Controlled magnesium ion delivery system for in situ bone tissue engineering

Magnesium cation (Mg2+) has been an emerging therapeutic agent for inducing vascularized bone regeneration. However, the therapeutic effects of current magnesium (Mg) -containing biomaterials are controversial due to the concentration- and stage-dependent behavior of Mg2+. Here, we first provide an overview of biochemical mechanism of Mg2+ in various concentrations and suggest that 2-10 mM Mg2+in vitro may be optimized. This review systematically summarizes and discusses several types of controlled Mg2+ delivery systems based on polymer-Mg composite scaffolds and Mg-containing hydrogels, as well as their design philosophy and several parameters that regulate Mg2+ release. Given that the continuous supply of Mg2+ may prevent biomineral deposition in the later stage of bone regeneration and maturation, we highlight the controlled delivery of Mg2+ based dual- or multi-ions system, especially for the hierarchical therapeutic ion release system, which shows enhanced biomineralization. Finally, the remaining challenges and perspectives of Mg-containing biomaterials for future in situ bone tissue engineering are discussed as well.