Development of magnesium-based biomaterials enabling controlled delivery of magnesium ions for in-situ bone regeneration

Abstract

Magnesium ions (Mg2+) have been extensively reported to have osteogenesis-stimulating capability through the promotion of osteoblastic activity and/or inhibition of osteoclastic activity. Nevertheless, high concentration of Mg2+ is harmful to the differentiation of osteogenic cells and causes disorder in the bone mineralization process. In our previous study, it is evidenced that the constant release of Mg2+ in the range of 50-200 ppm can significantly trigger new bone formation. In order to achieve stimulation of in-situ bone regeneration, I hypothesize that controlling the delivery of Mg2+ within a specific range (50-200 ppm) in local bony tissue environment can induce bone regeneration. Hence, to actualize this concept, I developed three kinds of Mg-based biomaterials with controllable Mg2+ delivery for bone regeneration.

The first design is a poly (lactic-co-glycolic acid)/Magnesium oxide-alendronate microsphere delivery system fabricated by the electrospraying technique. The poly (lactic-co-glycolic acid) (PLGA) widely used in drug delivery functions as a carrier to encapsulate magnesium oxide (MgO) nanoparticles for delivery of magnesium ion in local microenvironment. Alendronate is utilized to enable bone affinity property of the microsphere. As for the magnesium ion release profile, although sustained release of Mg2+ has been attained for two weeks in PBS, the release pattern is not zero-order in which Mg ion delivery cannot maintain at a constant level. Furthermore, the microsphere is unable to regulate outflow of Mg2+ within 50-200 ppm. Hence, I have to optimize our microsphere system with precisely control of Mg ion delivery at 50-200 ppm by introducing the core-shell structure.

The second design is a monodisperse core-shell microsphere delivery system that comprises PLGA biopolymer, alginate hydrogel, and MgO nanoparticles. The PLGA/MgO core acts as a reservoir of Mg2+, while the alginate shell is introduced to regulate accurately the outflow of Mg2+ ~50ppm for two weeks through its micro-porous structure. In addition, the core-shell microsphere system exhibits enhanced osteoblastic activity in vitro and stimulation of in-situ bone formation in a rat femur-defect model at post-surgery eight weeks. Interestingly, Young’s moduli of newly formed bone on the Mg-based core-shell microsphere group were found to be restored to ~96% of that of the surrounding matured bone indicating that the core-shell system with precisely controlled release of Mg2+ may potentially apply for in-situ clinical bone regeneration.

The third design is a titanium oxide (TiO2) surface-modified Mg implant. Rapid corrosion in vivo is the major concern of biodegradable Mg alloys in clinical applications. Surface modification is necessary for suppressing rapid corrosion and maintain the mechanical strength of Mg implants upon degradation. Also, regulation of Mg ion released from magnesium implants can be beneficial to osseointegration at the implant-bone interface. I employ the Ti and O dual plasma ion immersion implantation (PIII) technique to construct a TiO2 nanolayer on Mg implants. The TiO2 nanolayer significantly enhances the corrosion resistance of Mg substrates and promotes osteoblastic proliferation and differentiation in vitro and osteoconductivity in vivo due to controlled Mg ion release and less hydrogen gas generation. Moreover, the TiO2-containing nanolayer exhibits photoactive bacteria disinfection under UV irradiation.