以微流體液滴噴射氣做為質譜分析的進樣介面

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研究生：	陳柏穎 Chen, Po-yin
論文名稱：	以微流體液滴噴射氣做為質譜分析的進樣介面 Microfluidic Droplet Shooter as a Sample Injection Interface for Mass Spectrometry
指導教授：	北森武彥 Kitamori, Takehiko
口試委員:	嘉副裕 Kazoe, Yutaka 陳致真 Chen, Chih-Chen 森川響二郎 Morikawa, Kyojiro
學位類別：	碩士 Master
系所名稱：	工學院 - 動力機械工程學系 Department of Power Mechanical Engineering
論文出版年：	2022
畢業學年度：	110
語文別：	英文
論文頁數：	65
中文關鍵詞：	液滴微流體、氣浮液滴生成、質譜儀、數值分析、Rayleigh-Plateau不穩定性、單細胞蛋白質組學
外文關鍵詞：	Droplet-based Microfluidics, Air Floating Droplet Generation, Mass Spectrometry, Numerical Analysis, Rayleigh-Plateau Instability, Single-cell Proteomics
相關次數：	點閱：3 下載：0
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蛋白質組學使我們能夠更深入地了解可能推動臨床結果的細胞功能。然而，蛋白質組樣品製備涉及多個步驟，會導致樣品損失並降低反應效率，尤其是在單細胞分析濃度較低時。通常，由於樣品噴散，使用電噴霧電離(ESI)介面的傳統質譜儀(MS)分析效率非常低。在這項研究中，我們正在開發一種質譜接口，方法是將樣品噴射成具有可控尺寸和軌蹟的液滴，以實現約 100% 的注射效率。基於液滴的微流控技術已廣泛應用於化學和生物技術領域，因為微尺度下的物理特性可高精度的控制液滴特徵。不混溶的鞘液或表面活性劑通常用於產生微米級液滴。然而，兩者都成為蛋白質組分析的嚴重污染物。在此研究中，新介面的工作原理是在微流體系統中利用氣流而不是電喷物來產生液滴，慣性力將液滴輸送到質譜儀中，將樣品損失降到最小。然而，由於相對較低的物理特性（例如黏度、密度等），通過氣流來生成微尺度液滴仍然十分困難。因此，考慮到Rayleigh-Plateau不穩定性引起液滴生成的基本原理，本研究提出了一種基於兩步聚焦氣流的微流體噴射裝置，以實現千赫茲頻率下飛升的液滴生成。在這項研究中，飛升液滴的產生已通過實驗和數值模擬得到驗證。此外，通過計算液滴噴射後的傳輸和蒸發所需的條件，以針對不同MS系統進行優化。基於接近100%的樣品注入效率，與傳統的 ESI 接口相比，該接口有望提供高數個量級的檢測靈敏度。

Proteomics allows us to gain deeper insights into cellular functions that may drive clinical outcomes. However, proteomic sample preparation involves multiple steps, introducing sample loss and reduced reaction efficiency, especially when the substrate concentration is low as in the case of single-cell analysis. In particular, the efficiency of the conventional mass spectrometer (MS) interface by electrospray ionization (ESI) is dismally low due to the sample dispersion. In this study, we are developing an MS interface by ejecting the sample in droplets with controlled size and trajectory to achieve ~100% efficiency. Droplet-based microfluidics has been widely used in the field of chemistry and biotechnology since the physical characteristics under microscale can be used to control the droplet features with high accuracy and precision. Immiscible sheath fluids and/or surfactants are typically used for the generation of micrometer droplets. However, both become serious contaminants for proteomic analysis. The working principle of our new concept is that instead of ESI, streams of air-flow are utilized to generate droplets in a microfluidics system, and the inertial force thereof delivers the droplets into the mass spectrometer with a minimal sample loss. However, it is difficult to disperse microscale droplets by using airflow due to the relatively low physical properties (e.g., viscosity, density, etc.). Hence, considering the fundamental principle of droplet generation caused by Rayleigh-Plateau instability, a microfluidics shooter device with two-step focusing air-flow was proposed to realize femto- to pico-liter liquid droplet generation at kilohertz frequencies. In this study, the femtoliter droplet generation has been verified by both experiments and numerical simulation. In addition, the required conditions of droplet transportation and evaporation after shooting have been calculated to optimize the interface for different MS systems. Due to the approximate 100% sample injection efficiency, this interface is expected to provide orders of magnitude times higher detecting sensitivity compared with conventional ESI interfaces.

摘要    I
Abstract    II
Table of Contents    III
List of Symbols    V
Chapter 1 Introduction    1
1 Background    1
1.1 Microfluidics    1
1.2 High-Performance Liquid Chromatography    2
1.3 Mass Spectrometry    4
1.4 Liquid Chromatography-Mass Spectrometry Interfaces    6
2 Object and Motivation    8
2.1 Microfluidics as an LC-MS Interface    8
2.2 Single-Cell Analysis with Mass Spectrometry    9
Chapter 2 Fundamental Theory and Numerical Simulation    11
1 Droplet Generation Principle    11
2 Numerical Simulation    15
3 Simulation Results    18
Chapter 3 Shooter Device Fabrication    22
1 Material and Design    22
2 Nanochannel Fabrication    23
3 Microchannel Fabrication    26
4 Hole Drilling, Bonding, and Dicing    29
Chapter 4 Shooter Device Experiment    32
1 Experiment Setup    32
2 Hydrophobic Modification    32
3 Droplet Generation    34
3.1 Droplet Generation Phenomenon    34
3.2 Simulation and Experiment Comparison    37
4 Droplet Transportation    40
4.1 Shooting Conditions    40
4.2 Aero Fluidic Phenomenon at the Shooter Outlet    41
4.3 Forces Acting on Droplet    43
4.4 Analysis    45
Chapter 5 Interfacing to MS    47
1 Interfacing    47
1.1 Ionization Process    47
1.2 Interface Setup    48
2 Electrode    49
3 Droplet Vaporization    50
3.1 MS Inlet    50
3.2 Numerical Model    51
3.3 Results and Discussion    53
Chapter 6 Conclusion and Future Work    57
1 Conclusion    57
2 Future Works    58
2.1 Device    58
2.2 Interface    59
Appendix    60
References    61


                                

1. S.C Terry, J.H. Jerman, and J.B. Angell, A gas chromatograph air analyzer fabricated on a silicon wafer, IEEE Transactions on Electron Devices, Vol. 26, 1979, pp. 1880-1886.
2. A. Manz, N. Graber, and H.M. Widmer, Miniaturized total chemical analysis systems: A novel concept for chemical sensing, Sensors and Actuators B: Chemical, Vol. 1, 1990, pp 244-248.
3. D.R. Reyers, D. Iossifidis, P.-A. Auroux and A. Manz, Micro Total analysis systems. 1. Introduction, theory, and technology, Analytical Chemistry, Vol. 74, 2002, pp 2623-2636.
4. N. Convery and N. Gadegaard, 30 years of microfluidics, Micro and Nano Engineering, Vol. 2, 2019, pp 76-91.
5. O. Reynolds, An Experimental investigation of the circumstances which determine whether the motion of water shall be direct or sinuous, and of the law of resistance in parallel channels, Proceedings of the Royal Society of London, Vol. 35, 1883, pp 224-226.
6. A. Hibara, M. Tokeshi, K. Uchiyama, H. Hisamoto, and T. Kitamori, Integrated multilayer flow system on a microchip, Analytical Sciences, Vol. 17, 2001, pp. 89-93.
7. H. Hachiya, T. Matsumoto, K. Kanda, M. Tokeshi, and Y. Yoshida, Micro environmental gas analysis system by using gas-liquid two phase flow, Proc microTAS 2004, pp. 99-10.
8. L. S. Ettre and A. Zlatkis, 75 years of chromatography a historical dialogue, Journal of chromatography library, Vol. 17, 1979.
9. C. G. Horváth and S. R. Lipsky, Use of Liquid Ion Exchange Chromatography for the Separation of Organic Compounds, Nature, Vol. 211, 1966, pp 748-749.
10. J. Griffiths, A Brief History of Mass Spectrometry, Analytical Chemistry, Vol. 80, 2008, pp 5678-5683.
11. W. Paul and H. Steinwedel, Ein neues Massenspektrometer ohne Magnetfeld, Zeitschrift für Naturforschung, Vol. A8, 1953, pp. 448-450.
12. D. A. Skoog, D. M. West, F. J. Holler, and S. R. Crouch, Fundamentals of Analytical Chemistry, 9th ed., Cengage Learning, 2013.
13. Á. Somogyi, Mass spectrometry instrumentation and techniques, Medical Applications of Mass Spectrometry, 2008, pp. 93-140.
14. W. M. A. Niessen, Liquid Chromatography-Mass Spectrometry, 3rd ed., CRC Press, 2006.
15. M. Yamashita and J. Fenn, Electrospray ion source. Another variation on the free-jet theme, The Journal of Physical Chemistry, Vol. 88, Issue 20, 1984, pp. 4451-4459.
16. G. I. Taylor, Disintegration of Water Droplets in an Electric Field, Proceedings of the Royal Society A, Vol. 280, Issue 1382, 1964, pp. 383-397.
17. E. C. Horning, M. G. Horning, D. I. Carroll, I. Dzidic, and R. N. Stillwell, New Picogram Detection System Based on a Mass Spectrometer with an External Ionization Source at Atmospheric Pressure, Analytical Chemistry, Vol. 46, No. 6, 1973, pp. 936-943.
18. R. E. Ardrey, Liquid Chromatography-Mass Spectrometry: An Introduction, Wiley, 2003.
19. R. Seeman, M. Brinkmann, T. Pfohl, and S. Herminghaus, Droplet based microfluidics, Reports on Progress in Physics, Vol. 75, 2012.
20. J. Wang, J. Song, C. Li, X. Dai, X. Fang, X. Gong, and Z. Ye, Recent Advances in Single Cell Analysis Methods Based on Mass Spectrometry, Chinese Journal of Analytical Chemistry, Vol. 48, Issue 8, 2020, pp. 969-980.
21. T. Fujii, S. Matsuda, M. L. Tejedor, T. Esaki, I. Sakane, H. Mizuno, N. Tsuyama, and T. Masujima, Direct metabolomics for plant cells by live single-cell mass spectrometry, Nature Protocols, Vol. 10, No. 9, 2015, pp. 1445-56.
22. F. Hillenkamp, M. Karas, R. C. Beavis, and B. T. Chait, Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry of Biopolymers, Analytical Chemistry, Vol. 63, No. 24, 1991, pp. 1193-1203.
23. H. Yin and D. Marshall, Microfluidics for single cell analysis, Current Opinion in Biotechnology, Vol. 23, Issue 1, 2012, pp. 110-119,
24. T. Nakao, Y. Kazoe, E. Mori, K. Morikawa, T. Fukasawa, A. Yoshizaki, and T. Kitamori, Cytokine analysis on a countable number of molecules from living single cells on nanofluidic devices, Analyst, Vol. 144, 2019, pp. 7200-7208.
25. K. Yamamoto, K. Morikawa, H. Imanaka, K. Imamura, and T. Kitamori, Picoliter enzyme reactor on a nanofluidic device exceeding the bulk reaction rate, Analyst, Vol. 145, Issue 17, 2020, pp. 5801-5807.
26. R. Ishibashi, K. Mawatari, and T. Kitamori, Highly Efficient and Ultra-small Volume Separation by Pressure-Driven Liquid Chromatography in Extended Nanochannels, small, Vol. 8, Issue 8, 2012, pp. 1237-1242.
27. G. F. Christopher and S. L. Anna, Microfluidic methods for generating continuous droplet streams, Journal of Physics D, Vol. 40, 2007, pp. 319-326.
28. J. K. Nunes, S. S. H. Tsai, J. Wan, and H. A. Stone, Dripping and jetting in microfluidic multiphase flows applied to particle and fibre synthesis, Journal of Physics D, Vol. 46, 2013, 114002.
29. C. N. Baroud, F. Gallaire, and R. Dangla, Dynamics of microfluidic droplets, Lab on a Chip, Vol. 10, 2010, pp. 2032-2045.
30. J. Plateau, Statique expérimentale et théorique des liquides soumis aux seules forces moléculaires, Gauthier-Villars, Vol. 2, 1873, pp. 261.
31. J. W. S. Rayleigh, On the instability of jets, Proceedings of the London Mathematical Society, Vol. 1, No. 1, 1878, pp. 4-13.
32. W. Thomas, Hydrokinetic Solutions and Observations, Philosophical Magazine, Vol. 42, 1871, pp. 362-377.
33. H. V. Helmhholtz, Über discontinuierliche Flüssigkeits-Bewegungen, Monatsberichte der Königlichen Preussische Akademie der Wissenschaften zu Berlin, Vol. 23, 1868, pp. 215-228.
34. B. E. Rapp, Microfluidics: Modeling, Mechanics and Mathematics, Elsevier, 2017.
35. D. D. Joseph and J. C. Saut, Short-Wave Instabilities and Ill-Posed Initial-Value Problems, Theoretical and Computational Fluid Dynamics, Vol. 1, 1990, pp. 191-227.
36. T. Funada and D. D. Joseph, Viscous potential flow analysis of Kelvin-Helmholtz instability in a channel, Journal of Fluid Mechanics, Vol. 445, 2001, pp. 263-283.
37. G. G. Stoke, On the Effect of the Internal Friction of Fluids on the Motion of Pendulums, Transactions of the Cambridge Philosophical Society, Vol. 9, 1851, pp. 8-106.
38. J. U. Brackbill, D. B. Kothe, and C. Zemach, A Continuum Method for Modeling Surface Tension, Journal of Computational Physics, Vol. 100, 1992, pp. 335- 354.
39. S. Tomotika, On the Instability of a Cylindrical Thread of a Viscous Liquid Surrounded by Another Viscous Fluid, Proceedings of the Royal Society A, Vol. 150, 1935, pp. 322-337.
40. G. M. Whitesides, E. Ostuni, S. Takayama, X. Jiang, and D. E. Ingber, Soft lithography in biology and biochemistry. Annu. Rev. Biomed. Eng. Vol. 3, 2001, pp. 335-373.
41. J. N. Lee, C. Park, G. M. Whitesides, Solvent Compatibility of Poly(dimethylsiloxane)-Based Microfluidic Devices, Anal. Chem. 2003, Vol. 75, pp. 6544-6554.
42. T. Fukusawa, T. Hayashi, and Y. Horike, Conelike Defect in Deep Quartz Etching Employing Neutral Loop Discharge, Appl. Phys. Vol. 42, 2003, pp. 6691-6697.
43. M. J. Ahamed, D. Senkal, A. A. Trusov, and A.M. Shkel, Study of High Aspect Ratio NLD Plasma Etching and Postprocessing of Fused Silica and Borosilicate Glass, Journal of Microelectromechanical Systems, Vol. 24 (4), pp. 790-800.
44. K. Shoda, M. Tanaka, K. Mino, and Y. Kazoe, A Simple Low-Temperature Glass Bonding Process with Surface Activation by Oxygen Plasma for Micro/Nanofluidic Devices, Micromachines 2020, Vol. 11 (9), 804.
45. S. J. Marshall, S. C. Bayne, R. Baier, A. P. Tomsia, and G. W. Marshall, A review of adhesion science, Dental Materials, Vol. 26, 2010, pp. e11-e16.
46. AGC Inc., CYTOP Technical Brochure (EN), 2018.
47. K. Mawatari, T. Tsukahara, Y. Tanaka, Y. Kazoe, P. Dextras, and T. Kitamori, Extended-Nanofluidic Systems for Chemistry and Biotechnology, Imperial College Press, 2012.
48. Y. Kazoe, Y. Shimizu, K. Morikawa, Y. Terui, T. Irie, and T. Kitamori, Development of microfluidic droplet shooter and its application to interface for mass spectrometry, Sensors and Actuators B. Chemical, Vol. 340, 129957, 2021.
49. Z. Li, S. Mak, A. Sauretb, and H. Shum, Syringe-pump-induced fluctuation in all-aqueous microfluidic system implications for flow rate accuracy, Lab Chip, Vol. 14, 2014, pp. 744 – 749.
50. Y. Takagi, Y. Kazoe, and T. Kitamori, Generation of femtoliter liquid droplets in gas phase by microfluidic droplet shooter, Microfluidics and Nanofluidics, Vol. 25, 74, 2021.
51. A. Berjan, Convection Heat Transfer, 4th ed., Wiley, 2013.
52. H. Schlichting, Laminare strahlausbreitung, Zeitschrift für Angewandte Mathematik und Mechanik, Vol. 13, 1933, pp. 260-263.
53. J. S. Marshall and S. Li, Adhesive Particle Flow: A Discrete-Element Approach, 1st ed., Cambridge University Press, 2014.
54. C. W. Oseen, Über die Stokes'sche formel, und über eine verwandte Aufgabe in der Hydrodynamik, Arkiv för matematik, astronomi och fysik, Vol. 6, 1910, pp. 1-20.
55. P. G. Saffman, On the motion of small spheroidal particles in a viscous liquid, Journal of Fluid Mechanics, Vol. 1, 1956, pp. 540-553.
56. G. Magnus, Über die Abweichung der Geschosse, und: Über eine abfallende Erscheinung bei rotierenden Körpern, Annalen der Physik, Vol. 164, 1853, pp. 1-29.
57. S. I. Rubinow and J. B. Keller, The transverse force on a spinning sphere moving in a viscous fluid, Journal of Fluid Mechanics, Vol. 11, 1961, pp. 447-459.
58. S. T. Thornton and J. B. Marion, Classical Dynamics of Particles and Systems, 5th ed., Brooks Cole, 2003.
59. P. Kebarle and L. Tang, From Ions in Solution to Ions in the Gas Phase, Analytical Chemistry, Vol. 65, 1993, pp. 972A-986A.
60. Andrea Schmidt, Michael Karasa, and Thomas Dülcks, Effect of different solution flow rates on analyte ion signals in nano-ESI MS, or: when does ESI turn into nano-ESI?, Journal of the American Society for Mass Spectrometry, Vol. 14, Issue. 5, 2003, pp. 492-500.
61. B. B. Schneider and H. Javaheri, and T. R. Covey, Ion sampling effects under conditions of total solvent consumption, Rapid Communications in Mass Spectrometry, Vol. 20, 2006, pp. 1538-1544.
62. M. G. Ikonomou, A. T. Blades, and P. Kebarle, Electrospray-Ion Spray: A Comparison of Mechanisms and Performance, Analytical Chemistry, Vol. 63, 1991, pp. 1989-1998.
63. F. C. Walsh, The Overall Rates of Electrode Reactions: Faraday's Laws of Electrolysis, Transactions of the IMF, Vol. 69, Issue. 4, 1991, pp. 155-157.
64. J. C. Maxwell, Collected Scientific Papers, Cambridge, Vol. 11, pp. 625-647.
65. B. Abramzon and W. A. Sirignano, Droplet vaporization model for spray combustion calculations, International Journal of Heat and Mass Transfer, Vol. 32, 1989, pp. 1605-1618.
66. T. Allen, Particle Size Measurement, 1st ed., Springer, 1990.
67. W. Ranz and W. Marshall, Evaporation from Drops, Chemical Engineering Progress, Vol. 48, 1952, pp. 141-146.
68. E. M. Sparrow and J. L. Gregg, Similar Solutions for Free Convection from a Non-Isothermal Vertical Plate, ASME Journal of Heat Transfer, Vol. 80, pp. 379-386.
69. C. L. Yaw, Chemical Properties Handbook, McGraw-Hill, 1999.
70. Y. Takagi, Y. Kazoe, K. Morikawa, and T. Kitamori, Femtoliter-Droplet Mass Spectrometry Interface Utilizing Nanofluidics for Ultrasmall and High-Sensitivity Analysis, Analytical Chemistry, Vol. 94, 2022, pp. 10074-10081.

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