Testing of Flow-Based Microfluidic Biochips: Fault Modeling, Test Generation, and Experimental Demonstration

Recent advances in flow-based microfluidics have led to the emergence of biochemistry-on-a-chip as a new paradigm in clinical diagnostics and biomolecular recognition. However, a potential roadblock in the deployment of microfluidic biochips is the 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. Prior work on fault detection in biochips has been limited to digital (“droplet”) microfluidics and other electrode-based technology platforms. The paper proposes the first approach for automated testing of flow-based microfluidic biochips that are designed using membrane-based valves for flow control. The proposed test technique is based on a behavioral abstraction of physical defects in microchannels and valves. The flow paths and flow control in the microfluidic device are modeled as a logic circuit composed of Boolean gates, which allows test generation to be carried out using standard automatic test pattern generation tools. The tests derived using the logic circuit model are then mapped to fluidic operations involving pumps and pressure sensors in the biochip. Feedback from pressure sensors can be compared to expected responses based on the logic circuit model, whereby the types and positions of defects are identified. We show how a fabricated biochip can be tested using the proposed method, and demonstrate experimental results for two additional fabricated chips.

[1]  S. Quake,et al.  Versatile, fully automated, microfluidic cell culture system. , 2007, Analytical chemistry.

[2]  Vishwani D. Agrawal,et al.  Essentials of electronic testing for digital, memory, and mixed-signal VLSI circuits [Book Review] , 2000, IEEE Circuits and Devices Magazine.

[3]  Hans G. Kerkhoff Testing Microelectronic Biofluidic Systems , 2007, IEEE Design & Test of Computers.

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

[5]  Hiroshi Takahashi,et al.  On diagnosing multiple stuck-at faults using multiple and singlefault simulation in combinational circuits , 2002, IEEE Trans. Comput. Aided Des. Integr. Circuits Syst..

[6]  Joseph B Hiatt,et al.  Automated microfluidic chromatin immunoprecipitation from 2,000 cells. , 2009, Lab on a chip.

[7]  Richard A Mathies,et al.  High throughput DNA sequencing with a microfabricated 96-lane capillary array electrophoresis bioprocessor , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  K Jiang,et al.  Fabrication of hybrid nanostructured arrays using a PDMS/PDMS replication process. , 2012, Lab on a chip.

[9]  L. Griffith,et al.  A microfabricated array bioreactor for perfused 3D liver culture. , 2002, Biotechnology and bioengineering.

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

[11]  Andrew Richardson,et al.  An Oscillation-Based Technique for Degradation Monitoring of Sensing and Actuation Electrodes Within Microfluidic Systems , 2011, J. Electron. Test..

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

[13]  S. Quake,et al.  Monolithic microfabricated valves and pumps by multilayer soft lithography. , 2000, Science.

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

[15]  G. Whitesides,et al.  Soft lithography in biology and biochemistry. , 2001, Annual review of biomedical engineering.

[16]  J. Todd,et al.  Evaluation of single nucleotide polymorphism typing with invader on PCR amplicons and its automation. , 2000, Genome research.

[17]  G. Whitesides,et al.  Rapid Prototyping of Microfluidic Systems in Poly(dimethylsiloxane). , 1998, Analytical chemistry.

[18]  W. Tian,et al.  Introduction to Microfluidics , 2008 .

[19]  Krishnendu Chakrabarty,et al.  Design automation methods and tools for microfluidics-based biochips , 2006 .

[20]  Daniel C Leslie,et al.  Frequency-specific flow control in microfluidic circuits with passive elastomeric features , 2009 .

[21]  Jeffrey M. Perkel Life Science Technologies: Microfluidics—Bringing New Things to Life Science , 2008, Science.

[22]  S. Quake,et al.  Microfluidics: Fluid physics at the nanoliter scale , 2005 .

[23]  M. Abdelgawad Introduction to Microfluidics , 2006 .

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

[25]  Fei Su,et al.  Digital Microfluidic Biochips - Synthesis, Testing, and Reconfiguration Techniques , 2006 .