Zinc-doped calcium silicate additive accelerates early angiogenesis and bone regeneration of calcium phosphate cement by double bioactive ions stimulation and immunoregulation

Calcium phosphate cement (CPC), a popular injectable bone defect repairing material, has deficiencies in stimulating osteogenesis and angiogenesis. To overcome the weaknesses of CPC, zinc-doped calcium silicate (Zn-CS) which can release bioactive silicon (Si) and zinc (Zn) ions was introduced to CPC. The physicochemical and biological properties of CPC and its composites were evaluated. Firstly, the most effective addition content of calcium silicate (CaSiO3, CS) in promoting the in vitro osteogenesis was first sorted out. On this basis, the most effective Zn doping content in CS for improving osteogenic differentiation of CPC-based composites was screened out. Finally, the immunoregulation of CS/CPC and Zn-CS/CPC in promoting angiogenesis and osteogenesis was studied. The results showed that the most effective incorporation content of CS was 10 wt%. Zn at a doping content of 30 mol% in CS (30Zn-CS) further enhanced the osteogenic capacity of CS/CPC and simultaneously maintained excellent proangiogenic activity. CS/CPC and 30Zn-CS/CPC promoted the recruitment of macro-phages and enhanced M2 polarization while inhibiting M1 polarization, which was beneficial to the early vascularization as well as subsequent new bone formation. When implanted into the femoral condylar defects of rabbits, 30Zn-CS/CPC showed high in vivo materials degradation rate, angiogenesis and osteogenesis, due to the synergistic effects of Si and Zn on bio-stimulation and immunoregulation. This study shed light on the synergistic effects of Si and Zn on regulating the angiogenic, osteogenic, and immunoregulatory activity, and 30Zn-CS/CPC is expected to repair the lacunar bone defects effectively.