WO1998010273A1 - Methods and materials for optimization of electronic hybridization reactions - Google Patents

Methods and materials for optimization of electronic hybridization reactions Download PDF

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Publication number
WO1998010273A1
WO1998010273A1 PCT/US1997/014489 US9714489W WO9810273A1 WO 1998010273 A1 WO1998010273 A1 WO 1998010273A1 US 9714489 W US9714489 W US 9714489W WO 9810273 A1 WO9810273 A1 WO 9810273A1
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WO
WIPO (PCT)
Prior art keywords
buffer
hybridization
nucleic acids
target nucleic
factor
Prior art date
Application number
PCT/US1997/014489
Other languages
English (en)
French (fr)
Other versions
WO1998010273A9 (en
Inventor
Ronald George Sosnowski
William Frank Butler
Eugene Tu
Michael Irving Nerenberg
Michael James Heller
Original Assignee
Nanogen, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nanogen, Inc. filed Critical Nanogen, Inc.
Priority to EP97938378A priority Critical patent/EP1019711A4/en
Priority to JP51267698A priority patent/JP4213216B2/ja
Priority to BR9712800-7A priority patent/BR9712800A/pt
Priority to NZ334314A priority patent/NZ334314A/xx
Priority to CA002264780A priority patent/CA2264780C/en
Priority to AU40719/97A priority patent/AU723564B2/en
Publication of WO1998010273A1 publication Critical patent/WO1998010273A1/en
Publication of WO1998010273A9 publication Critical patent/WO1998010273A9/en

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Classifications

    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L29/00—Semiconductor devices specially adapted for rectifying, amplifying, oscillating or switching and having potential barriers; Capacitors or resistors having potential barriers, e.g. a PN-junction depletion layer or carrier concentration layer; Details of semiconductor bodies or of electrodes thereof ; Multistep manufacturing processes therefor
    • H01L29/66—Types of semiconductor device ; Multistep manufacturing processes therefor
    • H01L29/66007—Multistep manufacturing processes
    • H01L29/66075—Multistep manufacturing processes of devices having semiconductor bodies comprising group 14 or group 13/15 materials
    • H01L29/66227—Multistep manufacturing processes of devices having semiconductor bodies comprising group 14 or group 13/15 materials the devices being controllable only by the electric current supplied or the electric potential applied, to an electrode which does not carry the current to be rectified, amplified or switched, e.g. three-terminal devices
    • H01L29/66409—Unipolar field-effect transistors
    • H01L29/66477—Unipolar field-effect transistors with an insulated gate, i.e. MISFET
    • H01L29/6656—Unipolar field-effect transistors with an insulated gate, i.e. MISFET using multiple spacer layers, e.g. multiple sidewall spacers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6832—Enhancement of hybridisation reaction

Definitions

  • This invention relates to buffers and electrolytes for use in electronic devices adapted for medical diagnostic, biological and other uses. More particularly, it relates to buffers and electrolytes for advantageous use with DNA hybridization analysis carried out on microelectronic medical diagnostic devices.
  • APEX systems are able to perform a wide variety of functions which are advantageously used in molecular biology reactions, such as nucleic acid hybridizations, antibody/antigen reactions, clinical diagnostics, and biopolymer synthesis.
  • APEX-type devices utilize buffers and electrolytes for their operation.
  • a buffer has been defined as a chemical solution which is resistant to change in pH on the addition of acid or alkali. See., e.g., Dictionary of Biotechnology, Second Edition, James Coombs, Stockton Press. As stated there, "traditionally, buffers based on inorganic salts (phosphate, carbonate) and organic acid salts (acetate, citrate, succinate, glycine, maleate, barbiturates, etc.) were used in biological experiments.” It is the object of this invention to discover buffers and electrolytes which are advantageously used in molecular biology electronic devices which perform hybridizations, reactions, diagnostics or synthesis.
  • the following inventions relate to our discoveries concerning the various parameters, electrolytes (buffers) , and other conditions which improve or optimize the speed of DNA transport, the efficiency of DNA hybridization reactions, and the overall hybridization specificity in our APEX microelectronic chips and devices.
  • this invention relates to the discovery that low conductance zwitterionic buffer solutions, especially those containing the amino acid Histidine prepared at concentrations of 10-100 mM, preferably about 50 mM, and at or near the pi (isoelectric point -pH 7.47), provide optimal conditions for both rapid DNA transport and efficient hybridization reactions.
  • Hybridization efficiencies of at least a factor of 10 relative to the next best known buffer, Cysteine are achieved.
  • Test data demonstrate an approximately 50,000 fold increase in hybridization efficiency compared to Cysteine.
  • Fig. 1 is a plan view of a checkerboard arrangement utilizing a histidine buffer.
  • Genosensor impedance sensors
  • Optical and Electrical Methods and Apparatus for Molecular Detection 093/22678
  • dielectrophoresis devices see, e.g., Washizu 25 Journal of Electrostatics, 109-123, 1990
  • AC electric fields An important distinction related to these devices is that when these AC fields are applied, there is essentially no net current flow in any of these systems, i.e, there is no electrophoretic propulsion for transport of the charged molecules.
  • APEX type devices produce significant net direct current (DC) flow when a voltage is applied, which is recognized as "the signature of electrophoresis” .
  • electrophore- sis the migration of ions or charged particles is produced by electrical forces along the direction of the electric field gradient, and the relationship of current and voltage are important to this technology.
  • I is the electric current [A] .
  • the resistance of the solution is the reciprocal of the conductance which can be measured by a conductomete .
  • the conductance depends mainly on the ionic species of the buffer/electrolytes and their concentration; therefore these parameters are very important for electric field related molecular biology technology.
  • the basic current/voltage relationships are essentially the same for the APEX technology as for any other electrophoretic system, although the electric fields produced are in truly microscopic environments.
  • There are unique features of the APEX system regarding the various ways of sourcing the current and voltage, and how the current and voltage scenarios have been found to improve the performance of such systems . In particular, various DC pulsing procedures (linear and logarithmic gradients) appear to provide improved hybridization stringency.
  • the ionic strength and conductance are equivalent, i.e., the conductance will usually be proportional to the ionic strength.
  • buffering electrolytes phospr e, acetate, citrate, succinate, etc.
  • the ionic strength and conductance will usually be equivalent, i.e., conductance is proportional to the ionic strength.
  • an amino acid in its zwitterionic state ( " OOC-CH(R) -NH 3 *) will have a conductance value which will be approximately 1000 fold lower than when the " amino acid moiety" has a full net positive charge (HOOC-CH(R) -NH 2 * ⁇ > x" ) or a full negative charge (Y + ⁇ > " OOC-CH (R) -NH 2 ) .
  • a formal negative or positive charge develops on the amino acid moiety as it moves away from its pi, and the conductivity and ionic strength will begin to correlate.
  • the conductance will be much lower than is expected for that given ionic strength or concentration.
  • electrophoresis texts refer to the Good Buffers and amino acid buffers as having "low conductances at high ionic strength or concentration" (see page 88 of Capillary Electrophoresis: Principles and Practice", R. Kuhn and S. Hoffstetter, Springer - Verlag, 1993) .
  • a commonly used electrophoresis buffer “Tris-Borate” actually has a significantly lower conductivity than would be expected from its ionic strength or concentration. This may be due to the "tris cation” and “borate anion” forming a relatively stable zwitterionic complex in solution.
  • the conductivity of a 100 mM Tris-Borate solution was determined to be 694 ⁇ S/cm, which is approximately 20 times lower than would be expected from its ionic strength, and is roughly equiva- lent to a 5 mM sodium phosphate or sodium chloride solution.
  • Table 1 shows conductivity measurements of a number of transport buffers.
  • Amino acid buffers do have buffer properties at their pi's. While a given amino acid may or may not have its "highest buffering capacity" at its pi, it will have some degree of buffering capacity. Buffer capacity decreases by a factor of 10 for every pH unit difference between the pi and the pKa; those amino acids with three ionizable groups (histidine, cysteine, lysine, glutamic acid, aspartic acid, etc.) generally have higher buffering capacities at their pi's than those amino acids with only two dissociations (glycine, alanine, leucine, etc.).
  • Histidine has been proposed as a buffer for use in gel electrophoresis, see, e.g., U.S. Patent 4,936,963, but hybridization is not performed in such systems. Cysteine is in a more intermediate position, with regard to buffering capacity.
  • the pi of cysteine is 5.02, the pKa for the carboxyl group is 1.71, the pKa for the sulfhydryl is 8.33, and the pKa for amino group is 10.78.
  • An acid /base titration curve of 250 mM cysteine shows that cysteine has a better "buffering capacity" at ⁇ pH 5 than a 20 mM sodium phosphate. In the pH 4 to 6 range, the buffering capacity of cysteine is significantly better than 20 mM sodium phosphate, particularly at the higher pH.
  • Fig. 1 shows a plan view of an APEX chip using histidine.
  • the instant invention relates to our discoveries concerning the various parameters, electrolytes (buffers) , and other, conditions which improve or optimize the speed of DNA transport, the efficiency of DNA hybridization reactions, and the overall hybridization specificity in electric field molecular biology devices, especially APEX microelectronic chips and devices.
  • this invention relates to our discovery that low conductance zwitterionic buffer solutions containing the amino acid Histidine prepared at concentrations of 10-100 mM, especially about 50 mM, at or near the pi (isoelectric point -7.47), provide optimal conditions for both rapid electrophoretic DNA transport and efficient hybridization reactions. This advantage of the Histidine buffer is particularly important for the APEX chip type devices .
  • Table 2 shows the effect of various zwitterionic amino acid buffers [j ⁇ -Alanine, Taurine, Cysteine, Histidine, Lysine, and Sodium Phosphate (not a zwitterionic buffer) ] on the hybridizability of the transported target DNA to the specific capture DNA at the test site.
  • transport the conductivity generally correlates with transport under the same field conditions.
  • 3-Alanine, Taurine and Cysteine show excellent transport
  • Histidine shows good transport
  • Lysine and NaP0 4 show fair transport.
  • the DNA hybridization sensitivity is reported for "normal DNA" which has negatively charged polyanionic phosphate backbone.
  • Table 2 also reports the sensitivity for the streptavidin/biotin DNA probe capture affinity.
  • Table 2 clearly shows the correlation of DNA transport (accumulation) with low conductivity (j ⁇ -Alanine, Taurine, Cysteine, Histidine) .
  • the table shows good
  • Histidine is the only one which provides both good transport and good DNA/DNA hybridization efficiency. It is believed that the low conductivity of the Histidine buffer system accounts for the rapid DNA transport (accumulation) . There are several possible explanations as to why the Histidine buffer produces relatively efficient DNA/DNA hybridization.
  • One advantage may be the good buffering capacity of Histidine. With its pi at 7.47, Histidine will buffer well under both acidic or basic conditions (see A.L. Lehninger, Biochemistry, 2ed, Worth Publishers, New York, 1975, Fig. 4-9 on page 80) .
  • the APEX chip produces acid at the positive electrode where the DNA is accumulated for hybridization, and Histidine may effectively buffer these conditions.
  • DNA/DNA/Histidine may also form some type of stabilizing adduct from other electrochemical products being produced at the positive electrode (hydrogen peroxide, etc.) While the instant embodiment utilizes naturally occurring Histidine, this invention is fully applicable to other natural or synthetic compounds which have good buffering capacity, low conductivity (or zwitterionic characteristics) and have properties which allow DNA hybridization to be stabilized by charge stabilization or adduct formation.

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • General Physics & Mathematics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Power Engineering (AREA)
  • Microelectronics & Electronic Packaging (AREA)
  • Biophysics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Ceramic Engineering (AREA)
  • Manufacturing & Machinery (AREA)
  • Computer Hardware Design (AREA)
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  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
PCT/US1997/014489 1996-09-06 1997-08-18 Methods and materials for optimization of electronic hybridization reactions WO1998010273A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP97938378A EP1019711A4 (en) 1996-09-06 1997-08-18 METHODS AND MATERIALS FOR OPTIMIZING ELECTRONIC HYBRIDIZATION REACTIONS
JP51267698A JP4213216B2 (ja) 1996-09-06 1997-08-18 エレクトロニック・ハイブリダイゼーション反応の最適化のための方法および物質
BR9712800-7A BR9712800A (pt) 1996-09-06 1997-08-18 Processos e materias para otimização de reações de hibridização eletrônica
NZ334314A NZ334314A (en) 1996-09-06 1997-08-18 Methods and materials for optimization of electronic hybridization reactions
CA002264780A CA2264780C (en) 1996-09-06 1997-08-18 Methods and materials for optimization of electronic hybridization reactions
AU40719/97A AU723564B2 (en) 1996-09-06 1997-08-18 Methods and materials for optimization of electronic hybridization reactions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US70826296A 1996-09-06 1996-09-06
US08/708,262 1996-09-06

Publications (2)

Publication Number Publication Date
WO1998010273A1 true WO1998010273A1 (en) 1998-03-12
WO1998010273A9 WO1998010273A9 (en) 1998-07-23

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PCT/US1997/014489 WO1998010273A1 (en) 1996-09-06 1997-08-18 Methods and materials for optimization of electronic hybridization reactions

Country Status (9)

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EP (1) EP1019711A4 (ja)
JP (1) JP4213216B2 (ja)
KR (1) KR100591626B1 (ja)
CN (1) CN1180248C (ja)
AU (1) AU723564B2 (ja)
BR (1) BR9712800A (ja)
CA (1) CA2264780C (ja)
NZ (1) NZ334314A (ja)
WO (1) WO1998010273A1 (ja)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5964995A (en) * 1997-04-04 1999-10-12 Caliper Technologies Corp. Methods and systems for enhanced fluid transport
EP1036085A1 (en) * 1997-12-05 2000-09-20 Nanogen, Inc. Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics
US6238909B1 (en) * 1999-05-04 2001-05-29 Motorola, Inc. Method and apparatus for obtaining electric field-enhanced bioconjugation
US6468742B2 (en) 1993-11-01 2002-10-22 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip
US6492122B2 (en) 2000-11-09 2002-12-10 Nanogen, Inc. Quantitative analysis methods on active electronic microarrays
AU783169B2 (en) * 1999-09-27 2005-09-29 Monsanto Technology Llc Methods for determining oils in seeds
EP1643248A1 (en) * 2003-06-13 2006-04-05 Riken Substrate for biomolecule microarray, biomolecule microarray, device and method for interaction acceleration, and interaction detecting method
US7153687B2 (en) 2002-08-13 2006-12-26 Hong Kong Dna Chips Limited Apparatus and methods for detecting DNA in biological samples
EP1794181A2 (en) * 2004-09-23 2007-06-13 Nanogen, Inc. Methods and materials for optimization of electronic transportation and hybridization reactions
EP1842922A1 (en) * 2006-04-07 2007-10-10 Samsung Electronics Co., Ltd. Method of increasing specificity of nucleic acid hybridization using zwitterionic compound
US7309581B2 (en) * 2000-11-01 2007-12-18 Sysmex Corporation Method of staining, detection and counting bacteria, and a diluent for bacterial stain
US9127308B2 (en) 2002-03-07 2015-09-08 Atlas Genetics Limited Nucleic acid probes, their synthesis and use

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4936963A (en) * 1987-05-27 1990-06-26 Abbott Laboratories Polycationic buffers and method for gel electrophoresis of nucleic acids
US5436129A (en) * 1989-11-17 1995-07-25 Gene Tec Corp. Process for specimen handling for analysis of nucleic acids
US5593838A (en) * 1994-11-10 1997-01-14 David Sarnoff Research Center, Inc. Partitioned microelectronic device array

Family Cites Families (2)

* Cited by examiner, † Cited by third party
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US6017696A (en) * 1993-11-01 2000-01-25 Nanogen, Inc. Methods for electronic stringency control for molecular biological analysis and diagnostics
DE69533554T2 (de) * 1994-11-10 2005-01-27 Orchid Biosciences, Inc. Flüssigkeitsverteilungssystem

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4936963A (en) * 1987-05-27 1990-06-26 Abbott Laboratories Polycationic buffers and method for gel electrophoresis of nucleic acids
US5436129A (en) * 1989-11-17 1995-07-25 Gene Tec Corp. Process for specimen handling for analysis of nucleic acids
US5593838A (en) * 1994-11-10 1997-01-14 David Sarnoff Research Center, Inc. Partitioned microelectronic device array

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1019711A4 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6468742B2 (en) 1993-11-01 2002-10-22 Nanogen, Inc. Methods for determination of single nucleic acid polymorphisms using bioelectronic microchip
US6129826A (en) * 1997-04-04 2000-10-10 Caliper Technologies Corp. Methods and systems for enhanced fluid transport
US6471841B1 (en) 1997-04-04 2002-10-29 Caliper Technologies Corp. Methods and systems for enhanced fluid transport
US5964995A (en) * 1997-04-04 1999-10-12 Caliper Technologies Corp. Methods and systems for enhanced fluid transport
EP1036085A4 (en) * 1997-12-05 2004-11-17 Nanogen Inc SELF-ADDRESSING AND COMPOSITIONING INTEGRATED MICROELECTRONIC SYSTEMS, COMPONENT DEVICES, MECHANISMS, METHODS AND METHODS FOR MOLECULAR BIOLOGICAL ANALYSIS AND DETERMINATIONS
EP1036085A1 (en) * 1997-12-05 2000-09-20 Nanogen, Inc. Self-addressable self-assembling microelectronic integrated systems, component devices, mechanisms, methods, and procedures for molecular biological analysis and diagnostics
US6238909B1 (en) * 1999-05-04 2001-05-29 Motorola, Inc. Method and apparatus for obtaining electric field-enhanced bioconjugation
AU783169B2 (en) * 1999-09-27 2005-09-29 Monsanto Technology Llc Methods for determining oils in seeds
US7309581B2 (en) * 2000-11-01 2007-12-18 Sysmex Corporation Method of staining, detection and counting bacteria, and a diluent for bacterial stain
EP1341932A2 (en) * 2000-11-09 2003-09-10 Nanogen, Inc. Improved methods for gene expression monitoring on electronic microarrays
EP1341932A4 (en) * 2000-11-09 2005-11-23 Nanogen Inc IMPROVED METHODS OF MONITORING GENE EXPRESSION ON ELECTRONIC MICROARRAYS
US6492122B2 (en) 2000-11-09 2002-12-10 Nanogen, Inc. Quantitative analysis methods on active electronic microarrays
US10094800B2 (en) 2002-03-07 2018-10-09 Atlas Genetics Limited Assays and apparatus for detecting electrochemical active markers in an electric field
US9127308B2 (en) 2002-03-07 2015-09-08 Atlas Genetics Limited Nucleic acid probes, their synthesis and use
US7153687B2 (en) 2002-08-13 2006-12-26 Hong Kong Dna Chips Limited Apparatus and methods for detecting DNA in biological samples
US7749705B2 (en) 2002-08-13 2010-07-06 Hai Kang Life Corporation Limited Apparatus and methods for detecting DNA in biological samples
US8110669B2 (en) 2002-08-13 2012-02-07 Hai Kang Life Corporation Limited Apparatus and methods for detecting DNA in biological samples
US8198070B2 (en) 2002-08-13 2012-06-12 Hai Kang Life Corporation Limited Apparatus and methods for detecting DNA in biological samples
EP1643248A4 (en) * 2003-06-13 2008-05-14 Riken SUBSTRATE FOR BIOMOLECULE MICROARRAY, BIOMOLECULE MICROARRAY, DEVICE AND METHOD FOR ACCELERATING INTERACTIONS, AND METHOD FOR DETECTING INTERACTIONS
US7541195B2 (en) 2003-06-13 2009-06-02 Riken Substrate for biomolecule microarray, biomolecule microarray, device and method of promoting interaction, and method of detecting interaction
EP1643248A1 (en) * 2003-06-13 2006-04-05 Riken Substrate for biomolecule microarray, biomolecule microarray, device and method for interaction acceleration, and interaction detecting method
EP1794181A4 (en) * 2004-09-23 2009-02-25 Nanogen Inc METHODS AND MATERIALS FOR OPTIMIZING ELECTRONIC TRANSPORT AND HYBRIDIZATION REACTIONS
EP1794181A2 (en) * 2004-09-23 2007-06-13 Nanogen, Inc. Methods and materials for optimization of electronic transportation and hybridization reactions
EP1842922A1 (en) * 2006-04-07 2007-10-10 Samsung Electronics Co., Ltd. Method of increasing specificity of nucleic acid hybridization using zwitterionic compound
CN101886131B (zh) * 2006-04-07 2013-03-20 三星电子株式会社 用两性离子化合物提高核酸杂交特异性的方法

Also Published As

Publication number Publication date
CA2264780A1 (en) 1998-03-12
EP1019711A1 (en) 2000-07-19
CN1230255A (zh) 1999-09-29
EP1019711A4 (en) 2001-06-13
BR9712800A (pt) 1999-11-23
JP4213216B2 (ja) 2009-01-21
KR20010029477A (ko) 2001-04-06
CN1180248C (zh) 2004-12-15
KR100591626B1 (ko) 2006-06-20
CA2264780C (en) 2006-08-01
NZ334314A (en) 2000-09-29
AU723564B2 (en) 2000-08-31
AU4071997A (en) 1998-03-26
JP2001501301A (ja) 2001-01-30

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