Abstract

Periodontitis is a chronic inflammatory disease involving the destruction of periodontal supporting tissues and dysregulated host immune responses. Conventional therapies such as scaling and root planing with adjunctive antibiotics often inadequately control inflammation and lack regenerative capacity. Here, we developed an injectable multifunctional hydrogel by chemically cross‑linking hyaluronic acid (HA) and chondroitin sulphate (ChS) with 1,4‑butanediol diglycidyl ether (BDDE). Capitalizing on the strong anionic nature of ChS, the hydrogel efficiently adsorbed and stabilized a spectrum of cationic growth factors (GFs), including EGF and FGF, from mesenchymal stem cell‑conditioned medium. The resulting GF‑loaded hydrogel (HA/ChS@GFs) exhibited favorable injectability, controlled degradability, and sustained GFs release. In vitro , HA/ChS@GFs significantly enhanced cell proliferation and migration, scavenged reactive oxygen species (ROS), and reduced the proportion of pro‑inflammatory M1 macrophages. In a rat periodontitis model, the hydrogel effectively attenuated alveolar bone resorption, increased bone mineral density and bone volume fraction, and promoted periodontal tissue regeneration, all while demonstrating excellent biocompatibility and no systemic toxicity. These findings highlight HA/ChS@GFs as a promising cell‑free strategy to modulate the inflammatory microenvironment and drive functional regeneration in periodontitis.