Injectable hyaluronic acid hydrogel for corneal neovascularization management by inhibiting oxidative stress, inflammation and neovascularization

Schematic overview of the synthesis and functions of the injectable hydrogel for the treatment of alkali burn-induced CNV. • An injectable antioxidant hydrogel loaded with anti-angiogenic peptide was developed for corneal neovascularization therapy. • Hydrogel effectively eliminated free radicals, reduced apoptosis and inhibited macrophage M1 polarization. • Hydrogel could promote corneal repair and inhibit neovascularization to treat alkali burn-induced corneal neovascularization. Corneal neovascularization (CNV) represents a significant global contributor to vision impairment and blindness. Nonetheless, existing therapeutic modalities, including surgical interventions and pharmacological treatments, face challenges related to limited efficacy and potential adverse effects. In this study, we developed a hydrogel formulation for the targeted delivery of the anti-angiogenic peptide KV11 leveraging multiple physicochemical interactions among adipic dihydrazide-modified hyaluronic acid (AHA), protocatechuic aldehyde (PA), and MnO 2 . The incorporation of PA and MnO 2 conferred antioxidant properties to the hydrogel, enabling it to effectively scavenge DPPH free radicals and hydroxyl radicals. Therefore, the hydrogel demonstrated notable antioxidant and anti-apoptotic effects in human corneal epithelial cells (HCECs) and effectively inhibited M1 macrophage polarization in vitro . Additionally, the hydrogel formulation was capable of suppressing the migration and proliferation of endothelial cells. Treatment with the KV11-loaded hydrogel significantly ameliorated pathological corneal injury in a rat model of alkali burn-induced CNV. Furthermore, the hydrogel material demonstrated safety and non-toxicity to the ocular surface. This study designed a multifunctional HA hydrogel formulation by integrating materials with antioxidant properties, specifically PA and MnO 2 , along with KV11, effectively addressing the complex challenges posed by oxidative stress, acute inflammatory responses, and neovascularization, providing a promising strategy for the treatment of CNV.