The Coming of Age of Microfluidic Biochips: Design Automation, Test, and Error Recovery for Biochemistry-on-a-Chip

Advances in microfluidics have led to the emergence of biochip devices for automating laboratory procedures in biochemistry and molecular biology. These devices enable the precise control of nanoliter volumes of biochemical samples and reagents. As a result, non-traditional biomedical applications and markets (e.g., high-throughout DNA sequencing, portable and point-of-care clinical diagnostics, protein crystallization for drug discovery), and fundamentally new uses are opening up for ICs and systems.

However, continued growth depends on advances in design automation, automated testing, and error-recovery techniques. Design-automation tools are needed to ensure that biochips are as versatile as the macro-labs that they are intended to replace, and researchers can thereby envision an automated design flow for biochips, in the same way as design automation revolutionized IC design in the 80s and 90s. Advances in testing are needed for defect screening and quality assessment. Error recovery is needed to provide high confidence in the outcomes of biochemistry carried out on a chip.

This lecture will first provide an overview of market drivers such as immunoassays, DNA sequencing, clinical chemistry, etc., and electrowetting-based digital microfluidic biochips. The audience will next learn about design automation, design-for-testability, and reconfiguration aspects of microfluidic biochips. Synthesis tools will be described to map assay protocols from the lab bench to a droplet-based microfluidic platform and generate an optimized schedule of bioassay operations, the binding of assay operations to functional units, and the layout and droplet-flow paths for the biochip. The role of the digital microfluidic platform as a “programmable and reconfigurable processor” for biochemical applications will be highlighted. The speaker will describe testing techniques, as well as dynamic adaptation of bioassays through cyberphysical system integration and sensor-driven on-chip error recovery.

(Anticipated order of topics for the lecture)
  1. Technology and application drivers: Motivation and background, application drivers, physical principles of fluid flow, actuation methods, flow-based microfluidics, electrowetting-on-dielectric, review of micro-fabrication processes, applications to biochemistry, medicine, and laboratory procedures.
  2. Synthesis techniques: Mapping of biochemistry protocols to a chip (scheduling, binding, module placement, droplet routing), optimization under resource constraints (e.g., valve optimization and control-layer routing), pin-constrained chip design.
  3. Testing and design-for-testability: Defects, fault modeling, test generation, test planning, and reconfiguration techniques; fault diagnosis, experimental demonstration and key lessons learned.
  4. Demonstration of cyberphysical integration and error recovery: Chip fabrication, sensor integration, real-time error detection, control software design, and videos on autonomous error recovery.
No familiarity is required with biochemistry or fluid mechanics. The instructor will review basic concepts associated with biochemistry protocols and fluid flow. Some familiarity is expected with logic fault models (such as stuck-at and shorts), test generation for digital circuits, basic analog circuits for sensor design, graph theory and optimization, high-level synthesis in design automation, and design and analysis of algorithms.

The following books and papers are recommended as advance reading:

Y. Luo, K. Chakrabarty and T.-Y. Ho, Hardware/Software Co-Design and Optimization for Cyberphysical Integration in Digital Microfluidic Biochips, Springer, 2014.

Y. Zhao and K. Chakrabarty, Design and Testing of Digital Microfluidic Biochips, Springer, 2013.

K. Hu, F. Yu, T.-Y. Ho and K. Chakrabarty, "Testing of flow-based microfluidic biochips: Fault modeling, test generation, and experimental demonstration", IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, vol. 33, pp. 1463-1475, October 2014.

Y. Luo, K. Chakrabarty and T-Y. Ho, Error recovery in cyberphysical digital-microfluidic biochips, IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems, vol. 32, pp. 59-72, January 2013.

K. Hu. T. Anh-Dinh, T.-Y. Ho and K. Chakrabarty, Control-layer optimization for flow-based mVLSI microfluidic biochips", Proc. IEEE/ACM International Conference on Compilers, Architectures and Synthesis of Embedded Systems (CASES), 2014.

Attendees will learn about exciting developments at the intersection of biochemistry, engineering, and design of microfluidic biochips. Attendees will also be presented with a set of design and test challenges that lie ahead, as well as current state-of-the-art solutions to these problems. There will be an easy-to-understand presentation of basic concepts in immunoassays, lab-bench biochemistry, microfabrication, electrowetting, and fluid flow. The anticipated opportunities for electrical engineers, computer engineers, and computer scientists in this emerging field will be especially highlighted. Attendees will appreciate why microfluidic biochips have enabled scientists to develop a deeper understanding of a variety of chemical and biological phenomena. For example, 256 simultaneous time-lapse imaging experiments can be carried out today in 2048 single yeast cell traps for 32 different conditions. Biochips have been used to image mammalian cells in 1600, 4 nl-volume chambers for over 60 hours. A biochips with 4 chambers connected by optional communication channels has been successfully used for monitoring cell-cell interactions. Integrated high-performance separation columns with on-chip sample loading, gradient generation, detection and sample recovery have been demonstrated. Finally, microfluidic devices have recently been developed for hepatitis C vaccine design, and HIV, syphilis, and non-invasive prenatal tests.