Abstract

The hostile microenvironment following urethral injury, characterized by inadequate blood supply, compromised barrier function, and aberrant mechanical stimuli, drives the formation of urethral scars rather than functional tissue regeneration. To address this challenge, we developed a novel dual-sided Janus hydrogel scaffold (PCH@PVA) via a straightforward dipping-freeze-thaw method. Its basal layer, composed of poly(N-isopropylacrylamide), carboxymethyl cellulose, and heparin, not only exhibits anticoagulant activity to promote initial blood perfusion and nutrient/factor delivery but also actively remodels the regenerative microenvironment by enhancing cell proliferation, angiogenesis, and mitigating oxidative stress. Conversely, a polyvinyl alcohol (PVA) coating significantly augments the scaffold's mechanical robustness, enabling it to withstand urethral dilation while providing appropriate mechanical cues. This layer simultaneously re-establishes a reliable physical barrier against urine erosion and bacterial adhesion. In vivo evaluations demonstrated that the PCH@PVA scaffold markedly accelerates epithelial regeneration, promotes vascularization, enhances cellular proliferation, and suppresses collagen deposition, thereby effectively preventing urethral stricture. Mechanistic investigations further revealed that these restorative effects are closely associated with the modulation of the HIF-1 and Hippo signaling pathways. The integrated strategy of “active regulation and passive protection” presented in this work offers a promising solution for urethral tissue engineering and provides a new paradigm for tissue repair within other complex microenvironments.