23.3.1.2 Dual-Ion Substitution in HA

Dual-ion substitution is being regarded as a promising approach for enhancing

biological and physicochemical properties of HA. Primarily, both of the two

substituted ions are cations (Lowry et al. 2018; Robinson et al. 2017), whereas in

some cases the anion/anion (Landi et al. 2010; Fahami et al. 2016) and anion/cation

(Kumar et al. 2012; Kolmas et al. 2011) combinations have also been explored.

When two or more ions are present, they can have a synergistic or antagonistic effect

on properties of HA. It has been found that when Mg²⁺ and CO3

2
are co-substituted

in HA, there is a synergistic effect on the dissolution properties and crystallinity,

whereas when CO3

2
and F
are co-substituted in HA, there is an antagonistic effect

and F
is more dominant.

Zn²⁺ and Mg²⁺ co-substitution in HA enhances bone formation (Kaygili and

Keser 2015). Zn²⁺ ions are found to be more favorably substituted into Ca site in HA

as compared to Mg. With an increase in the content of Mg²⁺ and Zn²⁺, crystallinity,

cell parameters, and unit cell volume of HA decrease drastically and also show an

improved biocompatibility. In vitro studies demonstrated a notable improvement in

cell proliferation, attachment, and adhesion in comparison to stoichiometric

HA. Lowry et al. (2017) and Ullah et al. (2020) successfully substituted Zn and Sr

ions in HA by various methods. Zn²⁺ partially substituted for Ca²⁺, whereas Sr²⁺ got

completely substituted for Ca²⁺.

In vitro studies in human osteoblast-like MG63 cells for HA co-substituted with

Sr and Mg (SrMgHA) displayed an enhanced cell attachment, proliferation, and

differentiation (Geng et al. 2016). Landi et al. (2013) studied the extended release of

Mg during the bone regeneration process and also studied the anti-osteoporotic and

anticaries properties of Sr ion in SrMgHA. Yoruc and Aydinoglu (2017) synthesized

Na- and Mg-substituted HA by a precipitation technique. The in vitro study revealed

an improved bioactive behavior, as the growth of osteoblast cells was encouraging.

Dual

substitution

of

anions

presents

another

way

to

improve

the

cytocompatibility of HA. Investigations have been carried out with various

combinations of anions including Cl
, F
, and CO3

2
. Fahami et al. (2016) found

that the co-substitution of F
and Cl
in HA could counteract probable side effect of

Cl
, e.g., dementia in elderly patients. They also found that the addition of F
could

improve the differentiation and proliferation of bone cells.

The cation-anion co-substitution in HA can influence its morphology, lattice

parameters, crystallinity, and crystallite size. Douglas et al. (2017) observed

enhanced dissolution and reduced crystallinity in the case of CO3

2
and Mg2+

co-substituted HA. When carbonates are co-substituted with Sr²⁺ or Zn²⁺, bone

remodeling is enhanced. The combination of Zn and carbonate in HA hinders the

crystal growth. The dual substitution of CO3

2
and Sr2+ in HA helps in combining

bioactivity of carbonate and therapeutic function of Sr²⁺ to enhance the new bone

formation rate and osteointegration (Landi et al. 2008; Kumar et al. 2012).

With an increase in CO3

2
and Na+ content, the crystallite size of CO3

2
and Na+

co-substituted HA decreases (Zyman and Tkachenko 2013). The Sr and Si

co-substitution in HA helps in the substitution levels of both the elements.

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