Bioactive Multifunctional Hydrogel Scaffolds Remodel the Inflammatory Microenvironment and Osteogenic-Osteoclastic Homeostasis to Advance Osteoporotic Bone Defect Repair

Bone defect repair in patients with osteoporosis remains a major challenge due to the imbalance in bone metabolism and the inflammatory microenvironment with high levels of reactive oxygen species. To address these issues, a three-dimensional-printed bioactive multifunctional hydrogel scaffold consisting of a polycaprolactone skeleton and a gelatin/hyaluronic acid framework encapsulated with MgMn-layered double hydroxide nanosheets and calcium alendronate nanowires is constructed to promote osteoporotic bone defect repair. The as-prepared hydrogel scaffold continuously scavenges excess reactive oxygen species and generates oxygen through the multiple enzyme mimicry catalytic (catalase, superoxide dismutase, laccase, and hydroxyl radical scavenging) activities, regulates macrophage phenotype, and decreases the expression of pro-inflammatory cytokines, thereby improving the inflammatory microenvironment and alleviating hypoxia. Concurrently, the sustained release of alendronate and Mg²⁺ ions from the hydrogel scaffold inhibits osteoclast activities, while the released bioactive ions (Mg²⁺, Ca²⁺, and Mn³⁺) enhance osteoblast activities and promote osteogenic differentiation, which synergistically restore the balance of osteogenic-osteoclastic homeostasis. Animal experimental results reveal that the hydrogel scaffold can reconstruct the osteoclast/osteoblast balance and significantly accelerate bone tissue defect repair in the osteoporotic rats through synergistic effects of functional components in the implanted scaffold. These findings demonstrate the clinical potential of the as-prepared hydrogel scaffold in addressing the multifaceted complications of the pathological microenvironment and in enhancing osteoporotic bone defect repair.