Three-Dimensional Bioprinted Scaffolds Loaded with Multifunctional Magnesium-Based Metal–Organic Frameworks Improve the Senescence Microenvironment Prompting Aged Bone Defect Repair

Age-related bone defects cause disability and mortality in older individuals. During bone repair in older individuals, high oxidative stress and excessive inflammation in the senescent microenvironment (SME) lead to bone marrow mesenchymal stem cell (BMSC) senescence, thereby affecting bone regeneration. In this study, we prepared multifunctional magnesium (Mg) and cerium (Ce) ion-based metal-organic frameworks (MOFs) using a hydrothermal method and constructed a three-dimensional (3D) bioprinted scaffold to effectively scavenge reactive oxygen species (ROS) and sustainably release Mg2+ to improve the SME and age-related bone defect repair. Under oxidative stress, the scaffolds delayed the senescence of loaded BMSCs and promoted M2 macrophage polarization of RAW264.7 cells, further improving BMSC osteogenic differentiation. In addition, Mg2+ release promoted aldehyde dehydrogenase 3A1 expression through the activation of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway, thereby delaying BMSC senescence. Adding the Wnt/β-catenin agonist SKL2001 to the scaffolds further enhanced these effects. Finally, the composite scaffolds accelerated the repair of critical-sized calvarial defects in an aged rat model. In summary, these results demonstrated the value of improving the SME for delaying BMSC senescence using multifunctional Mg-Ce-MOF and SKL2001-based 3D-bioprinting scaffolds, thereby providing an effective strategy for promoting age-related bone defect repair.