. 2022 Aug 13;7(3):112. doi: 10.3390/biomimetics7030112

Table 1.

Main ions doping bone mineral and their biological effects.

Ion Substitution Site	Doping Ion	Main Effects
Ca²⁺	Mg²⁺	Magnesium ion is quantitatively the most important, typically amounting to around 6 mol%. In biological environment, magnesium boosts skeletal metabolism and bone growth, and its deficiency adversely affects all stages of skeletal metabolism, causing a decrease in osteoblastic and osteoclastic activities, osteopenia, and bone fragility [88,89].
	Sr²⁺	Strontium ion increases bone formation, the number of bone-forming sites, and bone mineral density, and reduces bone resorption, leading to a gain in bone mass and improved bone mechanical properties in animals and humans [90]. Strontium increases osteoblast activity and decreases osteoclast resorption, making it suitable for the treatment of osteoporosis [91].
	Zn²⁺	Zinc ion stimulates osteoblastic activity in vitro and inhibits bone resorption in vivo [45]. In addition, doping induces the segregation of bioactive ions on the material surface which makes them available for exchange with physiological fluids, preventing bacterial antibiotic resistance in hospitals during the postoperative period [86].
PO₄³⁻	SiO₄⁴⁻	Silicates are among the trace elements in HA involved in biological processes. SiO₄⁴⁻ substitution of phosphate ions site charge difference causes the formation of a Ca²⁺ partial vacancy for the equilibration of charge neutrality. Silicates enhance osteoblast cell proliferation compared with the pure HA phase and its depletion is often related to the deterioration in the proliferation and function of osteoblast due to osteoporosis and osteopenia [92,93,94].
	CO₃²⁻	The substitution of phosphate groups with carbonate ions is called B-type carbonation. B-type carbonation is present in young bone, which is subjected to remodeling processes, resulting in higher solubility [89,95].
OH⁻	Cl⁻	Chlorine ions in HA structure provide an acidic environment on the surface of bone that stimulates osteoclasts in the bone resorption process. Accordingly, this incorporation may be essential in the expansion of low pH to solubilize the alkaline salts of bone minerals and to digest the organic matrix by acid hydrolases, which are secreted by osteoclasts [96,97].
	F⁻	Fluorine ions substitution provides higher chemical and thermal stability. Moreover, the fluorine ion itself is known to suppress dental caries and stimulate the proliferation and differentiation of bone cells [97,98,99,100].
	CO₃²⁻	The carbonation of the hydroxyl site is called A-type substitution. Studies have found that biological apatites, such as dentin, phytolith, and dental calculus have an A–B mixed type carbonation (B > A), and kidney stones may be both A–B mixed and B-type [101]. In bone apatites, A-type carbonation concentration progressively increases with age and maturation as the resulting apatite is less soluble and less subjected to remodeling processes [89,95].