A pH-responsive injectable metformin hydrogel for regulating host immunity through the AMPK/NF-κB pathway in periodontitis therapy

Although plaque is the primary initiator of periodontitis, recent studies have shown that excessive activation of the host immune response also plays a significant role in periodontal tissue destruction. As a result, modulating the immune response, in addition to traditional plaque removal, has increasingly gained attention as an important therapeutic strategy for periodontitis. Metformin (Met), an AMPK activator, has demonstrated various applications, including immunomodulation. However, its high water solubility may lead to rapid diffusion from the local site, limiting its retention and sustained therapeutic effects in periodontal tissues. The development of pH-responsive delivery systems offers a promising solution, as inflammation typically creates an acidic microenvironment. This research focuses on the in situ cross-linking of carboxymethyl chitosan with the amino-aldehyde group of oxidized hyaluronic acid to form a hydrogel. Met was incorporated into the hydrogel through dynamic Schiff base interactions with OHA and physical entrapment, enabling local retention and pH-responsive controlled release. This material, with excellent injectability, self-healing properties, and biocompatibility, dissolves rapidly in the inflammatory microenvironment, allowing for targeted delivery and inhibition of pro-inflammatory factors. In vivo studies confirm its effectiveness in reducing alveolar bone resorption and inflammatory infiltration. Further research suggests that the AMPK/NF-κB signaling pathway is involved in its therapeutic effect on periodontitis.