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Fundamental Changes Ahead For Lab Instrumentation.

Market studies project high growth for lab-on-a-chip technologies, and these findings are supported by intense worldwide developmental efforts aimed at broadening the scope of microsystem applications.

1998 may be remembered as a watershed year for chemical analysis. The remarkable surge in microsystem technology that has occurred promises to profoundly change the landscape of chemical and biological instrumentation and laboratory science.

Ahead lies a revolutionary era of chip-based microanalytical methods, processing tools, and measurement techniques. The microchips involved combine micromachining technology, microfluidics, advanced sensors, and integrated microprocessors and control circuits. In the last four years, the "lab-on-a-chip" concept has been transformed from a visionary dream to a budding commercial reality with enormous economic potential.

In 1994, the Systems Planning Corp. (SPC), Arlington, Va., prepared a now widely cited market study on microelectromechanical systems (MEMS) for the federal government's Defense Advanced Research Projects Agency (DARPA). SPC will soon release an update that projects a microfluidics market of $3-4.5 billion by 2003. While 70% of this is attributed to inkjet printer applications, SPC sees the balance as being split equally between sensors and lab-on-a-chip applications. Its projected compound annual growth rate (CAGR) for the total microfluidics area is 25-35%.

Another microsystems market study just completed by a task force of the European Commission's Network of Excellence in Multi-functional Microsystems (NEXUS) is even more aggressive in its growth projections and market size estimates. The NEXUS report forecasts an average interim CAGR of 33% and a market of $2.8 billion for microstructure-based disposable assay devices alone by 2002. It also anticipates growth to $1 billion each for emerging drug delivery systems and lab-on-a-chip micro total analysis systems ([Mu]TAS) by 2002.

NIST's program for Nano and MEMS Technologies for Chemical Biosensors is significant because successful development of improved chemical and biosensor systems and manufacturing procedures will spill over into much broader U.S. industrial use of microfabrication technologies. To demonstrate the growing pervasiveness of microtechnology, the agency also cites other government activity in the micro-instrumentation area for chemical and biological analysis.

It notes, for example, that the National Science Foundation is considering a proposal to fund a consortium, which would include industry and academia, and accelerate the commercialization of chemical sensor technologies. Also mentioned is NASA and military-agency support of sensor development for applications that relate to biological and chemical warfare detection and underwater detection of mines and foreign military hardware.

NASA has a program aimed at developing sensors for monitoring enclosed environments, such as spacecraft and the Space Station, for microorganisms and other environmental contaminants. Called Sensors 2000, this effort is directed at developing systems that operate under zero gravity in an environment where replacement and repair are difficult or impossible.

DARPA is pursuing tissue-based biosensors for detection of chemical/biological warfare-agents as a means of predicting the physiological consequences of known and unknown agents.

Microfluidics is an essential element of these chip-based chemical analysis technologies. Advances in this specialty may lead to portable devices that allow chemical reactions to be performed more rapidly, precisely, and at significantly lower cost than can be accomplished today. One class of microfluidics chips--DNA arrays--is expected to reduce the cost of analyzing DNA samples and substantially increase the speed of analysis. Microfluidic chip technologies enable a substantial increase in the number of chemical reactions that can be performed concurrently. They are expected to profoundly affect optimization of reactions in combinatorial chemistry, drug screening, and polymerase chain reaction (PCR) DNA amplification, where speed, precision, and cost of reagents are important.

Instrumentation development and the creation of bioinformatics databases will also benefit. Some observers feel that microfluidics' greatest commercial impact may lie in the development of hand-held, disposable devices that allow complete and precise diagnoses to be performed by primary-care physicians in point-of-care settings.

Not surprisingly, 1998 was also a year of collaboration announcements. Hewlett-Packard, Palo Alto, Calif., teamed with Caliper Technologies, Palo Alto, Calif., and Perkin-Elmer, Norwalk, Conn., entered into an arrangement with ACLARA BioSciences, Hayward, Calif. Numerous other commercial and academic collaborations have also been established.

In assessing the potential impact of all of the positive economic signs and studies, a caveat is in order. Care must be exercised to ensure that a study's scope, definitions, and methodologies are understood. The SPC study, for example, references additional estimates, suggesting that DNA processing and analysis devices could reach the $10 billion level by 2005, yet this market level is not included in the SPC numbers. While microfluidic chips are now most often fabricated in glass or silicon substrates, low-cost, disposable plastic devices are widely acknowledged as the great economic hope for the future. One such prototype polymer microfluidic device was developed through a collaboration between the Bio/Chemical Microsystems group at the Technical Univ. of Denmark's Mikroelectronik Centret (MIC) (www. mic.dtu.dk/mic) in Lygnby, the Institute for Process Technology, and the commercial firm Nalge Nunc, all in Denmark.

MIC is also working on the European-funded MicroChem project, a joint effort between Denmark's largest industrial group, Danfoss, the French firm Lyonnaise des Eaux, and several other European institutes. MicroChem is aimed at developing [Mu]TAS.

At the recent [Mu]TAS '98 conference in Banff, Canada, MIC Bio/Chemical Microsystems group leader Pieter Telleman (pt@mic.dtu.dk) and colleagues described a microstructure for the isolation of fetal cells from maternal blood. This effort, directed at a safe alternative to conventional prenatal genetic diagnostic methods that might otherwise carry a substantial risk of fetal damage, is a collaboration between MIC; Rigshospitalet, Copenhagen; Evotec BioSystems, Hamburg, Germany; and a number of Danish biotechnology companies.

A new consortium project concerning biological microarray and chip technologies, called EURAY, involves the Danish biotechnology companies Exiqon, Vedbaek, Denmark, and Display Systems Biotech, Copenhagen, as well as Hvidovre Hospitalet, Hvidovre, Denmark. MIC researchers will investigate microarray technology for basic research, medical diagnostics, and drug discovery. Although the Danish model is cited here, a similar scenario is being played out at numerous other locations in Europe.

Today's predominant means of detecting reaction results in microfluidic chips is via laser-induced fluorescence of dye-tagged components. At [Mu]TAS'98, Alfredo Bruno (alfredo_emilio_bruno@ pharma.novartis.com) and colleagues at Novartis Pharma and the Univ. of Neuchatel in Switzerland reported an intriguing optical approach to examining the output of a chip-based, fluorescence, multiple-channel chemical analysis systems. The system consists of a fast (separations [is less than] 1min), multichannel, capillary electrophoresis unit and a fluorescence planar waveguide bioaffinity sensor. In a related presentation, Jean Roulet (jeanchristoffe.roulet@imt.unine.ch), from the Univ. of Neuchatel, suggested that micro-optical elements may enable integration of fluorescence detection systems directly into multilayer, aligned, bonded, and stacked [Mu]TAS assemblies.

Nanotech '98, a relatively small conference on micro- and nanoscale technologies for the biosciences, was held in Montreux, Switzerland, last November. It proved interesting for a number of reasons, not the least of which was that not only did attendees represent the usual complement of academic and research institutions, but included a remarkable 77 commercial organizations. This is a clear sign of where the next surge of activity in microsystems technology is heading.

At Nanotech, Andreas Manz of Imperial College, London, and Luc Bousse of Caliper Technologies presented a four-electrode glass capillary electrophoresis microstructure having one injection channel and 17 parallel channels. The channel structures were 10 x 50 [micro]m on a 500-[micro]m pitch. The separation time cited was 1 min.

Other organizations heard from at Montreux included: the Univ. of Hull, U.K., which reported on microreactor efforts; microParts, Dortmund, Germany, which discussed affordable plastic micromolded microstructures for disposable medical applications, microfluidics, and optical measurement; and Twente and Delft Universities in the Netherlands, which described a partnership aimed at developing separation and detection devices and analytical instrumentation for real-time control of fermentation and cellculture processes.

Again from the Univ. of Neuchatel was a miniaturized electrochemiluminescence (ECL) system for ECL-based assays. The system combines the electrode transducer and the photodetector in a single 5 x 6 mm silicon chip that directly couples the generated ECL with the photometric device. A polymeric spacer is photolithographically patterned at the wafer level to define the flow-channel geometry. The flow-injection-analysis cell is obtained by assembling the device with a top cover plate machined in Plexiglas.

Another Nanotech report came from Belgium's IMEC research facility in Leuven. K. Verhaegen (verhaegki@imec.be) and co-workers reported on a micromachined silicon chip that is capable of providing a high-throughput functional assay based on calorimetry. One particularly important application of this whole-cell biosensor is in drug discovery, where the binding assays that are commonly used to provide high throughput need to be complemented with a functional assay.

Looking toward future low-cost, mass production of plastic microfluidics chips, Holger Becker (holger. becker@jenoptik.com) of equipment maker Jenoptik Mikrotechnik, Jena, Germany, described hot embossing for polymer microchip replication. Process advantages include high structural accuracy, submicrometer reproducibility, and relatively low cost.

Chip cutting, via-hole drilling, and chip bonding to produce fully operational devices have been explored, and microfluidic structures have been fabricated. These include single-channel and multichannel electrophoretic devices as well as high aspect-ratio channels and holes for chromatographic structures, nanotiterplates, and pressure-driven systems like flow-through PCR chips.

V. Tvarozek (vltvar@elf.stuba. sk) and colleagues at the Slovak Univ. of Technology developed a silicon chip with a thin-film microarray of interdigitated gold or platinum electrodes having widths and spacings from 5 to 400 [micro]m. They used this array to determining the red blood cell sedimentation rate by impedance monitoring.

Reporting at [micro]TAS'98, S. Hannoe (hannoe@ilab.ntt.co.jp) from NTT Labs, Tokyo, demonstrated high chromatographic performance with a gas chromatograph spiral microcolumn that was formed in chromium-masked, anisotropically wet-etched silicon (~50 [mm.sup.2]) and coated with RF-sputtered (0.68 [micro]m) D-phenylalanine. Glass silicon anodic bonding enclosed the column, and ultrasonic machining and polyimide sealing achieved small dead-volume injection and detection end joints.

Also at Banff, T. Kitamori (tkita@hongo.ecc.u-tokyo.ac.jp) and researchers from Tokyo Univ. and Kanagawa Academy of Science and Technology described the fabrication of a non-fluorometric, non-electrophoretic, integrated-chemistry lab-on-a-chip based on thermal lens microscopy. They demonstrated microchannel (0.9-100 [micro]m in glass substrates) chelating reactions, rapid (thermally enhanced diffusion, ~1 msec) solvent extraction, and colorimetric metal ion detection at the [10.sup.-21] mole level. Confocal thermal lens microscopy induces a microscopic graded optical index region (i.e., a virtual lens) in the microchannels containing sample solutions. The probe beam intensity in the confocal system is easily monitored with a photodiode that provides high differential index detection sensitivity.

As a matter of national priorities for 21st century technology, Japan has established major thrusts in micromachine and bioscience technologies. A few examples can hardly described the breadth of activity, but they do illustrate a few of the research directions.

In Nagoya, at the November 1998 Mechatronics and Human Science Symposium, Koji Ikuta and colleagues from Nagoya Univ.'s School of Microsystem Engineering presented a prototype microfluidic biochemical reactor that has several unique features. The basic fabrication process for the reactor structure is a 5-[micro]m resolution, 3-D stereolithography technique using a UV-curable polymer. The reactor is formed atop a silicon substrate having a photodetector. Cell-free protein synthesis of luciferase was successfully carried out in the microreactor and monitored with the substrate photodiode. Still to be incorporated into the present reactor are control circuitry and micropumps.

Another example from the Nagoya meeting provides a further sense of activity both in chips and in microfluidic components. Shu-xiang Guo (guo@eng.kagawau.ac.jp) and researchers at Kagawa and Nagoya Universities and the Osaka National Research Institute described an acrylic prototype capsule micropump that uses two active one-way valves with membrane actuators of platinum plated Dupont Nation 117 perfluorosulfonic acid polymer, an ionic conducting polymer film. Application of a voltage swells the polymer, causing bending of the film toward the anode side. Flow of the prototype pump, when driven at ~2 Hz was 37.8 [Mu]L/min.

Canada has several centers of microfluidics activity for biomedical and chemical analysis applications. Among them are the Univ. of Alberta and the Alberta Microelectronics Corp. Accordingly, a number of reports in bio and microchemical analysis came from these two locations at [Mu]TAS '98.

Richard Mathies (rich@zinc. cchem.berkeley.edu) opened the Banff conference with an interesting analogy to the microelectronics industry's Moore's Law by noting that the technology rush in the area of array analysis since 1994 has generated a 10-fold increase every two years in both the number of samples per microplate and the throughput per microplate in samples per second. How long this rate is sustainable, he posited, is the question of the moment.

Also at Banff, Dean Matson at the Pacific Northwest National Laboratory, Richland, Wash. (dean.matson@pnl.gov), reported using direct-write laser micromachining to form 50- to 100-[micro]m wide, 50- to 150-[micro]m deep channels in various polymer materials. The channels were sealed with a PET (polyethylene terephthalate) sheet or with a gasket compressed between the machined surface and another flat polymer surface, or alternatively, were stripped out of a polyimide gasket that was sandwiched between two flat surfaces.

At [Mu]TAS'98, Cepheid, Sunnyvale, Calif., a manufacturer of a PCR-based DNA amplification systems, discussed development of a multichannel thermal cycler with integral optical detection. When coupled to special 100-[Mu]L disposable reaction tubes, the system allows independent rapid PCR reactions to be performed.

U.S. firms were well represented at Nanotech '98, with presentations offered by 10 American companies. J.P. Springhorn (spring-hornj@ ALXN.com) and researchers at Alexion Pharmaceuticals, New Haven, Conn., and Boston Univ., described a device that combines microelectronic silicon-based chip technology with microfluidics and compact disc-based reaction site indexing to carry out ultrahigh throughput drug screening. The use is comprised of a single, fully integrated, environmentally controlled unit providing sample loading, bioassay capabilities, and multiple detection schemes in 20,000 microwells arrayed radially on a 7.6-cm silicon diskette, the unit takes advantage of MEMS technology to provide microelectronic control of assay conditions on a per-well basis.

In a Montreux presentation by Orchid Biocomputer, Princeton, N.J., S. DeWitt described a microfluidic, chip-based system for the solid-phase organic synthesis of discrete compounds in a massively parallel array. Up to 50 nmole of a single compound can be generated in each 700-nL reaction well. The synthesis of up to 100 compounds on one chip employing 1-3 reaction steps has been achieved using electronic and/or pressure pumping.

The market projections presented above, and the examples of worldwide microfluidic chip activity, have hopefully provided a flavor of the development rush in microchip-based bio and chemical analysis. As the technology floodgates open further, and the wider scientific community applies what electronics microtechnologists have busied themselves with for a generation or more, microfluidics and biomedical/chemistry applications will grow rapidly. The NEXUS and other forecasts suggest that biotech applications will become a major component of the total micro-systems technology market, second only to applications in information technology. The implications for the future of MEMS, the entire microinstrumentation area, and, for that matter, society as a whole, are both profound and beneficial.
Potential Markets for
Microfluidics and Genomic Devices

Market                                 Annual Sales
                                  (millions of dollars)

In-vitro diagnostics                       19,000
Genomics                                      500
Electrophoresis                               700
Drug synthesis and extraction               1,300
Drug screening/pharmacological testing      1,900


Source: Lehman Brothers and others

Marshall is the editor of R&D Magazine's "Micromachine Devices" newsletter.
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Title Annotation:so-called lab-on-a-chip technologies
Author:Marshall, Sid
Publication:R & D
Geographic Code:1USA
Date:Feb 1, 1999
Words:2579
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