TY - JOUR
AU - Kricka, Larry, J
AB - Abstract Miniaturization has been a long-term trend in clinical diagnostics instrumentation. Now a range of new technologies, including micromachining and molecular self-assembly, are providing the means for further size reduction of analyzers to devices with micro- to nanometer dimensions and submicroliter volumes. Many analytical techniques (e.g., mass spectrometry and electrophoresis) have been successfully implemented on microchips made from silicon, glass, or plastic. The new impetus for miniaturization stems from the perceived benefits of faster, easier, less costly, and more convenient analyses and by the needs of the pharmaceutical industry for microscale, massively parallel drug discovery assays. Perfecting a user-friendly interface between a human and a microchip and determining the realistic lower limit for sample volume are key issues in the future implementation of these devices. Resolution of these issues will be important for the long-term success of microminiature analyzers; in the meantime, the scope, diversity, and rate of progress in the development of these devices promises products in the near future. Miniaturization of analytical and bioanalytical processes has become an important area of research and development during the past 10 years (1)(2)(3) , as a continuation of the general trend in size reduction of clinical laboratory analyzers. The original type of floor-standing analyzer (e.g., AGA Autochemist, Technicon SMAC) (4)(5) has been successively reduced in size, first to bench top and then to portable and hand-held devices. Micrometer-sized microchip devices, and ultimately nanometer-sized nanochip devices, represent the endpoint of this progression. A number of benefits are identifiable with miniaturization, notably reduction in manufacturing costs, ease of transport and shipping, and minimal space requirements in a laboratory. In addition, a microminiature device is easier to hold and manipulate, reduces requirements for power and consumable reagents, and offers the possibility of high-density testing and integration of individual steps in a multistep analytical process. Several factors are fueling current interests in miniaturization. These include point-of-care testing (6) , high throughput drug discovery (7) , detection of biological warfare agents (8) , and astrobiology ((9)). Analyzers for point-of-care testing need to be small, lightweight, and portable with low power requirements; all of these design goals can be achieved via miniaturization. In high throughput drug discovery, the sheer scale of testing (thousands of candidate drugs to be tested against thousands of biological targets) and the need to conserve the limited quantities of archival compounds or substances produced by combinatorial synthesis procedures (10) require high-density arrays of microvolume reaction vessels. The emerging demands to monitor and detect the release of biological warfare agents (e.g., Clostridium botulinum toxin and anthrax) by aggressors in a battlefield or by terrorists in a domestic situation may best be met by microminiature detection devices. Likewise, the limitations on space and weight for rocket payloads strongly supports miniaturization of analyzers designed for astrobiological tasks. The new generation of microminiature analyzers and the proposed nano-sized devices will be built on a scale that would have been difficult to comprehend when the first automatic analyzers were introduced into the clinical laboratory >30 years ago (11) . Dimensions of the smallest structures in microchips are typically 10–100 μm (the diameter of a human red cell is 7 μm), and the proposed nanochips will be several orders of magnitude smaller. In the current miniaturization trend, four main types of microminiature analytical devices are emerging: (a) high-density arrays of microreaction wells, (b) surface microarrays of reagents, (c) microchips, and (d) nanochips. High-density Arrays of Microreaction Wells The new emphasis on high throughput drug discovery methods in which vast numbers of candidate drugs are screened against equally large numbers of biological targets has generated new demands for microminiature analysis. Essential characteristics for an analytical drug discovery method include rapid, automated, and simultaneous testing of microvolumes of candidate drug compounds. Many of the compounds included in drug screening assays are archival and only available in a very limited quantity or are the products of combinatorial synthesis procedures and thus are only produced in microgram to milligram quantities. Conservation of valuable compounds is imperative, and miniaturization of assays is an immediate and viable route to this objective. The microplate has become the most popular format for drug discovery assays because it is readily integrated into an automated process and provides multiple simultaneous testing on a simple disposable device. The traditional 96-well format has proved inadequate and is being replaced by microplates with larger numbers of smaller wells (12)(13)(14)(15)(16)(17)(18) . These include plates with 192, 384, 864, 1536, 2025, 2288, 2304, 2400, 3456, 6144, 6500, 9600, and 20 000 wells with volumes that range from 125 μL to 50 nL. Microplates with 384 and 1536 wells (Fig. 1) are vying for acceptance as the new standard in high throughput screening; however, to date there has been no consensus on optimal well density or volume. These microminiaturized reaction devices have placed new demands on ancillary equipment. In response, a range of new micropipetting systems based on ink-jet principles (thermal-, solenoid-, or piezoelectric-actuated) have been developed for delivery of microliter to nanoliter volumes of sample or reagents (19)(20) . Injection molding is used for manufacture of most of the high-density microvolume microplate devices; however, other techniques such as polymer casting (16) and drilling (13) are also effective manufacturing techniques. Figure 1. Open in new tabDownload slide High-density microwell plates. (A) 384-split well microplate (Robbins Scientific); (B) 384-well microplate (Nalge Nunc International Corp); (C) 1536-well microplate (Greiner Labortechnik). Figure 1. Open in new tabDownload slide High-density microwell plates. (A) 384-split well microplate (Robbins Scientific); (B) 384-well microplate (Nalge Nunc International Corp); (C) 1536-well microplate (Greiner Labortechnik). A diverse range of analytical methods have been adapted to the new high-density, low-volume microwell format. Most are simple mix-and-measure type homogeneous assays, such as scintillation proximity assays, fluorescence polarization assays, time-resolved fluorescence assays, reporter genes, and enzyme assays. To date, there has been relatively less progress in formatting multistep separation assays, such as ELISA, to a high-density microwell format. Surface Microarrays of Reagents Fabrication of surface microarrays of nucleic acids (21)(22)(23)(24)(25)(26) and proteins ((27)(28)(29)(30)) at discrete locations on small chips is another important direction in miniaturization methods. Chips are typically in the size range of 1–2 cm2; the elements in the arrays vary from 1 to 200 μm but are usually 10–100 μm (diameter or length on side). Chips containing all 65 536 possible oligonucleotides in 8-nucleotide chains (8-mers) (22) and chips with 48 300 possible oligonucleotides in 20-nucleotide chains (20-mers) (25) are representative of the scale of array possible with this type of microminiature technology. Microarrays of polynucleic acids or proteins are produced by a number of methods. In situ combinatorial synthesis uses photolithographic masks to define discrete array locations for photodeprotection-type synthetic reactions (22)(24)(25) . In this way, an oligonucleotide or a polypeptide molecule is synthesized one base or one residue at a time on the surface of a glass chip. Synthesizing an n-mer requires 4 × n steps; thus 32 steps are required to synthesize the 65 536 possible 8-mers and 80 steps to produce the ∼1012 possible 20-mers. Alternatively, rubber spacers can be used to define orthogonal reaction channels on a glass surface (31) , or a 64-channel fluidic chemistry delivery system can be used to perform synthetic reactions at defined locations on a polypropylene chip (21) . Other options include direct attachment of preformed oligonucleotides to an activated chip surface (e.g., aminated polypropylene or polyacrylamide gel pads) (23) or attachment of pyrrole-substituted oligonucleotides to arrays of 50 μm × 50 μm polypyrrole-coated gold electrodes via electrosynthetic reactions (32) . Direct arraying of the reagent onto the chip can be by a deposition process using a syringe microdispenser (33) , an array of ink-jet print nozzles (25) , micropins (e.g., 100 μm thick, 1-nL transfer volume) (23) , or open-capillary tips (34) that are simply dipped into the substances to be arrayed. Table 1 (35)(36)(37)(38)(39)(40)(41)(42)(43)(44) lists examples of the applications of the array devices in immunological and genetic testing assays. Most devices are oligonucleotide, cDNA, or polypeptide arrays; however, arrays of unnatural polymers based on aminocarbamate monomers linked via a carbamate backbone have also been prepared (45) . Table 1. Applications of microarray devices. Arrayed reagent . Application . cDNA Inflammatory disease (35), human cancer (36), gene expression–heat shock-regulated genes (37), Arabidopsis genes (38) Oligonucleotide Oligonucleotide-olignucleotide interactions (39), human mitochondrial genome analysis (40), expression monitoring (41), HIV-1 strain identification (22), BRCA1 mutations (42), cystic fibrosis mutation detection (21), β-thalassemia mutations (43), hepatitis C genotyping (32), HLA typing (44) Antibody Simultaneous immunoassay (27,28), antimouse IgG assay (29) Arrayed reagent . Application . cDNA Inflammatory disease (35), human cancer (36), gene expression–heat shock-regulated genes (37), Arabidopsis genes (38) Oligonucleotide Oligonucleotide-olignucleotide interactions (39), human mitochondrial genome analysis (40), expression monitoring (41), HIV-1 strain identification (22), BRCA1 mutations (42), cystic fibrosis mutation detection (21), β-thalassemia mutations (43), hepatitis C genotyping (32), HLA typing (44) Antibody Simultaneous immunoassay (27,28), antimouse IgG assay (29) Open in new tab Table 1. Applications of microarray devices. Arrayed reagent . Application . cDNA Inflammatory disease (35), human cancer (36), gene expression–heat shock-regulated genes (37), Arabidopsis genes (38) Oligonucleotide Oligonucleotide-olignucleotide interactions (39), human mitochondrial genome analysis (40), expression monitoring (41), HIV-1 strain identification (22), BRCA1 mutations (42), cystic fibrosis mutation detection (21), β-thalassemia mutations (43), hepatitis C genotyping (32), HLA typing (44) Antibody Simultaneous immunoassay (27,28), antimouse IgG assay (29) Arrayed reagent . Application . cDNA Inflammatory disease (35), human cancer (36), gene expression–heat shock-regulated genes (37), Arabidopsis genes (38) Oligonucleotide Oligonucleotide-olignucleotide interactions (39), human mitochondrial genome analysis (40), expression monitoring (41), HIV-1 strain identification (22), BRCA1 mutations (42), cystic fibrosis mutation detection (21), β-thalassemia mutations (43), hepatitis C genotyping (32), HLA typing (44) Antibody Simultaneous immunoassay (27,28), antimouse IgG assay (29) Open in new tab Microchips A typical microchip is 1.5 cm × 1.5 cm in size and a few millimeters thick. Materials for microchip fabrication include silicon, glass, quartz, and plastics such as Teflon, polymethylmethacrylate, and polycarbonate (1)(2)(3) . In the case of silicon microchips, a range of fabrication techniques have been adopted from the microelectronics industry, including wet etching using KOH and reactive ion etching processes (46) . Other techniques include laser ablation/drilling, electrodischarge, injection molding, polymer casting, printing, and Lithographie Galvanoformung Abformung (LIGA) (46)(47)(48) . Ablation or drilling with a Nd:YAG laser offers a simple one-step process for fabrication of features <30 μm on a variety of materials. It is particularly useful for cutting curved and irregular shapes that are more problematic for conventional etching methods (47) . Hot embossing is emerging as a highly promising method of making plastic microchips; this is important because it would lead to high-volume low-cost continuous production methods that may be easier to implement than batch etching of silicon wafers for silicon-based microchips (Fig. 2). The range and scope of microchip assays and analyzers continue to grow; some recent examples of devices for different types of assays or analytical procedures are listed in Table 2 (49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73)(74) . Table 2. Microchip assays and analyzers. Application . Reference . Blood gas analyzer 49 Capillary electrophoresis 50–52 Cell analysis Isolation 12, 53, 54 Deformability 55 Motility 56 Flow cytometry 57 Enzymatic assays 58 Gas chromatography 59 Glucose analyzer 60 Immunoassay 61–64 Mass spectrometry 65–67 Nucleic acid amplification PCR 68–71 Multiplex PCR 72 DOP-PCR1 72 Probe ligation LCR 73 Restriction fragment analysis 74 Application . Reference . Blood gas analyzer 49 Capillary electrophoresis 50–52 Cell analysis Isolation 12, 53, 54 Deformability 55 Motility 56 Flow cytometry 57 Enzymatic assays 58 Gas chromatography 59 Glucose analyzer 60 Immunoassay 61–64 Mass spectrometry 65–67 Nucleic acid amplification PCR 68–71 Multiplex PCR 72 DOP-PCR1 72 Probe ligation LCR 73 Restriction fragment analysis 74 1 DOP, degenerate oligonucleotide primed; LCR, ligase chain reaction. Open in new tab Table 2. Microchip assays and analyzers. Application . Reference . Blood gas analyzer 49 Capillary electrophoresis 50–52 Cell analysis Isolation 12, 53, 54 Deformability 55 Motility 56 Flow cytometry 57 Enzymatic assays 58 Gas chromatography 59 Glucose analyzer 60 Immunoassay 61–64 Mass spectrometry 65–67 Nucleic acid amplification PCR 68–71 Multiplex PCR 72 DOP-PCR1 72 Probe ligation LCR 73 Restriction fragment analysis 74 Application . Reference . Blood gas analyzer 49 Capillary electrophoresis 50–52 Cell analysis Isolation 12, 53, 54 Deformability 55 Motility 56 Flow cytometry 57 Enzymatic assays 58 Gas chromatography 59 Glucose analyzer 60 Immunoassay 61–64 Mass spectrometry 65–67 Nucleic acid amplification PCR 68–71 Multiplex PCR 72 DOP-PCR1 72 Probe ligation LCR 73 Restriction fragment analysis 74 1 DOP, degenerate oligonucleotide primed; LCR, ligase chain reaction. Open in new tab Figure 2. Open in new tabDownload slide Polymethylmethacrylate microstructure produced by hot embossing. Channel width is 100 μm, depth is 25 μm. (JENOPTIK Mikrotechnik Gmbh). Figure 2. Open in new tabDownload slide Polymethylmethacrylate microstructure produced by hot embossing. Channel width is 100 μm, depth is 25 μm. (JENOPTIK Mikrotechnik Gmbh). Nanochips One vision of the future direction of miniaturization is nanochip devices that are built at the nanometer scale from individual atoms and molecules (75)(76)(77) . The nanotechnologist’s view is that the counterparts of machine components can be found among natural molecules and biological assemblies of molecules: for example, collagen is a cable, an antibody is a clamp, DNA is a memory device, and membrane proteins are pumps. Currently there are no examples of nanochips; however, progress in self-assembling molecular structures, e.g., 0.5-μm diameter, 30-μm long lipid tubules (78) , 0.7- to 0.8-nm diameter cyclic peptide nanotubes (79) , and the design and synthesis of molecules that mimic mechanical devices provide the grounds for some optimism for this avenue of development (e.g., recently, a metallocene molecular gear was successfully synthesized) (80) . Scaling Issues for Microanalytical Devices Implementation of microanalytical devices presents a series of issues related to the physical size of the device and the scale of the reaction volumes. If a human interface is anticipated, then a microanalytical device must be mounted or packaged into some type of holder or cartridge that provides a convenient means of introducing a sample. This approach has been adopted for the Affymetrix microarray chips (22) , microParts microspectrometers (microParts), and the i-STAT chip (i-STAT Corp.) (81) . Successive reduction in the volume of the sample analyzed in a microanalytical device may compromise analysis either because the measurement limit of the analytical method is exceeded or because the sample is no longer representative of the bulk specimen. For example, a 1-μL sample of a specimen containing an analyte at a concentration of 1 fmol/L contains 6020 molecules. Further reduction in sample size to 1 nL leads to a sample containing only 6 molecules of analyte, which may be substantially less than the detection limit of the analytical method formatted into the microchip. Analysis of rare cells poses yet another challenge for microminiaturized analysis. Fetal nucleated red cells are present in very low abundance in the maternal circulation. For example, 18 mL of maternal blood may only contain 20 fetal cells among a total cell population of nearly 108 nucleated cells (82)(83) . Sampling a microliter volume is unlikely to provide a sample containing even a single fetal cell; thus, other strategies are required, such as on-chip flow-through capture/concentration techniques. Another complication for microchip devices is evaporation of microvolumes of sample or reagent from the microchip, thus compromising the volumes metered into the device. This problem has been addressed by designing pipetting systems that automatically replace fluid lost by evaporation or by enclosing the chip in a controlled environment (84)(85) . Integration A key benefit of miniaturization is the prospect of integration of all of the steps in an analytical process into a single device. For bench-top analyzers, entire fluidic modules have been machined into transparent plastic blocks to provide both integration and some degree of miniaturization (e.g., UnifluidicsTM Technology, Bayer Corp.). For microchips, the range of components that have been miniaturized and that would be available as building blocks for fully-integrated analyzers is impressive and includes pumps, valves, lamps, filters, heaters, refrigeration, ion-selective electrodes, capillary electrophoresis, and electronic control circuitry (1)(86)(87) . Some of the analytical functions integrated into single-chip devices are listed in Table 3 (88)(89)(90)(91)(92)(93)(94)(95) . Most devices integrate the different analytical structures by interconnection on the surface of the chip. Three-dimensional integration can be achieved by stacking or by fabricating chips into interconnected layers (96)(97) . Integrating the sample preparation step required in an analytical procedure is an important goal, and white cell isolation from whole blood followed by PCR analysis has been successfully combined on a single 15 mm × 17 mm silicon-glass PCR filter chip (54) . Integration of an analytical procedure and detection is possible for a number of assays. For example, restriction fragment length polymorphism analysis can be performed on a glass microchip (∼20 mm × 30 mm) that mixes a DNA sample with a restriction enzyme, incubates the mixture, and then delivers the 0.7-nL reaction mixture to an on-chip capillary electrophoresis system for analysis (74) . Table 3. Combinations of components integrated into microanalytical systems. Component . Combinations of components . . . . . . . . . . . . . Microvalve ✓ ✓ ✓ Micropump ✓ ✓ ✓ ✓ ✓ Heater ✓ Electronic control circuitry ✓ Detector ✓ ✓ ✓ ✓ ✓ Reaction chamber ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ DNA isolation ✓ Microdialysis ✓ Cell isolation ✓ ✓ ✓ Cell lysis ✓ ✓ Fertilization ✓ PCR ✓ ✓ ✓ Capillary electrophoresis ✓ ✓ ✓ Enzymatic reaction ✓ Immunoassay ✓ Microarray ✓ Reference 54 70 74 62, 88 89 84 90 49 91 53 92, 93 94 95 Component . Combinations of components . . . . . . . . . . . . . Microvalve ✓ ✓ ✓ Micropump ✓ ✓ ✓ ✓ ✓ Heater ✓ Electronic control circuitry ✓ Detector ✓ ✓ ✓ ✓ ✓ Reaction chamber ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ DNA isolation ✓ Microdialysis ✓ Cell isolation ✓ ✓ ✓ Cell lysis ✓ ✓ Fertilization ✓ PCR ✓ ✓ ✓ Capillary electrophoresis ✓ ✓ ✓ Enzymatic reaction ✓ Immunoassay ✓ Microarray ✓ Reference 54 70 74 62, 88 89 84 90 49 91 53 92, 93 94 95 Open in new tab Table 3. Combinations of components integrated into microanalytical systems. Component . Combinations of components . . . . . . . . . . . . . Microvalve ✓ ✓ ✓ Micropump ✓ ✓ ✓ ✓ ✓ Heater ✓ Electronic control circuitry ✓ Detector ✓ ✓ ✓ ✓ ✓ Reaction chamber ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ DNA isolation ✓ Microdialysis ✓ Cell isolation ✓ ✓ ✓ Cell lysis ✓ ✓ Fertilization ✓ PCR ✓ ✓ ✓ Capillary electrophoresis ✓ ✓ ✓ Enzymatic reaction ✓ Immunoassay ✓ Microarray ✓ Reference 54 70 74 62, 88 89 84 90 49 91 53 92, 93 94 95 Component . Combinations of components . . . . . . . . . . . . . Microvalve ✓ ✓ ✓ Micropump ✓ ✓ ✓ ✓ ✓ Heater ✓ Electronic control circuitry ✓ Detector ✓ ✓ ✓ ✓ ✓ Reaction chamber ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ DNA isolation ✓ Microdialysis ✓ Cell isolation ✓ ✓ ✓ Cell lysis ✓ ✓ Fertilization ✓ PCR ✓ ✓ ✓ Capillary electrophoresis ✓ ✓ ✓ Enzymatic reaction ✓ Immunoassay ✓ Microarray ✓ Reference 54 70 74 62, 88 89 84 90 49 91 53 92, 93 94 95 Open in new tab Capillary electrophoresis in combination with laser-induced fluorescence is a popular on-chip detection option for integrated analysis because it is sensitive, versatile, and the sample volume required is low. It proved effective in the quantitation of bound and free fluorophore-labeled fractions in a competitive immunoassay for theophylline performed on a glass microchip. Steps involving mixing and incubating the sample and reagents and detecting the product (100-pL sample of reaction mixture) were performed on the chip. Quantitation of the bound and free fluorescein-labeled fractions took <1 min in a 58-μm wide, 7.5-cm-long, on-chip separation channel (88) . Another integrated microchip device utilizes a series of electrodes coated with DNA capture probes. The 200-μm diameter electrodes facilitate electronic hybridization, washing, and dehybridization within the chip. Positively biased electrodes facilitate capture of negatively charged DNA, and by changing the bias to negative, captured target can be dehybridized and transported to a reaction site. This “complexity reduction” device has been used to capture DNA sequences from complex mixtures and to quantitate captured target by means of a charge coupled device and a fluorophore label (e.g., Bodipy Texas Red) (92)(93) . Conclusions Miniaturization continues to be an important consideration in the design and development of many assays and analyzers. The escalating interest in high-throughput screening for drug discovery and the large-scale analysis required for genetic studies will continue to be major factors influencing miniaturization. There are already numerous examples of assays and analytical processes that have been successfully adapted to a microchip format, and the goal of a “lab-on-a-chip” is realistic. The emergence of microchips fabricated from plastics (98) will help eliminate some of the materials issues encountered with silicon devices (69) . One of the next major challenges in miniaturization is the development of nanotechnology and fabrication of nanochips. References 1 Kricka LJ, Wilding P. Micromechanics and nanotechnology. Kost GJ eds. Handbook of clinical automation robotics and optimization 1996 : 45 -77 John Wiley & Sons New York. . 2 Kricka LJ, Nozaki O, Wilding P. Micro-mechanics and nanotechnology–implications and applications in the clinical laboratory. J Int Fed Clin Chem 1994 ; 6 : 54 -59. 3 van den Berg A, Bergveld P, eds. Micro total analysis systems. Dordrecht: Kluwer Academic Publishers, 1995:311pp.. 4 Bokelund H. A review of the autochemist system in a hospital environment. Scand J Clin Lab Investig Suppl 1974 ; 140 : 9 -26. 5 Westgard JO, Carey RN, Feldbruegge DH, Jenkins LM. Performance studies on the Technicon “SMAC” analyzer: precision and comparison of values with methods in routine laboratory service. Clin Chem 1976 ; 22 : 489 -496. Crossref Search ADS PubMed 6 Dirks JL. Diagnostic blood analysis using point-of-care technology. AACN Clin Issues 1996 ; 7 : 249 -259. Crossref Search ADS PubMed 7 Devlin JP, ed. High throughput screening. New York: Marcel Dekker, 1997:673pp.. 8 Barnaby W. Biological weapons: an increasing threat. Med Confl Surviv 1997 ; 13 : 301 -313. Crossref Search ADS PubMed 9 Smith JM, Szathmary E. On the likelihood of habitable worlds. Nature 1996 ; 384 : 107 . Crossref Search ADS PubMed 10 Gallop MA, Barrett RW, Dower WJ, Fodor SPA, Gordon EM. Applications of combinatorial technologies to drug discovery. 1. Background and peptide combinatorial libraries. J Med Chem 1994 ; 37 : 1233 -1251. Crossref Search ADS PubMed 11 Alpert NL. Automated instruments for clinical chemistry: review and preview. Clin Chem 1969 ; 15 : 1198 -1209. Crossref Search ADS PubMed 12 Sasaki N. Development of high-throughput polymerase chain reaction system and its performance. Hokkaido J Med Sci 1997 ; 72 : 249 -259. PubMed 13 Sterrer S, Henco K. Fluorescence correlation spectroscopy (FCS)–as highly sensitive method to analyze drug/target interactions. J Receptors Signal Transduct Res 1997 ; 17 : 511 -520. Crossref Search ADS 14 Schullek JR, Butler JH, Ni ZJ, Chen D, Yuan Z. A high-density screening format for encoded combinatorial libraries: assay miniaturization and its application to enzymatic reactions. Anal Biochem 1997 ; 246 : 20 -29. Crossref Search ADS PubMed 15 Houston JG, Banks M. The chemical-biological interface: developments in automated and miniaturised screening technology. Curr Opin Biotechnol 1997 ; 8 : 734 -740. Crossref Search ADS PubMed 16 You AJ, Jackman RJ, Whitesides GM, Schreiber SL. Miniaturized arrayed assay format for detecting small molecule-protein interactions in cells. Chem Biol 1997 ; 4 : 969 -975. Crossref Search ADS PubMed 17 Maier E, Meier-Ewert S, Ahmadi AR, Curtis J, Lehrach H. Application of robotic technology to automated sequence fingerprint analysis by oligonucleotide hybridisation. J Biotechnol 1994 ; 35 : 191 -203. Crossref Search ADS PubMed 18 Kolb AJ. Introduction. Devlin JP eds. High throughput screening 1997 : 275 -278 Marcel Dekker New York. . 19 Rose D, Lemmo AV. Challenges in implementing high-density formats for high throughput screening. Lab Automat News 1997 ; 2 : 12 -19. 20 Fischer-Fruholz S. The handling of nanoliter samples on a chip. Am Lab 1998 ; Feb : 46 -51. 21 Matson RS, Rampal J, Pentoney SL, Anderson PD, Coassin P. Biopolymer synthesis on polypropylene supports: oligonucleotide arrays. Anal Chem 1995 ; 224 : 110 -116. 22 Lipschutz RJ, Fodor SPA. Advanced DNA sequencing technologies. Curr Opin Struct Biol 1994 ; 4 : 376 -380. Crossref Search ADS 23 Drobyshev A, Mologina N, Shick V, Pobedimskaya D, Yershov G, Mirzabekov A. Sequence analysis by hybridization with oligonucleotide microchip: identification of beta-thalassemia mutations. Gene 1997 ; 188 : 45 -52. Crossref Search ADS PubMed 24 Kozal MJ, Shah N, Shen N, Yang R, Fucini R, Merigan TC, et al. Extensive polymorphisms observed in HIV-1 clade B protease gene using high-density oligonucleotide arrays. Nat Med 1996 ; 2 : 753 -759. Crossref Search ADS PubMed 25 de Saizieu A, Certa U, Warrington J, Gray C, Keck W, Mous J. Bacterial transcript imaging by hybridization of total RNA to oligonucleotide arrays. Nat Biotechnol 1998 ; 16 : 45 -48. 26 Eggers M, Ehrlich D. A review of microfabricated devices for gene-based diagnostics. Hematol Pathol 1995 ; 9 : 1 -15. PubMed 27 Ekins R, Chu FW. Multianalyte microspot immunoassay–microanalytical “compact disk” of the future. Clin Chem 1991 ; 37 : 1955 -1967. Crossref Search ADS PubMed 28 Ekins R, Chu FW. Microspot®, array-based, multianalyte binding assays: the ultimate microanalytical technology?. Price CP Newman DJ eds. Principles and practice of immunoassay 2nd ed. 1997 : 625 -646 Stockton New York. . 29 Gushin D, Yershov G, Zaslavsky A, Gemmell A, Shick V, Proudnikov D, et al. Manual manufacturing of oligonucleotide, DNA, and protein microchips. Anal Biochem 1997 ; 250 : 203 -211. Crossref Search ADS PubMed 30 Fodor SPA, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D. Light-directed spatially addressable parallel chemical synthesis. Science 1991 ; 251 : 767 -773. Crossref Search ADS PubMed 31 Southern EM, Maskos U, Elder JK. Analyzing and comparing nucleic acid sequences by hybridization to arrays of oligonucleotides: evaluation using experimental models. Genomics 1992 ; 13 : 1008 -1017. Crossref Search ADS PubMed 32 Livache T, Fouque B, Roget A, Marchand J, Bidan G, Teole R, et al. Polypyrrole DNA chip on a silicon device: example of hepatitis C virus genotyping. Anal Biochem 1998 ; 255 : 188 -194. Crossref Search ADS PubMed 33 Beattie KL, Beattie WG, Meng L, Turner SL, Coral-Vasquez R, Smith DD, et al. Advances in genosensor research. Clin Chem 1995 ; 41 : 700 -706. Crossref Search ADS PubMed 34 Shalon D, Smith SJ, Brown PO. A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res 1996 ; 6 : 639 -645. Crossref Search ADS PubMed 35 Heller RA, Schena M, Chai A, Shalon D, Bedilion T, Gilmore J, et al. Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc Natl Acad Sci U S A 1997 ; 94 : 2150 -2155. Crossref Search ADS PubMed 36 DeRisi J, Penland L, Brown PO, Bittner ML, Meltzer PS, Ray M, et al. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat Genet 1996 ; 14 : 457 -460. Crossref Search ADS PubMed 37 Schena M, Shalon D, Heller R, Chai A, Brown PO, Davis RW. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc Natl Acad Sci U S A 1996 ; 93 : 10614 -10619. Crossref Search ADS PubMed 38 Schena M, Shalon D, Davis RW, Brown PO. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 1995 ; 270 : 467 -470. Crossref Search ADS PubMed 39 Maskos U, Southern EM. A novel method for the parallel analysis of multiple mutations in multiple samples. Nucleic Acids Res 1993 ; 21 : 2269 -2270. Crossref Search ADS PubMed 40 Chee M, Yang R, Hubbell E, Berno A, Huang XC, Stern D, et al. Accessing genetic information with high-density DNA arrays. Science 1906 ; 274 : 610 -614. 41 Lockart DJ, Dong H, Byrne MC, Follettie MT, Gallo MV, Chee MS, et al. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat Biotechnol 1996 ; 14 : 1675 -1680. Crossref Search ADS PubMed 42 Hacia JG, Brody LC, Chee MS, Fodor SPA, Collins FC. Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-color fluorescence analysis. Nat Genet 1996 ; 14 : 441 -447. Crossref Search ADS PubMed 43 Yershov G, Barsky V, Belgovskiy V, Kirillov E, Kreindlin E, Ivanov I, et al. DNA analysis and diagnostics on oligonucleotide microchips. Proc Natl Acad Sci U S A 1996 ; 93 : 4913 -4918. Crossref Search ADS PubMed 44 Sheldon EL, Briggs J, Bryan R, Cronin M, Oval M, McGall G, et al. Matrix DNA hybridization. Clin Chem 1993 ; 39 : 718 -719. Crossref Search ADS 45 Cho CY, Moran EJ, Cherry SR, Stephans JC, Fodor SPA, Adams CL, et al. An unnatural biopolymer. Science 1993 ; 261 : 1303 -1305. Crossref Search ADS PubMed 46 Petersen KE. Silicon as a mechanical material. Proc IEEE 1982 ; 70 : 420 -456. Crossref Search ADS 47 Hennink SC. Machining lasers. Photonics Spectra 1997 ; November : 116 -118. 48 Jackman RJ, Wilbur JL, Whitesides GM. Fabrication of submicrometer features on curved substrates by microcontact printing. Science 1995 ; 269 : 664 -666. Crossref Search ADS PubMed 49 Shoji S, Esashi M, Matsuo T. Prototype miniature blood gas analyser fabricated on a silicon wafer. Sensors Actuators 1988 ; 14 : 101 -107. Crossref Search ADS 50 Harrison DJ, Glavina PG, Manz A. Towards miniaturized electrophoresis and chemical analysis systems on silicon: an alternative to chemical sensors. Sensors Actuators 1993 ; B10 : 107 -116. 51 Effenhauser CS, Manz A, Widmer HM. Glass chips for high-speed capillary electrophoresis separations with submicrometer plate heights. Anal Chem 1993 ; 65 : 2637 -2642. Crossref Search ADS 52 Harrison DJ, Fluri K, Seiler K, Fan Z, Effenhauser CS, Manz A. Micromachining a miniaturized capillary electrophoresis-based chemical analysis system on a chip. Science 1993 ; 261 : 895 -897. Crossref Search ADS PubMed 53 Li PC, Harrison DJ. Transport, manipulation, and reaction of biological cells on-chip using electrokinetic effects. Anal Chem 1997 ; 69 : 1564 -1568. Crossref Search ADS PubMed 54 Wilding P, Kricka LJ, Cheng J, Hvichia GE, Shoffner MA, Fortina P. Integrated cell isolation and PCR analysis using microfilter-chambers. Anal Biochem 1998 ; 257 : 95 -100. Crossref Search ADS PubMed 55 Tracey MC, Greenaway RS, Das A, Kaye PH, Barnes AJ. A silicon micromachined device for use in blood cell deformability studies. IEEE Trans Biomed Eng 1995 ; 42 : 751 -761. Crossref Search ADS PubMed 56 Kricka LJ, Ji X, Nozaki O, Heyner S, Garside WT, Wilding P. Sperm testing with microfabricated glass-capped silicon microchannels. Clin Chem 1994 ; 40 : 1823 -1824. Crossref Search ADS 57 Sobek D, Senturia SD, Gray ML. Microfabricated fused silica flow chambers for flow cytometry. Technical Digest Solid-State Sensor and Actuator Workshop, Hilton Head, SC 1994 ; : 260 -263. 58 Hadd AG, Raymond DE, Halliwell JW, Jacobson SC, Ramsey JM. Microchip device for performing enzyme assays. Anal Chem 1997 ; 69 : 3407 -3412. Crossref Search ADS PubMed 59 Bruns MW. High-speed portable gas-chromatograph–silicon micromachining. Erdol Kohle Erdgas 1994 ; 47 : 80 -84. 60 Forssen L, Elderstig H, Eng L, Nordling M. Integration of an amperometric glucose sensor in a uTAS. van den Berg A Bergveld P eds. Micro total analytical systems 1995 : 203 -207 Kluwer Academic Publishers Dordrecht. . 61 Owicki JC, Bousse LJ, Hafeman DG, Kirk GL, Olson JD, Wada HG, et al. The light-addressable potentiometric sensor. Annu Rev Biophys Biomol Struct 1994 ; 23 : 87 -113. Crossref Search ADS PubMed 62 Chiem N, Harrison DJ. Microchip-based capillary electrophoresis for immunoassays: analysis of monoclonal antibodies and theophylline. Anal Chem 1997 ; 69 : 373 -378. Crossref Search ADS PubMed 63 Koutny LB, Schmalzing D, Taylor TA, Fuchs M. Microchip electrophoretic immunoassay for serum cortisol. Anal Chem 1996 ; 68 : 18 -22. Crossref Search ADS PubMed 64 Song MI, Iwata K, Yamada M, Yokoyama K, Takeuchi T, Tamiya E, Karube I. Multisample analysis using an array of microreactors for an alternating-current field-enhanced latex immunoassay. Anal Chem 1994 ; 66 : 778 -781. Crossref Search ADS PubMed 65 Xue Q, Dunayevskiy YM, Foret F, Karger BL. Integrated multichannel microchip electrospray ionization mass spectrometry: analysis of peptides from on-chip tryptic digestion of melittin. Rapid Commun Mass Spectrom 1997 ; 11 : 1253 -1256. Crossref Search ADS PubMed 66 Xue Q, Foret F, Dunayevskiy YM, Zavracky PM, McGruer NE, Karger BL. Multichannel microchip electrospray mass spectrometry. Anal Chem 1997 ; 69 : 426 -430. Crossref Search ADS PubMed 67 Feustel A, Muller J, Relling V. A microsystem mass spectrometer. van den Berg A Bergveld P eds. Micro total analytical systems 1995 : 299 -304 Kluwer Academic Publishers Dordrecht. . 68 Cheng J, Shoffner MA, Hvichia GE, Kricka LJ, Wilding P. Chip PCR. II. Investigation of different PCR amplification systems in microfabricated silicon-glass chips. Nucleic Acids Res 1996 ; 24 : 380 -385. Crossref Search ADS PubMed 69 Shoffner MA, Cheng J, Hvichia GE, Kricka LJ, Wilding P. Chip PCR. I. Surface passivation of microfabricated silicon-glass chips for PCR. Nucleic Acids Res 1996 ; 24 : 375 -379. Crossref Search ADS PubMed 70 Northrup MA, Gonzalez C, Lehew S, Hills R. Development of a PCR-microreactor. van den Berg A Bergveld P eds. Micro total analysis systems 1995 : 139 Kluwer Academic Publishers Dordrecht. . 71 Taylor TB, Winn-Deen ES, Picozza E, Woudenberg TM, Albin M. Optimization of the performance of the polymerase chain reaction in silicon-based microstructures. Nucleic Acids Res 1997 ; 25 : 3164 -3168. Crossref Search ADS PubMed 72 Cheng J, Waters LC, Fortina P, Hvichia GE, Ramsey JM, Kricka LJ, et al. Degenerate oligonucleotide primed-polymerase chain reaction and capillary electrophoretic analysis of human DNA on microchip-based devices. Anal Biochem 1998 ; 256 : 101 -106. 73 Cheng J, Shoffner MA, Mitchelson KR, Kricka LJ, Wilding P. Analysis of ligase chain reaction (LCR) products amplified in a silicon chip using entangled solution capillary electrophoresis (ESCE). J Chromatogr A 1996 ; 732 : 151 -158. Crossref Search ADS PubMed 74 Jacobson SC, Ramsey JM. Integrated microdevice for DNA restriction fragment analysis. Anal Chem 1996 ; 68 : 720 -723. Crossref Search ADS PubMed 75 Drexler KE. Molecular directions in nanotechnology. Nanotechnology 1991 ; 2 : 113 -118. Crossref Search ADS 76 Drexler E, Peterson C, Pergamit G. Unbounding the future. The nanotechnology revolution. New York: William Morrow and Co Inc., 1991:304pp.. 77 Fahy GM. Molecular nanotechnology. Clin Chem 1993 ; 39 : 2011 -2016. Crossref Search ADS PubMed 78 Schnur JM. Lipid tubules: a paradigm for molecularly engineered structures. Science 1993 ; 262 : 1669 -1676. Crossref Search ADS PubMed 79 Ghadiri MR, Granja JR, Milligan RA, McRee DE, Khazanovich N. Self-assembling organic nanotubes based on a cyclic peptide architecture. Science 1993 ; 366 : 324 -327. 80 Stevens AM, Richards CJ. A metallocene molecular gear. Tetrahedron Lett 1997 ; 38 : 7805 -7808. Crossref Search ADS 81 Erickson KA, Wilding P. Evaluation of a novel point-of-care system, the i-STAT portable clinical analyzer. Clin Chem 1993 ; 39 : 283 -287. Crossref Search ADS PubMed 82 Cheung M-C, Goldberg JD, Kan YW. Prenatal diagnosis of sickle cell anaemia and thalassemia by analysis of fetal cells in maternal blood. Nat Genet 1996 ; 14 : 264 -268. Crossref Search ADS PubMed 83 Williamson B. Towards prenatal diagnosis. Nat Genet 1996 ; 14 : 239 -240. Crossref Search ADS PubMed 84 Kricka LJ, Faro I, Heyner S, Garside WT, Fitzpatrick G, McKinnon G, et al. Micromachining and nanotechnology–a change in practice for the clinical laboratory: glass microchips for sperm selection and in vitro fertilization. Galteau M-M Delwaide P Siest G Henny J eds. Biologie Prospective: 9e Colloque de Pont-a-Mousson 1997 : 42 -46 J Libbey Montrouge. . 85 Kricka LJ, Faro I, Heyner S, Garside WT, Fitzpatrick G, Wilding P. Micromachined glass-glass microchips for in vitro fertilization. Clin Chem 1995 ; 41 : 1358 -1359. Crossref Search ADS 86 Shoji S, Esashi M. Microfabrication and microsensors. Appl Biochem Biotechnol 1993 ; 41 : 21 -34. Crossref Search ADS PubMed 87 Shoji S, Esashi M. Microflow devices and systems. J Micromech Microeng 1994 ; 4 : 157 -171. Crossref Search ADS 88 Chiem N, Harrison DJ. Microchip systems for immunoassay: an integrated immunoreactor with electrophoretic separation for serum theophylline determination. Clin Chem 1998 ; 44 : 591 -598. Crossref Search ADS PubMed 89 Eggers M, Hogan M, Reich RK, Lamture J, Ehrlich D, Hollis M, et al. A microchip for quantitative detection of molecules utilizing luminescent and radioisotope reporter groups. Biotechniques 1994 ; 17 : 516 -525. PubMed 90 Nakagawa S, Shoji S, Esashi M. A microchemical analyzing system integrated on a silicon chip. Proc IEEE-MEMS Workshop 1990 ; : 89 -94. 91 Walther I, van der Schoot BH, Jeanneret S, Arquint P, de Rooij NF, Gass V, et al. Development of a miniature bioreactor for continuous culture in a space laboratory. J Biotechnol 1994 ; 38 : 21 -32. Crossref Search ADS PubMed 92 Cheng J, Kricka LJ, Wilding P. Sample preparation in microstructured devices. Topics Curr Chem 1998 ; 194 : 215 -231. Crossref Search ADS 93 Sosnowski RG, Tu E, Butler WF, O’Connell JP, Heller MJ. Rapid determination of single base mismatch mutations in DNA hybrids by direct electric field control. Proc Natl Acad Sci U S A 1997 ; 94 : 1119 -1123. Crossref Search ADS PubMed 94 Waters LC, Jacobson SC, Kroutchinina N, Khandurina J, Foote RS, Ramsey JM. Microchip device for cell lysis, multiplex PCR amplification, and electrophoretic sizing. Anal Chem 1998 ; 70 : 158 -162. Crossref Search ADS PubMed 95 Freaney R, McShane A, Keaveny TV, McKenna M, Rabenstein K, Scheller FW, et al. Novel instrumentation for real-time monitoring using miniaturized flow systems with integrated biosensors. Ann Clin Biochem 1997 ; 34 : 291 -302. Crossref Search ADS PubMed 96 van der Schoot BH, Verpoorte E, Jeanneret S, Manz A, de Rooij NF. Microsystems for analysis in flowing solutions. van den Berg A Bergveld P eds. Micro total analytical systems 1995 : 181 -190 Kluwer Academic Publishers Dordrecht. . 97 Leach M. Discovery on a credit card. Drug Discov Today 1997 ; 2 : 253 -254. Crossref Search ADS 98 McCormick RM, Nelson RJ, Alonos-Amigo MG, Benvegnu DJ, Hooper HH. Microchannel electrophoretic separations of DNA in injection-molded plastic substrates. Anal Chem 1997 ; 69 : 2626 -2630. Crossref Search ADS PubMed © 1998 The American Association for Clinical Chemistry This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - Miniaturization of analytical systems
JO - Clinical Chemistry
DO - 10.1093/clinchem/44.9.2008
DA - 1998-09-01
UR - https://www.deepdyve.com/lp/oxford-university-press/miniaturization-of-analytical-systems-c9oIF0dbHR
SP - 2008
EP - 2014
VL - 44
IS - 9
DP - DeepDyve
ER -