Tandem Analysis by a Dual-Trap Miniature Mass Spectrometer

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Tandem Analysis Modes by a Dual-Trap Miniature Mass Spectrometer Xinwei Liu, Jiexun Bu, Xiaoyu Zhou, and Zheng Ouyang Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.8b03958 • Publication Date (Web): 16 Nov 2018 Downloaded from http://pubs.acs.org on November 16, 2018

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Analytical Chemistry

Tandem Analysis Modes by a Dual-Trap Miniature Mass Spectrometer Xinwei Liu1, Jiexun Bu2, Xiaoyu Zhou1*, Zheng Ouyang1* 1State

Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China;

2PURSPEC

Technologies Inc., Beijing 100084, China;

*Correspondence authors: Professor Zheng Ouyang Department of Precision Instrument Tsinghua University Beijing 100084, China Email: [email protected]

Professor Xiaoyu Zhou Department of Precision Instrument Tsinghua University Beijing 100084, China Email: [email protected]

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Abstract Miniature mass spectrometers are of an increasing interest for in in-situ analyses and their coupling with the ambient ionization sources is a valid path for direct analysis of complex samples. In this study, a miniature mass spectrometer using discontinuous atmospheric pressure interface was developed with a dual-LIT (linear ion trap) configuration. The comprehensive scan modes were enabled for tandem mass spectrometry analysis, which are critical for high quality qualitative and quantitative analysis. A real-time pressure control was implemented to facilitate the ion transfer and collision induced dissociation (CID). Beam-type CID could be performed for tandem analysis at a high number of stages. In-trap CID at high q could also be performed with the fragment ions accumulated in a second trap.

A precursor ion scan mode for analyzing target

analytes has also been demonstrated.

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Introduction Mass spectrometry (MS) is known as an analytical technology with high sensitivity, high specificity and wide applicability.

Miniaturization of the mass spectrometry (MS) systems is the

pathway to in situ analysis for application fields such as environmental monitoring1-3, food safety4,5, homeland security6, space exploration7-9, and point-of-care (POC) testing10,11. Size miniaturization of the system has always been a main goal; however, it has been recognized that the ease of use is an important factor to enlarge the scope of the practical use of miniature MS systems12,13 by end users with little analysis experience14. A typical example is the potential application for POC analysis, where regulated, simple operations much be used instead of versatile but complicated lab procedures.

The ambient ionization15-17 technologies, therefore, have been used to replace the

sample treatment and chromatography separation to develop direct analysis by mass spectrometry13.

Some of them, such as paper spray18,19, paper capillary spray20, extraction spray21,

low temperature plasma (LTP)22-24, and slug flow microextraction spray25, have been coupled with miniature MS systems to perform direct analysis. Previously, a desktop instrument mini 1214 and a wearable backpack mini S6 were developed with the ambient ionization sources in integrated packages. The coupling of ambient ionization sources and miniature mass spectrometers requires an efficient atmospheric pressure interface and the discontinuous atmospheric pressure interface (DAPI)26,27 has been developed for this purpose and used with ion trap mass analyzers28. In each cycle of MS analysis, the DAPI opens for a short time (about 20 ms) to introduce the ions produced in the atmospheric environment, and then closes to allow the vacuum pressure to drop back to 3



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millitorr range for performing the MS scan of the ions trapped. The ion introduction strategy enabled by DAPI can help to reduce significantly the capacity requirement for the pumping system of the mass spectrometers29, although with a compromise in the scan speed for MS and tandem mass spectrometry (MSn) analysis. With an efficient solution for atmospheric pressure interface, the analysis of non-volatile analytes in complex biological samples in condensed phases, such as biofluids or tissues, is now possible by miniature MS systems30,31. The MSn capability has been demonstrated to be important for complex mixture analysis and is even more so for miniature MS systems using ambient ionization for direct analysis of raw samples32-34. It facilitates the confirmation of the analyte identities and helps to improve the sensitivity by eliminating the chemical noises35,36. For this reason, ion traps have been used as a major type of mass analyzers for miniature mass spectrometers4,37,38, since multi-stage MSn can be performed with a single analyzer. In the history of developing MS instruments and methods for qualitative and quantitative analysis, a variety of comprehensive and effective scan modes have been created to perform MS/MS analysis, such as multi-reaction monitoring (MRM), precursor ion scan, neutral loss scan, etc.36,39,40 They were developed to allow high precision quantitation as well as fast screening of analytes of interest from complex mixtures. Triple quadrupole instruments have been the main type of instruments for the routine analysis using these scan modes.

In this work, we explored

the possibility of transferring the comprehensive scan modes to miniature mass spectrometers, without complicating the overall instrument configuration significantly. Dual-trap assemblies previously have been studied for various purposes41,42. Dual linear ion trap (LIT) configurations 4


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were recently introduced43,44 with mass-selective ion transfer between two traps. This concept was adopted for a newly designed miniature mass spectrometer in this study and a real-time pressure control was implemented to facilitate the tandem mass analysis in various modes. Highly efficient, mass-selective ion transfer was achieved between the ion traps, allowing MSn performed with a high number of stages. Beam-type CID and high q CID could be accomplished for structural analysis and/or identity confirmation. MRM as well as precursor ion scan could also be performed with this new instrument.

Experimental Reserpine (1 μg/mL), melezitose (2 μg/mL), imatinib (0.2 μg/mL) and imatinib-d8 (0.2 μg/mL) were purchased from Aladdin (Shanghai, China). Synthetic lipids standards, SM d18:1/18:1 (2 μg/mL), PC 16:0/18:1(9Z) (1 μg/mL) and PC P-18:0/18:1(9Z) (1 μg/mL), were purchased from Avanti Polar Lipids, Inc. (Alabaster, AL, USA) and were used without further purification. Methanol and water were purchased from Fisher Scientific (Fairlawn, NJ, USA) and were used to prepare the sample solvent (50/50, v/v). Nanoelectrospray ionization (nanoESI) at high voltages among 1200-1500 V was used for ionization.

Instrumentation The miniature dual-LIT MS system (Figure 1a and b) consisted of a DAPI used for ion introduction, two linear ion traps (LIT 1 and LIT 2) installed co-axially for ion manipulation, a gas leaking system designed for real-time pressure control, and an electron-multiplier (EM) detector. 5



The entire instrument was of 57 cm (length) x 24 cm (width) x 32 cm (height), weighed less than 20 kg and consumed a power less than 100 W. Each of the dual LITs has a nominal radius r0 of 4 mm for the RF electric field and a length of 51 mm. Dual phase radio-frequency (RF) voltages were used for driving the LITs, at frequencies of 1.10 MHz for LIT 1 and 1.25 MHz for LIT 2. Three mesh electrodes applied with DC voltages were installed for trapping and transferring ions in the z direction. Each of the two LITs could be used for mass analysis with axial mass-selective scan45, while having the other LIT operating as an RF-only ion guide for ion transfer. For MS scans acquiring spectra, AC excitation signal coupled through RF set an ejection q of 0.75 and a scan speed of about 10,000 Da/s was used. The vacuum chamber was of dimensions at 165 mm (length) × 80 mm (width) × 100 mm (height). A turbomolecular pump (30 L/s, HiPace 30, Pfeiffer Vacuum, Germany) was used with a two-stage diaphragm pump (5 L/min, MPU 1091, KNF Neuberger, USA). An ultimate vacuum pressure below 1 × 10−5 Torr could be achieved with the DAPI closed.

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Figure 1. Schematics for (a) the miniature mass spectrometer and (b) dual-LIT configuration. (c) Pressure variation during one scan cycle and the intensities of ions transferred from LIT 1 to LIT 2 at the pressure of (d) 4.3×10-3 Torr and (e) 4.2×10-4 Torr Results and discussion As shown in Figure 1c, when the DAPI opened for 15 ms, the in-vacuum pressure increased to about 100 mTorr and then gradually decreased. The ions generated by nanoESI of reserpine were introduced and trapped in LIT 1. The molecular ion [M+H]+ at m/z 609 were mass-selectively transferred to LIT 2, trapped until the pressure dropped to 0.5 mTorr, and then mass-analyzed. For the axial mass-selective transfer of m/z 609 ions from LIT 1, the RF voltage was fixed, corresponding to a low mass cutoff (LMCO) of m/z 134; a resonance excitation AC of 0.4 Vp-p was applied at a frequency of 78 kHz, corresponding to q1 = 0.2 for m/z 609. For LIT 2 catching the ejected ions, a LMCO of m/z 201 was set, corresponding to a q2 = 0.3 for m/z 609. The DC 7



floats for LIT 1 and LIT 2 were set as 2.5 V and -2.5 V, respectively.

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The Gate 2 voltage was set

as 3.5 V. The transferred ions were subsequently scanned out of LIT 2 at 0.1 mTorr for spectrum acquisition. It was found that the vacuum pressure had a significant impact on the ion transfer efficiency (Figure 1d and 1e). At relatively low pressures, the lack of collisions would lead to less efficient reduction of the ion kinetic energies46-49 so the ions could not be effectively trapped or cooled in LIT 2. In comparison with the ion transfer at a high pressure of 4.3×10-3 Torr (Figure 1d), only 10% of the reserpine ions could be caught in LIT 2 at 4.2×10-4 Torr (Figure 1e). For an effective control of the vacuum pressure in real time to study the ion transfer, a gas leaking system was implemented. A pulse valve (model series 9, Pulse Valves, Parker Hannifin, Inc., USA) was used to control the gas leaking. The leaked gas was transferred into the vacuum chamber through a stainless tube of i.d. 1.0 mm and o.d. 1/16 in., with its end fixed between LIT 1 and LIT 2 as shown in Figure 2a. The gas flux during the opening of the pulse valve was adjusted using stainless capillaries of different lengths and internal diameters for the inlet side of the pulse valve. Two gas introduction modes, pulsed and continuous, were used for comparison. In the pulsed mode, a gas inlet capillary of 50 mm in length, 1/16 in. o.d. and 0.01 in. i.d. was used, corresponding to a gas leaking speed of 7.3 mL/s. The gas was leaked in for 20 ms, starting with a 550 ms delay after the DAPI opening. Whereas in the continuous mode, an inlet capillary of 250 mm length, 1/16 in. o.d. and 0.005 in. i.d. was used, allowing a leaking speed of 0.4 mL/s50. The leaking valve was opened right after the DAPI was closed and was kept open through the rest of the scan circle (Figure 2b).

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Figure 2. (a) Schematic of the gas leaking system. (b) Pressure profiles of three operation modes, without gas leaking (blue), with pulsed (green) or continuous (red) gas leaking. (c) Intensities of ions transferred with different time delays. (d) Intensities of ions transferred for different number of turns. The vacuum pressure variation profiles measured for these two modes of gas leaking are shown in Figure 2b. Leaking of the gas in both modes extended the time for the pressure staying at 10-3 Torr level. For the continuous mode (red in Figure 2b), the amount of the gas leaked was negligible in comparison with that by DAPI; therefore, it did not affect the maximal pressure, which was determined by the gas introduction through DAPI. However, it did slow down the drop of the pressure after the DAPI was closed. Note that the pressure measurement was done for the background pressure in the vacuum manifold, not for inside of the LIT assembly, so the local 9



pressure at the point of gas leaking should be much higher. The mass-selective transfer of protonated reserpine ions at m/z 609 was characterized for the three pressure variation modes (Figure 2c), with ions transferred at different time delays and subsequently scanned out for intensity detection. With no gas leaking, the maximal ion transfer was achieved with a delay time of 400 ms after the DAPI opening (blue in Figure 2c), corresponding to a background pressure of 3.0 mTorr. In comparison, the use of pulsed gas leaking at 550 ms allowed another 200 ms for stable ion transfer (green in Figure 2c). The implementation of continuous gas leaking also enabled a longer time period for stable ion transfer, starting from 400 ms. The efficiencies for transferring ions before 400 ms, however, was lower than the other two modes, which should be due to the higher local pressure for the continuous leaking mode during the time period right after the DAPI closing. The ion transfer between the two LITs could be performed for multiple times, which could be used for relatively comprehensive ion manipulations. The ion transfer efficiency was firstly characterized, for up to 7 transfers, as shown in Figure 2d. For the odd number of ion transfers, the ions were finally trapped in LIT 2 before they were ejected to the detector directly during an axial MS scan. For the even number of ion transfers, the ions were finally trapped in LIT 1 and then scanned out toward the detector, with the LIT 2 set as an RF-only ion guide. With the intensities measured for the different rounds of mass-selective axial ejection (MSAE), the transfer efficiency was calculated as about 75% for each transfer event between the two LITs. This transfer efficiency is lower than those previously reported for ion transfer between LITs;51,52 however, please note that the difference is due to the mass selection during the axial transfer. 10


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The capability of performing multiple, mass-selective ion transfer between the two LITs enabled multi-stage, beam-type MSn analysis. The MS2 analysis traditionally was performed by the triple quadrupole mass spectrometers; however, more analyzer sections would be required53 to perform MSn analysis with n>2. The ping-pang style operation was previously demonstrated using a modified triple quadrupole instrument54,55 to perform MSn. It could also be easily implemented with the dual-LIT configuration. Although there was not a Q2 in the miniature instrument as the CID section, the area where the gas was leaked in could serve as a collision region. In practice, the beam-type CID was realized by increasing the voltage difference (VDC1-DC2) between the DC floats for LIT 1 and 2 (Figure 3a), as previously demonstrated43, which could also be treated as the collision energy. The MS2 spectra of protonated reserpine m/z 609 through beam-type CID were recorded at a VDC1-DC2 of 20 V (Figure 3b) and 40 V (Figure 3c) for comparison, with a much higher fragmentation efficiency observed for the latter case. In these experiments, pulsed gas leaking of 20 ms (with a 400 ms delay from DAPI opening) was used to raise the local pressure at the collision region.

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Figure 3. (a) Schematic for the DC potential along the ion transfer axis and setup for performing beam-type CID during mass-selective ion transfer. MS2 spectra of the protonated reserpine m/z 609 with collision energies at (b) VDC1-DC2 = 20 V and (c) VDC1-DC2 = 40 V. Beam-type CID MSn spectra of the sodiated melezitose m/z 527 with (d) n=2, (e) n=3 and (f) n=4. Pulsed gas leaking used for 20 ms, with a 400 ms delay from DAPI opening.

MSn analysis with n>2 was demonstrated for analysis of an oligosaccharide, which typically 12


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requires a higher number of MSn stages for structural analysis56,57. The precursor ions, sodiated melezitose at m/z 527, were generated by nanoESI. They were introduced into LIT 1 through DAPI and trapped for 400 ms before they were mass-selectively transferred to the LIT 2 with beam-type CID (Figure 3d); the fragment ions were caught by LIT 2 and m/z 365 was then selected to transfer back to LIT 1 with the second CID performed for MS3 analysis (Figure 3e); its fragment ion m/z 275 trapped by LIT 1 was transferred again for the third CID and the MS4 spectrum was obtained as shown in Figure 3f.

During each ion transfer, the fragment ions were cooled 200 ms in the

trap before the next mass-selective ion transfer or mass analysis was performed. For each massselective ion transfer, a 20 ms pulsed gas introduction was implemented to facilitate the beam-type CID and ion trapping. Ion manipulation using dual-LIT configuration also brought some unique advantages for the in-trap, low energy CID. It is well known that the “1/3” rule for the in-trap CID, which means the fragment ions with m/z values of 1/3 or lower of the precursor ions would not be effectively observed58. Generally, it would be highly desirable to excite the precursor ions at relatively high q values, since the trapping potential well depth would be deeper and efficiency would be higher for elevation of ion internal energy through the in-trap CID; however, the fragment ions produced at lower m/z ranges would then be outside the stability region and therefore not trapped or observed through subsequent MS scan. Typically, q around 0.3 is used for in-trap CID of the precursor ions, which corresponds to a low mass cutoff (LMCO) at about 1/3 of the m/z value of the precursor ion. The use of dual-LIT configuration could solve this issue by allowing the excitation of precursor ions at a high q in LIT 1 while trapping the fragment ions over a wide m/z range in LIT 13



2.

Figure 4. CID in LIT 1 for (a, b) protonated PC 16:0/18:1(9Z) at m/z 760 and (c, d) protonated reserpine at m/z 609, with fragment ions (a, c) trapped and analyzed in the same trap LIT 1 or (b, d) trapped and analyzed in the LIT 2. q = 0.6 was used for isolation and excitation of the precursor ions in LIT 1. For (b) and (d) q = 0.13, corresponding to LMCO of m/z 108, was used for trapping the fragment ions in LIT 2. As an example, no fragment ions could be observed for in-trap CID of protonated PC 16:0/18:1(9Z) at q1 = 0.6 for excitation when a single trap LIT 1 was used (Figure 4a) for both CID and MS analysis of the fragments. However, LIT 2 could be used to catch the fragment ions produced but not stably trapped in LIT 1. After the CID in LIT 1, the ions remained in LIT 1 could be transferred to LIT 2 and a subsequent MS scan by LIT 2 would yield a MS2 spectrum as shown 14


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in Figure 4b.

It clearly shows the fragment peak of high intensity at m/z 184, which could not be

well observed through normal in-trap CID. The analysis of protonated reserpine was of the similar case. A LMCO at about m/z 400 was enforced for trapping the fragment ion if the excitation of precursor ion m/z 609 was performed at q1 = 0.6 (Figure 4c); while the CID using the dual-LIT method would allow the observation of fragment ions with m/z values below 174 (Figure 4d). Transfer of the multiple reaction monitoring (MRM) and precursor ion scan (PIS) to the dual LIT system has also been explored. In a previous study43, we demonstrated that a good preservation of the intensity ratio between the analyte and internal standard (IS) ions could be achieved with the mass-selective ion transfer between two LITs.

In the current study, a true MRM mode was

demonstrated by measuring the intensity ratio of signature fragment ions produced from the analyte and IS precursor ions, viz. protonated imatinib m/z 494 and protonated imatinib-d8 m/z 502, respectively. These ions were produced through nanoESI of 200 ppb imatinib and imatinibd8 in sample solvent and introduced through the DAPI and trapped simultaneously in LIT 1 (Figure 5a). The protonated imatinib m/z 494 and m/z 502 were sequentially, mass-selectively transferred from LIT 1 (q1 = 0.6) to LIT 2 (q2 = 0.3), with beam-type CID MS2 analysis to obtain the intensity of the fragment ion m/z 394 (insets in Figure 5a).

The intensity ratios of m/z 394 were calculated

and plotted for 100 measurements as shown in Figure 5b. An RSD better than 12% could be obtained for the A/IS ratio measurement. Better quantitation performance could certainly be achieved using lab-scale triple quadrupole mass spectrometers.

For instance, RSDs better than 5%

has been achieved for direct analysis of therapeutic drugs in blood samples with IS properly incorporated.59 However, the achievement reported here is significant for performing on-site 15



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quantitative analysis in the future using miniature mass spectrometry systems. The precursor ion scan (PIS) is another scan mode that is very useful for identifying compounds for a classified group.

This was also explored for implementation using the dual-LIT

system using a mixture of lipids with same head group, SM d18:1/18:1, PC 16:0/18:1(9Z), PC P18:0/18:1(9Z), with precursor ions at m/z 729, 760 772 in protonated form and m/z 751, 782, 794 in sodiated form (Figure 5c), respectively. Their head group, however, could only be observed as a fragment ion m/z 184 though CID of the pronated precursor ions, not the sodiated60.

A

precursor ion scan monitoring the common head group ion by a triple quadruple instrument would produce a spectrum showing peaks only at m/z 729, 760 and 772. Using the dual-LIT miniature mass spectrometer to perform the precursor ion scan, the ions of interest trapped in LIT 1 could be sequentially, mass-selectively transferred to LIT 2 with beam-type CID, while having LIT 2 set for a MS scan over a narrow m/z range to monitor m/z 184. A series of spectra acquired through this scan mode for the lipids are shown in Figure 5e, which were used to reconstruct a spectrum for precursor ion scan as shown in Figure 5f. The demonstrated procedure might not be like the normal PIS performed by triple quadrupole mass spectrometers, which can identify all the precursors in a data independent fashion. However, the miniature mass spectrometry systems would be mostly useful for specialized applications with targeted chemical or biomarkers.

The scan mode demonstrated here would

allow a fast identification of a group of inter-related chemical markers with one introduction of the ions using the miniature instrument.

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Figure 5. (a) Multiple reaction monitoring (MRM) scan in drugs; (b) The A/IS ratios calculated with intensities of fragment ion m/z 394 a large number of scans. (c) MS scan by LIT 1 of a mixture of phosphocholine lipids; (d) schematic of scan function for precursor ion scan (PIS) using dualLIT system; (e) spectra observed for monitoring product ions (m/z 184) from different precursor ions; (f) reconstructed spectrum for PIS

CONCLUSION A miniature mass spectrometer with dual linear ion traps and discontinuous atmospheric 17



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pressure interface has been built for developing comprehensive scan modes for tandem mass spectrometry analysis.

This study represents a unique attempt for performing complex mass

analysis functions without the traditional instrumentation of large scales and complex configurations.

Tandem-in-space ion manipulations were enabled using the dual-LIT

configuration, facilitated with the real-time pressure control.

High energy beam-type CID could

be performed in addition to the low energy in-trap CID and MSn with n>2 were realized using two LITs in a ping-pang fashion with CID.

The development of a variety of scan modes for the

miniature MS system shows the potential of mass spectrometers with simple configurations and small sizes for performing comprehensive qualitative and quantitative analysis.

This is important

for direct analysis of complex samples using minimal or no sample pretreatment. Acknowledgement This work was supported by National Natural Science Foundation of China (Grant 21627807, 21705090). The authors thank Yue Ren and Kai Liu for helpful suggestions in the development of instrumentation and analytical methods.

Notes Z.O. is the founder of PURSPEC Technologies Inc.

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Tandem Analysis by a Dual-Trap Miniature Mass Spectrometer

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