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Microfluidics deals with the behavior, precise control and manipulation of microliter and nanoliter volumes of fluids. It is a multidisciplinary field comprising physics, chemistry, engineering and biotechnology, with practical applications to the design of systems in which such small volumes of fluids will be used. Microfluidics has emerged only in the 1990s and is used in the development of DNA chips, micro-propulsion, micro-thermal technologies, and lab-on-a-chip technology.

Microscale behavior of fluids

The behavior of fluids at the microscale can differ from 'macrofluidic' behavior in that factors such as surface tension, energy dissipation, and fluidic resistance start to dominate the system. Microfluidics studies how these behaviors change, and how they can be worked around, or exploited for new uses. At these scales (channel diameters of around 10 to several hundered micrometers) some interesting and unintuitive properties appear. The Reynolds number, which characterises the presence of turbulent flow, is extremely low, therefore the flow will remain laminar (two fluids joining for example will not mix because of this, the diffusion alone will cause the two compounds to mingle).

Key application areas

Advances in microfluidics technology are revolutionizing molecular biology procedures for enzymatic analysis (e.g., glucose and lactate assays), DNA analysis (e.g., polymerase chain reaction and high-throughput sequencing), and proteomics. The basic idea of microfluidic biochips is to integrate assay operations such as detection, as well as sample pre-treatment and sample preparation on one chip.

An emerging application area for biochips is clinical pathology, especially the immediate point-of-care diagnosis of diseases. In addition, microfluidics-based devices, capable of continuous sampling and real-time testing of air/water samples for biochemical toxins and other dangerous pathogens, can serve as an always-on "bio-smoke alarm" for early warning.

DNA chips (microarrays)

Early biochips were based on the concept of a DNA microarray, e.g., the GeneChip DNAarray from Affymetrix, which is a piece of glass, plastic or silicon substrate on which pieces of DNA (probes) are affixed in a microscopic array. Similar to a DNA microarray, a protein array is a miniature array where a multitude of different capture agents, most frequently monoclonal antibodies, are deposited on a chip surface; they are used to determine the presence and/or amount of proteins in biological samples, e.g., blood. A drawback of DNA and protein arrays is that they are neither reconfigurable nor scalable after manufacture.

Continuous-flow microfluidics

These technologies are based on the manipulation of continuous liquid flow through microfabricated channels. Actuation of liquid flow is implemented either by external pressure sources, external mechanical pumps, integrated mechanical micropumps, or by electrokinetic mechanisms. Continuous-flow microfluidic operation is the mainstream approach because it is easy to implement and less sensitive to protein fouling problems. Continuous-flow devices are adequate for many well-defined and simple biochemical applications, and for certain tasks such as chemical separation, but they are less suitable for tasks requiring a high degree of flexibility or complicated fluid manipulations. These closed-channel systems are inherently difficult to integrate and scale because the parameters that govern flow field vary along the flow path making the fluid flow at any one location dependent on the properties of the entire system. Permanently-etched microstructures also lead to limited reconfigurability and poor fault tolerance capability.

Digital (droplet-based) microfluidics

Alternatives to the above closed-channel continuous-flow systems include novel open structures, where discrete, independently controllable droplets are manipulated on a substrate. Following the analogy of microelectronics, this approach is referred to as digital microfluidics. By using discrete unit-volume droplets, a microfluidic function can be reduced to a set of repeated basic operations, i.e., moving one unit of fluid over one unit of distance. This "digitization" method facilitates the use of a hierarchical and cell-based approach for microfluidic biochip design. Therefore, digital microfluidics offers a flexible and scalable system architecture as well as high fault-tolerance capability. Moreover, because each droplet can be controlled independently, these systems also have dynamic reconfigurability, whereby groups of unit cells in a microfluidic array can be reconfigured to change their functionality during the concurrent execution of a set of bioassays. One common actuation method for digital microfluidics is electrowetting-on-dielectric (EWOD). One limiting factor for applying EWOD to biological samples is the surface fouling due to proteins severely damages the controllability of droplets.

CAD challenges for microfluidic biochips

As microfluidic biochips evolve into multifunctional and user-reconfigurable devices, their complexity is expected to become significant due to the need for multiple and concurrent biochemical operations on the chip. There is a need to deliver the same level of CAD support to the biochip designer that the semiconductor industry now takes for granted. Listed below are some important CAD problems for microfluidic biochips.

  • Specification, modeling, and system simulation: A typical top-down design flow for microfluidic biochips can be imagined along the similar lines as that for top-down integrated circuit design. First, biochip users (e.g., biochemists) provide the protocol for nano- and micro-scale bioassays. This protocol must be translated to a behavioral model that can be simulated and synthesized. This model can be used to perform behavioral-level simulation to verify the assay functionality at the high level. Efficient tools for reduced-order (compact) modeling and device simulation are also needed. These tools should model and simulate the laminar flow of nanoliter fluid volumes in microchannels, electrohydrodynamic effects, and the electrowetting phenomenon.

  • System-level synthesis: The goal of synthesis is to generate an optimized microfluidic array (with metrics such as area, throughput, and defect tolerance) for a given specification. It includes architectural-level synthesis (e.g., scheduling and resource binding) and geometry-level synthesis (e.g., module placement and electrical pin connections). A microfluidic module library must also be provided as an input of the synthesis procedure. This module library, analogous to a standard cell library used in cell-based VLSI design, includes different microfluidic functional modules, such as mixers and storage units. Each module must be experimentally characterized by its function (mixing, storing, detection, etc.) and parameters such as width, length, and operation duration.

  • Droplet routing: Droplet pathways need to be appropriately determined on a microfluidic array with placed modules and scheduled bioassay operations.

  • Design verification: The synthesis results must be coupled with detailed physical information from the module library to obtain a 3-D geometrical model, which can be can be used to perform physical-level simulation and design verification at the low level.

  • Test and reconfiguration: These techniques are needed to bypass faulty components. Bioassay operations bound to these faulty resources in the original design need to be remapped to other fault-free resources. Due to the strict resource constraints in the fabricated biochip, alterations in the resource binding, schedule, and physical design must be carried out carefully.
A system-level synthesis tool can allow the mapping of a set of bioassays to a biochip with defective unit cells. Thus we do not need to discard the defective biochip, thereby leading to higher yield and lower cost.

Additional Information

Videos of various microfluidic operations are available on the Web at //www.ee.duke.edu/research/microfluidics. There is growing interest in biochips in the CAD community. The 2005 DATE Conference included a well-attended "Biochips Day" event. The IEEE Transactions on CAD published a special issue on biochips in February 2006. The IEEE Design and Test magazine will publish a special issue on biochips in early 2007. A workshop on CAD for biochips was co-located with DATE 2006. The references listed below provide more information on the underlying technologies and early results on CAD tools for microfluidic biochips.

Tutorials and summaries

Conference and journal papers

  • T. Thorsen, S. Maerkl and S. Quake, "Microfluidic large-scale integration", Science, vol. 298, pp. 580-584, 2002
  • E. Verpoorte and N. F. De Rooij, "Microfluidics meets MEMS", Proceedings of the IEEE, vol. 91, pp. 930-953, 2003.
  • V. Srinivasan, V. K. Pamula, and R. B. Fair, "An integrated digital microfluidic lab-on-a-chip for clinical diagnostics on human physiological fluids," Lab on a Chip, pp. 310-315, 2004.
  • M. G. Pollack, R. B. Fair and A. D. Shenderov, "Electrowetting-based actuation of liquid droplets for microfluidic applications", Applied Physics Letters, vol. 77, pp. 1725-1726, 2000.
  • S. K. Cho, S. K. Fan, H. Moon, and C. J Kim, "Toward digital microfluidic circuits: creating, transporting, cutting and merging liquid droplets by electrowetting-based actuation", Proc. IEEE MEMS Conf., pp. 32-52. 2002.
  • A. N. Chatterjee and N.R. Aluru, "Combined circuit/device modeling and simulation of integrated microfluidic systems", Journal of Microelectromechanical Systems, vol. 14, pp. 81-95, 2005.
  • J. Zeng and F. T. Korsmeyer, "Principles of droplet electrohydrodynamics for lab-on-a-chip", Lab on a Chip, vol. 4, pp. 265-277, 2004.
  • F. Su and K. Chakrabarty, "Unified high-level synthesis and module placement for defect-tolerant microfluidic biochips", Proc. IEEE/ACM Design Automation Conference, pp. 825-830, 2005.
  • K. Chakrabarty and J. Zeng, "Design automation for microfluidics-based biochips", ACM Journal on Emerging Technologies in Computing Systems, vol. 1, pp. 186-223, December 2005.
  • F. Su, K. Chakrabarty and R. B. Fair, "Microfluidics-based biochips: technology issues, implementation platforms, and design automation challenges", IEEE Transactions on Computer-Aided Design of Integrated Circuits & Systems, vol. 25, pp. 211-223, February 2006.
  • T. Mukherjee, Design automation issues for biofluidic microchips, Proc. Int. Conf. CAD, 2005.

Books

Academic and government laboratories

Companies and non-profit projects

This article includes text from Krishnendu Chakrabarty's column in the ACM SIGDA e-newsletter.
Richard Fair, Fei Su and Vamsee Pamula also contributed to the original text which can be found at * and was wikified by Igor Markov.

Fluid dynamics | Nanotechnology | Biotechnology

Microfluidos | Microfluidique | Microfluido

 

This article is licensed under the GNU Free Documentation License. It uses material from the "Microfluidics".

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