Bifunctional injectable selenium‐containing polyurethane hydrogels for periodontal regeneration through endoplasmic reticulum stress modulation

Abstract Periodontitis causes progressive destruction of both periodontal soft and hard tissues, leading to tooth loss and functional impairment. Conventional treatments, such as mechanical debridement and antibiotic therapy, are often insufficient for effective regeneration due to persistent local inflammation and the complex architecture of gingival and alveolar bone defects. In this study, we developed a thermo‐responsive, injectable hydrogel composed of hydroxybutyl chitosan (HBC) and selenium‐containing polyurethane (SePU), which undergoes rapid sol‐gel transition at physiological temperature. SePU/HBC not only facilitated the adhesion and migration of human gingival fibroblasts but also effectively inhibited osteoclast formation and resorptive activity. Mechanistically, it efficiently scavenged intracellular reactive oxygen species and activated an ATF6‐mediated protective unfolded protein response, thereby re‐establishing endoplasmic reticulum function and preventing apoptosis. By integrating targeted stress modulation with bifunctional cellular regulation, SePU/HBC offers an innovative strategy for coordinated periodontal tissue regeneration, offering potential benefits in both early inflammation control and late‐stage defect repair.