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and its location relative to the collagen fibrils are poorly understood. Whether mineral forms within fibrils, outside them or a combination of the two remains contentious. There is evidence that mineral is initially deposited in the gaps within fibrils (between collinear collagen molecules) by a process of heterogeneous nucleation – a surface‐catalyzed or assisted nucleation process. However, there are those who argue that the data and the structural restraints imposed by collagen within the fibrils do not support or permit such an arrangement. Similarly, the morphology of the crystals is not universally accepted. There is evidence that mineral is deposited as needle‐like crystals, whereas others argue that it is really in the form of flakes or plates, which appear as needles when viewed from side on. There is general agreement though that the crystals are anisotropic: they are elongated along their crystallographic c‐axis, which is aligned parallel with the collagen fibrils. Schwarcz et al. [20] have recently proposed a model whereby mineral that is not in the form of apatite initially forms in the gap zones of fibrils. It then extends out into the extra‐fibrillar space where apatite crystals form sheets or lamellae that partially wrap around the fibrils (Figure 2.10). Several mineral lamellae may form around a single fibril, and lamellae surrounding one fibril and those of adjacent fibrils bind firmly together through strong bonds.
Figure 2.10 Schematic diagram showing progressive steps in the mineralization of collagen molecules in a single fibril, assuming that most mineral in bone is intrafibrillar. (a) Early mineralization in gap zones; (b) further mineralization extends into adjacent overlap zones.
Source: Landis et al. [23]. Reproduced with permission of Elsevier.
Mineralization
Mineralization of osteoid involves an interaction of processes that either promote or inhibit deposition. Initial nucleation of mineral may be enhanced by the formation or exposure of nucleators and by the removal or modification of inhibitors. However, details of the mechanisms involved and the location in, on or around the fibrils remain subjects of controversy. Many believe that specific atomic groups located in the gap zones of collagen fibrils are arranged in such a way as to induce heterogeneous nucleation of hydroxyapatite [24]. These nuclei subsequently expand by addition of further inorganic ions, so giving rise to crystals. Certain factors, principally non‐collagenous proteins, have been shown to promote or inhibit mineralization. For example, phosphoproteins, such as bone sialoprotein, bind calcium and thereby act as mineral nucleators. Conversely, proteoglycans may inhibit the process by masking critical zones or occupying essential spaces within fibrils, thereby reducing diffusion, chemical interaction and sequestration of calcium ions.
The role of matrix vesicles as initiators is also contentious. These small (20–200 nm) spherical bodies are derived from osteoblasts. They are found in osteoid and are often associated with small crystals of calcium phosphate. They are bound by a lipid membrane, which has a composition that is different to that of the parent cell. They are enriched in tissue non‐specific alkaline phosphatase (TNAP), nucleotide pyrophosphatase phosphodiesterase annexins among other factors that are known to promote mineral deposition. Calcium ions are also concentrated within the vesicles. While it is generally accepted that matrix vesicles play a role in initiating bone mineralization, its exact nature and extent is controversial.
In most healthy adult bones, the mineral fraction (proportion of dry weight accounted for by mineral) is between 60 and 70%. Fractions in this range engender material properties that provide an optimal compromise between strength, stiffness and toughness. Osteoblasts and osteocytes limit the ultimate extent of matrix mineralization through the adjustment of extracellular ion concentrations [25, 26]. Loss of these cells, for instance in osteonecrosis, is associated with hypermineralization, which can have profound effects on material properties causing bone to become brittle.
Function
Mineralization of bone matrix makes it appropriately stiff and strong to fulfil its primary roles. The physical nature of its primary functions means that the mechanical properties of bone as a material (tissue) and structure (whole bone) are critical. A vast body of literature documents the mechanical properties of bone from many different species. The degree of matrix mineralization, variation in matrix organization (microstructure), porosity and orientation of collagen fibres within the matrix all significantly influence the strength, stiffness and toughness of bone. A brief review of mechanical terminology follows to assist readers less familiar with these terms to understand the concepts that follow.
Figure 2.11 Graphical and schematic illustrations of the relationship between stress imposed on an object by a tensile load and deformation of the object.
Tissue (Material) Properties
When a load is applied to a material, it will deform. The load can be standardized per unit area, termed stress, and deformation quantified as change in length in relation to its original length, termed strain. The relationship between stress and strain reflects the stiffness, or Young's modulus, of the material (Figure 2.11). A material that deforms little as the stress is increased has a relatively high Young's modulus and is termed stiff, whereas one that has a low modulus is termed compliant or flexible. Many materials, including bone, behave in an elastic manner, deforming proportionally in relation to stress and recoiling to their original shape when the stress is removed (Figure 2.11). However, as the magnitudes of stress, and hence strain, rise, the distracting forces acting within the material increase. If the stress is so great as to strain the material to a point where the internal forces exceed a critical limit, it causes damage. This is referred to as the yield point, and if this is exceeded the structure will undergo plastic deformation and remain permanently deformed when the load is removed (Figure 2.12). If the stress is increased beyond the yield point, then the material will continue to strain to a point where it fails completely, termed its ultimate strain (Figure 2.13). The stress applied to reach this point defines the ultimate strength of the material. The degree of strain that a material can undergo between starting to yield and failure largely determines its energy absorbing capacity. A material that fails quickly after reaching its yield point absorbs little energy and is termed brittle. Conversely, one that undergoes significant plastic deformation absorbs relatively more energy and is termed tough (Figure 2.14).
Bone is a complex material, and there are many factors that affect its mechanical properties. It is a composite made of two different phases: collagen fibres and mineral crystals. The organic phase is relatively compliant, while the mineral endows rigidity. Variation in mineral content has a profound effect on the modulus and stiffness of bone but is less associated with strength [27]. Conversely, the organic component of bone is more related to its strength. The impact of this is apparent from studies that used radiation to disrupt collagen in bone samples. Bone density measurements remained the same with varying levels of collagen damage, but bone strength varied significantly in proportion to the level of collagen damage (Figure