Effects of Strontium-Doped β-Tricalcium Scaffold on Longitudinal Nuclear Factor-Kappa Beta and Vascular Endothelial Growth Factor Receptor-2 Promoter Activities during Healing in a Murine Critical-Size Bone Defect Model

It was hypothesized that strontium (Sr)-doped &beta
tricalcium phosphate (TCP)-based scaffolds have a positive effect on the regeneration of large bone defects (LBD). Readouts in our mice models were nuclear factor-kappa beta (NF-&kappa
B) activity and vascular endothelial growth factor receptor-2 (VEGFR-2) promoter activity during the healing process. A 2-mm critical-size femoral fracture was performed in transgenic NF-&kappa
B- and VEGFR-2-luciferase reporter mice. The fracture was filled with a 3D-printed &beta
TCP scaffold with or without Sr. A bioluminescence in-vivo imaging system was used to sequentially investigate NF-&kappa
B and VEGFR-2 expression for two months. After sacrifice, soft and osseous tissue formation in the fracture sites was histologically examined. NF-&kappa
B activity increased in the &beta
TCP + Sr group in the latter stage (day 40&ndash
60). VEGFR-2 activity increased in the + Sr group from days 0&ndash
15 but decreased and showed significantly less activity than the &beta
TCP and non-scaffold groups from days 40&ndash
60. The new bone formation and soft tissue formation in the + Sr group were significantly higher than in the &beta
TCP group, whereas the percentage of osseous tissue formation in the &beta
TCP group was significantly higher than in the &beta
TCP + Sr group. We analyzed longitudinal VEGFR-2 promoter activity and NF-&kappa
B activity profiles, as respective agents of angiogenesis and inflammation, during LBD healing. The extended inflammation phase and eventually more rapid resorption of scaffold caused by the addition of strontium accelerates temporary bridging of the fracture gaps. This finding has the potential to inform an improved treatment strategy for patients who suffer from osteoporosis.