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.