An injectable pH-responsive marine polysaccharide hydrogel (AE&LF@pOA) for sequential therapy of infected diabetic wounds

Chronic diabetic wound healing remains challenging owing to impaired angiogenesis, persistent inflammation, and a high risk of infection. To address these limitations, we developed an injectable, pH-responsive hydrogel based on dynamic crosslinking between phenylboronic acid-grafted oxidized agarose (pOA) and alginate oligosaccharide-conjugated ε-polylysine (AE). This hydrogel exhibits antibacterial and antioxidant properties, enabling on-demand drug release triggered by the acidic microenvironment of chronic wounds. To enhance therapeutic efficacy, low-molecular-weight fucoidan (LF), a potent pro-angiogenic marine polysaccharide, was encapsulated within the hydrogel. Physicochemical characterizations confirmed that the hydrogel possesses excellent structural stability, injectability, and pH-responsive sustained release properties for LF and AE. Subsequently, In vitro tests showed that the AE&LF@pOA hydrogel effectively controlled infection with a 77.3% antibacterial rate against Staphylococcus aureus and showed ROS scavenging activity. It also regulated the inflammatory response, reducing pro-inflammatory cytokines IL-1β and IL-6 by 53.8% and 64.4%, respectively while increasing anti-inflammatory cytokines IL-10 and TGF-β1 by 2.8-fold and 1.0-fold. Moreover, the hydrogel stimulated neovascularization, leading to a 4.7-fold increase in VEGF expression and a 50% increase in CD-31 microvessel density. Animal studies confirmed that the dressing accelerated macroscopic healing. The hydrogel accelerated wound closure to 85.8% by day 7, 2.7-fold higher than controls, with the residual wound area shrinking to just 1.4% by day 14. Histological analysis further demonstrated complete re-epithelialization to 80.3 μm thickness, and mature collagen deposition. Overall, this responsive hydrogel offers a promising strategy for treating chronic diabetic wounds.