Dynamically urethra-adapted and obligations-oriented trilayer hydrogels integrate scarless urethral repair

In urethral damage/stricture prevention, open and harsh urethral microenvironments and isotropic compression and swelling properties of exogenous implants render urethral repair intractable. Here a dynamically urethra-adapted and obligations-oriented trilayer hydrogel was engineered to integrate scarless urethral repair. Therein, the diethylacrylamide-hydroxyethylacrylamide (HEAm) (D-H) hydrogel layer featuring high anti-fouling performance prevent adhesions of bacterial and blood cells, and its poor swelling avoids urethra occlusion. The upper swellable and verteporfin (VP)-loaded N,N'-methylenebisacrylamide-poly (N-isopropylacrylamide) (BP) layer encourages urethra regeneration through expediting cell migration and proliferation. The rigid and water-resistant Zein middle layer opposes urine voiding-arised BP shedding, urethral diastole/contraction, inward BP swelling-arised urethra occlusion and urine permeation. Importantly, systematic proteomic and genomic analysis reveals that such hydrogel scaffolds expedite epithelial & vascular regenerations, attenuate tight cell junction, oppose inflammation microenvironment and regulate extracellular matrix secretion and metabolism to realize integrated urethral repair. The microenvironment-adaptable design concepts provide reliable rationales to engineer urethral regeneration scaffolds.