A Robust Miniature Mass Spectrometer with Continuous Atmospheric Pressure Interface

instruments

Article Mini 2000: A Robust Miniature Mass Spectrometer with Continuous Atmospheric Pressure Interface

Xiangzhi Meng 1, Xiaohua Zhang 2, Yanbing Zhai 1,* ID and Wei Xu 1,*

1 School of Life Science, Beijing Institute of Technology, Beijing 100081, China; [email protected] 2 Anyeep Instrumentation Company, Suzhou 215129, China; [email protected] * Correspondence: [email protected] (Y.Z.); [email protected] (W.X.)

Received: 25 December 2017; Accepted: 25 January 2018; Published: 26 January 2018

Abstract: A miniature mass spectrometer with continuous atmospheric pressure interface (CAPI) developed previously in our lab has proved to have high stability and rapid analysis speed. With the aim of achieving smaller size, better performance and easier maintenance, in this study, an upgraded miniature mass spectrometer with CAPI was developed, in which all components were optimized and redesigned into a packaged unit. Using a more powerful pumping system, better analytical performances were obtained for this system. The miniature mass spectrometer has the capability to perform tandem mass spectrometry, and could be coupled with ambient ionization sources for analysis of different samples. Good stability (signal relative standard deviation, RSD < 5%), high sensitivity (limit of detection, LOD 10 ng/mL), better than unit mass resolution, and a broad mass range (from 150 Da to 2000 Da) were obtained. Integrated with a tablet computer for system control, the miniature mass spectrometer has dimensions of 38 cm × 23 cm × 34 cm (length × width × height), and is 13 kg in total weight. The whole system is powered by an adapter with a power consumption of 200 watts in total.

Keywords: miniature mass spectrometer; continuous atmospheric pressure interface; ion trap; integrated instrument; robustness

1. Introduction Owing to its high sensitivity, high specificity, rapid response, and applicability to a wide range of chemical compounds, mass spectrometry (MS) has become a powerful technique for chemical and biological analysis. By measuring the mass-to-charge (m/z) ratio of ions, MS has capability of determining molecular weight and elucidating molecular structure. Traditionally, MS is usually performed in analytical laboratories by lab-based mass spectrometers, which are typically large in scale, time consuming, and complicated in operation for the procedures of sample analysis. However, the increasing demands of in situ analysis in many fields, such as environmental monitoring [1], public security [2,3], space exploration [4–9], and personal health care [10,11], call for the miniaturization of mass spectrometers. To perform in situ analyses, especially some in harsh environments, a miniature mass spectrometer with portability is also expected to have adequate performances in terms of sensitivity and MS resolution, as well as robustness and repeatability [12,13]. Up until now, different kinds of miniature mass spectrometers have been developed, mainly using an ion trap as the mass analyzer, which is connected with different atmospheric pressure interfaces (APIs), including the membrane inlet (MI) [14–17], discontinuous atmospheric pressure interface (DAPI) [10,18,19], and continuous atmospheric pressure interface (CAPI) [20,21]. Among these APIs, MI was the first one to be adopted in MS systems. On the basis of MI, lots of miniature mass spectrometers have been developed and applied for in situ analysis of volatile samples. Nevertheless, the MI-based miniature mass spectrometers

Instruments 2018, 2, 2; doi:10.3390/instruments2010002 www.mdpi.com/journal/instruments Instruments 2018, 2, 2 2 of 9 cannot couple with ionization sources in atmospheric pressure environments, and thereby have no ability to analyze nonvolatile samples. To overcome this problem, DAPI was developed by Purdue University in 2008 [19], which enabled the coupling of ambient ionization sources with miniature mass spectrometers. By introducing ions produced in atmosphere into the vacuum chamber in a pulsed way, miniature mass spectrometers with DAPI could analyze both volatile and nonvolatile samples when coupling with the corresponding ionization sources [22–27]. As a robust ion introduction method with high stability for ion transfer, CAPI has been developed in lab-scale MS systems, but not in mini MS until 2015, when the ﬁrst CAPI-based miniature mass spectrometer was developed by our group [20]. This miniature mass spectrometer utilizes a differential pumping system, as well as high-pressure ion trap operation. Taking advantage of CAPI, improvement of stability, robustness, and scan speed was achieved in this system. Following the development of mini MS with CAPI, an in-vacuum plasma ionization source [28] and miniature ion funnel [29] were then developed to enhance the analytical performance for in situ applications. With these techniques, for instance, limits of detection (LODs) of 10 ppbv and 50 ng/mL were obtained for both volatile and nonvolatile samples, respectively. Of course, the continuous atmospheric pressure interfaced mini MS can be equipped with two ionization sources in one instrument, an ambient ionization source and an in-vacuum ionization source, to alternately analyze both nonvolatile and volatile samples [30]. Based on mini MS with CAPI and related techniques developed previously, an upgraded instrument was developed in this work. With the aim of achieving smaller size, better performance and easier maintenance, many components of the system, including the vacuum manifold and electronics, were optimized and redesigned into a packaged unit. Conﬁgured with a tablet computer for system control, the mini MS has dimensions of 38 cm × 23 cm × 33 cm (length × width × height) and is 13 kg in total weight. The whole system is powered by an adapter with a power consumption of 200 watts in total. For analytical performances, good stability (signal relative standard deviation, RSD < 5%), high sensitivity (limit of detection, LOD 10 ng/mL), better than unit mass resolution, and broad mass range (from 150 Da to 2000 Da) were obtained. In addition, the miniature mass spectrometer is able to couple with different ambient ionization sources for complex sample analysis, together with tandem MS capability.

2. Experimental Section

2.1. Instrumentation Based on the miniature mass spectrometer with continuous atmospheric pressure interface developed previously in our lab, the instrument developed in this work also employed a CAPI. The miniature mass spectrometer had a two-stage vacuum chamber with differential vacuum pressures. The first chamber was connected to atmospheric pressure environment with a stainless-steel capillary (i.d. 0.25 mm), and a skimmer was placed between the first and second vacuum chamber. A miniature ion funnel was integrated in the first chamber as reported in detail previously [29]. A hyperbolic linear ion trap with dimensions of 4 × 4 mm (center to electrode distance) was placed in the second vacuum chamber, together with an ion detector, which consisted of an electron multiplier (EM, model 2500, Detector Technology Inc., Palmer, MA, USA) and a dynode assembled in a holder built in-house. To further improve the instrument performance mainly in terms of sensitivity and stability, a Hipace 80 (80 L/s, Pfeiffer Vacuum, Asslar, Germany) was used as the turbo pump, which has a pumping speed ~8 times that of the Hipace 10 used previously. The turbo pump was backed by a mechanical pump (50 L/min, Scroll Tech. Inc., Hangzhou, China). In addition, the length of the capillary was decreased from 20 cm to 10 cm, which brought an improvement in gas flow rate of ~2 times. Although gas flow rate of the current instrument was increased by using a shorter capillary, the background pressure in the ion trap region could be maintained at a lower value (~1 mTorr). To minimize the dimensions and maximize the robustness, this miniature mass spectrometer was redesigned and integrated into a whole unit. As shown in Figure1a, the structure of the Instruments 2018, 2, 2 3 of 9

Instruments 2018, 2, x 3 of 9 instrument could be separated into three parts, which were vacuum manifold with components inside,inside, pumping pumpingsystem, system, and and electronic electronic control control system. system. In In the the design, design, the the vacuum vacuum manifold manifold was was pumpedpumped by by two two pumps pumps located located below below it, and it, alland signals all signals needed needed were providedwere provided by the electronicby the electronic control system,control whichsystem, included which included RF coils RF for coils ion trapfor ion and trap ion and funnel, ion highfunnel, voltage high voltage modules, modules, control board.control RFboard. coils RF produced coils produced RF signals RF to signals drive theto drive ion trap the andion trap the ion and funnel, the ion whose funnel, maximum whose maximum output voltages output werevoltages around were 2000 around V0p and 2000 500 V0 Vp 0pand, respectively. 500 V0p, respectively. High DC voltages High DC for voltages EM, dynode for EM, and dynode ionization and sourceionization were source provided were by provided high voltage by highmodules. voltage All modules. DC signals All were DC provided signals were and controlled provided and by ancontrolled electronics by board an electronics based on aboard ﬁeld-programmable based on a field gate-programmable array (FPGA). gate This array circuit (FPGA). system This could circuit also generatesystem could AC signal also (0~10generate V0p )AC with signal stored (0~10 waveform V0p) with inverse stored Fourier waveform transform inverse (SWIFT) Fourier function transform to excite(SWIFT) ions function stored in to the excite ion ions trap. stored in the ion trap. FigureFigure1 b 1b shows shows the the photograph photograph of of the the packaged packaged miniature miniature mass mass spectrometer, spectrometer, which which has has dimensionsdimensions of of 38 38 cm cm× ×23 23 cm cm× ×34 34 cm cm (length (length× ×width width× × height).height). AnAn outsideoutside high-voltagehigh-voltage interface interface (HVI)(HVI) was was available, available, providing providing a a high high DC DC voltage voltage (0~ (0~±5000±5000 V)V) thatthat could could bebe used used for for ionization ionization sources.sources. Using Using a a cable cable connected connected with with the the HVI, HVI, the the high high voltage voltage could could be be easily easily applied applied to to the the ionizationionization sources. sources. AA tablettablet computercomputer (X5,(X5, TECLAST,TECLAST, Guangzhou, Guangzhou, China)China) waswas usedused asas the the control control terminal,terminal, which which could could communicate communicate with with instrument instrument control control electronics electronics either either by by a a wireless wireless method method (wireless(wireless ﬁdelity, fidelity, WIFI) WIFI) or or a a cable cable based based on on the the TCP/IP TCP/IP network network protocol. protocol. The The overall overall instrument instrument was was 1313 kg kg in in weight, weight, and and power-suppliedpower-supplied byby anan adapteradapter withwith a power consumption of 200 200 watt wattss in in total. total.

(a) RF coil-ion trap Signal amplifier (b) HV-ion source Tablet computer HV-dynode Manifold

Capillary inlet HV-EM XYZ platform

WIFI board cm

Cooling fan 34

HVI

FPGA electronics RF coil-ion funnel

FigureFigure 1. 1.3D 3D assembly assembly ( a(a);); and and photograph photograph ( b(b)) of of the the integrated integrated miniature miniature mass mass spectrometer. spectrometer.

2.2.2.2. Chemical Chemical Samples Samples MRFAMRFA (Met-Arg-Phe-Ala), (Met-Arg-Phe-Ala), reserpine, reserpine, DEET DEET (N (,N,-Diethyl-3-methylN-Diethyl-3-methyl benzoyl benzoyl amide), amide), rhodamine rhodamine b, PEGb, PEG 600 600 (Polyethylene (Polyethylene glycol glycol 600), 600), PEG PEG 1500 1500 (Polyethylene (Polyethylene glycol glycol 1500), 1500), and and caffeine caffeine were were allall purchasedpurchased from from Sigma Sigma Aldrich Aldrich (St. (St. Louis,Louis, MO,MO, USA).USA). HPLCHPLC gradegrade methanol methanol waswas purchased purchased from from FischerFischer Chemical Chemical (Fair (Fair Lawn, Lawn, NJ, NJ, USA), USA), puriﬁed purified water water was was purchasedpurchased fromfromWahaha Wahaha Inc. Inc.(Hangzhou, (Hangzhou, China).China). All All samples samples were were diluted diluted in in methanol–water methanol–water (1:1 (1:1v /v/vv).).

3.3. Results Results and and Discussion Discussion TheThe goal goal of of designing designing a miniaturea miniature mass mass spectrometer spectrometer is to is expand to expand the applications the applications of MS of and MS make and MSmake more MS and more more and suitable more for suitable real-time for and real on-site-time analysis. and on-site The analysis. instrument The further instrument developed further in thisdeveloped study represents in this study an upgrade represents to the an previousupgrade generations,to the previous and generations, is expected to and have is expected better analytical to have performances,better analytical including performances, stability including and repeatability, stability and sensitivity, repeatability, MS resolution, sensitivity, mass MS resolution, range, and mass the capabilityrange, and to couplethe capability with different to couple ambient with ionizationdifferent ambient sources. Asionization an overview, sources. the previousAs an overview, generation the ofprevious the CAPI generation mini MS have of the stability CAPI ofmini signal MS RSD have < stability 7%, sensitivity of signal of 50RSD ng/mL <7%, for sensitivity LOD, and of resolution 50 ng/mL offor better LOD, than and unit. resolution of better than unit.

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3.1.3.1. Instrument StabilityStability Stability and robustness are important ﬁgurefigure of merits for a MS system, especially for miniature mass spectrometers, which are expected to be used on site rather than in laboratory. Compared with MI and DAPI, a continuous atmospheric pressure interfac interfacee has been proven to be a more suitable interface for for miniature miniature MS, MS with, with high high stability stability and robustness. and robustness. The stable The pressure stable pressure in vacuum in chambers vacuum waschambers expected was to expected contribute to contribute to the stability to the of stability the instrument. of the instrument. To test the stabilityTo test the of thestability instrument of the developedinstrument in developed this study, in MRFA this study, with three MRFA different with three concentrations different (1concentrationsµg/mL, 5 µg/mL, (1 μg/ andmL 10, 5 µμg/g/mL)mL, wereand 10 used μg/ asmL samples.) were used Ionized as samples. by a nano-ESI Ionized source, by a nano the ion-ESI currents source, of the MRFA ion currents (m/z 524) of overMRFA 80 scan(m/z cycles524) over were 80 recordedscan cycles as shownwere recorded in Figure as2 .shown The inset in Figure table in2. FigureThe inset2 lists table the in relative Figure standard2 lists the deviationsrelative standard (RSDs) of deviations the ion intensities (RSDs) of over the 80 ion scan intensities cycles with over respect 80 scan with cycles different with concentrations. respect with Thedifferent result concentrations. shows that the The ion currentresult shows is stable that with the a ion RSD cu ofrrent <5%, is whichstable indicateswith a RSD that of high <5%, stability which wasindicates achieved that byhigh this stability mini MS. was achieved by this mini MS.

1 μg/mL 5 μg/mL 10 μg/mL 1000 800

600

400 Concentration (μg/mL) 1 5 10 RSD (%) 4.04 3.98 4.23 200

Lg[abundance]

0 10 20 30 40 50 60 70 80 90 Scan number FigureFigure 2.2. Abundances in log scale ofof MRFAMRFA ((mm//z 524) over 80 MS scans.

3.2.3.2. Sensitivity The sensitivity of the miniature mass spectrometerspectrometer with a continuouscontinuous atmospheric pressure interface is determined by many factors, including the the gas gas flow flow rate through the capillary capillary,, and the ion transfer efficiencyefficiency from the capillary exit to thethe ionion trap.trap. DifferentDifferent fromfrom previouslypreviously developeddeveloped miniature mass spectrometers with continuous atmospheric pressure interfaces,interfaces, the instrument in this study used a turboturbo molecule pump Hipace 80 instead of the Hipace 10, which was able to lower the pressure in in the the ion ion trap trap region, region, while while allowing allowing a reduction a reduction in inthe the length length of the of thecapillary capillary from from the the20 cm 20 cmused used previously previously to 10 to cm 10, cm, enhancing enhancing the the gas gas flow flow rate rate through through the the capi capillary.llary. In Inaddition, addition, a aminiature miniature ion ion funnel funnel was was also also integrated integrated into into the the mini mini MS MS system, system, which which has has been been demonstrated demonstrated to tohave have capability capability of increasing of increasing the theion iontransfer transfer efficiency efficiency by more by more than than 10 times 10 times [29]. [ 29Therefore,]. Therefore, the themini mini MS MSdeveloped developed in this in thisstudy study was was expected expected to have to have better better performance performance in terms in terms of sensitivity. of sensitivity. To Todemonstrate demonstrate the the sensitivity sensitivity of of the the instrument, instrument, experiments experiments were were performed performed using using MRFA MRFA and reserpinereserpine asas thethe testingtesting samples, samples, and and nano-ESI nano-ESI as as the the ionization ionization source. source. InIn experiments,experiments, thethe ionizationionization time was kept to to a a constant constant value value of of 100 100 ms, ms, and and tandem tandem MS MS was was employed employed to to isolate precursor ions for quantification.quantification. FigureFigure3 3plots plots the the calibration calibration curves curves of MRFAof MRFA (Figure (Figure3a) and3a) reserpineand reserpine (Figure (Fig3b).ure Limits3b). Limits of detection of detection (LODs) (LODs) of 0.01 ofµ 0.01g/mL μg/mL were achievedwere achieved for both for samples, both samples, and linear and dynamiclinear dynamic ranges (LDRs)ranges (LDRs)of 0.01–20 of µ 0.01g/mL–20 and μg/mL 0.01–25 and µ 0.01g/mL–25 were μg/mL obtained were obtained respectively respectively for MRFA for and MRFA reserpine and withreserpine good with linearities good linearities of R2 > 0.99. of R2 >0.99.

Instruments 2018, 2, 2 5 of 9 Instruments 2018, 2, x 5 of 9

(a) (b) 100 Instruments 2018100, 2, x 5 of 9 MRFA （m/z 524) Reserpine (m/z 609) (a) 75 LOD = 0.01 μg/ml (b) 75 LOD = 0.01 μg/ml 100 LDR = 0.01-20 μg/ml 100 LDR = 0.01-25 μg/ml 50 MRFA （m/z 524) 50 Reserpine (m/z 609) 75 LOD = 0.01 μg/ml 75 LOD = 0.01 μg/ml 25 25 LDR = 0.01-20y =μ g/ml0.8492x - 45.789 LDR = 0.01-25y μ =g/ml 0.2574x + 20.612 50 R² = 0.9992 50 R²= 0.9957

0 0 Relative abundance (%)

Relative abundance (%) 25 0 4 8y = 0.849212 x -1645.78920 25 0 5 10 y = 150.2574x20 + 20.61225 ConcentrationR² = (μg/ml) 0.9992 ConcentrationR² =(μ 0.9957g/ml)

0 0 Relative abundance (%)

Relative abundance (%) 0 FigureFigure4 3. 3.8Linear Linear12 dynamic dynamic16 ranges20 of of MRFA MRFA 0(a ()a and) and5 reserpine reserpine10 (b15). (b). 20 25 Concentration (μg/ml) Concentration (μg/ml) 3.3. MS Resolution 3.3. MS Resolution In general, MS resolutionFigure 3. Linear of an dynamic ion trap ranges could of MRFA be affected (a) and byreserpine buffer ( b gas). pressure in it. The presenceIn general, of buffer MS resolution gas is helpful of an for ion cooling trap could ions towards be affected the bycenter buffer of the gas ion pressure trap, but in at it. the The same presence 3.3. MS Resolution of buffertime, gas higher is helpful buffer gas for pressures cooling ions would towards broaden the mass center peaks of thein a ion mass trap, spectrum but at, theand same cause time, higherdegradation bufferIn general, gas of pressuresMS MS resolution. resolution would To of achieve broaden an ion an trap mass optimized could peaks be MS affectedin resolution, a mass byspectrum, buffer the buffer gas and pressuregas causepressure indegradation it. in The an of MSionpresence resolution. trap of of a buffer lab To-scale achievegas mass is helpful spectrometer an optimized for cooling is normallyMS ions resolution, towards kept thebelow the center 1 buffer mTorr. of the gas However, ion pressure trap, butthe in atpressure antheion same in trap of a lab-scalethetime, ion higher masstrap region spectrometer buffer of gasa miniature pressures is normally mass would spectrometer kept broaden below is mass1 typically mTorr. peaks However,limited in a massby the the spectrum pumping pressure, capacityand in the causeion of trap regionthedegradation of vacuum a miniature system.of MS massresolution. Especially spectrometer To for achieve mini ismass an typically optimized spectrometers limited MS resolution, with by the a CAPI, pumping the thebuffer background capacity gas pressure of pressure the in vacuuman ion trap of a lab-scale mass spectrometer is normally kept below 1 mTorr. However, the pressure in system.in the Especially ion trap forregion mini is mass relatively spectrometers high, which with results a CAPI, in reduced the background MS resolution. pressure For example, in the ion a trap backgroundthe ion trap regionpressure of aof miniature 6 mTorr andmass 3 spectrometer mTorr were achievedis typically in limited the first by and the secondpumping generation capacity of region is relatively high, which results in reduced MS resolution. For example, a background pressure CAPIthe vacuum-interfaced system. miniature Especially mass for spectrometers, mini mass spectrometers respectively. with a CAPI, the background pressure of 6 mTorrin theIn andionthis trap 3study, mTorr region the were buffer is relatively achieved gas pressure high, in the which in first the and resultsion secondtrap in region reduced generation was MS further resolution. of CAPI-interfaced lowered For to example, around miniature 1 a massmTorrbackground spectrometers, by using pressure pumps respectively. of with 6 mTorr much and higher 3 mTorr pumping were speed achieveds, which in theshould first be and beneficial second forgeneration improving of MSCAPIIn this resolution.-interfaced study, theTo miniature characterize buffer gas mass pressure MS spectrometers, resolution, in the the ion respectively. full trap width region at washalf maximum further lowered (FWHM) to a aroundt different 1 mTorr by usingscan Inrates pumps this was study, with recorded the much buffer and higher plotted gas pressure pumping in Figure in speeds, the4. MRFA ion trap which (m /regionz 524) should ionizedwas befurther by beneficial a lowerednano-ESI for to source improving around was 1 MS resolution.tested.mTorr byFWHM To using characterize of pumps ~2.7 Da with MS was much resolution, obtained higher at pumpingthe a scan full rate width speed of 14s at, ,which860 half Da/s,maximum should and bebetter beneficial (FWHM) than unit for at improvingresolution different scan rates(FWHMMS was resolution. recorded < 1 Da) To could and characterize plottedbe achieved MS in Figureresolution, when 4decreasing. MRFA the full (thewidthm /MSz at524) scan half ionizedrate maximum below by 1320(FWHM) a nano-ESI Da/s. a Thet different source result was tested.verifiedscan FWHM rates that was of MS ~2.7recorded resolution Da was and could obtainedplotted be improvedin atFigure a scan 4by. MRFA rate lowering of (m 14,860/ zthe 524) MS Da/s, ionized scan and rate. by better aAs nano shown than-ESI insource unit Figure resolution was 4, atested. FWHM FWHM of 0.3 of Da ~2.7 was Da achieved was obtained at a scan at a rate scan of rate 471 ofDa/s. 14,860 In practice,Da/s, and the better MS resolutionthan unit resolution of a mini (FWHM < 1 Da) could be achieved when decreasing the MS scan rate below 1320 Da/s. The result MS,(FWHM especiall < 1 Da)y with could high be buffer achieved gas pressures,when decreasing could be the optimized MS scan by rate adjusting below 1320 the scan Da/s. rate The to result meet verified that MS resolution could be improved by lowering the MS scan rate. As shown in Figure4, practicalverified that requirements MS resolution in different could be applications. improved by lowering the MS scan rate. As shown in Figure 4, a FWHMa FWHM of 0.3 of Da0.3 Da was was achieved achieved at at a a scan scan raterate ofof 471 Da/s. In In practice, practice, the theMS MSresolution resolution of a mini of a mini MS, especiallyMS, especiall withy with high high buffer buffer gas gas pressures, pressures, could14860 Da/s be be optimized optimized by by adjusting adjusting the thescan scan rate to rate meet to meet 3 practicalpractical requirements requirements in differentin different applications. applications. 2.7 1320 Da/s 14860 Da/s 3 0.8 2

） 2.7 3715 Da/s

Da 1320 Da/s

1.4 （ 0.8 2

） 1 3715 Da/s

471 Da/s Da

FWHM 0.3 1.4 （

1 0 471 Da/s 0 3000 6000 9000 12000 15000 FWHM 0.3 Scan rate（Da/s）

Figure 4. MS resolution (FWHM)0 at different scan rates using MRFA as sample ionized by nano-ESI. 0 3000 6000 9000 12000 15000

Scan rate（Da/s） Figure 4. MS resolution (FWHM) at different scan rates using MRFA as sample ionized by nano-ESI. Figure 4. MS resolution (FWHM) at different scan rates using MRFA as sample ionized by nano-ESI.

Instruments 2018, 2, 2 6 of 9 Instruments 2018, 2, x 6 of 9

3.4.3.4. Coupling Coupling with with Different Different Ambient Ambient Ionization Ionization Sources Sources AA signiﬁcant significant feature feature of of the the miniature miniature mass mass spectrometer spectrometer with with CAPI CAPI is is the the capability capability of of coupling coupling withwith different different ambient ambient ionization ionization sources, sources, which which enables enables the the rapid rapid analysis analysis of of complex complex samples samples on on site.site. ToTo demonstratedemonstrate this capability, APCI, APCI, paper paper spray spray and and nano nano-ESI-ESI were were coupled coupled with with the the mini mini MS MSdeveloped developed in this in this study study to analyze to analyze different different samples. samples. In experiments, In experiments, high high voltages voltages of 4 ofkV, 4 3 kV, kV, 3 kV,and and1 kV 1 were kV were applied applied for APCI, for APCI, paper paper spray, spray, and nano and- nano-ESI,ESI, respecti respectively.vely. Figure Figure 5 plots5 theplots mass the spectra mass spectraof different of different samples samples using the using three the ionization three ionization sources. sources. These mass These spectra mass were spectra recorded were recorded at a scan atrate a scan of 7500 rate Da/s. of 7500 As a Da/s. volatile As sample, a volatile DEET sample, was chosen DEET as was the chosenanalyte asfor the APCI, analyte and DEET for APCI, monomer and DEET(m/z 192), monomer dimer ((mm//zz 383)192), and dimer tripolymer (m/z 383) (m/ andz 574) tripolymer were all observed (m/z 574) in were its mass all observedspectrum in(Figure its mass 5a). spectrumThe inset (Figure of Figure5a). 5 Thea shows inset the of Figuretandem5a mass shows spectrum the tandem of m mass/z 192. spectrum In terms of of mnonvolatile/z 192. In termssamples, of nonvolatilerhodamine samples, B (10 μg/ rhodaminemL) and B MRFA (10 µg/mL) (10 μg/ andmL MRFA) were (10 analyzedµg/mL) by were paper analyzed spray by and paper nano spray-ESI, andrespectively. nano-ESI, Tandem respectively. mass Tandemspectra of mass rhodamine spectra ofB ( rhodamineFigure 5b) and B (Figure MRFA5 b)(Figure and MRFA 5c) were (Figure obtained.5c) wereThe obtained. tandem MS The experiments tandem MS experiments were conducted were by conducted first isolating by ﬁrst precursor isolating precursor ions using ions a SWIFT using awaveform, SWIFT waveform, and then and exciting then excitingand fragmenting and fragmenting precursor precursor ions with ions a resonant with a resonant AC signal. AC signal.

(a) (b) (c) APCI needle

MS inlet MS inlet MS inlet 4 kV 3 kV 1 kV APCI Paper spray Nano ESI [M+H]+ 119 100 192 m/z 443 m/z 192 100 399 100 288 m/z 524

271 75 75 192 75 [M+H]+ 453 50 50 443 50 100 150 200 250 300 507 489 [3M+H]+ 435 25 + 25 229 + [2M+H] 574 25 237 376 418 [M+H] 383 524

Relative abundance (%) 0 0 100 200 300 400 500 600 0 300 400 500 600 200 300 400 500 600 m/z m/z m/z

FigureFigure 5. 5.Mass Mass spectra spectra of of ( a(a)) DEET; DEET; ( b(b)) rhodamine rhodamine B; B; and and ( c(c)) MRFA MRFA coupling coupling with with different different ionization ionization sourcessources of of APCI, APCI, paper paper spray spray and and nano-ESI, nano-ESI, respectively. respectively.

3.5.3.5. Mass Mass Range Range ToTo meet meet the the analytical analytical requirements requirements of of different different samples, samples, a a miniature miniature mass mass spectrometer spectrometer should should havehave a a mass mass range range that that is wide is wide enough enough to cover to cover ions with ions various with various mass over mass charges over ascharges much as possible.much as Thepossible. mass range The mass of an range ion trap of massan ion spectrometer trap mass spectrometer is determined is by determ manyined factors, by includingmany factors, RF frequency, including maximumRF frequency, RF amplitude, maximum andRF amplitude, AC frequency and for AC resonance frequency ejection. for resonance In this study,ejection. RF In frequency this study, was RF optimizedfrequency atwas 930 optimized kHz, and aatmass 930 kHz, range and of 150–800a mass range Da was of obtained150–800 Da in thewas typical obtained operation in the modetypical (dipolaroperation resonance mode (dipolar AC, 310 resonance kHz). Figure AC,6a shows310 kHz). the massFigure spectrum 6a shows of the caffeine mass (10 spectrumµg/mL, ofm /caffeinez 195). Figure(10 μg/mL,6b plots m/ thez 195). mass Figure spectrum 6b plots of PEGthe mass 600 (nano-ESI, spectrum 10of PEGµg/mL), 600 (nano which-ESI, covers 10 μg/mL), a mass rangewhich fromcovers 500 a Da mass to 800 range Da. from To analyze 500 Da larger to 800 molecules, Da. To analyze mass range larger could molecules, be extended mass by range lowering could the be frequencyextended ofby thelowering dipolar the AC frequency excitation of signal.the dipolar As shownAC excitation in Figure signal.6c, the As mass shown spectrum in Figure of 6 PEGc, the 1500mass (nano-ESI, spectrum 10 ofµ PEGg/mL) 1500 was (nano obtained-ESI, when10 μg/mL) lowering was theobtained frequency when of lowering excitation the AC frequency to 160 kHz, of atexcitation which the AC mass to 160 range kHz, of at the which instrument the mass could range be of extended the instrument up to 2000 could Da. be Both extended singly up charged to 2000 and Da. doublyBoth singly charged charged ions wereand doubly observed charged in the ions mass were spectrum observed of PEG in the 1500. mass spectrum of PEG 1500.

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(a) (b) 100 552 100 Caffeine 596 195 ） PEG 600

） % 508 % 640

（ 75

（ 75 162 50 464 50 688 732 420

25 25 Relative abundance Relative Relative abundance Relative 0 0 150 200 250 300 350 300 400 500 600 700 800 900 m/z m/z (c) +2 888 PEG 1500

） 866 910 % 100 +1 844 932

（ 954 822 75 976 800 998 1538 1020 1494 1626 1714 1450 50 778 1582 1670 1758 1042 1406 1802 1846 756 1086 1274 1362 1890 1064 1318 1934 25 1230 734 1108 19782022 0 Relative abundance 800 1000 1200 1400 1600 1800 2000 m/z Figure 6. Mass range of the miniature mass spectrometer. Mass spectra of (a) caffeine and (b) PEG Figure 6. Mass range of the miniature mass spectrometer. Mass spectra of (a) caffeine and (b) PEG 600 600 recorded at AC ejection frequency of 310 kHz; (c) Mass spectrum of PEG 1500 recorded at AC recorded at AC ejection frequency of 310 kHz; (c) Mass spectrum of PEG 1500 recorded at AC ejection ejection frequency of 160 kHz. frequency of 160 kHz.

4. Conclusions 4. Conclusions In this study, an upgraded and integrated miniature mass spectrometer with CAPI has been In this study, an upgraded and integrated miniature mass spectrometer with CAPI has been developed. With a power consumption of 200 W, the instrument has dimensions of 38 cm × 23 cm × developed. With a power consumption of 200 W, the instrument has dimensions of 38 cm × 23 cm 33 cm (length × width × height) and a weight of 13 kg in total. As demonstrated using different × 33 cm (length × width × height) and a weight of 13 kg in total. As demonstrated using different ionization sources, including APCI, nano-ESI, and paper spray, the mini MS has good robustness and ionization sources, including APCI, nano-ESI, and paper spray, the mini MS has good robustness and repeatability (RSD < 5%) and high sensitivity (LOD = 10 ng/mL). MS resolution of better than unit repeatability (RSD < 5%) and high sensitivity (LOD = 10 ng/mL). MS resolution of better than unit could be achieved by adjusting MS scan rate. It has a mass range of 150–800 Da in normal scan mode, could be achieved by adjusting MS scan rate. It has a mass range of 150–800 Da in normal scan mode, and could be extended up to 2000 Da by lowering the AC resonance frequency. and could be extended up to 2000 Da by lowering the AC resonance frequency.

Acknowledgments:Acknowledgments: This work was supported by NNSF (21475010, 61635003), BNSF (16L00065) and State Key Laboratory of Explosion Science and Technology (YBKT16-17).(YBKT16-17). Author Contributions: Wei Xu and YanbingYanbing ZhaiZhai conceivedconceived andand designeddesigned thethe experiments;experiments; Xiangzhi Meng performedperformed the experiments; Xiaohua Zhang analyzed the data; YanbingYanbing ZhaiZhai wrotewrote thethe paper.paper.

ConflictsConﬂicts ofof Interest:Interest: The authors declare nono conﬂictconflict ofof interest.interest.

References

1. Lebedev, A.T. EnvironmentalEnvironmental massmass spectrometry.spectrometry.Rev. Rev. Anal.Anal. Chem.Chem. 20132013,, 66,, 163–189.163–189. [CrossRef][PubMed] 2. Moore, D.S. Instrumentation Instrumentation for for trace trace detection detection of of high high explosives. explosives. Rev.Rev. Sci. Sci. Instrum. Instrum. 20042004, 75, 75, 2499, 2499–2512.–2512. 3. Nilles,[CrossRef J.M.;] Connell, T.R.; Durst, H.D. Quantitation of Chemical Warfare Agents Using the Direct Analysis 3. inNilles, Real J.M.;Time Connell, (DART) T.R.;Technique. Durst, H.D.Anal. QuantitationChem. 2009, 81 of, Chemical6744–6749. Warfare Agents Using the Direct Analysis 4. Hoffman,in Real Time J.H.; (DART) Hodges, Technique. R.R.; Wright,Anal. Chem.W.W.; 2009Blevins,, 81, 6744–6749.V.A.; Duerksen, [CrossRef K.D.;][ PubMedBrooks, L.D.] Pioneer Venus 4. SounderHoffman, Probe J.H.; Neutral Hodges, Gas R.R.; Mass Wright, Spectrometer. W.W.; Blevins, IEEE Trans V.A.;. Geosci. Duerksen, Remote K.D.; Sens. Brooks, 1980, 18 L.D., 80 Pioneer–84. Venus 5. Niemann,Sounder Probe H.B.; Neutral Atreya, Gas S.K.; Mass Bauer, Spectrometer. S.J.; Biemann,IEEE K.; Trans. Block, Geosci. B.P.; RemoteCarignan, Sens. G.R.;1980 Donahue, 18, 80–84., T.M.; [CrossRef Frost,] 5. R.L.;Niemann, Gautier, H.B.; D.; Atreya, Haberman, S.K.; J.A.; Bauer, et S.J.;al. The Biemann, Gas Chromatograph K.; Block, B.P.; Mass Carignan, Spectrometer G.R.; Donahue, for the Huygens T.M.; Frost, Probe. R.L.; SpaceGautier, Sci. D.;Rev. Haberman, 2002, 104, 553 J.A.;–591. et al. The Gas Chromatograph Mass Spectrometer for the Huygens Probe. 6. VonSpace Zahn, Sci. Rev. U.;2002 Fricke,, 104 , K.H.; 553–591. Hunten, [CrossRef D.M.;] Krankowsky, D.; Mauersberger, K.; Nier, A.O. The upper atmosphere of Venus during morning conditions. J. Geophys. Res. Space Phys. 1980, 85, 7829–7840.

Instruments 2018, 2, 2 8 of 9

6. Von Zahn, U.; Fricke, K.H.; Hunten, D.M.; Krankowsky, D.; Mauersberger, K.; Nier, A.O. The upper atmosphere of Venus during morning conditions. J. Geophys. Res. Space Phys. 1980, 85, 7829–7840. [CrossRef] 7. Hofer, L.; Wurz, P.; Buch, A.; Cabane, M.; Coll, P.; Coscia, D.; Gerasimov, M.; Lasi, D.; Sapgir, A.; Szopa, C.; et al. Prototype of the gas chromatograph–mass spectrometer to investigate volatile species in the lunar soil for the Luna-Resurs mission. Planet. Space Sci. 2015, 111, 126–133. [CrossRef] 8. Meyer, S.; Tulej, M.; Wurz, P. Mass spectrometry of planetary exospheres at high relative velocity: Direct comparison of open-and closed-source measurements. Geosci. Instrum. Methods Data Syst. 2017, 6, 1–8. [CrossRef] 9. Riedo, A.; Bieler, A.; Neuland, M.; Tulej, M.; Wurz, P. Performance evaluation of a miniature laser ablation time-of-ﬂight mass spectrometer designed for in situ investigations in planetary space research. J. Mass Spectrom. 2013, 48, 1–15. [CrossRef][PubMed] 10. Li, L.; Chen, T.; Ren, Y.; Hendricks, P.I.; Cooks, R.G.; Ouyang, Z. Mini 12, miniature mass spectrometer for clinical and other applications—Introduction and characterization. Anal. Chem. 2014, 86, 2909–2916. [CrossRef][PubMed] 11. Cooks, R.G.; Manicke, N.E.; Dill, A.L.; Ifa, D.R.; Eberlin, L.S.; Costa, A.B.; Wang, H.; Huang, G.; Ouyang, Z. New ionization methods and miniature mass spectrometers for biomedicine: DESI imaging for cancer diagnostics and paper spray ionization for therapeutic drug monitoring. Faraday Discuss. 2011, 149, 247–267. [CrossRef][PubMed] 12. Ouyang, Z.; Cooks, R.G. Miniature mass spectrometers. Annu. Rev. Anal. Chem. 2009, 2, 187–214. [CrossRef] [PubMed] 13. Snyder, D.T.; Pulliam, C.J.; Ouyang, Z.; Cooks, R.G. Miniature and fieldable mass spectrometers: Recent advances. Anal. Chem. 2015, 88, 2–29. [CrossRef] [PubMed] 14. Ketola, R.A.; Kotiaho, T.; Cisper, M.E.; Allen, T.M. Environmental applications of membrane introduction mass spectrometry. J. Mass Spectrom. 2002, 37, 457–476. [CrossRef][PubMed] 15. Janfelt, C.; Frandsen, H.; Lauritsen, F.R. Characterization of a mini membrane inlet mass spectrometer for on-site detection of contaminants in both aqueous and liquid organic samples. Rapid Commun. Mass Spectrom. 2006, 20, 1441–1446. [CrossRef][PubMed] 16. Johnson, R.; Cooks, R.; Allen, T.; Cisper, M.; Hemberger, P. Membrane introduction mass spectrometry: Trends and applications. Mass Spectrom. Rev. 2000, 19, 1–37. [CrossRef] 17. Bell, R.J.; Davey, N.G.; Martinsen, M.; Collin-Hansen, C.; Krogh, E.T.; Gill, C.G. A ﬁeld-portable membrane introduction mass spectrometer for real-time quantitation and spatial mapping of atmospheric and aqueous contaminants. J. Am. Soc. Mass Spectrom. 2015, 26, 212–223. [CrossRef][PubMed] 18. Hendricks, P.I.; Dalgleish, J.K.; Shelley, J.T.; Kirleis, M.A.; Mcnicholas, M.T.; Li, L.; Chen, T.; Chen, C.; Duncan, J.; Boudreau, F.J.; et al. Autonomous in Situ Analysis and Real-Time Chemical Detection Using a Backpack Miniature Mass Spectrometer: Concept, Instrumentation Development, and Performance. Anal. Chem. 2014, 86, 2900–2908. [CrossRef][PubMed] 19. Gao, L.; Cooks, R.G.; Ouyang, Z. Breaking the pumping speed barrier in mass spectrometry: Discontinuous atmospheric pressure interface. Anal. Chem. 2008, 80, 4026–4032. [CrossRef][PubMed] 20. Zhai, Y.; Feng, Y.; Wei, Y.; Wang, Y.; Xu, W. Development of a miniature mass spectrometer with continuous atmospheric pressure interface. Analyst 2015, 140, 3406–3414. [CrossRef][PubMed] 21. Jiang, T.; Zhang, H.; Yang, T.; Zhai, Y.; Wei, X.; Xu, H.; Zhao, X.; Li, D.; Wei, X. A “Brick Mass Spectrometer” Driven by a Sinusoidal Frequency Scanning Technique. Anal. Chem. 2017, 89, 5578–5584. [CrossRef] [PubMed] 22. He, M.; Xue, Z.; Zhang, Y.; Huang, Z.; Fang, X.; Qu, F.; Ouyang, Z.; Xu, W. Development and Characterizations of a Miniature Capillary Electrophoresis Mass Spectrometry System. Anal. Chem. 2015, 87, 2236–2241. [CrossRef][PubMed] 23. Jjunju, F.P.M.; Maher, S.; Li, A.; Syed, S.U.A.H.; Smith, B.; Heeren, R.M.A.; Taylor, S.K.; Cooks, R.G. Hand-held portable desorption atmospheric pressure chemical ionization ion source for in situ analysis of nitroaromatic explosives. Anal. Chem. 2015, 87, 10047–10055. [CrossRef][PubMed] 24. Wang, X.; Zhou, X.; Ouyang, Z. Direct Analysis of Nonvolatile Chemical Compounds on Surfaces Using a Hand-Held Mass Spectrometer with Synchronized Discharge Ionization Function. Anal. Chem. 2016, 88, 826–831. [CrossRef][PubMed] 25. Chen, T.; Ouyang, Z. Synchronized discharge ionization for analysis of volatile organic compounds using a hand-held ion trap mass spectrometer. Anal. Chem. 2013, 85, 1767–1772. [CrossRef][PubMed] Instruments 2018, 2, 2 9 of 9

26. Harper, J.D.; Charipar, N.; Mulligan, C.C.; Zhang, X.; Cooks, R.G.; Ouyang, Z. Low-temperature plasma probe for ambient desorption ionization. Anal. Chem. 2008, 80, 9097–9104. [CrossRef][PubMed] 27. Liu, J.; Wang, H.; Manicke, N.E.; Lin, J.; Cooks, R.G.; Ouyang, Z. Development, characterization, and application of paper spray ionization. Anal. Chem. 2010, 82, 2463–2471. [CrossRef][PubMed] 28. Zhai, Y.; Jiang, T.; Huang, G.; Wei, Y.; Xu, W. An aerodynamic assisted miniature mass spectrometer for enhanced volatile sample analysis. Analyst 2016, 141, 5404–5411. [CrossRef][PubMed] 29. Zhai, Y.; Zhang, X.; Xu, H.; Zheng, Y.; Yuan, T.; Xu, W. Mini Mass Spectrometer Integrated with a Miniature Ion Funnel. Anal. Chem. 2017, 89, 4177–4183. [CrossRef][PubMed] 30. Si, X.; Hu, L.; Xu, W.; Li, H.; Li, C. A Dual-Source Miniature Mass Spectrometer with Improved Sensitivity. Int. J. Mass Spectrom. 2017, 423, 15–19. [CrossRef]

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