Lab-on-a-chip

Lab-on-a-chip (LOC) is a term for devices that integrate (multiple) laboratory functions on a single chip of only millimeters to a few square centimeters in size and that are capable of handling extremely small fluid volumes down to less than pico liters. Lab-on-a-chip devices are a subset of MEMS devices and often indicated by "Micro Total Analysis Systems" (µTAS) as well. Microfluidics is a broader term that describes also mechanical flow control devices like pumps and valves or sensors like flowmeters and viscometers. However, strictly regarded "Lab-on-a-Chip" indicates generally the scaling of single or multiple lab processes down to chip-format, whereas "µTAS" is dedicated to the integration of the total sequence of lab processes to perform chemical analysis. The term "Lab-on-a-Chip" was introduced later on when it turned out that µTAS technologies were more widely applicable than only for analysis purposes.

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History

After the discovery of microtechnology (~1958) for realizing integrated semiconductor structures for microelectronic chips, these lithography-based technologies were soon applied in pressure sensor manufacturing (1966) as well. Due to further development of these usually CMOS-compatibility limited processes, a tool box became available to create micrometre or sub-micrometre sized mechanical structures in silicon wafers as well: the Micro Electro Mechanical Systems (MEMS) era (also indicated with Micro System Technology - MST) had started.

Next to pressure sensors, airbag sensors and other mechanically movable structures, fluid handling devices were developed. Examples are: channels (capillary connections), mixers, valves, pumps and dosing devices. The first LOC analysis system was a gas chromatograph, developed in 1975 by S.C. Terry - Stanford University. However, only at the end of the 1980’s, and beginning of the 1990’s, the LOC research started to seriously grow as a few research groups in Europe developed micropumps, flowsensors and the concepts for integrated fluid treatments for analysis systems. These µTAS concepts demonstrated that integration of pre-treatment steps, usually done at lab-scale, could extend the simple sensor functionality towards a complete laboratory analysis, including e.g. additional cleaning and separation steps.

A big boost in research and commercial interest came in the mid 1990’s, when µTAS technologies turned out to provide interesting tooling for genomics applications, like capillary electrophoresis and DNA microarrays. A big boost in research support also came from the military, especially from DARPA (Defense Advanced Research Projects Agency), for their interest in portable bio/chemical warfare agent detection systems. The added value was not only limited to integration of lab processes for analysis but also the characteristic possibilities of individual components and the application to other, non-analysis, lab processes. Hence the term "Lab-on-a-Chip" was introduced.

Although the application of LOCs is still novel and modest, a growing interest of companies and applied research groups is observed in different fields such as analysis (e.g. chemical analysis, environmental monitoring, medical diagnostics and cellomics) but also in synthetic chemistry (e.g. rapid screening and microreactors for pharmaceutics). Besides further application developments, research in LOC systems is expected to extend towards downscaling of fluid handling structures as well, by using nanotechnology. Sub-micrometre and nano-sized channels, DNA labyrinths, single cell detection an analysis and nano-sensors might become feasible that allow new ways of interaction with biological species and large molecules. One commercially very successful example for LOCs in life science is the development of automated patch clamp chips, that allowed for drastically increased throughput for drug screening in the pharmaceutical industry.

Chip materials and fabrication technologies

The basis for most LOC fabrication processes is photolithography. Initially most processes were in silicon, as these well-developed technologies were directly derived from semiconductor fabrication. Because of demands for e.g. specific optical characteristics, bio- or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, deposition and bonding, PDMS processing (e.g., soft lithography), thick-film- and stereolithography as well as fast replication methods via electroplating, injection molding and embossing. Furthermore the LOC field more and more exceeds the borders between lithography-based microsystem technology, nano technology and precision engineering.

Advantages of LOCs

LOCs may provide advantages, very specifically for their applications. Typical advantages are:

• low fluid volumes consumption, because of the low internal chip volumes, which is beneficial for e.g. environmental pollution (less waste), lower costs of expensive reagents and less sample fluid is used for diagnostics
• higher analysis and control speed of the chip and better efficiency due to short mixing times (short diffusion distances), fast heating (short distances, high wall surface to fluid volume ratios, small heat capacities)
• better process control because of a faster response of the system (e.g. thermal control for exothermic chemical reactions)
• compactness of the systems, due to large integration of functionality and small volumes
• massive parallelization due to compactness, which allows high-throughput analysis
• lower fabrication costs, allowing cost-effective disposable chips, fabricated in mass production
• safer platform for chemical, radioactive or biological studies because of large integration of functionality and low stored fluid volumes and energies

Disadvantages of LOCs

• novel technology and therefore not fully developed yet
• physical effects like capillary forces and chemical effects of channel surfaces become more dominant and make LOC systems behave differently and sometimes more complex than conventional lab equipment
• detection principles may not always scale down in a positive way, leading to low signal to noise ratios

Examples of what you can do with the LOC

• Real-time PCR ;detect bacteria, viruses and cancers.
• Immunoassay ; detect bacteria, viruses and cancers based on antigen-antibody reactions.
• Dielectrophoresis detecting cancer cells and bacteria.
• Blood sample preparation ; can crack cells to extract DNA.
• Cellular lab-on-a-chip for single-cell analysis.
• Ion channel screening

Europe

• BIOS: The Lab-on-a-Chip Group, MESA+ Research Institute, The Netherlands
• ISAS: Instutute for Analytical Sciences, Germany
• Belder Research Group, University of Leipzig, Germany
• Institut für Mikrotechnik Mainz GmbH, Mainz, Germany
• KTH - Microsystem Technology Group, Sweden
• MIC - Department of Micro and Nanotechnology, Technical University of Denmark, Denmark
• Centre for Nano and Microsystem at the University of Teesside, UK
• Research Group SynBioC, Ghent University

Asia and Australia

• Kitamori Lab, Japan
• Micro/Nano Research Laboratory, Monash University, Melbourne, Australia

Journals

• "Lab on a Chip"
• "Journal of Microelectromechanical Systems"
• "Journal of Micromechanics and Microengineering"

Conferences

• ASME ICNMM 2008 The 6th ASME Intl. Conference on Nanochannels, Microchannels and Minichannels - Darmstadt, Germany - Jun 23-25, 2008
• µTAS 2008 - 12th Intl. Conference on Miniaturized Systems for Chemistry and Life Sciences - San Diego, California, USA - Oct 12-16, 2008

Manufacturers

• Micronit Microfluidics, Enschede, Netherlands
• Micralyne Inc., Lab-on-a-chip manufacturer, Edmonton, Canada
• Spinx-Technologies, Programmable assays based on Microfluidics, Geneva, Switzerland

Books

• (2003) Edwin Oosterbroek & A. van den Berg (eds.): Lab-on-a-Chip: Miniaturized systems for (bio)chemical analysis and synthesis, Elsevier Science, second edition, 402 pages. ISBN 0444511008.
• (2004) Geschke, Klank & Telleman, eds.: Microsystem Engineering of Lab-on-a-chip Devices, 1st ed, John Wiley & Sons. ISBN 3-527-30733-8.

References

• 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