Periodontitis is a leading cause of tooth loss in adults and imposes a significant burden on societies and economies globally [1]. Periodontal tissue inflammation is not only a main trigger of oral diseases, but also exhibits a close relationship with other systemic tissues [2], [3]. Numerous studies have demonstrated that periodontal pathogens and their metabolites contribute significantly to systemic diseases via ectopic migration, colonization, expansion, subsequent inflammatory activation and abnormal immune response [4]. To date, over 50 diseases have been linked to periodontitis, including cardiovascular diseases, Alzheimer’s disease and inflammatory bowel disease (IBD), with IBD receiving particular attention [5], [6], [7]. Both periodontitis and IBD are chronic inflammatory diseases influenced by microbial and host immune factors. Periodontitis and IBD do not represent two entirely separate diseases in the conventional sense but rather form an “oral-intestinal axis” that affects each other [8]. For example, oral periodontal pathogens may colonize the intestine, causing intestinal microecological imbalance and activating intestinal immune response, thus aggravating intestinal inflammation [9]. This correlation is also reflected in treatment. For instance, certain medications employed in IBD treatment, such as lactobacilli, steroids, and vitamin D, have been demonstrated to mitigate periodontitis by alleviating intestinal inflammation-induced damage [5], [10], [11]. This suggests that controlling one of the two diseases often facilitates the improvement of the other disease as well.

The current conventional drug for the treatment of IBD is MSZ, which exhibits a broad spectrum of pharmacological activities, including anti-inflammatory, antibacterial, antifungal, anti-amyloid, and gastroprotective effects [12]. Meanwhile, MSZ, as a kind of NSAIDs, inhibits the production of cyclooxygenase-2 (COX-2). COX-2 in turn catalyzes the conversion of arachidonic acid (AA) to prostaglandin E2 (PGE2), which has been shown to be a key inflammatory mediator that promotes alveolar bone resorption [13]. However, the effects of MSZ on periodontitis have not been extensively reported. Given the established correlation between IBD and periodontitis, as well as the favorable pharmacological properties of MSZ, we hypothesize that MSZ may exhibit therapeutic potential in the management of periodontitis.

Currently, the primary modes of administration for periodontitis treatment involve systemic and local administration [14]. While systemic drugs administration is a commonly employed clinical approach, it is also associated with certain limitations, including gastrointestinal adverse reactions, allergic reactions and low local drug concentrations in periodontal pockets [15]. Moreover, long-term drug use can easily induce the production of drug-resistant strains, result in dysbiosis and superinfection, and trigger chronic inflammation that cannot be resolved [16]. However, the local administration of the sustained-release preparation can minimize the adverse reactions of systemic administration while maintain an effective drug concentration at the lesion site. Among various sustained-release formulations, injectable hydrogel possesses several advantages, such as simple preparation, convenient use, and low toxicity. It can be easily administered into irregularly shaped periodontal pockets to ensure high concentration and even distribution of the drug in the target area [17], [18]. Chitosan (CS), as a polycationic polymer, is able to react with negatively charged β-GP to form a network via ionic bridges between the polymer chains, thereby forming a hydrogel at 37 °C [19], [20]. The incorporation of gelatin shortened the gelation time by facilitating crosslinking between CS and β-GP through electrostatic interactions between the cationic and anionic groups of the polymers [21]. In this study, we employed a MSZ/CS/β-GP/gel hydrogel for animal experiments to achieve localized sustained drug release.

In this study, we successfully achieved sustained release of MSZ using CS/β-GP/gel hydrogel as a carrier and demonstrated its excellent biocompatibility both in vivo and in vitro. MSZ exhibited a significant anti-inflammatory effect in vitro, and in the rat periodontitis model, the MSZ/CS/β-GP/gel hydrogel effectively inhibited periodontal tissue inflammation and bone absorption, thereby creating favorable conditions for periodontal tissue regeneration (Fig. 1). These findings provide a robust theoretical foundation for the potential clinical application of MSZ in the treatment of periodontitis.