Injectable hyaluronic acid hydrogel for corneal neovascularization management by inhibiting oxidative stress, inflammation and 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 MnO₂. The incorporation of PA and MnO₂ 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 MnO₂, 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.