A Miniature Particle Mass Spectrometer | Analytical Chemistry

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A miniature particle mass spectrometer Xi Huang, Jinlong Jiang, Yiming Zhang, Lingpeng Zhan, Chaozi Liu, Caiqiao Xiong, and Zongxiu Nie Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.9b01069 • Publication Date (Web): 18 Jul 2019 Downloaded from pubs.acs.org on July 19, 2019

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Analytical Chemistry

A miniature particle mass spectrometer Xi Huang1,3, Jinlong Jiang2, Yiming Zhang1,3, Lingpeng Zhan1,3, Chaozi Liu1,3, Caiqiao Xiong*1,3, Zongxiu Nie*1,3,4 1 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China 2 School of Electronic Engineering, Jiujiang University, Jiujiang 332005, China 3 University of Chinese Academy of Sciences, Beijing 100049, China 4 National Center for Mass Spectrometry in Beijing, Beijing 100190, China Xi Huang and Jinlong Jiang contribute equally to the article.

ABSTRACT: Microparticles play important roles in our life. Besides chemical compositions and morphology, the size of microparticles will also decide their behavior in environment or organisms. Weighing the mass of microparticles by mass spectrometry is a useful method to characterize their size. In this article, a miniature particle mass spectrometer with aerodynamic desorption/ionization ion source has been developed. We used a compact main control board to produce AC voltage for trapping and ejecting the particles. The sampling process and data acquisition were also controlled by this board. We utilized this instrument to measure polystyrene spheres, silica particles and mice red blood cells. Mass distributions of these particles were obtained rapidly with good accuracy.

Introduction Microparticles such as aerosols, cells, powder material, etc., has gained more and more attention for their important roles in air pollution, medicine and material synthesis1. Microparticles can exhibit various functions according to their size and density2. As an example, the severe pollution of PM2.5, an inhaling aerosol in micrometer size, has been threatening the health of human in worldwide3-4. Weighing the mass of particles by mass spectrometry is a useful method to characterize size of particles5-7. Since particles in nano- or micro- size often has ultra-high mass (beyond 1 MDa), measuring these particles demands special ionization source, mass analyzer and detector contrast with small molecule mass spectrometers. As common soft ionization sources, electrospray (ESI)7 and matrix-assisted laser desorption/ ionization (MALDI)8,9 have been adapted to ionize microparticles. However, to perform ESI spray containing bioparticles, additional precautions must be taken carefully to avoid pathogen threats. For MALDI, the direct irradiation of laser will split cells for their fragile cytomembrane. A much more general ionization method for particle called laser-induced acoustic desorption (LIAD) was developed by Chang group10-11. LIAD provides soft ionization and high sensitivity but its sampling can not be operated in atmospheric pressure. Recently, our group developed an ambient ionization method——aerodynamic desorption (AD)12. In the AD ionization source, we used a discontinuous atmospheric interface (DAPI)13 for sampling. When the DAPI was triggered, a pulsed air flow caused by pressure difference would desorb microparticles on the target plate. Following ionization was completed in the vacuum chamber by corona discharge. The AD method provides high sensitivity, good sample compatibility, and low time cost. Moreover, the AD source needs no additional laser, high voltage or gas so that it is suitable as an ionization source for a miniature mass spectrometer. Nowadays, miniature mass spectrometers are developed with the demand of in situ chemical analysis in the fields of environmental monitoring, clinical diagnosis, and space exploration14-15. There were miniature mass spectrometers equipped with ion trap16-17, quadrupole mass filter18-19 and time-

of-flight20-21. Most of them were applied to analyze small molecules. Herein, a miniature particle mass spectrometer (Mini PMS) has been developed for rapid measurements of microparticles and cells. In this device, we combined an AD ionization source, a quadrupole ion trap (QIT) and a Faraday disc charge detector. The Mini PMS was applied for the analysis of polystyrene spheres, silica particles and mice red blood cells (RBCs). Device The configuration of the Mini PMS is shown in Figure 1. All components are assembled into an aluminum case 225 mm in length, 220 in width and 145 in height (Figure S1A). The total weight of the instrument is 7 kg. The maximum power consumption, when vacuum system and AC frequency are running, is below 45 W. A computer program written by Labview controls the analysis processes and data recording. Sample Introduction and Ionization Source The AD ionization source was applied to desorb and ionize particles. The transfer tube in AD ionization source consisted of stainless-steel capillary 1 (1.0 mm i.d., 1.6 mm o.d., 2.0 cm length), stainless-steel capillary 2 (0.50 mm i.d., 1.6 mm o.d., 8.0 cm length), and a silicone tube (1.6 mm i.d., 3.2 mm o.d., and 3 cm length). The silicone was pressed by a pinch valve (390NC24330, ASCO Valve Inc., USA), connecting capillary 1 and 2 from each side. The channel would be opened briefly when the pinch valve was triggered by a 0/24 V square wave signal (Figure S1B). The suspension or powder of particles were dropped on the glass slide. After drying, the glass slide was pressed against the capillary 1 for sampling. When the valve was opened briefly, particles would be desorbed by the pulling of air and carried into the vacuum chamber. Corona discharge happened when the air contacted the electrode with AC voltage. Such discharge would ionize particles in the vacuum chamber. Mass Analyzer and Detector The mass analyzer was a quadrupole ion trap (QIT). The QIT consisted of two hyperbolic electrodes as end caps and a ring

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Figure 1. Components of the Mini PMS. The quadrupole ion trap and charge detector are in the mass analyzer chamber.

Figure 2. (A) Schematic diagram of the control electronics of the Mini PMS. (B) For sampling of microparticles, DAPI was opened briefly for 4 ms. After trapping, the frequency of AC voltage on the ring electrode swept from 450 to 150 Hz.


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Analytical Chemistry electrode (10 mm in radius). The exit of the capillary 2 was 5 mm far from the ion entrance orifice of the ring electrode. The QIT performed mass-selective instability ejection by linearly decreasing the AC frequency on the ring electrode22. The Faraday disk charge detector would collect image charge induced by the ejected particles. The m/Z of the particle was derived from the ejection time and charge number Z was determined by the intensity given by the detector. Vacuum system A turbo molecular pump (Hipace 10, Pfeiffer vacuum Inc., Germany) and a rough pump (PM25210-84.3, KNF Neuberger, Inc., USA) were combined to vacuate the mass analyzer chamber. It took about 3 minutes to reach the working pressure (~0.1 Pa). The pressure in the chamber was measured by a Pirani gauge (TPR 280, Pfeiffer vacuum Inc., Germany). When we opened DAPI for 4 ms to sample particles, the pressure of chamber would raise from 0.1 to 0.3 Pa then fall back to 0.1 Pa in a few seconds. The frequency scanning should begin at least 3 seconds after the DAPI trigger, otherwise a too early scanning would cause an abnormal baseline in mass spectrum (Figure S2). Electronics Control The electronics control system of the particle mini MS is shown in Figure 2. The control/DAQ board (NIU SB-625), which played the role of a brain, could open DAPI, trap or eject particles, and receive signal from the charge detector. The 0/24 V pulse DC signal was applied to open the pinch valve. An AC sine wave was amplified to 1000 times by the voltage amplifier (MATSUSADA AS-06B5) then applied to the ring electrodes of the QIT. A program based on Labview could set related parameters such as frequency, amplitude, duration time, etc. (Figure S3). The AC sine wave could be calculated as following formula：

{

𝑉𝑠𝑖𝑛 (2𝜋𝑓0𝑡 + 𝜑0), 0 ≤ 𝑡 < 𝑡0 1 𝑥(𝑡) = 𝑉𝑠𝑖𝑛 (2𝜋(𝑓0𝑡 + 𝑘𝑡2) + 𝜑0), 𝑡0 ≤ 𝑡 < 𝑡𝑒 2 x(t) was the AC sine wave in certain moment t. to was the initial time begin to decrease the frequency. fo was a constant trapping frequency when t< to. te was the end time for scanning frequency. V was a constant voltage during whole time. k was the change rate of frequency, which could be calculated by k=(fe-f0)/(te-t0).

. Experimental 2.98 μm polystyrene spheres was purchased from the National Institute of Standards and Technology (NIST). Polystyrene spheres of other size (1 μm, 1.5 μm, 5 μm, 7 μm, 10 μm diameter) and 4 μm silica particles were purchased from Suzhou Nanomicro Technology Co., Ltd. These particles were directly dropped on the glass as suspension or dry powder. The healthy Kunming mouse’s red blood cells were provided by the Key Laboratory of Analytical Chemistry for Living Biosystems, Chinese Academy of Science. These RBCs were washed by phosphate buffer saline (PBS) then soaked in 0.25% glutaric dialdehyde PBS solution for an hour to fix cytomembrane. After washed by PBS again, the fixed RBCs were dropped on the glass and dried by air. The glass smeared with particles was pressed against the steel capillary to sampling. For the sampling of these microparticles, the DAPI was opened briefly for 4 ms. For trapping and ejecting particles, the

AC voltage on the ring electrode was set as 600 V with endcaps grounded. For 2.98 μm polystyrene spheres and RBCs, the frequency swept from 450 to 150 Hz in 5 seconds. For 5 μm, 7 μm, 10 μm polystyrene spheres and 4 μm silica particles, the frequency swept from 450 to 50 Hz in 6 seconds. For 1 μm and 1.5 μm polystyrene spheres, the frequency swept from 2000 to 1000 Hz in 5 seconds. After several hundreds of particles were measured, mass histograms were plotted in Origin 8.0. Results and Discussion We measured the mass distribution of NIST 2.98 μm standard polystyrene (PS) spheres firstly. A typical mass spectrum is shown in Figure 3A. Each peak in this mass spectrum shows a particle with its specific mass. After calculating 267 such peaks from 60 mass spectrums (4.5 particles per spectrum), we obtained the mass distribution of polystyrene spheres particles (Figure 3B). Using Gauss-plot fitting, the observed mean mass was determined as 9.82×1012 Da. Since the known mean mass of NIST standard polystyrene micro-particles are 8.80×1012 Da23,24, this mass difference was corrected by a correction factor, which was determined as 1.13 in this experiment. This correction factor was used to calibrate the sample of which mass around 1×1013 12. The standard deviation (SD) of the mass distribution was 2.03×1012 Da and the coefficient of variance (CV) was 20.7%. Theoretically, the coefficient of variance of the measured mass distribution has relationship CV2=CVs2+CVi2. where CVs and CVi are the coefficient of variance caused by the sample and the instrument, respectively. As the CVs of the 2.98 μm polystyrene spheres is 1.6%23, the CVi of the Mini PMS instrument was determined as 20.6%, which represent its mass resolution. The lab-scale size particle mass spectrometer provided CVi value in 15.1% for the same polystyrene spheres sample, calculated by 246 particles from 31 mass spectrums (8 particles per spectrum). In conventional ion trap instruments, helium is often used as buffer gas to reduce ion kinetic energy. This cooling process aids in ion trapping and condenses ions in the center of ion trap, which enhances mass resolution and sensitivity25. Therefore, the lack of helium in our Mini PMS would sacrifice some mass resolution and sensitivity. The ideal open duration of the DAPI was 0.3~0.5 ms. The signal would be poor if the open duration was too short. However, if the open duration was longer than 0.6 ms, it would bring too much air into the vacuum chamber, causing severe discharge and harming the charge detector. We counted the charge number Z of each polystyrene spheres particle. From the distribution of charge number Z, we found that polystyrene spheres ionized in the Mini PMS had higher charge number than the lab-scale PMS (Figure 4). Since in the Mini PMS, the volume of vacuum chamber was much smaller and working pressure (0.1 Pa) was lower than the lab-scale PMS (3 Pa), the entering of air pulse would cause an obvious turbulence for pressure and stronger ionization process, which brought more charge for particles. Besides, when a particle carried more charge, it was less likely to form cluster with each other for their coulomb repulsion. As shown in Figure 1B, there were less dimer or trimer cluster in the mass histrogram of the Mini PMS. To evaluate the accuracy of the Mini PMS, we measured 4 μm silica particles of which expected mean mass was 4.15 ×1013 Da with density 2.10 g/cm3. 5 μm polystyrene spheres with expected mean mass 4.07×1013 Da was chosen to calibrate the mass difference caused by the Mini PMS. After calibration, the



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Figure 4. Charge distributions of polystyrene spheres standards obtained by the miniature and lab-scale particle mass spectrometer. Figure 3. (A) A mass spectrum of 2.98 μm polystyrene spheres. The height and location of each peak represents the charge number Z and m/Z of a corresponding particle (B) Mass histogram of 2.98 μm polystyrene spheres. The mass histogram contained 267 particles from 60 mass spectrums for Mini PMS and 246 particles from 31 mass spectrums for lab-scale PMS. mean mass of 4 μm silica particles was determined as 4.18 ± 0.93 ×1013. The mass accuracy was defined as the relative error of the mean mass of 4 μm silica particles, which was determined as 0.7 %. It showed that the mass accuracy of Mini PMS was as good as the lab-scale instrument (Figure S4 and Table S1). To evaluate the mass range of the Mini PMS, a series of polystyrene spheres with diameter from 1 μm to 10 μm were analyzed. The optimal mass range for the Mini PMS was 1×1012 to 1014 Da (Table S1). In this mass range, the measurement for polystyrene spheres could be done within 30 minutes. Stricted by the sensitivity of the Mini PMS, particles smaller or larger than this mass range were hard to be detected. Although the measurment time for each sample by Mini PMS was longer than the lab-scale PMS (within 20 minutes), the Mini PMS cost much less time (3 minutes) to reach working vacuum than the lab-scale PMS (60 minutes). Therefore, the Mini PMS had advantage as a mobile instrument on in-situ analysis. The size of red blood cells can be used to classify anemia in different type. To evaluate the size of blood cells, a promising method is to weigh the mass of cells by particle mass spectrometer. The Mini PMS was applied to red blood cells (RBCs) from a healthy mouse, as shown in Figure 5. After calibration by 2.98 μm polystyrene spheres. The mean mass was determined as 1.06×1013 Da, which corresponds to a mean corpuscular weight of 17.6 pg, and the SD value in this measurement was 3.40×1012 Da (CV= 33.7%). This mean corpuscular weight value was very similar to the previously result (18.4 pg) from the lab-scale size particle mass spectrometer26.

Conclusion The miniature particle mass spectrometer is able to provide fast and accurate analysis for particles. Moreover, experiments using Mini PMS are more saving in space and power thanks to the compact instrument design. In further works, we will improve the AD source for liquid or aerosol sampling. More environmental and biological sample such as PM 2.5, bacteria, tumor cells, etc. will be analyzed by the Mini PMS in situ.

Figure 5. Mass histograms of mice red blood cells. This mass histogram contained 298 particles obtained from 60 mass spectrums.


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Analytical Chemistry (9) Peng, W. P.; Yang, Y. C.; Kang, M. W.; Lee, Y. T.; Chang, H. C. J Am Chem Soc 2004, 126, 11766-11767.

ASSOCIATED CONTENT supplementary material The supplementary material is available free of charge on the ACS publication website.

(10) Peng, W. P.; Yang, Y. C.; Kang, M. W.; Tzeng, Y. K.; Nie, Z.; Chang, H. C.; Chang, W.; Chen, C. H. Angew Chem Int Ed Engl 2006, 45, 1423-1426.

Figures S1−S4 and Table S1 (PDF)

(11) Peng, W. P.; Lin, H. C.; Chu, M. L.; Chang, H. C.; Lin, N. H.; Yu, A. L.; Chen, C. H. Anal Chem 2008, 80, 2524-2530.

AUTHOR INFORMATION

(12) Xiong, C.; Zhou, X.; Wang, J.; Zhang, N.; Peng, W. P.; Chang, H. C.; Nie, Z. Anal Chem 2013, 85, 4370-4375.

Corresponding Author

(13) Gao, L.; Cooks, R. G.; Ouyang, Z. Anal Chem 2008, 80, 40264032.

* E-mail: [email protected]; [email protected]

(14) Ma, X. X.; Ouyang, Z. Trac-Trend Anal Chem 2016, 85, 10-19.

ACKNOWLEDGMENT This work was supported by grants from the National Natural Sciences Foundation of China (Grant Nos. 21625504, 21827807, 21505140, 21621062, 21475139, 21675160, 21127901 and 21790390/21790392) and Chinese Academy of Sciences.

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A Miniature Particle Mass Spectrometer | Analytical Chemistry

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