Substitution degree-regulated alginate-catechol hydrogels for oral ulcer healing.

Oral ulcers are common inflammatory lesions of the oral mucosa, yet their local treatment remains challenging because the moist and dynamic oral environment limits the retention and efficacy of conventional formulations. Herein, we developed a series of bioadhesive alginate-catechol (Alg-cat) hydrogels with different degrees of substitution (DS) and systematically investigated the influence of DS on their physicochemical properties, biological performance, and therapeutic effects on oral ulcer healing. The hydrogels were characterized by structural analyses, swelling and degradation tests, adhesion and mechanical measurements, antioxidant and antibacterial assays, and biocompatibility evaluation. The results showed that DS critically regulated hydrogel performance. Increasing DS enhanced network density, mechanical strength, reactive oxygen species (ROS) scavenging ability, and antibacterial activity, whereas adhesion and deformability reached optimal levels at an intermediate DS. Among all formulations, the Alg-cat hydrogel with a DS of 17.5% exhibited the most balanced properties, including the highest adhesion strength, favorable mechanical adaptability, strong antioxidant and antibacterial activities, and good biocompatibility. In a rat oral ulcer model, this optimized hydrogel significantly accelerated wound healing, with efficacy comparable to that of a dexamethasone patch after 5 days of treatment. Further analyses demonstrated that it reduced inflammatory cell infiltration, promoted collagen deposition and epithelial regeneration, regulated inflammatory cytokine expression, and facilitated macrophage polarization toward the M2 phenotype. Overall, this study identifies DS as a key determinant of catechol-grafted alginate hydrogel performance and highlights the optimized Alg-cat hydrogel as a promising drug-free therapeutic platform for oral ulcer treatment.