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The comparison is made to unveil the similarities and differences in both physiological and pathological/
ectopic mineralization. In addition, current approaches, with a focus on modulating crystal formation and
growth on the progression of pathological mineralization, are discussed.

OVERVIEW OF THE PHYSIOLOGICAL MINERALIZATION PROCESS
The mineralization of self-assembled organic matrices results in the formation of hard tissues in the body,
and its level (or the proportion of mineral contents in the tissue) varies from around 65% in the bone to
close to 100% in dental enamel [Figure 1] [37,38] . The fundamental form of both bone and teeth crystals is
apatite. Its compositions and structures can be modified by accommodating a wide range of ion
substitutions via cell uptake [39,40] . The investigation regarding the nucleation process of apatite in solution
started several decades ago, attempting to unveil the mystery of mineralization [41-45] . Along with the
emergence of edge-cutting equipment and the accumulation of knowledge over the years, a multi-stage
nucleation process of apatite in aqueous solution was demonstrated to start with the aggregation of charged
pre-nucleation complexes, [Ca(HPO ) ] (Ca/P(calcium/phosphorus) = 0.3-0.4) . After the formation of
[46]
4-
4 3
2-
ribbon-like calcium-deficient o phosphates (OCPs), [~Ca (HPO ) (PO ) ] (Ca/P = 1.0) and elongated plate-
4 4
6
4 2
like OCPs, [Ca (HPO ) (PO ) ] (Ca/P = 1.33) from amorphous calcium phosphates (ACPs), apatite is finally
4 4
4 2
8
generated . It has been suggested that the evolution of the OCP structure to apatite occurred through the
[46]
elimination of the hydrated shell on the surface of the nanocrystalline [37,47] . The hydrated shell on the surface
of freshly precipitated apatite contains exchangeable ionic species and some proteins [37,48] . During the
maturation of apatite in the solution, ions in the hydrated shell are easily exchanged, accompanied by
proteins within the shell, and it leads to reduced surface reactivity and increasingly stable apatite [37,49] . This
suggests that metals (such as Ca, magnesium (Mg), sodium (Na), potassium (K), etc.), and possibly other
ions are incorporated structurally into the collagenous matrices of calcified tissues . In earlier
[50]
investigations of the composition of trace elements in human cortical bone and beef tendons, researchers
have documented a regularity in the appearance of certain trace metals, namely copper (Cu), iron (Fe), and
zinc (Zn) [23,51,52] . Additionally, non-metal trace element, e.g., fluoride (F), has also been physio-chemically
[53]
linked with the bone mineral matrix .
Mineralization of bone
A similar crystal formation mechanism was proposed in bone based on the similarity of XRD patterns of
bone mineral and crystal formed from the ACP in an aqueous solution [41-43,45] . Bone minerals can be modeled
as carbonate hydroxyapatite (CHAp) with a wide range of substitutions of hydroxide (OH ) and phosphate
-
(PO ) by carbonate (CO ) on the lattice and the substitutions of Ca by other metal ions, such as
2-
2+
3-
4
3
2+
2+
strontium (Sr ), Mg , etc. [Figure 3] [49,54] . Its composition can vary depending on species, location, diet, sex,
age, and pathological conditions [37,55-57] . The substitution of carbonate results in the contraction of the a-axis
[58]
and the expansion of the c-axis of the unit cell, as well as a decrease in crystallinity . The presence of
vacancies on the apatite crystals results in lower binding energies, thus, more soluble than stoichiometric
hydroxyapatite (HAp) [25,59,60] . During the formation of bone minerals, ACP nanospheres formed on the site
of bone formation or supplemented through blood are delivered and deposited within the collagen matrix
by cells and further transformed into plate-like apatite via intermediates that resemble OCPs [44,61-63] . While
[63]
Crane et al. (2006) suggest this possibility, the finding remains unreplicated and is not widely accepted .
However, recent evidence has shown the presence of OCPs in bone, specifically in combination with the
[64]
protein osteocalcin . This suggests that OCPs may play a role in bone mineral formation, although further
research is needed to fully understand this process. Moreover, bone mineralization is much more
complicated with the involvement of extensive biological additives, acting as promoters or inhibitors, such
as proteins, trace ions, and some small organic molecules [42,65] .