Bone homeostasis is maintained in a series of highly complicated events orchestrated by: (a) interactions among different types of cells, mainly mesenchymal stem cells (MSCs), osteoprogenitor cells, osteoblasts, osteoclasts, and osteocytes, and (b) interactions of cells with extracellular matrix in a localized microenvironment, and (c) interactions of cells with components in surrounding biological milieus, such as organics (amino acids, enzymes, hormones, fatty acids, neurotransmitters, sugars, vitamins, etc.), inorganics (inorganic ions or groups, such as calcium, phosphate, potassium, sodium, carbonate, etc.), as well as waste products from cell metabolism (Figure 1) [9]. Naturally, the localized ionic microenvironment is maintained by the balance between bone-forming cells, osteoblasts, and bone-resorbing cells, osteoclasts, during the bone remodeling process [18] (Figure 2). Specifically, osteoclasts firmly attaching to the bone surface could achieve a pH fall to a limit value of pH 3.0 or less for dissolving the bone mineral and favor collagen degradation by secreting lysosomal proteinases [19]. Organics in this microenvironment have been extensively studied since the last century, especially cell-secreted growth factors that play roles in bone formation, such as TGF-β (transforming growth factor-beta), FGF (fibroblast growth factor), BMP (bone morphogenetic proteins), IGF-I (insulin-like growth factors I), etc. [20]. Inorganics in this microenvironment have also been extensively studied because they are essential for the bone mineral formation, and quality of the mineralized tissue, either liberated from bone or circulating in body fluid. Moreover, ions from the localized microenvironment are now considered to consist of crystal components and molecular modulators in many biological processes in bone remodeling, i.e., bone formation and resorption [3,9,21,22]. The list of inorganic ions and ionic groups that affect bone metabolism and homeostasis as signaling molecules has dramatically increased in the past decades. More previously less-studied elements in the periodic table have been surprisingly found to play a role in the etiology and pathogenesis of some bone diseases or the modulation of cellular activities, especially metallic elements, because they are prone to lose electrons to form positively charged ions and tend to dissolve in biological fluids or be attracted by negatively charged biological molecules, proteins, or DNAs, to form active metal complexes [3,4,23].

Bone mineral, known as biological apatite, is incorporated in collagen fibrils, arranged with a c-axis parallel to the direction of fibrils, with lengths of 30–50 nm, widths of 15–30 nm, and thicknesses of 2–10 nm [24]. Biological apatite has been modeled as hexagonal carbonated hydroxyapatite based on X-ray diffraction (XRD) results, with the lattice parameters of a = b = 9.432 Å, c = 6.881 Å, and γ = 120°. Hydroxyl ions (OH⁻), parallel to the c-axis, are positioned on the screw axes at every one-half of the unit cell, pointing in opposite directions to neighboring OH⁻s. Tetrahedral phosphate ions (PO₄³⁻), immobilized by calcium ions (Ca²⁺) interspersed among them, as well as marginal calcium ions (Ca²⁺), shared with neighbor unit cell. Notably, steric interference between adjacent OH⁻s in hexagonal hydroxyapatite unit cells could be overcome by vacancy or replacement of an OH⁻ by impurity ions, the most likely event in organisms, or by conversion of hexagonal to monoclinic space group at high temperature, rearranging adjacent OH⁻s to a uniform direction [25,26].

The accumulation of most inorganics in the body can be attributed to the formation of apatite crystals in bone, with distinguished content and composition among species and individuals, resulting from differed preferences on elements in different species, variations in diet, and relative abundance in the environment [27,28]. During bone resorption, ions and ionic groups will be liberated from CaP based network into the local microenvironment in acidic conditions, participating in local bone remodeling or being carried away by physiological fluid. Therefore, ions and ionic groups entering the localized microenvironment are determined by the composition of bone minerals and vice versa. Specifically, the content and level of ions and ionic groups in the localized biological milieu affect the formation of the bone mineral through ionic substitution and, consequently, the properties of the final crystalline product in the mineral phase [29,30,31,32]. For example, OH⁻ (minor site) or PO₄³⁻ (primary site) sites could be replaced by CO₃²⁻, forming type A and B carbonated hydroxyapatite, respectively. PO₄³⁻ site could also be replaced by hydrolyzed phosphate (HPO₄²⁻) structure in mature bone, while OH⁻ could be substituted with florin (F⁻), chlorin (Cl⁻) ion, or orthosilicic acid (SiO₄⁴⁻) structure [29,30,32]. Moreover, ionic substitutions also happen where Ca²⁺ is replaced by other metals, such as sodium (Na⁺), potassium (K⁺), magnesium (Mg²⁺), zinc (Zn²⁺), manganese (Mn²⁺), cobalt (Co²⁺), strontium (Sr²⁺), iron (Fe²⁺), copper (Cu²⁺). Ionic exchange in biological apatite alters crystalline structures, resulting in modified crystal size, growth rate, and properties. Compared with stoichiometric or geological apatite crystals, biological apatite crystals have smaller crystallite sizes, less ordered crystal structure, lower crystallinity, and higher solubility (Figure 3) [3,33]. The influences of different ions or ionic groups on biological apatite crystals are balanced by each other. For example, substitutions of PO₄³⁻ by CO₃²⁻ and of Ca²⁺ by Zn²⁺ or Mg²⁺ inhibit crystal growth, increase crystal disorder and solubility, and lower the crystallinity [29,30,34]. Replacements of Ca²⁺ by Al³⁺, La^2+, or Fe²⁺ accelerate crystal growth, and replacement of OH⁻ by F⁻ on the lattice reduces the solubility [29,30,34]. Additionally, replacing OH⁻ with SiO₄⁴⁻ causes a contraction on the a-axis and an expansion on the c-axis of the crystal lattice [35]; replacing Ca²⁺ with Sr²⁺ causes an expansion on both the a- and c-axes [4].

During bone trauma, such as a fracture, bone healing starts with the invasion of blood into the traumatic space. A microenvironment is formed along with blood clots and calluses, where cells interact with components in the extracellular matrix and extracellular fluid. However, the localized microenvironment will be altered at the implantation site with the involvement of inorganic biomaterials due to extensive interactions between biomaterials and the microenvironment [16]. The contribution of inorganic biomaterial at the implantation site to the healing process can never be underestimated because many biomaterial intrinsic features, including parameters (composition, structure, topography), and properties (crystallinity, dissolution profile, surface charge), can make a difference in the localized microenvironment and cellular interactions, as well as cellular activities, and consequently the bone formation process (Figure 4) [16]. Therefore, understanding the influence of biomaterials on components in the localized ionic microenvironment shall guide the design of future inorganic biomaterials for bone grafting. Active roles of ions as molecular modulators upon many cellular activities during bone remodeling provide the material with more possibilities other than structural support and protein/cell entrapping.