Injectable Gypsogenin‐Based Composite Hydrogel Enhances Osteoporotic Bone Regeneration by Alleviating Oxidative Injury via Promoting AMPKα Phosphorylation

Abstract Osteoporosis is characterized by an imbalance between osteoblasts and osteoclasts coupling and excessive oxidative stress in the bone microenvironment that impairs bone defect healing and increases the risk of non‐union. In this study, an injectable gypsogenin (GN)‐based organic–inorganic composite hydrogel (CCT/nHA@GN) is developed to treat osteoporotic bone defects. The hydrogel is made by grafting sodium citrate (SC) and nano‐hydroxyapatite (nHA)/GN nanoparticles onto carboxymethylated chitosan (CMCS). GN is a natural small‐molecule saponin, which shows biocompatibility and anti‐oxidant properties. The resulting hydrogel shows a well‐defined porous structure, favorable degradability, controlled drug‐release properties, and suitable rheological characteristics. Importantly, it reverses the differentiation fate of bone marrow‐derived mesenchymal stem cells (BMSCs) from osteoporotic patients and promotes angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, it activates the AMPKα‐FOXO3a‐CAT/MnSOD signaling pathway via AMPKα phosphorylation, thereby augmenting antioxidant stress capacity, promoting osteogenesis, inhibiting osteoclastogenesis, and ultimately rectifying the disrupted bone microenvironment. In vivo studies reveal that the bone volume to total volume (BV/TV) ratio of bones regenerated with the CCT/nHA@GN hydrogel is 2.85 times higher than that of the control group. In conclusion, these findings suggest that the injectable CCT/nHA@GN hydrogel can be a promising alternative material for the treatment of osteoporotic bone defects.