AbstractAbstractSilk fibroin (SF) have been increasingly used as bone substitutes in tissue engineering (TE) due to their sufficient mechanical strength, good biocompatibility, osteoconductive, and controllable degradation rates. The SF scaffold as a 3D-matrix allows and stimulates the proliferation, attachment and differentiation of stem cells toward osteogenic cells. Herein, we have summarized the applications of SF for regeneration of bone defects in a comprehensive manner. Additionally, we have discussed three critical factors for osteogenesis regulation, including biological (cells and growth factors), physical (mechanics and morphology), and chemical (composition) aspects with their current drawbacks and future perspective of SF in bone TE.Graphical AbstractKeywords: Bone tissue engineeringextracellular matrixregenerationScaffoldSilk fibroinstem cell Disclosure statementNo conflict of interest was reported by the author(s).Additional informationFundingThis study was supported by Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran [Finance code 66827].