Abstract: Tissue engineering aims to offer large-scale replacement of damaged organs using implants with the combination of cells, growth factors and scaffolds. However, the intra/peri-implant region is exposed to severe hypoxic stress and oxidative stress during the early stage of implantation with bone graft materials, which endangers the survival, proliferation and differentiation of seed cells within the implants as well as the host cells surrounding the implants. If the bone graft material could spontaneously and intelligently regulate the hypoxic stress and oxidative stress to a moderate level, it will facilitate the vascularization of the implants and the rapid regeneration of the bone tissue. In this review, we will first introduce the signaling pathways of cellular response under hypoxic stress and oxidative stress, then present the classical material designs and examples in response to hypoxic stress and oxidative stress. And finally, we will address the important role of epigenetic mechanisms in the regulation of hypoxic stress and oxidative stress and describe the potential applications and prospective smart bone graft materials based on novel epigenetic factors against hypoxic stress and oxidative stress in bone repair. The main content of this review is summarized in the following graphical abstract.

Key words: Hypoxic stress, Oxidative stress, Bone repair, Bone graft material, Epigenetic regulation