Controlled release of magnesium ions from PLA microsphere-chitosan hydrogel complex for enhancing osteogenic and angiogenic activities in vitro

Magnesium ions (Mg 2+ ) play an essential role in the metabolism and regeneration of bone tissue. Appropriate amounts of Mg 2+ have been shown to promote osteogenic differentiation of bone-derived cells and angiogenesis of endothelial cells. However, the initial burst release of Mg 2+ may compromise the osteogenic effect, so the controlled release of Mg 2+ is the critical consideration of the magnesium-containing tissue-engineered bone materials. This study proposes a microsphere-hydrogel complex to enhance the sustained-release effect and prolong the release cycle of Mg 2+ . For the initial release of Mg 2+ , polylactic acid (PLA) microspheres containing MgO and MgCO 3 were fabricated with uniform morphology. Further microspheres were incorporated into the chitosan-based hydrogel to form microsphere- hydrogel complex for extended release. The complex demonstrated effective sustained release of Mg 2+ over a period exceeding 28 days. In vitro cell experiments, CS/PLA@MgO-MgCO 3 significantly enhanced migration and osteogenic differentiation of MC3T3-E1. Meanwhile, it can facilitate the generation of blood vessels in HUVECs. In conclusion, the magnesium-loaded microsphere-hydrogel complex achieves excellent dual sustained-release properties with an extended-release cycle while enhancing vascularized osteogenic activity in vitro , showing promising prospects for clinical application in bone defect treatment.