Hydrogel-mediated delivery of Annexin A1 peptide modulates inflammation and tissue remodelling in ligature-induced murine periodontitis

Periodontitis is characterized by chronic inflammation and progressive alveolar bone loss. This study evaluated whether local delivery of an Annexin A1 N-terminal mimetic peptide (Ac 2–26 ) incorporated into an anionic carboxymethylcellulose hydrogel (Hydrogel/AnxA1 2–26 ) modulates inflammation and tissue remodelling in ligature-induced periodontitis in wild-type (WT) and Annexin A1 knockout (AnxA1 −/− ) mice. Ligature-induced periodontitis was established around the maxillary first molars of C57BL/6 WT and AnxA1 −/− mice. Animals received local applications of Hydrogel/AnxA1 2–26 or vehicle three times per week for 7 or 14 days. Inflammatory infiltrate, mucosal mast cells, and collagen deposition were assessed histologically. Tnf-α , Mmp-13 , and Runx2 expression were measured by RT-PCR. Osteoclast numbers and bone volume were determined by histomorphometry and micro-computed tomography. Hydrogel treatment was well tolerated. In WT mice, Hydrogel/AnxA1 2–26 reduced leukocyte infiltration, decreased Tnf-α and Mmp-13 expression, preserved collagen fibres, and lowered osteoclast numbers at 7 days. AnxA1 − / − mice displayed exacerbated inflammation, greater mast cell density, elevated pro-inflammatory gene expression, reduced collagen deposition and increased bone loss compared with WT animals, collectively demonstrating the indispensable physiological role of endogenous AnxA1 in restraining periodontal tissue destruction. Local delivery of AnxA1-derived peptide attenuated inflammation, reduced osteoclast numbers at 7 days and favoured matrix remodelling in experimental periodontitis; however, it did not significantly prevent alveolar bone resorption as measured by μCT, suggesting that further optimisation of peptide dosing and delivery duration is required for hard-tissue protection. The diminished soft-tissue response observed in AnxA1 − / − mice highlights the physiological role of Annexin A1 and supports hydrogel-based peptide delivery as a candidate platform for adjunctive periodontal therapy, pending optimisation of dosing parameters.