Environmental Response Temporal Release Injectable Hydrogel for Controlled Growth Factor Release to Enhance Inflammatory Periodontal Bone Defect Regeneration

Abstract

Regeneration of periodontal bone defects in an inflammatory microenvironment remains challenging due to oxidative stress and excessive bone resorption. Although various biomaterials have been developed, current strategies often fail to address the combined obstacles of immune dysregulation, oxidative damage, and bone loss. An injectable multifunctional hydrogel (HTF@HA) with a dynamic borate ester cross‐linked network is designed to provide environmental responsiveness and temporal release of bioactive factors. Under acidic and oxidative conditions, the hydrogel degrades more rapidly and preferentially releases antioxidative and anti‐inflammatory components, facilitating macrophage polarization toward the M2 phenotype and alleviating inflammation. During the subsequent repair phase, calcium‐phosphate interactions mediate the sustained release of concentrated growth factors (CGF) and low‐dose bone morphogenetic protein‐2 (BMP‐2), supporting osteogenic differentiation and angiogenesis. In vitro, HTF@HA exhibits high biocompatibility, antioxidative capacity, anti‐inflammatory effects, and significant enhancement of periodontal ligament stem cell osteogenesis and endothelial cell angiogenesis under inflammatory conditions. Animal studies confirm that the hydrogel promoted new bone and vessel formation (p < 0.001), and at a BMP‐2 dose of 50 µg/L, it achieved bone regeneration comparable to high‐dose BMP‐2 (500 µg/L, p > 0.05). Overall, HTF@HA provides a promising injectable biomaterial with “anti‐inflammatory‐antioxidant‐regenerative” synergy for treating inflammation‐associated periodontal bone defects.