The effect of Hypoxia-Inducible Factor-1a stabilization on bone regeneration during distraction osteogenesis: A systematic review of animal studies

Objective

This systematic review described Hypoxia-Inducible Factor-1a stabilization or upregulation approaches along with underlying signaling pathways and assessed bone regeneration, angiogenesis, and consolidation time during DO in animal models.

Design

A comprehensive and systematic search of electronic databases including PubMed, Scopus, and ScienceDirect was performed till December 26, 2023. The search was limited to English articles, and no time restrictions were applied.

Results

A total of 14 studies met the inclusion criteria and were included for final review. Four methods have been shown to activate the HIF pathway including genetic, pharmacological, mechanical, and cell preconditioning approaches. Deferoxamine (DFO) was administered as a pharmacological hypoxia-mimicking agent in many studies reporting acceptable outcomes on bone regeneration and acceleration of bone consolation. Applying mechanical loads at the optimal rate and amplitude serves as a minimally invasive approach with acceptable results. HIF-related signaling pathways increase osteogenesis and angiogenesis during DO, potentially through VHL/HIF-1a/VEGF, Wnt/β-catenin, and Mesenchymal-Epithelial transition (MET) signaling pathways.

Conclusion

Activation of HIF-related signaling pathways enhances and accelerates bone regeneration during the consolidation phase of distraction osteogenesis. The most feasible approach with the least side effects must be selected for further clinical studies.