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Dual‐Controlled Release of Icariin/Mg2+ from Biodegradable Microspheres and Their Synergistic Upregulation Effect on Bone Regeneration

Current scaffolds applied for bone tissue engineering are still lacking sufficient osteogenic capacity to induce efficient bone regeneration. Biodegradable microsphere‐type scaffolds are designed to achieve the dual‐controlled release of a Chinese medicine (i.e., icariin, ICA) and a bioactive ion (i.e., Mg2+), in order to achieve their synergistic effect on inducing osteogenesis. The hydrophobic icariin is preloaded onto MgO/MgCO3 (1:1 in weight ratio) particles at different amounts and then the particles are encapsulated into biodegradable poly(lactide‐co‐glycolide) (PLGA) microspheres (PMI) at a fixed fraction (20 wt%). Continuous releases of Mg2+ ion and icariin from the microspheres are detected, showing dependence on icariin amounts. At an optimized moderate loading amount, the resulting PMI‐M microspheres display the strongest activation effect on cell biological behaviors among all the designs. By implanting the PMI‐M microspheres into rat calvarial defects for 16 weeks, it is found that they can effectively enhance new bone formation, presenting significantly higher capacity in inducing osteogenesis than PMg (containing MgO/MgCO3 but without icariin) and blank PLGA microspheres. Clearly, the released Mg2+ ions are beneficial to osteogenesis, and the coincorporation of icariin exerts supplemental effects in inducing new bone formation, which suggest a promising strategy to regenerate severe bone injuries by designing a dual‐release system.