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The regenerative repair of large bone defects is a major problem in orthopedics and clinical medicine. The key problem is the lack of ability of existing bone graft materials to promote osteogenesis and angiogenesis. Previous studies have shown that the osteogenic or angiogenic abilities of these materials could be significantly improved by adding miRNA or small-molecule drugs to bone graft materials; however, the synergistic effect arising from this combination is not clear. Therefore, we proposed to construct a dual drug delivery system that could simultaneously achieve the co-encapsulation and co-delivery of miRNA and small-molecule drugs to explore the effect of a dual drug delivery system on bone repair. In this study, we constructed dual-sized pore structure calcium-silicon nanospheres (DPNPs) and achieved the co-encapsulation of miR-210, angiogenic gene drugs, and simvastatin (Siv), a small-molecule osteogenic drug, through metal-ion coordination and physical adsorption. In vitro and in vivo osteogenic and angiogenic experiments showed that the dual drug delivery system (Siv/DPNP/miR-210) exhibited better properties than those of the individual unloaded and single drug-loaded systems and could significantly accelerate the process of bone repair, which provides a novel strategy for the regeneration and repair of bone defects.

Melatonin (MT) has been served as promising osteogenic factor to promote osteogenesis. However, the direct injection of MT is accompanied by its fast diffusion and rapid degradation, which can significantly affect the repairing of bone defects. The sustainable release of MT from scaffolds would greatly enhance bone regeneration, but it has never been studied. Herein, we have demonstrated the decoration of MT molecules into the 3D-printed beta-tricalcium phosphate (β-TCP) scaffolds by utilizing the dopamine-based mussel-inspired chemistry. The slower release of MT from the scaffolds was achieved, and bone mesenchymal stem cells demonstrated great viability and proliferation ability within the scaffolds. Remarkably, a significantly higher expression of osteogenic-genes was achieved in the MT decorated scaffolds in the presence of dopamine. These scaffolds were then implanted into rat calvarial defect sites for the in vivo bone regeneration investigation. Micro-computed tomography (micro-CT), bone mineral density and histological analysis clearly revealed that the scaffolds with MT decoration exhibited the highest percentage of new bone ingrowth. These results demonstrate that the decoration of MT into the 3D-printed β-TCP scaffolds could be a facile and highly efficient strategy to promote bone regeneration.