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Bioimaging By Secondary Ion Mass Spectrometry

Lesi Cai , Meng-Chan Xia , Zhanping Li , Sichun Zhang , Xinrong Zhang

Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (1) : 97 -110.

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Progress in Chemistry ›› 2021, Vol. 33 ›› Issue (1) : 97-110 DOI: 10.7536/PC200458
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Bioimaging By Secondary Ion Mass Spectrometry
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Abstract

Secondary ion mass spectrometry(SIMS), as the highest spatial resolution mass spectrometry imaging technique, holds label-free, high sensitivity, multi-component detection advantages and sub-micron high spatial resolution imaging advantage, providing new analysis method to study life science problems. SIMS has been widely used in cell biology, tissue pathological physiology, biological medicine, clinical medicine and other fields. This paper reviews the progress of SIMS imaging in biological tissue, cell, bionic biofilm and other bio-samples.

Contents

1 Introduction

2 SIMS chemical imaging at tissue level

2.1 Chemical imaging of animal tissue section

2.2 Chemical imaging of plant tissue section

2.3 Chemical imaging of bionic biofilm

3 SIMS chemical imaging at single-cell level

3.1 Endogenous substances analysis

3.2 Exogenous substance analysis

3.3 Cell classification based on SIMS fingerprint

4 SIMS chemical imaging of other bio-samples

5 Conclusion and outlook

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Keywords

SIMS / mass spectrometry imaging / bio-analysis / single-cell analysis / life science

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Lesi Cai, Meng-Chan Xia, Zhanping Li, Sichun Zhang, Xinrong Zhang. Bioimaging By Secondary Ion Mass Spectrometry. Progress in Chemistry, 2021, 33(1): 97-110 DOI:10.7536/PC200458

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1 Introduction

Secondary Ion Mass Spectrometry (SIMS) is a label-free, highly sensitive, multi-component Mass spectrometric detection function, and also has the ability of high spatial resolution imaging at submicron and nanometer levels, which is an important mass spectrometric imaging technology. The main working principle of secondary ion mass spectrometry is to bombard the surface of a sample with a focused high-energy primary ion beam. The primary ions penetrating the surface of the sample enter a certain depth and undergo cascade collisions, which cause a series of physical and chemical changes in the surface atoms of the sample and sputter secondary ions on the surface. The sputtered secondary ions are separated by a mass analyzer according to the mass-to-charge ratio to obtain a mass spectrogram; At the same time, the computer records the intensity of the ion signal on each pixel point and the corresponding spatial coordinate information, and generates an ion image through computer processing.
The development history of secondary ion mass spectrometry can be traced back to the phenomenon of "secondary rays" first observed by Thomson, a British physicist, in the metal plate collision experiment in 1910, that is, the phenomenon of neutral particles and positively charged ions produced by ion initiation[1]. Subsequently, from 1936 to 1937, Aront and Milligan analyzed the energy distribution and ion yield of negatively charged secondary ions produced by positive ion beam bombardment with the help of magnetic field deflection, which was regarded as the pioneer of secondary ion mass spectrometer[2,3]. Herzog and Viehboeck conducted in-depth research on the basic theory of secondary ions and jointly developed the first secondary ion mass spectrometer in 1949[4]. With the advent of the space century, the first commercial secondary ion mass spectrometer for micro-area analysis was developed to analyze the element distribution and isotopic composition information of outer space materials brought back to Earth by astronauts[5]. In the 1970s, Beninghoven led the research team to develop the world's first commercial instrument of Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMS)[6,7]. Through the unremitting efforts of their team and other colleagues, TOF-SIMS has become an indispensable and important analytical tool in the field of surface and interface research. Faced with the complexity of detection samples and the diversification of detection requirements, SIMS instruments with tandem and hybrid mass analyzers have emerged in recent years, such as the SIMS equipment with TOF-Orbitrap hybrid mass analyzers developed by Passarelli in 2017.It is called 3D-OrbiSIMS (Figure 1), which combines the powerful substance identification capability of Orbitrap mass analyzer while maintaining the advantages of SIMS micron to submicron spatial resolution, and has become one of the most advanced SIMS systems at present, with broad application prospects in life science, medical analysis and other research fields[8].
SIMS instruments began to attract wide attention in the first half of the 20th century, and then developed rapidly under the impetus of the semiconductor industry[3,4][9,10]. Early secondary ion mass spectrometry was mainly used for material analysis in industry, and had unique capabilities for chemical identification of ultra-low level charge carriers in semiconductor materials and characterization of device layer structure.With its high sensitivity and excellent depth resolution, SIMS technology has been widely used in many fields of material detection and analysis, including functional ceramics, glass, biological films, metal alloys and polymer materials[11][12][13][14][15]. SIMS is also used in the study of cosmic astrochemistry and biogeochemistry[16]. Cosmologists use SIMS to trace elements in meteorite materials and study the abundance distribution of natural isotopes (such as carbon, nitrogen, oxygen, magnesium, aluminum, silicon, sulfur and other elements) to understand the physical and chemical processes in the early solar system[17,18]. Geoscientists use SIMS to date minerals, identify mineral facies on basalt surfaces, and detect biological melanin residues on fossil samples[19][20][21]. In addition, SIMS technology has also been applied to the research of criminal investigation science, especially in fingerprint imaging and the detection of chemical substances such as drugs, explosives and toxic residues[22 ⇓~24].
With the advent of the biological century, secondary ion mass spectrometry (SIMS) has been applied to many fields of life science, involving various types of samples, such as biomimetic biomembrane systems, animal and plant tissue sections, animal cells and so on.Significant achievements have been made in the study of life science issues such as the formation of phospholipid driven biomembrane microdomains, the mechanism of molecular changes in cell division, and the metabolic distribution of drugs in cells[25][26][27,28][29][30][31]. In the analysis of biological samples, the Imaging Mass Spectrometry technologies (Imaging Mass Spectrometry, IMS) developed rapidly with SIMS technology include Matrix Assisted Laser Desorption Ionization Mass Spectrometry (Matrix Assisted Laser Desorption Ionization-Mass Spectrometry, MALDI-MS), Desorption Electrospray Ionization Mass Spectrometry (Desorption Electrospray Ionization-Mass Spectrometry, DESI-MS), Laser Ablation-Plasma Mass Spectrometry (Laser Ablation Inductively Co up[32,33][34 ⇓~36][37 ⇓~39][40,41]. MALDI-MS is suitable for the analysis of proteins, peptides, phospholipids and other substances with large molecular weight, DESI-MS is suitable for the analysis of small molecular metabolites, and ICP-MS has unique advantages in the analysis of metal elements and single isotopes[34,42,43][39,44,45][46 ⇓~48]. SIMS is not only suitable for elemental analysis, but also for the analysis of small organic molecules with molecular weight below 1000 Da[8,26,27]. The spatial resolution of imaging mass spectrometry determines the scale range of the research object and the accuracy of imaging, and improving the imaging resolution is the common development demand of mass spectrometry imaging technology. From the point of view of spatial resolution, the imaging resolution of MALDI-MS is generally 50 ~ 100 μm, and the spatial resolution of DESI-MS imaging biological samples is usually between tens and hundreds of microns.However, the spatial resolution of LA-ICP-MS can reach 40 μm under certain operating conditions, while the spatial resolution of LA-ICP-MS is usually between 10 and 100 μm, which is above micron level and suitable for imaging whole tissue sections or even complete individual sections[36,43,49,50][39,51,52][53][41]. Although it has been reported that MALDI-MS can improve the resolution to 1. 4 μm, SIMS technology is the most powerful means to achieve high spatial resolution imaging of mass spectrometry at submicron and nanometer levels, especially suitable for mass spectrometry imaging at single cell and subcellular levels[54][8,28,55].
Nano-SIMS can achieve the highest spatial resolution mass spectrometry imaging in biological mass spectrometry research at present, and the lateral resolution can reach 50 nm[55]. In the process of testing, a large number of ions are implanted into the surface of the sample, which will cause damage to the surface of the sample. It is mainly used for element and isotope analysis, but the detection limit of trace elements is one order of magnitude higher than that of TOF-SIMS. TOF-SIMS can reduce the damage to the sample surface to less than 1% of the monatomic/molecular layer (almost no damage to the sample surface) because the dose of ions implanted into the sample surface at one time is much lower than that of Nano-SIMS, so TOF-SIMS can not only detect monatomic ions or fragment ions with low mass number,It can also detect fragment ions or molecular ions with high mass number, and has the functions of biological organic molecule analysis and multi-component simultaneous analysis. It also has the functions of depth profile analysis and 3D imaging like Nano-SIMS, and has become the most widely used SIMS technology in biological imaging research[26,56,57].

2 Study on SIMS Chemical Imaging at the Level of Biological Tissue

SIMS has been widely used in the imaging analysis of specific biomolecules or labeled elements in tissue section samples because of its excellent mass spectrometry analysis ability and high spatial resolution imaging advantages[26]. In the chemical imaging analysis of biological tissue slices, the biomolecules detected by SIMS are generally small molecular metabolites with molecular weight below 1000 Da, mainly phospholipids and fatty acids. Elements commonly detected by SIMS include bioendogenous elements, drug-specific elements, or other labeled elements. Various tissue samples can be used for SIMS analysis, including various animal organ slices, plant organ slices and other biomimetic biological structure systems[26][25].

2.1 Study of chemical imaging in animal tissue section

Imaging small molecule compounds of medical significance, such as drugs or biomarkers, on the surface of tissue slices is becoming a new standard for life and health research[58]. In the mass spectrometry imaging technology, TOF-SIMS can provide a fine spatial distribution image of specific organic molecules on the surface of the slice. Lipid is an important analytical object in SIMS analysis of animal tissue sections. Lipid is not only an energy storage substance, but also an important signal molecule, neurotransmitter or precursor molecule regulating cell proliferation, apoptosis and other life activities[59 ⇓~61]. In 2004, Johansson et al used TOF-SIMS to image the frozen sections of rat brain, showing the distribution of cholesterol, sulfatide, phosphatidylcholine and other biomolecules in the brain sections, which attracted wide attention[62]. Benabdellah et al. Also used TOF-SIMS to carry out fine imaging on rat brain slices, and compared the respective advantages of SIMS and MALDI imaging methods. The two analysis methods had different response intensities to different types of phospholipid signals.MALDI is more suitable for the detection of large molecular weight substances, while SIMS can achieve higher imaging resolution and does not require the addition of exogenous matrix molecules, so they can complement each other well and be applied to the phospholipid imaging study of brain slices (Fig. 2a)[63]. Brunelle et al., on the one hand, stained the rat brain slices after TOF-SIMS surface analysis with Hematoxylin-Eosin (HE), and on the other hand, used TOF-SIMS for lipid localization after HE staining of the samples. The experimental results proved that the high vacuum conditions required for TOF-SRMS imaging did not interfere with staining and identification of brain structures[64]. In addition to brain slices, TOF-SIMS has also been used for lipid imaging analysis in liver, small intestine, skeletal muscle and other tissues[65]. Debois et al. Used TOF-SIMS to image and analyze the lipid distribution of non-alcoholic steatotic liver and healthy liver.Areas of steatosis were found to be differentiated based on elevated cholesterol levels and decreased oxidative stress intensity of linoleic acid, alpha-tocopherol, and some glycerides, showing significant differences from healthy tissue, suggesting that the development of lesions is associated with early metabolic disturbances (Fig. 2b)[66]. Richter et al. performed TOF-SIMS imaging on mouse intestinal tissue slices and found that phosphatidylinositol appeared on the lumen side together with free fatty acids, showing the selective distribution pattern of fatty acid chain length at the cellular level for the first time[67]. TOF-SIMS has also been used to detect and image fatty acids, diacylglycerides (DAGs), triacylglycerides (TAGs) and other lipid metabolites in skeletal muscle samples of mice and humans to study the effects of muscle health and related diseases on lipid metabolism (Fig. 2C)[68,69]. In addition to endogenous substances, SIMS can also be used to image and detect exogenous substances in tissues, such as silica nanoparticles in lung tissue and benzalkonium chloride in eye tissue[70][71].
Nano-SIMS has both Nano-scale spatial resolution and ultra-high detection sensitivity in elemental analysis, and the most remarkable research achievement in tissue level Imaging is the development of MIBI (Mutiplexed Ion Beam Imaging) system. Nolan et al. developed a Nano-SIMS-based MIBI technique to immunostain formalin-fixed, paraffin-embedded tissue sections by coupling a single isotope metal label to the antibody, and to image tissue in situ protein expression using secondary ion mass spectrometry imaging stable metal isotope-labeled antibody-labeled antigens[72]. Based on the advantages of high spatial resolution imaging, high sensitivity and multi-component analysis of SIMS, multiple channels can be imaged simultaneously, which breaks through the limitation of detection channels caused by spectral overlap in traditional immunofluorescence technology. Then, Angelo and others replaced the original magnetic field analyzer with a TOF analyzer and built a MIBI-TOF system to further expand the number of channels that can be analyzed simultaneously[73]. They used MIBI-TOF system to achieve simultaneous imaging of 36 proteins in tissue sections of 41 triple-negative breast cancer patients, with imaging resolution reaching subcellular level, showing the tissue structure of tumor immune microenvironment, including cell composition, spatial arrangement and regulatory protein expression, providing a framework for the application of MIBI to immuno-oncology. MIBI technology can provide new insights into the pathogenesis of diseases, and is of great value in basic research, drug discovery and clinical diagnosis.

2.2 Chemical imaging studies in plant tissues

Plant tissue section is also an important analysis object of SIMS imaging research. Tokareva et al. analyzed and studied the sample preparation techniques and proposed a rigorous sample preparation method for characterizing metals, lignin and polysaccharides in wood[74]. Metzner et al. developed an element- and isotope-specific imaging method based on Cryo-TOF-SIMS to monitor the material transport pathways and processes in xylem and related tissues by adding sodium (Na), potassium (K), rubidium (Rb) and 41K tracers to the stems of common beans[75]. SIMS imaging showed that tracers Rb, 41K and Na were enriched in xylem vessels and surrounding tissues. By superimposing the Cryo-TOF-SIMS images on the corresponding SEM images, the correlation between nutrient images and subcellular structures can be established, which can be used to study the relationship between dynamics and structural functions in the process of plant nutrient transport (Fig. 3A). Kuroda et al. Also used Cryo-TOF-SIMS and SEM to analyze freeze-dried tissue sections of Cryptomeria japonica, and imaged potassium, ferruginol and water molecules in the sections[76]. In organic molecular analysis, Zhou et al. measured the spatial distribution of syringyl (S) and guaiacyl (G) lignins in larger areas and individual cell walls of poplar (Populus trichocarpa) wood sections by TOF-SIMS, which was the first time that the spatial distribution of S and G lignins was visualized in situ[77]. Fu et al used TOF-SIMS to study Larix olgensis. In the high spatial resolution image of 400 nm, fatty acids, triglycerides and phytosterols were mainly colocalized in the first ring, and resin acids were the main components of resin tubes in secondary xylem, mainly distributed in the outer layer of secondary xylem[78]. Trindade et al. Introduced the concept of algorithm to perform Principal Component Analysis (PCA) and Non-negative Matrix Factorization (NMF) on TOF-SIMS data collected from the surface of Scottish fir samples, with the help of two standard samples of lignin and cellulose.The NMF results reduced the dimensionality of the data to represent the two compounds of lignin and cellulose covered on the surface, and found that the difference in the relative content of lignin and cellulose in early and late wood was consistent with the anatomical structure of wood.This makes multivariate analysis a potential way to distinguish wood species and potential ages based on the natural composition of the wood[79].
In addition to the two-dimensional imaging work, the study of plant sections using SIMS depth profiling and 3D imaging functions has also been reported. Jung et al. analyzed and imaged cellulose and lignin in stress wood tissues on poplar branches by oxygen gun sputter ablation and $Bi_{3}^{+}$ ion gun, analyzed the content differences of cellulose and lignin in gelatinous layer, secondary cell wall and cell corner, and reconstructed 3D images of cellulose (m/Z 127 and 145) and lignin (m/Z 137, 151, 167 and 181) signals (Fig. 3B)[80]. The spatial distribution information of biomolecules displayed by 3D chemical imaging data is helpful to understand the close relationship between cell structure and component spatial distribution, which is very important for the study of spatial local chemical effects of wood material biotransformation, biofuel pretreatment and genetic variation.

2.3 Chemical imaging in biomimetic biomembrane structures

The construction of phospholipid biomimetic membrane system is helpful to understand the interaction between different phospholipids and between phospholipids and other substances on the membrane, and to further understand the function of cell membrane. The main body of the cell membrane is formed by a complex array of phospholipids, which play an important role in membrane dynamics, protein alignment and signal transduction. TOF-SIMS is particularly suitable for the imaging of small phospholipid molecules and plays an important role in the study of simulated membrane systems and cell membranes[81 ⇓~83]. Sostarecz et al. Used TOF-SIMS to study the mechanism of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) on the formation of cholesterol (CH) regionalization on the lipid membrane, and compared the degree of cholesterol regionalization by using biomimetic membranes formed by different proportions of PC, PE and CH in the simulation monolayer system[29]. The imaging results showed that CH and PC formed homogeneous distribution in PC and CH membranes, and no cholesterol concentration area was formed. However, in the process of PE membrane formation, CH formed a concentrated region, which indicated that phosphatidylethanolamine was the key factor to induce cholesterol regionalization. Subsequently, Zheng et al. carried out TOF-SIMS label-free detection in a three-component simulated membrane system to evaluate the interaction between phospholipids[84]. The results showed that cholesterol was encapsulated by sphingomyelin, and the formation of this phenomenon was driven by the saturation of the acyl chain of phospholipids, rather than the head hydrogen bonding and polarity. Phosphatidylcholine (PC) and sphingomyelin (SM) have different head chemical groups, different nitrogen contents lead to different polarities and different abilities to form hydrogen bonds. Four control trials were conducted by combining PC, SM, and CH with different acyl chain saturations. The intensity and distribution of different phospholipids and the intensity distribution of mono cholesterol on the membrane were compared by imaging analysis, and it was found that the cholesterol concentration area had a high degree of coincidence with the saturated acyl chain area.However, the differences in the chemical structure of the head groups of SM or PC had no significant effect on the formation of cholesterol concentrated regions, suggesting that the formation of lipid rafts co-located with sphingomyelin and cholesterol on the cell membrane was mainly due to the high saturation of the acyl chains of sphingomyelin. The study of SIMS imaging in biomimetic membrane system extends the molecular level study of SIMS imaging technology in complex life processes, and provides basic research data and theoretical support for life science based on biomimetic membrane system. In addition to lipid biomembranes, SIMS has also been applied to molecular imaging studies at the tissue level, such as bacterial biomembranes[85].

3 SIMS chemical imaging study at single cell level

Compared with other imaging mass spectrometry, SIMS has nano-scale spatial resolution, which makes it more advantageous in cytochemical imaging and becomes an irreplaceable analytical tool in single cell imaging research[86 ⇓~88]. Nano-SIMS is mainly used to image endogenous elements and externally labeled isotopes in cells, and can achieve Nano-scale spatial resolution. TOF-SIMS can simultaneously image elements and organic molecules, including phospholipids, amino acids, nucleic acids and other biomolecules and their characteristic fragments, with a spatial resolution of 200 nm. SIMS is more suitable for the analysis of small molecules (m/Z < 500 Da) due to the low yield of secondary ions and serious fragmentation of molecules with large molecular weight.However, the powerful chemical imaging ability of SIMS still provides a new solution for biological science research at the cellular level[87,88]. Scientists have also continuously improved the detection ability of SIMS for macromolecular substances through matrix enhancement and the development of cluster ion sources[89,90][91,92].

3.1 Cell endogenous substance analysis

In the study of cell imaging based on SIMS technology, the cell composition is complex and the matrix interference effect is serious. In order to obtain the effective biomolecular information in a single cell, especially the endogenous substance signal, the preparation technology of cell sample is very important. Current cell preparation methods for SIMS detection can be divided into two basic categories: chemical fixation or lyophilization. In the TOF-SIMS imaging study of human fibroblasts, Malm et al., combined with SEM and other means, systematically compared the two fixation methods of freeze-fixation and chemical fixation, and the two drying methods of freeze-drying and ethanol dehydration[93]. The results showed that cryopreservation (plunge freezing) could preserve the cell morphology, intact cell membrane and normal ratio of K+/Na+ inside and outside the membrane, while glutaraldehyde fixation could obtain better cell membrane fine structure and similar phospholipid signal, but could not maintain the normal ratio of K+/Na+ inside and outside the membrane. The freeze-drying method can obtain better dried cell samples, while the polar phospholipids are dissolved in ethanol, and the ethanol extracts the phospholipids from the cell membrane, so the ethanol drying method greatly reduces the phospholipid signal. Brison et al. Discussed in detail the effect of sample preparation methods on cell samples in their in-depth analysis of HeLa cells, and concluded that the most effective treatment options were ammonium acetate washing, liquid ethane treatment, and lyophilization[94]. The method obtains the best ratio of the K+/Na+ inside and outside the cells, which indicates that the cells before sample preparation have good activity, are well preserved in morphology, have high integrity of cell membranes, and are minimally damaged. Chemical fixation methods often cause cell membranes to become disordered, and there is evidence that lyophilization and formaldehyde fixation after formalin fixation can rupture cell membranes[95][96]. However, the use of glutaraldehyde as a fixative crosslinks the amino groups in phosphoserine and phosphoethanolamine, which are important components of the inner leaf of the cell membrane, whereas formaldehyde does not. The membrane components of NIH/3T3 cells fixed with glutaraldehyde were not disturbed, and the phospholipid m/Z 184 peak of hTERT-BJ1 fibroblasts fixed with glutaraldehyde also showed that the membrane was not damaged[97][93]. Therefore, the two methods have their own advantages and disadvantages, and it is particularly important to select the appropriate sample preparation method according to the experimental purpose and the key detection object.With the optimization and maturity of the sample preparation method, SIMS imaging shows its unique advantages in the field of life science analysis.
In 2004, Ewing et al. Reported in Science that the highly curved membrane structure in the mating process of Tetrahymena was imaged by TOF-SIMS to study the molecular mechanism involved in the process of biological fusion[30]. The mass spectrum image shows that the content of phosphatidylcholine (the $C_{5}H_{15}NPO_{4}^{+}$,m/z 184 of the head group fragment), which is a low bending lipid, decreases in the fusion membrane region during the mating process of Tetrahymena, and there are a large number of highly bending fusion pores. In addition, mass spectrometry imaging and principal component analysis showed a significant increase in the content of highly curved phosphoethanolamine (head group fragment $C_{5}H_{9}NPO_{3}^{+}$,m/z 126, a cone-shaped non-lamellar phospholipid similar to phosphatidylethanolamine PE) in the fusion region. This evidence suggests that the biological fusion process may involve, or in fact is driven by, a heterogeneous lipid redistribution process in the fusion region. Subsequently, they used SIMS imaging to further study the driving mechanism of membrane region formation during mating in single-celled organisms[98]. Through SIMS image analysis of various States of Tetrahymena during mating (Fig. 4A), the content and distribution changes of phosphatidylcholine (head group fragment $C_{5}H_{15}NPO_{4}^{+}$,m/z 184), which refers to lecithin and sphingomyelin, were detected with the ubiquitous hydrocarbon fragment $C_{5}H_{9}^{+}$(m/z 69) as the internal standard. In combination with SIMS measurements such as line scan, the formation of phospholipid domains was demonstrated, confirming that the reduction of lamellar phospholipid lecithin during cell binding occurred after, rather than before, the membrane structural change. Sweedler et al. imaged neuronal cells by TOF-SIMS, and the imaging results showed that vitamin E was located at the junction of cell body and synapse of single neuronal cells, and the distribution and enrichment of biomolecules in subcellular areas were observed in single cells (Fig. 4B). The results provided evidence for the theory that vitamin E deficiency leads to reduced axonal transport[99]. The above research has made the world pay attention to TOF-SIMS as a high-resolution in situ imaging mass spectrometry technology, which can provide new ideas for complex biological problems and promote the development of life analytical chemistry, especially the development of single cell analysis technology[100].
3D imaging is one of the unique advantages of TOF-SIMS in the field of single cell research, which can reveal the three-dimensional spatial distribution of metabolites in cells, thus further explaining the biological metabolic pathways and molecular mechanisms. The typical 3D imaging method is to use the double ion gun method to collect mass spectrum images, that is, the analysis gun collects data information, the sputtering gun sputters and erodes molecular layers alternately, layer by layer, and the accumulated images collected are processed by software to reconstruct cell 3D images (Figure 5A). Nygren et al reconstructed the chemical 3D image of thyroid cancer cells and found that the Na+ was in the outermost layer of the cell, the peak of K+ and phosphatidylcholine fragments (m/Z 184) was in the inner lobe of the cell membrane, and the peak of phosphatidylcholine fragments (m/Z 86) was in the nucleic acid region[56]. Because the cells are not stereoscopically flat, the 3D reconstruction data is obtained from the non-planar 2D image. In order to obtain a more accurate 3D chemical image of the whole cell, it is necessary to strictly control the sputtering rate in depth analysis and carry out Z axis correction in the later stage. Robinson et al. Developed the 3D data system Z-axis correction software ZCorrectorGUI applied to TOF-SIMS, and obtained the three-dimensional image of chemical molecules of intact NIH/3T3 cells (as shown in Fig. 5B), which was the first 3D calibration observation of phospholipid enriched subcellular regions[101]. The 3D imaging of endogenous metal ions and organic molecules in cells also lays a foundation for the later drug research and the spatial distribution of biomarkers in cells.

3.2 Analysis of extracellular substances

Drugs and their metabolites, isotope markers, element substitution biomolecules and other exogenous substances have also become important analysis objects in SIMS cytochemical imaging research, which are used to study major life science issues such as drug metabolism, drug action mechanism, genetic variation and so on at the cellular level[102,103][104][105]. Nano-SIMS is more advantageous for highly sensitive detection and ultra-high spatial resolution imaging of elements and stable isotopes in cells (Fig. 6a). In the study of life science problems, Peteranderl et al. Of Harvard Medical School developed a method for measuring isotope ratios in situ in cells by culturing cells with glycine labeled with 13C or 15N.The isotope ratios of 13C/12C and 15N/14N in cells are measured, which can be directly detected and imaged at the subcellular scale and used as labels to observe the operation of biomolecules in cells[106]. Lechene et al. Used 15N labeled thymine to culture stem cells, and used Nano-SIMS to image and analyze the DNA molecules of dividing cells, to explore whether the distribution of DNA molecules in the process of stem cells providing genetic material to tissue progeny cells conforms to the "immortal chain" hypothesis.It provides direct evidence of non-random template chain separation in small intestinal tissue under physiological conditions, and applies the detection and imaging capabilities of SIMS to the study of metabolism and cell fate[105]. In the field of biomedical research, Legin et al. Used Nano-SIMS to characterize the subcellular distribution of cisplatin labeled with 15N in human colon cancer cells. The imaging results showed that platinum was enriched in the phosphorus-rich chromatin region of cells, which verified the binding affinity effect between platinum and DNA, indicating that DNA was the key target of drugs[107]. Croisy et al. Used Nano-SIMS to study the ultrastructural localization of the clinically used N-2-diethylaminoethyl-4-iodobenzamide (BZA) drug in melanoma, and showed the colocalization of iodine signals and melanin signals in the cells, both located in the melanosomes (Fig. 6B)[108]. In addition, they used 15N to label exogenous peptides and track the cellular internalization of drug-carrying molecules[55]. As shown in Figure 6a, the Nano-SIMS imaging results show the precise spatial localization of the 15N labeled peptide on the cell membrane, which is helpful to study the binding process of tumor-targeting drugs and cell membrane glycolipid receptors. Nano-SIMS has also been used to study the biological toxicity of nuclear pollution and environmental pollution to animals and microorganisms. Galle et al. Used the imaging capabilities of Nano-SIMS isotope analysis to identify the natural isotope 127I and 129I in the thyroid glands of iodine-deficient rats exposed to 129I isotopes[109]. 127I was found in the cytoplasm of thyroid cells, while 129I was found in the colloid of thyroid follicles. This application is of great significance for determining the location and exposure level of radioactive iodine isotopes in nuclear accidents. Madsen et al. Used CAMECA IMS-3f-SIMS ion microscopy to image single bacteria in phenol-treated soil labeled with 13C, showing the results of molecular heterogeneity among bacteria, expanding the application prospects of SIMS in microbiology and biogeochemistry[110].
TOF-SIMS can simultaneously analyze drugs, drug metabolites and changes in cellular components caused by drugs. Passarelli et al. Used TOF-SIMS to study the absorption of amiodarone, an antiarrhythmic drug, in cells, and realized 3D visualization of drugs and metabolites in single cells by combining high lateral resolution and multi-component imaging[111]. At therapeutic doses, intact molecular ions of the label-free drug compound amiodarone (m/Z 646.0) and its metabolite deethylamiodarone (m/Z 618.0) were successfully detected in macrophages (NR8383 cell line). Through spatial recognition, amiodarone ions were mostly distributed in the membrane and surface regions in macrophages, and were absent in the nuclear region. Similar spatial distribution results were observed for metabolite ions. The 3D spatial distribution of drug characteristic iodine and nuclear marker molecular fragments (m/Z 134, 158.9, 180.9) is shown in Figure 6 C. Subsequently, Dollery's team also used TOF-SIMS imaging technology to further study the absorption differences of amiodarone in different cell types (human embryonic kidney cell HEK293, cervical cancer cell HeLa, liver cancer cell HepG2)[112]. Similarly, Vanbellingen et al. used TOF-SIMS to study the effects of the B-cell lymphoma 2 (Bcl-2) inhibitor ABT-737 on the A-172 human glioblastoma cell line, localizing and recognizing intact, unlabeled drug molecular ions (m/z 811.26,C42H44ClN6O5 S 2 -, [M-H]-), and signature ions)[31]. 3D chemical imaging showed that ABT-737 was mainly distributed in the subsurface area of cells, but not in the nucleus. Ewing et al studied the effect of cisplatin on cell membrane phospholipids at the cellular level by TOF-SIMS imaging analysis, and the experimental results showed that the abundance of different lipids and their derivatives was significantly affected by cisplatin.Especially, the abundance of phosphatidylcholine and cholesterol decreased, which proved that cisplatin affected the extracellular release process to some extent by changing the lipid composition of cell membrane[113]. Wang Fuyi et al. Have studied the mechanism of action of metal anticancer drugs in cells for a long time by combining SIMS imaging technology and fluorescence imaging technology, and Long Yitao et al. Have also studied the changes of cell surface lipid composition caused by silver nanoparticles at the single cell level by TOF-SIMS[114][115]. Recently, Benkovic et al. reported on Science a novel GCIB-SIMS using carbon dioxide molecular clusters (CO2 ) n +) as the ion source, and used the instrument to image the active intermediates labeled by 15N in the phospholipid, nucleotide and purine biosynthesis pathways in HeLa cells, revealing the formation of purine bodies in specific "metabolic compartments" of the de novo purine synthesis pathway[116]. This kind of work shows the advantages of TOF-SIMS in single cell analysis, which can not only be used to distinguish the distribution of substances in different regions of the cell, but also to detect multiple components, reflecting the spatial and content relationship between drugs and cell metabolites, and becoming a powerful analytical tool for cell life science and drug metabolism research.

3.3 Study on Cell Typing Based on Secondary Ion Mass Spectrometry Fingerprint

The study of cell typing based on mass spectrometry fingerprint is one of the most concerned research directions in the field of life science by secondary ion mass spectrometry. Over the past 150 years, scientists have been committed to the classification and recognition of cells from various perspectives, such as cell morphology, cell distribution in tissues and organs, cell function in the body, etc. Cell typing and feature recognition are the basis and prerequisite for major life science research such as life trajectory of embryonic development and cancer pathogenesis[117,118][119,120]. With the development of detection technology, precise identification and typing of cells at the molecular level of genetic material, proteins and metabolites have further refined the differentiation and definition of cell types, and promoted the discovery of new cell types or subtypes and subtypes in a class of cells[118 ⇓~120][121 ⇓~123][124,125].
TOF-SIMS has the advantage of high spatial resolution imaging in single cell analysis, and can provide abundant spectral peak information, which can come from proteins, nucleic acids, metabolites and other biomolecules, so it can reflect the subtle differences in protein expression, metabolic activity and cell structure between cell samples, which is very conducive to accurate cell typing at the single cell level. In 2006, Kulp et al. Reported the imaging and classification of breast cancer cell lines MCF7, T47D and MDA-MB-231 based on TOF-SIMS mass spectrum peaks of single cells combined with PCA.The morphological difference of different types of cell and that component difference of characteristic ions such as phospholipids, amino acids and the like at the molecular level are analyze, and the morphological difference among different cells is observed through imaging, thereby creating a new method for cell typing research at the molecular level based on TOF-SIMS peak fingerprints[126]. Kraft et al. Used TOF-SIMS data combined with multivariate analysis to identify the differentiation status of single hematopoietic cells (HCs) isolated from mouse bone marrow[127]. Partial Least Squares-Discriminant Analysis (PLS-DA) was performed on SIMS data to accurately classify the three differentiation States (hematopoietic stem and progenitor cells, common lymphoid progenitor cells, and mature B cells) in the process of B lymphocyte proliferation and differentiation at the molecular level according to the differential statistical characteristics of phospholipid, amino acid, and fatty acid fragments (Fig. 7A). Ratner et al. used PCA and PLS-DA algorithms to process TOF-SIMS data, classified NIH/3T3 mouse fibroblasts and primary rat esophageal epithelial cells (REEC cell line) in a polyculture system, and observed the spatial distribution of different cells by showing pixels with different mass spectral statistical characteristics in space according to mass spectral imaging data[96]. Subsequently, Lekka et al. Used PCA analysis of TOF-SIMS mass spectrometry data to achieve bladder cancer cell typing at the single cell level, and distinguished the differences in phospholipids, fatty acids, amino acids, alpha-tocopherol, cholesterol and other substances in HCV29, HT1376, T24 and HTB9 cells[128]. Robinson et al. Also used PCA analysis of TOF-SIMS data to classify eight breast cancer cell lines MDA-MB-231, BT549, HCC1395, HS578t, BT474, MCF7, HCC1428, and T47D, as shown in fig. 7B, focusing on the differences in phospholipid composition among the three breast cancer subtypes of Triple Negative cell lines, ER + and PR + receptor positive (PR) cell lines, and ER +, PR +, and HER2 + cell lines[129]. These works provide theoretical and data support for the application of SIMS in the field of cell typing, and provide new methods for the study of cell typing at the molecular level.

4 SIMS Chemical Imaging Studies of Other Biological Samples

TOF-SIMS has submicron spatial resolution and powerful mass spectrometry detection function, which can be used for the detection of various biological samples. For example, SIMS can clearly image the fine structural features of fingerprints, and many pollutants, including illegal drugs, gunshot residue (GSR) and daily necessities, can be detected in fingerprint residues using TOF-SIMS[23,130][24,131,132][133]. TOF-SIMS has also been used to extend the study of fingerprints, such as the determination of the deposition sequence of overlapping latent fingerprints and the determination of the age of fingerprints[134][135]. Although TOF-SIMS has been widely used in the detection of biological samples in criminal investigation, only small molecular ions (m/Z < 500) can be obtained in conventional detection. In response to this problem, our research group developed graphene oxide matrix enhanced SIMS technology, which significantly improved the secondary ion yield of highly toxic alkaloids and antibiotics (m/Z > 600) with large molecular weight, and imaged the fine sweat pore structure on a single papillary line of the fingerprint (Fig. 8)[22].
Phospholipid vesicles are vesicles composed of amphiphilic lipid molecules, which are widely used in biomedical and biochemical fields[136][137,138]. Optical electron microscopy and atomic force microscopy can accurately image the microtopography of these vesicles, but can not provide molecular information[139][140]. Based on the advantages of SIMS for lipid detection, such as high sensitivity, label-free, and high spatial resolution imaging, TOF-SIMS can not only image vesicles, but also provide chemical information of vesicle molecular composition[141,142]. However, in many early studies, phospholipid vesicles can only be analyzed by detecting and imaging the fragment ion C5H12N+ of phospholipids and the O 4 + of C5H15NP[141,142]. Graphene oxide matrix-enhanced SIMS was used to image the complete molecular ions of phospholipids in vesicles, which improved the molecular identification ability of TOF-SIMS and expanded the application scope of SIMS in chemical imaging of biological samples[90].
Biological microarray is one of the key research technologies in biology[143,144]. In the preparation of biological microarray chips, it is necessary to accurately characterize the chemical structure and spatial distribution information of biomolecules on the microarray surface[145 ⇓~147]. SIMS can provide both chemical composition information and high spatial resolution images at micron and submicron levels, and has been widely used in the detection and analysis of DNA, protein and other biological microarray chips[148 ⇓~150][147,151,152]. For example, Castner et al. Used a commercial polyacrylamide-based microarray chip combined with single-stranded DNA (ssDNA) to obtain the spatial distribution, chemical composition and hybridization efficiency of the DNA array through TOF-SIMS. The imaging results showed that DNA molecules were distributed in the planned microregions, and the DNA components in each microregion were uniformly distributed[149]. In the analysis of protein microarray chip, Yang et al. Used the characteristic ions of biotin and streptavidin on the TOF-SIMS imaging chip to effectively verify the array distribution of protein molecules on the chip, and also provided the information of residual reagents, which provided important data support for the improvement of chip preparation process[147]. In recent years, TOF-SIMS has also been applied to the analysis of array-patterned cell samples[153,154]. For example, Lee et al. imaged a streptavidin protein microarray using TOF-SIMS and imaged a patterned array of hamster ovary cells bound to the protein array[153]; Wu et al., combined with array single cell capture method, used TOF-SIMS high-throughput detection and imaging of biomolecules in arrayed cells to study the early phenotypic changes of HeLa cells induced by drugs, and analyzed the main molecular sources of phenotypic changes[154]. From DNA to proteins, from molecules to whole cells, SIMS has always played an important role in the analysis of patterned and arrayed biological samples by virtue of its chemical detection and high-resolution imaging advantages.

5 Conclusion and prospect

Secondary ion mass spectrometry (SIMS) has become the mainstream frontier technology for histochemical imaging, single cell and subcellular structure chemical imaging analysis, and has been widely used in the study of life science issues. At present, the biggest challenge of SIMS technology in biological imaging research is the low yield of secondary ions and serious fragmentation of higher molecular weight biomolecules, which greatly reduces its detection sensitivity and imaging resolution, and limits the detection and application scope of SIMS. Starting from the problems of life science, developing new SIMS analysis systems to meet various needs and solve specific biological problems is the mainstream development trend of SIMS research in the future. On the instrument, the ionization efficiency of secondary ions of high molecular weight biomolecules can be improved by developing new ion sources[116]. Through the design of a new mass analyzer, the detection efficiency of secondary ions is improved, and the two are combined to improve the detection sensitivity of SIMS for high molecular weight biomolecules from the perspective of instrumentation[8]. In sample preparation, matrix enhancement techniques can be used to avoid or reduce excessive fragmentation and further improve the secondary ion yield of high molecular weight biomolecules[22,90]. In the aspect of SIMS data processing, we can deeply mine the biological information contained in SIMS fingerprints by combining the development of bioinformatics and statistical algorithms[127 ⇓~129]. As the highest spatial resolution mass spectrometry imaging technology, secondary ion mass spectrometry will play a greater role in basic life sciences, clinical medicine, drug research and development and other important fields.

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Funding

21621003

the National Key R&D Program of China(2018YFA0702600)

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