Hydrogel-Mediated Sustained Co-Delivery of Biflavonoids Modulates Inflammation and Promotes Diabetic Wound Healing

Persistent inflammation, impaired angiogenesis, and dysregulated extracellular matrix remodeling hinder diabetic wound healing. Although polyphenols may help counteract these processes, their therapeutic potential is constrained by poor local retention and uncontrolled release. To address these limitations, an oxidized alginate/N-succinyl chitosan (OAlg/NSC) Schiff-base hydrogel was developed for the sustained co-delivery of daphnodorin B (DpB) and 3′,8″-binaringenin (BN), using dynamic crosslinking between alginate aldehydes and chitosan primary amines under physiological conditions. The hydrogel’s physicochemical properties were then characterized by assessing its swelling behavior, chemical structure using FTIR spectroscopy, and in vitro release profile. Its sustained biflavonoid delivery was evaluated in a streptozotocin/nicotinamide-induced diabetic excisional wound model in BALB/c mice. The cytocompatibility of free biflavonoids and formulated hydrogels was assessed in RAW 264.7 macrophages. Both biflavonoids were cytocompatible at concentrations below 20 µM. In LPS-stimulated macrophages, BN preferentially downregulated Tnf expression, whereas DpB upregulated Il10 expression, as determined by RT-qPCR. In vivo, biflavonoid-loaded hydrogels accelerated wound closure, enhanced re-epithelialization and collagen deposition, reduced inflammatory cell infiltration, and increased CD34 immunoreactivity, indicating improved tissue repair and neovascularization. These findings suggest that the OAlg/NSC hydrogel is a promising platform for sustained biflavonoid delivery, with the combined delivery of DpB and BN potentially enhancing diabetic wound healing through coordinated modulation of inflammation and promotion of tissue regeneration.