Microenvironment-responsive dual-network hydrogel with stage-adapted release promotes diabetic bone regeneration.

Abstract

Diabetic bone regeneration is severely hindered by hyperglycemia-induced inflammation and microangiopathy. In this case, conventional drug strategies show limited efficacy. Inspired by the natural polyphenol structure, this study engineered a dual-network self-assembled hydrogel with glucose responsiveness and stage-adapted release characteristics. Punicalagin (PUN), a natural floral tannin with anti-inflammatory and antioxidant properties, contains abundant catechol groups. Based on the primary network formed by dynamic phenylboronic ester bonds, the hydrogel responds sensitively to the local hyperglycemia microenvironment. The stable secondary cross-linking formed by metal-polyphenol coordination endows the hydrogel with excellent mechanical properties. Rapidly released PUN reduces excessive inflammation by inhibiting pro-inflammatory cytokines and promoting macrophage polarization toward the regenerative M2 phenotype. The sustained release of cobalt ions (Co²⁺) promotes endothelial cell viability. In vivo results show that the synergistic effect of the two bioactive components regulates the osteoimmune microenvironment, accelerates the reconstruction of the functional vascular network, and ultimately facilitates bone regeneration. In this process, Co-Gel-PUN (CGP) hydrogel regulated the osteogenic microenvironment by inhibiting the JAK2/STAT1 pathway. The proposed "immune-angiogenesis" dual-regulatory strategy provides an effective therapeutic paradigm for diabetic bone regeneration.