Keyword
Biomineralization, Crystallization,
Calcification, Raman spectroscopy, Analytical Chemistry
Introduction
The main mineral components of the organism are produced by
biomineralization, which is an important factor affecting the
development of bone and teeth mineralization in the
organism.[1–4] In addition, biomineralization is
closely related to cardiovascular diseases, urological diseases, and
liver and kidney stones.[5–8] The
biomineralization process of teeth, bones, and pathological stones is
outlined as intracellular mineralization and extracellular
mineralization, a process of crystallization of hydroxyapatite and
calcium carbonate under the regulation of organic
matter.[9–12] At the molecular level, it is a
kind of ordered hierarchical regulation and assembly of macromolecules,
which leads to the crystallization and growth of the inorganic mineral
phase.[13–15] The organic phase assembles, and
the inorganic phase nucleates, crystallizes, and
grows.[16–18] Self-assembly of insoluble organic
matter in specific cellular or tissue regions constructs the mineralized
microenvironment, which includes organic macromolecular structure,
orientation, and mineralization sites.[19–21] The
ions required for mineralization are nucleated at specific sites in the
microenvironment by weak interactions such as hydrogen bonding,
electrostatic forces, and van der Waals
forces.[1,4,22,23] During the growth of the
inorganic phase, the size, morphology, orientation, and structure of the
crystals are regulated by the organic matter of the
organism.[24–26] The inorganic phase acquires a
multi-level assembly structure by graded
regulation.[27]
Physiological mineralization is one of the most important
biomineralization processes in biological
development.[28–30] Mineralization processes such
as enamel, dentin, bone, and cartilage mineralization are typical
hierarchical self-assembly mineralization among
others.[28,29,31] The enamel organ is formed by
odontoblasts and ameloblasts at specific developmental periods and is
subdivided into the bud, cap, and terminal
phases.[32–34] Thus the enamel and dentin
mineralization involves close interaction with odontoblasts and
ameloblasts. Among the signaling pathways, wingless (Wnt), DNA mismatch
repair homeobox 1/2 (Msx1/2), bone morphogenetic protein (Bmp), and
runt-related transcription factors 2
(Runx2), and disheveled homologous 2
(Dlx2) are involved in the
mineralization process of enamel and
dentin.[2,34–37] These signaling proteins
regulate the expression and secretion of ameloblastin
(AMBN), amelogenin
(AMELX), enamelin
(ENAM), alkaline phosphatase, matrix
metalloproteinase 20 (MMP20) (ALP) and kallikrein-related peptidase 4
(KLK4).[38–42]This process occurs after the tenth week of embryonic in humans and
after the 13th day of embryonic in mice. Apoptosis of enamel-forming
cells at a later stage of development results in the failure of enamel
regeneration, which is different from bone
mineralization.[22,43,44] Bone formation also
begins at the embryonic stage, during which mesenchymal cells aggregate
to form a cohesive mass that approximates the shape and location of the
bone.[45–47] Then, they differentiate into
osteoblasts, osteoclasts, and osteocytes, which eventually participate
in bone mineralization.[48,49] Osteoblasts induce
to become terminally differentiated cells that produce extracellular
matrix proteins such as collagen and promote bone
mineralization.[50,51] Osteoclasts have the
opposite function of maintaining the dynamic balance of bone
mineralization. The biological understanding of this process has been
well-reviewed and summarized.[2,50,52–54] In
contrast, the physicochemical properties of the inorganic and organic
phases during mineralization have not been further reviewed and
understood, although some research progress has been made recently.
Pathological mineralization is different in vivo for the
hierarchical self-assembly mineralization process. The simplest example
is the occurrence of calculus, which is caused by bacteria on the enamel
surface forming a biofilm that further induces the onset of
mineralization.[55–59] The end-stage of
atherosclerosis is pathological mineralization, which generally begins
with lipid and complex sugar accumulation, hemorrhage, and thrombosis,
followed by fibrous tissue proliferation and mineral
crystallization.[7,60–62] Urinary stones are a
complex of calcium oxalate and carbonate apatite, which is also due to
pathological mineralization.[8,63,64] Or
mineralized nodules that occur in malignant tissues, such as breast
cancer.[65–68] Interestingly, some studies have
used this type of mineralization to induce intracellular mineralization
in tumor cells for tumor therapy or fluorescence
detection.[69–71] The gold nanoparticles or
nanoclusters produced by this intracellular mineralization may be
nucleic acid-induced for their nucleation.[72–75]A better understanding of the mechanisms underlying pathological
mineralization and how biomolecules regulate the physicochemical
properties of the inorganic phase is crucial.
Therefore, in this review, we have reviewed the hierarchical
self-assembly mineralization process and discussed the specific changes
in physicochemical properties during physiological and pathological
mineralization summarized in terms of molecular vibrational spectroscopy
(Scheme ). The important role of Raman spectroscopy in revealing
the physicochemical properties of biomineralization is elucidated and
the relevant experimental conditions of Raman spectroscopy for
illustrating tissues or microenvironments that induce biomineralizationin vivo and in vitro experiments are also exploited
(Figure 1a ). From these studies, it is possible to reveal the
dynamic structural changes of inorganic and organic phases during the
special process of biomineralization, including chemical bonding,
crystal size, crystal orientation, organic component content, etc.
(Figure 1b ). And the advance of recent research progress of
Raman spectroscopy for illustrating the unique biomineralization process
is evaluated and discussed (Figure 1c ). This review article
aims to explore the nature of the hierarchical self-assembly
mineralization process and provide fundamental evidence for an
understanding of why and how the specific alteration of physicochemical
properties occurs during the related biomineralization process. The
hierarchical self-assembly mineralization process could significantly
contribute to the formulation of new biomineralization nano-structures,
which offers new strategies for realizing the early theranostics of some
difficult diseases like heart diseases and cancers.