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Page 2 of 21 Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05

INTRODUCTION
Biomineralization, an emerging interdisciplinary field, deals with the formation, structure, and mechanical
[1]
strength of naturally formed mineralized tissues . The skeleton of animals provides mechanical support to
counteract gravitational forces on land and hydrostatic pressure in the depths of the oceans. As a highly
complex and exquisitely organized organ, the skeleton is structurally, and hence mechanically,
heterogeneous owing to spatial distributions in the shape, size, and composition of its constituent building
[2]
blocks, the mineralized collagen fibrils .
Nature produces a diverse assortment of mineralized structures with a high degree of complexity. These
hierarchical structures exhibit superior mechanical strength and are, therefore, of great interest to
[3-5]
researchers in the disciplines of biotechnology and biomedical engineering. Biomineralization on a template
of organic molecules is used by many organisms to produce inorganic-organic nanocomposites that result
[7]
[6]
in highly ordered multifunctional materials. The biosynthesis of bacterial magnetosome , eggshell ,
molluscan shell , dental structures , and skeletal system are all examples of biologically controlled
[10]
[9]
[8]
mineral formation through organic/inorganic recognition and interaction. In the skeleton, for example, the
organic matrix consists primarily of the fibrous protein collagen and around 10% of other non-collagenous
proteins (NCPs) [1,11] [Figure 1]. The inorganic phase is composed of tightly packed nanocrystals made of
calcium phosphates (CaPs) with the incorporation of a number of essential trace elements.
In the field of biomaterial development, the ex vivo bioactivity of the material is often predicted by
[12]
examining the formation of an apatite layer on its surface in a simulated body fluid (SBF) . Notably, slight
differences in the SAED patterns of SBF-originated apatite on a Titanium substrate and bone apatite
resulted from the random and ordered orientations, respectively, of apatite crystals [Figure 2] [12-14] . However,
there are other differences between SBF-derived apatite and bone apatite in terms of possible defects on the
lattice of bone apatite due to the incorporation of trace elements in the body and crystal sizes affected by
cells and cell-secreted bio-factors [15,16] .

Calcification has been increasingly recognized as an important component to fully understand the
pathology of some diseases. For instance, the types of breast cancer have been shown to be related to the
properties of calcification in the breast [17-19] . The utilization of advanced characterization techniques within
the field of material science has facilitated significant advancements in our comprehension of the formation
of pathological crystals, such as X-ray diffraction (XRD), spectroscopic, and electron microscopic
techniques [20,21] . By comparing to crystals in physiological mineralization, understanding the characteristics
and behaviors of crystals involved in pathological or ectopic calcification can offer valuable insights into the
underlying mechanisms of calcification-related disorders. This knowledge may enable the development of
novel disease management strategies.

Physiological mineralization is a complex process that is essential for the development of well-organized
structures in bone and teeth . The intricate process occurs only in specific regions [23,24] . The regulation of
[22]
physiological mineralization is well-coordinated, involving both inhibitory and stimulatory factors. Some
proteins, including osteopontin (OPN), matrix Gla protein, and pyrophosphate (PPi), have been identified
as inhibitors of mineralization [22,25] . In contrast, other factors, such as matrix vesicles that contain calcium
(Ca) and inorganic phosphate (Pi), apoptotic bodies, and tissue non-specific alkaline phosphatase, have
been shown to facilitate the initiation of mineralization [26-28] .

On the other hand, pathological/ectopic mineralization occurs in soft tissues and is associated with disease
conditions or medical conditions, such as injury, inflammation, and aging, causing significant morbidity