Citrate Improves Collagen Mineralization via Interface Wetting: A Physicochemical Understanding of Biomineralization Control

Biological hard tissues such as bones always contain extremely high levels of citrate, which is believed to play an important role in bone formation as well as in osteoporosis treatments. However, its mechanism on biomineralization is not elucidated. Here, it is found that the adsorbed citrate molecules on collagen fibrils can significantly reduce the interfacial energy between the biological matrix and the amorphous calcium phosphate precursor to enhance their wetting effect at the early biomineralization stage, sequentially facilitating the intrafibrillar formation of hydroxyapatite to produce an inorganic–organic composite. It is demonstrated experimentally that only collagen fibrils containing ≈8.2 wt% of bound citrate (close to the level in biological bone) can reach the full mineralization as those in natural bones. The effect of citrate on the promotion of the collagen mineralization degree is also confirmed by in vitro dentin repair. This finding demonstrates the importance of interfacial controls in biomineralization and more generally, provides a physicochemical view about the regulation effect of small biomolecules on the biomineralization front. A high level of citrate‐pretreated collagen fibrils can significantly reduce the interfacial energy between the biological matrix and amorphous calcium phosphate precursors at the early mineralization stage, which sequentially facilitates intrafibrillar mineralization and produces an inorganic–organic composite using a wetting effect. This finding demonstrates the importance of interfacial controls in biomineralization.