier function of the urethral epithelium to effectively resist urine erosion and bacterial infection during the early stage of repair. The regenerative layer is a protocatechualdehyde-modified SIS multifunctional scaffold that mimics the porous structure of the urethral submucosa and provides an extracellular matrix-like regenerative microenvironment. In vivo investigations confirm that the scaffold effectively accelerates urethral re-epithelialization, preserves urethral patency, and markedly reduces fibrotic deposition, achieving functional restoration. Further transcriptome analysis revealed that the scaffold attenuates urine-triggered inflammatory response and while activating epithelial regenerative programs by remodeling regenerative microenvironment, thereby providing favorable conditions for scar-free urethral healing. This spatiotemporal design enables in situ, orderly, and scar-free urethral reconstruction, providing a proof of concept for stage-specific urethral repair.