Microfluidic very large-scale integration for biochips: Technology, testing and fault-tolerant design

Microfluidic biochips are replacing the conventional biochemical analyzers by integrating all the necessary functions for biochemical analysis using microfluidics. Biochips are used in many application areas, such as, in vitro diagnostics, drug discovery, biotech and ecology. The focus of this paper is on continuous-flow biochips, where the basic building block is a microvalve. By combining these microvalves, more complex units such as mixers, switches, multiplexers can be built, hence the name of the technology, “microfluidic Very Large-Scale Integration” (mVLSI). A roadblock in the deployment of microfluidic biochips is their low reliability and lack of test techniques to screen defective devices before they are used for biochemical analysis. Defective chips lead to repetition of experiments, which is undesirable due to high reagent cost and limited availability of samples. This paper presents the state-of-the-art in the mVLSI platforms and emerging research challenges in the area of continuous-flow microfluidics, focusing on testing techniques and fault-tolerant design.

[1]  Philip Brisk,et al.  Simulated annealing-based placement for microfluidic large scale integration (mLSI) chips , 2014, 2014 22nd International Conference on Very Large Scale Integration (VLSI-SoC).

[2]  Tsung-Yi Ho,et al.  A top-down synthesis methodology for flow-based microfluidic biochips considering valve-switching minimization , 2013, ISPD '13.

[3]  S. Quake,et al.  Multistep Synthesis of a Radiolabeled Imaging Probe Using Integrated Microfluidics , 2005, Science.

[4]  Stephen R. Quake,et al.  A Microfabricated Rotary Pump , 2001 .

[5]  Paul Pop,et al.  Architectural synthesis of flow-based microfluidic large-scale integration biochips , 2012, CASES '12.

[6]  Krishnendu Chakrabarty,et al.  Digital Microfluidic Biochips - Design Automation and Optimization , 2010 .

[7]  Y. K. Cheung,et al.  1 Supplementary Information for : Microfluidics-based diagnostics of infectious diseases in the developing world , 2011 .

[8]  Ismail Emre Araci,et al.  Microfluidic very large scale integration (mVLSI) with integrated micromechanical valves. , 2012, Lab on a chip.

[9]  Krishnendu Chakrabarty,et al.  Fault Modeling and Functional Test Methods for Digital Microfluidic Biochips , 2009, IEEE Transactions on Biomedical Circuits and Systems.

[10]  Jessica Melin,et al.  Microfluidic large-scale integration: the evolution of design rules for biological automation. , 2007, Annual review of biophysics and biomolecular structure.

[11]  Stephen R. Quake,et al.  Molecular biology on a microfluidic chip , 2006 .

[12]  Marc Madou,et al.  Numerical modeling and experimental validation of uniform microchamber filling in centrifugal microfluidics. , 2010, Lab on a chip.

[13]  Yanju Wang,et al.  Integrated microfluidic and imaging platform for a kinase activity radioassay to analyze minute patient cancer samples. , 2010, Cancer research.

[14]  Kai Hu,et al.  Testing of Flow-Based Microfluidic Biochips: Fault Modeling, Test Generation, and Experimental Demonstration , 2014, IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems.

[15]  D. T. Lee,et al.  An efficient bi-criteria flow channel routing algorithm for flow-based microfluidic biochips , 2014, 2014 51st ACM/EDAC/IEEE Design Automation Conference (DAC).

[16]  G. Whitesides.  The origins and the future of microfluidics , 2006, Nature.

[17]  S. Quake,et al.  Systematic investigation of protein phase behavior with a microfluidic formulator. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Paul Pop,et al.  System-level modeling and synthesis of flow-based microfluidic biochips , 2011, 2011 Proceedings of the 14th International Conference on Compilers, Architectures and Synthesis for Embedded Systems (CASES).

[19]  Paul C. Blainey,et al.  Digital MDA for enumeration of total nucleic acid contamination , 2010, Nucleic acids research.

[20]  H. C. Fan,et al.  Noninvasive diagnosis of fetal aneuploidy by shotgun sequencing DNA from maternal blood , 2008, Proceedings of the National Academy of Sciences.

[21]  Vincent Studer,et al.  A nanoliter-scale nucleic acid processor with parallel architecture , 2004, Nature Biotechnology.

[22]  Paul Pop,et al.  Application-specific fault-tolerant architecture synthesis for digital microfluidic biochips , 2013, 2013 18th Asia and South Pacific Design Automation Conference (ASP-DAC).

[23]  S. Quake,et al.  Microfluidic Large-Scale Integration , 2002, Science.

[24]  Shimon Even,et al.  An Algorithm for Determining Whether the Connectivity of a Graph is at Least k , 1973, SIAM J. Comput..

[25]  Tsung-Yi Ho,et al.  A clique-based approach to find binding and scheduling result in flow-based microfluidic biochips , 2013, 2013 18th Asia and South Pacific Design Automation Conference (ASP-DAC).

[26]  Wilfried Mokwa,et al.  Numerical analysis and characterization of bionic valves for microfluidic PDMS-based systems , 2007 .

[27]  S. Quake,et al.  Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis , 2008, Nature Biotechnology.

[28]  Jesus Rodriguez-Manzano,et al.  Digital biology and chemistry. , 2014, Lab on a chip.

[29]  Tsung-Yi Ho,et al.  Control synthesis for the flow-based microfluidic large-scale integration biochips , 2013, 2013 18th Asia and South Pacific Design Automation Conference (ASP-DAC).

[30]  Philip Brisk,et al.  Recent developments in microfluidic large scale integration. , 2014, Current opinion in biotechnology.

[31]  R. Zengerle,et al.  Microfluidic lab-on-a-chip platforms: requirements, characteristics and applications. , 2010, Chemical Society reviews.

[32]  Stephen R Quake,et al.  Microfluidic single-cell mRNA isolation and analysis. , 2006, Analytical chemistry.

[33]  Stephen R Quake,et al.  Dissecting genomic diversity, one cell at a time , 2013, Nature Methods.