WO2009132667A1 - Procédé permettant de déceler et/ou de déterminer la concentration d'un ligand - Google Patents

Procédé permettant de déceler et/ou de déterminer la concentration d'un ligand Download PDF

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Publication number
WO2009132667A1
WO2009132667A1 PCT/EP2008/003496 EP2008003496W WO2009132667A1 WO 2009132667 A1 WO2009132667 A1 WO 2009132667A1 EP 2008003496 W EP2008003496 W EP 2008003496W WO 2009132667 A1 WO2009132667 A1 WO 2009132667A1
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WO
WIPO (PCT)
Prior art keywords
receptor
solution
ligand
sensor
ligands
Prior art date
Application number
PCT/EP2008/003496
Other languages
German (de)
English (en)
Inventor
Holger Klapproth
Sonja Mohry
Johannes Baader
Ingo Freund
Original Assignee
Micronas Gmbh
Micronas Holding Gmbh
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 Micronas Gmbh, Micronas Holding Gmbh filed Critical Micronas Gmbh
Priority to PCT/EP2008/003496 priority Critical patent/WO2009132667A1/fr
Publication of WO2009132667A1 publication Critical patent/WO2009132667A1/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
    • 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
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors

Definitions

  • the invention relates to a method for detecting and / or determining the concentration of at least one ligand contained in a solution to be analyzed, which has a charge or is bound to one, a) wherein a carrier surface is provided on which at least one of the ligands b) wherein at least one sensor is provided, c) wherein the solution for binding at least one ligand to the receptor is brought into contact with the latter, d) during which the solution is in contact with the receptor, between an electrode and applying to a counter electrode an electrical voltage through the electric field of which the ligands are moved relative to the receptor in the solution, e) after which ligands which are not bound to a receptor are removed from the detection range of the sensor, f) and with the help of the sensor dependent on the binding of the receptor to the ligand s measuring signal is detected.
  • a measuring chamber which has an interior cavity serving as a sample receiving space having a bottom, a ceiling and side boundary walls.
  • the bottom has a carrier surface; are immobilized on the receptors that are specific for a DNA ligand to be detected.
  • An electrode is inserted in the bottom underneath the receptors, and a counter electrode is inserted in a wall area of the ceiling opposite this.
  • the electrode and the counter electrode each consist of a transparent, electrically conductive material and are each spaced from the inner cavity by an insulating layer.
  • a solution containing the ligands to be detected is filled in the inner cavity of the measuring chamber in such a way that it comes into contact with the receptors.
  • an electrical is applied between the electrode and the back electrode, which generates an electric field in the solution.
  • the field exerts Coulomb forces on the ligands which move the ligands toward the electrode.
  • the ligands come into contact with the receptors and bind to them.
  • the inner cavity of the measuring chamber is rinsed with a rinsing agent to remove ligands not bound to a receptor from the inner cavity.
  • the binding of the ligands to the receptors is detected by means of an optical marker with which the ligands are labeled.
  • the receptor-ligand-marker complexes remaining in the measuring chamber are irradiated with excitation radiation, which excites the markers to emit fluorescence radiation. This is detected with the help of the provided sensor.
  • the method has the disadvantage that it requires a relatively large amount of equipment.
  • the at least one sensor is arranged on the carrier surface and has at least one electrically conductive region, and that the at least one electrically conductive region of the sensor is used as the electrode.
  • the sensor thus fulfills a dual function and, in addition to detecting the measurement signal, is also used as an electrode for generating an electrical field causing a migration movement of the ligands.
  • the process according to the invention can thereby be carried out in a simple manner.
  • the at least one receptor may be a nucleic acid or a derivative thereof (DNA, RNA, PNA, LNA, oligonucleotides, plasmids, chromosomes), a peptide, a protein (enzyme, protein, oligopeptides, cellular receptor protein and its complexes, peptide hormone, antibodies and its Fragments), a carbohydrate and its derivatives, in particular a glycosylated protein and a ⁇ -glycoside, a fat, a fatty acid and / or a lipid.
  • the electrode and / or the counterelectrode are spaced from the solution to be analyzed by an electrical insulation layer become. This avoids that the solution is electrolytically decomposed by the application of electrical voltage.
  • the senor is a semiconductor sensor having at least a first semiconductor zone and a second semiconductor zone cooperating therewith, the first semiconductor zone being used as the electrode. It is even possible that the second semiconductor zone is used as the counter electrode. The electric field can then be generated without an additional electrode in the solution.
  • an optical radiation is generated, wherein a photodiode sensitive to the optical radiation is used as the semiconductor sensor.
  • the electrical voltage is chosen smaller than the breakdown voltage of the photodiode. Since the photodiode is arranged close to the receptor, it can capture the optical radiation in a correspondingly large space segment. In this case, it is possible to dispense with a collecting lens arranged upstream of the photodiode.
  • an ion-selective field effect transistor is used as the semiconductor sensor.
  • the binding of the ligand to the receptor can therefore also be detected capacitively.
  • the polarity of the voltage present between the electrode and the counterelectrode is changed at least once prior to the detection of the measuring signal. This allows a more even distribution of the ligands in the solution to be achieved.
  • the voltage is applied between the electrode and the counter electrode in such a way that ligands which are not bound to a receptor are removed from the receptor
  • Detection range of the sensor are removed. This can be achieved, in particular, by applying a voltage of opposite polarity between the electrode and the counterelectrode after binding the ligand to the receptor for a sufficient period of time. This can be an eventual Sp ⁇ lvorg ⁇ ng to remove the unbound Lig ⁇ nden shortened or even completely saved.
  • the ligands exhibit a concentration difference at at least two spaced-apart locations of the solution, and if the spatial distribution of the field strength of the electric field in the solution is chosen such that the ligands are bound by the electric field in the sense of a
  • This procedure can be applied even in a method in which the electrode (s) and the counter electrode (s) are provided in addition to the sensor.
  • the spatial distribution of the field strength is preferably produced by applying different electrical potential profiles to at least two electrodes spaced apart from one another and / or to at least two counter-electrodes spaced apart from one another.
  • the field strength pattern of the electric field located between the electrodes and the counterelectrodes can be selected as a function of measurement and / or estimated values for the respectively present ligand concentration. If, during the execution of the method, the solution is delimited laterally by walls, for example, of a measuring chamber, a greater field strength can be generated at locations adjacent to the walls, in particular in corner regions of the measuring chamber, than at locations which are further away from the walls , As a result, a uniform concentration distribution of the ligands is made possible in the measuring chamber.
  • the potential curves are chosen such that the electric field moves relative to the receptor in the solution.
  • This can be achieved in particular by successively applying an electrical voltage to electrode arrangements arranged in a row, each consisting of an electrode and a counterelectrode assigned to it, in order to generate an electrical traveling field progressing in the direction of extension of the row.
  • the ligand is labeled with an electrically charged molecule before and / or during the contacting of the solution with the receptor, which is bound directly and / or indirectly via at least one other molecule to the ligand.
  • This can be done, for example, by first binding an antibody that is specific for the ligand to the strongly charged molecule, and then binding the antibody-molecule complex thus formed to the ligand.
  • the pH of the solution is preferably adjusted so that the majority of the molecules in the solution have a polarity opposite to the polarity of the molecule with which the ligand is labeled.
  • the migration of the ligand to the receptor can be accelerated or the field strength of the electric field applied between the electrode and the counter electrode can be reduced.
  • the latter is particularly advantageous if the anode is used as the electrode and the cathode of a reverse biased photodiode is used as the opposite electrode.
  • the voltage can then be chosen smaller than the breakdown voltage of the photodiode.
  • the electrically charged molecule is an acid, in particular polyacrylic acid.
  • an acid in particular polyacrylic acid.
  • FIG. 1 shows a partial cross section through a biochip having a carrier, on the surface of which receptors are immobilized, wherein a ligand-containing solution is arranged on the carrier,
  • FIG 3 shows a partial cross section through a measuring chamber whose inner cavity is filled with a ligand-containing solution, wherein at the bottom of the inner cavity receptors are immobilized, and
  • a measuring device 3 which has a carrier with a carrier surface 4.
  • a plurality of laterally spaced test sites 5 are provided on the carrier surface 4, on which receptors ⁇ are immobilized, which are binding-specific for the ligands 2.
  • the carrier has a semiconductor substrate 7 of a first charge carrier type; on which a first electrical insulation layer 8 is arranged, whose surface facing away from the substrate 7 forms the support surface 4.
  • sensors 9 are inserted under the test sites, which are each configured as photodiodes in the embodiments shown in Fig. 1-3.
  • FIG. 2 shows that the photodiodes each have an approximately trough-shaped first semiconductor zone 10 and a second semiconductor zone cooperating therewith, which is formed by the substrate 7 and adjoins the first semiconductor zone 10.
  • ⁇ renz Scheme between the first semiconductor zone 10 and the substrate
  • Substrate 7 are electrically connected via metallizations 12 with inputs of a Messsignalerfas- sungs Rhein 13 and with a voltage source 14 or connectable.
  • the carrier forms part of a boundary wall of a measuring chamber only partially shown in the drawing, which has an inlet and a drain and is filled with a buffer and / or Spülfiüsstechnik.
  • a buffer and / or Spülfiüsstechnik To analyze the solution 1, it is introduced through the feed into the measuring chamber such that the solution 1 comes into contact with the carrier surface 4 and the receptors immobil immobilized thereon.
  • the ligands 2 contained in the solution 1 each have an electrical charge of a first polarity.
  • the solution contains 1 more, partially charged, partially uncharged molecules 15.
  • the pH of the solution 1 is adjusted so that at least ⁇ %, in particular at least 75% and preferably at least 90% of the molecules 15 each no electric charge or electrical Have charge of a second polarity.
  • an electrical voltage is applied between the first semiconductor zone 10 and the substrate 7 with the aid of the voltage source 14, which generates an electric field in the solution 1 in Fig. 1 and 3 is indicated schematically by dashed lines.
  • the polarity of the voltage source 14 is chosen so that the photodiodes are reverse-connected. In this case, a charge carrier depletion occurs in the space charge zone 11
  • FIG. 1 shows that the field lines of the electric field at the test sites 5 extend approximately orthogonally to the carrier surface 4.
  • the electric field causes 2 Coulomb forces on the charges of the ligands, which move the ligands 2 in the solution 1 to the receptors ⁇ . This considerably shortens the time during which the solution 1 must be in contact with the receptors, so that the ligands 5 bind to the receptors ⁇ .
  • molecules 15 having a charge of the second polarity are moved away from the receptorsteur by Coulomb forces acting in the reverse direction.
  • the electrical voltage is applied longer to the first semiconductor zone 10 of the photodiode located at the relevant test site 5 than to a photodiode connected to a test point 5 is arranged, which has a smaller distance to the line or is arranged on the line.
  • the electrical voltages between the individual first semiconductor zones 10 and the substrate 7 can also be reversed one or more times in order to redistribute the ligands 2 and / or the molecules 15 in the solution.
  • a rinsing liquid is passed through the measuring chamber to remove ligands 2 which are not bound to a receptor aus from the measuring chamber. Then, a luminescence radiation is generated at the test sites 5 as a function of the binding of the ligand 2 to the receptor ⁇ .
  • the Lumi The fluorescence can be excited by an excitation radiation and / or a chemiluminescent substrate on the ligand 2 itself and / or a marker which is directly and / or indirectly bound thereto and not shown in detail in the drawing.
  • the photocurrent is measured at the individual photodiodes using the measuring signal detection device 13 in each case. This is a measure of the concentration of ligands in solution 1.
  • the voltages for generating the electric field in the solution 1 located in the measuring chamber are respectively applied between the first semiconductor zone 10 of the sensor 9 located at the relevant test site 5 and a counterelectrode 16 at one of the test site 5 opposite wall region of the boundary wall of the measuring chamber is arranged. Between the ⁇ egenelektroden l ⁇ and the solution 1, a second electrical insulation layer 17 is arranged in each case.
  • the counterelectrodes 1 are positioned relative to the test sites 5 in such a way that the field lines of the electric field respectively arranged between the counterelectrode 1 and the first semiconductor zone 10 associated therewith extend normal to the carrier surface 4.
  • the counter electrodes 1 ' are laterally spaced from one another and can be connected to a first connection of the voltage source 14 independently of one another via a switch 18 assigned to them.
  • a second terminal of the voltage source 14 is connected via the Meßsignalerfdssungs Rheinen 13 with the first semiconductor regions 10.
  • the photodiodes are biased in the reverse direction by means of a second voltage source 19.
  • the counterelectrodes 1 ' are connected to the first terminal of the voltage source 14 by corresponding actuation of the switches 18 in order to apply the voltage.
  • the switches 18 are again actuated to disconnect the counterelectrodes l ⁇ from the first terminal of the voltage source 14. Then any, remaining in the measuring chamber free ligand 2 by a Rinsing step removed from the measuring chamber and it is the luminescence radiation generated as a function of the binding of the ligands 2 to the receptors ⁇ . The luminescence radiation is detected by means of the sensors 9.
  • the photodiodes can be used as sensors 9 and ion-selective field effect transistors.
  • the ion-selective field-effect transistors have a first semiconductor zone 10 serving as a source, a second semiconductor zone formed by the substrate 7, and a third semiconductor zone 20 serving as a drain on the first semiconductor zone 10 and the third semiconductor zone 20 are each Tannenfömig embedded in the substrate 7 and laterally spaced from each other by a channel region 21.
  • the first semiconductor zone 10 and the second semiconductor zone 20 are connected to metallizations 12.
  • the metallizations 12, the semiconductor zones 10, 20 and the substrate 7 are spaced from the solution by an electrical insulation layer.
  • receptors ⁇ are immobilized.
  • an electrical voltage can be applied between at least two of the semiconductor zones 7, 10, 20 and / or between at least one of the semiconductor zones 7, 10, 20 and at least one metallic outer electrode 16 spaced therefrom ,
  • the measurement signal measured is an electric current between the drain and the source dependent on the binding of the ligand 2 to the receptor ⁇ .
  • the following steps are carried out - provision of a carrier surface 4 on which at least one ligand 2 binding-specific receptor ⁇ is immobilized,

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  • Health & Medical Sciences (AREA)
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  • Urology & Nephrology (AREA)
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Abstract

L'invention concerne un procédé permettant de déceler et/ou de déterminer la concentration d'au moins un ligand (2) contenu dans une solution à analyser (1), qui présente une charge ou qui est lié à une telle charge, procédé comprenant les étapes suivantes : préparation d'une surface-support (4) sur laquelle est immobilisé au moins un récepteur (6) spécifique d'une liaison à des ligands (2); préparation d'au moins un détecteur (9) sur la surface-support (4), présentant au moins une zone électroconductrice; mise en contact de la solution (1) avec le récepteur (6), de manière à lier le ligand (2) avec le récepteur (6); application d'une tension électrique entre une zone électroconductrice du détecteur (9) et une contre-électrode, pendant que la solution (1) est en contact avec ledit récepteur (6), de façon que les ligands (2) soient déplacés dans un champ électrique dans la solution, par rapport au récepteur (6); élimination des ligands (2) qui ne sont pas liés à un récepteur (6); dans la zone de détection du détecteur (9), détection, à l'aide du détecteur (9), d'un signal de mesure dépendant de la liaison du récepteur (6) avec le ligand (2).
PCT/EP2008/003496 2008-04-30 2008-04-30 Procédé permettant de déceler et/ou de déterminer la concentration d'un ligand WO2009132667A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2008/003496 WO2009132667A1 (fr) 2008-04-30 2008-04-30 Procédé permettant de déceler et/ou de déterminer la concentration d'un ligand

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2008/003496 WO2009132667A1 (fr) 2008-04-30 2008-04-30 Procédé permettant de déceler et/ou de déterminer la concentration d'un ligand

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WO2009132667A1 true WO2009132667A1 (fr) 2009-11-05

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001836A1 (fr) * 1994-07-07 1996-01-25 Nanogen, Inc. Systemes et dispositifs microelectroniques a auto-adressage et auto-assemblage destines a des analyses et diagnostics de biologie moleculaire
WO2002031481A2 (fr) * 2000-10-10 2002-04-18 Nanogen, Inc. Dispositif et procede d'immobilisation electrique acceleree et de detection des molecules
DE10125021A1 (de) * 2001-05-22 2002-12-05 Infineon Technologies Ag Sensorchip-Anordnung und Verfahren zum Erfassen von Molekülen einer zu untersuchenden Flüssigkeit unter Verwendung der Sensorchip-Anordnung
WO2003083134A1 (fr) * 2002-04-03 2003-10-09 Infineon Technologies Ag Detecteur permettant une determination qualitative et quantitative d'oligomeres et polymeres (bio)organiques, procede d'analyse associe et procede de production du detecteur
DE10259820A1 (de) * 2002-12-19 2004-07-01 Siemens Ag DNA-Chip mit Mikroarray aus Mikroelektrodensystemen
GB2406175A (en) * 2003-09-19 2005-03-23 Univ Cambridge Tech Detection of molecular interactions using field effect transistors (FETs)
WO2006040142A2 (fr) * 2004-10-13 2006-04-20 Micronas Gmbh Procede de mise en evidence et/ou de determination de la concentration d'au moins un ligand

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996001836A1 (fr) * 1994-07-07 1996-01-25 Nanogen, Inc. Systemes et dispositifs microelectroniques a auto-adressage et auto-assemblage destines a des analyses et diagnostics de biologie moleculaire
WO2002031481A2 (fr) * 2000-10-10 2002-04-18 Nanogen, Inc. Dispositif et procede d'immobilisation electrique acceleree et de detection des molecules
DE10125021A1 (de) * 2001-05-22 2002-12-05 Infineon Technologies Ag Sensorchip-Anordnung und Verfahren zum Erfassen von Molekülen einer zu untersuchenden Flüssigkeit unter Verwendung der Sensorchip-Anordnung
WO2003083134A1 (fr) * 2002-04-03 2003-10-09 Infineon Technologies Ag Detecteur permettant une determination qualitative et quantitative d'oligomeres et polymeres (bio)organiques, procede d'analyse associe et procede de production du detecteur
DE10259820A1 (de) * 2002-12-19 2004-07-01 Siemens Ag DNA-Chip mit Mikroarray aus Mikroelektrodensystemen
GB2406175A (en) * 2003-09-19 2005-03-23 Univ Cambridge Tech Detection of molecular interactions using field effect transistors (FETs)
WO2006040142A2 (fr) * 2004-10-13 2006-04-20 Micronas Gmbh Procede de mise en evidence et/ou de determination de la concentration d'au moins un ligand

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