The therapeutic potential of oxygen tension manipulation via hypoxia inducible factors and mimicking agents in guided bone regeneration. A review

Intraoral bone grafting is routinely employed for implant site development prior or simultaneously to implant placement. Bone graft consolidation is a complex biological process depending on the formation of blood vessels into the augmented area. It is highly regulated by the angiogenesis and osteogenesis coupling phenomenon. The vascular system apart from supplying nutrients and oxygen to the developing and regenerating bone, also delivers critical signals which stimulate mesenchymal cell differentiation towards an osteogenic phenotype. Hypoxia inducible factors (HIFs) and mimicking agents (HMAs) (or alternatively HIF stabilizing agents) are considered to act as key stimulators of blood vessel formation. Under normoxia, HIFs are rapidly degraded. However, their degradation is prevented under hypoxia, which in turn, triggers angiogenesis. Hence, the major role of HMAs is to prevent degradation of HIFs under normoxic conditions. Recent studies suggest that HIFs and HMAs trigger the initiation and promotion of angiogenic-osteogenic cascade events. In vitro and animal studies involving genetic manipulation of individual components of the HIFs and HMAs have provided clues to how angiogenic-osteogenic coupling is achieved. Evidence from preclinical studies further suggests that topical application of HMAs enhance angiogenesis in intraoral augmented sites. In this article, we review the current understanding of the cellular and molecular mechanisms responsible for angiogenic-osteogenic coupling. We also discuss the therapeutic manipulation of HIFs and HMAs in intraoral bone repair and regeneration. Such discoveries suggest promising approaches for the development of novel therapies to improve intraoral bone repair and regeneration procedures.