Portable Mass Spectrometry System: Instrumentation, Applications, and Path to ‘omics Analysis

Abstract

Mass spectrometry (MS) is an information rich analytical technique and plays a key role in various ‘omics studies. Standard mass spectrometers are bulky and operate at high vacuum, which hinder their adoption by the broader community and utility in field applications. Developing portable mass spectrometers can significantly expand the application scope and user groups of MS analysis. This review discusses the basics and recent advancements in the development of key components of portable mass spectrometers including ionization source, mass analyzer, detector, and vacuum system. Further, major areas where portable mass spectrometers are applied are also discussed. Finally, a perspective on the further development of portable mass spectrometers including the potential benefits for ‘omics analysis is provided.

1. Introduction

Mass spectrometry (MS) is a powerful analytical technique that can reveal both qualitative and quantitative information of the analytes based on their respective mass-to-charge ratios (m/z) and abundances [1, 2]. It has become an indispensable tool in diverse areas including ‘omics analyses, pharmaceutical analysis [3], forensics [4], environmental monitoring [5], and defense [6]. While laboratory-based MS offers tremendous value to many applications, the bulkiness of a standard mass spectrometer, the requirement for peripheral vacuum and electronic systems, and the high acquisition cost hinder the potential of MS analysis for a broader audience. Driven by the goal of expanding the accessibility and applicability of MS analysis, the efforts of miniaturizing MS instrumentation started since the 1970s [7]. The past two decades have witnessed rapid acceleration in the evolution of portable mass spectrometers facilitated by the development of microfabrication techniques, precise machining, integrated circuits, and improved tools for computational modeling [8–11]. With the expansion of MS users, the demand of applying MS analysis to new scenarios and new locations also promoted increased investment in developing portable mass spectrometers [12–14].

In 2016, Cooks and coworkers presented a comprehensive review on both the instrumentation and applications of portable mass spectrometry systems [15]. In recent years, several excellent reviews focusing on various aspects of portable mass spectrometers have been presented [16–20]. This review aims to provide a comprehensive summary of recent progress in both the instrumentation and applications of portable mass spectrometers and our perspective on their connection to ‘omics analyses. For the instrumentation section, we present key components of a portable mass spectrometer including ionization source, mass analyzer, detector, and vacuum system, and highlight the recent developments in these areas. Following the instrumentation, we discuss the present and potential applications of portable mass spectrometers in space exploration, environmental monitoring, forensic analysis, defense, and clinical applications. Finally, we provide a perspective on the future development of portable mass spectrometers and potential benefits of portable MS for ‘omics analyses. It should be noted that in this review, we use the term “portable” to represent mass spectrometers that are compact and smaller than standard mass spectrometers. Strictly speaking, many of the mass spectrometers discussed here are “transportable” not “portable”, but they still represent significant reductions in size and power compared to standard instruments.

2. Instrumentation of portable mass spectrometers

2.1. Sampling Interface and Ionization

To be detected by MS, analytes must carry charge(s) in the gas phase before entering the mass analyzer. The process of adding charge(s) to the analytes is called ionization [21]. Every mass spectrometer must be equipped with at least one ionization source to function. To date, many strategies have been developed to accommodate the ionization of a wide variety of analytes and samples. The ionization process determines which analytes can be detected and how the samples are ultimately introduced to the mass spectrometer. Depending on the ionization source, different sampling interfaces and procedures are necessary. For portable mass spectrometers, the choice of ionization source and sampling interfaces is of great importance as the availability of sample processing and introduction techniques are often limited. Although many laboratory MS ionization methods can be adopted by portable mass spectrometers, most must be further modified to accommodate the special requirement and limitation of portable mass spectrometers. In this section, we discuss the major ionization strategies that have been adopted by portable mass spectrometers and the recent developments in these strategies.

2.1.1. Electron ionization

Electron ionization (EI, also called electron impact ionization in early literature), was one of the most commonly used ionization methods for MS analysis. It utilizes the interaction between electrons and gas phase molecules to ionize the molecules [22, 23]. EI often generates fragment ions during the ionization process. With the development of softer ionization techniques, EI has become less favored for many applications. However, EI remains an attractive ionization strategy for portable mass spectrometers. The ionization unit for EI is relatively simple and compact. This allows easy integration between the ionization source and the ion optics, providing a relatively simple frontend unit for portable mass spectrometers. In addition, its propensity to produce fragment ions can facilitate compound identification. The resolving power for portable mass spectrometers is often limited. Therefore, using fragmentation for compound identification is necessary. To date, EI has been adopted as the ionization source by several commercial portable mass spectrometers, including portable GC-MS instruments [24]. Additionally, portable mass spectrometers equipped with EI have been demonstrated for rapid analysis of small organic molecules, and volatile thermally stable compounds. However, a major limitation for EI is its inability to study non-volatile molecules and thermally labile compounds.

In recent years, modifications to the standard EI system to further improve the performance of EI, especially for portable systems, have been reported. First, several groups focused on the filament material to improve the electron generation performance. Particularly, carbon nanotubes (CNTs) were studied extensively for the EI process. CNTs have the advantages of high power efficiency, high current density, and stable performance for long-term usage, which are attractive features for field portable systems. The use of miniaturized CNT filaments has demonstrated increased ionization efficiency and reduced power consumption [25–27]. Recently, Radauscher et al. [28] used CNT as the cold cathode emitter and low temperature co-fired ceramic (LTCC) to make a scaffold for the whole system, which reduced its power consumption and longevity (Figure 1a). These studies showed that the use of CNT as the filament material is an effective means of improving the EI source for portable applications with improved ionization efficiency and reduced power consumption.

Figure 1.

a) EI source in a miniature mass spectrometer using CNT as the filament material. Adopted from [28]. Copyright 2017 International Journal of Mass Spectrometry. b) Paper cone spray ionization coupled to a MassTech MT Explorer 50. Adopted from [45]. Copyright 2022 International Journal of Mass Spectrometry. c) The low temperature plasma ionization source for potable mass spectrometers. Adopted from [62]. Copyright 2016 Forensic Chemistry. d) Schematic of low-pressure dielectric barrier discharge ionization source. Adopted from [64]. Copyright 2013 American Chemical Science.

In addition to developing new filament materials, research efforts have also been made to optimize and reduce the size of the EI unit [29]. Li et al. [30] designed a miniature EI source which employs two identical rhenium–tungsten filaments featuring longer lifetime and improved stability with a power consumption of 15 W. Meng et al. [31] developed the ionization chamber with a dimension of 12 × 12 × 7 mm³ and an exit slit that is 1 mm wide. Yan et al. [32] reported that increasing the exit slit to 1.5 mm further improved the ionization efficiency.

2.1.2. Electrospray ionization (ESI)

ESI is a soft ionization technique for liquid samples that generates ions by applying a high voltage to a liquid to produce a spray of charged droplets. It is the most popular ionization source for benchtop mass spectrometers due to its excellent performance, capability of ionizing a wide range of molecules, and compatibility with various separation techniques [33]. It has also been adopted for portable mass spectrometers. Keil et al. [34] coupled an ESI source with Mini 10 mass spectrometer using a customized high voltage supply and nitrogen nebulization gas. Although it is feasible to use a standard ESI source for portable mass spectrometers, the need for nebulization gas and flow control systems complicates the MS operation and increases the bulkiness of the system. Using high pressure nebulization gas also increases the burden of the vacuum system, which may lead to a decrease in ion detection performance. Therefore, a standard ESI source is typically not a popular choice for portable mass spectrometers.

Practically, nanoelectrospray ionization (nESI), using smaller emitter tips (typically less than 50 μm), is a preferred option for portable mass spectrometers, because nESI does not require nebulization gas and offers improved ionization efficiency. It has been coupled with various portable mass spectrometers. Ren at al. [35] combined the plug flow microextraction with nESI for rapid analysis of biofluids using a quadrupole mass spectrometer. By controlling the movement of the sample and extraction plugs, the extraction process was turned on and off on demand to achieve real-time monitoring of amino acids in a urine sample, HIV therapeutic drug in whole blood, and nonpolar pesticides in an oil sample.

2.1.3. Paper spray ionization (PSI)

While nESI has many advantages for portable mass spectrometers, its robustness is not ideal for many field applications as the emitter can be easily damaged or clogged, affecting the reproducibility and quantification performance. Ouyang et al., [36] reported a simple ESI setup based on paper substrates, termed paper spray ionization (PSI), for MS analysis in 2010. Typically, solid or liquid samples can be loaded onto the surface of paper with a macroscopically sharp point. Analytes are transported to the sharp point by solvent wicking in a porous cellulose or semi-fiber, and ions are generated by a high electric voltage. PSI is a simple, rapid, low cost, and flexible electrospray platform. Therefore, it has become a popular ionization technique among portable mass spectrometers. It has been used in many Mini-series portable mass spectrometers for dry blood spot analysis, and detection of therapeutic drugs and synthetic cannabinoids in blood samples, fungicides on fruits, and alkyl quaternary ammonium salts in a complex oil matrix [37–43]. In addition to the standard PSI setup, the geometry and the material of the paper substrate can be tailored to offer optimal performance for specific applications. For example, instead of using a paper tip with a planar triangle shape, paper cone spray ionization (PCSI) employed a triangular-pyramidal paper substrate [44]. In addition to working as a sample container, this three-dimensional paper cone also served as an analyte transport channel, in situ solid-liquid extraction chamber, and an electrospray emitter. Brown et al. [45] introduced a 3D printed PCSI source combined with a MT Explorer 50 portable mass spectrometer for the rapid, on-site detection of substantial solid compounds and trace analytes in solid matrices (Figure 1b). The 3D printed cone structure is rigid enough to scoop bulk samples while maintaining the sharp tip that is necessary for efficient ionization. This automated 3D-PCSI-MS system successfully identified the cannabinoids doped into commercial smoking tobacco, chemical warfare agent simulants on fabric, and per- and polyfluoroalkyl substances in soil. Instead of using paper, Pulliam et al. [46] used a cutting leaf as ESI substrate for ionizing endogenous phytochemicals directly from the plant material. The portable equipment was demonstrated for rapid herbicide detection for grass blades from a lawn.

2.1.4. Desorption electrospray ionization (DESI)

DESI is the first reported ambient ionization technique that directly ionizes samples under atmospheric conditions [34]. Since then, numerous ambient ionization techniques have been developed [47]. DESI offers unique advantages for combing with portable mass spectrometers as minimal sample preparation and rapid analysis are desired for portable MS analysis. DESI generates primary microdroplets of solvent to which impact at the sample surface, where analytes are extracted and ionized. DESI can be performed at ambient capillary temperatures, with 3 kV spray voltage and 80~120 psi nebulization gas flow. DESI has been coupled with miniature ion trap mass spectrometers for various applications including in situ detection of agricultural chemicals, active ingredients in pharmaceutical preparations, reaction monitoring, forensic analysis, and explosives and chemical warfare agent simulants from different surfaces [34, 48, 49]. Additionally, herbicides on different surfaces ranging from leaves, fruits or vegetables, alkaloids in plant tissues, explosives, and air monitoring were all investigated in their natural state. However, for an instrument employing DESI, high gas and solvent flow would affect its usage in portable MS, resulting in high requirements on the pumping capacity of the minimal vacuum pump system. Additionally, the requirement of a nebulization gas would affect the spatial and weight factors for any portable MS application.

2.1.5. Photo ionization (PI)

PI sources typically utilize a vacuum ultraviolet (VUV) light such as that provided by discharge lamps, excimer lamps, or synchrotron radiation to ionize volatile analytes. Mass spectrometric techniques based on PI are well-suited for the detection of organic molecules without promoting ion fragmentation, the online analysis of complex gas mixtures and the real-time monitoring of online analytical reactions due to the high sensitivity, selectivity, and inherent softness of PI [50]. Xue et al. [51] used single photo ionization (SPI) with a digital linear ion trap mass spectrometer to detect volatile organic compounds (VOCs) including benzene, toluene, xylene, and monochlorobenzene with minimal background interference. Huang et al. [52] combined VUV lamp-based SPI with photoelectron ionization (PEI) for a portable time-of-flight (TOF) mass spectrometer for online gas monitoring. The combined ion source was able to ionize analytes having a large range of ionization energy. The total power consumption of this ionization source was 1.5 W with the VUV lamp, which is ~10 times lower than the traditional filament-based EI source. The performance of the portable TOF instrument achieved a mass resolution of 1100 for SO₂, and a LOD of 0.005 ppm for benzene, toluene, and xylene. Wu et al. [53] employed a dual ionization source including EI and PI for the analysis of gasoline samples. The added EI source can provide structural information associated with gasoline from different classes. A pulse amplifier was applied to control the VUV lamp to avoid the photoelectric effect for strong noise signals and to extend the lifetime of the detector. Atmospheric pressure PI (APPI) could potentially further simplify the ionization process with an efficient design to introduce UV photons. Capillary APPI (cAPPI) was reported to improve ion transmission efficiency using a heated capillary having a confined window through which UV photons are allowed to enter the source [54].

2.1.6. Atmospheric pressure chemical ionization (APCI)

APCI is another widely used ionization method for standard mass spectrometers, especially for non-polar compounds that are difficult to ionize by ESI. APCI has also been adopted by portable mass spectrometers for forensic, clinical and environmental sciences because of its simplicity, sensitivity, and softness [55–57]. For example, Heaney et al. [58] combined the APCI ion source with Advion Expression CMS to study volatile organic compounds from exhaled breath samples. The standard APCI ion source was modified to incorporate a heated Venturi pump to provide a stable suction pressure for sample injection. The breath sample was then transported from a mask to the APCI ion source in less than 1 s and reacted with the APCI gas under 5 kV corona discharge voltage. The system demonstrated real-time monitoring of VOCs including menthone, and acetone in exhaled breath samples, which are potential biomarkers for Type I diabetes. A LOD of 51 ppt was demonstrated for menthone, which is comparable to results achieved by commercial bench-top mass spectrometers.

2.1.7. Plasma based ambient ionization

Plasma-based ionization is another ambient ionization method that has been used by portable mass spectrometers. It relies on an electrical discharge typically formed between two electrodes to generate ions in the gas phase [59]. Due to its straightforward setup, rapid analysis, and minimum sample preparation requirements, it is suitable for many field portable applications [60]. Depending on the source setup, several plasma-based ionization sources have been demonstrated for portable mass spectrometers including plasma-based direct analysis in real time (DART), low temperature plasma (LTP), and dielectric barrier discharge ionization (DBDI), and glow discharge electron impact (GDEI). Brown et al. [61] reported the coupling of DART with a MT Explorer 50 mass spectrometer for the detection of illicit drugs such as 4-Bromomethcathinone, black tar heroin, and 4-methylethcathinone at the site of storage. A handheld, wireless LTP source coupled with a miniature ion trap mass spectrometer has been implemented to detect a gaseous, liquid, or solid samples without any sample preparation [62] (Figure 1c). The LTP source is compact and low power consumption. It can be powered by a 7.4-V Li-polymer battery and continue to operate for ~8 h in an integrated chamber having a weight less than 0.9 kg [63]. Kumano et al. [64] combined discontinuous sample gas introduction with low pressure DBDI for effective ionization (Figure 1d). The barrier discharge was induced using two discharge electrodes driven by 3 kV and 10 kHz AC voltage, generating a low-pressure plasma for ionizing molecules in the gas phase. This DBDI source was demonstrated to detect controlled substances in liquid samples at 1 ppm level. GDEI has also been utilized by portable mass spectrometers. The performance of GDEI source was evaluated with Mini-series systems (Mini 10 and 11) [65, 66] and a microelectromechanical system (MEMS) mass spectrometer [67].

2.1.8. Matrix-assisted laser desorption/ionization (MALDI)

MALDI is an ionization method that employs a laser to desorb analytes from a matrix to produce ions with little fragmentation even for large molecules, such as DNA, proteins, polysaccharides, polymers, dendrimers, and other macromolecules. MALDI has been adopted by commercial compact mass spectrometers including the Bruker Microflex LRF and SHIMADZU MALDI mini-1. Since MALDI requires sample preparation and loading samples into a vacuum chamber for high ion transmission efficiency, it can complicate the operation of portable MS analysis [68, 69]. Nevertheless, MALDI has been combined with a portable TOF mass analyzer for detecting both small molecules and peptides from protein digests in the 1990s [70, 71]. To eliminate the requirement of vacuum for sample introduction, atmospheric pressure MALDI (APMALDI) has been reported. For APMALDI, several approaches have been reported to improve the transmission efficiency of ions including the creation of ions on-axis with an aperture/tube by positioning the laser beam directly on-axis with such an aperture, as well as the utilization of electrical focusing to push ions into the aperture [72]. Currently, APMALDI is compatible with the MassTech MT Explorer instrument for the direct analysis of untreated samples at atmospheric pressures using a laser output frequency up to 10 kHz.

2.1.9. Hyphenated techniques

Coupling MS detection with various separation techniques including liquid chromatography (LC), gas chromatography (GC), and capillary electrophoresis (CE) has become a standard approach for analyzing complex samples. The added separation capability provides increased peak capacity which couples multiplicatively with the MS separation to provide enhanced peak capacity (ability to resolve individual mixture components) [73, 74]. Therefore, hyphenated techniques can improve the capability of portable mass spectrometers in analyzing and extracting more information from complex samples. Among the separation techniques, GC is the most mature to be coupled with portable mass spectrometers due to the simplicity and low-pressure requirement. That is, for a GC-MS instrument, EI is the major ionization source [75]; the production of ions under high vacuum conditions is highly suited for their interrogation by the mass analyzer as this process also occurs under high vacuum conditions. When coupled with portable mass spectrometers, miniaturizing GC systems should consider the heat requirements and the gas requirements that a specific portable MS system can sustain. A column with a diameter of 50 μm i.d and a length of 3 m, presented a fast separation, and the low gas flow used for this system allowed for the decreased vacuum requirements of the portable MS system [76]. Modification of the column size (e.g., diameter and length) were carried out for low vacuum and weight constraints of the MS system [77–79]. To date, multiple companies have developed a commercial miniature GC system, including Torion T-9 (14.5 kg and 38 × 39 × 23 cm), Griffin G510 (16.4 kg and 34 × 34 × 40 cm), Hapsite ER (19 kg and 46 × 18 × 18 cm) and 990 Micro GC System (7.3 kg and 28 × 14.5 × 33 cm).

While portable LC has been reported, a complete portable LC-MS system remains to be demonstrated [80–82]. Currently, several compact benchtop mass spectrometers are demonstrated to be coupled with LC for analyzing complex samples, which holds great potential for ‘omics analysis with low cost. For example, the Microsaic 3500 MiD instrument has been coupled with HPLC, which demonstrated sensitivity that is comparable to that of a traditional bulk MS system in the selected ion monitoring (SIM) mode, enabling the detection of known components at trace levels (ppm) [83, 84]. Clinical assays for measuring vitamin D2/D3 have been demonstrated using a portable MS system (Advion Expression CMS) in conjunction with HPLC separation [85].

2.2. Analyzer

The mass analyzer is the major component of a mass spectrometer that separates ions based on their m/z values. The performance and working characteristics of a mass spectrometer are entirely dependent on the mass analyzer [86, 87]. To develop portable mass spectrometers, a key step is to miniaturize mass analyzers while minimizing the loss of performance (sensitivity, mass accuracy, and resolution). To date, many types of mass analyzer have been miniaturized to reduce the overall footprint of portable mass spectrometers [88–90]. In this section, we discuss the mass analyzers that have been adopted by portable mass spectrometers and the recent development of miniaturized mass analyzers.

2.2.1. Ion trap (IT)

For portable mass spectrometers, the ion trap is the most popular choice of mass analyzer to date. Compared with other mass analyzers, the ion trap is typically smaller and more compact, which is desired for miniaturized systems. Since the mass resolution of ion traps does not depend on the scale of the length of the trap, it suffers less performance degradation with miniaturization. More importantly, the ion trap can operate at higher pressures thereby reducing the demand for the vacuum system, which is particularly important for portable mass spectrometers. To date, both 2D and 3D ion traps have been miniaturized. The first ion trap that was developed was a 3D quadrupole ion trap (QIT) with hyperbolic geometry that was initially used solely as a mass filter and not a mass analyzer [91]. While the QIT was effective, the hyperbolic geometry of the electrode makes it difficult to miniaturize. A cylindrical ion trap (CIT) was later demonstrated to be a viable setup for an ion trap mass analyzer [92, 93]. For miniaturized ion traps, the CIT has become a favored option due to its simple geometry which facilitates the fabrication of small electrodes. CITs with radii down to tens of μm have been fabricated using microfabrication techniques [94]. Based on the theoretical analysis by Goeringer et al. [95], the resolution for ion traps is proportional to the driving frequency and inversely proportional to the trap pressure. Thus, increasing the driving RF frequency is a practical way to improve the performance and/or reduce the requirement for high vacuum conditions. Practically, to employ higher RF frequency, the driving voltage must be reduced, which can be achieved by further decreasing the size of the ion trap. Kornienko et al. [96] reported a miniaturized CIT (r=0.5 mm) that achieved a m/z range of ~400 and FWHM of 0.25 m/z, which was driven at frequency of 5.8 MHz and RF voltage of 195 V. In 2016, Ramsey and coworkers [97] further increased the driving frequency to ~10 MHz to allow mass analysis at a pressure >1 Torr of helium, achieving peak widths ~ 1 m/z for volatile organic compounds (Figure 2a). >1 Torr operation pressure enables the use of smaller vacuum pumps, which may significantly decrease the overall footprint of a mass spectrometer. A later study also reported successful mass analysis at a pressure just under 1 Torr of ambient air using high frequency CIT but with decreased mass resolution [98]. The limitation of miniaturized CITs is the lower trapping capacity compared to larger traps, leading to low performance and sensitivity. Increasing the number of CITs or fabricating CIT arrays has been explored to increase the trapping capacity, but a limited gain in performance and a significant increase in complexity and machining precision complicates the wide adoption of these methods [92].

Figure 2.

Mass analyzers for portable mass spectrometers. a) A microscale CIT for high pressure MS. Adopted from [97]. Copyright 2016 Analytical Chemistry. b) Configuration of a LIT-based portable mass spectrometer. Adopted from [102]. Copyright 2019 Royal Society of Chemistry. c) Miniature TOF mass spectrometer: MULTUM-S II. Adopted from [10]. Copyright 2010 American Chemical Society. d) Miniature magnetic sector mass analyzer. Adopted from [124]. Copyright 2016 Journal of The American Society for Mass Spectrometry.

As opposed to focusing ions to a central point in the 3D ion trap, 2D ion traps confine ions in two dimensions allowing one free dimension for ion translocation thereby increasing the trapping capacity [99, 100]. Several geometries have been reported for miniaturized mass spectrometers including the linear ion trap (LIT) [101–103], rectilinear ion trap (RIT) [9], and toroidal ion trap (TIT) [12]. Due to its simplicity and increased trapping capacity, the LIT has been used as the mass analyzer in several portable mass spectrometers. Xu and coworkers [101, 104] optimized two-stage pumping system to develop a LIT-based miniaturized mass spectrometer. To further improve the performance of the system, a 3-stage vacuum system and an ion funnel were developed with a continuous atmospheric pressure interface. A resolving power up to 4060 was achieved at m/z 609 using a scan rate of 495 Da/s; remarkably, unit mass resolution was achieved at a scan rate of 6000 Da/s. The LIT operated at 1 mTorr pressure and was driven at 1.028 MHz and ~2800 Vpp. When combined with a discontinuous sub atmospheric pressure interface, Huo et al. [105] achieved a mass resolution of 2800 at m/z 837 with a scan rate of 1015 Da/s. Liu et al. [102] reported the adoption of dual LIT for a portable mass spectrometer. The dual LIT facilitated MS/MS and MRM analyses and even achieved MS⁴ for reserpine using beam-type collision-induced dissociation CID. (Figure 2b) Later, the dual LIT analyzer was demonstrated to perform ion mobility separation for a portable mass spectrometer [106].

Another 2D ion trap design is RIT, which has been adopted by Mini-series portable mass spectrometers [107]. The RIT creates a quadrupolar RF trapping field in the xy plane using 2 pairs of rectangular electrodes. The trapping capacity can be extended in the z direction using a pair of z electrodes. Thus, the power consumption decreased as the miniaturization of the ion trap dimension, whereas the trapping capacity was compensated in the z dimension. Based on the RIT configuration, unit mass resolution and a mass range ~1000 m/z have been achieved with a power consumption of ~35–65 W. TIT is another design for increasing the trapping capacity of an ion trap as reported by Lambert et al. [108] It achieves increased trapping capacity by allowing a circular ring to trap ions. A miniaturized version of the toroidal ion trap was reported in 2006 [109]. The miniaturization decreases the required voltage from ~15 kV to ~1 kV. The toroidal ion trap was operated at a RF frequency of 1.9 MHz and voltages of 700–1200 V_pp voltages. Based on the toroidal ion trap, a hand-portable GC-MS system was later reported by Contreras et al. [110] for detecting chemical warfare agents.

2.2.2. Quadrupole (Q) analyzer

The quadrupole mass analyzer is another popular option for miniaturized mass spectrometers due to its simplicity, relatively small dimensions, and low cost. It has been adopted by many small bench-top mass spectrometers, especially for usage requiring the coupling of chromatographic separations. For portable mass spectrometers, the stringent vacuum requirements of the mass analyzer can be reduced as the quadrupole is miniaturized because of the reduction in mean free path. The key component of a quadrupole analyzer is the 4-rod electrodes that are precisely aligned. The typical diameter and length of each rod electrode is ~6 mm and ~100 mm, respectively [111], whereas miniaturized quadrupole analyzer typically has a radius of 0.5 mm and length of 10–30 mm [112, 113]. The development of MEMS fabrication techniques has enabled smaller and more integrated quadruple analyzer. Malcom et al. [114] reported a MEMS quadrupole mass filter with ~0.5 mm diameter and 30 mm long steel rod electrodes. The electrodes were anchored and aligned using microfabricated silicon structures. Based on the microfabricated quadrupole analyzer, a portable mass spectrometer weighing 14.9 kg was developed and achieved a 5 ppm LOD using a 15 s sampling time. Wright et al. [115] reported the first miniature triple quadrupole mass spectrometer. The ion source, quadrupole ion guides and ion filters and the vacuum interface were all micro engineered. The triple quadrupole system operated at a pressure of ~0.1 mTorr and was coupled with HPLC separation and included multiple reaction monitoring (MRM) capability.

2.2.3. Time of flight (TOF) analyzer

The TOF analyzer is a conceptually straightforward method for measuring the m/z of ions based on their flight time in a field-free drift region. The mass resolution for a TOF analyzer is proportional to the flight path of the ions. Therefore, for portable mass spectrometers, reducing the size of a TOF analyzer leads to a decrease in analyzer performance. Despite the challenges, the simple setup and unique high m/z range advantage of a TOF analyzer has led to the development of miniaturized TOF analyzer. The first miniaturized TOF analyzer (Tiny-TOF) was reported in 1995 by Bryden et al. [70], at Johns Hopkins Applied Physics Laboratory. The TOF analyzer was 20 cm long and weighed 500 g. Utilizing the end-plate reflectron setup, the effective mass resolution was improved for miniaturized TOF analyzers. Cotter et al. [116] demonstrated a mass range up to that required for 3000 amu peptide and oligonucleotide analysis. Shimma et al. [10] reported a high-resolution miniature TOF (MULTUM-S II) using a multiturn TOF leading to an infinite flight path (Figure 2c). In the multiturn TOF, high and low resolution can be observed based on how complete the cycle is. The resolution was shown to be greater than previously achieved for MULTUM-S with reported LODs in the low ppb range [117]. MEMS fabrication techniques have also been used to develop integrated microTOF analyzer [118]. Vigne et al. [119] reported a MEMS TOF that integrated an ionization chamber, electrostatic lenses, an orthogonal injection port, and a reflectron with a footprint of 1*1cm. The system was demonstrated for gas flow analysis by detecting sub-100 ppm alkane fragments in helium. In addition to improving effective flight path, minimizing the initial temporal and spatial distribution of ions is desired, which requires optimal coordination with the ionization source. Ionization methods that can generate large amounts of ions in short periods of time are desired. Typically, laser pulse-based ionization methods (e.g., MALDI) work well for a TOF analyzer. For portable mass spectrometers, EI and cold electron sources [120] that are optimized to generate large number of ions in short time have also been coupled with TOF.

2.2.4. Magnetic sector analyzer

The magnetic sector analyzer is the earliest mass analyzer that is based on the deflection of ions in motion by a magnetic field. While magnetic sector analyzers feature high resolution and high dynamic range for conventional mass spectrometers, its space dependent performance nature and the requirement for a high vacuum have limited its adoption by portable mass spectrometers. Therefore, compared with the above-mentioned mass analyzers, the current adoption of magnetic sector analyzers for portable MS work is diminished. Sinha et al. [121] reported the first miniaturized magnetic sector analyzer for coupling with portable GC instrument in 1991. here, the mass spectrograph type detection allowed high rate of ion detection rate in order to capture the GC chromatograph. The miniaturization of the analyzer was enabled by the development of powerful Nd-Fe-B type permanent magnet [31, 32, 122, 123]. The mass range achieved was 40–240 m/z. Later reports have described strategies for improving the performance of the magnetic sector analyzer including the use of a double focusing setup and optimization of the ion optics and the magnetic field uniformity. In recent years, the development of array detectors for optical imaging and computational imaging opened a new avenue for improving magnetic sector analyzer. Russell et al. [124] and Vyas et al. [125] employed a coded-aperture method to improve the throughput of magnetic sector analyzers without sacrificing mass resolution. (Figure 2d)

2.3. Detector

An ion detector in a mass spectrometer converts a current of mass separated ions into measured electronic signals. Common MS detectors including Faraday cups (FC), electron multipliers (EM), microchannel plates (MCPs), and a focal plane detector have all been adopted by portable mass spectrometers.

To date, EM is the most common detector used in portable MS system for quantitative analysis due to their high sensitivity and good stability in terms of signal amplification and low noise production [9, 31, 38, 62, 92, 102, 123, 126–128]. MCPs, sharing similar operation principles with EM, can provide an image of the particle distribution that EM cannot. At the same time, multiple plates stacked together in the chevron configuration can generate strong signal amplification with high spatial information [29, 129–131]. The drawback of EMs and MCPs for portable systems is the usage of a high voltage, resulting in the requirement for a high-voltage power source. The plate is also easily contaminated by the ions, which may affect the lifetime of the detectors, especially under the low vacuum conditions that are used by portable mass spectrometers.

A FC detector has also been applied in a portable mass spectrometer system due to its simple structure, robustness, and high flexibility to integrate with the mass analyzer. Blasé et al. incorporated a multi-Faraday cup collector as their detection element. By using an array of five faraday cups, data for multiple ion beams were collected simultaneously. Simultaneously monitoring multiple ion beams enabled the detection of isotopic ratios of analytes [132]. Tang et al. [133] described a low noise Faraday cup and implemented it in a miniaturized mass spectrometer. This design included a circuit board with a metal disc to collect ions and a shielding shell that served as a preamplifier to inhibit electrical interferences. An additional mesh grid placed between the ion collection disc and exit aided in the suppression of secondary electrons produced by ions impinging on metal surfaces. The main disadvantage of a FC detector is the limited sensitivity compared to EM and MCP types. The FC itself offers no gain for the ion signals. Amplification must be carried out in the circuitry that gauges the current. The focal plane detector is typically used with magnetic sector analyzers, which consists of three components: a microchannel plate, a phosphor screen, and an additional detector array such as a charge-couple device (CCD) array system or other array detectors [132].

2.4. Vacuum system

The vacuum system is the key limiting factor in achieving high performance and small footprint portable mass spectrometers. The performance of a mass spectrometer is highly dependent on the vacuum level of the system. However, achieving high vacuum conditions is not a trivial task. For conventional mass spectrometers, multi-stage pumping system including mechanical and turbomolecular pumps are often employed to maintain the desired vacuum level. For portable systems, the pumping capability and the stability and sensitivity of the entire system must be balanced due to the limitation in power and system footprint requirements. We have discussed efforts in adapting ionization methods, mass analyzers, and detection schemes for low vacuum condition in the above sections. Here we focus on the development of vacuum systems for portable mass spectrometers.

Due to limitations in suitable vacuum systems for portable mass spectrometers (see below), the interface between atmospheric pressure and vacuum regions must be carefully designed. A continuous atmospheric pressure interface (CAPI) is widely used in standard mass spectrometers and easy to implement [134]. However, it increases the burden on the vacuum system. When the vacuum capability is limited, the performance of the mass spectrometer will be affected. To overcome this limitation, the discontinuous atmospheric pressure interface (DAPI) was introduced, which consists of two stainless steel tubes, silicone tubes and pinch valves. The DPAI effectively separates the vacuum from the atmospheric pressure. The injection port is always closed except for sampling, so the vacuum can reach an optimal level without the need of increasing pumping capacity. A wide range of ionization methods have benefited from the DAPI interface [63, 127, 135–137].

One strategy to reduce the size of the vacuum system is to separate the backup pump from the main system. In this case, the backup was first used to bring down the system pressure, and a portable, low-power ion pump was used to maintain the vacuum for mass spectrometer operation [138]. A major downside of such a mass spectrometer is that sample loading is limited to pulsed injection to prevent over pressurizing the system. Currently, most portable mass spectrometers are still equipped with a two-stage vacuum system that is a scaled-down version of standard mass spectrometers. In portable systems, diaphragm pumps are used for the backing stage in place of rotary vane pumps usually used in conventional mass spectrometers. The number of diaphragm pumps is a key factor to determine the size of the mass spectrometer. This type of pump can provide pressures up to 2 Torr. On the other hand, turbo-molecular pumps are still the only dependable option for achieving high vacuum in miniature instruments. Two types of commercial turbo pumps are commonly used: the ATH 31 series (1.2 kg, 30 liters/s; manufactured by Alcatel Vacuum Technology Corporation) and the Pfeiffer TPD 011 (2 kg, 10 liters/s; manufactured by Pfeiffer Vacuum, Inc.TM). The combination of a two-stage diaphragm pump and the turbo pump has been used in many miniature mass spectrometers [9, 139–144]. Chen et al. [145] reported a 5-pump vacuum system to achieve fast scan speeds with DAPI interface (Figure 3a). Two backup pumps (KnF N 84.3 diaphragm pump and Creare 350g scroll pump) and three high vacuum pumps (Creare 130 g drag, Creare 550 turbo pump, and Pfeiffer HiPace 10 turbo pumps) were used, which has a combined weight of 3.8 kg. The signal intensity and stability for DAPI interface was improved by using a lengthy, thin tube to extend the connection between the high-vacuum pump and the back pump. Li et al. [102] reported a lightweight three-stage vacuum system for a CAPI-equipped linear ion trap mass spectrometer (Figure 3b). In this design, a back pump with a pumping speed of 27 L/s and a high vacuum turbo-molecular pump with a pumping speed of 60 L/s were combined. To supply the turbo-molecular pump and the vacuum manifold with the ideal pressure, a scroll pump with a pumping speed of 20 L/min was employed. The three-stage vacuum system allowed smooth pressure transition from atmospheric to 0.5 mTorr while using CAPI. In addition to the conventional pumping scheme, alternative strategies that can miniaturize the whole pumping system have also been explored including putter-ion pumps, and Knudsen pumps [146–149]. Although proof-of-concept has been demonstrated for MS applications, these systems have not been widely adopted by commercial portable mass spectrometers due to the limitations in performance.

Figure 3.

Vacuum systems for portable mass spectrometers. a) A 5-pump vacuum system for a portable mass spectrometer. Adopted from [145]. Copyright 2015 Journal of The American Society for Mass Spectrometry. b) A 3-stage vacuum system for portable LIT mass spectrometer with CAPI. Adopted from [102]. Copyright 2019 Royal Society of Chemistry.

2.5. Commercial portable MS systems

Currently, many portable mass spectrometers are available on the market that integrate the above-mentioned individual components to a compact standalone system. Table 1 compares the major specs of portable mass spectrometers that are currently available on the market.

Table 1.

Comparison of commercial portable mass spectrometers

Name	Vendor	Ionization	Analyzer	Mass Range	Resolution	Weight (kg)	Dimensions (cm)	Power Source	MS/MS	Reference
Expression CMS	Advion	API; APCI; EI.	Q	10–2000	R = 0.5 – 0.7	32	28 × 66 × 56	N/A	YES	[58, 150, 151]
cheMSense600™	Griffin Analytical Technologies, Inc.	EI	CIT	425	Unit Mass Resolution	25	44.5 × 48.3 × 26.4	110–240 VAC or 24 VDC	YES	[152]
3500 MiD	Microsaic Systems	ESI, API.	Q	<800	NO	27	N/A	220–300 W	N/A	[83]
4000 Mid	Microsaic Systems	ESI, API.	Q	50–800	R=0.7 amu	32	N/A	250–300 W	NO	[153]
4500 MiD	Microsaic Systems	ESI	TQ	50–1400	R = 0.7 amu	32	55 × 35 × 25	250–300 W	YES	[154, 155]
Guardion-7™	Torion Technologies, Inc.	EI	TIT	50–500	R = 270 (at m/z 222)	12.7	47 × 36 × 18 cm	80 W (100–120 VAC or battery DC)	YES	[110]
MALDImini-1	SHIMADZU	MALDI	Digital-IT	650– 70000	N/A	25	268 × 385 × 320	AC 100 to 240 V, 50/60 Hz, 960 VA	YES	[156]
MT Explorer 50	MassTech	ESI; MALDI; APCI.	3D-IT	35–2500	R= 6000 (at 2000 Da)	34	30.5 × 43 × 51	500 W (AC/DC Line Power; 115, 220 V AC and/or 28 V DC)	YES	[45, 61]
MT Explorer 30	MassTech	ESI; nESI; sESI; APCI; MALDI.	3D-IT	30–2000	R = 0.5 amu	16.7	20.3 × 30.5 × 33	AC and DC (battery) power	YES	[157]
Mini 10, 11, 12, S	Purdue University	DAPI (MIMS, GDEI, APCI, ESI, DESI, LTP)	RIT	700/1500/900/1000	R=700/R=750/R = 500 (m/z 281)/R= 1–2 amu	10/8.5/25/10	32 × 22 × 19/22 × 12 × 18/50 × 56 × 42/30.5 × 29.5 × 12.5	70 W/35 W/50 W/65 W	YES	[9, 38, 62, 127]
Mini 14	Purdue University and Tsinghua University	DAPI (DESI, LTP, PS, PCS)	RIT	>2000	R= 0.4 amu	12	26.5 × 26.5 × 37	Battery power (20.3 Ah) for more than 3 h	YES	[158]
Mini β	PurSpec Technologies, Inc	DAPI	RIT	50–2000	R= 0.6 amu	22	55 × 24 × 31	70W	YES	[159, 160]
Cell	PurSpec Technologies, Inc	DAPI	IT	N/A	N/A	8.5	55 × 25 × 15	Internal battery or external power supply	YES	[161]
MMS-100	1st Detect Inc.	EI	CIT	400	R < 0.5 amu	8	19 × 33 × 23	< 45 W on average; 65 W max	YES	[162]
Palm portable MS	Samyang Chemical Co.	EI	CIT	45–300	R= 3 amu	1.5	8.2 × 7.7 × 24.5	5 W	NO	[138]
Portability™/Continuity™ Transportable Mass Spectrometer	BaySPEC	API; ESI; APCI; EI.	LIT	650/50–1200	N/A	10/10	33 × 23 × 41/33 × 33 × 43	N/A	YES	[163]
M 908/MX 908	908 Devices Inc.	API; ESI; APCI.	CIT	55–400/460	N/A	2/3.9	22 ×18.5 × 7.6/29.8 × 21.6 ×12.2	4+ hr on battery	YES	[164]
Mars 400 plus	Focused Photonics Inc. (Hangzhou, China)	EI	3D-IT	30–550	N/A	< 19	42 × 36 × 20	24 V DC	NO	[88]
DT 100	Guangzhou HeXin Inc.	EI	LIT	652	N/A	< 15	45.5 × 45.1 ×22.1	N/A	NO	[165]
MM2	BRUKER	EI	Q	1–520	R = 0.1 amu	35	440 × 307 × 428	24 V DC	NO	[166]
Xevo TQ-S micro Triple Quadrupole	Waters	ESI, APCI, nESI.	TQ	2–2048	R = 0.5 amu		35.6 × 60 × 93	500 W	YES	[167]
JEOL InfiTOF MS	JEOL Solutions for Innovation	DART; GC; MALDI.	TOF	1–1000	R = 0.003 amu	40	43 × 62.5 × 55.2	N/A	NO	[168]

3. Applications of portable mass spectrometer

3.1. Space exploration

The need for MS analysis in space exploration missions is an important driver of miniaturizing mass spectrometers, especially in the early years. Every mass spectrometer that has been deployed for space missions should be considered as a portable mass spectrometer. Due to the limitations in the payload for space missions, the mass spectrometer must be compact and light weight, and exhibit low power consumption, robust operation, and a high tolerance to the harsh environment, as well as be automated [169]. Since the portable GC-MS system in the Viking I Mars lander detected water and carbon dioxide [170], portable mass spectrometers have greatly advanced our understanding of the chemistry information for various space targets. Several mission-specific mass spectrometers have been developed to characterize space plasmas, including the Active Magnetospheric Particle Tracer Explorers (AMPTE) [171], STEREO mission containing Plasma and Super-thermal Ion Composition (PLASTIC) and In-situ Measurements of Particles and CME Transients (IMPACT) [172, 173], Cassini plasma spectrometer (CAPS) [174], analyzer of space plasmas and energetic atoms (ASPERA) [175], NASA’s MESSENGER spacecraft with energetic particle and plasma spectrometer (EPPS) [176], and Rosetta plasma consortium-ion composition analyzer (RPCICA) [177]. These instruments identified primarily singly charged ions (e.g., H⁺, N⁺, CH₄⁺, Na⁺) in plasma and probed the solar wind interactions with a comet’s plasma environment. In addition to space plasmas, particles in space are another important target for space mass spectrometers. To study the chemical composition of space particles, particle impact ionization was employed. Notably, two TOF based analyzers have been deployed for analyzing space particles, cometary secondary ion mass analyzer (COSIMA) [178] and Cassini cosmic dust analyzer (CDA) [179], which revealed the chemical composition of interstellar particles and particles in Saturn’s E-ring. In recent years, an important focus for space MS mission is the search of exoplanet life. Mass spectrometers that can probe small organic molecules including methane and amino acid have been or will be deployed to Mars, including Mars Science Laboratory (MSL) mission and Mars Organic Molecule Analyzer (MOMA) [180]. The Surface Analysis at Mars (SAM) [181, 182], as part of the Mars Science Laboratory (MSL) mission, can measure light isotopes and volatiles. Organics can be extracted by heating or by chemical extraction and isotopic measurements of carbon in CO₂ evaluated in the presence of chlorobenzene and similar organics. MOMA will be placed in the ExoMars rover to detect biomarkers for life [183, 184]. It has been demonstrated for the isotopic and elemental composition measurements of rocks and meteorites as well as the determination of aromatic organics, amino acids, and nucleotides. Recently, an orbitrap-based laser ablation mass spectrometer is being developed for improving the detection capability for biomarkers [180, 185]. The instrument, named CosmOrbitrap, has achieved ultrahigh mass resolution (m/Δm ≥ 120,000 FWHM), and high mass accuracy at 3.2 ppm, and quantification of isotopic abundances with better than 1% precision.

3.2. Forensic science

Many application scenarios in forensic analysis can benefit from the analytical capability of portable mass spectrometers. Examples include the onsite detection of illicit drugs, the rapid identification of explosives, chemical warfare agent (CWA), ignitable liquids, and volatile organic compounds (VOCs), and the analysis of human biological traces (including hair, nail, and fingerprints) at the scene. Due to the complex nature of various kinds of illicit drugs, portable mass spectrometers can facilitate the search and conviction of perpetrators of crime by law enforcement officials and provide real time information on site [14, 48, 186–192]. Ma et al. [40] utilized a PI source on the Mini 12 system to analyze cannabinoids directly. The MS/MS capability enabled by the miniature ion trap mass analyzer is important for identifying the five representative synthetic cannabinoids with adequate sensitivity and quantitative precision for on-site chemical analysis. Drug residue such as that from fentanyl, heroin, cocaine, and mephedrone on different types of surfaces were detected in the field by a FLIR Systems CIT mass spectrometer [193]. In this study, paper-based strips with cut triangles were used as the substrate to detect drug residue as low as 500 ng on a plastic cup, door handle (Figure 4a) and identification card. Sensitive detection at the mid nanogram range enables this valuable tool for the searching of vehicles or other locations of interest as well as security screening at airports or other locations. Brown et al. [61] coupled DART ionization with the MassTech MT Explorer 50 for confirmatory analysis of the authenticity of controlled substances using a library of MS and MS/MS spectra. This DART based system enabled the identification of drugs at low level (oxycodone/acetaminophen = 1/65) in complex mixtures. Commercial portable GC-MS options (Torion system and FLIR Griffin instrument) are being evaluated as a potentially suitable tool for field-based screening of the presence of illicit drugs and adulterants [194–197].

Figure 4.

Applications of portable mass spectrometer. a). Direct detection of illicit drugs on sample surfaces. Adopted from [193]. Copyright 2017 Analytical Methods. b) Detection of agrochemical residues on apple surfaces. Adopted from [217]. Copyright 2011 Royal Society of Chemistry. c) MS sampling probe for in-vivo analysis. Adopted from [226]. Copyright 2013 Analytical Chemistry. d) Sampling by swab and direct analysis using touch spray MS. Adopted from [227]. Copyright 2014 Analyst.

Detecting explosives and chemical and biological warfare agents onsite with high sensitivity is of great importance to forensic analysis, public safety, and defense. Portable mass spectrometers have been extensively studied for this task as they can provide definitive information on the identity of dangerous chemicals. The detection of CWA or CWA simulants or explosives on different surfaces such as human fingers, cotton, gloves, wood or glass [62, 198], or in shipping containers [199] or in the air [200] have been demonstrated using various portable mass spectrometers (Mini S and Mini 11.5, portable membrane inlet mass spectrometer, minimal CIT analyzer). Hashimoto et al. [201] reported the detection of explosives-laden vapor at concentrations below 25 ppb with a 3 s automated sampling approach using a portable linear ion trap mass spectrometer. The rapid screening for trace explosives at the airport with sensitivity at the level of ng was demonstrated by Vikov et al. [202] Puffs of air were sampled to detect trace explosives from passenger particles. Takada et al. [203, 204] demonstrated a high throughput (3 seconds/person) portable mass spectrometer (wire ICT) for identifying triacetone triperoxide vapor released by travelers and luggage at an airport and a train station. Field testing of ignitable liquid residues in arson cases could help to indicate whether the fire may have been deliberately set. Arson scenes are often too complex to find relevant pieces of evidence to send to the laboratory for further analysis to aid fire investigators, which calls for methods that can detect ignitable liquid residues in situ. Alexander et al. reported the use of a commercially available GC-MS (TRIDION-9) system to detect four ignitable liquids (petrol, mineral turpentine, kerosene, and diesel) with a volume as low as 0.1 μL on different substrate matrices in less than 2 min [205].

VOC emitted from exhaled breath, sweat or other biological secretions unique to the individual in terms of gender, age, lifestyle and medication can be useful in screening for human smuggling in ports, in monitoring disorder biomarkers for potential disease, or in detecting markers of buried human bodies in forensic investigations [199]. Giannoukos et al. [206] used membrane inlet mass spectrometer (MIMS) with a weight of 23 kg to detect variations in VOCs (O₂, CO₂, acetone, isoprene, and lactic acid) at low ppb concentrations in a room with a human presence. The in situ MIMS system intended to quantify and qualify VOC was also evaluated in the field. A portable underwater mass spectrometer (33kg) was used to acquire MS spectra with a rate of 0.7 –3.6 s/sample for 2–3 h and was remotely controlled to probe the composition of surface water and organics relevant to industrial spills [207–209]. Rodriguez et al. [195] used a commercial portable GC–MS (Griffin G510) to detect VOCs in the field at sub-ng levels with recovery rates ranging from 3–89% for all VOCs tested.

3.3. Environmental monitoring

Environmental monitoring typically involves sampling at various geographical locations. Applying portable MS to environmental analysis can sharply reduce the turnaround time for environmental samples characterization, provide more up to date information for relevant parties, and increase the frequency and coverage of environmental sample testing [210]. VOCs are also an important class of molecules for environmental monitoring, which can come from the emission of vehicles, the use of pesticides, and natural emissions [77]. Makas et al. [211] reported a portable GC-MS system for an isothermal separation that required no down time required to change temperatures between analyses. They achieved successful detection of tributyl phosphate in atmosphere in low ppt levels at a throughput of one sample per minute. Sokol et al. [212] used the Mini 10.5 to examine traces of hydrocarbons as well as organic compounds comprising nitrogen, oxygen, sulfur, and chlorine in the vapor phase and in aqueous solutions. Low detection limits at the ppt and ppb level of benzene, toluene, and xylene mixtures in air and in aqueous solution was achieved.

Environmental toxins are important targets that are preferred to be analyzed in the field by MS. A portable desorption APCI (DAPCI) mode for in situ analysis and detection of nitrobenzene explosives absorbed on surface was demonstrated. [213]. 2,4,6-trinitrotoluene was detected and quantified with a LOD of 5.8 pg with good quantitative linearity (R²=0.9986). Reduced sulfur compounds including methyl mercaptan and dimethyl sulfide were also detected by a portable mass spectrometer with ppb level sensitivity. [214]. Other toxic compounds such as benzene, toluene, and ethylbenzene in air was quantified in the field without any sample preparation having LODs at the ppb level using APCI on the Mini 10.5 system [57]. Nonvolatile toxic chemicals such as trinitrotoluene, malathion, fenitrothion, tetryl, and cocaine were ionized on the surface of an apple. MS/MS analyses were also able to be performed which improved the sensitivity of such a technique.

In addition, a portable MS system was used to monitor the growth of a plant by screening volatile emissions. Wong et al. [13] used a portable GC-MS equipment for on-site screening of biogenic volatile emissions from living plant leaves. Headspace solid phase microextraction (HS-SPME) was employed and pass the compounds through GC system to extract leaf oil emissions.

Ensuring food quality and safety is another area portable MS can offer significant value. There are many contaminants and residues in food that may cause food safety concerns including pesticides, veterinary medications and growth-promoting chemicals, environmental contaminants, contaminants from food processing and packaging materials [215]. Portable MS can expand the coverage and increase the frequency of food testing. [216]. Soparawalla et al. [217] used a Mini 10.5 system to detect agrochemical residues from the apples (Figure 4b). MS/MS was performed to identify the chemicals on the apples and oranges directly. Portable mass spectrometers have also been demonstrated to detect food additives in the milk, pesticide residues on the food [63, 218], the fungicide in the tree leaves [46], and fentanyl and its derivatives from cola, milk and beer [219]. In addition, Gerbig et al. [220] performed food authentication analysis using different types of ambient ionization techniques like ESI, DESI and LTP with a portable mass spectrometer.

3.4. Biological analysis and clinical applications

Standard mass spectrometers have been widely used in biological analysis and have revolutionized the manner in which biological systems are probed. Despite their comparatively decreased performance, portable mass spectrometers could still offer unique advantages for certain applications including rapid therapeutic agents monitoring, point of care testing of biomarkers, and complex sample analysis [221]. Portable MS is a powerful tool for quantifying small therapeutic molecules and its metabolites without the need of any chemical labeling. Combined with ambient ionization methods such as PSI and DESI, drug molecules detection and quantification in dry blood spots, whole blood, human skin, and urine have been demonstrated with portable mass spectrometers. For detecting and measuring jatropha-derived phorbol esters toxins, Wickramasekara et al. [222] developed the MT Explorer 50 portable MS equipment with PS as the ionization source. Using phorbol 12,13-didecanoate as a standard, it was discovered that the LOD and limit of quantification (LOQ) were 0.175 and 0.3 g/mL, respectively. Portable MS has also been used to monitor volatile anaesthetic agents (halothane, isoflurane and sevoflurane) [223]. Methane accumulation in anaesthetic rebreathing systems, and exhaled carbon dioxide and oxygen concentrations have been measured for rapid exhaled gas analysis.

In addition to monitoring drug molecules, portable MS also has great potential for point of care (POC) testing of biomarkers in biofluids [224]. Coupled with a homemade MS system using laser ionization, Zhai et al. [134] developed a portable mass spectrometer to analyze peptides, proteins, and drugs in complex matrices including blood and urine, which facilitated biomarker detections in POC testing. Additionally, portable MS has enabled many unconventional medical testing including the detection of lung cancer breath markers, the analysis of lipidomic profiles on distinct cancer tissue types, the monitoring of in vivo chemical information in surgical and endoscopic procedures, and the detection of bacterial lipids originating by swabs for clinical diagnosis of strep throat, which hold great potential to improve diagnosis and prognosis of complex diseases [225–228]. For example, Chen et al. designed a sampling probe to seal the sample probe against the rat brain tissue section, intact kidney and intestine for desorption ionization (Figure 4c). The profiles of lipids and fatty acids that were detected in the rat brain tissues matched those reported in previous studies using desorption electrospray ionization analysis. Additionally, a diaphragm pump was used to push the gas into the MS inlet, protecting the sample surface and making this sampling probe more useful for clinical diagnosis. Jarmusch et al. employed medical swabs for touch spray ionization with the high voltage applied at the end of the swab for strep throat diagnosis (Figure 4d). The lipid profiles of pathogenic bacteria (S. pyogenes) were quickly obtained, which were comparable to results from standard lab procedures. Recently, mass spectrometry has also been used for intraoperative applications for real-time monitoring and detection of important biomarkers by employing direct sampling/ionization systems such as DESI, MassSpec Pen, and rapid evaporative ionization mass spectrometry (REIMS) [159, 229–233]. While existing demonstrations are still based on benchtop mass spectrometers, portable mass spectrometry systems hold great potential to improve the accessibility and reduce the cost for intraoperative mass spectrometry applications.

4. Perspective

Efforts in the development of miniaturized mass spectrometers have achieved tremendous success resulting in capable small mass spectrometers that are commercially available for diverse applications. While it is undeniable that portable MS is a valuable tool for chemical and biological analysis, its adoption is still at the earliest stages. Further expansion of the pool of potential users and applications calls for advancement in both instrumentation and applications.

First, ease of use is an important factor that influences the broad adoption of portable mass spectrometers. Unlike laboratory-based MS experiments which are performed by skilled MS personnel, a large percentage of users of portable mass spectrometers may have limited experience in the operation of a mass spectrometer. Making the front end easy to use and the data interpretation/presentation easy to understand can decrease the barrier for adoption. Depending on the complexity of the sample matrix and the property of target analytes, extensive sample preparation procedures may be necessary. Techniques that can streamline and automate the pretreatment steps should be developed. For example, by integrating the ionization source with the sample preparation steps, streamlined analysis of target from complex matrices can be achieved [234, 235]. For data interpretation, mass spectra are not straightforward to many users. Programs that help interpretate MS results should be developed, taking advantage of modern connectivity, cloud-based computing, and AI.

Second, due to the complexity of mass spectrometers, the purchase of a commercial instrument is the only option for most end users who perform MS analyses. To improve the accessibility of MS analysis, decreasing the cost of instruments is paramount as the cost of a standard mass spectrometer is formidable to many users and entities. In this regard, portable mass spectrometers may play a crucial role in expanding the user base for MS analysis. The development of simplified and miniaturized instrumentation may also decrease the cost of the entire system so that more interested groups can afford MS analysis offering reasonable performance. Increasing the accessibility and affordability of MS analysis could diversify the users of MS, which, in return, will lead to new applications for portable mass spectrometers.

Having briefly considered two areas in which future improvements in field portable mass spectrometers would be highly beneficial, one might ask about the relationship to the ‘omics world. How might developments toward improved field portable MS capabilities affect proteomics or metabolomics analyses? Here it is useful to briefly consider the divergent paths of instrumentation development for field portable MS experiments versus those in the area of ‘omics analyses. It can be argued that these paths are shifted 180 degrees; for example, for ‘omics analyses, over the years, the trend has been to develop more complex and costly instrumentation. This has been pursued to largely gain analysis efficiencies with regard to the identification and quantitation of individual biomolecule sample components. Examples include the use of an increasing variety of ion optics and mass analyzers and combinations thereof. This has generally increased the size and cost of high-end instrumentation whereas a goal in field portable MS instrumentation is to follow the opposite developmental path.

Despite the divergence in development strategies, there exist opportunities for portable MS development to significantly impact the ‘omics world. It is therefore instructive to briefly consider how such benefit might arise. The first area to consider is the path of size reduction while retaining or even gaining functionality (e.g., MSⁿ capabilities) and sensitivity. Although highly mobile MS platforms may be difficult to be applied in the most complex ‘omics analyses due to the significant compromise in performance, it may be utilized for targeted analysis. Recently, Chiang et al. reported targeted quantification of peptides using a dual LIT mass spectrometer [236]. In addition, efforts in miniaturizing mass spectrometers can lead to significantly more compact and less costly benchtop instrumentation which can be applied to ‘omics projects. Providing ‘omics analysis capability to a much larger army of scientists will have a significant impact. First, there is a division of labor gain as many more researchers can perform different analyses for specific projects. Relatedly, a significantly expanded repertoire of ‘omics projects can be undertaken with the increased accessibility to MS instrumentation by new researchers.

Much of the discussion above describes the latest developments in MS instrumentation components for field portable systems. For mass analyzers, pumping systems, and detectors, to a large degree it is possible to extrapolate the trajectory of component development into the future. That is, mass analyzers development will continue to focus on increasing sensitivity, m/z range, and resolution under higher pressure conditions. Pumping systems will continue to develop along the lines of greater efficiency for smaller size and weight. Finally, detectors will continue to focus on improving sensitivity while operating under the stringent conditions imposed by field portable systems. Less clear is the direction of ion source development for field portable MS systems and applications. Here, our perspective of future development in ionization source is provided as this is an active area of research in which we are involved. Notably, the difficulty in predicting the direction of future ion source development arises from the explosive growth in ambient ionization source innovation and development in recent years as described below. Admittedly, much of the discussion above focuses on ionization source development for applications apart from those encountered in the ‘omics world. This results largely on a developmental focus on ionization sources for different types of analytes such as those that do not originate in the aqueous environment. Because ‘omics applications are relegated to the aqueous world containing large low vapor pressure molecules, miniature ionization methods that can effectively handle biomolecules hold great potential to improve the performance of portable mass spectrometers for ‘omics analysis. For example, inlet ionization methods developed by Trimpin and coworkers do not require additional power input while allowing analysis of biomolecules. Using solvent-assisted inlet ionization (SAII), sensitive LC-MS analyses such as those desired in ‘omics experiments was demonstrated. Using mechanical based ionization methods, such as vibrating sharp-edge spray ionization (VSSI), can effectively stabilize LC-MS experiments without the need of bulky nebulization gas system while providing improved sensitivity, which is desired for ‘omics experiments using portable mass spectrometers [237, 238]. Recently, VSSI has also been employed to serve as a robust capillary electrophoresis (CE)-MS interface to allow for the rapid and sensitive separation and MS characterization of proteins and peptides under nanoflow conditions (absence of a sheath flow) [239].

Mechanical based ionization sources could also be valuable for structural ‘omics or native MS analyses. For native MS type samples of proteins and oligonucleotides, field-enabled VSSI has been demonstrated to provide ~10-to-100-fold enhancements in ionization efficiency relative to state-of-the-art ESI [240]. In separate studies, Bier and coworkers introduced mechanospray ionization (MoSI) involving the production of a droplet plume emanating from micron-sized holes placed on a piezoelectric transducer to which a liquid sample is passed [241]. In native MoSI was shown to provide lower charge states for protein ions under native MS conditions compared with traditional ESI.

One of the greatest challenges encountered in ‘omics experiments is that of the sample complexity. In spray-based ionization methods, the heterogeneous nature of the sample presents problems for the detection of low abundance and/or low ionizing species in the presence of higher abundance / higher ionizing species. Condensed-phase separations to some degree mitigate against such problems by providing a pre-ionization separation allowing for the detection of troublesome species. That said, for comparative analyses such as those encountered in bottom-up proteomics work or untargeted metabolomics analyses) even the combination of chromatographic steps with MS does not provide the combined peak capacity sufficient to isolate all compounds for individual introduction to the ionization source. Therefore, the development of ionization sources that can enhance the ionization of troublesome compounds in the presence of higher signal species is desired. Recently, surface acoustic wave nebulization (SAWN) has been coupled with an electrical discharge source to enhance the ionization of a low signal species in the presence of a high signal compound. Similarly, nESI coupled with APCI was demonstrated in a similar fashion. More recently, cVSSI coupled with APCI has shown a similar utility [242]. This work showed extended capability in the form of enhanced ionization for aqueous samples which are better suited to ‘omics type molecules.

Abbreviations:

APCI

atmospheric pressure chemical ionization

API

atmospheric pressure ionization

CAPI

continuous atmospheric pressure interface

CE

capillary electrophoresis

CIT

cylindrical ion trap

CNTs

carbon nanotubes

CWA

chemical warfare agents

DAPI

discontinuous atmospheric pressure ionization

DART

direct analysis in real-time

DBDI

dielectric barrier discharge ionization

DESI

desorption electrospray ionization

EI

electron ionization

EM

electron multiplier

ESI

electrospray ionization

FC

faraday cups

GDEI

glow discharge electron impact

IT

ion trap

LC

liquid chromatography

LIT

linear ion trap

LOD

limit of detection

LOQ

limit of quantification

LTP

low-temperature plasma

MALDI

matrix-assisted laser desorption/ionization

MCP

microchannel plate

MEMS

microelectromechanical system

MIMS

membrane inlet mass spectrometry

m/z

mass-to-charge ratio

nESI

nanoelectrospray ionization

PCS

paper capillary spray

PI

photo ionization

POC

point of care

PSI

paper spray ionization

Q

quadrupole analyzer

QIT

quadrupole ion trap

RIT

rectilinear ion trap

sESI

secondary electrospray ionization

TIT

toroidal ion trap

TOF

time-of-flight analyzer

TQ

triple quadrupole analyzer

VOC

volatile organic compound

VUV

vacuum ultraviolet