Dual-ion delivery for synergistic angiogenesis and bactericidal capacity with silica-based microsphere

Inhibition of bacterial growth with the simultaneous promotion of angiogenesis has been challenging in the repair and regeneration of infected tissues. Here, we aim to tackle this issue through the use of cobalt-doped silicate microspheres that can sustainably release dual ions (silicate and cobalt) at therapeutically-relevant doses. The cobalt was doped up to 2.5 wt% within a sol-gel silicate glass network, and microspheres with the size of ∼300 μm were generated by an emulsification method. The cobalt and silicate ions released were shown to synergistically upregulate key angiogenic genes, such as HIF1-α, VEGF and the receptor KDR. Moreover, the incorporation of ions promoted the polarization, migration, homing and sprouting angiogenesis of endothelial cells. Neo-vascular formation was significantly higher in the dual-ion delivered microspheres, as evidenced in a chicken chorioallantoic membrane model. When cultured with bacterial species, the cobalt-doped microspheres effectively inhibited bacteria growth in both indirect or direct contacts. Of note, the bacteria/endothelial cell coculture model proved the efficacy of dual-ion releasing microcarriers for maintaining the endothelial survivability against bacterial contamination and their cell-cell junction. The current study demonstrates the multiple actions (proangiogenic and antibacterial) of silicate and cobalt ions released from microspheres, and the concept provided here can be extensively applied to repair and regenerate infected tissues as a growth factor- or drug-free delivery system. STATEMENT OF SIGNIFICANCE: While several ions have been introduced to biomaterials for therapeutic purposes, relaying the effects of antibacterial into tissue regenerative (e.g., angiogenesis) has been a significant challenge. In this study, we aim to develop a biomaterial platform that has the capacity of both 'antibacterial' and 'proangiogenic' from a microsphere sustainably releasing multiple ions (herein cobalt and silicate). Here, dual-actions of the microspheres revealed the stimulated endothelial functions as well as the inhibited growth of different bacterial species. In particular, protecting endothelial survivability against bacterial contamination was reported using the bacterial/endothelial co-culture model. The current concept of drug-free yet multiple-ion delivery biomaterials can be applicable for the repair and regeneration of infected tissues with dual actions of angiogenesis and suppressing bacterial activity.