Microfluidics



Microfluidics deals with the behavior, precise control and manipulation of microliter and nanoliter volumes of fluids. It is a multidisciplinary field intersecting engineering, physics, chemistry, microtechnology 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 small scales (channel diameters of around 10 to several hundred micrometers) some interesting and unintuitive properties appear. The Reynolds number, which characterizes the presence of turbulent flow, is extremely low, thus the flow will remain laminar. Thus, two fluids joining will not mix readily via turbulence, so diffusion alone must cause the two fluids 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.

Process monitoring capabilities in continuous-flow systems can be achieved with highly sensitive microfluidic flow sensors which offer resolutions down to the nano litre range.

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. Another recently developed technology is based on acoustically induced droplet transport employing Surface Acoustic Waves.

Acoustic droplet ejection (ADE)
Acoustic droplet ejection uses a pulse of ultrasound to move low volumes of fluids (typically nanoliters or picoliters) without any physical contact. This technology focuses acoustic energy into a fluid sample in order to eject droplets as small as a millionth of a millionth of a liter (picoliter = 10-12 liter). ADE technology is a very gentle process, and it can be used to transfer proteins, high molecular weight DNA and live cells without damage or loss of viability. This feature makes the technology suitable for a wide variety of applications including proteomics and cell-based assays.

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 used to perform physical-level simulation and design verification at the low level.

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.
 * 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.

External information

 * μFluids@Home (Distributed Computing Project)
 * Biomicrofluidics, an open-source peer-reviewed journal published by the American Institute of Physics

Tutorials and summaries

 * MIFLUS - Microfluidics Terminology tree
 * Living La Vida LOC(a): A Brief Insight into the World of "Lab on a Chip" and Microfluidics - A review from the Science Creative Quarterly

Conference and journal papers

 * H. Gau, S. Herminghaus, P. Lenz, R. Lipowsky, "Liquid Morphologies on Structured Surfaces: From Microchannels to Microchips", Science (283), 1999
 * 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
 * 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
 * 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
 * C. Priest, S. Herminghaus, and R. Seemann, "Generation of Monodisperse Gel Emulsions in a Microfluidic Device", Appl. Phys. Lett. (88), 2006

Books




Microfluidos Microfluidique Microfluido Микрогидродинамика