Abstract
We present a combinatorial dilution device using a three-layer microfluidic network that can produce systematic variations of buffer and additive solutions in a combinatorial fashion for high throughput screening and optimization. A proof-of-concept device providing seven combinations (ABC/D, AB/D, BC/D, AC/D, A/D, B/D, and C/D) of three additive samples (A, B, and C) into a buffer solution (D) has been demonstrated. Such combinations are often used in simplex-centroid mixture DOE (design of experiments), useful techniques to minimize the experimental efforts at maximal information output with systematic variations of large-scale components. Based on mathematical and electrical modeling and computational fluid dynamic simulation, the device has been designed, fabricated, and characterized.
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References
Assay Guidance Manual Version 5.0. (2008) Eli Lilly and Company and NIH Chemical Genomics Center. http://www.ncgc.nih.gov/guidance/manual_toc.html
Breslauer DN, Lee PJ et al (2006) Microfluidics-based systems biology. Mol Biosyst 2(2):97–112
Campbell K, Groisman A (2007) Generation of complex concentration profiles in microchannels in a logarithmically small number of steps. Lab Chip 7(2):264–272
Cooksey GA, Sip CG et al (2009) A multi-purpose microfluidic perfusion system with combinatorial choice of inputs, mixtures, gradient patterns, and flow rates. Lab Chip 9(3):417–426
Dertinger SKW, Chiu DT et al (2001) Generation of gradients having complex shapes using microfluidic networks. Anal Chem 73(6):1240–1246
Dittrich PS, Manz A (2006) Lab-on-a-chip: microfluidics in drug discovery. Nat Rev Drug Discov 5(3):210–218
Garcia-Egido E, Spikmans V et al (2003) Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system. Lab Chip 3(2):73–76
Greve F, Seemann L et al (2007) A hybrid microsystem for parallel perfusion experiments on living cells. J Micromech Microeng 17(8):1721–1730
Hattori K, Sugiura S et al (2009) Generation of arbitrary monotonic concentration profiles by a serial dilution microfluidic network composed of microchannels with a high fluidic-resistance ratio. Lab Chip. doi:10.1039/b816995k
Holden MA, Kumar S et al (2003) Generating fixed concentration arrays in a microfluidic device. Sens Actuators B 92(1–2):199–207
Irimia D, Geba DA et al (2006) Universal microfluidic gradient generator. Anal Chem 78(10):3472–3477
Islam RS, Tisi D et al (2007) Framework for the rapid optimization of soluble protein expression in Escherichia coli combining microscale experiments and statistical experimental design. Biotechnol Prog 23(4):785–793
Ismagilov RF, Ng JMK et al (2001) Microfluidic arrays of fluid–fluid diffusional contacts as detection elements and combinatorial tools. Anal Chem 73(21):5207–5213
Jacobson SC, McKnight TE et al (1999) Microfluidic devices for electrokinetically driven parallel and serial mixing. Anal Chem 71(20):4455–4459
Jeon NL, Dertinger SKW et al (2000) Generation of solution and surface gradients using microfluidic systems. Langmuir 16(22):8311–8316
Kang JH, Um E et al (2009) Fabrication of a poly(dimethylsiloxane) membrane with well-defined through-holes for three-dimensional microfluidic networks. J Micromech Microeng 19:045027 (6 pp)
Kikutani Y, Horiuchi T et al (2002) Glass microchip with three-dimensional microchannel network for 2 × 2 parallel synthesis. Lab Chip 2(4):188–192
Kikutani Y, Ueno M et al (2005) Continuous-flow chemical processing in three-dimensional microchannel network for on-chip integration of multiple reactions in a combinatorial mode. QSAR Comb Sci 24(6):742–757
Kim C, Lee K et al (2008) A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations. Lab Chip 8(3):473–479
Kirsten G, Maier WF (2004) Strategies for the discovery of new catalysts with combinatorial chemistry. Appl Surf Sci 223(1–3):87–101
Lee K, Kim C et al (2009) Generalized serial dilution module for monotonic and arbitrary microfluidic gradient generators. Lab Chip 9(5):709–717
Liu MC, Ho D et al (2008) Monolithic fabrication of three-dimensional microfluidic networks for constructing cell culture array with an integrated combinatorial mixer. Sens Actuators B 129(2):826–833
Maier WF, Stowe K et al (2007) Combinatorial and high-throughput materials science. Angew Chem Int Ed 46(32):6016–6067
Muteki K, MacGregor JF et al (2007) Mixture designs and models for the simultaneous selection of ingredients and their ratios. Chemom Intell Lab Syst 86(1):17–25
Narasimhan B, Mallapragada SK, Porter MD (2007) Combinatorial materials science. Wiley, New York
Neils C, Tyree Z et al (2004) Combinatorial mixing of microfluidic streams. Lab Chip 4(4):342–350
Pereira SRM, Clerc F et al (2007) Optimisation methodologies and algorithms for research on catalysis employing high-throughput methods: comparison using the selox benchmark. Comb Chem High Throughput Screen 10(2):149–159
Schudel BR, Choi CJ, Cunningham BT, Kenis PJA (2009) Microfluidic chip for combinatorial mixing and screening of assays. Lab Chip 9:1676–1680
Singh B, Dahiya M et al (2005) Optimizing drug delivery systems using systematic “design of experiments”. Part II: retrospect and prospects. Crit Rev Therap Drug Carr Syst 22(3):215–294
Smith CG, O’Donnell JT (2006) The process of new drug discovery and development. Informa Health Care, New York
Timbrell JA (2000) Principles of biochemical toxicology. Taylor & Francis, London
Tye H (2004) Application of statistical ‘design of experiments’ methods in drug discovery. Drug Discov Today 9(11):485–491
Walker GM, Monteiro-Riviere N et al (2007) A linear dilution microfluidic device for cytotoxicity assays. Lab Chip 7(2):226–232
Webster DC (2008) Combinatorial and high-throughput methods in macromolecular materials research and development. Macromol Chem Phys 209(3):237–246
Yang K, EI-Haik BS (2008) Design for six sigma: a roadmap for product development, McGraw-Hill Professional, New York
Yu ZTF, Kamei KI et al (2009) Integrated microfluidic devices for combinatorial cell-based assays. Biomed Microdevices 11(3):547–555
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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.
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Lee, K., Kim, C., Jung, G. et al. Microfluidic network-based combinatorial dilution device for high throughput screening and optimization. Microfluid Nanofluid 8, 677–685 (2010). https://doi.org/10.1007/s10404-009-0500-z
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DOI: https://doi.org/10.1007/s10404-009-0500-z