Advances in Ambient Ionization for Mass Spectrometry

CHINESE JOURNAL OF ANALYTICAL CHEMISTRY Volume 46, Issue 11, November 2018 Online English edition of the Chinese language journal

Cite this article as: Chinese J. Anal. Chem., 2018, 46(11): 1703–1713

REVIEW

Advances in Ambient Ionization for Mass Spectrometry ZHANG Xing-Lei1, ZHANG Hua2, WANG Xin-Chen1, HUANG Ke-Ke2, WANG Dan1, CHEN Huan-Wen1,* 1 2

East China University of Technology, Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation, Nanchang 330013, China State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012, China

Abstract: Over the past decade, ambient mass spectrometry (AMS) has become an important scientific research tool which has been widely used in various important fields such as pharmaceuticals, food, environment, public safety, clinic diagnosis and so on. Ambient ionization technology, as the key for AMS analysis, allows the direct sampling/ionization of analytes from raw practical samples without any sample pretreatment, and has greatly improved the analytical efficiency. At present, nearly 100 of different ambient ionization technologies have been developed for the study of complex solid, gaseous, liquid, and even viscous samples. Herein, the ambient ionization methods were introduced in the aspect of energy and charge transfer process, and the new ambient ionization devices developed in the recent 5 years were briefly summarized and discussed. Furthermore, the advantages and disadvantages of the ambient ionization technology and the possible development direction of atmospheric ionization technology in the future were prospected. Key Words: Mass spectrometry; Ambient ionization; Direct analysis; Energy and charge transfer process; Review

1

Introduction

The proposal of desorption electrospray ionization (DESI) in 2004 allows ambient mass spectrometry analysis of complex samples without any sample pretreatment, greatly improving the analytical efficiency. Since then, ambient mass spectrometry (AMS) has been one of the most significant fields of mass spectrometry study. Over around ten years’ development, AMS has been widely used and is exerting greater influences in various fields, as shown by the research tide in ambient ionization technology around the world. By July 2018, search on the Web of Science with “ambient mass spectrometry” as the key word revealed 7680 literature records, of which over 700 every year were published in the past two years, showing a steady rise. Besides, hundreds of ionization techniques have been developed in the world for different analytical objects and purposes. With the competence of withstanding different complex matrix and ambient ionization under atmospheric pressure, those methods

have been employed in various fields, such as omics analysis[1–3], living organism analysis[4,5], environment test[6], drug quality assessment[7,8], food safety analysis[9], criminal investigation[10] and mass spectrometry imaging[11]. Furthermore, through years of researches, domestic ambient ionization techniques, represented by DESI[12], DART[13], EESI[14], LTP[15], DBDI[16] and DAPCI[17], have proved to be theoretically mature and practically valuable. Currently, there have been references[18‒20] making a summary, classification or outlook on ionization techniques from the perspectives of research and application of ionization mechanism. In this paper, the ambient ionization methods are introduced in the aspects of energy and charge transfer process, and the ambient ionization devices developed in the last 5 years are briefly summarized. Furthermore, the advantages and disadvantages of the ambient ionization technology are discussed, and the possible development direction of atmospheric ionization technology in the future is prospected.

________________________ Received 4 August 2018; accepted 30 August 2018 *Corresponding author. E-mail: [email protected] This work was supported by the National Natural Science Foundation of China (Nos. 21727812, 21675021), the Science and Technology Planning Project at the Ministry of Science and Technology of Jiangxi Province, China (No. 2010BNB00900), and the Jiangxi Key Laboratory for Mass Spectrometry and Instrumentation Open Foundation of China (No. JXMS201612). Copyright © 2018, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. Published by Elsevier Limited. All rights reserved. DOI: 10.1016/S1872-2040(18)61122-3

ZHANG Xing-Lei et al. / Chinese Journal of Analytical Chemistry, 2018, 46(11): 1703–1713

2

Basic Principles

Based on the differences of ionized energy sources (such as electricity, light, heat, sound, etc.), the energy coupling forms of ambient ionization technology mainly include spray ionization, electric field ionization, photoionization and thermal ionization. One ambient ionization technology either applies a single form of energy, or a combination of multiple forms to achieve ionization of target sample. Aiming at the diversity of actual sample morphology (including solid, liquid, gas, colloids, and even heterogeneous morphology, etc.), our group proposed two-dimensional and three-dimensional models for directly preparing target molecular ions and summarized the transferring process of energy/charge in different phase states[18]. In two-dimensional model, the energy/charge carrier collides with the real sample directly in the plane, and transfers the energy load to the target molecule to achieve surface desorption ionization. This model is suitable for surface analysis or mass spectrometry. In three-dimensional model, the energy/charge carrier mixes with the real sample in the space and transfers the energy load to the target molecule, during which time extraction ionization completes, thus further strengthening the carrier’s resistance to the matrix. Due to this point, it is applicable to various complicated mass spectrometry analysis of live organism (such as blood, urine, sewage, etc.) and samples. In order to achieve satisfactory analysis results, it is of practical sense to choose the carrier and transfer modes reasonably according to the physical and chemical properties and state of the actual sample. The ionization techniques of different energy forms are summarized as below. 2.1

Spray ionization

The spray ionization technology takes the charged droplet as the primary reagent ion and transfers its energy load to the complex matrix sample so as to realize the ambient ionization of the tested object. The ionization process generally includes two steps: (1) using sheath gas or electric field to generate charged droplets in the liquid, in which primary reagent ions with certain energy are formed, such as ultrasonic spray or electrospray; (2) making the primary reagent ions carrying energy contact and interact with the samples under test directly in two-dimensional surface or three-dimensional space[18], during which the ionization of the substances under test is realized through the transferring of energy and charge. As the actual samples exist in the form of solid, liquid, gas, colloid or even non-uniform form, various ambient ionization technologies based on spray ionization emerge one after another in order to cater for different sample analysis, such as extractive electrpspray ionization (EESI)[21], desorption sonic spray ionization (DeSSI)[22], air flow assisted ionization (AFAI)[23], fused droplet electrospray ionization (FDESI)[24],

nano extractive electrospray ionization (nanoEESI)[25], and tissue-spray ionization (TSI)[26]. Among them, DESI is a classical method for the preparation of target molecular ions on two-dimensional surface in a direct way. The pending substance was absorbed and ionized on the surface of the sample through charged liquid droplets prepared by ESI and energy load is transferred on two-dimensional surface to realize ionization of the target substance. DeSSI can produce small charged droplets by means of ultrasonic spray (no extra voltage). Free from extra electric field, those droplets have mild ionization energy. In particular, EESI uses electrospray channels and sample channels respectively to make collision and fusion of the charged droplets and neutral sample spray in a relatively wide three-dimensional space, where the energy load transfers between each other in the three-dimensional space and the ions to be measured are obtained. As a result, the complex matrix has its bearing capacity further improved. As a mild ionization technology milder than ESI, EESI is not only helpful in the application researches, such as chemical reaction monitoring and living tissue analysis, but also promising in non-destructive analysis of living organism. This technique can also be used for ambient mass spectrometry analysis of strongly polar materials and biomacromolecules. 2.2

Electric field ionization

The primary ion production technologies based on electric field discharge mainly include atmospheric pressure chemical ionization (APCI) and plasma ionization generated by atmospheric pressure corona discharge and glow discharge. Direct analysis in real time (DART) works out when several kilovolts are added between porous electrode and pin electrode discharge indoor. In this way, the glow discharges and makes He or N2 molecules in the form of gas turn into excited state. As a result, in the body cavity generates plasma jet containing ions, electrons and excited state gas. The plasma jet goes out from the DART outlet to the surface of samples, which will be processed under heat-assisted desorption and ionization. Suitable for rapid ionization of small molecular compounds, DART has been widely used in the analysis of food, drugs, metabolites, etc. For example, Jagerdeo et al[27] used DART-MS for direct analysis and detection of metabolites in urine. Li et al[28] used DART-QTOF-MS to establish a rapid screening method for synthetic hypoglycemic drugs artificially doped in traditional Chinese medicine health care products. Dielectric discharge barrier ionization (DBDI)[29] is a non-equilibrium gas discharge technology characterized by inserted insulating medium in corona discharge space. The medium stampedes discharge through gas and meanwhile produces a large number of electrons, ions and excited-state atoms of plasma extending far away from the discharge area, thus low temperature plasma probe (LTP)[15] can be obtained.

ZHANG Xing-Lei et al. / Chinese Journal of Analytical Chemistry, 2018, 46(11): 1703–1713

The generated plume is rather thin, and hence it is named as LTP. Huang et al[30] employed LTP to detect melamine in whole milk, fish and milk powder. The detection limit reached 250 ng mL–1, and analysis of a single sample took only 0.5 min. The temperature of plasma generated through LTP is about 30 °C, and the insulator is isolated from high voltage, so the LTP cannot only be employed directly on the skin to detect chemicals such as cocaine but also help make mass spectrometry imaging[16] of stamps on calligraphy and painting. Other electric field ionization techniques include extractive atmospheric pressure chemical ionization (EAPCI)[31], plasma assisted desorption ionization (PADI)[32], desorption atmospheric pressure chemical ionization (DAPCI)[33,34], and helium atmospheric pressure glow discharge ionization (HAPGDI)[35], etc. As the energy provided by Corona discharge, glow discharge or plasma is much more than that by ESI, such kind of ionization technology performs better for low polarity or even non-polar compounds in terms of ionization ability.

molecular ionization. Thermal desorption chemical ionization (TDCI)[43], through pyrolysis of ionic compound reagent, produce a large amount of high concentrated reagent ions, which collide with the analyst molecules in the samples and makes possible the ionization of the latter. This technology is free from high-pressure gas and has high sensitivity. Besides, as it adopts room temperature ionic liquids as ionization reagent, the process is non-toxic and pollution-free. Thermal ionization is suitable for the analysis and detection of weak polar and non-polar compounds due to high reactivity and ionization ability of cations and anions produced by the pyrolysis of ionic compound reagents. Moreover, the selective ionization of the substances to be tested can be achieved by using specific reagent ions to improve the analytical sensitivity. Other thermal ionization technique composes of laser diode thermal desorption (LDTD)[44], atmospheric pressure thermal desorption ionization (APTDI)[45], rapid evaporative ionization (REI)[46], etc.

2.3

3

Photoionization

With ultraviolet, infrared and laser as energy sources, photoionization generates primary ions by direct photoionization or matrix-assisted laser ionization. This method often does not require high voltage, spray solvent or gas to help conduct ionization, and has low power consumption. Besides, a selected reasonable wavelength can ionize the pending substance substantially, reducing the interference of matrix material. The sample can be rapidly gasified and ionized as this technology boasts advantages of high laser resolution, good direction sense and high energy. Photoionization techniques include desorption atmospheric pressure photo ionization (DAPPI)[36], atmospheric pressure laser matrix-assisted desorption ionization (APMALDI)[37,38], atmospheric pressure laser desorption/ionization (APLDI)[39], etc. Additionally, different forms of energy can be coupled in a certain way to combine the advantages of different energy sources, improving the ionization efficiency and analysis performance of the target object. For example, laser ionization can be combined with electrospray ionization technology to improve ionization effect and meet the spatial resolution requirements of the analysis. Such laser ionization methods developed recently include laser-induced acoustic desorption and electrospray ionization (LIAD/ESI)[40], matrix-assisted laser desorption electrospray ionization (MALDESI)[41], and electrospray-assisted laser desorption ionization (ELDI)[42] and so on. 2.4

Thermal ionization

Termal ionization technique uses the energy of high temperature and thermal radiation photons to induce

New advances in ionization technologies over the last five years

Representative ambient ionization techniques developed in the last five years are summarized in Table 1, and some typical ones are briefly introduced. 3.1

Substrate electrospray ionization

Substrate electrospray ionization, as an ambient ionization technology, has developed rapidly in recent years. Through solid phase carrier matrix instead of the traditional capillary, this method features simplicity, convenience and quickness. This kind of technology works out when the sample gathers on the solid phase carrier substrate (such as filter paper[74], toothpicks[75], coating blade[76], glass[77], aluminum foil paper[78], pen point[53], string[79] etc.). Under electric field, on the surface of the carrier substrate with a certain volume of solvent, electrospray is generated for mass spectrometry detection, so as to realize the ambient mass spectrometry analysis of the samples (as shown in Fig.1). Among them, representative ionization technologies mainly include paper spray (PS)[74], wooden tip spray (WTS)[75] and coated blade spray (CBS)[80], etc. This kind of ambient ionization technology has obtained widespread application. For example, paper spray mass spectrometry (PS-MS) can be used to examine drug levels in the blood both qualitatively and quantitatively, and thus has been applied in fields such as food, criminal detection analysis[74]. Also, the advanced paper chip technology[81] can help conduct high throughput analysis of complex samples by combining paper chips with LTP ionization technique. In addition, researchers have developed modified surface of traditional filter paper or wooden toothpick with functional materials in recent years. The surface of paper matrix is

ZHANG Xing-Lei et al. / Chinese Journal of Analytical Chemistry, 2018, 46(11): 1703–1713

Table 1 Summary of the ambient ionization methods developed in recent 5 years Ionization energy

Spray ionization

Electric field ionization (corona/glow discharge, plasma)

Technology

Ref.

2013

[47]

Analysis of bulk samples/animal and plant tissue, urine, milk, blood, etc

Desorption electro-flow focusing ionization (DEFFI)

DEFFI separated the jet charging region from the external environment, analytes were ionized by charged energetic droplets/ cocaine, explosives RDX

2013

[48]

Coated blade spray (CBS)

SPME was used for the separation and enrichment of substances in complex matrix, plasma, urine, etc

2014

[49]

Touch spray (TS)

A needle was used to pick up micro droplets of samples; application of voltage caused field-induced droplet emission/ mouse brain tissue, therapeutic drug, etc

2014

[50]

Laser ablation-liquid vortex capture/electrospray ionization (LVC-ESI)

Three sampling methods: laser ablation spot sampling, laser ablation raster sampling, and laser cut and drop sampling/single cells of Chlamydomonas reinhardtii

2015

[51]

Relay electrospray ionization (rESI)

The ionization is triggered by charge deposition onto the capillary/ phosphopeptides, drugs, etc

2015

[52]

Ballpoint electrospray ionization (BP-ESI)

Samples can be stored in the hollow space in the ballpoint socket, convenient sampling/ amino acids, flavonoids, etc

2016

[53]

Single-probe MS technique (Single-probe)

Extraction of cellular contents; single cell analysis was performed/HeLa cell line

2016

[54]

Membrane electrospray ionization (MESI)

MESI utilized two layers of dialysis membrane, which can be used to determine bacterial aminoglycoside resistance/bacterial

2016

[8]

Substrate-coated illumination droplet spray ionization (SCI-DSI)

2017

[55]

Real-time monitoring of photocatalytic reaction/cyclophosphamide

Fast eruption desorption ionization (FEDI)

The sample was heated and erupted from tube to the atmosphere and analyte ions generated in the process of triboelectrification/ glucose, etc

2018

[56]

Microwave plasma torch (MPT)

Rapid identification of active ingredients in tablets was achieved by adjusting the energy of desorption ionization of the ion source without mass spectrometry

2013

[7]

2013

[57]

2013

[58]

2014

[59]

2015

[60]

VaPI can be switched between transmission mode and laser ablation sampling mode/drug tablets, synthetic nucleobase mixtures Without a supply of carrier or discharge gas; NAI applied high voltage between a nanotip and a metal plate to generate a plasma/caffeine, phenylalanine Efficient for analyzing low/nonpolar organic compounds/polycyclic aromatic hydrocarbons, organometallic compounds, etc A nanotip and the mass spectrometer inlet were used as electrodes, and a piece of coverslip was used as a sample plate as well as an insulating dielectric barrier/ amino acids, pharmaceuticals, etc

2016

[61]

2016

[62]

2016

[63]

2017

[64]

The pulsed infrared (IR) output caused desorption and the desorbed molecules were ionized by a vacuum ultraviolet lamp/aromatic compounds (pyrene, etc) Laser beam triggered desorption and ionization and a spray of liquid droplets deliver the ionized analytes to a mass spectrometer/lysine, HEK cells, etc The object to be measured was photoionized in the CPI device; CPI device was directly connected to the extended capillary inlet of the MS, high ion transfer efficiency to the vacuum of MS was achieved/polar (caffeine) and nonpolar (benzo-[a]pyrene) compounds The fragmentation patterns can be obtained simultaneously by adjusting postionization laser energy/dyes

2015

[65]

2016

[66]

2015

[67]

2018

[68]

Rapid identification of cancer tissue and paracancerous tissue by the aerosols generated during electrosurgical dissection /liver, lung, breast, etc No requirement of voltages, laser beams and spray gases, but just using small size of n-butane flame/fruit peels and vegetable

2013

[69]

2015

[70]

Microwave-induced plasma desorption/ionization (MIPDI) Microfabricated Glow Discharge Plasma (MFGDP) High-power pulsed microplasma jet (HPPMJ) Aerosol flowing atmospheric-pressure afterglow (AeroFAPA) Vacuum-assisted plasma ion source (VaPI) Nanotip ambient ionization (NAI)

Surface desorption dielectric-barrier discharge ionization (SDDBDI) Laser desorption lamp ionization (LDLI) Laser desorption/ionization droplet delivery (LDIDD) Desorption capillary photoionization (DCPI) Laser desorption laser postionization (LDPI) Thermal ionization

Publishing time (year)

Internal extractive electrospray ionization (iEESI)

Carbon fiber ionization (CFI)

Photoionization

Feature/sample

Rapid evaporative ionization (REI) Ambient flame ionization (AFI)

Simple device with relatively high temperature/drug, amino acid etc Low power (4 W); molecule analyzed weights up to 1.5 kDa; simple device/ pharmaceuticals, amino acid, cholesterol, urea, etc The plasma was generated by coupling a microhollow cathode discharge and pulsed high-power supply/ human skin, ibuprofen, etc The analytes in aerosols were ionized by a helium glow discharge plasma/ methanol, oleic acid, etc

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Table 1 (Continued) Ionization energy Thermal ionization Integrated multiple energy forms

Technology

Feature/sample

Flame-induced atmospheric pressure chemical ionization (FAPCI)

A flame was used to directly desorb and ionize the analytes on sample surfaces/drugs tablets, etc

MasSpec Pen

Nondestructive diagnosis of human cancer tissues/breast, lung, etc

Integrated ambient ionization source (iAmIS)

The iAmIS platform integrated multiple ionization techniques providing flexible ionization modes

Publishing time (year)

Ref.

2016

[71]

2017

[72]

2018

[73]

Fig.1 Schematic diagram of (A) substrate electrospray ionization[75] and (B) coated blade spray ionization[92]

transformed by functional materials such as platinum nanoparticles/nanotubes[82], silica[83], zirconia[84], carbon nanotubes[85,86], metal organic frame (MOF) materials[87], polystyrene microspheres[88], trichlorosilane [89] (3,3,3-trifluoropropyl) , etc; and the surface of wooden toothpick is embellished by functional hydrophobic groups (C18), alkaline groups (‒NH2) and acidic groups (‒SO3H)[75,90], to improve selectivity of carrier matrix sampling and ionization efficiency. As a result, fast analysis of trace substance in complex samples can be realized. Furthermore, molecularly imprinted membrane electrospray ionization (MIM-ESI)[91] and CBS[76,92,93] technology are also characterized by selective adsorption of solid carrier matrix, thus improving the selectivity and sensitivity of both methods. 3.2

Internal extraction electrospray ionization technology (IEESI)

Developed on the basis of electrospray extraction ionization (EESI), internal extraction electrospray ionization can make ambient mass spectrometry analysis of chemical components in whole samples[2,47]. As shown in Fig.2, when iEESI is used to analyze the whole sample, the charged extraction solvent is

injected directly into the sample, and the solvent extracts the chemical components inside. Under the electric field, extraction liquid generates electrospray at the front end of the sample, thus achieving direct mass spectrometry analysis of the chemical components inside. Unlike the common technique of ambient ionization of surface sampling, this technique can directly obtain qualitative or quantitative information of the components within plant or animal tissue samples. At present, iEESI-MS has been applied in many fields. For example, in the study of plant metabolism, it can obtain the endogenous metabolite information of plant tissue samples and undertake a quick analysis of multiple plant tissues[2]. In food safety monitoring, this technology can be used to detect various illegal additives in meat products in a quick and sensitive manner[94]. In clinical diagnosis, iEESI-MS can be employed to rapidly differentiate cancer tissues and paracancerous tissues, helping identify cancer lesions[47,95]. In addition, on the basis of the analysis of integral samples of animal and plant tissues, this method can be improved so as to cater for liquid complex sample analysis. That is to say, the samples are extracted with solid phase extraction by using functional materials and the material of the enriched target is prepared into an iEESI-MS integral sample, and then iEESI-MS analysis is conducted. This technology has facilitated rapid MS analysis of polycyclic aromatic hydrocarbons in human urine[96], antibiotics[97] in milk samples and hemoglobin[94] in blood. 3.3

Fig.2 Schematic diagram of iEESI-MS[2]

Single-cell ionization technology

Single-cell analysis has become a research hotspot in the

ZHANG Xing-Lei et al. / Chinese Journal of Analytical Chemistry, 2018, 46(11): 1703–1713

field of analytical chemistry in recent years. The reported techniques cover single-cell fluorescence imaging, single-cell electrochemistry and single-cell mass spectrometry. Among them, single-cell mass spectrometry is targeted as an important research direction for single-cell analysis because of its high sensitivity and high flux. Hence, single-cell ionization technology is undoubtedly a key to single-cell mass spectrometry[98]. At present, ionization methods for single cell mass spectrometry analysis are undertaken mainly by direct extraction of cell contents for nanoESI-MS, followed by ionization and desorption[98]. Specifically, nanoESI-MS is performed by ambient absorption of the liquid in a single cell with a micron-sized capillary tube. The analysis methods mainly include live single-cell video-MS[99], capillary microsampling ESI-MS[100], internal electrode capillary pressure probe ESI-MS[101], induced nanoESI-MS[102], etc. For example, internal electrode capillary pressure probe ESI-MS works as shown in Fig.3A by using the micron (tip diameter 0.2-5 μm) capillary to drain the cellular liquid in cells directly and then conducting nanoESI-MS analysis[100]. Ionization after extraction is mainly achieved by combining liquid-liquid microextraction or solid-liquid microextraction to extract intracellular components after ambient ionization, and general methods include single-probe MS[103], PESI[104,105], surface coated probe (SCP)-nanoESI[106], direct sampling probe (DSP)[107], etc. The methods of desorption ionization for single-cell analysis mainly include DESI[108,109], EASI[110], LAESI[111], LDIDD[66], etc. Figure 3B shows single-probe MS technology. This method uses a dual-channel sprinkler head, in which the extractant is injected into the cell by one channel. The extractant is discharged by another sprayer to conduct nanoESI-MS[103] after liquid-liquid microextraction of the chemical components in the cell. Figure 3C shows the probe electrospray mass spectrometry based on the printed sample. The printed sample is used to get tiny drops containing single cells, which fall to the tip of the probe under the action of gravity for PESI-MS[105]. At present, although single-cell mass spectrometry has been implemented with a number of technologies, the detection sensitivity and spatial resolution of single cells still need to be further improved due to their small

Fig.3

size (at fL to pL level) and large differences in the concentration of different substances within the cells. 3.4

Multifunctional integrated ion source

Integrated ambient ionization source (iAmIS)[72] is an integrated plant containing a variety of forms of ionization energy technology taking advantages of different ambient ionization technologies. The integrated ion source reassembles FAPA, DART, DBDI, LTP, ESI and LDI into the same ion source device (Fig.4). In the analysis of sample, the unique advantages of different ionization source modules can be integrated. According to the properties of the target object, different ion source modules can be selected to directly ionize the sample, which improves the ionization efficiency of the ion source and results in better analytical performance. For example, the iAmIS source can be used to analyze polar and weak polar compounds[72].

4

Outlook

Applicable value of ambient mass spectrometry has been verified after years of development because of its ability of processing complex matrix samples like living organism in situ in a rapid, real-time and on-line manner. Besides, technological advances in this field along with technology diversification, device miniaturization, more functional positioning and quantitative analysis also accelerate the progress of ambient mass spectrometry. However, there are still common issues to be solved. On one hand, researches on ambient ionization theory are not thorough enough. In other words, if the energy and charge transfer mechanism of ambient ionization can be further understood, the ionization device can be optimized and the analytical performance of these technologies can be elevated. On the other hand, industrialization of instruments and equipment needs to be strengthened because it is still hard to employ theory into plants. Limited precision manufacturing conditions along with immaturity of mechanism research restrict the industrialization and mass production of the developed devices. Consequently,

Schematic diagram of (A) capillary microsampling ESI-MS[100], (B) single-probe MS[103], and (C) PESI-MS for single cell mass spectrometry[105]

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[16] Zhang S C, Zhang X R. Scientia Sinica Chimica, 2014, 5: 680–686 [17] Chen H W, Zheng J, Zhang X, Luo M B, Wang Z C, Qiao X L. J. Mass Spectrom., 2007, 42(8): 1045–1056 [18] Chen H W, Hu B, Zhang X. Chinese J. Anal. Chem., 2010, 38(8): 1069–1088 [19] Chen H W, Zhang H, Wang H D, Huang K K, Yuan L. Scientia Sinica Chimica, 2014, 44(5): 789–794 [20] Zheng Q, Hao C. Annu. Rev. Anal. Chem., 2016, 9(1): 411–448 [21] Chen H W, Venter A, Cooks R G. Chem. Commun., 2006, Fig.4 Schematic diagram of iAmIS[73]

42(19): 2042–2044 [22] Haddad R, Sparrapan R, Eberlin M N. Rapid Commun. Mass

only few properly-researched ionization techniques have been combined with mass spectrometer to realize industrialization and miniaturization while most ionizing technologies work out still on the basis of laboratory equipment.

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