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• Bionic hierarchical scaffold fabricated by 3D-printing and surface mineralization. • The obtained biomimetic multi-structured scaffolds facilitate bone regeneration. • Regulation of cell fate in activated PI3K/AKT/mTOR signaling were confirmed. • Hydroxyapatite coating accelerates osseointegration and enhance bone-augmentation. • A two-step method enriches and guides the design of modified bone graft materials. The architecture and surface modifications have been regarded as effective methods to enhance the biological response of biomaterials in bone tissue engineering. The porous architecture of the implantation was essential conditions for bone regeneration. Meanwhile, the design of biomimetic hydroxyapatite (HAp) coating on porous scaffolds was demonstrated to strengthen the bioactivity and stimulate osteogenesis. However, bioactive bio-ceramics such as β-tricalcium phosphate (β-TCP) and calcium silicate (CS) with superior apatite-forming ability were reported to present better osteogenic activity than that of HAp. Hence in this study, 3D-printed interconnected porous bioactive ceramics β-TCP/CS scaffold was fabricated and the biomimetic HAp apatite coating were constructed in situ via hydrothermal reaction, and the effects of HAp apatite layer on the fate of mouse bone mesenchymal stem cells (mBMSCs) and the potential mechanisms were explored. The results indicated that HAp apatite coating enhanced cell proliferation, alkaline phosphatase (ALP) activity, and osteogenic gene expression. Furthermore, PI3K/AKT/mTOR signaling pathway is proved to have an important impact on cellular functions. The present results demonstrated that the key molecules of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) were activated after the biomimetic hydroxyapatite coating were constructed on the 3D-printed ceramic scaffolds. Besides, the activated influence on the protein expression of Runx2 and BMP2 could be suppressed after the treatment of inhibitor HY-10358. In vivo studies showed that the constructed HAp coating promoted bone formation and strengthen the bone quality. These results suggest that biomimetic HAp coating constructed on the 3D-printed bioactive composite scaffolds could strengthen the bioactivity and the obtained biomimetic multi-structured scaffolds might be a potential alternative bone graft for bone regeneration. [ABSTRACT FROM AUTHOR]