Integrated Calendar

The formation of biominerals such as bone, teeth and shells occurs under tight biological control, where a 3-dimensional organic matrix framework composed of proteins and polysaccharides directly interacts with the growing mineral and controls all aspects of its formation: crystal nucleation, growth, morphology and overall properties. In bone, collagen fibrils act as a scaffold and template into which a highly organized array of oriented carbonated hydroxyapatite nanocrystals nucleate and grow. The formation of the mineral phase is controlled by an interplay between the collagen fibril and a family of highly acidic non-collagenous proteins (NCPs). The precise role of these components, however is unknown. Here, we employed a biomimetic system to investigate the mechanisms through which collagen, together with the NCPs, controls hydroxyapatite nucleation, growth and orientation during bone formation.
Combining cryo-transmission electron microscopy and cryo-electron tomography with molecular modelling, we show that the structure, supramolecular assembly and charge distribution of collagen can control two important stages in mineralization: infiltration of a disordered, amorphous calcium phosphate precursor phase into the fibril and its subsequent nucleation into oriented apatite crystals. To further understand how collagen controls hydroxyapatite formation, we exploited its mineral-templating properties to control the formation of other types of minerals, namely calcium carbonate and iron oxide. We demonstrate that there are two different mechanisms by which collagen controls mineral formation: the first is by templating mineral morphology, which is done by providing a confined environment in which the crystals nucleate and grow. This mechanism is not specific to hydroxyapatite, and can be extended to other minerals as well. The control over crystal orientation, on the other hand, is specific to hydroxyapatite, and depends on the coordination of calcium and phosphate ions by the 3-dimensional architecture of the nucleation site formed by the charged amino acids of collagen. Our results highlight the importance of collagen as an active scaffold in directing and controlling osteogenesis. Importantly, the formation of oriented arrays of nanocrystals in the collagen during osteogenesis is the result of specific interactions between the collagen and the calcium phosphate.