Supplemental Magnesium Gluconate Enhances Scaffold‐Mediated New Bone Formation and Natural Bone Healing by Angiogenic‐ and Wnt Signal‐Associated Osteogenic Activation

ABSTRACT Local implantation or supplementation of magnesium gluconate (MgG) is being investigated as an effective approach to bone repair. Although studies have highlighted the possible mechanisms in Mg ion‐stimulated new bone formation, the role of MgG in healing bone defects and the signaling mechanisms are not yet completely understood. In this study, we explored how supplemental MgG has bone‐specific beneficial effects by delivering MgG locally and orally in animal models. We fabricated MgG‐incorporated (CMC‐M) and ‐free chitosan (CMC) scaffolds with good microstructures and biocompatible properties. Implantation with CMC‐M enhanced bone healing in rat model of mandible defects, compared with CMC, by activating Wnt signals and Wnt‐related osteogenic and angiogenic molecules. Oral supplementation with MgG also stimulated bone healing in mouse model of femoral defects along with the increases in Wnt3a and angiogenic and osteogenic factors. Supplemental MgG did not alter nature bone accrual and bone marrow (BM) microenvironment in adult mouse model, but enhanced the functioning of BM stromal cells (BMSCs). Furthermore, MgG directly stimulated the induction of Wnt signaling‐, angiogenesis‐, and osteogenesis‐related molecules in cultures of BMSCs, as well as triggered the migration of endothelial cells. These results suggest that supplemental MgG improves bone repair in a way that is synergistically enhanced by Wnt signal‐associated angiogenic and osteogenic molecules. Overall, this study indicates that supplemental MgG might ameliorate oxidative damage in the BM, improve the functionality of BM stem cells, and maintain BM‐microenvironmental homeostasis.