Bacitracin-regulated injectable PHEMA hydrogels with intrinsic mild negative swelling for soft tissue repair

Abstract

Injectable hydrogels are attractive for minimally invasive soft-tissue repair, yet most systems undergo post-gelation swelling in aqueous environments, leading to dimensional instability and progressive mechanical deterioration. Here, we report a bacitracin-regulated poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogel that exhibits in situ gelation together with intrinsic mild negative swelling under hydrated conditions. In this system, bacitracin serves as a multifunctional molecular regulator that not only accelerates gel formation under mild conditions but also modulates postgelation network evolution through multivalent hydrogen bonding and hydrophobic associations with PHEMA chains. As a result, the hydrogel undergoes a distinct hydration-driven network evolution rather than conventional swelling expansion, leading to spontaneous but mild volumetric contraction and improved structural stability in aqueous environments. Notably, this negative swelling behavior occurs directly under physiologically relevant hydrated conditions and without a pronounced overswelling stage. The resulting hydrogel displays enhanced mechanical robustness, resistance to water-induced structural degradation, and concentration-dependent antibacterial activity. By further incorporating estradiol-loaded mesoporous silica nanoparticles, the dimensionally stable network enables sustained bioactive release and promotes vaginal wound healing in vivo. More broadly, this work identifies bacitracinregulated hydration-driven network evolution as a route to controlling post-gelation volume behavior in injectable hydrogels and provides a design principle for soft-tissue repair in moist physiological environments.