Novel application of bergapten and quercetin with anti-bacterial, osteogenesis-potentiating, and anti-inflammation tri-effects.

The bacteria-mediated inflammatory conditions adversely affect the osseointegration process of endosseous implants, which can even lead to implant malfunction or failure. Local drug delivery has been designed to exert anti-inflammatory and antibacterial activities, but whether this strategy has an effect on the compromised osseointegration under inflammation has rarely been studied. The present study focused on the osteoinductive efficacy of two known phytoestrogens [bergapten (BP) and quercetin (QE)] on implant sites under multiple bacteria-infected conditions in situ. Furthermore, the gene expression profiles of rat bone mesenchymal stem cells (rBMSCs) treated with BP and QE in the presence of Porphyromonas gingivalis-derived lipopolysaccharide were identified. The results showed that both drugs, especially QE, had significant potentiating effects on promoting osteogenic differentiation of rBMSCs, resisting multiple pathogens, and reducing inflammatory activity. Meanwhile, RNA sequencing analysis highlighted the enriched gene ontology terms and the differentially expressed genes (Vps25, Il1r2, Csf3, Efemp1, and Ccl20) that might play essential roles in regulating the above tri-effects, which provided the basis for the drug delivery system to be used as a novel therapeutic strategy for integrating peri-implant health. Overall, our study confirmed that QE appeared to outperform BP in osteogenesis and bacterial killing but not in anti-inflammation. Moreover, both drugs possess favorable tri-effects and can serve as the pivotal agents for the drug delivery system to boost osseointegration at inflammatory implant sites.