Direct Analysis of Aqueous Solutions and Untreated Biological Samples Using Nanoelectrospray Ionization Mass Spectrometry with Pipette Tip in Series with High-Ohmic Resistor as Ion Source

  • Matiur Rahman
  • Debo WuEmail author
  • Konstantin Chingin
Research Article


Commercially available disposable plastic pipette tip with the inner diameter of ca. 120 μm in series with a high-ohmic resistor (10 GΩ) was adapted as a low-cost alternative ion source for high-throughput nanoelectrospray mass spectrometry (nESI-MS) analysis of a variety of samples, especially aqueous solutions, without sample pretreatment. The use of high-ohmic resistor enabled the formation of stable electrospray of aqueous solutions at ambient conditions. In addition, corona discharge was avoided even with a high voltage applied. Quantitative analysis of vitamin B in water was successfully conducted by tip-ESI. The results exhibited a good linearity (R ˃ 0.9983), a low detection limit (0.25 ng/mL), and a wide dynamic response range (0.25–1000 ng/mL). Our study revealed that tip-ESI not only performed equally well to capillary nESI in terms of flow rate (˂ 100 nL/min), signal sensitivity, and sample consumption, but also offered a number of additional advantages, including better signal duration, tolerance to high analyte concentration (> 100 μg/mL) and high ionizing voltage (up to 6 kV), and obviation of tip clogging and corona discharge. High compatibility of tip-ESI with various kinds of samples (aqueous, viscous, solid, or bulk biological samples) makes it a promising tool for direct MS analysis.


Pipette tip Resistor Aqueous solution Direct analysis Clogging 



This work was supported by the National Key Scientific Instrument Development Projects (2011YQ14015008), Department of Science and Technology of Jiangxi Province (No. 20165BCB19013), Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT) (No. IRT13054 & IRT17R20), and International Science & Technology Cooperation Program (No. 2015DFA40290).

Supplementary material

13361_2019_2142_MOESM1_ESM.docx (2.4 mb)
ESM 1 (DOCX 2499 kb)


  1. 1.
    Coscia, F., Watters, K.M., Curtis, M., Eckert, M.A., Chiang, C.Y., Tyanova, S., Montag, A., Lastra, R.R., Lengyel, E., Mann, M.: Integrative proteomic profiling of ovarian cancer cell lines reveals precursor cell associated proteins and functional status. Nat. Commun. 7, 1–14 (2016). CrossRefGoogle Scholar
  2. 2.
    Fujii, T., Matsuda, S., Tejedor, M.L., Esaki, T., Sakane, I., Mizuno, H., Tsuyama, N., Masujima, T.: Direct metabolomics for plant cells by live single-cell mass spectrometry. Nat. Protoc. 10, 1445–1456 (2015). CrossRefGoogle Scholar
  3. 3.
    Brügger, B., Erben, G., Sandhoff, R., Wieland, F.T., Lehmann, W.D.: Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. Proc. Natl. Acad. Sci. U. S. A. 94, 2339–2344 (1997)CrossRefGoogle Scholar
  4. 4.
    Juraschek, R., Dülcks, T., Karas, M.: Nanoelectrospray-more than just a minimized-flow electrospray ionization source. J. Am. Soc. Mass Spectrom. 10, 300–308 (1999)CrossRefGoogle Scholar
  5. 5.
    Gibson, G.T.T., Mugo, S.M., Oleschuk, R.D.: Nanoelectrospray emitters: trends and perspective. Mass Spectrom. (Tokyo, Japan). 28, 918–936 (2009). Google Scholar
  6. 6.
    Kirby, A.E., Jebrail, M.J., Yang, H., Wheeler, A.R.: Folded emitters for nanoelectrospray ionization mass spectrometry. Rapid Commun. Mass Spectrom. 24, 3425–3431 (2010). CrossRefGoogle Scholar
  7. 7.
    Dyson, P.J., Khalaila, I., Luettgen, S., McIndoe, J.S., Zhao, D.: Direct probe electrospray (and nanospray) ionization mass spectrometry of neat ionic liquids. Chem. Commun. 10, 2204–2205 (2004). CrossRefGoogle Scholar
  8. 8.
    Hiraoka, K., Nishidate, K., Mori, K., Asakawa, D., Suzuki, S.: Development of probe electrospray using a solid needle. Rapid Commun. Mass Spectrom. 21, 3139–3144 (2007). CrossRefGoogle Scholar
  9. 9.
    Kuo, C.-P., Shiea, J.: Application of direct electrospray probe to analyze biological compounds and to couple to solid-phase microextraction to detect trace surfactants in aqueous solution. Anal. Chem. 71, 4413–4417 (1999). CrossRefGoogle Scholar
  10. 10.
    Jeng, J., Shiea, J.: Electrospray ionization from a droplet deposited on a surface-modified glass rod. Rapid Commun. Mass Spectrom. 17, 1709–1713 (2003). CrossRefGoogle Scholar
  11. 11.
    Jeng, J., Lin, C.H., Shiea, J.: Electrospray from nanostructured tungsten oxide surfaces with ultralow sample volume. Anal. Chem. 77, 8170–8173 (2005). CrossRefGoogle Scholar
  12. 12.
    Liu, J., Wang, H., Manicke, N.E., Lin, J.M., Cooks, R.G., Ouyang, Z.: Development, characterization, and application of paper spray ionization. Anal. Chem. 82, 2463–2471 (2010). CrossRefGoogle Scholar
  13. 13.
    Zhang, J.I., Li, X., Ouyang, Z., Cooks, R.G.: Direct analysis of steviol glycosides from Stevia leaves by ambient ionization mass spectrometry performed on whole leaves. Analyst. 137, 3091–3098 (2012). CrossRefGoogle Scholar
  14. 14.
    Liu, J., Wang, H., Cooks, R.G., Ouyang, Z.: Leaf spray: direct chemical analysis of plant material and living plants by mass spectrometry. Anal. Chem. 83, 7608–7613 (2011). CrossRefGoogle Scholar
  15. 15.
    Hu, B., So, P.-K., Chen, H., Yao, Z.-P.: Electrospray ionization using wooden tips. Anal. Chem. 83, 8201–8207 (2011). CrossRefGoogle Scholar
  16. 16.
    Yao, Y.-N., Hu, B.: Analyte-substrate interactions at functionalized tip electrospray ionization mass spectrometry: Molecular mechanisms and applications. J. Mass Spectrom. JMS. 53, 1222–1229 (2018). CrossRefGoogle Scholar
  17. 17.
    Aksyonov, S., Williams, P.: Electrospray ionization using disposable plastic pipette tips. Rapid Commun. Mass Spectrom. 15, 1890–1891 (2001)CrossRefGoogle Scholar
  18. 18.
    Huang, Y.-Q., You, J.-Q., Yuan, B.-F., Feng, Y.-Q.: Sample preparation and direct electrospray ionization on a tip column for rapid mass spectrometry analysis of complex samples. Analyst. 137, 4593–4597 (2012). CrossRefGoogle Scholar
  19. 19.
    Wang, H., So, P.-K., Yao, Z.-P.: Direct analysis of herbal powders by pipette-tip electrospray ionization mass spectrometry. Anal. Chim. Acta. 809, 109–116 (2014). CrossRefGoogle Scholar
  20. 20.
    Zhong, X., Qiao, L., Stauffer, G., Liu, B., Girault, H.H.: On-chip spyhole nanoelectrospray ionization mass spectrometry for sensitive biomarker detection in small volumes. J. Am. Soc. Mass Spectrom. 29, 1538–1545 (2018). CrossRefGoogle Scholar
  21. 21.
    Gasilova, N., Yu, Q., Qiao, L., Girault, H.H.: On-chip spyhole mass spectrometry for droplet-based microfluidics. Angew. Chemie - Int. Ed. 53, 4408–4412 (2014). CrossRefGoogle Scholar
  22. 22.
    Liu, J., Ro, K.W., Busman, M., Knapp, D.R.: Electrospray ionization with a pointed carbon fiber emitter. Anal. Chem. 76, 3599–3606 (2004). CrossRefGoogle Scholar
  23. 23.
    Wu, M.-X., Wang, H.-Y., Zhang, J.-T., Guo, Y.-L.: Multifunctional carbon fiber ionization mass spectrometry. Anal. Chem. 88, 9547–9553 (2016). CrossRefGoogle Scholar
  24. 24.
    Hu, B., So, P.-K., Yao, Z.-P.: Electrospray ionization with aluminum foil: a versatile mass spectrometric technique. Anal. Chim. Acta. 817, 1–8 (2014). CrossRefGoogle Scholar
  25. 25.
    Ji, B., Xia, B., Gao, Y., Ma, F., Ding, L., Zhou, Y.: Generating electrospray ionization on ballpoint tips. Anal. Chem. 88, 5072–5079 (2016). CrossRefGoogle Scholar
  26. 26.
    Joshi, S., Zuilhof, H., Van Beek, T.A., Nielen, M.W.F.: Biochip spray: simplified coupling of surface plasmon resonance biosensing and mass spectrometry. Anal. Chem. 89, 1427–1432 (2017). CrossRefGoogle Scholar
  27. 27.
    Gómez-Ríos, G.A., Pawliszyn, J.: Development of coated blade spray ionization mass spectrometry for the quantitation of target analytes present in complex matrices. Angew. Chemie - Int. Ed. 53, 14503–14507 (2014). CrossRefGoogle Scholar
  28. 28.
    Pirro, V., Llor, R.S., Jarmusch, A.K., Alfaro, C.M., Cohen-Gadol, A.A., Hattab, E.M., Cooks, R.G.: Analysis of human gliomas by swab touch spray-mass spectrometry: applications to intraoperative assessment of surgical margins and presence of oncometabolites. Analyst. 142, 4058–4066 (2017). CrossRefGoogle Scholar
  29. 29.
    Rahman, M.M., Hiraoka, K., Chen, L.C.: Realizing nano electrospray ionization using disposable pipette tips under super atmospheric pressure. Analyst. 139, 610–617 (2014). CrossRefGoogle Scholar
  30. 30.
    Mandal, M.K., Yoshimura, K., Saha, S., Yu, Z., Takeda, S., Hiraoka, K.: Biomolecular analysis and biological tissue diagnostics by electrospray ionization with a metal wire inserted gel-loading tip. Anal. Chem. 86, 987–992 (2014). CrossRefGoogle Scholar
  31. 31.
    Hecht, M., Evard, H., Takkis, K., Veigure, R.T., Aro, R., Lohmus, R., Herodes, K., Leito, I., Kipper, K.: Sponge spray-reaching new dimensions of direct sampling and analysis by MS. Anal. Chem. 89, 11592–11597 (2017). CrossRefGoogle Scholar
  32. 32.
    Zhang, H., Li, N., Wang, Y., Zhao, D., He, J., You, H., Jiang, J.: Real-time monitoring of the degradation of Cu(II)-EDTA in H2O2/UV using illumination-assisted droplet spray ionization mass spectrometry. Chemosphere. 184, 932–938 (2017). CrossRefGoogle Scholar
  33. 33.
    Jackson, G.S., Enke, C.G.: Electrical equivalence of electrospray ionization with conducting and nonconducting needles. Anal. Chem. 71, 3777–3784 (1999)CrossRefGoogle Scholar
  34. 34.
    Chen, L.C., Mandal, M.K., Hiraoka, K.: Super-atmospheric pressure electrospray ion source: applied to aqueous solution. J. Am. Soc. Mass Spectrom. 22, 2108–2114 (2011). CrossRefGoogle Scholar
  35. 35.
    Chen, L.C., Mandal, M.K., Hiraoka, K.: High pressure (>1 atm) electrospray ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 22, 539–544 (2011). CrossRefGoogle Scholar
  36. 36.
    Chen, L.C., Rahman, M.M., Hiraoka, K.: Super-atmospheric pressure chemical ionization mass spectrometry. J. Mass Spectrom. 48, 392–398 (2013). CrossRefGoogle Scholar
  37. 37.
    Rahman, M.M., Chen, L.C., Hiraoka, K.: Development of high-pressure probe electrospray ionization for aqueous solution. Rapid Commun. Mass Spectrom. 27, 68–74 (2013). CrossRefGoogle Scholar
  38. 38.
    Rahman, M.M., Mandal, M.K., Hiraoka, K., Chen, L.C.: High pressure nanoelectrospray ionization mass spectrometry for analysis of aqueous solutions. Analyst. 138, 6316–6322 (2013). CrossRefGoogle Scholar
  39. 39.
    McClory, P.J., Håkansson, K.: Corona discharge suppression in negative ion mode nanoelectrospray ionization via trifluoroethanol addition. Anal. Chem. 89, 10188–10193 (2017). CrossRefGoogle Scholar
  40. 40.
    Bruins, A.P., Covey, T.R., Henion, J.D.: Ion spray interface for combined liquid chromatography/atmospheric pressure ionization mass spectrometry. Anal. Chem. 59, 2642–2646 (1987). CrossRefGoogle Scholar
  41. 41.
    Takáts, Z., Wiseman, J.M., Gologan, B., Cooks, R.G.: Electrosonic spray ionization. A gentle technique for generating folded proteins and protein complexes in the gas phase and for studying ion-molecule reactions at atmospheric pressure. Anal. Chem. 76, 4050–4058 (2004). CrossRefGoogle Scholar
  42. 42.
    Fenn, J.B., Mann, M., Meng, C.K., Wong, S.F., Whitehouse, C.M.: Electrospray ionization for mass spectrometry of large biomolecules. Science (80-. ). 246, 64–71 (1989). CrossRefGoogle Scholar
  43. 43.
    Ikonomou, M.G., Blades, A.T., Kebarle, P.: Electrospray mass spectrometry of methanol and water solutions suppression of electric discharge with SF6gas. J. Am. Soc. Mass Spectrom. 2, 497–505 (1991). CrossRefGoogle Scholar
  44. 44.
    El-Faramawy, A., Siu, K.W.M., Thomson, B.A.: Efficiency of nano-electrospray ionization. J. Am. Soc. Mass Spectrom. 16, 1702–1707 (2005). CrossRefGoogle Scholar
  45. 45.
    Chen, H., Venter, A., Cooks, R.G.: Extractive electrospray ionization for direct analysis of undiluted urine, milk and other complex mixtures without sample preparation. Chem. Commun. 2042–2044 (2006).
  46. 46.
    Chen, H., Wortmann, A., Zhang, W., Zenobi, R.: Rapid in vivo fingerprinting of nonvolatile compounds in breath by extractive electrospray ionization quadrupole time-of-flight mass spectrometry. Angew. Chemie - Int. Ed. 46, 580–583 (2007). CrossRefGoogle Scholar
  47. 47.
    Chen, H., Yang, S., Li, M., Hu, B., Li, J., Wang, J.: Sensitive detection of native proteins using extractive electrospray ionization mass spectrometry. Angew. Chemie - Int. Ed. 49, 3053–3056 (2010). CrossRefGoogle Scholar
  48. 48.
    Chen, H., Yang, S., Wortmann, A., Zenobi, R.: Neutral desorption sampling of living objects for rapid analysis by extractive electrospray ionization mass spectrometry. Angew. Chemie - Int. Ed. 46, 7591–7594 (2007). CrossRefGoogle Scholar
  49. 49.
    Luo, M., Hu, B., Zhang, X., Peng, D., Chen, H., Zhang, L., Huan, Y.: Spectrometry for sensitive detection of uranyl species in natural water samples. Anal. Chem. 82, 282–289 (2010)CrossRefGoogle Scholar
  50. 50.
    Chen, H., Zenobi, R.: Neutral desorption sampling of biological surfaces for rapid chemical characterization by extractive electrospray ionization mass spectrometry. Nat. Protoc. 3, 1467–1475 (2008). CrossRefGoogle Scholar
  51. 51.
    Zhu, L., Gamez, G., Chen, H., Chingin, K., Zenobi, R.: Rapid detection of melamine in untreated milk and wheat gluten by ultrasound-assisted extractive electrospray ionization mass spectrometry (EESI-MS). Chem. Commun. 559–561 (2009).
  52. 52.
    Aksyonov, S., Williams, P.: Electrospray ionization using disposable plastic pipette tips. Rapid Commun. Mass Spectrom. 15, 1890–1891 (2001). CrossRefGoogle Scholar
  53. 53.
    Kumar, S., Singh, A., Kumar, B., Singh, B., Bahadur, L., Lal, M.: Simultaneous quantitative determination of bioactive terpene indole alkaloids in ethanolic extracts of Catharanthus roseus (L.) G. Don by ultra high performance liquid chromatography-tandem mass spectrometry. J. Pharm. Biomed. Anal. 151, 32–41 (2018). CrossRefGoogle Scholar
  54. 54.
    Hisiger, S., Jolicoeur, M.: Analysis of Catharanthus roseus alkaloids by HPLC. Phytochem. Rev. 6, 207–234 (2007). CrossRefGoogle Scholar
  55. 55.
    Zhou, H., Tai, Y., Sun, C., Pan, Y.: Rapid identification of Vinca alkaloids by direct-injection electrospray ionisation tandem mass spectrometry and confirmation by high-performance liquid chromatography - Mass spectrometry. Phytochem. Anal. 16, 328–333 (2005). CrossRefGoogle Scholar
  56. 56.
    Wilm, M., Mann, M.: Analytical properties of the nanoelectrospray ion source. Anal. Chem. 68, 1–8 (1996). CrossRefGoogle Scholar
  57. 57.
    Lazar, I.M., Lee, M.L.: Effect of electrospray needle voltage on electroosmotic flow in capillary electrophoresis-mass spectrometry. J. Am. Soc. Mass Spectrom. 10, 261–264 (1999). CrossRefGoogle Scholar
  58. 58.
    Peng, Y., Zhang, S., Wen, F., Ma, X., Yang, C., Zhang, X.: In vivo nanoelectrospray for the localization of bioactive molecules in plants by mass spectrometry. Anal. Chem. 84, 3058–3062 (2012). CrossRefGoogle Scholar
  59. 59.
    Hall, Z., Chu, Y., Griffin, J.L.: Liquid extraction surface analysis mass spectrometry method for identifying the presence and severity of nonalcoholic fatty liver disease. Anal. Chem. 89, 5161–5170 (2017). CrossRefGoogle Scholar
  60. 60.
    Sarsby, J., Griffiths, R.L., Race, A.M., Bunch, J., Randall, E.C., Creese, A.J., Cooper, H.J.: Liquid extraction surface analysis mass spectrometry coupled with field asymmetric waveform ion mobility spectrometry for analysis of intact proteins from biological substrates. Anal. Chem. 87, 6794–6800 (2015). CrossRefGoogle Scholar
  61. 61.
    Usmanov, D.T., Mandal, M.K., Hiraoka, K., Ninomiya, S., Wada, H., Matsumura, M., Sanada-Morimura, S., Nonami, H., Yamabe, S.: Dipping probe electrospray ionization/mass spectrometry for direct on-site and low-invasive food analysis. Food Chem. 260, 53–60 (2018). CrossRefGoogle Scholar
  62. 62.
    Hu, B., Yao, Z.-P.: Detection of native proteins using solid-substrate electrospray ionization mass spectrometry with nonpolar solvents. Anal. Chim. Acta. 1004, 51–57 (2018). CrossRefGoogle Scholar
  63. 63.
    Cooks, R.G., Zhang, D., Koch, K.J., Gozzo, F.C., Eberlin, M.N.: Chiroselective self-directed octamerization of serine: implications for homochirogenesis. Anal. Chem. 73, 3646–3655 (2001). CrossRefGoogle Scholar
  64. 64.
    Hu, B., Lai, Y.-H., So, P.-K., Chen, H., Yao, Z.-P.: Direct ionization of biological tissue for mass spectrometric analysis. Analyst. 137, 3613–3619 (2012). CrossRefGoogle Scholar
  65. 65.
    Huang, X., Song, F., Liu, Z., Liu, S.: Structural characterization and identification of dibenzocyclooctadiene lignans in Fructus Schisandrae using electrospray ionization ion trap multiple-stage tandem mass spectrometry and electrospray ionization Fourier transform ion cyclotron resonance mul. Anal. Chim. Acta. 615, 124–135 (2008). CrossRefGoogle Scholar
  66. 66.
    Xin, H., Fengrui, S., Zhiqiang, L., Shuying, L.: Applications of modern mass spectrometry and its coupling technologies in Schisandrae fruits chemical research. World Sci. Technol. 11, 115–119 (2009). CrossRefGoogle Scholar
  67. 67.
    Wu, W., Liang, Z., Zhao, Z., Cai, Z.: Direct analysis of alkaloid profiling in plant tissue by using matrix-assisted laser desorption/ionization mass spectrometry. J. Mass Spectrom. 42, 58–69.

Copyright information

© American Society for Mass Spectrometry 2019

Authors and Affiliations

  1. 1.Jiangxi Key Laboratory for Mass Spectrometry and InstrumentationEast China University of TechnologyNanchangPeople’s Republic of China

Personalised recommendations