dna microarray technology - CiteSeerX

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Annu. Rev. Biomed. Eng. 2002. 4:129–53 doi: 10.1146/annurev.bioeng.4.020702.153438 c 2002 by Annual Reviews. All rights reserved Copyright °

DNA MICROARRAY TECHNOLOGY: Devices, Systems, and Applications Michael J. Heller Departments of Bioengineering/Electronic and Computer Engineering, University of California, San Diego, La Jolla, California 92093; e-mail: [email protected]

Key Words DNA arrays, DNA chips, DNA microchips, DNA devices, DNA hybridization ■ Abstract In this review, recent advances in DNA microarray technology and their applications are examined. The many varieties of DNA microarray or DNA chip devices and systems are described along with their methods for fabrication and their use. This includes both high-density microarrays for high-throughput screening applications and lower-density microarrays for various diagnostic applications. The methods for microarray fabrication that are reviewed include various inkjet and microjet deposition or spotting technologies and processes, in situ or on-chip photolithographic oligonucleotide synthesis processes, and electronic DNA probe addressing processes. The DNA microarray hybridization applications reviewed include the important areas of gene expression analysis and genotyping for point mutations, single nucleotide polymorphisms (SNPs), and short tandem repeats (STRs). In addition to the many molecular biological and genomic research uses, this review covers applications of microarray devices and systems for pharmacogenomic research and drug discovery, infectious and genetic disease and cancer diagnostics, and forensic and genetic identification purposes. Additionally, microarray technology being developed and applied to new areas of proteomic and cellular analysis are reviewed.

CONTENTS INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REVIEWS ON MICROARRAY TECHNOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . MICROARRAY DEVICES AND SYSTEMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High-Density Microarrays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microelectronic Array Technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New Microarray Technologies, Chemistries, and Detection Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . MICROARRAY INFORMATICS AND APPLICATIONS . . . . . . . . . . . . . . . . . . . . . SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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INTRODUCTION A variety of DNA microarray and DNA chip devices and systems have now been developed and commercialized. These devices allow DNA and/or RNA hybridization analysis to be carried out in microminiaturized highly parallel formats. DNA microarray hybridization applications are usually directed at gene expression analysis or screening samples for single nucleotide polymorphisms (SNPs). In addition to the molecular biologically related analyses and genomic research applications, such microarray systems are also being used for pharmacogenomic research, infectious and genetic disease and cancer diagnostics, and forensic and genetic identification purposes. Microarray technology continues to improve in performance aspects regarding sensitivity and selectivity and in becoming a more economical research tool. The use of DNA microarrays will continue to revolutionize genetic analysis and many important diagnostic areas. Additionally, microarray technology that has been developed for DNA analysis is now also being applied to new areas of proteomic and cellular analysis. DNA hybridization microarrays are generally fabricated on glass, silicon, or plastic substrates. The microarrays may have from a hundred to many thousands of test sites that can range in size from 10 to 500 microns. High-density microarrays may have up to 106 test sites in a 1–2-cm2 area. DNA probes are selectively spotted or addressed to individual test sites by a variety of techniques. Probes can include synthetic oligonucleotides, amplicons, or larger DNA/RNA fragments. The DNA probes can be either covalently or noncovalently attached to support material. Depending on the array format, probes can be the target DNA or RNA sequences to which other “reporter probes” would subsequently be hybridized. The actual construction of microarrays involves the immobilization or in situ synthesis of DNA probes onto the specific test sites of the solid support or substrate material. High-density DNA arrays can be fabricated using physical delivery techniques (e.g., inkjet or microjet deposition technology) that allow the dispensing and spotting of nano/picoliter volumes onto the specific test site locations on the microarray. In some cases, the probes or oligonucleotides on the microarrays are synthesized in situ using a photolithographic process. Microarray devices with lower densities of test sites have been developed that provide direct electronic detection of the hybridization reactions. Active electronic microarray devices that provide electronic addressing or spotting of probes as well as rapid high-performance hybridization analysis are now also available for research and diagnostic applications. The successful implementation of microarray technologies has required the development of many methods and techniques for fabricating the microarrays and spotting the probes, for carrying out and detecting the hybridization reactions, and informatics for analyzing the data. DNA hybridization analysis on microarrays usually involves detecting the signal generated by the binding of a reporter probe (fluorescent, chemiluminescent, colorimetric, radioisotope, etc.) to the target DNA sequence. The microarray is scanned or imaged to obtain the complete hybridization

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pattern. Fluorescence scanning/imaging or mass spectroscopy are two of the more common methods used for the “reading” of the microarrays. For high-density type microarrays, a variety of bioinformatic tools have been used to reduce the complex data into useful information. The automation of DNA microarray systems greatly facilitates their use and ease of operation and helps to eliminate many of the human errors that would be involved in manually carrying out the multiplex hybridization analyses. The development of microarray technology has depended on the integration of many different disciplines such as molecular biology, genetics, advanced microfabrication and micromachining technologies, nucleic acid chemistry, surface chemistry, analytical chemistry, software, and robotics and automation. Microarray technology represents a truly successful synergy of these many different scientific and engineering fields. The following sections include a composite of recent general reviews and comments on microarray technologies and their applications; an overview of the important microarraying technologies, with selected examples of microarray technologies that have utilized techniques from the microelectronics industry; and a final overview of the numerous applications of DNA microarrays in research and diagnostics.

REVIEWS ON MICROARRAY TECHNOLOGY An early history and overview of the microarray field has been provided by Edwin M. Southern (1). This review begins with the first simple DNA arrays, which were called “dot blots,” and progresses through the development of inkjet and lightdirected fabrication of high-density microarrays. Ekins & Chu have provided another review on the origins of microarrays and their applications (2). In 1998, Mark Schena provided two reviews that describe using gene expression microarrays as a discovery platform for functional genomics (3, 4). Robert Service provides an interesting overview of microarray applications for gene expression and its potential for revolutionizing drug discovery and diagnostics (5). Other early reviews include state-of-the-art development of DNA chips (6) and use of microarrays for gene expression applications (7, 8). Early in 1999, a series of reviews appeared in Nature Genetics that included discussions of microarray fabrication and detection techniques (9), the use of microarrays for gene expression analysis (10, 11), the use of oligonucleotide arrays for resequencing and mutation analysis (12), and the potential for microarray technology in drug discovery and pharmacogenomic applications (13). The issue also contained a review on important molecular interactions that can take place on microarrays (14). Thompson & Furtado provide another review on the use of high-density oligonucleotide arrays for DNA analysis (15). Further reviews include expression profiling in cancer (16), different techniques for expression profiling on DNA microarrays (17), and the development of automated microarray systems for mutation analysis (18). Freeman and coworkers provide a review on carrying out gene expression analysis on single-cell samples (19). Because the development and applications of DNA microarray technology began to expand during the late 1990s, a large number of reviews appear in the year

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2000. Wang provides an encompassing survey and summary of the area (20). In addition to DNA microarrays, his review includes background on the closely related areas of DNA sensors and lab-on-a-chip technology. Meldrum provides another encompassing review on the automation of genomics (21). In addition to a good overview of microarrays and future technologies, this review also contains information on the advancement of important DNA sequencing technologies and their role in the genome project. The sections on microarraying and future technologies provide a compilation of the many companies that are now involved in DNA microarrays and related areas. A further series of reviews give good coverage of the many gene expression techniques and applications being carried out (22–24). Freeman and coworkers provide another review on the fundamentals of using microarrays for gene expression (25). A series of general reviews on microarray technology and applications have been prepared by Bednar (26), Burke (27), and Jain (28). Stewart provides a review on making and using microarrays derived from a short course given at the Cold Spring Harbor Laboratory (29). Other, more specific, reviews include the use of DNA microarrays and combinatorial chemical libraries for drug discovery applications (30), the use of microchips as a specific genetic tool in psychiatry (31), and the impact of functional genomics and microarray technology on the modern pathology laboratory (32). Zanders (33) and Jain (34) review gene expression analysis as an aid to the identification of drug targets and for applications in pharmacogenomics. Ivanov et al. (35) provide a review of DNA microarray technology for antimicrobial drug discovery applications. Cunningham (36) provides a good overview of the new genomics and proteomics and its importance to drug discovery and development. More recent general reviews on microarrays for gene expression include those by Hughes & Shoemaker (37) and Deyholos & Galbraith (38) on high-density microarrays for gene expression analysis and by Nelson (39) on microarrays maturing as a gene expression tool. More specialized reviews on microarrays and gene expression include the use of microarrays for studying the aging process in mice (40) and genome-wide expression analysis for plant cell–modulated genes (41). A number of important reviews have appeared related to the use of microarrays for cancer research and diagnostics. These include more general reviews by Kallioniemi (42) on biochips in cancer research and Polyak & Riggins (43) on serial analysis of gene expression techniques and the implications for cancer research. More specific reviews include those on microarrays for breast cancer research (44), gene expression analysis for maturation and cell death in acute promyelocytic leukemia (45), microarrays in pediatric cancer research (46), and using microarrays for identifying prostate cancer markers (47). In the area of microarrays for microbiological applications, several general reviews are available (48, 49). More specific reviews are available on DNA microarray analyses of host-pathogen interactions (50) and the use of microarrays for the molecular diagnosis of mycobacteria (51). More generalized reviews in the medical-related areas include microarrays for disease gene discovery (52), microarrays in medicine (53), microarrays for molecular pathology (54), and a review by Eyster & Lindahl on DNA microarrays and their application

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to clinical medicine (55). Special reviews have been prepared on using microarrays to study human alcoholism (56) and the potential for using microarrays for environmental health applications (57). Some of the most recent reviews and overviews include Kricka (58) on the potential of microarrays to be the personal laboratories of the twenty-first century, Blohm & Guiseppi-Elie (59) on new developments in microarray technology, Davenport (60) on data standards for microarrays, and Becker (61) on issues related to sharing of cDNA microarray data. A large number of companies have been involved in the development of DNA microarrays and the associated systems and applications. Table 1 gives a compilation of some the main companies involved in DNA microarray/DNA chip areas. Meldrum provides a good overview of many of these companies and their products in the sections on microarraying (21). Further descriptions of some of the companies are provided in his “future technologies” section. This section gives a good review of those systems that utilize mass spectrometry for detection and analysis. The section on new biochips reviews several of the more exotic approaches such as micron-scale bead arrays, electronic DNA chips, and several of the so-called TABLE 1 Producers of microarrays, Biochips, and lab-on-a-chip devices Company

Description of device or system

References

ACLARA Bio Sciences, Inc. (Mountain View, CA)

LabCard—device uses electric fields to move fluids through capillaries on chips for the miniaturization and integration of complex, multistep biochemistry processes.

64, 65

Affymetrix, Inc. (Santa Clara, CA)

GeneChip—high-density arrays produced by photolithographic process for gene expression and genotyping.

66, 67, 68, 69, 70, 71

Caliper Technologies Corp. (Mountain View, CA)

LabChip—microfluidic devices with active fluid control and parallel processing for variety of genome analysis procedures including molecular purification and high-speed DNA separations.

72

Clinical Micro Sensors (Pasadena, CA)

Low-density array with electrochemical sensing for point-of-care diagnostic applications.

Gamera Bioscience Corp. (Medford, MA)

LabCD System—“lab-on-a-disc” microfluidic platform uses a modified CD player and disposable compact disc to perform a variety of microscale analytical processes.

Gene Machines (San Carlos, CA)

Omni Grid is a high-performance, multi-axis robot for arraying samples onto glass slides and membranes.

Genetix Ltd. (Christchurch, UK)

Q Array is a dedicated microarrayer with 16-pin microarraying head for spotting slides. (Continued )

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TABLE 1 (Continued) Company

Description of device or system

References

Gene Trace Systems, Inc. (Alameda, CA)

High-throughput, automated mass spectrometry systems with liquid-phase expression technology for gene discovery, gene expression analysis, genotyping, and mutation scanning.

73, 74, 75

Hewlett Packard Company (Palo Alto, CA)

A thermal jet spotting system to produce cDNA microarrays.

Hyseq, Inc. (Sunnyvale, CA)

Hyseq HyChip—a universal sequencing chip based on sequencing-by-hybridization (SBH) technology.

76, 77

Illumina, Inc. (San Diego, CA)

BeadArray—fiber-optic self-assembled addressable arrays are filled with optically encoded libraries of 3–5-µm diameter beads to simultaneously process millions of assays.

78

Incyte Microarray Systems (Fremont, CA)

GEM or gene expression microarrays.

Intelligent Bio-Instruments (Cambridge, MA)

High-throughput microarraying system that can dispense from 12 to 64 spots onto multiple glass slides.

Nanogen, Inc. (San Diego, CA)

Molecular Biology Workstation and NanoChip— an active programmable electronic matrix chip that has addressable locations for genotypying applications.

79, 80, 81, 82, 83

Orchid BioSciences, Inc. (Princeton, NJ)

Developing microfluidic glass chips to enable high-throughput chemical synthesis, genomics, DNA analysis, screening, and diagnostics.

84

Packard Instrument Company (Meriden, CT)

BioChip Arrayer with four PiezoTip piezoelectric drop-on-demand tips provides noncontact dispensing for arraying onto glass, filters, and HydroGel substrates.

Rosetta Inpharmatics, Inc. (Kirkland, WA)

FlexJet inkjet-based microarrays available only through scientific collaborations.

85

Sequnome (San Diego, CA)

High-throughput resequencing array that uses a MALDI-TOF mass spectrometer for subsequent detection and identification of DNA fragments, used for SNP and genotyping.

86

TeleChem International, Inc. (Sunnyvale, CA)

ChipMaker 2 and ChipMaker 3 microspotting devices with noncontact, inkjet-type dispensers.

Vysis, Inc. (Downers Grove, IL)

GenoSensor—a genomic array system for addressing gene copy number.

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lab-on-a-chip technologies. Wang also provides another encompassing review that includes good sections on DNA biosensors, DNA microarrays, and lab-on-a-chip technologies (20). Additionally, several new monographs on DNA microarray technologies are now available. Mark Schena has edited a volume titled DNA Microarrays: A Practical Approach (85), and Jang B. Rampal has edited another volume titled DNA Arrays: Methods and Protocols (86). A short review on some recent patents in the microarray area has appeared in Nature Biotechnology (87). Although microarray patent coverage is not the intent of this chapter, it is strongly recommended that anyone who plans to do active research and development in the microarray area carry out a good patent search. This is particularly important before investing time and money in development work. Considerable research and development in the microarray area is now carried out by the biotechnology industry, which will generally patent the technology before publishing the work.

MICROARRAY DEVICES AND SYSTEMS In the past several years, many different microarray technologies, devices, and instrument systems have been developed and are now commercially available for producing DNA microarrays. These microarrays and systems are being used for gene expression, genotyping, and other applications. A number of different methods have been developed for creating microarrays, including various techniques for using them (88). Many microarray spotting technologies and techniques now exist. Two of the more important spotting techniques used are the pin-based fluid transfer systems (3, 4, 89–93) and the piezo-based inkjet dispenser systems (94–96). Other methods for preparing DNA arrays include the use of photolithography for the in situ synthesis of high-density DNA microarrays, developed by Affymetrix, as well as the electronic-based addressing of microarrays developed by Nanogen. Both of these methods are discussed below. For further reviews and discussions on other methods for preparing microarrays and the associated techniques and technologies, see References (24, 97–99).

High-Density Microarrays High-density DNA arrays manufactured by Affymetrix provide a massively parallel approach to DNA hybridization analysis that is having a significant impact on genomic research and diagnostics. In the early 1990s, Steve Fodor and colleagues at Affymetrix began to develop photolithographic techniques (used by computer chip manufacturers) to carry out the parallel synthesis of large numbers of oligonucleotides on solid surfaces (64, 65). This light-directed synthesis has enabled the large-scale manufacture of arrays containing hundreds of thousands of oligonucleotide probe sequences on glass slides, or “chips,” less than 2 cm2 in size (100). This method is now used by Affymetrix to produce the high-density GeneChip® probe arrays, which are finding use for the detection and analysis of point mutations and SNPs and for gene expression studies (66–69).

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The Affymetrix in situ process combines DNA synthesis chemistry with photolithography techniques from the microelectronic industry. In this process, 50 terminal protecting groups are selectively removed from growing oligonucleotide chains in predefined regions of a glass substrate by controlled exposure of light through photolithographic masks (64, 65, 100). The glass substrate, or chip, is first covalently modified with a silane reagent to provide hydroxyalkyl groups, which serve as the initial synthesis sites. These sites are then extended with linker groups protected with special photolabile protecting groups. When specific regions of the surface are exposed to light (through masks), the protecting groups are selectively removed, allowing the sites to now be coupled with the next appropriate nucleoside phosphoramidite monomer. The monomers, which are also protected at their 50 position with a photolabile group, are coupled to the substrate using standard phosphoramidite DNA synthesis protocols. The current methodology employs nucleoside monomers protected with a photo-removable 50 -(O-methyl6-nitropiperonyloxycarbonyl) (MeNPOC) group (64, 65, 100). The cycles of photodeprotection and nucleotide addition are repeated to build any given array of oligonucleotide sequences. The average stepwise efficiency of oligonucleotide synthesis is approximately 90%–95%. This value is the result of the average yield of the photochemical deprotection step after exhaustive photolysis (102). Many of the semi-automated manufacturing techniques and lithography tools used in the GeneChip® array production process were adapted from the microelectronics industry. The Affymetrix method for highly parallel synthesis of oligonucleotide (probe) sequences provides an excellent process for making high-density microarrays. With this process, a complete set, or subset, of all probe sequences of length n requires 4n synthesis steps. By way of example, a complete array of all possible 10-mer probes (1,048,576 sequences) would require only 40 process cycles. Currently, arrays made using photolithographic synthesis have individual probe features 24 × 24 microns on a 1.6-cm2 size chip. The technology will ultimately allow arrays to be fabricated with densities >106 sequences/cm2, which corresponds to a feature size of less than 102 microns. Typical arrays comprise customized sets of probes that may range from 14 to 25 bases in length. Factors such as high probe density (∼120 pmol/cm2), special hybridization stringency conditions, and the use of comparative-intensity algorithms for data analysis allow accurate sequence information to be “read” from these arrays with single-base resolution (68). Although other photolabile protecting groups and processes have been described that may be applicable for light-directed DNA array synthesis, they have not been used extensively (103–105). McGall and coworkers at Affymetrix continue to achieve higher photolysis rates, synthesis yields, and spatial resolution, and have also developed photolithographic methods for fabricating DNA arrays that utilize polymeric photoresist films as the photoimageable component (100, 106, 107). One such polymer film contains a chemically amplified photoacid generator, which creates localized acid development adjacent to the substrate surface when exposed to light. This localized acid results in direct removal of 4,40 -dimethoxytrityl

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(DMT) protecting groups from the oligonucleotide chains. This high-resolution photoresist-based process may enable the production of oligonucleotide arrays with features on the order of five microns in size. McGall & Fidanza also describe other methods (100) for the synthesis of photolabile MeNPOC nucleoside phosphoramidite building blocks for standard 30 –50 as well as 50 –30 photolithographic synthesis, and for using “modified” 20 -0-methyl and 2,6-diaminopurine nucleosides. These methods can be used to synthesize arrays with improved hybridization affinities for A/T-rich probe sequences. Several nonstandard probe chemistries may be used to impart specific properties to an array. For example, the “reverse” (50 –30 ) synthesis to the support at the 50 end leaves the 30 end available for later enzymatic extension or ligation reactions (108). These “reverse” arrays can be synthesized using 30 -MeNPOC 50 -phosphoramidate monomers and have characteristics nearly equivalent to the standard 30 –50 arrays. McGall & Fidanza (100) outline the photolithographic synthesis method, general protocols for determining photochemical deprotection rates and yields for oligonucleotide synthesis based on surface fluorescence, and procedures based on hybridization for comparing the array performance characteristics of new chemistries and protocols. Oligonucleotide arrays with many thousands of probe sequences will have a fairly broad range of hybridization thermodynamics. This can produce a corresponding range of signal intensities when they are hybridized with labeled target sequences (100). A/T-rich probe sequences frequently display lower hybridization intensities than do more stable sequences with high G/C content. This is a particular concern when very stringent hybridization conditions are required to break up secondary structure in certain RNA targets or to increase the discrimination of arrays when used for the analysis of high-complexity mRNA samples (66, 109). The use of TMAC1 has been explored as a means of improving hybridization to A/T-rich probe sequences, but has limited use due to its toxicity and corrosiveness (110). Nevertheless, the sensitivity of A/T-rich probe sequences in arrays can be improved by the introduction of certain nucleotide analogs that improve the overall duplex stability. The replacement of deoxyadenosine (dA) with analogs such as 20 -deoxy-2,6-diaminopurine (dD) has been suggested as a means of enhancing the stability of A-rich sequences (111–115); however, the stabilizing effect is not entirely uniform for all sequences. The use of dD in 10-mer arrays was found to have only a small impact on hybridization of a complementary oligonucleotide, 50 -fluorescein-rCTGAACGGTA-30 . However, it was found to stabilize duplexes in RNA targets and probes with poly-dA tracts (100, 114, 115). Good overall improvement in RNA hybridization intensities is observed when both the deoxyadenosine (dA) and Thymidine (T) in the probe sequences are replaced with 20 -O-methyl-2,6-diaminopurine (20 -OMe-D) and the 20 -O-methyl5-methyluridine (20 -OMe-5-Me-U) analogs, respectively. This is primarily due to their stabilizing effect on duplex formation with complementary RNA target sequences (116). 20 -0-alkyl-modified oligonucleotides that were used as antisense therapeutic agents have more recently been used to improve probes for RNA

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detection (117). McGall & Fidanza (100, p. 97) have shown that the substitution of dA and T in 10-mer probe arrays with the 20 -OMe-D and 20 -OMe-5-Me-U analogs can increase the relative hybridization intensity two- to threefold. Improved hybridization sensitivity for A/T-rich RNA targets has been shown on human immunodeficiency virus (HIV) PRT 440 resequencing GeneChip® probe arrays with 20-mer dD and 20 -OMe-5-Me-U substituted probe array. In these experiments, the analogs increased the “base-call” accuracy of the array from 88.6% to 98.6% (100). In this work, sample preparation, labeling, and the microarray hybridizations were carried out according to published protocols (67, 118). The use of these nucleotide analogs has also led to a reduction in the length of the probes (12- to 14-mers) that are needed to obtain performance characteristics previously obtained using arrays with longer (>20-mer) probes. The value of using such improved high-density GeneChip® probe arrays has been demonstrated for analyzing drug resistance traits in HIV (119). Finally, the further improvement of hybridization performance of short probe arrays is also needed for the development of generic mutation detection microarrays based on using sets of all n-mer sequences (67).

Microelectronic Array Technology Microelectronic chip/array devices developed by Nanogen again combine many aspects of technology from the microelectronics industry to uniquely improve molecular biology techniques such as DNA hybridization. Microelectronic arrays provide high-performance hybridization that overcomes many of the problems of passive array hybridization techniques. These active microelectronic array devices have the ability to produce reconfigurable electric fields (more specifically electrophoretic fields) on the microarray surface that allow rapid and controlled transport of charged DNA/RNA molecules to any test site (77–80). These microelectronic array devices are able to increase the DNA hybridization rate by concentration of probe/target DNA at the test site. Reversing the electric field on the test site produces an electronic stringency effect, which can greatly improve hybridization specificity and ability to discriminate point mutation and SNPs. In addition to DNA and RNA molecules, these devices have the ability to selectively transport any charged entity, which can include proteins (antibodies, enzymes, etc.), cells, nanoparticles, and semiconductor microstructures. The manufacture of microelectronic array devices utilizes a variety of microfabrication, photolithography, and other microelectronic technologies. Microelectronic arrays have been designed and fabricated with 25, 100, 400, and 10,000 test-sites or microlocations. The 100-test-site chip, which has been commercialized by Nanogen, has 80-micron diameter test sites/microlocations with underlying platinum microelectrodes, and 20 auxiliary outer microelectrodes (Figure 1A). The outer group of microelectrodes provides encompassing electric fields for concentrating DNA from the bulk sample solution to specific testsites/microlocations. The 100-test-site DNA chip is less than 1 cm in size, with the active test-site array area being approximately 2 mm in size. The microelectronic

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arrays or chips are fabricated on silicon wafers, having a base structure of silicon with an insulating layer of silicon dioxide. The microelectrode structures are platinum with connecting gold wires. Silicon dioxide or silicon nitride is used to cover and insulate the conducting wires, but not the surface of the platinum microelectrode structures. Important to the device function is the permeation layer that overcoats the underlying microelectrodes (77–81). The permeation layer, composed of a porous hydrogel material (agarose or polyacrylamide), allows the array to be run at current levels (>100 nanoamperes) and voltages (>1.2 volts). This layer serves to protect the sensitive DNA hybridization reactions from the adverse electrochemical oxidation and reduction effects that occur on the actual microelectrode (platinum) surface during active operation. The permeation layer also ameliorates the adverse effects of electrolysis products (H+, OH−, O2, H2, free radicals, etc.) on the sensitive hybridization and affinity reactions. The permeation layer is impregnated with a coupling agent (streptavidin, chemical agent, etc.) that allows for the subsequent attachment of DNA probes. The permeation layer and its proper manufacture are important to the performance of the device (78–81). The ability to use silicon and microlithography for fabrication of the DNA chips allows a wide variety of devices to be designed and tested. Higherdensity arrays with 400 and 10,000 test-sites have been developed (Figure 1B,C). These higher-density devices have on-chip CMOS control elements that can regulate the currents and voltages to each of the test sites on the array (120). The semiconductor control elements are located in the underlying silicon structure and are not exposed to the aqueous samples that are applied to the chip surface. To facilitate both the rapid electrophoretic transport of DNA molecules and their efficient hybridization, special zwitterionic buffer species with low conductivity properties have been utilized. Histidine has been found to be particularly effective for electronic hybridization (79–81). The 100-test-site microelectronic chip or array device is incorporated into a cartridge package (NanoChipTM cartridge) that provides for the electronic, optical, and fluidic interfacing. A complete instrument system (NanoChipTM Molecular Biology Workstation) provides a chip loader component, fluorescent detection/reader component, and computer control interface and data display screen component. The probe-loading component allows oligonucleotide probes or target molecules (DNA, RNA, PCR amplicons, etc.) to be selectively addressed to the array test-sites, providing the end-user with “make your own chip” capabilities (80, 81). When the electric field is adjusted to the appropriate level, it can be used to affect the selective dehybridization of the hybridized DNA sequences from the attached complementary probe. This novel parameter is called electronic stringency and it provides a powerful and rapid method for single-base mismatch discrimination analysis of point mutations and SNPs (77–81, 121). Electronic hybridization allows most genotyping applications, which can include point mutations, SNPs, and STRs, to be carried out rapidly with high accuracy and reliability. Target DNA can be basically any size, with sequences up to 1000 nucleotides having been genotyped. Gilles and other workers have demonstrated the advantages of electronic stringency for genotyping human mannose binding protein (MBP) SNPs (121). In this work, the electronic

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array-based genotyping results for 22 blinded MBP quadra-allelic samples, and 13 blinded D allele samples were in 100% agreement with conventional DNA sequencing results. In another type of assay called base stacking, the captured target DNA is first hybridized with a stabilized or helper probe and then with a set of fluorescent reporter probes (122). STRs represent another important class of polymorphisms with applications in forensics, human identification, and diagnostics. The typical STR loci are selected groups of four nucleotide repeats that are represented in the human population by 4 to 15 alleles (123, 124). Unlike SNPs, STRs are more difficult to analyze by hybridization techniques and are generally not done by hybridization technologies that rely on passive techniques (125, 126). However, electronic hybridization techniques have been proven to overcome these problems and allow STR analysis to be reliably performed on microelectronic arrays (122). In addition to SNP and STR genotyping applications already described, other applications include gene expression analysis, on-chip or in-situ DNA amplification (127–129), immunoassays and protein-protein interactions (130, 131), sample-to-answer systems, electronic cell separations, viral and bacterial identification, biowarfare/bioterrorism agent detection devices (132–134), use of electric fields for particle manipulations, semiconductor device pick, and place and for potential micro/nanofabrication applications (77, 135–137).

New Microarray Technologies, Chemistries, and Detection Methods A variety of additional technologies are being developed for making microarrays and techniques for improving their performance. Considerable efforts are being carried out related to better methods for preparing oligonucleotides and other types of DNA probes (also discussed in the section on high density microarrays), and new procedures are being created for their attachment or immobilization onto support materials. There are also new advancements relating to the detection of hybridization reactions that occur on the surface of the arrays. LeProust and coworkers have reported a new digitally light-directed synthesis method that permits microarray platforms to be designed that can carry out rapid reaction optimization on a combinatorial basis (138). Galbraith and coworkers have described techniques for printing DNA microarrays using the Biomek 2000 laboratory automation workstation (139), Stillman & Tonkinson have described new “FAST” slides that provide novel surface characteristics for preparing microarrays (140), and Thompson and coworkers have described techniques that allow researchers to build their own microarrayer from readily available materials and components (141). With regard to methods for deposition of DNA and oligonucleotides, Hicks and coworkers describe methods for the modification of an automated liquid-handling system for reagent-jet nanoliter-level dispensing (142), Okamoto and coworkers describe methods for the fabrication microarrays with covalent attachment of DNA using bubble jet technology (143), and Hughes and coworkers describe methods for carrying out expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer (144). Regarding quality control issues, Diehl and coworkers

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discuss methods for manufacturing DNA microarrays with high spot homogeneity and reduced background signal (145). With regard to hybridization techniques on microarrays, Mir & Southern provide guidance on how to determine the influence of DNA structure on hybridization using oligonucleotide arrays (146). Maldonado-Rodriguez & Beattie have described new methods for the analysis of nucleic acids using a tandem hybridization technique on oligonucleotide microarrays (147). In other work on hybridization methodology, Belosludtsev and coworkers describe how near-instantaneous cation-independent nucleic acid hybridization can be carried out on DNA microarrays (148). Additionally, considerable effort has gone into methods and techniques related to immobilization and attachment of probes and oligonucleotides onto various support or substrate materials. Zammatteo and coworkers have carried out comparison studies between different strategies for the covalent attachment of DNA to glass surfaces in order to improve DNA microarray performance (149), and Lindroos and coworkers have carried out comparison studies of immobilization chemistries for minisequencing applications on oligonucleotide microarrays (150). Work on polyacrylamide gel-immobilized microarrays for nucleic acids and proteins analysis has been carried out by Zlatanova & Mirzabekov (151). Belosludtsev and coworkers have developed DNA microarrays based on noncovalent oligonucleotide attachment for hybridization in two dimensions (152). Procedures for the fabrication of DNA microarrays using unmodified oligonucleotide probes have been developed by Call and coworkers (153). Special techniques for the characterization of oligodeoxyribonucleotide synthesis on glass plates have been developed by LeProust and coworkers (154). Zhang and coworkers have developed reproducible and inexpensive procedures for the preparation of oligonucleotide probe arrays (155). Vernon and coworkers have demonstrated reproducibility for alternative probe synthesis approaches for gene expression profiling with arrays (156), and Kane and coworkers have developed assessment techniques for determining the sensitivity and specificity of 50-mer oligonucleotide probes on microarrays (157). Detection is another important area in which improvements are being made and new technologies are being developed. Because it is so widely used for microarray analysis, considerable efforts are always being carried out on fluorescent detection. Dixon & Damaskinos have reported on improvements in confocal scanning devices for microarrays (158). New high-resolution near-infrared imaging techniques for DNA microarrays with time-resolved acquisition of fluorescence lifetimes have been reported by Waddell and coworkers (159). Marti and coworkers have reported on new developments in quantitative fluorescence calibration for analyzing cells and microarrays (160). Battaglia and coworkers have developed techniques for using SYBR green for nondestructive fluorescent staining on microarrays (161). This technique may prove useful as it eliminates the need for using labeled probes, which adds expense to the overall cost of hybridization assays. The use of surface plasmon resonance imaging for DNA and RNA hybridization adsorption on DNA microarrays has been carried out by Nelson and coworkers (162). This technique may allow the microarray detection system to be reduced in overall size. van De Rijke and coworkers have developed methods for using up-converting phosphor

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reporters for nucleic acid microarray analysis (163). This technology has the potential to provide more detection sensitivity. Another novel detection technique that may improve sensitivity by utilizing dendrimer technology has been described by Stears and coworkers (164). Numerous advancements in detection technology have also been made using nonfluorescent techniques. Whitney and coworkers describe using radioactive 33-P probes to carry out hybridization to glass cDNA microarrays for DNA samples from neural tissue (165). The detection of mitochondrial single nucleotide polymorphisms (SNPs) using a primer elongation reaction on oligonucleotide microarrays has been reported by Erdogan and coworkers (166). In the area of direct hybridization sensing, Umek and coworkers report on using electronic detection of nucleic acids for molecular diagnostics (167). In the area of mass-spectrometry-based detection, Stomakhin and coworkers report on DNA sequence analysis by hybridization using MALDI mass spectrometry identification of 5-mers contiguously stacked to microchip oligonucleotides (168).

MICROARRAY INFORMATICS AND APPLICATIONS In general, DNA microarray hybridization applications are usually directed at gene expression analysis or for point mutation/SNP analysis. In addition to these important molecular biological and genomic research applications, microarray systems are also used for pharmacogenomic research, for infectious and genetic disease and cancer diagnostics, and for forensic and genetic identification purposes. Additionally, microarray technologies are now used for many proteomic and cellbased applications. These devices and systems that carry out various multiplex analyses in highly parallel formats produce enormous amounts of data. This is particularly true in the case of the high-density microarrays. Thus, considerable efforts have gone into data acquisition and bioinformatic tools that are able to reduce the complex data into useful information. With regard to the issue of managing large amounts of information, Rao & Bond have provided an appropriate review titled Microarrays: Managing the Data Deluge (169). Troyanskaya provides information on missing value estimation methods for DNA microarrays (170), and Baldi & Long discuss a Bayesian framework for the analysis of microarray expression data and for regularized t-test and managing statistical inferences of gene changes (171). Reviews are provided on the analysis of variance in gene expression microarray data (172) and methods for identification of novel small RNAs using comparative genomics on microarrays (173). Ideker and coworkers have discussed testing methods for differentially expressed genes by maximum-likelihood analysis of microarray data (174), and Kerr & Churchill discuss statistical designs for gene expression analysis of microarray data (175). Further discussions on bioinformatic methods for gene expression analysis are provided by Newton and coworkers (176), Lee and coworkers (177), and Scherf and coworkers (178). An enormous number of publications have now appeared on the uses of microarrays for gene expression, point mutations, SNPs, and for pharmacogenomic and

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diagnostic applications. The following is a compilation of microarray publications on some of the broad areas of application: general applications of microarrays for gene expression analysis (179–181); gene expression analysis on high-density microarrays (182, 183); gene expression analysis for cancer (184–191); gene expression analysis for drug discovery, metabolism, and toxicity (192, 193); gene expression analysis for neuroscience applications (194–196); gene expression analysis for microbiological and infectious disease (197–200); use of microarrays for genotyping (201–204); general articles on use of microarrays for cancer (205, 206); infectious disease diagnostics (207–209); use of microarrays for disease diagnostics (210–212); and applications of microarrays for plant biology (213–215). In addition to microarrays for DNA hybridization analysis, considerable efforts are now being directed at the development and use of microarrays for proteomic applications (216–220) and microarrays for the immobilization of cell and tissue samples (221, 222).

SUMMARY The development of DNA microarray, biochip, and lab-on-a-chip technologies continues at a very rapid pace. These new technologies represent a highly interdisciplinary and synergist effort, with contributions from a range of scientific and engineering fields that have previously not worked together as closely. This includes molecular biologists, geneticists, chemists, physicists, mathematicians, microfabrication scientists, computer scientists, and various types of engineers. The miniaturization of this technology has been achieved by using many of the microfabrication processes that have revolutionized the microelectronics and computer industry. Microarray technologies are rapidly advancing with numerous applications in gene expression, genotyping, and pharmacogenomics. The technology is now also making an impact in the area of medical diagnostics, in particular, for cancer, genetic, and infectious disease applications. As the technology continues to advance, it will most certainly lead to the development of a new generation of “point of care” diagnostic devices and systems. Finally, DNA microarray technology is also forming the basis for a new generation of devices for proteomic and cell biology applications. The Annual Review of Biomedical Engineering is online at http://bioeng.annualreviews.org

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Figure 1 (A) An active microelectronic DNA array device with 100 test-sites or microlocations. The test-sites are approximately 80 microns in diameter, with an underlying platinum electrode. A ring of another twenty microelectrodes that can be used as counter electrodes surrounds the test-sites. (B) Wafer containing 400 test-site active microelectronic array devices. These devices contain underlying CMOS control elements for on-chip current and voltage control and regulation. (C ) View of an individual 10,000 test-site active microelectronic array device. These devices contain underlying CMOS control elements for on-chip current and voltage control and regulation.

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