Microsystem Technologies

, Volume 21, Issue 3, pp 539–548 | Cite as

“From microtiter plates to droplets” tools for micro-fluidic droplet processing

  • Jialan Cao
  • Steffen Schneider
  • Robert Schultheiß
  • Andreas Schober
  • J. Michael Köhler
  • G. Alexander Groß
Technical Paper

Abstract

Droplet-based microfluidic allows high throughput experimentation in with low volume droplets. Essential fluidic process steps are on the one hand the proper control of the droplet composition and on the other hand the droplet processing, manipulation and storage. Beside integrated fluidic chips, standard PTFE-tubings and fluid connectors can be used in combination with appropriate pumps to realize almost all necessary fluidic processes. The segmented flow technique usually operates with droplets of about 100–500 nL volume. These droplets are embedded in an immiscible fluid and confined by channel walls. For the integration of segmented flow applications in established research workflows—which are usually base on microtiter plates—robotic interface tools for parallel/serial and serial/parallel transfer operations are necessary. Especially dose–response experiments are well suited for the segmented flow technique. We developed different transfer tools including an automated “gradient take-up tool” for the generation of segment sequences with gradually changing composition of the individual droplets. The general working principles are introduced and the fluidic characterizations are given. As exemplary application for a dose–response experiment the inhibitory effect of antibiotic tetracycline on Escherichia coli bacteria cultivated inside nanoliter droplets was investigated.

Notes

Acknowledgments

Financial support from the BMWI-Project “PharmTest” FKZ:KS2731202AK0, BMBF-Project “BactoKat” FKZ:031A161A, and the German Federal Environmental Foundation (DBU 20009/009) is gratefully acknowledged.

References

  1. Agresti JJ, Antipov E, Abate AR, Ahn K, Rowat AC, Baret J-C, Marquez M, Klibanov AM, Griffiths AD, Weitz DA (2010) Ultrahigh-throughput screening in drop-based microfluidics for directed evolution. Proc Natl Acad Sci USA 107(9):4004–4009. doi: 10.1073/pnas.0910781107 CrossRefGoogle Scholar
  2. Brouzes E, Medkova M, Savenelli N, Marran D, Twardowski M, Hutchison JB, Rothberg JM, Link DR, Perrimon N, Samuels ML (2009) Droplet microfluidic technology for single-cell high-throughput screening. Proc Natl Acad Sci USA 106(34):14195–14200. doi: 10.1073/pnas.0903542106 CrossRefGoogle Scholar
  3. Cao J, Kürsten D, Schneider S, Knauer A, Günther PM, Köhler JM (2012a) Uncovering toxicological complexity by multi-dimensional screenings in microsegmented flow: modulation of antibiotic interference by nanoparticles. Lab Chip 12(3):474–484. doi: 10.1039/c1lc20584f CrossRefGoogle Scholar
  4. Cao JL, Kürsten D, Schneider S, Köhler JM (2012b) Stimulation and inhibition of bacterial growth by caffeine dependent on chloramphenicol and a phenolic uncoupler-A ternary toxicity study using microfluid segment technique. J Biomed Nanotechnol 8(5):770–778. doi: 10.1166/jbn.2012.1447 CrossRefGoogle Scholar
  5. Chalmers G, Kozak GK, Hillyer E, Reid-Smith RJ, Boerlin P (2010) Low minimum inhibitory concentrations associated with the tetracycline-resistance gene tet(C) in Escherichia coli. Can J Vet Res-Rev Can Rech Vet 74(2):145–148Google Scholar
  6. Clausell-Tormos J, Merten CA (2012) Micro segmented-flow in biochemical and cell-based assays. Front Biosci (Elite Ed) 4:1768–1779CrossRefGoogle Scholar
  7. Clausell-Tormos J, Griffiths AD, Merten CA (2010) An automated two-phase microfluidic system for kinetic analyses and the screening of compound libraries. Lab Chip 10(10):1302–1307. doi: 10.1039/b921754a CrossRefGoogle Scholar
  8. Du W-B, Sun M, Gu S-Q, Zhu Y, Fang Q (2010) Automated microfluidic screening assay platform based on drop lab. Anal Chem 82(23):9941–9947. doi: 10.1021/ac1020479 CrossRefGoogle Scholar
  9. Funfak A, Hartung R, Cao J, Martin K, Wiesmueller K-H, Wolfbeis OS, Köhler JM (2009) Highly resolved dose-response functions for drug-modulated bacteria cultivation obtained by fluorometric and photometric flow-through sensing in microsegmented flow. Sens Actuators B Chem 142(1):66–72. doi: 10.1016/j.snb.2009.07.017 CrossRefGoogle Scholar
  10. Hartung R, Brösing A, Sczcepankiewicz G, Liebert U, Haefner N, Duerst M, Felbel J, Lassner D, Köhler JM (2009) Application of an asymmetric helical tube reactor for fast identification of gene transcripts of pathogenic viruses by micro flow-through PCR. Biomed Microdevices 11(3):685–692. doi: 10.1007/s10544-008-9280-6 CrossRefGoogle Scholar
  11. Hatakeyama T, Chen DL, Ismagilov RF (2006) Microgram-scale testing of reaction conditions in solution using nanoliter plugs in microfluidics with detection by MALDI-MS. J Am Chem Soc 128(8):2518–2519. doi: 10.1021/ja057720w CrossRefGoogle Scholar
  12. Hosokawa K, Fujii T, Endo I (1999) Handling of picoliter liquid samples in a poly(dimethylsiloxane)-based microfluidic device. Anal Chem 71(20):4781–4785. doi: 10.1021/ac990571d CrossRefGoogle Scholar
  13. Köhler JM, Henkel T, Grodrian A, Kirner T, Roth M, Martin K, Metze J (2004) Digital reaction technology by micro segmented flow—components, concepts and applications. Chem Eng J 101(1–3):201–216. doi: 10.1016/j.cej.2003.11.025 CrossRefGoogle Scholar
  14. Ma HC, 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(2):177–187. doi: 10.1089/adt.2005.3.177 CrossRefGoogle Scholar
  15. Migliore L, Rotini A, Thaller MC (2013) Low doses of tetracycline trigger the E. Coli growth: a case of hormetic response. Dose Response. doi: 10.2203/dose-response.13-002.Migliore Google Scholar
  16. Miller OJ, El Harrak A, Mangeat T, Baret J-C, Frenz L, El Debs B, Mayot E, Samuels ML, Rooney EK, Dieu P, Galvan M, Link DR, Griffiths AD (2012) High-resolution dose-response screening using droplet-based microfluidics. Proc Natl Acad Sci USA 109(2):378–383. doi: 10.1073/pnas.1113324109 CrossRefGoogle Scholar
  17. Schemberg J, Grodrian A, Römer R, Gastrock G, Lemke K (2009) Online optical detection of food contaminants in microdroplets. Eng Life Sci 9(5):391–397. doi: 10.1002/elsc.200800127 CrossRefGoogle Scholar
  18. Schumacher JT, Grodrian A, Lemke K, Römer R, Metze J (2008) System development for generating homogeneous cell suspensions and transporting them in microfluidic devices. Eng Life Sci 8(1):49–55. doi: 10.1002/elsc.200720224 CrossRefGoogle Scholar
  19. Song H, Chen DL, Ismagilov RF (2006) Reactions in droplets in microflulidic channels. Angew Chem Int Ed 45(44):7336–7356. doi: 10.1002/anie.200601554 CrossRefGoogle Scholar
  20. Stanley CE, Wootton RCR, deMello AJ (2012) Continuous and segmented flow microfluidics: applications in high-throughput chemistry and biology. Chimia 66(3):88–98. doi: 10.2533/chimia.2012.88 CrossRefGoogle Scholar
  21. Wood KB, Cluzel P (2012) Trade-offs between drug toxicity and benefit in the multi-antibiotic resistance system underlie optimal growth of E. coli. BMC Syst Biol 6:48. doi: 10.1186/1752-0509-6-48 CrossRefGoogle Scholar
  22. Wu J, Zhang M, Li X, Wen W (2012) Multiple and high-throughput droplet reactions via combination of microsampling technique and microfluidic chip. Anal Chem 84(22):9689–9693. doi: 10.1021/ac302249h CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Jialan Cao
    • 1
  • Steffen Schneider
    • 1
  • Robert Schultheiß
    • 3
  • Andreas Schober
    • 2
  • J. Michael Köhler
    • 1
  • G. Alexander Groß
    • 1
  1. 1.Department of Physical Chemistry and Microreaction Technology, Institute of Chemistry and BiotechnologyIlmenau University of TechnologyIlmenauGermany
  2. 2.Department of Nano-Biosystem Technology, Institute of Chemistry and BiotechnologyIlmenau University of TechnologyIlmenauGermany
  3. 3.Innovative Laborsysteme Stützerbach, ILS-Stützerbach GmbHStützerbachGermany

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