Encapsulated vaterite-calcite CaCO3 particles loaded with Mg2+ and Cu2+ ions with sustained release promoting osteogenesis and angiogenesis

Abstract

Bioactive cations, including calcium, copper and magnesium, have shown the potential to become the alternative to protein growth factor-based therapeutics for bone healing. Ion substitutions are less costly, more stable, and more effective at low concentrations. Although they have been shown to be effective in providing bone grafts with more biological functions, the precise control of ion release kinetics is still a challenge. Moreover, the synergistic effect of three or more metal ions on bone regeneration has rarely been studied. In this study, vaterite-calcite CaCO3 particles were loaded with copper (Cu2+) and magnesium (Mg2+). The polyelectrolyte multilayer (PEM) was deposited on CaCuMg-CO3 particles via layer-by-layer technique to further improve the stability and biocompatibility of the particles and to enable controlled release of multiple metal ions. The PEM coated microcapsules were successfully combined with collagen at the outmost layer, providing a further stimulating microenvironment for bone regeneration. The in vitro release studies showed remarkably stable release of Cu2+ in 2 months without initial burst release. Mg2+ was released in relatively low concentration in the first 7 days. Cell culture studies showed that CaCuMg-PEM-Col microcapsules stimulated cell proliferation, extracellular maturation and mineralization more effectively than blank control and other microcapsules without collagen adsorption (Ca-PEM, CaCu-PEM, CaMg-PEM, CaCuMg-PEM). In addition, the CaCuMg-PEM-Col microcapsules showed positive effects on osteogenesis and angiogenesis in gene expression studies. The results indicate that such a functional and controllable delivery system of multiple bioactive ions might be a safer, simpler and more efficient alternative of protein growth factor-based therapeutics for bone regeneration. It also provides an effective method for functionalizing bone grafts for bone tissue engineering.

Evaluation of Injectable Composite Material Comprising Biphasic Bone Substitutes and Crosslinked Collagen

“…To achieve the integration of collagen into the porous BBS, the adsorption of collagen on differently charged surfaces was investigated via a quartz crystal microbalance (QCM) and measurements of δ ‐potential in our previous studies. [ 36 ] Our findings indicated that collagen can be stably adsorbed on both negatively and positively charged surfaces because of its amphipathic nature. Therefore, the negatively charged BBS used in this study favored the adsorption of collagen under the specific process conditions with a net positive charge.…”

Vascularization Reconstruction Strategies in Craniofacial Bone Regeneration

“…In the context of biomaterials for craniofacial bone regeneration, the use of inorganic cations such as Ca 2+ , magnesium (Mg 2+ ), and silicon (Si 4+ ) has gained attention due to their influence on mechanical and biological properties crucial for bone regeneration [18,[65][66][67][68]. These cations do also play significant roles in neovascularization, which are crucial aspects of craniofacial bone regeneration [69][70][71][72]. Wang et al displayed a sustained release of Mg 2+ from the piezoelectric Whitlockite scaffold and promoted angiogenic differentiation of BMSCs in vitro.…”

The Use of Collagen-Based Materials in Bone Tissue Engineering

“…These studies remain controversial and have yet to be explored. Another promising direction is the synergistic effects of multiple bioactive cations on vascularization and bone defect repair, which is a much safer and simpler option [ 157 ].…”