WO1996005326A1 - Methode et dispositif de detection magnetique de proteines et d'acides nucleiques - Google Patents

Methode et dispositif de detection magnetique de proteines et d'acides nucleiques Download PDF

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Publication number
WO1996005326A1
WO1996005326A1 PCT/US1995/010503 US9510503W WO9605326A1 WO 1996005326 A1 WO1996005326 A1 WO 1996005326A1 US 9510503 W US9510503 W US 9510503W WO 9605326 A1 WO9605326 A1 WO 9605326A1
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Prior art keywords
die
substance
magnetic
substrate
marker
Prior art date
Application number
PCT/US1995/010503
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English (en)
Inventor
John S. Fox
Original Assignee
Fox John S
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 Fox John S filed Critical Fox John S
Priority to AU33305/95A priority Critical patent/AU3330595A/en
Publication of WO1996005326A1 publication Critical patent/WO1996005326A1/fr

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    • 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
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • 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
    • C12Q1/6816—Hybridisation assays characterised by the detection means
    • C12Q1/6825—Nucleic acid detection involving sensors
    • 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
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation

Definitions

  • the present invention relates generally to biochemical assays, and more particularly to non- radioactive assay techniques for detecting the presence of nucleic acids and proteins.
  • Biochemical assays performed both on extracts and in situ, for determining the presence and concentration of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), protein, and antibodies in tissue, cells, including E. Coli cells, or serum samples have wide application. For instance, by simply detecting whether a particular sample contains DNA, it can be ascertained whether a DNA amplification procedure that has been performed on the sample (e.g., polymerase chain reaction) has been successful. Also, by determining the quantity of DNA in a particular sample, many attributes of the sample, as well as the effectiveness of whatever laboratory procedure the sample may have undergone, can be usefully ascertained.
  • biochemical assay techniques have been introduced for analyzing the presence and/or amount of nucleic acid or protein in a sample.
  • Existing techniques include binding a chemiluminescent, fluoriscent, phosphorescent, or radioactive marker, or a colorimetric marker, to the nucleic acid or protein in me sample sought to be assayed, and then employing analytical techniques corresponding to the particular type of assay.
  • nucleic acid/protein assay techniques An example of existing nucleic acid/protein assay techniques is disclosed in European Patent application serial no. 85200854.9 to Jannsen Pharmaceutica of Belgium ("the Jannsen application").
  • the Jannsen application a process is disclosed for staining proteins and nucleic acids in a sample with colloidal metal particles, which bind to the nucleic acids/proteins.
  • the metal particles generate a color signal that can be analyzed using spectrophotometry to measure the amount of nucleic acid/protein in the sample being assayed.
  • a device that uses colorimetric principles is sold by Invitrogen of San Diego, California under the trade name "DNA DipStickTM" ("the Invitrogen technology").
  • a sample substance which contains DNA is deposited on a membrane made of, e.g., nylon, other polymer, or nitrocellulose, and allowed to dry.
  • the membrane is dipped into a colloid solution that contains suspended iron-chloride (FeCy, causing the FeCl 2 to bond with die DNA molecules.
  • a developing agent which includes potassium ferrocyanide is added, causing the color of the FeCl 2 (and, hence, the membrane with DNA) to change.
  • the membrane is dried and colorimetrically analyzed to assay the concentration of DNA in the sample.
  • an object of the present invention to provide a method and apparatus for non-radioactively assaying a sample for nucleic acid, protein, or antibody concentration.
  • Another object of the present invention is to provide a method and apparatus for determining the concentration of nucleic acids, proteins, or antibodies in a sample which is repeatable, i.e., which uses a reagent having a relatively long shelf life, and which can be easily performed.
  • Still another object of the present invention is to provide a method and apparatus for determining the concentration of nucleic acids, proteins, or antibodies in a sample which is easy to use and cost-effective.
  • a biochemical assay apparatus includes a substrate and a substance which is deposited on the substrate, with the substance including a constituent in the group consisting of: nucleic acids, proteins, and antibodies.
  • a marker is bound to the constituent, and the marker generates a magnetic signal.
  • a sensor senses the magnetic signal of the marker and generates a detection signal in response thereto to indicate the presence of the constituent.
  • the detection signal is representative of the quantity of the constituent on the substrate.
  • a correlator can be provided for correlating the detection signal to a quantity of the constituent.
  • the marker is magnetic, and can be ferromagnetic, ferrimagnetic, paramagnetic, or superparamagnetic.
  • the marker includes a plurality of colloidal iron particles, each of which defines a respective magnetic moment, and the magnetic moments of the particles are substantially aligned with each other.
  • the constituent is deoxyribonucleic acid (DNA)
  • the marker is colloidal iron
  • the sensor is a magnetic field sensor
  • the substrate is a nylon matrix.
  • an assay device for detecting the presence of nucleic acids, proteins, and antibodies includes a magnetically marked substance in the group consisting of nucleic acids, proteins, and antibodies.
  • the apparatus further includes a magnetic sensor which is positioned adjacent the substance for generating a detection signal representative of the presence of the substance.
  • a mediod for detecting the presence of a substance in the group consisting of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), protein, and antibodies.
  • the method of the present invention includes binding a magnetic material to the substance, with die magnetic material having a magnetic property. Additionally, the method includes sensing the magnetic property to thereby determine the presence of the substance.
  • an apparatus for assaying the presence of a magnetically labelled biomolecule in a sample suspected of containing the biomolecule includes a support for the sample. Also, the apparatus includes means for sensing the magnetic label and producing a signal in relation thereto, the sensing means being proximate the support. Further, die apparatus includes output means in communication with the sensing means for presenting the signal produced when the magnetically labelled biomolecule is present in the sample.
  • a method for detecting the presence of a biomolecule in a sample suspected of containing die biomolecule.
  • the method includes combining the sample with a colloidal iron reagent to form an admixture thereof, and then maintaining the admixture under predetermined reaction conditions to form an iron-biomolecule complex.
  • the iron- biomolecule complex is separated from any excess iron reagent, and then the iron-biomolecule complex is magnetically sensed to detect die presence of the biomolecule.
  • Figure 1 is a perspective view of a DNA-impregnated substrate juxtaposed with a magnetic sensor, with the sensor and supporting signal processing components shown schematically and the detector housing shown in phantom; and
  • Figure 2 is a flow chart of the method of the present invention for magnetically detecting DNA.
  • a support or substrate is shown upon which has been deposited a substance 12 by means disclosed below.
  • the substrate 10 is made of a polymeric material, and is preferably a thin, parallelepiped- shaped nylon membrane of the type marketed by Invitrogen of San Diego, California under die trade name "DNA DipStickTM". It is to be understood, however, diat other substrate materials, i.e., supports, may be used, e.g., porous webs, nitrocellulose, silica, agarouse gels, or polyacrylamide gels, which are appropriate for holding the substances disclosed herein.
  • die substance 12 is a biological substance that includes at least one constituent element 14 in the group consisting of deoxyribonucleic acid (DNA) molecules, ribonucleic acid (RNA) molecules, protein molecules, and antibody molecules.
  • the substance 12 could be derived from any body fluid, e.g., cerebral-spinal fluid, or from other tissue samples or cells, e.g., E. Coli cells, for which it is desired to ascertain the concentration, in the body fluid, of DNA, RNA, proteins, or antibodies.
  • the substance 12 could be a substance processed by, e.g., polymerase chain reaction (PCR) amplification techniques, for which it is desired to ascertain d e concentration of DNA in the substance after PCR amplification.
  • PCR polymerase chain reaction
  • each magnetic marker 16 is chemically bound to each constituent element 14 by means disclosed below to establish a magnetically labelled biomolecule.
  • each magnetic marker 16 is a charged colloidal ferrous chloride (FeCy molecule which binds to the associated constituent element 14.
  • FeCy molecule which binds to the associated constituent element 14.
  • the number of markers 16 on the substrate 12 is generally linearly proportional to the number of constituent elements 14 on die substrate 12 and, hence, is generally linearly proportional to the concentration of the constituent elements 14 in the substance 12.
  • the term "colloidal ferrous chloride” is meant to include dispersions of particles, e.g., sols, consisting of a metal, metal compound or nuclei coated with a metal or metal compound.
  • the marker 16 can include other constituents that exhibit magnetic properties such as ferromagnetism, ferrimagnetism, paramagnetism, or superparamagnetism.
  • the marker 16 can be a ferromagnetic marker in the group including iron, cobalt, nickel, ferrous oxide, ferrous hydroxide and other ferrous alloys, and rare earth elements with atomic numbers between sixty four and sixty nine (64-69), inclusive.
  • die marker 16 can be a ferrimagnetic marker in me group consisting of magnetite (Fe 3 0 4 ), maghemite (Fe ⁇ C ⁇ ,), and other mixed oxides.
  • the marker 16 can be made of a ferromagnetic or ferrimagnetic material, die magnetic property of which is the generation of a magnetic field.
  • die marker 16 can be made of a paramagnetic or superparamagnetic material, i.e., a material die magnetic property of which is d e tendency to attract a magnet, such as d e superparamagnetic material that is disclosed by Vassiliou et al. in J. Appl. Physics 73 (10), 15 May 1993, page 5109.
  • the marker of the present invention generates a magnetic signal, and as intended by the present invention, this magnetic signal can be, e.g., die magnetic field generated by ferromagnetic and ferrimagnetic materials, or die attraction for magnets characteristic of paramagnetic and superparamagnetic materials.
  • each marker 16 When d e marker 16 is magnetic, each marker 16 generates a magnetic moment, represented in Figure 1 by field lines 18. As can appreciated in reference to Figure 1, in die presently preferred embodiment the magnetic moments of the markers 16 are aligned, i.e., the field lines 18 are generally parallel to each other.
  • the markers 16 together generate a magnetic field that is representative of die concentration of the constituent element 14 in the substance 12. Consequently, die substrate 10 can be juxtaposed with a magnetic sensor 20 and moved past the magnetic sensor 20, causing the magnetic field of die markers 16 to variably permeate the sensor 20 and d ereby cause the sensor 20 to generate a detection signal in response thereto to indicate die presence of the constituent element 14.
  • the magnetic sensor 20 can be any magnetic sensor that is suitable, when the substrate 10 is moved next to it, for generating a detection signal having a sensitivity that is appropriate for me particular application of die present invention, e.g., mere detection of DNA on the substrate 10 or measurement of the concentration of DNA on the substance 12.
  • the sensor 20 can be an inductive read head, e.g., the read head used in a Toshiba model KT-53 stereo cassette.
  • the senor 20 can be a magnetoresistive (MR) read head, such as die read heads used in certain existing disk drives and/or the MR heads made by IBM of Armonk New York or Eastman Kodak Co. of Rochester New York and disclosed by Smidi et al. in Jour, of App. Physics 69(8), 15 April 1991, page 5082.
  • MR magnetoresistive
  • the sensor 20 is an MR head that is embedded in a chip, the chip can be formed with a channel and the substance 12 deposited in die channel for assaying.
  • the senor 20 can be a magnetic force microscope, SQUID sensor, metal film Hall-effect device, or a ultra-high sensitivity susceptometer (for sensing paramagnetic and superparamagnetic markers) such as die device disclosed by Slade et al. in IEEE TRANSACTIONS ON MAGNETICS, vol. 23, no.5, September, 1992, page 3132.
  • the sensor 20 is electrically connected to a signal processor 22 diat receives die detection signal and generates a signal representative of the concentration of the constituent element 14, e.g., DNA in the substance 12 in response thereto.
  • the signal processor 22 includes signal processing circuitry known in the art for processing signals from magnetic sensors, as well as a correlator 22a for generating a DNA concentration signal based upon die detection signal from the magnetic sensor 20.
  • the correlator 22a can be a programmable chip or a microprocessor.
  • die correlator 22a correlates the detection signal with a concentration of the constituent element 14 in the substance 12, with die correlation being linearly dependent on the strength of the detection signal. Then, die correlator 22a generates a DNA concentration signal in response which is representative of die concentration of e constituent element 14 in the substance 12.
  • diat die correlator 22a can be calibrated to generate accurate DNA concentration signals by means well-known in the art, e.g., by passing several substrates having known quantities of DNA deposited diereon next to die sensor 20 and correlating die resulting detection signals to die known concentrations.
  • die signal from the signal processor 22 can be sent to an output device 24.
  • the output device 24 can be any suitable device, e.g., headphones, audio-visual computer display, or analog meter, which generates a sensory indication of the detection signal.
  • a transporter 26 can be provided, and die substrate 10 can be positioned on die transporter 26 to move the substrate 10 past die sensor 20 in the direction of die arrow 28.
  • the sensor 20 can be moved past the substrate 10 in die direction of the arrow 28 and in a direction normal thereto, in a raster-scan type motion, to generate a two-dimensional data output, e.g., an image, having an "x" dimension and a "y" dimension.
  • the two-dimensional data output can be transformed into a three-dimensional output wherein the third dimension (“z" dimension) represents magnetic signal intensity.
  • the entire combination of structure disclosed above can be disposed in a housing 30.
  • d e DNA sample is prepared as desired by means well-known in the art. More particularly, as one example d e substance 12 can be disposed in a gel, or a slab gel, or a capillary gel, and die constituent element 14, i.e., DNA in the embodiment shown, can then be separated in d e gel by, e.g., electrophoresis. Then, the gel in which the substance 12 is disposed can function as a substrate, or the gelatinized substance 12 deposited onto a membrane.
  • die substance 12 widi constituent element 14 e.g., DNA
  • die substrate 10 die substance 12 widi constituent element 14, e.g., DNA
  • die substrate 10 about one microliter (1.0 ⁇ l) of substance 12 is deposited onto die substrate 10.
  • the substance 12 is allowed to dry for about five to fifteen minutes.
  • the substance 12 can be UV cross-linked to die substrate 10.
  • a suitable wash solution can contain about 0.1 normal hydrochloric acid (HC1), and can be provided by Invitrogen of San Diego, California as part of Invitrogen's "DNA DipStickTM kit".
  • HC1 normal hydrochloric acid
  • die substrate 10 is disposed in a colloidal iron coupling solution for about three minutes, to diereby bond die markers 16 widi die constituent element 14 (DNA).
  • the substrate 10 is disposed in a colloidal iron reagent to form an admixture of the reagent and magnetically labelled constituent element 14 (DNA).
  • the colloidal iron coupling solution can be procured from Invitrogen of San Diego, California.
  • die Invitrogen coupling solution contains cacodylic acid.
  • the substrate 10 is disposed in distilled water for about twenty seconds to separate any excess iron reagent from die substance 12, and dien, at block 44, die substrate 10 preferably is disposed in a developing solution for about three minutes, to enhance the magnetic signal.
  • the developing solution includes potassium ferrocyanide, and can be procured from Invitrogen.
  • die substrate 10 After disposing die substrate 10 in the developing solution, die substrate 10 is disposed in a wash solution at block 46 for about twenty seconds. Then, at block 48, die substrate 10 is dried.
  • the magnetic moments of the markers 16 are aligned widi each odier. This can be accomplished naturally by the Earth's magnetic field, but is more preferably accomplished by juxtaposing the substrate 10 with a strong permanent magnet.
  • the substrate 10 is juxtaposed with the magnetic sensor 20 and moved relative to e sensor 20 to cause the sensor 20 to generate the detection signal.
  • d e substrate 10 is closely juxtaposed with die sensor 20. More preferably, the substrate 10 is distanced from die sensor 20 by only a few microns or less, in order to improve the sensitivity of die present invention.
  • the correlator 22a receives the detection signal from the sensor 20 and correlates it to a concentration of me constituent element 14 in the substance 12.
  • the above-described steps were performed using a substrate 10 which was a DNA DipStickTM diat had been colorimetrically assayed according to die Invitrogen DNA DipStickTM Instruction Manual, available from Invitrogen and incorporated herein by reference.
  • the substrate 10 having DNA deposited thereon was moved past a Toshiba model KT-53 stereo cassette read head magnetic sensor 20.
  • the output device 24 was a set of headphones, and an audible signal was heard on die headphones when the portions of die substrate 10 that had been colorimetrically indicated as containing DNA were moved past the magnetic sensor 20.
  • the concentration of DNA diat was magnetically sensed was colorimetrically assayed at one half nanograms per microliter (0.5ng/ ⁇ l).
  • diat die present invention fully contemplates odier mediods for combining the substrate 10 with substance 12, constituent element 14, and marker 16.
  • the constituent element 14 is DNA
  • the marker 16 can be bound to the DNA during electrophoretic separation of the DNA in a gel substrate.
  • the DNA can be disposed in a gel, the gel deposited on a membrane substrate, and men the gel removed from die substrate, leaving behind die DNA.
  • Alternative mediods of combining me substrate 10 with substance 12, constituent element 14, and marker 16 may become apparent and known in the art, and used in conjunction with the principles disclosed herein, widiout departing from die scope of the appended claims.

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Abstract

Dispositif de titrage biochimique permettant de détecter la présence d'ARN, d'ADN, de protéines ou d'anticorps (14). Ce dispositif comprend un composé colloïdal comportant un constituant marqueur magnétique (16) qui se lie à l'ADN, à l'ARN, à la protéine ou à l'anticorps (14) que l'on souhaite détecter. L'ADN, l'ARN, la protéine ou l'anticorps (14) présentant ce marqueur magnétique (16) est ensuite juxtaposé à un capteur magnétique (20), lequel capteur (20) génère un signal de détection exprimant la présence de cet ADN, ARN, protéine ou anticorps (14). Le signal de détection peut être corrélé à une quantité donnée d'ADN, d'ARN, de protéines ou d'anticorps (14). L'invention porte également sur la méthode de détection de la présence d'ARN, d'ADN, de protéines ou d'anticorps mettant en ÷uvre les principes du magnétisme.
PCT/US1995/010503 1994-08-17 1995-08-17 Methode et dispositif de detection magnetique de proteines et d'acides nucleiques WO1996005326A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33305/95A AU3330595A (en) 1994-08-17 1995-08-17 Method and apparatus for magnetically detecting proteins and nucleic acids

Applications Claiming Priority (2)

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US29195694A 1994-08-17 1994-08-17
US08/291,956 1994-08-17

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WO1996005326A1 true WO1996005326A1 (fr) 1996-02-22

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000046600A2 (fr) * 1999-02-03 2000-08-10 Europäisches Laboratorium für Molekularbiologie (EMBL) Procede de detection d'analytes dans un echantillon pour essai et support de mesure y relatif
DE19939208A1 (de) * 1999-02-17 2000-09-07 Kilian Hennes Verfahren zum Darstellen von biologisch aktivierten ferromagnetischen Partikeln sowie Vorrichtung dafür
EP1146338A1 (fr) * 1999-11-19 2001-10-17 Hitachi Software Engineering Co., Ltd. Lecteur de biopuce et reactif de marquage
EP1210461A1 (fr) * 1999-08-21 2002-06-05 John S. Fox Detection a grande sensibilite de biomolecules, au moyen de particules magnetiques
US6743639B1 (en) 1999-10-13 2004-06-01 Nve Corporation Magnetizable bead detector
US6875621B2 (en) 1999-10-13 2005-04-05 Nve Corporation Magnetizable bead detector
US7391091B2 (en) 2004-09-29 2008-06-24 Nve Corporation Magnetic particle flow detector
GB2447356A (en) * 2007-03-07 2008-09-10 Byotrol Plc Methods and Apparatus For Detection of a Substance Bound To Magnetic Particles

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0165633A2 (fr) * 1984-06-22 1985-12-27 Janssen Pharmaceutica N.V. Procédé de coloration de protéines et d'acides nucléiques
JPS63302367A (ja) * 1987-06-01 1988-12-09 Nippon Telegr & Teleph Corp <Ntt> 磁気免疫測定方法および測定装置

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0165633A2 (fr) * 1984-06-22 1985-12-27 Janssen Pharmaceutica N.V. Procédé de coloration de protéines et d'acides nucléiques
JPS63302367A (ja) * 1987-06-01 1988-12-09 Nippon Telegr & Teleph Corp <Ntt> 磁気免疫測定方法および測定装置

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOPHYSICAL JOURNAL, Volume 52, issued October 1987, VALBERG et al., "Magnetic Particle Motions Within Living Cells, Physical Therapy and Techniques", pages 537-550. *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000046600A2 (fr) * 1999-02-03 2000-08-10 Europäisches Laboratorium für Molekularbiologie (EMBL) Procede de detection d'analytes dans un echantillon pour essai et support de mesure y relatif
WO2000046600A3 (fr) * 1999-02-03 2001-11-01 Europ Lab Molekularbiolog Procede de detection d'analytes dans un echantillon pour essai et support de mesure y relatif
DE19939208A1 (de) * 1999-02-17 2000-09-07 Kilian Hennes Verfahren zum Darstellen von biologisch aktivierten ferromagnetischen Partikeln sowie Vorrichtung dafür
DE19939208C2 (de) * 1999-02-17 2001-05-17 Kilian Hennes Verfahren zum Darstellen von biologisch aktivierten induktivitätsändernden Partikeln zu deren Nachweis und Zählen sowie Vorrichtung dafür
EP1210461A4 (fr) * 1999-08-21 2005-11-23 John S Fox Detection a grande sensibilite de biomolecules, au moyen de particules magnetiques
EP1210461A1 (fr) * 1999-08-21 2002-06-05 John S. Fox Detection a grande sensibilite de biomolecules, au moyen de particules magnetiques
US6875621B2 (en) 1999-10-13 2005-04-05 Nve Corporation Magnetizable bead detector
US6743639B1 (en) 1999-10-13 2004-06-01 Nve Corporation Magnetizable bead detector
US7235969B2 (en) 1999-10-13 2007-06-26 Nve Corporation Thin-film structure magnetizable bead detector
US7238539B2 (en) 1999-10-13 2007-07-03 Nve Corporation Magnetizable bead detector
US9063090B2 (en) 1999-10-13 2015-06-23 Nve Corporation Method for fabricating thin-film structure magnetizable bead detector
EP1146338A4 (fr) * 1999-11-19 2004-09-22 Hitachi Software Eng Lecteur de biopuce et reactif de marquage
EP1146338A1 (fr) * 1999-11-19 2001-10-17 Hitachi Software Engineering Co., Ltd. Lecteur de biopuce et reactif de marquage
US7391091B2 (en) 2004-09-29 2008-06-24 Nve Corporation Magnetic particle flow detector
US7609054B2 (en) 2004-09-29 2009-10-27 Nve Corporation Magnetic particle flow detector
GB2447356A (en) * 2007-03-07 2008-09-10 Byotrol Plc Methods and Apparatus For Detection of a Substance Bound To Magnetic Particles
WO2008107691A1 (fr) * 2007-03-07 2008-09-12 Byotrol Plc Procédés et appareil de détection de particule

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