261:"Random" fabrication, in which the sensors are placed at arbitrary positions on the chip, is an alternative to the serial method. The tedious and expensive positioning process is not required, enabling the use of parallelized self-assembly techniques. In this approach, large batches of identical sensors can be produced; sensors from each batch are then combined and assembled into an array. A non-coordinate based encoding scheme must be used to identify each sensor. As the figure shows, such a design was first demonstrated (and later commercialized by Illumina) using functionalized beads placed randomly in the wells of an etched
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309:, monitoring disease progression or monitoring treatment. Performing multiple analyses simultaneously, described as multiplexing, allows a significant reduction in processing time and the amount of patient sample required. Biochip Array Technology is a novel application of a familiar methodology, using sandwich, competitive and antibody-capture
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324:(CCD) camera. The CCD camera is a sensitive and high-resolution sensor able to accurately detect and quantify very low levels of light. The test regions are located using a grid pattern then the chemiluminescence signals are analysed by imaging software to rapidly and simultaneously quantify the individual analytes.
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grid) on the substrate. Various means exist to achieve the placement, but typically robotic micro-pipetting or micro-printing systems are used to place tiny spots of sensor material on the chip surface. Because each sensor is unique, only a few spots can be placed at a time. The low-throughput nature
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at a time. One lithography step is needed per base type; thus, a total of four steps is required per nucleotide level. Although this technique is very powerful in that many sensors can be created simultaneously, it is currently only feasible for creating short DNA strands (15–25 nucleotides).
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are engineered substrates ("miniaturized laboratories") that can host large numbers of simultaneous biochemical reactions. One of the goals of biochip technology is to efficiently screen large numbers of biological analytes, with potential applications ranging from disease diagnosis to detection of
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the sensor molecules to the substrate medium. The fabrication of microarrays is non-trivial and is a major economic and technological hurdle that may ultimately decide the success of future biochip platforms. The primary manufacturing challenge is the process of placing each sensor at a specific
44:
are under investigation for applications in biomedical fields. In a digital microfluidic biochip, a group of (adjacent) cells in the microfluidic array can be configured to work as storage, functional operations, as well as for transporting fluid droplets dynamically.
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As noted above, most microarrays consist of a
Cartesian grid of sensors. This approach is used chiefly to map or "encode" the coordinate of each sensor to its function. Sensors in these arrays typically use a universal signalling technique
120:(PCR) technique, a method for amplifying DNA concentrations. This discovery made possible the detection of extremely small quantities of DNA in samples. Secondly in 1986 Hood and co-workers devised a method to label DNA molecules with
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Reliability and cost factors limit the number of photolithography steps that can be done. Furthermore, light-directed combinatorial synthesis techniques are not currently possible for proteins or other sensing molecules.
61:, invented in 1922 by Hughes. The basic concept of using exchange sites to create permselective membranes was used to develop other ion sensors in subsequent years. For example, a K sensor was produced by incorporating
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The microarray—the dense, two-dimensional grid of biosensors—is the critical component of a biochip platform. Typically, the sensors are deposited on a flat substrate, which may either be passive
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can also be produced using biochips. Randox
Laboratories Ltd. launched Evidence, the first protein Biochip Array Technology analyzer in 2003. In protein Biochip Array Technology, the biochip replaces the
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Alexander, F., Eggert, S., Wiest, J.: Skin-on-a-chip: Transepithelial electrical resistance and extracellular acidification measurements through an automated air-liquid interface, Genes, 2018, 9/2, 114;
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cable. Each bead was uniquely encoded with a fluorescent signature. However, this encoding scheme is limited in the number of unique dye combinations that can be used and successfully differentiated.
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L. M. Smith, J. Z. Sanders, R. J. Kaiser, P. Hughes, C. Dodd, C. R. Connell, C. Heiner, S. B. H. Kent, and L. E. Hood, "Fluorescence detection in automated DNA sequence analysis,"
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Figure 1. Biochips are a platform that require, in addition to microarray technology, transduction and signal processing technologies to output the results of sensing experiments.
313:. The difference from conventional immunoassays is that, the capture ligands are covalently attached to the surface of the biochip in an ordered array rather than in solution.
163:, to signal processing—require a true multidisciplinary approach, making the barrier to entry steep. One of the first commercial biochips was introduced by
555:, J. Cheng and L. J. Kricka, eds., ch. Technology Options and Applications of DNA Microarrays, pp. 185–216, Harwood Academic Publishers, Philadelphia, 2001
167:. Their "GeneChip" products contain thousands of individual DNA sensors for use in sensing defects, or single nucleotide polymorphisms (SNPs), in genes such as
487:, J. S. Schultz and R. F. Taylor, eds., ch. Introduction to Chemical and Biological Sensors, pp. 1–10, Institute of Physics Publishing, Philadelphia, 1996
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A. C. Pease, D. Solas, E. J. Sullivan, M. T. Cronin, C. P. Holmes, and S. P. Fodor, "Light-generated oligonucleotide arrays for rapid DNA sequence analysis,"
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Figure 1 shows the make up of a typical biochip platform. The actual sensing component (or "chip") is just one piece of a complete analysis system.
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In sandwich assays an enzyme-labelled antibody is used; in competitive assays an enzyme-labelled antigen is used. On antibody-antigen binding a
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S. P. Fodor, J. L. Read, M. C. Pirrung, L. Stryer, A. T. Lu, and D. Solas, "Light-directed, spatially addressable parallel chemical analysis,"
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G. MacBeath, A. N. Koehler, and S. L. Schreiber, "Printing small molecules as microarrays and detecting protein-ligand interactions en masse,"
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M. Schena, D. Shalon, R. W. Davis, and P. O. Brown, "Quantitative monitoring of gene expression patterns with a complementary DNA microarray,"
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strands could be used as a basis for DNA sensing. Two additional developments enabled the technology used in modern DNA-based. First, in 1983
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as the reaction platform. The biochip is used to simultaneously analyze a panel of related tests in a single sample, producing a
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F. J. Steemers, J. A. Ferguson, and D. R. Walt, "Screening unlabeled DNA targets with randomly-ordered fiber-optic gene arrays,"
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K. L. Michael, L. C. Taylor, S. L. Schultz, and D. R. Walt, "Randomly ordered addressable high-density optical sensor arrays,"
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fluorescence), thus making coordinates their only identifying feature. These arrays must be made using a serial process (
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100:(working separately) enabled researchers to directly read the genetic codes that provide instructions for
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output. The multiple technologies needed to make a successful biochip—from sensing chemistry, to
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requiring multiple, sequential steps) to ensure that each sensor is placed at the correct position.
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W. S. Hughes, "The potential difference between glass and electrolytes in contact with water,"
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F. Sanger, S. Nicklen, and A. R. Coulson, "DNA sequencing with chainterminating inhibitors,"
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instead of radiolabels, thus enabling hybridization experiments to be observed optically.
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must be done to translate the actual sensing event (DNA binding,
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profile. The patient profile can be used in disease screening,
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A. M. Maxam and W. Gilbert, "A new method for sequencing DNA,"
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research that continues to the present day. The development of
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179:(related to breast cancer). The chips are produced by using
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The development started with early work on the underlying
237:) in which a series of microlithography steps is used to
455:"High-Level Synthesis of Digital Microfluidic Biochips"
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Protein biochip array and other microarray technologies
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of this process results in high manufacturing costs.
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devices that perform or assist signal transduction.
23:Hundreds of gel drops are visible on the biochip.
334:For details about other array technologies, see
147:) into a format understandable by a computer (
76:announced their discovery of the now familiar
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320:reaction produces light. Detection is by a
485:Handbook of Chemical and Biological Sensors
183:techniques traditionally used to fabricate
16:Substrates performing biochemical reactions
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327:Biochips are also used in the field of
331:e.g. in skin-on-a-chip applications.
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501:Lehninger Principles of Biochemistry
503:, Worth Publishers, New York, 2000
483:J. S. Schultz and R. F. Taylor in
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84:molecules and set the stage for
429:Single nucleotide polymorphism
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581:121, pp. 7967–7968, 1999
42:digital microfluidic biochips
633:70, pp. 1242–1248, 1998
607:91, pp. 5022–5026, 1994
529:74, pp. 5463–5467, 1977
499:D. L. Nelson and M. M. Cox,
474:44, pp. 2860–2866, 1922
379:Chemical compound microarray
290:chemical compound microarray
594:251, pp. 767–773, 1991
568:270, pp. 467–470, 1995
104:. This research showed how
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516:74, pp. 560–564, 1977
239:combinatorially synthesize
542:321, pp. 61–67, 1986
225:position (typically on a
171:(a tumor suppressor) and
151:, light intensity, mass,
118:polymerase chain reaction
620:18, pp. 91–94, 2000
108:of complementary single
605:Proc. Natl. Acad. Sci.
527:Proc. Natl. Acad. Sci.
514:Proc. Natl. Acad. Sci.
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203:image of a DNA biochip
191:Microarray fabrication
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92:techniques in 1977 by
65:into a thin membrane.
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322:charge-coupled device
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40:agents. For example,
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649:10.3390/genes9020114
631:Analytical Chemistry
618:Nature Biotechnology
394:Magnetic immunoassay
336:Antibody microarray
286:antibody microarray
282:protein microarrays
276:are not limited to
185:integrated circuits
141:oxidation/reduction
553:Biochip Technology
460:. Duke University.
414:Planar Patch Clamp
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59:glass pH electrode
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677:Molecular biology
579:J. Am. Chem. Soc.
472:J. Am. Chem. Soc.
434:Tissue microarray
370:Technology portal
318:chemiluminescence
218:Surface chemistry
102:protein synthesis
29:molecular biology
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137:Transduction
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78:double helix
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38:bioterrorism
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692:Microarrays
404:Nanosensors
274:Microarrays
263:fiber optic
220:is used to
114:Kary Mullis
63:valinomycin
687:Proteomics
661:Categories
441:References
424:Sequencing
280:analysis;
243:nucleotide
235:Affymetrix
165:Affymetrix
90:sequencing
307:diagnosis
297:plate or
227:Cartesian
68:In 1953,
682:Genomics
342:See also
86:genetics
33:biochips
592:Science
566:Science
303:patient
299:cuvette
149:voltage
94:Gilbert
49:History
540:Nature
201:Sarfus
98:Sanger
70:Watson
55:sensor
458:(PDF)
295:ELISA
177:BRCA2
173:BRCA1
74:Crick
256:i.e.
252:e.g.
210:e.g.
175:and
153:etc.
145:etc.
96:and
72:and
645:doi
278:DNA
199:3D
169:p53
82:DNA
27:In
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492:^
338:.
288:,
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