Evaporation of phosphate species during thermal treatment (> 400 °C) of calcium phosphates leads to the formation of an alkaline layer on their surface. The aim of this study was to evaluate the hypothesis that the biological response of thermally treated calcium phosphates is modified by the presence of such an alkaline layer on their surface. For this purpose, 0.125-0.180 mm α- and β-tricalcium phosphate (TCP) granules were obtained by crushing and size classification, with some being subjected to thermal treatment at 500 °C. The four types of granules (α-TCP, β-TCP, α-TCP-500 °C, and β-TCP-500 °C) were implanted subcutaneously and orthotopically in rats. Sham operations served as control. Subcutaneously, α-TCP and β-TCP induced significantly more multinucleated giant cells (MNGCs) than calcined granules. Most of the induced MNGCs were TRAP-negative, CD-68 positive and cathepsin K-negative, reflecting a typical indication of a reaction with a foreign body. The vessel density was significantly higher in the α-TCP and β-TCP groups than it was in the α-TCP-500 °C and β-TCP-500 °C groups. In the femur model, β-TCP-500 °C induced significantly more new bone formation than that induced by β-TCP. The granule size was also significantly larger in the β-TCP-500 °C group, making it more resistant to degradation than β-TCP. The MNGC density was higher in the α-TCP and β-TCP groups than in the α-TCP-500 °C and β-TCP-500 °C groups, including cathepsin-positive, CD-68 positive, TRAP-positive and TRAP-negative MNGCs. In conclusion, this study confirms that the biological response of calcium phosphates was affected by the presence of an alkaline layer on their surface. Thermally-treated α-TCP and β-TCP granules produced significantly fewer MNGCs and were significantly less degraded than non-thermally-treated α-TCP and β-TCP granules. Thermally treating α-TCP and β-TCP granules shifts the reaction from a foreign body reaction towards a physiological reaction by downregulating the number of induced MNGCs and enhancing degradation resistance.
