In Situ Click Chemistry Forming pH/ROS‐Responsive and Antifouling Hydrogel to Prevent Intrauterine Adhesion and Restore Fertility

Intrauterine adhesion (IUA) leads to abortion and infertility that poses a severe threat to female reproductive and psychological health. The highly oxidative microenvironment and fibrosis of the endometrial wound are critical factors driving IUA pathogenesis. Here, a pH and reactive oxygen species (ROS) dual-responsive hydrogel (DRH) with antifouling property, which could be gelated in situ click chemistry, was developed to effectively treat IUA via anti-oxidative and anti-fibrosis. This DRH was prepared by a dual-crosslinking structure, which was based on the thiol-ene click chemistry reaction of poly(ethylene glycol) diacrylate (PEGDA), 4-arm poly(ethylene glycol) acrylate (4-arm-PEG-AC) and dithiothreitol (DTT), coupled with borate ester bonds between borax and DTT. This DRH presented excellent antifouling and good ROS scavenging, which reduced protein and cell adhesion, as well as alleviated oxidative stress. Additionally, the DRH also exhibited pH and ROS responsiveness, enabling degradation in the intrauterine microenvironment. In the rat endometrial injury model, the DRH successfully exerted an effective therapeutic effect on IUA, and thus eventually restored fertility by attenuating the endometrial oxidative damage, inhibiting the activation of myofibroblasts, and reducing epithelial-mesenchymal transition.