Catalyst-modulated hydrogel dynamics for decoupling viscoelasticity and directing macrophage fate for diabetic wound healing

Dynamic hydrogels can regulate immune responses, but decoupling bond exchange kinetics from static mechanical properties remains challenging. Here, we present a catalyst-mediated strategy to independently tune hydrogel network dynamics without altering crosslinking density or stiffness. A reversible acylhydrazone-based hydrogel system was constructed using lysozyme and PEG, with 4-amino-DL-phenylalanine (4a-Phe) as a catalyst to modulate bond exchange rates. This strategy enables effective decoupling of hydrogel viscoelasticity, allowing precise modulation of stress relaxation rates (τ_1/2) from 50 to 15 min, while maintaining nearly identical storage moduli (G'). The impact of hydrogel network dynamics on macrophage behavior was systematically investigated. Hydrogels with enhanced network dynamics significantly activated the JAK/STAT signaling pathway, promoting macrophage M2 polarization. These immunomodulatory effects fostered a pro-regenerative microenvironment, enhancing granulation tissue formation, angiogenesis, and accelerating wound closure in a diabetic mouse model. These findings underscore the significant potential of dynamic hydrogels in materiobiology, offering a novel approach to bridging materials science with immunoregulatory regenerative medicine.