Microfluidic network-based combinatorial dilution device for high throughput screening and optimization

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.

[1]  J. Timbrell Principles of biochemical toxicology , 1991 .

[2]  Russel J. Mumper,et al.  The Process of New Drug Discovery and Development, 2nd Edition , 1992 .

[3]  S. Jacobson,et al.  Microfluidic devices for electrokinetically driven parallel and serial mixing , 1999 .

[4]  G. Whitesides,et al.  Generation of Solution and Surface Gradients Using Microfluidic Systems , 2000 .

[5]  G. Whitesides,et al.  Generation of Gradients Having Complex Shapes Using Microfluidic Networks , 2001 .

[6]  G. Whitesides,et al.  Microfluidic arrays of fluid-fluid diffusional contacts as detection elements and combinatorial tools. , 2001, Analytical chemistry.

[7]  M. Tokeshi,et al.  Glass microchip with three-dimensional microchannel network for 2 x 2 parallel synthesis. , 2002, Lab on a chip.

[8]  Eduardo Garcia-Egido,et al.  Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system. , 2003, Lab on a chip.

[9]  P. Cremer,et al.  Generating fixed concentration arrays in a microfluidic device , 2003 .

[10]  B. Finlayson,et al.  Combinatorial mixing of microfluidic streams. , 2004, Lab on a chip.

[11]  W. Maier,et al.  Strategies for the discovery of new catalysts with combinatorial chemistry , 2004 .

[12]  Heather Tye Application of statistical 'design of experiments' methods in drug discovery. , 2004, Drug discovery today.

[13]  M. Tokeshi,et al.  Continuous‐Flow Chemical Processing in Three‐Dimensional Microchannel Network for On‐Chip Integration of Multiple Reactions in a Combinatorial Mode , 2005 .

[14]  Bhupinder Singh,et al.  Optimizing drug delivery systems using systematic "design of experiments." Part II: retrospect and prospects. , 2005, Critical reviews in therapeutic drug carrier systems.

[15]  M. Toner,et al.  Universal microfluidic gradient generator. , 2006, Analytical chemistry.

[16]  A. Manz,et al.  Lab-on-a-chip: microfluidics in drug discovery , 2006, Nature Reviews Drug Discovery.

[17]  Luke P. Lee,et al.  Microfluidics-based systems biology. , 2006, Molecular bioSystems.

[18]  M. S. Levy,et al.  Framework for the Rapid Optimization of Soluble Protein Expression in Escherichia coli Combining Microscale Experiments and Statistical Experimental Design , 2007, Biotechnology progress.

[19]  J. Macgregor,et al.  Mixture designs and models for the simultaneous selection of ingredients and their ratios , 2007 .

[20]  N. Monteiro-Riviere,et al.  A linear dilution microfluidic device for cytotoxicity assays. , 2007, Lab on a chip.

[21]  W. Maier,et al.  Combinatorial and high-throughput materials science. , 2007, Angewandte Chemie.

[22]  B. Narasimhan,et al.  Combinatorial materials science , 2007 .

[23]  A. Groisman,et al.  Generation of complex concentration profiles in microchannels in a logarithmically small number of steps. , 2007, Lab on a chip.

[24]  Frédéric Clerc,et al.  Optimisation methodologies and algorithms for research on catalysis employing high-throughput methods: comparison using the Selox benchmark. , 2007, Combinatorial chemistry & high throughput screening.

[25]  A. Hierlemann,et al.  A hybrid microsystem for parallel perfusion experiments on living cells , 2007 .

[26]  D. Webster Combinatorial and High‐Throughput Methods in Macromolecular Materials Research and Development , 2008 .

[27]  Y. Tai,et al.  Monolithic fabrication of three-dimensional microfluidic networks for constructing cell culture array with an integrated combinatorial mixer , 2008 .

[28]  J. Kang,et al.  A serial dilution microfluidic device using a ladder network generating logarithmic or linear concentrations. , 2008, Lab on a chip.

[29]  A. Folch,et al.  A multi-purpose microfluidic perfusion system with combinatorial choice of inputs, mixtures, gradient patterns, and flow rates. , 2009, Lab on a chip.

[30]  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. , 2009, Lab on a chip.

[31]  H. Tseng,et al.  Integrated microfluidic devices for combinatorial cell-based assays , 2009, Biomedical microdevices.

[32]  Joo H. Kang,et al.  Fabrication of a poly(dimethylsiloxane) membrane with well-defined through-holes for three-dimensional microfluidic networks , 2009 .

[33]  K. Oh,et al.  Generalized serial dilution module for monotonic and arbitrary microfluidic gradient generators. , 2009, Lab on a chip.

[34]  Charles J. Choi,et al.  Microfluidic chip for combinatorial mixing and screening of assays. , 2009, Lab on a Chip.