No-Observed-Effect Level of Silver Phosphate in Carbonate Apatite Artificial Bone on Initial Bone Regeneration

Fracture-related infections require both treatments for bacteria removal and bone reconstruction. The use of combined broadspectrum antibacterial silver compounds and artificial bone with high osteogenic activity is considered to be an effective strategy for achieving these treatments in one surgery. However, silver compounds are toxic for living tissues even at low concentrations. Herein, we investigated the no-observed-effect level (NOEL) of silver phosphate (Ag3PO4) in a bone substitute composed of carbonate apatite (CO(3)Ap), a bone mineral, using in vitro and in vivo experiments. In vitro experiments demonstrated that the CO(3)Ap artificial bone containing >= 0.1 wt % Ag3PO4 exerted antibacterial effects against Staphylococcus epidermidis, while those containing wt % Ag3PO4 did not affect cellular adhesion, proliferation, differentiation, and calcification of osteoblast-like MC3T3-E1 cells. In vivo experiments demonstrated that the CO(3)Ap artificial bone containing wt % Ag3PO4 replaced a new bone to the same levels as those without Ag3PO4 4 weeks after implantation into the bone defect of the rabbit femur condyle. However, the CO(3)Ap artificial bone containing <= 0.3 wt % Ag3PO4 caused an inflammatory reaction, whereas those containing wt <= 0.1% Ag3PO4 did not. Thus, both bone regeneration and infection control without any adverse effects were achieved using the CO(3)Ap artificial bone containing 0.1 wt % Ag3PO4, indicating that the NOEL of Ag3PO4 was 0.1 wt %. Our results provide an effective strategy for the treatments of fracture-related infections.

Automated summary

Fracture-related infections require treatments targeting bacteria removal and bone reconstruction. The use of Ag3PO4 in CO(3)Ap artificial bone at 0.1 wt% level demonstrated antibacterial effects without adverse effects, while higher concentrations caused inflammation.