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Handheld Miniature Ion Trap Mass Spectrometers Zheng Ouyang, Robert J. Noll, and R. Graham Cooks Purdue University For field applications, “miniature” and “rapid” have become almost synonymous, yet these small mass spectrometers are not useful if performance is too severely compromised. (To listen to a podcast about this feature, please go to the Analytical Chemistry website at pubs. acs.org/journal/ancham.) MS is widely regarded as the gold standard for chemical analysis with respect to selectivity, detection limits, and broad applicability. However, mass spectrometers are comparatively delicate instruments, partly a consequence of the need for a vacuum system into which the sample is introduced. There have long been efforts at direct MS analysis of complex mixtures,1 but extensive sample cleanup and increasingly sophisticated multianalyzers have been involved. These considerations have limited the applications of MS outside the laboratory. It is striking that although progress in many areas of technology is strongly associated with miniaturization, this correlation is barely evident in MS. Nevertheless, for many applications of MS, in situ experiments would have significant advantages over laboratory measurements, even if there are significant losses in analytical performance. Some applications of immediate interest include environmental monitoring (especially surveys that require large numbers of samples), quality control, food safety, forensics, security and public safety, and clinical diagnostics. The objective of this article is to summarize recent progress in developing handheld miniature mass spectrometers. Note that the focus is on complete systems, not particular components, even important ones like the mass analyzer. ON THE SMALL SIDE Interest in small mass analyzers stretches back several decades. For example, a hyperbolic ion trap analyzer the size of a quarter with a 2.5-mm radius and an m/z range of 70,000 was reported in 1991.2 A Mattauch-Herzog-type, nonscanning, double-focusing sector mass analyzer was reported in 1991, and a very small, double-focusing, crossed electric- and magnetic-field sector analyzer was described in 2001.3,4 Recent work by Ramsey, Austin, Short, and others has advanced small analyzers further, and the 10.1021/ac900292w CCC: $40.75 2009 American Chemical Society Published on Web 03/12/2009
emphasis is increasingly turning to microelectromechanical systems (MEMS)-fabricated mass analyzers.5-8 However, only in the past decadesand especially in the past 5 yearsshas significant progress been made in the development of small, low-power, portable, autonomous mass spectrometer systems; some have progressed to the point of commercialization. A review in 2000 summarized the mass analyzers used in miniature instruments, showing examples of virtually all the common types, including quadrupole mass filters, quadrupole ion traps, magnetic sector fields, TOF, and FT ion cyclotron resonance instruments.9 More recent work has seen the commercialization of a novel toroidal ion trap system.10 A website devoted to small instruments and a conference series on MS in harsh environments prominently features handheld mass spectrometers (www.gcms. Analytical Chemistry, Vol. 81, No. 7, April 1, 2009
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Table 1. Handheld mass spectrometers Instrument
Weight Power (kg) (W)
Mini 10 Mini 11 ChemCube/ChemPack
10 4 14
70 30 50
Guardion-7
11
75
Suitcase TOF Palm-Portable (without pump) Griffin Analytical 600 Portable GC/MS O. I. Analytical
1.5
5
25 6.4 18
42 75
Mass analyzer
MS/MS?
Sample introduction or ionization mode
Mass range (m/z)/ resolution (R)
Reference
Rectilinear ion trap Rectilinear ion trap Quadrupole mass filter on chip Miniature toroidal ion trap Miniature TOF Miniature CIT
Yes Yes No
MIMS, direct leak, ESI, DESI MIMS, direct leak, ESI, DESI SPME, EI
550/550 2000/100 400/100
14 17 13
Yes
SPME, EI
500/500
10, 24
No No
MALDI sample plate Pulsed gas leak, EI
50,000/30 300/150
Miniature CIT Full-size QIT Mattauch-Herzog sector
Yes No No
MIMS, direct leak Mini GC/preconcentration Direct gas leak, EI
425/400 100/220 300/300
25 26 www.griffinanalytical.com 27 29
MIMS, membrane inlet MS; SPME, solid-phase microextraction; QIT, quadrupole ion trap; EI, electron impact.
Table 2. Characteristics of ion trap mass analyzers for use in miniature mass spectrometers Desired characteristic
Reason for the characteristic
Ion trap suitability
High pressure tolerance Miniaturization Tandem MS High ion currents
Pumping limitations of small instruments Minimize system size and weight Analyze complex samples Maximize signal strength
Tolerates pressure best Easily miniaturized, optimized geometry Single miniature ion trap can be used Arrays of small traps can be multiplexed to increase ion current
de). This article updates the 2000 review, and Table 1 lists some of the individual systems and their principal features, including power and weight. Most miniature (hand-portable) systems use conventionally fabricated components, including mass analyzers. MEMS-based analyzers and other components, including ion sources and detectors, are now appearing in conference presentations. Note that the entire mass spectrometer system, not the mass analyzer itself, is the focus of this article. Miniature mass spectrometers are of most interest in field applications, where speed of analysis is invariably a high priority. So important is this factor that “miniature” and “rapid” are almost synonymous in discussions of small instruments. In spite of this double requirement, miniature mass spectrometers are not useful if performance is too severely compromised. Analysis of complex mixtures must be possiblestherefore, if chromatography is not an option (it is often too slow for on-line work), then tandem MS, ion mobility, or exact mass measurements must be available. Of these choices, only tandem MS is currently available on small systems. The need for rapid in situ measurements in miniaturized systems places even more demands than usual on sample introduction. In laboratory instruments, high performance can be achieved by implementing slow but complete separations. But in portable miniature instruments, sample introduction systems need to be able to handle solid-, liquid-, and vapor-phase samples at rates compatible with in situ analysis. Membrane interfaces and solid-phase sorbent systems are useful in vapor-phase and some solution-phase analyses and can be implemented in conjunction with traditional electron ionization or chemical ionization methods, including atmospheric-pressure chemical ionization. However, the analysis of solid samples and nonvolatile compounds in solution requires modern desorption or spray ionization methods, which we discuss in this article. 2422
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ION-TRAP-BASED MINIATURE INSTRUMENTS Many miniature mass spectrometers are based on ion trap technology.11 The reasons for the choice of the ion trap as the mass analyzer in our program as well as at Brigham Young University, Oak Ridge National Laboratory, the University of North Carolina, the University of South Florida, and the Defence Evaluation and Research Agency (U.K.) are summarized in Table 2.5,7,10,12 Two contrasting approaches to building small, capable mass spectrometer systems can be taken. In the “bottom-up” approach, the scale of interest is chosen, and components are built and assembled on that scale. This approach is being used by Syms and co-workers.13 They concentrate on quadrupole mass filter analyzers and MEMS methods, although their current ChemCube/ChemPack instrument is a hybrid of MEMS and conventional technology. The “top-down” approach starts with a macroscale instrument and, in an iterative fashion, reduces component sizes while maintaining performance. We have used the relatively safe, but slow, top-down approach over the past decade.14-16 We were able to produce small ion trap mass analyzers, first by using the simplified cylindrical ion trap (CIT) geometry and later by modifying the geometry of the high-ion-capacity linear ion trap to the simplified, easily miniaturized rectilinear ion trap. These capabilities allowed and facilitated shrinkage of the sizes of the other mass spectrometer components, especially the rf supply and the vacuum system. This inwardly spiraling characteristic of mass spectrometer miniaturization has a remarkable self-reinforcing aspect, with obvious parallels to Moore’s law in computer science. The result has been a series of instruments of decreasing size, weight, and power consumption. REPRESENTATIVE MINIATURE ION TRAP INSTRUMENTS To illustrate the difficulties that remain in developing highly capable handheld mass spectrometers, as well as the capabilities
Figure 1. Performance characteristics of the Mini 10 for some simple samples. All data acquired using EI ionization. (a) The instrument. (b) Calibration curve for naphthalene dissolved in water, with a limit of detection of 3 ppb and a linear dynamic range of 1000. (c) Mass spectrum of toluene, showing unit resolution of the two main ion peaks at m/z 91 and 92. (d) Mass spectrum of perfluorotributylamine, a common m/z calibration compound, showing an upper m/z limit >500. (e) Single-stage mass spectrum of methyl salicylate, a chemical weapon simulant, followed by (f) isolation using stored waveform inverse FT of the molecular ion at m/z 152. (g) In turn, the parent ion is subjected to CID, creating characteristic ion fragments. (h) The ion fragment at 120 is in turn isolated and subjected to CID, resulting in the “third-generation” tandem mass spectrum.14
of currently available instruments, we describe two ion trap instruments, the Mini 10 and Mini 11, which were built by our team in 2005 and 2006.14,17 For the Mini 10, data are acquired with preset scan functions for MS or MSn analysis. Peaks of interest are identified and used for compound recognition with custom software running on the local instrument computer or a remote central computer. A library containing peak lists and pre-acquired calibration curves for targeted analytes is used for compound matching. The Mini 10 uses a commercial turbomolecular high-vacuum pump (the Pfeiffer TPD 011) with a pumping speed of 11 L/s at ultimate vacuum, whereas the Mini 11 uses a much smaller, 500-g turbopump (Creare) with a pumping speed of 5 L/s. The Mini 10 has a small built-in Windows-capable computer; the Mini 11 is controlled wirelessly. Both instruments have GPS, can send and receive data, and can be controlled remotely (in the case of the Mini 11, via a personal digital assistant). Both use the same 4 × 5 × 40 mm rectilinear ion trap and therefore display almost identical performance, which includes an m/z range of 550 with unit resolution and an extended range with lower resolution. Although a conventional electron impact (EI) ion source was used for early experiments with the Mini 10, it was later replaced by a glow discharge EI source. An atmospheric interface was installed recently to allow ESI and desorption ESI (DESI). Sample introduction can be accomplished in several ways: by direct injection of gas or vapor into the vacuum manifold, injection of gas-phase or solution-phase samples via a membrane introduction system, injection of gas-phase samples by a solid-phase sorption system, and direct sampling of liquid-phase samples via a simple atmospheric inlet system that consists of a long, thin, capillary tube.14,18,19 The performance of the Mini 10 is summarized in Figure 1, which also illustrates its multistage (MSn) capabilities,
Figure 2. Cocaine on money. (a) Protonated cocaine molecule at m/z 304 shown on banknote by conventional geometry DESI. MS and (inset) MS/MS data provided by the Mini 10. (b) Mass spectrum from 10 ng cocaine on Teflon by using geometry-independent DESI. (Adapted from Ref. 19.)
including ion isolation and product ion (MS/MS) spectra produced by collision-induced dissociation (CID). The instrument can be used to determine toxic compounds in air by using a solid sorbent that is selective for particular compound classes. For toxic gases, such as phosgene, ethylene oxide, sulfur dioxide, acrylonitrile, cyanogen chloride, hydrogen cyanide, acrolein, formaldehyde, and ethyl parathion, a 1-minute preconcentration time is required. Detection limits range from 800 ppt to 3 ppm, depending on the analyte. For these particular compounds, a linear dynamic range of 1-2 orders of magnitude was obtained over the concentration range (sub-parts per billion to parts per million) for all analytes.18 Drugs and other compounds in solution can be examined by passing the analyte solution over a membrane that is then heated Analytical Chemistry, Vol. 81, No. 7, April 1, 2009
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Figure 3. The combination of ambient ionization by DESI with a miniature mass spectrometer by means of a suitable interface could result in an instrument for personal use. (Adapted from Ref. 28.)
to release the analyte into the vacuum system. Short and co-workers have extensively explored membrane introduction in their work on trace chemicals in seawater. For analytes that are amenable to this technique, it is one of the simplest and most reliable sample introduction methods available.20 The use of miniature mass spectrometers for the direct in situ study of solid environmental samples requires the implementation of DESI, direct analysis in real time, or a similar ambient ionization method. Such experiments have been undertaken with the Mini 10 for the detection of cocaine on banknotes, in which both important variants of DESI were used to obtain spectra (Figure 2). DISADVANTAGES AND FUTURE IMPROVEMENTS Experience with miniature mass spectrometers reveals a number of shortcomings. First, almost all quantitative measures of performance, including resolution and detection limits, are poorer than those obtained with the corresponding conventional laboratory instrumentation; this is due primarily to mechanical errors being relatively large compared to the scale of the miniaturized system. Less obviously, the need to conserve power means that the systems are typically not heated, and this can cause sample carryover with some types of sample introduction methods. Recent developments have revealed numerous ways in which these miniature systems can be improved and further reduced in size. The improvements include operation at higher pressure, routinely at 15 mtorr, which can be facilitated by using pressuretolerant electron multipliers.19 By operating at a very low Mathieu parameter, the mass range can be extended by a factor of 100, which allows the mass spectra of intact proteins to be recorded with handheld mass spectrometers.21 Multiplexed operation of several smaller rectilinear ion traps has been demonstrated.22 Most important, the interface (“wand”) connecting the ion source and the mass spectrometer is now receiving much attention in an effort to increase efficiency and allow standoff detection. A PERSONAL MASS SPEC The combination of two existing technologies, the miniature mass spectrometer and DESI, could lead to a new instrument that allows direct analysis of samples of almost any type in the ambient environment. Both technologies have been reduced to practice separately, but their routine combination, which promises to be far more powerful than the individual systems, requires implementation of several new inventions. The instrument resulting from these combined techniques, effectively a personal mass spectrometer, could be a disruptive technology (Figure 3). Such a technology will have a variety of applications, including examination of tissue for disease; examination of biological fluids 2424
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for temporal variations that might indicate disease; and detection of dangerous and toxic compounds on surfaces, in water, and elsewhere. Examining tissue for disease includes finding tumor margins by analyzing the lipid distributions in tissue sections sent to pathology during surgery,23 noninvasive examination of skin lesions, and examination of needle biopsies in the doctor’s office. The measurements made on biological fluids could include metabolomics studies, characterization of inborn errors of metabolism, and self-monitoring of biological fluids, an application for which regulatory permissions will have to develop along with the technology. Some of these applications will be used by medical professionals, but others will be performed by individuals who have a strong motivation to monitor their own health, in the context of obesity or diabetes, for example. In such cases, a personal mass spectrometer might become as useful and ubiquitous as the personal computer is today, however unlikely it may seem at present. ACKNOWLEDGMENT We are grateful for scientific collaboration with Griffin Analytical Technologies, a division of ICx, and Prosolia. We thank those experts in ion trap and miniature mass spectrometer technology who kindly commented on earlier drafts of this article. We also acknowledge support over the years of this general project by the Office of Naval Research; the Transportation Security Administration; the National Science Foundation; the Homeland Security Advanced Research Projects Agency; and the Department of Homeland Security, Science and Technology Division, Chem/Bio R&D Section. Thanks to Liang Gao for providing the figure that is the basis for the cover and the art on the opening page. Zheng Ouyang is an assistant professor of biomedical engineering at Purdue University who is interested in MS instrumentation and its application in chemical and biomedical analysis. Robert J. Noll is the managing director of the Center for Analytical Instrumentation Development and a research scientist in the Aston Laboratory for Mass Spectrometry at Purdue. His research interests include physical chemistry, MS, chemometrics, miniature instrumentation, and the Orbitrap analyzer. R. Graham Cooks is a professor at Purdue and is interested in all aspects of MS, from ion motion to ion chemistry, in small instruments and large, and in applications across the sciences. Address correspondence about this article to Cooks at Purdue University, Chemistry Department, 560 Oval Dr., West Lafayette, IN 47907.
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