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The application of calcium phosphates and their nanoparticles have been received great attention. However, hydroxyapatite (HAP) is not suggested in dental therapy to repair the damaged enamel directly although this compound has a similar chemical composition to enamel. We note that the size-effects of HAP are not taken into account in the previous studies as these artificial particles frequently have sizes of hundreds of nanometres. It has recently been revealed that the basic building blocks of enamel are 20-40 nm HAP nanoparticles. We suggest that the repair effect of HAP can be greatly improved if its dimensions can be reduced to the scale of the natural building blocks. Compared with conventional HAP and nano amorphous calcium phosphate (ACP), our in vitro experimental results demonstrate the advantages of 20 nm HAP in enamel repairs. The results of scanning electron microscopy, confocal laser scanning microscopy, quantitative measurement of the adsorption, dissolution kinetics, and nanoindentation, show the strong affinity, excellent biocompatibility, mechanical improvement, and the enhancement of erosion-free by using 20 nm particles as the repairing agent. However, these excellent in vitro repair effects cannot be observed when conventional HAP and ACP are applied. Clearly, nano HAP with a size of 20 nm shares similar characteristics to the natural building blocks of enamel so that it may be used as an effective repair material and anticaries agent. Our current study highlights the analogues of nano building blocks of biominerals during biomedical applications, which provide a novel pathway for biomimetic repair.

Magnesium ions (Mg 2+ ) are widely present in biological fluids, and they are suggested as the vital factors that inhibit spontaneous hydroxyapatite (HAP) precipitation in nature. However, the regulation mechanisms of Mg 2+ on HAP crystallization are still under intensive debates. We find that a typical precipitation of HAP from supersaturated solutions should include five stages: s1, formation of ion clusters and amorphous calcium phosphate (ACP); s2, stabilization of ACP; s3, transformation from ACP to HAP via dissolution and crystallization; s4, classical crystal growth of HAP; s5, HAP aging under a near equilibrium state. Actually, Mg 2+ ions exhibit different inhibitory effects on these stages. The ions have a negligible influence on the kinetics of initial ACP formation in solutions (s1) and final aging of crystals (s5). Rather, the ions can either adsorb onto or incorporate into the ACP precursor particles during s1. In s2, the lifetime of ACP in solution is extended significantly by both two types of Mg 2+ ions. However, the absorbed ones are more effective than the incorporated ones on the inhibition of the phase transformation from ACP to HAP in this s2. In stages of s3 and s4, it is only surface Mg 2+ ions that retard crystal growth of HAP and the incorporated Mg 2+ become inert. These detailed findings reveal how Mg 2+ ions affect the crystallization process of HAP mineralization from supersaturation. Such a detailed understanding can provide a chemical strategy for precise regulation of HAP formation kinetics in intermediate phase mediated crystallization.

The interaction between protein molecules and the hydroxyapatite (HAP) crystal is an important research topic in many fields. However, the nature of their noncovalent bonding is still not clear at the atomic level. In this work, molecular dynamics simulation, steered molecular dynamics simulation, and quantum chemistry calculations were used to study the adsorption-desorption dynamics of BMP-2 on HAP (001) surface. The results suggest that there are three types of functional groups through which BMP-2 can interact with HAP crystallite, and they are -OH, -NH(2), and -COO(-). Based on the different orientations of protein, each might interact with HAP crystallite individually, or, two or three of them can work cooperatively. Concerning the mechanisms of interaction, it is found that the water-bridged H-bond plays an important role, which is the main force for groups without net charges. If there were more than one set of adsorption groups for a certain orientation of protein, the adsorption-desorption process would likely be stepwise. On the contrary, if there were only one set, there would be only the key-adsorption period. The results of density functional theory calculations confirm the actual existence of this type of water-bridged H-bond. Furthermore, it is also found that the CHARMM27 force field could provide correct structural information qualitatively, although the data are slightly different from those obtained by UB3LYP/6-31G* method.

The regeneration of tooth enamel, the hardest biological tissue, remains a considerable challenge because its complicated and well-aligned apatite structure has not been duplicated artificially. We herein reveal that a rationally designed material composed of calcium phosphate ion clusters can be used to produce a precursor layer to induce the epitaxial crystal growth of enamel apatite, which mimics the biomineralization crystalline-amorphous frontier of hard tissue development in nature. After repair, the damaged enamel can be recovered completely because its hierarchical structure and mechanical properties are identical to those of natural enamel. The suggested phase transformation–based epitaxial growth follows a promising strategy for enamel regeneration and, more generally, for biomimetic reproduction of materials with complicated structure.

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.

The regulation mechanism of organic additives on the crystallization of inorganic crystal is fundamentally important in biomineralization. Experimentally, it was found that the amino acids glycine (Gly) and glutamic acid (Glu) could lead to the formation of rod- and plate-like hydroxyapatite (HAP) crystallites, respectively. The detailed adsorption behavior of Gly and Glu on HAP crystal faces was studied by molecular dynamics (MD) simulation. The specific adsorption sites and patterns of Gly and Glu on the (100) and (001) faces of HAP crystals were revealed at the atomic level. The amino acids adsorbed on the HAP (001) and (100) faces with their positive amino groups occupied vacant calcium sites, and their negative carboxylate groups occupied vacant P or OH sites precisely and formed an ordered adsorption layer. The atomic force microscopy pulling simulation and free energy calculation showed that Glu was much more difficult to depart from the HAP (001) face than that from the (100) face. This result indicated that Glu preferred to adsorb strongly onto the HAP (001) face, which resulted in the formation of plate-like HAP. However, Gly did not show any significantly preferential adsorption between these two HAP faces. Thus, the habits of HAP, rod-like crystallites, were not altered during the HAP crystallization in the presence of Gly. Combined with experimental results, our study demonstrated that the MD simulation of interfacial structures could improve our understanding of biological regulation in mineralization processes at the atomic level.