System-Level Modeling and Synthesis Techniques for Flow-Based Microfluidic Very Large Scale Integration Biochips

Microfluidic biochips integrate different biochemical analysis functionalities on-chip and offer several advantages over the conventional biochemical laboratories. In this thesis, we focus on the flow-based biochips. The basic building block of such a chip is a valve which can be fabricated at very high densities, e.g., 1 million valves per cm 2. By combining these valves, more complex units such as mixers, switches, multiplexers can be built up and the technology is therefore referred to as microfluidic Very Large Scale Integration (mVLSI). The manufacturing technology for the mVLSI biochips has advanced faster than Moore's law. However, the design methodologies are still manual and bottom-up. Designers use drawing tools, e.g., AutoCAD, to manually design the chip. In order to run the experiments, applications are manually mapped onto the valves of the chips (analogous to exposure of gate-level details in electronic integrated circuits). Since mVLSI chips can easily have thousands of valves, the manual process can be very time-consuming, error-prone and result in inefficient designs and mappings. We propose, for the first time to our knowledge, a top-down modeling and synthesis methodology for the mVLSI biochips. We propose a modeling framework for the components and the biochip architecture. Using these models, we present an architectural synthesis methodology (covering steps from the schematic design to the physical synthesis), generating an application-specific mVLSI biochip. We also propose a framework for mapping the biochemical applications onto the mVLSI biochips, binding and scheduling the operations and performing fluid routing. A control synthesis framework for determining the exact valve activation sequence required to execute the application is also proposed. In order to reduce the macro-assembly around the chip and enhance chip scalability, we propose an approach for the biochip pin count minimization. We also propose a throughput maximization scheme for the cell culture mVLSI biochips, saving time and reducing costs. We have extensively evaluated the ii proposed approaches using real-life case studies and synthetic benchmarks. The proposed framework is expected to facilitate programmability and automation, enabling the emergence of a large biochip market. in partial fulfilment of the requirements for acquiring the Ph.D. degree in engineering. The thesis proposes a top-down synthesis methodology for the modeling and synthesis of the flow-based microfluidic Very Large Scale Integration (mVLSI) biochips. Acknowledgements I would like to start off by sending out a resounding thanks to my supervisors Paul Pop and Jan Madsen for their exceptional guidance, invaluable close involvement with …

[1]  H. Le,et al.  Progress and Trends in Ink-jet Printing Technology , 1998, Journal of Imaging Science and Technology.

[2]  Krishnendu Chakrabarty,et al.  Cross-contamination avoidance for droplet routing in digital microfluidic biochips , 2009, 2009 Design, Automation & Test in Europe Conference & Exhibition.

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

[4]  T. N. Vijaykumar,et al.  Automatic volume management for programmable microfluidics , 2008, PLDI '08.

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

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

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

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

[9]  Alain Hertz,et al.  Using tabu search techniques for graph coloring , 1987, Computing.

[10]  Paul Pop,et al.  Cell Culture Microfluidic Biochips: Experimental Throughput Maximization , 2011, 2011 5th International Conference on Bioinformatics and Biomedical Engineering.

[11]  Jeffrey M. Perkel,et al.  Microfluidics—Bringing New Things to Life Science , 2008 .

[12]  D. Coen,et al.  Enzymatic Amplification of DNA by PCR: Standard Procedures and Optimization , 2001, Current protocols in cell biology.

[13]  W. Janzen,et al.  High-throughput screening: advances in assay technologies. , 1997, Current opinion in chemical biology.

[14]  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.

[15]  Paul Pop,et al.  Modeling and simulation framework for flow-based microfluidic biochips , 2013, 2013 Symposium on Design, Test, Integration and Packaging of MEMS/MOEMS (DTIP).

[16]  Oliver Sinnen,et al.  Task Scheduling for Parallel Systems , 2007, Wiley series on parallel and distributed computing.

[17]  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.

[18]  S. Terry,et al.  A gas chromatographic air analyzer fabricated on a silicon wafer , 1979, IEEE Transactions on Electron Devices.

[19]  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).

[20]  Yi Zhu,et al.  Heuristic methods for graph coloring problems , 2005, SAC '05.

[21]  David Sabourin,et al.  A self-contained, programmable microfluidic cell culture system with real-time microscopy access , 2012, Biomedical microdevices.

[22]  Giovanni De Micheli,et al.  Synthesis and Optimization of Digital Circuits , 1994 .

[23]  裕幸 飯田,et al.  International Technology Roadmap for Semiconductors 2003の要求清浄度について - シリコンウエハ表面と雰囲気環境に要求される清浄度, 分析方法の現状について - , 2004 .

[24]  Paul Pop,et al.  Recent research and emerging challenges in the System-Level Design of digital microfluidic biochips , 2011, 2011 IEEE International SOC Conference.

[25]  Fred W. Glover,et al.  Tabu Search , 1997, Handbook of Heuristics.

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

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

[28]  David R. Karger,et al.  Approximate graph coloring by semidefinite programming , 1998, JACM.

[29]  A. Manz,et al.  Miniaturized total chemical analysis systems: A novel concept for chemical sensing , 1990 .

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

[31]  J. Madsen,et al.  Synthesis of biochemical applications on flow-based microfluidic biochips using constraint programming , 2012, 2012 Symposium on Design, Test, Integration and Packaging of MEMS/MOEMS.

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

[33]  R. J. Mack,et al.  VLSI physical design automation: theory and practice , 1996 .

[34]  Shuichi Shoji,et al.  Prototype miniature blood gas analyser fabricated on a silicon wafer , 1988 .

[35]  Philippe Coussy,et al.  High-Level Synthesis: from Algorithm to Digital Circuit , 2008 .

[36]  R. Fair,et al.  Electrowetting-based actuation of droplets for integrated microfluidics. , 2002, Lab on a chip.

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

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

[39]  William Thies,et al.  Biocoder: A programming language for standardizing and automating biology protocols , 2010, Journal of biological engineering.

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

[41]  K. Jensen,et al.  Cells on chips , 2006, Nature.

[42]  Fei Su,et al.  Concurrent testing of droplet-based microfluidic systems for multiplexed biomedical assays , 2004 .

[43]  Alison Stacey,et al.  Routine quality control testing of cell cultures : detection of Mycoplasma. , 2000, Methods in molecular medicine.

[44]  T. N. Vijaykumar,et al.  Aquacore: a programmable architecture for microfluidics , 2007, ISCA '07.

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

[46]  Jeffrey D. Ullman,et al.  NP-Complete Scheduling Problems , 1975, J. Comput. Syst. Sci..

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

[48]  Krzysztof Kuchcinski,et al.  Constraints-driven scheduling and resource assignment , 2003, TODE.

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

[50]  Robin A. Felder,et al.  A Review of Cell Culture Automation , 2002 .

[51]  Paul Pop,et al.  System-level modeling and simulation of the cell culture microfluidic biochip ProCell , 2010, 2010 Symposium on Design Test Integration and Packaging of MEMS/MOEMS (DTIP).

[52]  Jong Wook Hong,et al.  Integrated nanoliter systems , 2003, Nature Biotechnology.

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

[54]  William Thies,et al.  Digital microfluidics using soft lithography. , 2006, Lab on a chip.

[55]  Nada Amin,et al.  Computer-aided design for microfluidic chips based on multilayer soft lithography , 2009, 2009 IEEE International Conference on Computer Design.

[56]  Fei Su,et al.  High-level synthesis of digital microfluidic biochips , 2008, JETC.

[57]  Wei Duan,et al.  Lab-on-a-chip: a component view , 2010 .

[58]  D. J. Harrison,et al.  Micromachining a Miniaturized Capillary Electrophoresis-Based Chemical Analysis System on a Chip , 1993, Science.

[59]  Richard B. Fair,et al.  Digital microfluidics: is a true lab-on-a-chip possible? , 2007 .

[60]  H. Lintel,et al.  A piezoelectric micropump based on micromachining of silicon , 1988 .

[61]  V. Ts. Vanchikov Special form of laminar liquid flow in hydraulic devices , 2008 .

[62]  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).

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

[64]  Stephen R Quake,et al.  Solving the "world-to-chip" interface problem with a microfluidic matrix. , 2003, Analytical chemistry.

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