Macro Opportunities in Microfluidics

Courtesy of Advalytix When it comes to technology, great things really do come in small packages. "Smaller" is usually not only faster, but often better, and more economical. Microfluidic technology, the underlying principle for "lab-on-a-chip" devices, promises reduced sample and reagent consumption, decreased waste, and speedier processing.1,2 The resulting gadgets generally are amenable to the time- and labor-saving fantastic four: automation, integration, modularization, and parallelization. Some growing pains are expected as any new family of technologies makes its way into the marketplace, and microfluidics is no exception. Since The Scientist's last review of this sector,3 a number of companies, including Aclara BioSciences, have left the arena, and others, such as Celtor, have closed up shop. On the flip side, the microfluidic marketplace is continually expanding; Applied Biosystems has recently added a microfluidic product line to its portfolio, and companies such as MicroFluidic Systems and 454 Life Sciences are inching closer to product launch. "Two of today's most prevalent trends in microfluidics are higher integration to add more functionalities on a particular chip, and increased modularity so that chips can interface with multiple instruments," says Nate Cosper, industry manager for drug discovery and clinical diagnostics for market analyst Frost & Sullivan. One of the industry's primary drivers, he says, is Big Pharma. "Drug-discovery companies are becoming increasingly focused on reducing costs to offset expected decreases in future revenue due to significantly more drugs going off-patent," Cosper explains. Microfluidics know-how isn't just for the pharmaceutical industry; other sectors also will benefit as microfluidic companies seek to make the most of their hard-gained expertise. "Our initial commercialization focus has been the pharmaceutical industry, but through strategic partnerships with other companies, we hope to expand our target industries," says Julie Wood, senior director of corporate communications at Caliper Technologies. She cites, for instance, potential product lines in diagnostics, genomics, and chemical analyses. Microfluidics isn't just for high-throughput (HT) environments, either; it also can benefit laboratories that have a high volume of the same types of experiments, albeit at lower throughput levels. The Caliper 1000 from Caliper Technologies, and the Agilent 2100 bioanalyzer from Agilent Technologies both support this segment of the market. Companies looking to get into this market will find a crowded field and stiff competition. What follows is our annual alphabet soup of microfluidics device providers and developers. Potential applications span the gamut from microarray printing to drug delivery, but this overview focuses primarily on integrated devices for bioseparations and analyses. Courtesy of BioProcessors (top); Courtesy of Fluidigm (bottom) FLUIDIC CPUs: (top) BioProcessors' SimCell platform allows researchers to perform cell culture experiments for drug discovery and development within miniaturized bioreactors. (bottom) This tiny 'fluidic microprocessor', the key component of Fluidigm's new TOPAZ Crystallizer, offers researchers a completely new method for crystallization screening. MICROFLUIDICS, A TO Z Branford, Conn.-based 454 Life Sciences, a subsidiary of New Haven, Conn.-based CuraGen, has developed a prototype instrument that massively parallelizes sequencing reactions for whole-genome analysis. Multiplexed amplification and sequencing reactions take place in the 75- picoliter wells of the company's high-density (~300,000 well) PicoTiter™ plates. Sequencing is accomplished with synthesis reactions, which produce light that is captured by the instrument's detection system. The current configuration will support resequencing of many strains of viruses and bacteria, and ultimately the de novo sequencing of bacterial and viral genomes. The ArrayBooster™ from Brunnthal, Germany-based Advalytix employs surface acoustic wave (SAW)-based nanopumps for sample agitation during DNA- and protein-microarray experiments.4 Advalytix also custom develops microfluidic systems for a variety of applications; the company's chips harness SAW technology to control the movement of individual droplets along fluidic tracks. Palo Alto, Calif.-based Agilent Technologies offers the multipurpose Agilent 2100 bioanalyzer, which employs planar LabChips developed by Caliper. The Agilent 2100 performs a diverse range of analyses, including the sizing and real-time quantification of DNA, RNA, and proteins,5 as well as flow cytometry- based cellular analyses. "Interest in this system is growing rapidly; we have already sold more than 1,800 bioanalyzers and over half-a-million LabChips," notes Christina Maehr, Agilent's press relations manager. Foster City, Calif.-based Applied Biosystems has made its debut into the microfluidic marketplace with the 7900HT Micro Fluidic Card for high-throughput, parallel analyses of gene expression patterns using real-time, quantitative PCR. The card's 384 microchambers are connected to eight sample-loading ports by microchannels, effectively making it a "low-density, custom array" for gene expression analyses; researchers specify their own card content online by selecting from the company's Assays-on-Demand™ gene expression products. The assays are processed using the ABI PRISM 7900HT Sequence Detection System. Salt Lake City-based BioMicro Systems offers the Microarray User Interface (MAUI®), a four-bay modular hybridization system that employs the company's passive fluid control (PFC™) technology to integrate, automate, and optimize hybridization on microscope slide arrays. The company also provides custom development services. BioProcessors of Woburn, Mass., is developing a microfluidic platform (SimCell®) that miniaturizes, automates, and parallelizes cellular studies. Its applications include drug development and discovery, ADMET (adsorption, distribution, metabolism, excretion, and toxicity) evaluations, and bioprocess development. According to a recent press release, this technology will enable researchers to conduct "massively parallel cell culturing experiments while varying multiple environmental parameters, such as temperature, pH, and media conditions simultaneously." BioProcessors says the technology can be used to grow and study cells from simple bacterial and fungal systems to complex mammalian cells and tissues. The company anticipates that a prototype platform will be fully developed within a year. Validation studies for Woburn, Mass.-based BioTrove's Living Chip™ microfluidic system are underway. This system consists of about 25,000 microchannels in a stackable microplate format, along with associated robotics and imaging equipment, and can screen roughly one million compounds per day. "Once compound reformatting is performed, screens can be done with little or no robotics," notes Robert Hess, BioTrove's vice president of business development. Also on the horizon is a 100,000-channel circular chip for protein-engineering applications that involve the screening of limiting dilutions of bacteria. The Caliper® 250 drug-discovery system from Mountain View, Calif.-based Caliper Technologies miniaturizes, integrates, and automates a variety of enzymatic and cellular assays. Originally, this system employed four-sipper chips for the analysis of assays performed "off-chip" in microtiter plates. Customers can now choose between four- or 12-sipper chips for higher-throughput capabilities. Caliper also offers the AMS 90 SE, for HT sizing and quantification of DNA, and the Caliper 1000, a benchtop instrument for molecular diagnostics applications that the company plans to market with Bacterial BarCodes of Houston. Cepheid of Sunnyvale, Calif., plans later this year to introduce its GeneXpert™ technology, which integrates macroscale and microfluidic technologies to enable automated DNA extraction and sequence detection in portable units. Potential uses include applications in basic life sciences research, molecular diagnostics, pharmacogenomic profiling for individualized therapeutic planning, and the detection of food contaminants and bioweapons. Livermore, Calif.-based Eksigent Technologies' eight-channel NanoLC system for nanoscale HPLC (high-performance liquid chromatography) has applications in drug discovery and proteomics, and a single-channel version supports protein identification using LC/MS (liquid chromatography-mass spectrometry). The company's EKPumps are used for microscale combinatorial synthesis, liquid-handling systems, and portable medical devices. South San Francisco-based Fluidigm recently launched the Topaz Crystallizer,6 a microfluidic platform for protein crystallization that employs a disposable chip fabricated using multilayer, soft-lithography techniques.3,5 With just three microliters of protein sample, researchers can simultaneously screen 144 conditions corresponding to 48 different crystallizing reagents at three reagent-to-protein ratios per trial. "We are optimistic that the Topaz Crystallizer will transform protein crystallization into a clear-cut discovery process realizable by even those without prior experience with conventional crys-tallization techniques," says Kristin Spataro, Topaz product manager. GenoMEMS of Woburn, Mass., in partnership with Shimadzu Biotech of Kyoto, Japan, plans to launch a fully automated microfluidic sequencer later this year. Dubbed the BioMEMS-768, this system employs two relatively large chips (25 x 50 cm) housing 384 microfluidic channels each. According to GenoMEMS, the BioMEMS-768 will increase the throughput of DNA-sequencing analyses several fold compared to the rates possible using currently available capillary electrophoresis-based instruments. The Gyrolab™ MALDI SP1 from Gyros of Uppsala, Sweden, streamlines sample preparation prior to MALDI-MS (matrix-assisted laser desorption/ionization mass spectrometry). Designed for Gyros' Gyrolab Workstation, this "microfluidic CD" (compact disc) performs MS sample preparation on-disc. It also supports an alternative preparation method that modifies peptides for chemically assisted fragmentation-based sequencing. As many as 96 samples can be processed simultaneously within and crystallized directly onto each microfluidic CD prior to analysis, and the Gyrolab Workstation can accommodate up to five CDs per run. Kits enabling use with MALDI-TOF (time-of-flight) instruments from Bruker Daltonics of Billerica, Mass., or Manchester, UK-based Kratos Analytical are currently available; kits for interfacing with instruments from other manufacturers are under development. Micro Chemical Systems of East Yorkshire, UK, custom develops disposable/reusable microfluidic devices that perform microchemical reactions, with applications including basic research, industrial-scale reaction development, and compound synthesis. In partnership with Herts, UK-based Syrris, Micro Chemical Systems recently launched the Microreactor Development Kit, which is designed to help scientists explore the world of microchemical reactions. A product development company that works in partnership with instrument and distribution organizations to develop end-user systems for chemistry laboratories and the pharmaceutical sector, Syrris also is developing its own microfluidic system for microchemical reactions. The company anticipates product launch in 2004. Pleasanton, Calif.-based MicroFluidic System's three- dimensional microfluidic technology (3-D Fluidics™) can be employed in HT, parallelized laboratory systems, and even battery-powered, portable equipment. The company is currently developing systems employing its reusable chips for applications ranging from PCR sample preparation to biodefense monitoring. Nanostream of Pasadena, Calif., is slated to begin shipping its new, parallelized liquid chromatography system to customers in June. Developed to enable rapid sample analysis in drug discovery, this system's standard microfluidic chips will contain 24 channels packed with C-18 material for simultaneous separations. Nanostream also custom develops and mass produces microfluidic systems employing its modular Snap-n-Flow™ approach. Surface Logix of Brighton, Mass., uses soft-lithography techniques and proprietary surface chemistries to develop protein- and cell-based assays for drug discovery and development. The company also develops integrated suites of protein and cellular assays for applications in oncology, inflammation, and infectious disease. The LabCD™-ADMET system from Tecan of Männedorf, Switzerland, supports a wide range of secondary drug-candidate assays, including cytochrome P450- inhibition assays to uncover drug-drug interactions, and serum protein-binding assays. This system employs disposable microfluidic CDs that operate on the company's Genesis 150 automated platform and Ultra plate reader. The XeoChip™ platform from Houston-based Xeotron is designed to replace conventional microarraying and library-screening methods with a microfluidic alternative (see related article, p. 46). The company's photo-generated reagent chemistry controls the generation of acidic or basic building blocks needed for the synthesis of probes or library constituents directly within the hundreds to thousands of nanoscale chambers in a given Xeochip. Courtesy of Agilent Technologies ENGINEERING SERVICES For those looking to develop their own customized chips, a number of companies provide microfluidic system-development services. Grosserkmannsdorf, Germany-based GeSiM custom develops and manufactures microfluidic chips from silicon, glass, ceramics, and synthetics for a wide range of applications, and also offers a considerable line of micropipetting products. Redmond, Wash.-based Micronics develops custom systems employing thin-film, laminate-based, card-like microfluidic devices. These "lab cards" harness laminar flow diffusion for on-card mixing, separation, and detection of molecules, cells, and particles.5 "We can rapidly generate prototypes for a wide variety of on-card amplification and detection applications, including those employing the polymerase chain reaction, nucleic acid sequence-based amplification, or surface plasmon resonance," says Karen Hedine, president of Micronics. "Our early-access products, including a low-pulse pump system and off-the-shelf lab cards, help researchers benefit from microfluidics in developing new assays, testing chemistries, and experimenting with smaller sample and reagent volumes," she adds. In addition to its benchtop system and disposable chips for microfluidic capillary electrophoresis, Micronit Microfluidics of Enschede, Netherlands will custom develop, prototype, and manufacture microfluidics devices at low or high volume. Micronit says it will design and produce glass microfluidic devices for "almost any" application. The company is also experienced with silicon microfluidics; one of its more creative solutions in this arena has been the development of microneedles for painless blood collection and drug delivery. Other companies that offer design, prototyping, and/or manufacturing services for microfluidic applications include Åmic of Uppsala, Sweden; BioMicro Systems of Salt Lake City; Innovative Micro Technology of Santa Barbara, Calif.; Intelligent Micropatterning of St. Petersburg, Fla.; Kionix of Ithaca, NY; LioniX of Enschede, Netherlands; Mezzo Systems of Baton Rouge, La.; Micralyne of Edmonton, Alberta; Microfluidic ChipShop of Jena, Germany; Micromotive Mikrotechnik of Mainz, Germany; Mimotec of Sion, Switzerland; Nanostructures of Santa Clara, Calif.; Protron Mikrotechnik of Bremen, Germany; Scandinavian Micro Biodevices of Lyngby, Denmark, Silex Microsystems of Kista, Sweden; and thinXXS of Mainz/Zweibrücken, Germany. Corning IntelliSense of Wilmington, Mass., offers custom development and manufacturing services, too, as well as software tools for designing microfluidic devices. Software for designing/simulating microfluidic devices also is available from companies such as Coventor of Cary, NC, and Huntsville, Ala.-based CFD Research, which also offers engineering services. Deborah A. Fitzgerald (biotechnology@consultant.com) is a freelance writer in Gulf Breeze, Fla. References 1. T. Chován, A. Guttman, "Microfabricated devices in biotechnology and biochemical processing," Trends Biotech, 20:116-22, 2002. 2. D.R. Meldrum, M.R. Holl, "Microscale bioanalytical systems," Science, 297:1197-8, 2002. 3. D.A. Fitzgerald, "Riding the microfluidic wave," The Scientist, 16[23]:40-3, Nov. 25, 2002. 4. A. Constans, "Nano-quakes," The Scientist, 17[7]:48, April 7, 2003. 5. D.A. Fitzgerald, "Making every nanoliter count", The Scientist, 15[21]:22, Oct. 29, 2001. 6. C. Yanicek, "Accelerated protein crystallization with FID," The Scientist, 17[8]:44, Apr. 21, 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

Macro Opportunities in Microfluidics

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