One-Pot Preparation of an Antioxidant, Anti-Inflammatory, and Analgesic Hydrogel for Oral Mucosal Lesions

Oral mucosal lesions present significant therapeutic challenges due to the complex oral environment and limitations of conventional biomaterials in clinical application. In this study, we introduced an innovative tannic acid-reinforced gelatin hydrogel (Gel-TA) incorporated with cannabidiol (CBD), engineered as a multifunctional dressing to address antioxidant, anti-inflammatory, and analgesic requirements for oral wound management. The Gel-TA hydrogel was constructed through noncovalent interactions, including hydrogen bonding, hydrophobic interactions, and π-π stacking, resulting in a significantly enhanced compressive modulus and improved mucosal adhesion strength compared with pure gelatin. The gel-sol transition temperature increased to approximately 44 °C, rendering it suitable for application in the oral environment. CBD encapsulation enabled sustained drug release kinetics, achieving and maintaining therapeutic concentrations (85% cumulative release over 24 h) in artificial saliva. <i>In vivo</i> studies demonstrated that the hydrogel significantly accelerated wound healing and enhanced epithelial regeneration, with treated wounds achieving 73.4% closure within 3 days compared to 45.1% in untreated controls (<i>p</i> < 0.05). Histopathological analysis revealed a 60.05% reduction in inflammatory cytokine infiltration and a 2.8-fold increase in collagen deposition. The dual-action therapeutic platform combined structural stability with bioactive functionality, creating a protective niche that modulated the wound microenvironment through via three synergistic mechanisms: (1) mechanical barrier formation, (2) oxidative stress mitigation (93.8% ROS scavenging capacity), and (3) prolonged analgesic efficacy. This rationally designed hydrogel system offered a clinically translatable solution for oral mucosal regeneration, addressing both biological healing requirements and patient comfort through its tunable physicochemical properties and controlled therapeutic delivery.