Time‐Sequential and Multi‐Functional 3D Printed MgO2/PLGA Scaffold Developed as a Novel Biodegradable and Bioactive Bone Substitute for Challenging Postsurgical Osteosarcoma Treatment

Abstract Osteosarcoma (OS) is the most commonly occurring primary bone malignant tumor. The clinical postsurgical OS treatment faces big challenges for the staged therapeutic requirements of early anti‐tumor, anti‐bacterial, and long‐lasting osteogenesis. Herein, multi‐functional bioactive scaffolds with time‐sequential functions of preventing tumor recurrence, inhibiting bacterial infection, and promoting bone defect repair are designed as a novel strategy. Nanocomposite scaffold magnesium peroxide (MgO 2 )/poly (lactide‐ co ‐glycolide) is prepared by low‐temperature 3D printing for controllable releasing magnesium ions (Mg 2+ ) and reactive oxygen species in a time‐sequential manner. The scaffold with 20 wt% MgO 2 (20MP) is verified with desired mechanical properties, as well as exhibits staged release behavior of bioactive elements with hydrogen peroxide (H 2 O 2 ) release for the first 3 weeks, and long‐lasting Mg 2+ release for 12 weeks. The released H 2 O 2 initiates chemodynamic therapy to induce apoptosis and ferroptosis in tumor cells, along with activating the anticancer immune microenvironment by M1 polarization of macrophages. The released Mg 2+ subsequently enhances bone repair by activating the Wnt3a/GSK‐3β/β‐catenin signaling pathway to promote osteogenic differentiation of bone marrow mesenchymal stem cells and create osteopromotive immune microenvironment by M2 polarization of macrophages. In conclusion, the multi‐functional 20MP scaffold demonstrates time‐sequential therapeutic properties as an innovative strategy for OS‐associated bone defect treatment.