Revisiting the physical and chemical nature of the mineral component of bone

The physico-chemical characteristics of bone mineral remain heavily debated. On the nanoscale, bone mineral resides both inside and outside the collagen fibril as distinct compartments fused together into a cohesive continuum. On the micrometre level, larger aggregates are arranged in a staggered pattern described as crossfibrillar tessellation. Unlike geological and synthetic hydroxy(l)apatite, bone mineral is a unique form of apatite deficient in calcium and hydroxyl ions with distinctive carbonate and acid phosphate substitutions (CHAp), together with a minor contribution of amorphous calcium phosphate as a surface layer around a crystalline core of CHAp. In mammalian bone, an amorphous solid phase has not been observed, though an age-dependent shift in the amorphous-to-crystalline character is observed. Although octacalcium phosphate has been postulated as a bone mineral precursor, there is inconsistent evidence of calcium phosphate phases other than CHAp in the extracellular matrix. In association with micropetrosis, magnesium whitlockite is occasionally detected, indicating pathological calcification rather than a true extracellular matrix component. Therefore, the terms 'biomimetic' or 'bone-like' should be used cautiously in descriptions of synthetic biomaterials. The practice of reporting the calcium-to-phosphorus ratio (Ca/P) as proxy for bone mineral maturity oversimplifies the chemistry since both Ca²⁺ and PO₄^3- ions are partially substituted. Moreover, non-mineral sources of phosphorus are ignored. Alternative compositional metrics should be considered. In the context of bone tissue and bone mineral, the term 'mature' must be used carefully, with clear criteria that consider both compositional and structural parameters and the potential impact on mechanical properties. STATEMENT OF SIGNIFICANCE: Bone mineral exhibits a unique hierarchical structure and is classified into intrafibrillar and extrafibrillar mineral compartments with distinct physico-chemical characteristics. The dynamic nature of bone mineral, i.e., evolving chemical composition and physical form, is poorly understood. For instance, bone mineral is frequently described as "hydroxy(l)apatite", even though the OH^- content of mature bone mineral is negligible. Moreover, the calcium-to-phosphorus ratio is often taken as an indicator of bone mineral maturity without acknowledging substitutions at calcium and phosphate sites. This review takes a comprehensive look at the structure and composition of bone mineral, highlighting how experimental data are misinterpreted and unresolved concerns that warrant further investigation, which have implications for characterisation of bone material properties and development of bone repair biomaterials.