Biomaterial-mediated remodelling of the inflammatory microenvironment: a pH/ROS-responsive EGCG–metformin hydrogel for infected diabetic wound regeneration

Abstract

Introduction Diabetic chronic wounds resist healing because persistent bacterial infection, excessive reactive oxygen species (ROS), unresolved pro-inflammatory responses, impaired angiogenesis, and defective tissue remodelling act simultaneously and reinforce one another. We therefore developed an injectable, microenvironment-responsive nanocomposite hydrogel, AP@EM-gel, to target these interconnected pathological processes. Methods AP@EM-gel was constructed from dopamine-grafted alginate (Alg-DA), phenylboronic-acid-modified ε-poly-L-lysine (EPBA), and co-assembled epigallocatechin gallate–metformin nanoparticles (EGCG-MET NPs). Its physicochemical properties, pH/ROS-responsive drug release, antibacterial and antioxidant activities, cytocompatibility, pro-angiogenic effects, and macrophage-modulating capacity were evaluated in vitro. Therapeutic efficacy was further assessed in a streptozotocin-induced diabetic rat model of Staphylococcus aureus-infected full-thickness wounds. Results Dynamic boronate-ester crosslinking produced a self-healing and injectable network that released approximately 73% of EGCG and 68% of metformin under combined pH 6.4 and H2O2 conditions, compared with approximately 38% and 36%, respectively, at pH 7.4. AP@EM-gel achieved antibacterial rates of approximately 93% against S. aureus and 91% against Escherichia coli, exhibited broad-spectrum radical-scavenging activity, and showed favourable cyto- and haemocompatibility. It restored VEGF and bFGF expression in oxidatively stressed endothelial cells and promoted macrophage repolarisation toward the reparative M2 phenotype. In vivo, AP@EM-gel produced near-complete wound closure by day 14 and improved bacterial clearance, re-epithelialisation, collagen organisation, angiogenesis, and inflammatory resolution compared with the commercial dressing. Discussion AP@EM-gel simultaneously interrupts infection, oxidative stress, dysregulated macrophage polarisation, and impaired angiogenesis. This pathology-responsive, multi-target hydrogel represents a promising smart dressing for infected diabetic wound regeneration.