Immune-involved cell communications have recently been introduced as key role players in the fate of mesenchymal stem cells in making bone tissue. In this study, a drug delivery system for bone (re)generation based on copper-doped mesoporous bioactive glass nanoparticles (BGNPs) was developed to codeliver copper as a biologically active ion and icariin as an anti-inflammatory agent. This design was based on temporal inflammation fluctuations from proinflammatory to anti-inflammatory during bone generation. Three in vitro models were performed with human mesenchymal stem cells (hMSCs) to verify the osteo-immunomodulatory effects of released copper ions and icariin: nonstimulated, co-conditioned with macrophage medium and co-cultured with macrophages. Both icariin and copper showed increased levels of alkaline phosphatase activation, indicating a direct osteogenic effect. Copper-doped BGNPs showed the highest increase of osteo-immunogenic properties in a mineralization assay and also induced short-term inflammation. However, the mineralization dropped in copper doped BGNPs after loading with icariin due to copper-icariin chelate formation and inhibition of the early inflammatory phase in the immune-stimulated in vitro models. In the absence of copper, the direct osteogenic properties of icariin overtook its osteo-immunogenic inhibition and increased calcification. Overall, BGNPs doped with 5 mol % copper and no icariin showed the highest bone-forming capacity.
Keywords: Bone regeneration; Flavonoid; Immunomodulatory; Inflammation; Tissue engineering.