Calcium and phosphate ions as simple signaling molecules with versatile osteoinductivity

Due to the continually increasing clinical need to heal large bone defects, synthetic bone graft substitutes have become ever more necessary with calcium phosphates (CaP) widely used due to their similarity to the mineral component of bone. In this research, different concentrations of calcium ions (Ca2+), phosphate ions (P-i), or their combination were provided to mesenchymal stem cells (MSCs) to evaluate their influence on proliferation and differentiation. The results suggest that 1-16 mM Ca2+ and 1-8 mM P-i is osteoinductive, but not cytotoxic. Furthermore, three distinct calcium phosphates (i.e. monobasic, dibasic, and hydroxyapatite) with different dissolution rates were investigated for their Ca2+ and P-i release. These biomaterials were then adjusted to release ion concentrations within the established therapeutics window for which MSC bioactivity was assessed. These findings suggest that CaP-based biomaterials can be leveraged to achieve Ca2+ and P-i dose-dependent osteoinduction for bone regenerative engineering applications.