Bone is a hierarchically structured composite material which, in addition to its obvious biological value, has been well studied by the materials engineering community because of its unique structure and mechanical properties. This article will review the existing bone literature, with emphasis on the prevailing theories regarding bone formation and structure, which lay the groundwork for proposing a new model to explain how intrafibrillar mineralization of collagen can be achieved during bone formation. Intrafibrillar refers to the fact that growth of the mineral phase is somehow directed by the collagen matrix, which leads to a nanostructured architecture consisting of uniaxially oriented nanocrystals of hydroxyapatite embedded within and roughly [0 0 11 aligned parallel to the long collagen fibril axes. Secondary (osteonal) bone, the focus of this review, is a laminated organic-inorganic composite composed primarily of collagen, hydroxyapatite, and water; but minor constituents, such as non-collagenous proteins (NCPs), are also present and are thought to play an important role in bone formation. To date, there has been no clear understanding of the role of these NCPs, although it has been generally assumed that the NCPs regulate solution crystal growth via some type of 'epitaxial' relationship between specific crystallographic faces and specific protein conformers. Indeed, 'epitaxial' relationships have been calculated; but in practice, it has not been demonstrated that intrafibrillar mineralization can be accomplished via this route. Because of the difficulty in examining biomineralization processes in vivo, the authors of this article have turned to using in vitro model systems to investigate the possible physicochemical mechanisms that may be involved in biomineralization. In the case of bone biomineral, we have now been able to duplicate the most fundamental level of bone structure, the interpenetrating nanostructured architecture, using relatively simple anionic polypeptides that mimic the polyanionic character of the NCPs. We propose that the charged polymer acts as a process-directing agent, by which the conventional solution crystallization is converted into a precursor process. This polymer-induced liquid-precursor (PILP) process generates an amorphous liquid-phase mineral precursor to hydroxyapatite which facilitates intrafibrillar mineralization of type-I collagen because the fluidic character of the amorphous precursor phase enables it to be drawn into the nanoscopic gaps and grooves of collagen fibrils by capillary action. The precursor then solidifies and crystallizes upon loss of hydration waters into the more thermodynamically stable phase, leaving the collagen fibrils embedded with nanoscopic hydroxyapatite (HA) crystals. Electron diffraction patterns of the highly mineralized collagen fibrils are nearly identical to those of natural bone, indicating that the HA crystallites are preferentially aligned with [0 0 1] orientation along the collagen fibril axes. In addition, studies of etched samples of natural bone and our mineralized collagen suggest that the long accepted '' deck of cards '' model of bone's nanostructured architecture is not entirely accurate.Most importantly, this in vitro model demonstrates that a highly specific, epitaxial-type interaction with NCPs is not needed to stimulate crystal nucleation and regulate crystal orientation, as has long been assumed. Instead, we propose that collagen is the primary template for crystal organization, but with the important caveat that this templating occurs only for crystals formed from an infiltrated amorphous precursor. These results suggest that the 25-year-old debate regarding bone formation via an amorphous precursor phase needs to be revisited. From a biomedical perspective, in addition to providing possible insight into the role of NCPs in bone formation, this in vitro system may pave the way toward the ultimate goal of fabricating a synthetic bone substitute that not only has a composition similar to bone, but has comparable mechanical properties and bioresorptive potential as natural bone. From a materials chemistry perspective, the non-specificity of the PILP process and capillary infiltration mechanism suggests that non-biological materials could also be fabricated into nanostructured composites using this '' biomimetic '' strategy. (c) 2007 Elsevier B.V. All fights reserved.
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