Bioactive Glass−Coupled Gelatin Hydrogels Based on Hydroxycarbonate Apatite/Borate Nanostructures for Release-Regulated Angio-genic Oral Mucosal Regeneration

Abstract

Oral ulcers are common and highly recurrent oral mucosal disorders whose clinical treatment is hindered by the limited retention of topical therapeutics, uncontrolled release of bioactive agents, and inadequate angiogenesis in the wound microenvironment, resulting in delayed healing and suboptimal tissue regeneration. To address these critical challenges, a functional composite hydrogel (hydroxycarbonate-apatite/borate nanostructured bioactive glass-coupled gelatin hydrogel, HCA/borate BG-coupled gelatin hydrogel) was engineered by incorporating nanoscale borate bioactive glass decorated with an amorphous hydroxycarbonate apatite layer (hydroxycarbonate-apatite/borate nanostructured bioactive glass, HCA/borate BG) into a biomimetic gelatin matrix. This design leverages hydrogen-bonding between the gelatin’s functional groups and the PO43− or −OH moieties on the HCA/borate BG surface, reinforcing the hydrogel lattice and ensuring the sustained delivery of therapeutic ions. The gelatin matrix further physically encapsulates the bioactive glass, reducing direct exposure at the wound interface and prolonging its therapeutic efficacy. In vitro, HCA/borate BG-coupled gelatin hydrogel significantly enhanced endothelial cell and fibroblast proliferation and migration, indicating pronounced pro-angiogenic activity. In a rat oral mucosal defect model, HCA/borate BG-coupled gelatin hydrogel upregulated angiogenesis-related markers, accelerated wound closure, and reduced scar formation compared with controls. Importantly, no toxic degradation products were detected during treatment. Overall, this study presents a mechanistically rational and biocompatible hydrogel platform that overcomes key limitations of current oral ulcer therapies and provides a promising translational strategy for the clinical treatment of oral mucosal defects.