ECM-Derived Biomimetic Adhesive Patch Regulating the Inflammatory Microenvironment to Accelerate Oral Ulcer Healing.

The effective management of oral ulcers is hindered by the constantly moist oral environment and persistently dysregulated inflammatory microenvironment. Inspired by the hierarchical architecture of native mucosa, we engineered a biomimetic bilayer patch to achieve immune modulation and synergistic tissue regeneration. Compositionally mimicking the bioactive lamina propria, the patch features a bioadhesive inner layer enriched with dopamine-modified esophageal mucosa decellularized extracellular matrix (eECM-DA) to specifically recapitulate the native biochemical niche, embedded within hyaluronic acid methacrylate (HAMA) networks loaded with dexamethasone (Dex). Structurally mimicking the protective epithelial barrier, this inner matrix was coupled with a hydrophobic ethylcellulose (EC) backing to shield against saliva erosion. After contact with the moist oral environment, this eECM-DA/HAMA/EC-Dex (EDH/EC-Dex) bilayer patch rapidly contacts the wound and displaces interfacial water to achieve robust wet adhesion. Functionally, the EDH/EC-Dex patch actively reprogrammed the inflammatory milieu in LPS-stimulated macrophages by modulating JAK-STAT signaling and antioxidant networks, thereby driving inflammation resolution and promoting orderly regulation of the ulcer microenvironment. In a rat oral ulcer model, EDH/EC-Dex patches demonstrated superior efficacy in accelerating re-epithelialization and functional recovery compared to commercial products. This work introduces an immune-modulatory, ECM-derived platform, offering a promising strategy for oral ulcer management and broader tissue engineering applications. STATEMENT OF SIGNIFICANCE: A mucosa-inspired bilayer patch is developed for treating oral ulcers. This ECM-derived patch achieves robust wet adhesion and provides a protective barrier against saliva erosion through its bioadhesive inner layer and hydrophobic backing. Mechanistically, it actively regulates JAK-STAT signaling and antioxidant networks, effectively reprogramming the dysregulated inflammatory microenvironment to promote rapid re-epithelialization and functional recovery. This study offers a translatable biomaterial strategy for improving clinical management of oral ulcers.