A comparative study between a miniaturized liquid junction built in a capillary gap and semi-open capillaries for nL sample infusion to mass spectrometry

  • Sahar Ghiasikhou
  • Adrien Marchand
  • Renato ZenobiEmail author
Research Paper


This study introduces a novel design for a microfluidic element used in a high-throughput screening mass spectrometer autosampler. The original design of the sampler consists of a liquid bridge formed in a micrometer gap between two capillaries. This liquid bridge is used to receive the sample, which is later ionized and analyzed by mass spectrometry. However, this liquid bridge is difficult to establish and maintain for long time periods, making the screening of large libraries of compounds a tedious task. The improvement described here consists in replacing the liquid bridge by a single pierced capillary, called “semi-open capillary”. The fabrication of semi-open capillaries is explained. To achieve an optimum structure, two different machining methods were tested, laser ablation and electro-discharge micromachining. The advantages of this design over the previous one include reduction of the dead volume and that of the sample dilution, as well as higher stability. Characterizations of the repeatability and the limit of detection (LOD) show that the optimized semi-open capillary leads to nearly twofold lower LOD when compared to the original liquid bridge.

Graphical Abstract


High-throughput screening Capillary gap sampler Semi-open capillary Laser ablation Electro-discharging machining Sensitivity 



We gratefully thank Dr. Christof Fattinger (Roche) for his support in sampler development and Professor Ying Zhu (Department Chemistry, Zhejiang University) for helping in optimizing the structure of the hole. Moreover, we thank the Scientific Center for Optical and Electron Microscopy (ScopeM), a central technology platform of ETH Zurich, for providing us with resources and services in electron microscopy, the ETH Physics workshop for performing EDM for semi-open capillary preparation, and the SuSoS company in Dübendorf for providing us with a PFAND solution and for recording XPS data. Finally, we thank the Swiss National Science Foundation (SNSF) for funding this project (Grant Nos. 200020-159929 & 200020-178765).

Supplementary material

10404_2019_2229_MOESM1_ESM.docx (426 kb)
Supplementary material 1 (DOCX 422 kb)


  1. Bleicher KH, Böhm H-J, Müller K, Alanine AI (2003) Hit and lead generation: beyond high-throughput screening. Nat Rev Drug Discov 2:369–378CrossRefGoogle Scholar
  2. Chen H, Talaty NN, Takáts Z, Cooks RG (2005) Desorption electrospray ionization mass spectrometry for high-throughput analysis of pharmaceutical samples in the ambient environment. Anal Chem 77:6915–6927CrossRefGoogle Scholar
  3. Chen YG, Kowtoniuk WE, Agarwal I, Shen Y, Liu DR (2009) LC/MS analysis of cellular RNA reveals NAD-linked RNA. Nat Chem Biol 5:879–881CrossRefGoogle Scholar
  4. Chen Q, Wu J, Zhang Y, Lin J-M (2012) Qualitative and quantitative analysis of tumor cell metabolism via stable isotope labeling assisted microfluidic chip electrospray ionization mass spectrometry. Anal Chem 84:1695–1701CrossRefGoogle Scholar
  5. Chu Y-H, Dunayevskiy YM, Kirby DP, Vouros P, Karger BL (1996) Affinity capillary electrophoresis—mass spectrometry for screening combinatorial libraries. J Am Chem Soc 118:7827–7835CrossRefGoogle Scholar
  6. Drug discovery market worldwide by segment 2025 forecast|Statistic. Statista. Accessed 21 June 2018
  7. Ducrée J et al (2007) The centrifugal microfluidic Bio-Disk platform. J Micromec Microeng 17:S103CrossRefGoogle Scholar
  8. Fiehn O et al (2000) Metabolite profiling for plant functional genomics. Nat Biotechnol 18:1157–1161CrossRefGoogle Scholar
  9. Ghiasikhou S, Fabricio da Silva M, Zhu Y, Zenobi R (2017) The capillary gap sampler, a new microfluidic platform for direct coupling of automated solid-phase microextraction with ESI-MS. Anal Bioanal Chem 409:6873–6883CrossRefGoogle Scholar
  10. Gorkin R et al (2010) Centrifugal microfluidics for biomedical applications. Lab Chip 10:1758–1773CrossRefGoogle Scholar
  11. How Sinker EDM Machining Works. Accessed: 28 June 2018
  12. Jian W et al (2011) Evaluation of a high-throughput online solid phase extraction-tandem mass spectrometry system for in vivo bioanalytical studies. Anal Chem 83:8259–8266CrossRefGoogle Scholar
  13. Jin D-Q, Zhu Y, Fang Q (2014) Swan probe: a nanoliter-scale and high-throughput sampling interface for coupling electrospray ionization mass spectrometry with microfluidic droplet array and multiwell plate. Anal Chem 86:10796–10803CrossRefGoogle Scholar
  14. Keller M, Naue J, Zengerle R, von Stetten F, Schmidt U (2015) Automated forensic animal family identification by nested PCR and melt curve analysis on an off-the-shelf thermocycler augmented with a centrifugal microfluidic disk segment. PLoS ONE 10:e0131845CrossRefGoogle Scholar
  15. Laser ablation (2018) WikipediaGoogle Scholar
  16. Ma H, Horiuchi KY, Wang Y, Kucharewicz SA, Diamond SL (2005) Nanoliter homogenous ultra-high throughput screening microarray for lead discoveries and IC50 profiling. Assay Drug Dev Technol 3:177–187CrossRefGoogle Scholar
  17. Mao S, Zhang J, Li H, Lin J-M (2013) Strategy for signaling molecule detection by using an integrated microfluidic device coupled with mass spectrometry to study cell-to-cell communication. Anal Chem 85:868–876CrossRefGoogle Scholar
  18. Neu V, Steiner R, Müller S, Fattinger C, Zenobi R (2013) Development and characterization of a capillary gap sampler as new microfluidic device for fast and direct analysis of low sample amounts by ESI-MS. Anal Chem 85:4628–4635CrossRefGoogle Scholar
  19. Neu V, Dörig P, Fattinger C, Müller S, Zenobi R (2016) Characterization of a miniaturized liquid bridge for nL sample infusion: a comparative study of sample flush-out behavior using flow simulations and direct ESI-MS analysis. Microfluid Nanofluidics 20:62CrossRefGoogle Scholar
  20. Ozbal CC et al (2004) High throughput screening via mass spectrometry: a case study using acetylcholinesterase. Assay Drug Dev Technol 2:373–381CrossRefGoogle Scholar
  21. Rodenstein M, Zürcher S, Tosatti SGP, Spencer ND (2010) Fabricating chemical gradients on oxide surfaces by means of fluorinated, catechol-based, self-assembled monolayers. Langmuir 26:16211–16220CrossRefGoogle Scholar
  22. Sreekumar A et al (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457:910–914CrossRefGoogle Scholar
  23. Stark T, Wollmann N, Lösch S, Hofmann T (2011) Quantitation of resveratrol in red wines by means of stable isotope dilution analysis—ultra-performance liquid chromatography—quan-time-of-flight mass spectrometry and cross validation. Anal Chem 83:3398–3405CrossRefGoogle Scholar
  24. Strohmeier O et al (2015) Automated nucleic acid extraction from whole blood, B. subtilis, E. coli, and Rift Valley fever virus on a centrifugal microfluidic LabDisk. RSC Adv 5:32144–32150CrossRefGoogle Scholar
  25. Sun S, Kennedy RT (2014) Droplet electrospray ionization mass spectrometry for high throughput screening for enzyme inhibitors. Anal Chem 86:9309–9314CrossRefGoogle Scholar
  26. van Reenen A, de Jong AM, den Toonder JMJ, Prins MWJ (2014) Integrated lab-on-chip biosensing systems based on magnetic particle actuation—a comprehensive review. Lab Chip 14:1966–1986CrossRefGoogle Scholar
  27. Wan H et al (2003) High-throughput screening of pKa values of pharmaceuticals by pressure-assisted capillary electrophoresis and mass spectrometry. Rapid Commun Mass Spectrom 17:2639–2648CrossRefGoogle Scholar
  28. Wohlfarth C (2008) Surface tension of pure liquids and binary liquid mixtures: (supplement to IV/16). Springer, BerlinGoogle Scholar
  29. Zhang S, Pelt CKV (2004) Chip-based nanoelectrospray mass spectrometry for protein characterization. Expert Rev. Proteomics 1:449–468CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Chemistry and Applied BiosciencesETH ZurichZurichSwitzerland

Personalised recommendations