Injectable pH-responsive hydrogel with effects of immunomodulation and osteogenesis for repairing of diabetic bone defects

DMSN/Ca/Ce/GSH exhibits pH responsiveness and excellent osteoconductivity. • Ce 3+ /Ce 4+ and GSH achieved pH-responsive release under high glucose conditions and targeted the improvement of mitochondrial function. • Hydrogel modulates the inflammatory microenvironment through ionic effects and GSH. • Hydrogel accelerates angiogenesis and bone regeneration in diabetic bone defects. Diabetes is a chronic disease characterized by persistent hyperglycemia, which creates a pathological microenvironment that impairs bone regeneration. In diabetic conditions, inflammation, excessive reactive oxygen species (ROS) and mitochondrial dysfunction disrupt angiogenesis and hinder bone regeneration homeostasis. To address these challenges, this study developed an injectable hydrogel specifically designed to modulate the diabetic microenvironment and facilitate the repair of diabetes-related bone defects. The hydrogel is composed of pH-responsive drug-loaded dendritic mesoporous silica nanoparticles, hydrazide-modified carboxymethyl chitosan and oxidized hyaluronic acid. During the initial treatment phase, the acidic diabetic microenvironment destabilized the hydrogel network (crosslinked via Schiff base bonds), triggering the release of drug-loaded nanoparticles into the high ROS microenvironment. Subsequently, pH-responsive amide bonds and acid-degradable nanoparticles enabled the sustained release of Cerium ion (Ce 3+ /Ce 4+ ) and reduced glutathione (GSH). The synergistic antioxidant activity of Ce 3+ /Ce 4+ and GSH effectively scavenged ROS, mitigated oxidative stress induced by high glucose levels and restored mitochondrial function in the diabetic microenvironment. At later stages, the hydrogel transformed into a regenerative scaffold, accelerating angiogenesis and promoting osteogenesis. In summary, this pH-responsive hydrogel facilitates the targeted release of Ce 3+ /Ce 4+ and GSH under high glucose conditions and improves mitochondrial function, establishing a multi-component synergistic intervention strategy to disrupt the pathological cascade of diabetic bone defects. By combining ion-based action with drug delivery, this innovative hydrogel accelerates angiogenesis and bone regeneration, offering a promising therapeutic avenue for repair of bone defects in diabetic patients. Download: Download high-res image (306KB) Download: Download full-size image