Boosting the Sensitivity and Selectivity of a Miniature Mass

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Boosting the Sensitivity and Selectivity of a Miniature Mass Spectrometer Using a Hybrid Ion Funnel Yanbing Zhai, Qian Xu, Yang Tang, Siyu Liu, Dayu Li, and Wei Xu Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01770 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 29, 2019

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Analytical Chemistry

Boosting the Sensitivity and Selectivity of a Miniature Mass Spectrometer Using a Hybrid Ion Funnel

Yanbing Zhai,1 Qian Xu,1 Yang Tang,1 Siyu Liu,1 Dayu Li,2 and Wei Xu1*

1School

of Life Science, Beijing Institute of Technology, Beijing 100081, China

2School

of Computer Science and Engineering, Northeastern University, Shenyang,

110819, China

*Corresponding Author: Wei Xu School of Life Science Beijing Institute of Technology Haidian, Beijing, 100081, China Email: [email protected] Website: http://www.escience.cn/people/weixu

1

ACS Paragon Plus Environment

Analytical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract Besides high portability, high analytical performances are also crucial concerns for a miniature mass spectrometer to meet the demands in in-situ analysis. As a continuous effort in improving analytical performances of the miniature mass spectrometer with continuous atmospheric pressure interface, a hybrid ion funnel was developed and coupled into the system in this study. The hybrid ion funnel was consisted of a rectangular ion funnel region and a planar quadrupole field region, which were fabricated by the printed circuit board technology. After systematic optimization, a limit of detection of 1 ng/mL was obtained, which was improved by 10 folds relative to that of 10 ng/mL previously reported for the miniature mass spectrometer. Besides improved ion transmission efficiency, this hybrid ion funnel was also capable of filtering ions according to their mobilities, thus improving the system selectivity. This capability was demonstrated by separation and selective transmission of protein ions at different charge states, reserpine in PEG background and isobaric peptide ions. Resolution of this system was also tested by analyzing isotopic peaks of reserpine. The ppb-level detection sensitivity and isotope resolving capability achieved in this work would greatly expand the application range of miniature mass spectrometers.

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1. Introduction With high portability and increasingly improved performances, a miniature mass spectrometer has become one of the most powerful tools for in-situ analysis. The developments of miniature mass spectrometers have expanded mass spectrometry (MS) into more and more in-situ analytical fields, including space exploration,1-4 environmental monitoring,5-7 public safety,8, 9 and clinical healthcare.10, 11 By coupling with a variety of ambient ionization sources,12, 13 a miniature mass spectrometer could effectively analyze samples with minimum sample preparations.14-16 Significant efforts have been paid over the past decades in mass spectrometer miniaturization,17, 18 which was started with the miniaturization of mass analyzers.19 By means of micro-electromechanical systems (MEMS) and other advanced fabrication techniques,20-23 various mass analyzers, such as ion traps,24-26 quadrupole mass filters,27, 28

time of flight (TOF) as well as their arrays,29-31 have been miniaturized even in

micrometer-size. Miniaturized mass analyzers could be operated at lowered RF voltages and higher buffer gas pressures, which was helpful for the miniaturization of a mass spectrometer by shrinking electronic and vacuum systems. Miniaturized vacuum system design, specifically the atmospheric pressure interface (API) has always been a critical factor for MS system miniaturization. It determines ion introduction pathway and instrument capability with different ionization sources, but also largely determines size and power consumption of the whole system. Membrane inlets32,

33

or capillary inlets with ultralow gas flow rate34,

35

were first

adopted by miniature mass spectrometers. Limited by semi-permeability of the membrane, this type of instruments has been used for volatile sample analyses. In 2008, a discontinuous atmospheric pressure interface (DAPI)36 was developed and employed for the development of miniature mass spectrometers, so that the introduction of ions from atmospheric environment to vacuum was enabled. As a variant of DAPI, a pulsed pinhole atmospheric pressure interface was also developed afterwards.37 With the capability of coupling with ambient ionization sources, DAPI based systems could analyze both volatile and non-volatile samples.38-40 Based on differential pumping vacuum design and high-pressure ion trap operation, a miniature mass spectrometer with continuous atmospheric pressure interface (CAPI) was also developed in 2015,41 which shows the merits of high stability, scan speed and repeatability. The analyses of volatile and non-volatile samples have also been realized by coupling CAPI interfaced miniature mass spectrometer with either in-vacuum plasma ionization source42 or ambient ionization sources, such as nano electrospray (nano-ESI), paper spray and atmospheric pressure laserspray ionization.43, 44 However, the minimization of instrument size and power consumption typically 3



accompanies degradations of system performances. For instance, a miniature vacuum pumping system requires reduced gas intake rate and the introduction of minimum or even no buffer gases, which would harm sensitivity and resolution of the system. Smaller electronic driving systems would also limit mass range of a miniature mass spectrometer. As a result, there is still a gap between the current analytical performances of a miniature mass spectrometer and the analytical demands in some practical applications, especially when sub-ppb level sensitivity and high quantitation accuracy are required, such as in pesticide residue analyses and point-of-care testings. To fill this gap, researches have been focusing on improving the analytical performances of miniature mass spectrometers. A dual-trap design was implemented on the DAPI based miniature mass spectrometer to improve its duty cycle and quantitation accuracy.45, 46 A miniaturized ion funnel was developed and integrated into the CAPI based miniature mass spectrometer, by which system sensitivity and resolution were improved by 20 times and ~2 times, respectively.47 A sinusoidal frequency scanning technique was developed to extend mass range of a CAPI based “brick” mass spectrometer.48 More recently, mass resolution of the “brick” mass spectrometer was further improved by applying a new ion ejection method: the quadrupole enhanced dipolar resonance ejection.49 As a continuous effort in improving analytical performances of the CAPI based MS system, a hybrid ion funnel was developed in this study and integrated into the first vacuum stage of a CAPI based miniature mass spectrometer. This ion funnel has two regions: a rectangular ion funnel region at the ion entrance and a planar quadrupole field region at the ion exit. These two regions were designed and integrated together using the printed circuit board (PCB) technology, which has also been employed in the fabrication of structures for lossless ion manipulations (SLIM).50 With the help of this hybrid ion funnel, a sensitivity of 1 ng/mL in terms of limit of detection (LOD) was obtained, which is ~10 folds better compared to the same system with a conventional shaped miniature ion funnel. Besides improved ion transmission efficiency, this hybrid ion funnel was also capable of filtering ions according to their mobilities, which was in agreement with the explanation of variable low-mass filtering of an electrodynamic ion funnel reported previously.51 As proof-of-principle demonstrations, protein ions at different charge states, reserpine in PEG background and isobaric peptide ions were separated and selectively transferred into the later ion trap for further analyses. Resolution of this system was tested by analyzing isotopic peaks of reserpine.

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diameter) through joint pads. This rectangular ion funnel region has a 10 mm opening (H1), and it shrinks to 4 mm at its exit (H2). To collect more diffused ions and focus them into a smaller beam, the first 10 electrodes in the rectangular ion funnel region have a same length of 10 mm (L1), and the second 10 electrodes have decreased lengths from L1 = 10 mm to L2 = 4 mm. As shown Figure 1b, all the pad electrodes have a width (We) of 1 mm and a spacing (S1) of 1 mm between adjacent electrodes. As shown in Figure 1c, two radio frequency (RF) signals with opposite phases were coupled to adjacent electrodes, and a DC gradient exist along the z-direction of the funnel (from DC0 to DC1). The planar quadrupole region was consisted of 30 pairs of pad electrodes, which were classified as central electrodes and side electrodes and were all fabricated on two parallel boards with a constant distance of 4 mm. All the pad electrodes in the planar quadrupole region have a length of 4 mm, and a 0.5 mm gap (S2) exists between a central electrode and a side electrode. A first RF (RF-) was applied on all central electrodes, and the opposite phased RF+ was applied on all side electrodes (Figure 1c). A DC gradient was generated along the z-direction of the planar quadrupole region by applying a series of DC voltages between DC1 and DCQ. As shown in the inset of Figure 1a, the final signal applied to each side electrode was –VRF+UDC(i) and VRF+UDC(i) on each central electrode (i was the electrode number). By using resistor networks, linear DC potential gradient exist in both the rectangular ion funnel and planar quadrupole regions. Figure 1d is a photo of the fabricated hybrid ion funnel, which has a total length of ~6 cm. The lengths of rectangular ion funnel region and planar quadrupole field region were 40 mm and 20 mm, respectively. PCB dielectric material was removed between each pad electrode to avoid charge accumulation and help the dissipation of gas flows. 2.3 Instrumentation The instrument used in this study was modified from the miniature mass spectrometer with continuous atmospheric pressure interface, which has been developed in our lab and reported in our previous publications.41, 47, 52 Briefly, the miniMS has a two-stage vacuum chamber, which is differentially pumped by the combination of a scroll mechanical pump (50 L/min, NE5)#O@# Scroll Tech Inc., China) and a turbo pump (80 L/s, Hipace 80, Pfeiffer Inc., Germany). The first vacuum chamber was connected to the atmospheric environment with a stainless-steel capillary (i.d. 0.25 mm, 10 cm in length) and to the second one by a skimmer pinhole (i.d. 0.5 mm). Finally, the pressures in two vacuum chambers were maintained at ~4.5 Torr and ~1.5 mTorr, respectively. As shown in Figure 1e, the hybrid ion funnel developed in 6


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this study was placed at the first vacuum chamber, while a linear ion trap with hyperbolic electrodes (x0 = y0 = 4 mm, z0 = 40 mm) and an electron multiplier used as ion detector were located at the second vacuum chamber. Different from the previous designs, an additional electrode (e2) was placed between skimmer (e1) and the front end cap (e3) of the ion trap with a same distance of 3 mm. Both e2 and e3 were made of 1 mm thick stainless-steel plates with 0.3 mm central holes (i.d.). These three electrodes were used as an Einzel lens to improve the ion transmission efficiency from skimmer into ion trap. In addition, the increased distance of the ion trap from the skimmer could decrease background pressure inside the ion trap, and eventually enhance mass resolution of ion trap, which will be illustrated in detail in a following section of this paper. A nanoESI source was employed in this study to generate ions, which has a tip diameter of ~ 3 P&3 3. Results and discussion 3.1 Electric field distribution in the hybrid ion funnel Electric field distribution within the hybrid ion funnel was simulated through Comsol Multiphysics 4.3 (Comsol Inc., Stockholm, Sweden). Figure 2a plots the overall electric field distribution on the x-z plane of the hybrid ion funnel. Since adjacent electrodes in the rectangular ion funnel region has 180 degree out of phase RF signals, a field free region exists at the center of the funnel. Figure 2b and 2c plot the electric field distributions on the x-y plane at opening (z = 0 mm) and exit of the rectangular ion funnel region (z = 36 mm). With shrunk field free radius, ion beams could be confined to a smaller diameter, and transferred into the planar quadrupole region. The planar quadrupole region has an opening of 4 by 4 mm, and the field distribution is similar to that of a linear ion trap (figure 2d). With the quadrupole rf field, ions entering this region would be further focused towards center of the quadrupole region. Since the rf field in this region has no z-direction component, smaller low mass cut-off effect is expected in this hybrid funnel design.

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turbulence/flow close to the capillary exit are dominant in this region. DC0 and DC1 were then grounded in later experiments. In this study, the DC voltage applied to the exit of the planar quadrupole region (DCQ) was found to be a critical factor, which determines ion transmission efficiency and ion filtering function of the hybrid ion funnel. Figure 3c plots the relative abundances of the three singly charged ions (m/z 267, m/z 443, and m/z 609) at different DCQ voltages. With increased DCQ voltages for all samples, their ion abundances increased to the highest values and then dropped sharply. Different cutoff DCQ voltages were obtained for different single-charged ions: 55 V for atenolol, 80 V for rhodamine b, and 90 V for reserpine. Ion intensity will quickly drop to zero after this cutoff voltage. Similar experiments were further conducted using two samples with the same m/z ratio but different charges: MRFA (10 P 4& > and angiotensin II (10 P 4& >3 The relative abundances of single-charged MRFA ([MRFA+H]+, m/z 524) and doubly charged angiotensin II ions ([angiotensin II+2H]2+, m/z 524) were plotted in Figure 3d. Similar phenomena were observed, in which a cutoff voltage exist for each type of ions. However, a cutoff voltage of ~70 V was observed for angiotensin II, while ~75 V for MRFA. Results suggest that ions could be selectively filtered and separated based on their charge states and sizes, which would be further analyzed in the following section. The DC voltages applied on the Einzel lens were also optimized with results shown in Figure S1. As a result, optimized voltages of 8 V, -30 V, and 2 V were applied to e1, e2, and e3, respectively. After optimizations, ion transmission performance of the hybrid ion funnel developed in this study was compared with that of the miniature ion funnel developed previously. Figure 3e shows the mass spectra of tuning mix recorded by the same miniature mass spectrometer with two ion funnels, and DCQ was set at 60 V. Stronger ion intensities at m/z 322, 622 and 922 were observed with the hybrid ion funnel, especially at the low mass end. For instance, an intensity enhancement of ~ 2 times were achieved at 622, while the ion at 322 were not even observed with the conventional miniature ion funnel, confirming that planar quadrupole could help reduce the low mass cutoff effect. 3.3 Mobility based ion filtering As revealed earlier in Figure 3c and 3d, the DCQ voltage applied to the exit of planar quadrupole could filter either single charged ions with different m/z ratios or ions with same m/z ratio but different charges. This ion filtering effect could be interpreted as follows. While the rf field in the planar quadrupole region is confining ions in the x-y plane, there is a DC electric field (created by DCQ and DC1) along the z direction. Since DCQ is higher than DC1, this DC electric field will push ions backwards and counter balance with the gas flow. The mean free path of ions at a pressure of 4-5 10


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Torr is very small (< 0.1 mm), and ion neutral collisions could be modeled as a drag force. As a result, ions in the planar quadrupole field region will be carried forward by the gas flow while pushed backward by the DC electric field. According to ion mobility theory, ion drift velocity (vdrift) is defined by the product of the mobility coefficient (K) and the DC electric field (E). To block ions from passing through the electric field, their drift velocity must be larger than the gas velocity (in Equation 1) vdrift = KE > vgas

(1)

The mobility coefficient can be expressed via ion collision cross section (CCS, V> as follows: 1/2

(

=

)

(2)

where n is the buffer gas number density, kb is the Boltzmann constant, T is the temperature, ze is the ion charge, mr is the reduced mass of the buffer gas and ion collision pair defined as mr = mM/(m+M), in which m is the mass of the ion, M is the mass of the buffer gas. Combining Equation (1) and (2), a relationship between DCQ with respect to the ion mass, ion charge and CCS can be obtained (Equation (3)). For an ion with mass much heavier than that of the buffer gas molecule, mr is approximately equal to the buffer gas mass (M), and K varies only with ion charge (ze) and CCS ( ). Therefore, a higher DCQ voltage is needed to filter ions with lower charge states or ions with larger CCSs, which agrees with the results shown in Figure 3c and 3d. >

(

)

1/2 gas

(3)

As the first demonstration, different charge states of cytochrome C ions were selectively filtered by applying different DCQ voltages. Multiply charged cytochrome C (50 P 4& > ions were generated by the nanoESI source. As shown in Figure 4a, when a relatively small DCQ voltage (60 V) was applied, ions with charge states from 18+ to 11+ could all be well observed in the mass spectrum. With increased DCQ voltage, ions at higher charge states would start to disappear (Figure 4b and 4c). At a DCQ voltage of 85 V, a strong filtering effect were achieved for high charge state ions (14+ to 18+), and ions with charge states from 15+ to 10+ were shown in the mass spectrum.

11



15+ 825 16+ 773

DCQ = 60 V

600

17+ 728 18+ 687

400 200

450

14+ 884 13+ 952 12+ 1031

0 600 450

800

16+

(b)

160

11+

1000

1200

14+

DCQ = 80 V

(c) 15+

80 16+

12+

800

1000

609 570

0 200

300

400

500

600

526

DCQ = 70 V

207

482

700

(g) 609 570

438 300

400

500

600

609

700

(h)

114

38

10+

0 200

0 800

526

11+

15+

600

482

DCQ = 80 V

(d)

700

(f)

394

150

276

600

76

14+

40

1200

12+

120 80

500

609

438

0 200 152

13+

DCQ = 85 V

400

69

11+

0 600

570

138

13+

40

526

300

800

120

160

300

DCQ = 60 V

14+ 13+ 12+

(e)

306

0 200 600

1200

0 600

438

350 150

11+ 1124

1000

17+

394

482

450

300 150

DCQ = 30 V

300

15+

DCQ = 75 V

600

(a)

Abundance

800

Abundance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1000

1200

300

400

500

600

700

m/z

m/z

Figure 4. Mass spectra of cytochrome C obtained at different DCQ voltages of (a) 60 V, (b) 75 V, (c) 80 V, and (d) 85 V. Mass spectra of reserpine mixed with PEG 300 obtained at DCQ voltages of (e) 30 V, (f) 60 V, (g) 70 V, and (h) 80 V. In practical applications, miniature mass spectrometers are not expected or specialized in covering a broad mass range for unknown sample identification, but rather target molecule analyses in the database. With the ion filtering capability, the hybrid ion funnel developed herein would be beneficial for the detection of target analyte in complex matrix in terms of removing solvent clusters and impurities, thus improving the selectivity of target analytes. To demonstrate this capability, a mixture sample containing relatively low concentration target molecules was prepared. In experiments, reserpine with a concentration of 0.5 P 4& was mixed with a PEG 300 solution (25 P 4& > (1:1 in volume ratio). With ~ 50 times lower in concentration, peak intensity of reserpine ions (m/z 609) were lower than that of PEG 300 when DCQ was set at low voltage (Figure 4e). Interference peaks from PEG 300 could be effectively filtered when this DCQ voltage was increased. At ~80 V, PEG 300 ions could be totally removed from the mass spectrum and reserpine becomes the dominant peak in the spectrum (Figure 4h). With limited resources, the resolution of a miniature ion trap mass spectrometer is

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typically on the level of unit mass resolution. Therefore, the identification of ions with close m/z ratios has always been a challenge. With capability of filtering ions based on their mobilities, the hybrid ion funnel developed in this work could be used as an ion pre-separation device to overcome the limitation of MS resolution for the analysis of isobaric ions. As a proof-of-concept demonstration, a peptide mixture of MRFA (5 P 4& > and angiotensin II (2.5 P 4& > was analyzed. Figure 5a shows the mass spectrum obtained at a DCQ voltage of 60 V, in which protonated MRFA ions ([MRFA+H]+) and doubly charged angiotensin II ions ([Angiotensin II+2H]2+) were presented as the overlapped peak of m/z 524. Sodium adduct ([Angiotensin II+Na]2+, m/z 534) and calcium adduct ([Angiotensin II+K]2+, m/z 542) were also observed. The existence of angiotensin II ions mixed with MRFA ions at m/z 524 was also verified by tandem MS as shown in Figure 5c. Product ions of MRFA (noted in blue) and angiotensin II (noted in red) were both presented in the tandem mass spectrum. Possessing two charges, angiotensin II ions at 524 would be filtered and blocked first with increased DCQ voltages (Equation 2). As shown in Figure 5b, only one prominent peak at m/z 524 was observed in the mass spectrum, when the DCQ voltage was increased to 80 V. Figure 5d plot the corresponding tandem mass spectrum, in which only the fragments of MRFA were observed, suggesting that angiotensin II ions were effectively filtered by the hybrid ion funnel.

(a)

524

Abundance

6000

[Angiotensin II+2H]2+

[MRFA+H]+

(b)

(c) 600

*

288 DCQ = 60 V

500

4500 534 [Angiotensin II+Na]2+

3000

542 [Angiotensin II+K]2+

“N” - MRFA- “C” “N” - DRVYIHPF - “C”

DCQ = 60 V 0 400 450 500 550 600 650 700

271

300

4000

524

*

100 0 (d) 500

[MRFA+H]+

m/z 524

*

400

* * 453 * 435 418

*

229 263

376

200

300 *

288

DCQ = 80 V

*

489 * 507 466 513

200

1500

Abundance

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


400

500

“N” - MRFA- “C”

400

3000

m/z 524

*

271

300 2000

200 1000

*

*

100 DCQ = 80 V

0 400 450 500 550 600 650 700

600

435 * * 453 418

*

229

376

*

489 * 507 524

0 200

300

m/z

400

500

600

m/z

Figure 5. Mass spectra of the mixture of MRFA and angiotensin II recorded at DCQ voltages of (a) 60 V, and (b) 80 V. Tandem mass spectra of ions at m/z 524 obtained by CID at DCQ voltages of (c) 60 V, and (d) 80 V.

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3.5 Sensitivity and mass resolution characterization Improvement in ion transmission efficiency through the ion funnel would result in increased MS detection sensitivity. Previously a detection sensitivity of 10 ng/mL was achieved with the mini MS system equipped with the conventional miniature ion funnel.52 Detection sensitivity of the same mini MS system integrated with the hybrid ion funnel was then tested. In this experiment, reserpine was analyzed, and ions at m/z 609 was used for quantitation. Figure 6a plots relative abundances of reserpine ion (m/z 609) with respect to its concentrations, in which a LOD of 1 ng/mL was obtained. Figure 6b plots the corresponding tandem MS of reserpine at 1 ng/mL. Results suggest that the integration of the hybrid ion funnel and Einzel lens could effectively increase

100

(c)

Reserpine LOD = 1 ng/mL

75

100

609.3

50

@ 5000 Da/s

1.2 Da

50

y = 7.5982x - 77.334

Relative abundance (%)

(a)

Relative abundance (%)

ion transmission efficiency by ~ 10 folds.

25

R2 = 0.9977 0 0

200

400

600

800

1000

Concentration (ng/mL)

(b) Relative abundance (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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609

100

m/z 609

397

0 100

609.3

@ 1600 Da/s

0.7 Da

50

610.3 611.3 0 100

609.3

75

@ 800 Da/s

448 50 25 0 200

0.5 Da

50

610.3 611.3

1 ng/mL 300

400

500

600

700

0 600

800

603

606

609

612

615

618

m/z

m/z

Figure 6. (a) The linear quantitation curve for reserpine with a LOD of 1 ng/mL. (b) The tandem mass spectrum of reserpine at 1 ng/mL. (c) Mass spectra of reserpine ions obtained at different scan rates. With the hybrid ion funnel and the Einzel lens, the LIT is actually placed further away from the both the capillary exit and the pinhole. Distance between the pinhole and the LIT was increased from 2 mm to 7 mm. As a result, buffer gas pressures within the LIT could be further decreased, which would facilitate MS analysis. The improved MS resolution was characterized by analyzing reserpine ions in terms of full widths at half maximum (FWHM). As illustrated in Figure 6c, decreased FWHMs were achieved 14


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(from 1.2 Da to 0.5 Da) when the scan rate was lowered from 5000 Da/s to 800 Da/s. Furthermore, isotopic peaks of reserpine ions (m/z 610.3, 611.3) were clearly observed in the mass spectra when using slower scan rates, such as 1600 Da/s and 800 Da/s.

15



Conclusions A hybrid ion funnel has been developed in this work and integrated into the miniature mass spectrometer with a continuous atmospheric pressure interface. Consisted with a rectangular ion funnel and a segmented planar quadrupole, the hybrid ion funnel was characterized in terms of RF electric field distribution and the effects of voltages on ion transmission efficiency. Besides effectively transfer ions into the second vacuum stage, the hybrid ion funnel could selectively filter ions according to their mobilities through the application of a DC electric field in the quadrupole region. As proof-of-concept demonstrations, target analyte identification in complex matrix and isobaric ion analysis were demonstrated. After optimization, sensitivity of the miniature MS system was improved by ~ 10 times, with a LOD from 10 ng/mL to 1 ng/mL. Ppb level detection sensitivity and isotope resolving capability would greatly expand the application range of miniature mass spectrometers.

Acknowledgments This work was supported by NNSF (21874016, 61635003), China Postdoctoral Science Foundation (2018M640071).

Supporting Information The optimization of DC voltages on electrodes of Einzel lens.

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