WO2001050131A1 - Reseau tridimensionnel servant a detecter des biomolecules - Google Patents

Reseau tridimensionnel servant a detecter des biomolecules Download PDF

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Publication number
WO2001050131A1
WO2001050131A1 PCT/US2001/000421 US0100421W WO0150131A1 WO 2001050131 A1 WO2001050131 A1 WO 2001050131A1 US 0100421 W US0100421 W US 0100421W WO 0150131 A1 WO0150131 A1 WO 0150131A1
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WO
WIPO (PCT)
Prior art keywords
impedance
voltammetry
pores
porous substrate
probes
Prior art date
Application number
PCT/US2001/000421
Other languages
English (en)
Inventor
Changming Li
Song Shi
George Maracas
Vi-En Choong
Original Assignee
Motorola, 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 Motorola, Inc. filed Critical Motorola, Inc.
Priority to AU27670/01A priority Critical patent/AU2767001A/en
Publication of WO2001050131A1 publication Critical patent/WO2001050131A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
    • G01N33/5438—Electrodes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • 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
    • C12Q1/6834—Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837—Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277—Apparatus
    • B01J2219/00497—Features relating to the solid phase supports
    • B01J2219/00527—Sheets
    • B01J2219/00529—DNA chips
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00639—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium
    • B01J2219/00641—Making arrays on substantially continuous surfaces the compounds being trapped in or bound to a porous medium the porous medium being continuous, e.g. porous oxide substrates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583—Features relative to the processes being carried out
    • B01J2219/00603—Making arrays on substantially continuous surfaces
    • B01J2219/00659—Two-dimensional arrays
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718—Type of compounds synthesised
    • B01J2219/0072—Organic compounds
    • B01J2219/00722—Nucleotides
    • C—CHEMISTRY; METALLURGY
    • C40—COMBINATORIAL TECHNOLOGY
    • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
    • C40B40/00—Libraries per se, e.g. arrays, mixtures
    • C40B40/04—Libraries containing only organic compounds
    • C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof

Definitions

  • This invention relates to an apparatus for detecting molecular interactions.
  • the invention relates to biochip arrays manufactured in part from porous media. More particularly, the invention relates to a biochip array that is fabricated from a porous substrate with metal, metal oxides, metal nitrides, or metal carbides deposited on a porous surface thereof, and even more particularly to a polymeric porous hydrogel substrate deposited on the porous surface with a layer of an electrically-conductive material.
  • Microfabricated arrays (biochips) of oligonucleotides, nucleic acids, or peptides have utility in a wide variety of applications, including DNA and RNA sequence analysis, diagnostics of genetic diseases, gene polymorphism studies, analysis of gene expression, and studies of receptor-ligand interactions.
  • biochip fabrication large numbers of probe molecules are bound to small, defined regions of a substrate.
  • Glass slides, silicon wafers, or polymeric hydrogels may be used as a biochip substrate, with a two-dimensional or three-dimensional substrate surface utilized for probe attachment.
  • three-dimensional immobilization substrates offer an advantage of increased sensitivity.
  • porous hydrogel media While the inherent three-dimensional structure of porous hydrogel media can be advantageous for loading probe molecules such as oligonucleotides, it also poses additional challenges for immobilization chemistry.
  • the use of porous hydrogel media in the fabrication of bioarrays, for example, is restricted by complicated probe attachment chemistries, which often result in inconsistent probe attachment yield, thus increasing the cost of quality control.
  • polymeric hydrogels are not electronically conductive, arrays made with such hydrogels are not suitable for electrical or electrochemical detection of molecular interactions, particularly bioarrays as defined herein.
  • the invention provides an apparatus for detecting molecular interactions.
  • the invention provides a biochip array manufactured in part from porous media. More particularly, the invention provides a biochip array that is fabricated from a porous substrate with a conductive material, e.g., metal or metal oxides, deposited (in some embodiments, plated) on a porous surface thereof.
  • the invention provides a polymeric, porous hydrogel substrate with a conductive material deposited on the porous surface of the hydrogel.
  • the conductive substance is a metal, metal oxide, metal nitride, or metal carbide.
  • the invention provides a three-dimensional media compatible with electrical and/or electrochemical detection techniques including impedance, AC impedance, impedance spectroscopy, cyclic voltammetry, alternating cyclic voltammetry, stripping voltammetry, pulse voltammetry, square wave voltammetry, AC voltammetry, hydrodynamic modulation voltammetry, conductance, potential step method, potentiometric measurements, amperometric measurements, current step method, and combinations thereof, for detecting interactions between molecules, particularly biomolecules.
  • electrical and/or electrochemical detection techniques including impedance, AC impedance, impedance spectroscopy, cyclic voltammetry, alternating cyclic voltammetry, stripping voltammetry, pulse voltammetry, square wave voltammetry, AC voltammetry, hydrodynamic modulation voltammetry, conductance, potential step method, potentiometric measurements, amperometric measurements, current step method, and combinations thereof, for detecting interactions between molecules, particularly biomolecules.
  • the apparatus of the present invention can be used to detect molecular interactions between probes immobilized on the porous surface of the porous substrate and target molecules in a sample reaction mixture.
  • Preferred probe molecules include but are not limited to oligonucleotides, nucleic acids, or peptides.
  • the apparatus of the present invention offers several advantages.
  • One advantage is that the metallic surface of the deposited polymeric hydrogel array permits probe molecules to be attached to the substrate using a simpler reaction chemistry than that required for the attachment of probe molecules to the porous hydrogel media itself.
  • oligonucleotide probe molecules modified by having a thiol group can be attached to a gold-plated polymeric hydrogel array using self-assembly techniques known to those with skill in the art.
  • the metallic surface of conductive porous substrates of the present invention permits electrical and/or electrochemical detection methods such as impedance, AC impedance, impedance spectroscopy, cyclic voltammetry, alternating cyclic voltammetry, stripping voltammetry, pulse voltammetry, square wave voltammetry, AC voltammetry, hydrodynamic modulation voltammetry, conductance, potential step method, potentiometric measurements, amperometric measurements, current step method, and combinations thereof, to be used for assaying molecular interactions between immobilized probe molecules and biomolecules in a reaction mixture.
  • electrical and/or electrochemical detection methods such as impedance, AC impedance, impedance spectroscopy, cyclic voltammetry, alternating cyclic voltammetry, stripping voltammetry, pulse voltammetry, square wave voltammetry, AC voltammetry, hydrodynamic modulation voltammetry, conductance, potential step method, potentiometric measurements, amperometric measurements, current step
  • the pore size of the porous media can be controlled by varying process conditions such as temperature, monomer and/or crosslinker concentration, concentration of the plating solution and time of conductive material deposition. This is desirable for optimizing diffusion kinetics for biomolecules having different sizes or conformations.
  • the hydrogel substrate of the present invention which is fabricated in part from a three-dimensional substrate, does not require the complex manufacturing steps that are necessary for producing three-dimensional structures from other types of substrate materials.
  • Figure 1 illustrates a scanning electron micrograph (0-300 nm scale) of a hydrogel array following 40 minutes of electroless gold plating.
  • the apparatus of the present invention is comprised of a solid substrate, a porous media placed on one (preferably, the top) surface of the solid substrate, and a layer of conductive material deposited on a porous surface of the porous media.
  • biological probe molecules are immobilized on the conductive surface of the porous media.
  • Complimentary targets may or may not additionally comprise an optical tag or radiolabel.
  • the apparatus further comprises a means for detection of probe-target interactions wherein the target molecule carries an optical tag or radiolabel.
  • a plurality of probe molecules are attached to the porous media to provide a bioarray.
  • bioarray refers to an ordered spatial arrangement of immobilized biomolecules or polymeric anchoring structures on a solid supporting substrate.
  • Preferred probe molecules include nucleic acids, oligonucleotides, peptides, ligands, antibodies and antigens; oligonucleotides are the most preferred probe species.
  • the solid substrate in the embodiment advantageously can be made of glass, ceramic, plastic, semiconductor wafer such as silicon or gallium-arsenic, or printed circuit board (PCB).
  • semiconductor wafer such as silicon or gallium-arsenic
  • PCB printed circuit board
  • the probes are oligonucleotide probes having a sequence comprising from about 10 to about 100 nucleotide residues, and said probes are attached to the conductive porous surface of the porous media using techniques known to those with skill in the art.
  • the probes are peptides, such as receptors, ligands, antibodies, antigens, or synthetic peptides, and said probes are attached to the conductive porous surface of the porous media using techniques known to those with skill in the art.
  • the probes are covalently attached to the surface of the pores of the porous substrate.
  • the method of the present invention is used to detect single base mismatches within nucleic acid probe-target complexes. In other embodiments, the method of the present invention is used to quantify target molecules in a reaction mixture for gene expression analyses.
  • the conductive layer in the apparatus in accordance with the present invention may be most advantageously fabricated using electroplating, electroless plating, thermal deposition, or plasma enhanced chemical vapor deposition (PECVD) techniques.
  • the conductive layer is affixed using an electroless plating technique.
  • the conductive layer is a metal. More preferably, the conductive layer is a porous film of a metal, such as gold, platinum, titanium, or copper, or a metal oxide, a metal nitride, a metal carbide, or carbon (graphite).
  • the porous media of the present invention may be a conductive or nonconductive polymer.
  • Non-limiting examples of the porous media of the invention include polyacrylamide gel, agarose gel, cellular gel, polyethylene glycol, polypyrrole, carbon, carbides, oxides, nitrides, or other suitable materials known to those with skill in the art.
  • the porous media is a polyacrylamide gel (termed a "hydrogel” herein).
  • the porous hydrogel media of the present invention may be produced using sol-gel, aerogel, or other fabrication techniques known to those with skill in the art.
  • the porous media of the present invention may be plated or thermally deposited with conductive materials, including metals such as gold, copper, nickel, aluminum, platinum, and silver, metal oxides such as tin oxide, zinc oxide and indium tin oxide, metal nitrides such as nobium nitride, or metal carbides such as tin carbide.
  • the porous media is plated with gold.
  • the porous media is removed from the metal layer by exposure, for example, in a surfactant solution at 100°C.
  • the metal plating or deposition of conductive material used to fabricate the apparatus of the present invention is preferably biocompatible with the molecular reactions to be performed on the bioarray.
  • the biocompatibility of the plated surface of the porous substrate is enhanced by coating the bioarray with a conformal compound such as parylene.
  • molecular interactions between an immobilized probe and target molecule are detected by contacting a plurality of probes immobilized onto the surface of the pores of a porous substrate, and wherein a thin conductive layer has been placed in contact with the surface of the porous substrate, with an electrolyte solution, detecting an electrical signal in a plurality of pores of the porous substrate, exposing the porous substrate to a reaction mixture containing a target molecule in order to generate probe-target complexes, and detecting an electrical signal in the pores of the porous substrate.
  • target molecules additionally comprise an electrical or electrochemical reporter, optical tag, or radiolabel.
  • the apparatus of the present invention is used for the electrical and/or electrochemical detection of molecular interactions between immobilized probe molecules and biomolecules in a particular reaction mixture.
  • Electrical and/or electrochemical detection methods including, but not limited to, impedance, AC impedance, impedance spectroscopy, cyclic voltammetry, alternating cyclic voltammetry, stripping voltammetry, pulse voltammetry, square wave voltammetry, AC voltammetry, hydrodynamic modulation voltammetry, conductance, potential step method, potentiometric measurements, amperometric measurements, current step method, and combinations thereof, can be used with the apparatus of the present invention.
  • the electrical or electrochemical detection method is AC impedance and the AC impedance is measured over a range of frequencies prior to and after exposing the plurality of probes immobilized onto the surface of the pores of the apparatus of the present invention to a reaction mixture containing a target molecule.
  • AC impedance is measured by transient methods with AC signal perturbation superimposed upon a DC potential applied to an electrochemical cell.
  • AC impedance is measured by impedance analyzer, lock-in amplifier, AC bridge, AC voltammetry, or combinations thereof.
  • Electrochemically-labeled target molecules useful in the methods of the present invention may be prepared by labeling suitable target molecules with any electrochemically-distinctive oxidation/reduction (redox) reporter that does not interfere with the molecular interaction to be detected.
  • redox electrochemically-distinctive oxidation/reduction
  • target molecules are labeled with electrochemical reporter groups comprising a transition metal complex, most preferably containing a transition metal ion that is ruthenium, cobalt, iron, or osmium.
  • target molecules may be labeled with the following non-limiting examples of electrochemically-active moieties:
  • Redox moieties useful against an aqueous saturated calomel reference electrode include: 1 ,4-benzoquinone, ferrocene, tetracyanoquinodimethane, N,N,N',N'- tetramethyl-p-phenylenediamine, or tetrathiafulvalene;
  • Redox moieties useful against an Ag/AgCl reference electrode include: 9- aminoacridine, acridine orange, aclarubicin, daunomycin, doxorubicin, pirarubicin, ethidium bromide, ethidium monoazide, chlortetracycline, tetracycline, minocycline, Hoechst 33258, Hoechst 33342, 7-aminoactinomycin D, Chromomycin A 3 , mithramycin A, Vinblastine, Rifampicin, Os(bipyridine) 2 (dipyridophenazine) 2 + , Co(bipyridine) 3 3+ , or Fe-bleomycin.
  • the electrochemically-active moiety comprising the electrochemically active reporter-labeled target molecule of the method of the present invention is optionally linked to the target molecule through a linker, preferably having a length of from about 10 to about 20 Angstroms.
  • the linker can be an organic moiety such as a hydrocarbon chain (CH 2 ) n , where n is an integer from about 1 to about 20, or can comprise an ether, ester, carboxyamide, or thioether moiety, or a combination thereof.
  • the linker can also be an inorganic moiety such as siloxane (O-Si-O). The length of the linker is selected so that the electrochemically-active moiety does not interfere with the molecular interaction to be detected.
  • Electrochemical contact is advantageously provided using an electrolyte solution in contact with each of the hydrogel porous microelectrodes of the invention.
  • Electrolyte solutions useful in the apparatus and methods of the invention include any electrolyte solution at physiologically-relevant ionic strength (equivalent to about 0.15 M NaCl) and neutral pH.
  • Examples of electrolyte solutions useful with the apparatus and methods of the invention include but are not limited to phosphate buffered saline, HEPES buffered solutions, and sodium bicarbonate buffered solutions.
  • the electrolyte solution comprises metal, non-metal, or polymerized cations that are ion-conductive and capable of reacting with probes or probe-target complexes.
  • Polyacrylamide hydrogel arrays were fabricated on glass slides with dimensions of 3 in. by 1 in.
  • the hydrogel array was photopolymerized on the glass slide using bisacrylamide as cross-linking agent at a final concentration of 5%.
  • the polymerized hydrogel pads had final dimensions of 100 ⁇ m by 100 ⁇ m, a thickness of 25 ⁇ m and a pad to pad distance of 300 ⁇ m.
  • the size of the complete array was 28 test sites by 28 test sites.
  • the hydrogel arrays were hydrated in water for one hour. During hydration, electroless plating solution (Oremerse Mn, obtained from Technic Inc., Cranston, RI), containing 0.25 g/gal.
  • Figure 1 illustrates scanning electron micrographs (0-300nm scale) of a hydrogel array following 40 min. of electroless gold plating. After 40 min. of plating in an electroless plating solution as described above, a porous gold matrix was obtained as illustrated by scanning electron micrograph (0-300nm scale) in Figure 1. Oligonucleotide probes modified with a thiol linker are attached to the porous gold matrix using conventional thiol-gold attachment chemistries well known in the art.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Wood Science & Technology (AREA)
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  • Urology & Nephrology (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cell Biology (AREA)
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  • Biophysics (AREA)
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  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

L'invention concerne un dispositif servant à détecter des interactions moléculaires compatibles avec des moyens de détection électrique et électrochimique. Elle concerne, plus particulièrement, un ensemble de détection biomoléculaire fabriqué à partir d'un substrat poreux sur lequel est déposée une couche conductrice, de façon plus spécifique, un substrat poreux recouvert d'un plaquage métallique, et de façon encore plus spécifique, un substrat d'hydrogel poreux revêtu d'un plaquage de métal.
PCT/US2001/000421 2000-01-06 2001-01-05 Reseau tridimensionnel servant a detecter des biomolecules WO2001050131A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27670/01A AU2767001A (en) 2000-01-06 2001-01-05 Three-dimensional network for biomolecule detection

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US47933200A 2000-01-06 2000-01-06
US09/479,332 2000-01-06

Publications (1)

Publication Number Publication Date
WO2001050131A1 true WO2001050131A1 (fr) 2001-07-12

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AU (1) AU2767001A (fr)
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001061053A2 (fr) * 2000-02-17 2001-08-23 Motorola, Inc. Capteurs de proteines et peptides mettant en oeuvre des procedes de detection
DE10142691A1 (de) * 2001-08-31 2003-03-27 Infineon Technologies Ag Verfahren zum Nachweis biochemischer Reaktionen sowie eine Vorrichtung hierfür
US6787339B1 (en) 2000-10-02 2004-09-07 Motorola, Inc. Microfluidic devices having embedded metal conductors and methods of fabricating said devices
US6962822B2 (en) 2002-08-07 2005-11-08 International Business Machines Corporation Discrete nano-textured structures in biomolecular arrays, and method of use
EP1629884A1 (fr) * 2004-08-25 2006-03-01 Roche Diagnostics GmbH Support réutilisable pour la fabrication des microréseaux a ADN
WO2006037527A1 (fr) * 2004-09-30 2006-04-13 Pamgene Bv Supports poreux solides masques permettant un echange aise et rapide de reactifs destine a accelerer des microreseaux a electrodes
US7928038B2 (en) 2006-11-21 2011-04-19 Applied Biosystems, Llc Intermediates and methods for forming passivated surfaces on oxide layers and articles produced thereby
US7955798B2 (en) 2004-08-25 2011-06-07 Roche Diagnostics Operations, Inc. Reusable substrate for DNA microarray production
US8173198B2 (en) 2008-07-23 2012-05-08 Life Technologies Corporation Deposition of metal oxides onto surfaces as an immobilization vehicle for carboxylated or phophated particles or polymers
CN106153891A (zh) * 2015-04-09 2016-11-23 清华大学 三维生物标志物检测装置、制备方法及检测生物标志物的方法

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001061053A3 (fr) * 2000-02-17 2002-03-14 Motorola Inc Capteurs de proteines et peptides mettant en oeuvre des procedes de detection
US6824669B1 (en) 2000-02-17 2004-11-30 Motorola, Inc. Protein and peptide sensors using electrical detection methods
WO2001061053A2 (fr) * 2000-02-17 2001-08-23 Motorola, Inc. Capteurs de proteines et peptides mettant en oeuvre des procedes de detection
US6787339B1 (en) 2000-10-02 2004-09-07 Motorola, Inc. Microfluidic devices having embedded metal conductors and methods of fabricating said devices
DE10142691B4 (de) * 2001-08-31 2006-04-20 Infineon Technologies Ag Verfahren zum Nachweis biochemischer Reaktionen sowie eine Vorrichtung hierfür
DE10142691A1 (de) * 2001-08-31 2003-03-27 Infineon Technologies Ag Verfahren zum Nachweis biochemischer Reaktionen sowie eine Vorrichtung hierfür
US7354777B2 (en) 2002-08-07 2008-04-08 International Business Machines Corporation Discrete nano-textured structures in biomolecular arrays, and method of use
US6962822B2 (en) 2002-08-07 2005-11-08 International Business Machines Corporation Discrete nano-textured structures in biomolecular arrays, and method of use
EP1629884A1 (fr) * 2004-08-25 2006-03-01 Roche Diagnostics GmbH Support réutilisable pour la fabrication des microréseaux a ADN
US7955798B2 (en) 2004-08-25 2011-06-07 Roche Diagnostics Operations, Inc. Reusable substrate for DNA microarray production
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