WO2011149249A2 - Biocapteur électrique pour la détection d'un échantillon infinitésimal - Google Patents

Biocapteur électrique pour la détection d'un échantillon infinitésimal Download PDF

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WO2011149249A2
WO2011149249A2 PCT/KR2011/003799 KR2011003799W WO2011149249A2 WO 2011149249 A2 WO2011149249 A2 WO 2011149249A2 KR 2011003799 W KR2011003799 W KR 2011003799W WO 2011149249 A2 WO2011149249 A2 WO 2011149249A2
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nano
gold
biosensor
receptor molecule
electrode
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PCT/KR2011/003799
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English (en)
Korean (ko)
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WO2011149249A3 (fr
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김민곤
신용범
안준형
이태한
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한국생명공학연구원
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Publication of WO2011149249A3 publication Critical patent/WO2011149249A3/fr

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    • 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
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/04—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating resistance
    • G01N27/12—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance by investigating resistance of a solid body in dependence upon absorption of a fluid; of a solid body in dependence upon reaction with a fluid, for detecting components in the fluid
    • G01N27/125—Composition of the body, e.g. the composition of its sensitive layer
    • G01N27/127—Composition of the body, e.g. the composition of its sensitive layer comprising nanoparticles
    • 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
    • G01N33/54306—Solid-phase reaction mechanisms
    • 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

Definitions

  • the present invention relates to an electric biosensor for detecting a trace amount of a sample, and more specifically, (a) to fabricate a biosensor by immobilizing a receptor molecule that selectively binds to a target material of analysis on an electrically insulated nano-electrode chip.
  • step (b) adding and reacting a sample containing a target substance selectively binding to the receptor molecule to the biosensor; (c) treating and reacting the gold nanoparticles to the nano-electrode chip reacted with the sample containing the target material; (d) treating and reducing gold ions around the reacted gold nanoparticles; And (e) measuring an electrical conductivity or impedance of the nano-electrode chip of which the gold ions are reduced to detect a target substance that specifically binds to the receptor molecule. It is about.
  • an enzyme-linked immunosorbent assay (ELISA) method which first immobilizes an antibody on a matrix, and prepares a sample solution in which an antigenic protein is mixed on the surface where the antibody is immobilized. After reacting for a certain time, a detection antibody that selectively binds to the antigenic protein on the surface to which the antigenic protein is bound is bound, and then a reaction substance capable of causing the enzyme to develop color or fluorescence by binding an enzyme to the detection antibody. It is a method of quantitating a small amount of antigenic protein by adding a color or fluorescence reaction to occur.
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA method has been used as an effective method for measuring trace antigen proteins
  • the analysis range of antigen proteins is about 10 pg / ml ⁇ 1 ng / ml, and only one antigen protein can be analyzed at a time.
  • the disadvantage is that a large amount of sample is required to analyze various antigenic proteins.
  • the present inventors have diligently tried to develop a method for the electrical detection of a trace amount sample using a biosensor.
  • the biosensor was manufactured by immobilizing a receptor molecule that selectively binds to a target material on an electrically insulated nano-electrode chip.
  • the trace amount of the target material is easily measured. It was confirmed that the present invention can be completed.
  • An object of the present invention is to provide a method for the electrical detection of the trace amount sample using a biosensor.
  • the present invention comprises the steps of: (a) manufacturing a biosensor by immobilizing a receptor molecule that selectively binds to the target material of analysis on the electrically insulated nano-electrode chip; (b) adding and reacting a sample containing a target substance selectively binding to the receptor molecule to the biosensor; (c) treating and reacting the gold nanoparticles to the nano-electrode chip reacted with the sample containing the target material; (d) treating and reducing gold ions around the reacted gold nanoparticles; And (e) measuring an electrical conductivity or impedance of the nano-electrode chip of which the gold ions are reduced to detect a target substance that specifically binds to the receptor molecule.
  • FIG. 1 is a schematic diagram illustrating a measurement method of a target material using a nano-electrode biosensor coupled by a gold nanoparticle-gold ion reduction reaction and a schematic diagram of a chromium electrode biosensor having an electrode interval of 400 nm.
  • A gold ion reduction solution without gold nanoparticles
  • B gold ion reduction solution with gold nanoparticles bound to antibodies
  • C comparison of absorbance over time at 970 nm
  • SEM scanning electron microscope
  • FIG. 4 is an image (A), and SEM images (B and C) of a 400 nm chromium electrode made by the method of Example 2.
  • FIG. 4 is an image (A), and SEM images (B and C) of a 400 nm chromium electrode made by the method of Example 2.
  • FIG. 5 shows the current of the electrode before the reduction of the gold ions to the electrode to which the gold nanoparticles were fixed for 0 pg / ml, 100 pg / ml, and 100 ng / ml of the IL5 antigen, by using a DC current-voltage method.
  • SEM 7 is a Scanning Electron Microscope (SEM) image of the surface of silicon oxide between chromium electrodes prepared by the method of Example 2 for concentrations of 0 pg / ml, 100 pg / ml, 100 ng / ml IL5 antigen to be.
  • FIG. 8 shows the results of measuring the current of the H1N1 virus 0 PFU and 10 3 PFU by using DC current-voltage method on the electrode before the reduction of gold ions to the electrode to which the gold nanoparticles were fixed (A: 0 PFU covered. 10 3 PFU (-)) and the current after reduction of gold ions (B: 0 PFU covered; 10 3 PFU (-)).
  • a biosensor by immobilizing a receptor molecule that selectively binds to the target material to be analyzed on an electrically insulated nano-electrode chip; (b) adding and reacting a sample containing a target substance selectively binding to the receptor molecule to the biosensor; (c) treating and reacting the gold nanoparticles to the nano-electrode chip reacted with the sample containing the target material; (d) treating and reducing gold ions around the reacted gold nanoparticles; And (e) measuring an electrical conductivity or impedance of the nano-electrode chip of which the gold ions are reduced to detect a target substance specifically binding to the receptor molecule. It is about.
  • the nano-electrode chip can be produced by a process selected from the group consisting of photolithography, electron beam lithography, ion-focused lithography and nanoimprinting, the interval between the electrodes in the nano-electrode chip is As demonstrated in the experiment, any nano-electrode chip having a spacing of 1 ⁇ m or less may be applicable, for example, 10 nm to 1 ⁇ m, but is not limited thereto.
  • nano-electrode chip means that a gap between electrodes constituting a generally known biochip is 1 ⁇ m or less or 100 nm or less.
  • the method for measuring electrical conductivity or impedance in the present invention is not particularly limited, and any conventional electrical detection method may be applied to the present invention without limitation.
  • the substrate may be a silicon wafer, glass, or the like
  • the electrode may be chromium, titanium, gold, or the like.
  • one embodiment of the present invention exemplifies IL5 and H1N1 viruses as target substances, but in addition to this, various cytokine, various enzymes, proteins (eg, interleukin), DNA, RNA, microorganisms, viruses, animal cells, plant cells , Organ cells and neurons may be applicable, and the receptor molecule may be selected from the group consisting of antibodies, DNA, aptamers, peptide nucleic acids (PNAs), and ligands.
  • PNAs peptide nucleic acids
  • the gold nanoparticles in the step (c) may be characterized in that the binding to the target material using the additional sensing receptor molecules capable of binding to the target material.
  • the receptor molecule may be an antibody and an antigen-binding agent, with the target substance as an antigen, and thus, detection using the sandwich method as exemplified in the examples may be performed, and at this time, an additional agent for detecting a target substance may be used.
  • Sensing receptor molecules are needed.
  • Such further sensing receptor molecules may also be selected from the group consisting of antibodies, DNA, aptamers, peptide nucleic acids (PNAs) and ligands.
  • the gold nanoparticles may be characterized in that the size of 2nm ⁇ 100nm.
  • the gold nanoparticles can be prepared by mixing gold ions with a reducing agent, and are readily available commercially from reagent companies such as Sigma.
  • the present invention provides the advantage that by using a gold nanoparticle-nano electrode, by reducing the gold ions, one gold nanoparticle can be connected to the electrode during the reduction reaction to increase the current intensity to increase the analysis sensitivity do.
  • the measurement method of the present invention as shown in the following examples, it is possible to detect the target substance at a low concentration of about 1 pg / ml, or even in the case of viruses, 10 PFU. By confirming that the electrical detection is possible, it was confirmed that the detection of a very small amount of sample is possible.
  • the surface of the silicon oxide substrate is modified with an amine group, and then the surface of the substrate modified with the amine group is modified with a biotin group.
  • streptavidin is immobilized on the surface of the substrate modified with the biotin group
  • the biotin-coupled antibody is immobilized.
  • the antigen is reacted, and the gold nanoparticle-bound antibody is reacted to measure sandwich immunity.
  • a gold reduction solution is induced by using a gold chloride solution and a hydroxylamine solution to generate a metal reduction product on the substrate surface. do. After washing the substrate, it can be observed by scanning electron microscopy (SEM) that the precipitate is formed by drying with nitrogen gas.
  • the gold ions are reduced to the gold ions and the reduced electrode respectively, the current flows after the current, after measuring the current, the gold ions are reduced It can be seen that the conductivity of the electrode is increased compared to the electrode that is not reduced, and the current value increases as the concentration of the antigen increases.
  • the concentration of the target substance to be analyzed can be measured.
  • a reducing material obtained through a reduction reaction of gold nanoparticles-gold ions to an electrically insulated nano-electrode chip fills the nano-gap to flow an electric current.
  • a biosensor for detection FIG. 1.
  • the silicon oxide substrate (16 ⁇ 16 mm) was immersed in a solution of 95% sulfuric acid and 30% hydrogen peroxide solution at a volume ratio of 3: 1 at 60 to 65 ° C. for 20 minutes, followed by distilled water and ethanol.
  • the washed silicon oxide substrate was immersed in an ethanol solution dissolved in 1% 3-aminopropyltrimethoxysilane (3-aminopropyltrimethoxysilane, Aldrich, St. Louis, MO, USA) for 1 hour, then washed with ethanol, 100 Treatment at 1 ° C. for 1 hour allowed the substrate surface to be modified with an amine group.
  • the rate buffer solution pH 4.0 was reacted with time.
  • FIG. 2 illustrates a process of forming a reduced product reacted with gold nanoparticles in a liquid phase by using the reducing solution prepared above.
  • gold ions are formed after 5 minutes and 10 minutes. It was confirmed that the maximum afterwards.
  • Figure 3 shows a scanning electron microscope (Scanning Electron Microscope, SEM) image of the silicon oxide substrate prepared above, as a result of confirming the size of the gold nanoparticles according to the reduction time (reduction time) of the gold ions, the reduction time will be longer As the size of the gold nanoparticles gradually increased, it was confirmed that the reduction reaction was about 1 ⁇ m after 7 minutes. This result means that nano-electrodes having a gap of 1 ⁇ m or less can be electrically connected by gold ion reduction.
  • Example 2 IL5 Detection Using Gold Nanoparticle-Gold Ion Reduction at 400 nm Chromium Electrode
  • a 400 nm chromium electrode was prepared by a stepper photolithography process and an electron beam deposition process (FIG. 4). After the silicon oxide film was formed on the silicon wafer by low pressure chemical vapor deposition (LPCVD), the pattern was first patterned by stepper photolithography to form a line having a 400 nm line width on the surface. Cr 100 nm was deposited by a thermal evaporator.
  • Figure 4 shows an SEM image of the electrode (that is, interdigitated electrode) manufactured by the above process, it can be seen that the electrode insulated at intervals of 400 nm.
  • the prepared electrode was immersed in a solution of 95% sulfuric acid and 30% hydrogen peroxide solution at a volume ratio of 3: 1 at 60 to 65 ° C. for 20 minutes, and then washed with distilled water and ethanol.
  • the washed electrode was immersed in an ethanol solution in which 1% 3-aminopropyltrimethoxysilane (Aldrich, St. Louis, MO, USA) was dissolved for 1 hour, washed with ethanol, and then washed at 100 ° C. After processing for 1 hour, the silicon oxide surface between the chromium electrodes was modified with an amine group.
  • NHS-LC-biotin (10 mg / ml) dissolved in dimethyl sulfooxide (DMSO, dimethy sulfoxide, SImga-Aldrich, St. Louis, MO, USA) at a concentration of 10 mg / ml ( NHS-LC-biotin, Thermo sciences, Rockford, IL, USA) was treated with a solution adjusted to a concentration of 1 mg / ml with PBS buffer, and reacted at room temperature for 1 hour to replace an amine group with a biotin group.
  • DMSO dimethyl sulfooxide
  • SImga-Aldrich SImga-Aldrich, St. Louis, MO, USA
  • streptavidin Streptavidin, SImga-Aldrich, St. Louis, MO, USA
  • PBS buffer pH 7.4
  • the biotin-bound IL5 antibody was immobilized on the surface of streptavidin, and the antigen-antibody reaction was performed at an concentration of 0 pg / ml-100 ng / ml.
  • the IL5 antibody with 10 nm gold nanoparticles was reacted with the antigen immobilized on the surface, followed by 25 mM gold tetrachloride (HAuCl 4 , hydrogen tetrachlorideaurate (III), Aldrich, Millwauke, WI, USA) and 5 mM hydroxylamine.
  • 10 mM citrate buffer (pH 4.0) dissolved in (hydroxylamine hydrochloride, Sigma, St. Louis, MO, USA) was reacted for 10 minutes to reduce gold ions to gold nanoparticles.
  • the currents of the electrodes in which the gold ions were not reduced and the electrodes in which the gold ions were reduced were measured.
  • FIG. 6 is a graph showing the current value for 1 V after the gold ion reduction according to the concentration of IL5 antigen, it was confirmed that the current value increases as the concentration of the antigen increases.
  • Example 3 H1N1 Virus Detection Using Gold Nanoparticle-Gold Ion Reduction at 400 nm Titanium Electrodes
  • a 400 nm titanium electrode was fabricated by a stepper photolithography process and an electron beam deposition process.
  • a silicon oxide film was formed on the silicon wafer by low pressure chemical vapor deposition (LPCVD), and then patterned by stepper photolithography to form a line having a 400 nm line width on the surface.
  • Titanium 30 nm was deposited by thermal evaporator.
  • the silicon oxide surface between the titanium electrodes was made into the streptavidin surface in the same manner as in Example 2. Then, biotin-bound H1N1 virus antibody (rabbit polyclonal) was immobilized on the surface of streptavidin, 17 ⁇ l of H1N1 virus solution (suspended in pH 7.4 PBS buffer) was reacted on the sensor surface, and the amount of virus reacted was 0. , 10 1 , 10 2 , and 10 3 PFU (plaque forming units).
  • each electrode was washed with PBS and reacted with a H1N1 antibody (mouse monoclonal) with 10 nm gold nanoparticles followed by 25 mM gold tetrachloride (HAuCl 4 , hydrogen tetrachlorideaurate (III), Aldrich, Millwauke, WI, USA). And 10 mM citrate buffer (pH 4.0) dissolved in 5 mM hydroxylamine (Sigma, St. Louis, MO, USA) were reacted for 10 minutes to reduce gold ions to gold nanoparticles.
  • the electrical detection method of the trace amount sample using the biosensor according to the present invention can not only connect between the nano-electrodes by one gold nanoparticle-gold ion reduction reaction, but also between the electrically insulated nano-electrodes
  • the electrical conductivity is increased by increasing the electrical conductivity, so that the measurement sensitivity is high, the trace sample can be quantitatively analyzed, and the selectively bound antigen-antibody binding can be measured very simply by an electrical method.

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Abstract

La présente invention concerne un biocapteur électrique pour la détection d'un échantillon infinitésimal. Plus spécifiquement, la présente invention concerne un procédé de détection électrique d'un échantillon infinitésimal comprenant les étapes de : (a) préparation d'un biocapteur par fixation, sur une puce à nano-électrodes électriquement isolées d'une molécule de récepteur qui est sélectivement couplée à une substance cible à soumettre à un dosage ; (b) ajout d'un échantillon qui contient la substance cible sélectivement couplée à la molécule de récepteur, au biocapteur pour la réaction ; (c) traitement de la puce à nano-électrodes qui a réagi avec l'échantillon contenant la substance cible et réaction avec des nanoparticules d'or ; (d) traitement des régions périphériques des nanoparticules d'or ayant réagi, avec des ions or afin d'induire une réduction des ions or ; et (e) mesure de la conductivité ou de l'impédance électrique de la puce à nano-électrodes dans laquelle les ions or ont été réduits, détectant ainsi une substance cible qui est spécifiquement liée à la molécule de récepteur. Le procédé de détection électrique d'un échantillon infinitésimal à l'aide du biocapteur selon la présente invention non seulement interconnecte des nano-électrodes par une seule réaction de réduction entre des nanoparticules d'or et des ions or, mais il interconnecte également électriquement les nano-électrodes électriquement isolées, de telle sorte que la conductivité électrique soit augmentée. Ainsi, la sensibilité de mesure est élevée, le dosage quantitatif d'un échantillon infinitésimal devient possible et une liaison sélective antigène-anticorps peut être mesurée par un procédé électrique très simple.
PCT/KR2011/003799 2010-05-24 2011-05-24 Biocapteur électrique pour la détection d'un échantillon infinitésimal WO2011149249A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015182918A1 (fr) * 2014-05-28 2015-12-03 주식회사 미코 Biocapteur possandant un nanoespace

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Publication number Priority date Publication date Assignee Title
KR101875135B1 (ko) * 2016-07-04 2018-07-06 부산대학교 산학협력단 교류 전위 변조 마이크로플루이딕 채널을 이용한 압타머 선별 방법

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US20050176051A1 (en) * 1998-12-23 2005-08-11 Genetrix B.V. Affinity sensor for detecting specific molecular binding events and use thereof
EP1516174B1 (fr) * 2002-06-24 2007-12-26 Universite Catholique De Louvain Procede et dispositif de detection haute sensibilite de presence d'adn et d'autres sondes
US20080241964A1 (en) * 2007-03-27 2008-10-02 Canon Kabushiki Kaisha Material for improving sensitivity of magnetic sensor and method thereof
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SILVANA ANDREESCU ET AL.: 'Steudies of the Binding and Signaling of Surface- immobilized Periplasmic Glucose Receptors on Gold Nanoparticles: A Glucose Biosensor Application' ANALYTICAL BIOCHEMISTRY vol. 375, no. 2, 2008, pages 282 - 290 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015182918A1 (fr) * 2014-05-28 2015-12-03 주식회사 미코 Biocapteur possandant un nanoespace

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