Dual pH/glucose-responsive berberine-loaded bioactive glass/carboxymethyl chitosan hydrogel for promoting diabetic wound healing

Diabetic wounds are characterized by a complex pathological microenvironment involving hyperglycemia-induced oxidative stress, persistent inflammation, bacterial infection and impaired matrix remodeling. In this study, we developed BBGgel, an injectable pH- and glucose-responsive carboxymethyl chitosan/genipin hydrogel incorporating berberine-loaded bioactive glass nanoparticles, for sustained drug delivery and wound microenvironment modulation. BBGgel could be injected to fill irregular wound beds, absorb wound exudate, and rapidly recover its network structure after mechanical disruption. Berberine was efficiently loaded into the bioactive glass nanoparticles with an encapsulation efficiency of 77.06% and released from the hydrogel in a sustained manner over 9 days, with release kinetics responsive to both pH and glucose levels. The 10% BBGgel formulation promotes L929 fibroblast viability and migration, while attenuating H2O2-induced intracellular reactive oxygen species (ROS) accumulation. In LPS-stimulated RAW264.7 macrophages, pretreatment with 10% BBGgel downregulated pro-inflammatory genes (IL-6, iNOS) while upregulating anti-inflammatory genes (Arg-1, IL-10). BBGgel also exhibited antibacterial activity against both S. aureus and E. coli in vitro. In a streptozotocin-induced diabetic rat model, histological evaluation of BBGgel-treated wounds showed more organized tissue architecture and enhanced collagen deposition. Collectively, these findings suggest that BBGgel represents a promising candidate as a multifunctional pH- and glucose-responsive hydrogel dressing for diabetic wound repair.