Regulation of immune response by bioactive ions released from silicate bioceramics for bone regeneration.

Silicate bioceramics have been considered to possess a wide prospect of clinical application for orthopedic tissue regeneration due to their excellent osteogenesis and angiogenesis. However, the mechanism for silicate bioceramics stimulating bone formation is not fully understood. The host immune defense to implants is proved to greatly influence the osteogenesis and new bone formation, but up to now, few studies are focused on the silicate bioceramics modulated host immune responses. In our present study, two representative silicate bioceramics, akermanite (AKT) and nagelschmidtite (NAGEL) were used as model materials to investigate the inflammation responses in vitro and in vivo, and β-tricalcium phosphate (β-TCP) bioceramics were used as a control. It was found that the mouse macrophage cell RAW264.7 that cultured on AKT and NAGEL bioceramics displayed not only less viability and proliferation, but also a significant less inflammatory cytokine secretion than those on β-TCP in vitro. The formation of foreign body giant cells and fibrous capsules, the invasion of macrophages, as well as the detected inflammatory cytokines around the implanted materials were much lower in both AKT and NAGEL bioceramic groups as compared with those in the β-TCP controls in vivo. Furthermore, it was found that not just the certain concentration of extracellular Si-containing ionic products released from the silicate bioceramics, but also the separate Si, Mg and Ca ions revealed the activity to inhibit the macrophage inflammatory responses by the way of suppressing the activated inflammatory MAPK and NF-κB signaling pathway and promoting the caspase-dependent apoptosis of macrophages. In general, our study suggests that the silicate bioceramics could regulate immune responses by altering the ionic microenvironment between the implants and hosts, which may offer new insight about the mechanism of the bioactivity of silicate bioceramics in bone regeneration and provide profitable guidance for designing new biomaterials for bone tissue engineering. STATEMENT OF SIGNIFICANCE: Silicate bioceramics have been widely used for orthopedic tissue regeneration because of their excellent characteristics in bone formation. However, there are few studies concerning their interrelationships with the host immune defense that has been proved to greatly influence osteogenesis. In our present study, the akermanite and nagelschmidtite were used as two representative silicate bioceramics to investigate the inflammation responses in vitro and in vivo; and for the first time, the bioactive ions released from the silicate bioceramics were discovered to regulate the macrophage immune responses through both inhibiting the inflammatory signaling and activating apoptosis of macrophages. Our findings in this study may not only increase the understanding in osteogenic activity of silicate bioceramics, but also provide profitable guidance for designing and manufacturing new biomaterials for bone tissue engineering.