Skip to main content
Log in

2-layer based microfluidic concentration generator by hybrid serial and volumetric dilutions

  • Published:
Biomedical Microdevices Aims and scope Submit manuscript

Abstract

We present a 2-layer based microfluidic concentration generator by a hybrid of a serial and a volumetric dilution for dose-response experiments in drug screening. The hybrid dilution method using 2-layer based microfluidic network significantly reduces the total number of cascaded serial dilution stages. The proposed strategy is capable of generating a large number of universal stepwise monotonic concentrations with a wide range of logarithmic and linear scales. We have studied an equivalent electrical circuit to that of the 2-layer based microfluidic network, where the only variable parameter is channel length. We have designed a microfluidic dilution generator simultaneously covering 14 doses with a combination of 4-order logarithmic and 4-point linear concentrations. The design has been verified by a commercial circuit analysis software (e.g., P-Spice) for the electrical circuit analysis and a computational fluid dynamics software (e.g., CFD-ACE+) for the microfluidic circuit analysis. As a real-life application of the proposed dilution generator, we have successfully performed a dose-response experiment using MCF-7 human breast cancer cells. We expect that the proposed dilution method will be useful to study not only high throughput drug screening but also optimization in biology, chemistry, medicine, and material sciences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • D. Amarie, J.A. Glazier et al., Compact microfluidic structures for generating spatial and temporal gradients. Anal. Chem. 79(24), 9471–9477 (2007)

    Article  Google Scholar 

  • K. Campbell, A. Groisman, Generation of complex concentration profiles in microchannels in a logarithmically small number of steps. Lab Chip 7(2), 264–72 (2007)

    Article  Google Scholar 

  • J.K. Chang, H. Bang et al., Fabrication of the PDMS microchip for serially diluting sample with buffer. Microsystem Technologies-Micro-and Nanosystems-Information Storage and Processing Systems 9(8), 555–558 (2003)

    Google Scholar 

  • S.K.W. Dertinger, D.T. Chiu et al., Generation of gradients having complex shapes using microfluidic networks. Anal. Chem. 73(6), 1240–1246 (2001)

    Article  Google Scholar 

  • P.S. Dittrich, A. Manz, Lab-on-a-chip: microfluidics in drug discovery. Nat. Rev. Drug. Discov. 5(3), 210–218 (2006)

    Article  Google Scholar 

  • F. Greve, L. Seemann et al., A hybrid microsystem for parallel perfusion experiments on living cells. J. Micromechanics Microengineering 17(8), 1721–1730 (2007)

    Article  Google Scholar 

  • K. Hattori, S. Sugiura et al., Generation of arbitrary monotonic concentration profiles by a serial dilution microfluidic network composed of microchannels with a high fluidic-resistance ratio. Lab Chip 9, 1763–1772 (2009)

    Article  Google Scholar 

  • Eli Lilly and Company and the National Institutes of Health Chemical Genomics Center (2008). Assay guidance manual 5.0 (http://www.ncgc.nih.gov/guidance/)

  • J.G. Hong, J.B. Edel et al., Micro- and nanofluidic systems for high-throughput biological screening. Drug Discov. Today 14(3–4), 134–146 (2009)

    Article  Google Scholar 

  • D. Irimia, S.Y. Liu et al., Microfluidic system for measuring neutrophil migratory responses to fast switches of chemical gradients. Lab Chip 6(2), 191–198 (2006)

    Article  Google Scholar 

  • R.F. Ismagilov, J.M.K. Ng et al., Microfluidic arrays of fluid-fluid diffusional contacts as detection elements and combinatorial tools. Anal. Chem. 73(21), 5207–5213 (2001)

    Article  Google Scholar 

  • S.C. Jacobson, T.E. McKnight et al., Microfluidic devices for electrokinetically driven parallel and serial mixing. Anal. Chem. 71(20), 4455–4459 (1999)

    Article  Google Scholar 

  • X.Y. Jiang, J.M.K. Ng et al., A miniaturized, parallel, serially diluted immunoassay for analyzing multiple antigens. J. Am. Chem. Soc. 125(18), 5294–5295 (2003)

    Article  Google Scholar 

  • T.M. Keenan, A. Folch, Biomolecular gardients in cell culture systems. Lab Chip 8, 34–57 (2008)

    Article  Google Scholar 

  • L. Kim, M.D. Vahey et al., Microfluidic arrays for logarithmically perfused embryonic stem cell culture. Lab Chip 6(3), 394–406 (2006)

    Article  Google Scholar 

  • C. Kim, K. Lee et al., A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations. Lab Chip 8(3), 473–479 (2008)

    Article  Google Scholar 

  • K. Lee, C. Kim et al., Generalized serial dilution module for monotonic and arbitrary microfluidic gradient generators. Lab Chip 9(5), 709–717 (2009)

    Article  Google Scholar 

  • F. Lin, W. Saadi et al., Generation of dynamic temporal and spatial concentration gradients using microfluidic devices. Lab Chip 4(3), 164–167 (2004)

    Article  Google Scholar 

  • C. Neils, Z. Tyree et al., Combinatorial mixing of microfluidic streams. Lab Chip 4(4), 342–350 (2004)

    Article  Google Scholar 

  • J. Olechno, J. Shieh et al., Improving IC50 results with acoustic droplet ejection. JALA 11, 240–246 (2006)

    Google Scholar 

  • B.M. Paegel, W.H. Grover et al., Microfluidic serial dilution circuit. Anal. Chem. 78(21), 7522–7527 (2006)

    Article  Google Scholar 

  • C. G. Smith, J. T. O’Donnell, The process of new drug discovery and development. (Informa Health Care, 2006)

  • J.A. Timbrell, Principles of biochemical toxicology. (Taylor & Francis, 2000)

  • B.H. Weigl, R.L. Bardell et al., Lab-on-a-chip for drug development. Adv. Drug Deliv. Rev. 55(3), 349–377 (2003)

    Article  Google Scholar 

  • M. Yamada, T. Hirano et al., A microfluidic flow distributor generating stepwise concentrations for high-throughput biochemical processing. Lab Chip 6(2), 179–184 (2006)

    Article  Google Scholar 

  • A. Yang, D.L. Cardona et al., Subacute cytotoxicity testing with cultured human lung cells. Toxicol. In Vitro 16(1), 33–39 (2002)

    Article  Google Scholar 

Download references

Acknowledgment

This work was supported in part by the National Science Foundation under ECCS/EPDT program (contract #0736501) and the NYSTAR Faculty Development program. This research was supported in part by the Intelligent Microsystem Center, which is carrying out one of the 21st Century’s Frontier R&D Projects sponsored by the Korea Ministry of Commerce, Industry and Energy.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kwang W. Oh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, K., Kim, C., Kim, Y. et al. 2-layer based microfluidic concentration generator by hybrid serial and volumetric dilutions. Biomed Microdevices 12, 297–309 (2010). https://doi.org/10.1007/s10544-009-9385-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10544-009-9385-6

Keywords

Navigation