WO2015046577A1 - Capteur, procédé de détection, système de détection et dispositif de détection - Google Patents

Capteur, procédé de détection, système de détection et dispositif de détection Download PDF

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Publication number
WO2015046577A1
WO2015046577A1 PCT/JP2014/076134 JP2014076134W WO2015046577A1 WO 2015046577 A1 WO2015046577 A1 WO 2015046577A1 JP 2014076134 W JP2014076134 W JP 2014076134W WO 2015046577 A1 WO2015046577 A1 WO 2015046577A1
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WIPO (PCT)
Prior art keywords
binding
sensor
detection
ohdg
substance
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Application number
PCT/JP2014/076134
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English (en)
Japanese (ja)
Inventor
竜司 米田
和博 西薗
顕嗣 山本
安田　隆則
慎之介 仲村
広治 丹羽
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京セラ株式会社
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Publication of WO2015046577A1 publication Critical patent/WO2015046577A1/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
    • G01N33/53—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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G01N29/022—Fluid sensors based on microsensors, e.g. quartz crystal-microbalance [QCM], surface acoustic wave [SAW] devices, tuning forks, cantilevers, flexural plate wave [FPW] devices
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/22—Details, e.g. general constructional or apparatus details
    • G01N29/222—Constructional or flow details for analysing fluids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/025—Change of phase or condition
    • G01N2291/0255—(Bio)chemical reactions, e.g. on biosensors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/025—Change of phase or condition
    • G01N2291/0256—Adsorption, desorption, surface mass change, e.g. on biosensors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/04—Wave modes and trajectories
    • G01N2291/042—Wave modes
    • G01N2291/0423—Surface waves, e.g. Rayleigh waves, Love waves

Definitions

  • the present invention relates to a sensor, a detection method, a detection system, and a detection apparatus.
  • a detection method for detecting a change in the state of the substrate surface For example, there is a sensor that measures the properties or components of a specimen solution using an ELISA (Enzyme Linked Immuno Solvent Assay) method or a surface acoustic wave.
  • ELISA Enzyme Linked Immuno Solvent Assay
  • the conventional method has a problem that 8-OHdG cannot be measured easily and accurately in a short time.
  • the disclosed sensor is located on the surface of the substrate, the first IDT (InterDigital Transducer) electrode that generates an elastic wave, and is located on the surface of the substrate, and propagates from the first IDT electrode. It is located in the propagation path of the second IDT electrode that receives the elastic wave and the elastic wave that propagates from the first IDT electrode to the second IDT electrode, and can bind to a specific binding substance that can bind to 8-OHdG in the specimen. And a detection unit having a simple coupling unit.
  • IDT InterDigital Transducer
  • FIG. 1 is a perspective view of a sensor according to an embodiment of the present invention.
  • FIG. 2 is an exploded perspective view of the first cover member and the second cover member.
  • FIG. 3 is a perspective view of the sensor shown in FIG. 1 with the fourth base body removed.
  • 4A is a cross-sectional view taken along the line IVa-IVa 'of
  • FIG. 4B is a cross-sectional view taken along line IVb-IVb ′ of FIG.
  • FIG. 5 is a perspective view of a detection element used in the sensor shown in FIG.
  • FIG. 6 is a plan view of the detection element shown in FIG. 5 with the first and second joining members removed.
  • FIG. 7 is a cross-sectional view showing a modified example of the sensor according to the embodiment of the present invention.
  • FIG. 1 is a perspective view of a sensor according to an embodiment of the present invention.
  • FIG. 2 is an exploded perspective view of the first cover member and the second cover member.
  • FIG. 3 is a perspective
  • FIG. 8 is a cross-sectional view showing another modified example of the sensor according to the embodiment of the present invention.
  • FIG. 9 is a perspective view showing an example of a sensor when a cover member is joined to a base.
  • FIG. 10 is a perspective view showing an example of the sensor when one half of the cover member is removed.
  • FIG. 11A is a cross-sectional view illustrating an example of a sensor when a cover member is bonded to a base.
  • FIG. 11B is a cross-sectional view illustrating an example of a sensor when a cover member is bonded to a base.
  • FIG. 12 is a perspective view showing an example of a modified example of the sensor according to the embodiment of the present invention.
  • FIG. 13 is a perspective view showing an example of a modification of the sensor according to the embodiment of the present invention.
  • FIG. 14 is a diagram showing 8-OHdG.
  • FIG. 15A is a diagram illustrating an example of the detection unit of the sensor according to the embodiment of the present invention.
  • FIG. 15B is a diagram illustrating an example of the detection unit of the sensor according to the embodiment of the present invention.
  • FIG. 16 is a diagram illustrating an example of a technique for producing a detection unit of a sensor according to an embodiment of the present invention.
  • FIG. 17A is a diagram for explaining a model of a part of the detection unit of the sensor according to the embodiment of the present invention.
  • FIG. 17B is a diagram for describing a part of the detection unit of the sensor according to the embodiment of the present invention as a model.
  • FIG. 18 is a diagram for explaining a process of binding a specific binding substance to the detection unit of the sensor according to the embodiment of the present invention.
  • FIG. 19 is a diagram for explaining a process of binding a specific binding substance to the detection unit of the sensor according to the embodiment of the present invention.
  • FIG. 20 is a plan view showing a detection element of the sensor according to the embodiment of the present invention.
  • FIG. 21 is a diagram illustrating an example of a detection method according to the embodiment of the present invention.
  • FIG. 22 is a diagram showing the results of Examples 1 to 4 and Comparative Examples 1 to 4.
  • the disclosed sensor includes a base.
  • the disclosed sensor includes a first IDT (InterDigital Transducer) electrode that is located on the surface of the substrate and generates an elastic wave.
  • the disclosed sensor includes a second IDT electrode that is located on the surface of the base and receives an elastic wave propagating from the first IDT electrode.
  • the disclosed sensor is located in the propagation path of the elastic wave propagating from the first IDT electrode to the second IDT electrode, and has a binding part capable of binding to a specific binding substance capable of binding to 8-OHdG in the specimen. A part.
  • the disclosed detection method is a detection method for determining whether 8-OHdG is contained in a specimen.
  • the disclosed detection method is, for example, an elastic wave propagating from a first IDT (InterDigital Transducer) electrode that generates an elastic wave to a second IDT electrode that receives the elastic wave propagating from the first IDT electrode on the surface of the substrate.
  • the method includes a step of bringing the specimen brought into contact with the specific binding substance into contact with the detection unit of the sensor.
  • the method includes a step of detecting whether 8-OHdG is contained in the specimen by detecting the binding between the specific binding substance and the binding portion generated in the above step.
  • the disclosed detection system is located on a propagation path of an elastic wave propagating from a first IDT (InterDigital Transducer) electrode that generates elastic waves to a second IDT electrode that receives elastic waves propagating from the first IDT electrode on the surface of the substrate.
  • a sensor having a detection part having a binding part capable of binding to a specific binding substance capable of binding to 8-OHdG in the specimen is provided in the part to be tested. Detection that detects whether 8-OHdG is contained in the specimen by contacting the specimen that has been brought into contact with the specific binding substance with the detection part of the sensor and detecting the binding between the specific binding substance and the binding part. Have the device.
  • the disclosed detection apparatus is located on a propagation path of an elastic wave propagating from a first IDT (InterDigital Transducer) electrode that generates elastic waves to a second IDT electrode that receives elastic waves propagating from the first IDT electrode on the surface of the substrate.
  • a first IDT InterDigital Transducer
  • a second IDT electrode that receives elastic waves propagating from the first IDT electrode on the surface of the substrate.
  • a binding portion is provided in a propagation path of an elastic wave propagating from the first IDT electrode to the second IDT electrode and can bind to a specific binding substance capable of binding to 8-OHdG in the specimen.
  • 8-OHdG is used for health management and disease diagnosis. For example, hypertension, obesity, non-alcoholic hepatitis, Alzheimer's dementia, cancer, diabetes, myocardial infarction, stroke and other cardiovascular diseases, muscle atrophy Used as a marker for lateral sclerosis (neurological disorder).
  • the disclosed sensor can be used in a detection method for detecting a change in the state of the substrate surface.
  • the disclosed sensor includes a measurement cell used for measurement by an SPR (Surface Plasmon Resonance) apparatus, a SAW (Surface Acoustic Wave) sensor, a QCM (Quarts Crystal Microbalance, crystal oscillator microbalance method). ) A crystal sensor or the like.
  • the sensor is preferably a SAW sensor from the viewpoint of miniaturization.
  • FIG. 1 is a perspective view of a sensor according to an embodiment of the present invention.
  • the sensor 100 as the SAW sensor is bonded to the first cover member 1 and the first cover member 1 in which the base body 10 is located on the upper surface, for example.
  • at least one of the first cover member 1 and the second cover member 2 is provided between the inlet 14 through which the sample flows and the first cover member 1 and the second cover member 2.
  • It has a groove 15 (hereinafter also referred to as a flow path 15) extending from the inlet 14 to at least the surface of the substrate 10.
  • the first cover member 1 has a concave portion that accommodates at least a part of the base body 10 on the upper surface
  • the second cover member 2 has a groove portion 15.
  • the sensor 100 as the SAW sensor is located on the surface of the base body 10 in an example of the embodiment, and generates details of an elastic wave that propagates toward a detection unit 13 (see FIG. 3) described later. It has 1 IDT (InterDigital Transducer) electrode.
  • the sensor 100 has a second IDT electrode that is located on the surface of the base body 10 and receives an elastic wave that has passed through the detection unit 13.
  • the sensor 100 includes a first bonding member that is bonded to the upper surface of the base body 10 and has a first vibration space sealed between the upper surface of the base body 10.
  • the sensor 100 includes a second bonding member that is bonded to the upper surface of the base body 10 and has a second vibration space that is sealed between the upper surface of the base body 10.
  • the first vibration space is located on the first IDT electrode
  • the second vibration space is located on the second IDT electrode.
  • the senor 100 as a SAW sensor will be described in detail with reference to the drawings as appropriate.
  • the same code shall be attached
  • the size of each member, the distance between members, and the like are schematically illustrated, and may differ from actual ones.
  • the sensor 100 may have either direction upward or downward, but for the sake of convenience, an orthogonal coordinate system xyz is defined below, and the positive side in the z direction is defined as the upper side and the lower side for convenience. The following terms shall be used.
  • the sensor 100 mainly includes a first cover member 1, a second cover member 2, and a detection element 3.
  • the first cover member 1 includes a first base 1a and a second base 1b stacked on the first base 1a.
  • the second cover member 2 includes a third base 2a stacked on the second base 1b and It has the 4th base 2b laminated on the 3rd base 2a.
  • the detection element 3 is a surface acoustic wave element, and mainly includes a base 10, a first IDT electrode 11, a second IDT electrode 12, and a detection unit 13.
  • the first cover member 1 and the second cover member 2 are bonded together, and the detection element 3 is housed inside the bonded first cover member 1 and second cover member 2.
  • the first cover member 1 has a recess 5 on the upper surface, and the detection element 3 is disposed in the recess 5.
  • the second cover member 2 has an inlet 14 that is an inlet of a sample solution at an end portion in the longitudinal direction (x direction), and from the inlet 14 toward a portion immediately above the detection element 3.
  • An extended groove 15 is provided.
  • the groove portion 15 is indicated by a broken line in order to indicate the position of the groove portion 15.
  • the sample solution is a solution that is a target for detecting whether 8-OHdG is contained or the concentration of 8-OHdG is detected.
  • FIG. 2 is an exploded perspective view of the first cover member 1 and the second cover member 2.
  • the first cover member 1 includes the first base 1a and the second base 1b stacked on the first base 1a.
  • the first base 1a constituting the first cover member 1 has a flat plate shape, and its thickness is, for example, 0.1 mm to 0.5 mm.
  • the planar shape of the first base 1a is generally rectangular, but one end in the longitudinal direction is an arc shape protruding outward.
  • the length of the first substrate 1a in the x direction is, for example, 1 cm to 5 cm, and the length in the y direction is, for example, 1 cm to 3 cm.
  • the second substrate 1b is bonded to the upper surface of the first substrate 1a.
  • the second base 1b has a flat frame shape in which a through hole 4 for forming a recess is provided in a flat plate, and the thickness thereof is, for example, 0.1 mm to 0.5 mm.
  • the outer shape when viewed in plan is substantially the same as that of the first substrate 1a, and the length in the x direction and the length in the y direction are also substantially the same as those of the first substrate 1a.
  • a concave portion 5 is formed in the first cover member 1 by joining the second base 1b provided with the through hole 4 for forming the concave portion to the flat first base 1a. That is, the upper surface of the first base 1 a located inside the through hole 4 for forming recesses is the bottom surface of the recess 5, and the inner wall of the through hole 4 for forming recesses is the inner wall of the recess 5.
  • the terminal 6 and the wiring 7 routed from the terminal 6 to the through hole 4 for forming the recess are formed on the upper surface of the second base 1b.
  • the portion where the terminal 6 is formed is a portion that is actually inserted when the sensor 100 is inserted into an external measuring instrument (not shown), and is electrically connected to the external measuring instrument via the terminal 6. Will be. Further, the terminal 6 and the detection element 3 are electrically connected through a wiring 7 or the like. Then, a signal from an external measuring instrument is input to the sensor 100 via the terminal 6, and a signal from the sensor 100 is output to the external measuring instrument via the terminal 6.
  • the second cover member 2 includes the third base 2a stacked on the second base 1b and the fourth base 2b stacked on the third base 2a.
  • a second cover member 2 is joined to the upper surface of the first cover member 1 composed of the first base 1a and the second base 1b.
  • the second cover member 2 has a third base 2a and a fourth base 2b.
  • the third substrate 2a is bonded to the upper surface of the second substrate 1b.
  • the third base 2a has a flat plate shape, and its thickness is, for example, 0.1 mm to 0.5 mm.
  • the planar shape of the third base 2a is generally rectangular, but one end in the longitudinal direction has an arc shape protruding outward as in the first base 1a and the second base 1b.
  • the length of the third base 2a in the x direction is slightly shorter than the length of the second base 1b in the x direction so that the terminals 6 formed on the second base 1b are exposed. 4.8 cm.
  • the length in the y direction is, for example, 1 cm to 3 cm as in the first base 1a and the second base 1b.
  • a notch 8 is formed in the third base 2a.
  • the notch 8 is a portion in which the third base 2a is cut out from the apex at one end of the third base 2a in the arc shape toward the other end in the x direction.
  • the notch 8 is for forming the groove 15.
  • a first through hole 16 and a second through hole 17 that penetrate the third base body 2a in the thickness direction are formed on both sides of the notch 8 of the third base body 2a.
  • a portion between the first through hole 16 and the notch 8 of the third base 2a serves as a first partition 25 that partitions the groove 15 and the space formed by the first through hole 16 as will be described later. Further, a portion between the second through hole 17 and the notch 8 of the third base 2 a becomes a second partition part 26 that partitions the groove 15 and the space formed by the second through hole 17.
  • the fourth substrate 2b is bonded to the upper surface of the third substrate 2a.
  • the fourth base 2b has a flat plate shape and has a thickness of, for example, 0.1 mm to 0.5 mm.
  • the outer shape when viewed in plan is substantially the same as that of the third substrate 2a, and the length in the x direction and the length in the y direction are also substantially the same as those of the third substrate 2a.
  • the fourth base 2b is joined to the third base 2a in which the notch 8 is formed, whereby the groove 15 is formed on the lower surface of the second cover member 2. That is, the lower surface of the fourth base 2 b located inside the notch 8 becomes the bottom surface of the groove 15, and the inner wall of the notch 8 becomes the inner wall of the groove 15.
  • the groove 15 extends from the inflow port 14 to at least a region directly above the detection unit 13, and the cross-sectional shape is, for example, a rectangular shape.
  • a third through hole 18 is formed in the fourth base 2b so as to penetrate the fourth base 2b in the thickness direction.
  • the third through hole 18 is located on the end of the notch 8 when the fourth base 2b is laminated on the third base 2a. Therefore, the end portion of the groove portion 15 is connected to the third through hole 18.
  • the third through hole 18 is for releasing the air in the groove 15 to the outside.
  • the first base 1a, the second base 1b, the third base 2a, and the fourth base 2b are made of, for example, paper, plastic, celluloid, ceramics, or the like. These substrates can all be formed of the same material. By forming all of these substrates from the same material, the thermal expansion coefficients of the respective substrates can be made substantially uniform, so that deformation due to the difference in the thermal expansion coefficients of the respective substrates is suppressed.
  • the detection unit 13 may be coated with a biomaterial, but some of the detection unit 13 is easily deteriorated by external light such as ultraviolet rays. In that case, an opaque material having a light shielding property may be used as the material of the first cover member 1 and the second cover member 2.
  • the second cover member 2 in which the groove 15 is formed may be formed of a material that is nearly transparent. In this case, the state of the sample solution flowing in the flow channel 15 can be visually confirmed.
  • FIG. 5 is a perspective view of the detection element 3
  • FIG. 6 is a plan view of the detection element 3 with the first bonding member 21 and the second bonding member 22 removed.
  • the detection element 3 includes a base 10, a detection unit 13 disposed on the upper surface of the base 10, a first IDT electrode 11, a second IDT electrode 12, a first extraction electrode 19, and a second extraction electrode 20.
  • the substrate 10 is made of, for example, a single crystal substrate having piezoelectricity such as lithium tantalate (LiTaO 3 ) single crystal, lithium niobate (LiNbO 3 ) single crystal, or quartz.
  • the planar shape and various dimensions of the substrate 10 may be set as appropriate.
  • the thickness of the substrate 10 is 0.3 mm to 1 mm.
  • the first IDT electrode 11 has a pair of comb electrodes as shown in FIG. Each comb electrode has two bus bars facing each other and a plurality of electrode fingers extending from each bus bar to the other bus bar side. The pair of comb electrodes are arranged so that a plurality of electrode fingers mesh with each other.
  • the second IDT electrode 12 is configured similarly to the first IDT electrode 11.
  • the first IDT electrode 11 and the second IDT electrode 12 constitute a transversal IDT electrode.
  • the first IDT electrode 11 is for generating a predetermined surface acoustic wave (SAW), and the second IDT electrode 12 is for receiving the SAW generated by the first IDT electrode 11.
  • the first IDT electrode 11 and the second IDT electrode 12 are arranged in the same straight line so that the second IDT electrode 12 can receive the SAW generated in the first IDT electrode 11.
  • the frequency characteristics can be designed using parameters such as the number of electrode fingers of the first IDT electrode 11 and the second IDT electrode 12, the distance between adjacent electrode fingers, the width of intersection of the electrode fingers, and the like.
  • SAWs excited by the IDT electrodes there are various vibration modes.
  • the detection element 3 uses a vibration mode of a transverse wave called an SH wave.
  • an elastic member for suppressing SAW reflection may be provided outside the first IDT electrode 11 and the second IDT electrode 12 in the SAW propagation direction (y direction).
  • the SAW frequency can be set, for example, within a range of several megahertz (MHz) to several gigahertz (GHz). In particular, if it is several hundred MHz to 2 GHz, it is practical, and downsizing of the detection element 3 and thus downsizing of the sensor 100 can be realized.
  • the first IDT electrode 11 is connected to the first extraction electrode 19.
  • the first extraction electrode 19 is extracted from the first IDT electrode 11 to the side opposite to the detection unit 13, and the end 19 e of the first extraction electrode 19 is electrically connected to the wiring 7 provided on the first cover member 1. Yes.
  • the second IDT electrode 12 is connected to the second extraction electrode 20.
  • the second extraction electrode 20 is extracted from the second IDT electrode 12 to the side opposite to the detection unit 13, and the end 20 e of the second extraction electrode 20 is electrically connected to the wiring 7.
  • the first IDT electrode 11, the second IDT electrode 12, the first extraction electrode 19 and the second extraction electrode 20 are made of, for example, aluminum, an alloy of aluminum and copper, or gold. These electrodes may have a multilayer structure. In the case of a multilayer structure, for example, the first layer is made of titanium or chromium, and the second layer is made of aluminum, an aluminum alloy, or gold.
  • the first IDT electrode 11 and the second IDT electrode 12 are covered with a protective film (not shown).
  • the protective film contributes to preventing oxidation of the first IDT electrode 11 and the second IDT electrode 12.
  • the protective film is made of, for example, silicon oxide, aluminum oxide, zinc oxide, titanium oxide, silicon nitride, or silicon.
  • the thickness of the protective film is, for example, about 1/10 (10 to 30 nm) of the thickness of the first IDT electrode 11 and the second IDT electrode 12.
  • the protective film may be formed over the entire top surface of the substrate 10 so as to expose the end 19e of the first extraction electrode 19 and the end 20e of the second extraction electrode 20.
  • the detection unit 13 is provided between the first IDT electrode 11 and the second IDT electrode 12. Specifically, the detection unit 13 is provided in a propagation path of an elastic wave propagating from the first IDT electrode 11 to the second IDT electrode 12, and is a binding unit that can bind to a specific binding substance 210 that can bind to 8-OHdG.
  • the detection unit 13 includes, for example, a fixed film 200 and a coupling part fixed on the surface of the fixed film 200 (see FIGS. 15A and 15B).
  • the fixed film 200 has, for example, a gold film or a gold two-layer structure formed on chromium.
  • a protective film 41 see FIGS. 11A and 11B described later may be interposed between the base 10 and the fixed film 200. The details of the detection unit 13 will be described later and will not be described.
  • the sensor 100 is provided with two sets.
  • FIG. 6 shows an example in which two sets described above are provided.
  • the present invention is not limited to this.
  • a reference electrode is used instead of the detection unit 13. May be used as a reference portion.
  • the first IDT electrode 11 is covered with a first joining member 21 as shown in FIG.
  • the first joining member 21 is located on the upper surface of the base 10 and is hollow inside.
  • a hollow portion of the first bonding member 21 in a state where the first bonding member 21 is placed on the upper surface of the base body 10 is the first vibration space 23.
  • the first IDT electrode 11 is sealed in the first vibration space 23. Thereby, the first IDT electrode 11 is isolated from the outside air and the sample solution, and the first IDT electrode 11 can be protected. Further, by securing the first vibration space 23, it is possible to suppress the deterioration of the characteristics of the SAW excited in the first IDT electrode 11.
  • the second IDT electrode 12 is covered with a second bonding member 22 as shown in FIG.
  • the second joining member 22 is also located on the upper surface of the substrate 10 like the first joining member 21, and the inside is hollow as shown in FIG. 4A.
  • a hollow portion of the second bonding member 22 in a state where the second bonding member 22 is placed on the upper surface of the base body 10 is the second vibration space 24.
  • the second IDT electrode 12 is sealed in the second vibration space 24. Thereby, the second IDT electrode 12 is isolated from the outside air and the sample solution, and the second IDT electrode 12 can be protected. Further, by securing the second vibration space 24, it is possible to suppress the deterioration of the characteristics of the SAW received at the second IDT electrode 12.
  • the first vibration space 23 and the second vibration space 24 may have a rectangular parallelepiped shape, may have a dome shape when viewed in cross-section, and may have an elliptical shape when viewed in plan. Any shape may be used in accordance with the shape and arrangement of the IDT electrode.
  • the first joining member 21 includes a rectangular frame fixed to the upper surface of the base 10 so as to surround the two first IDT electrodes 11 arranged along the x direction, and a frame so as to close the opening of the frame. It consists of a lid fixed to the body. Such a structure can be formed, for example, by forming a resin film using a photosensitive resin material and patterning the resin film by a photolithography method or the like.
  • the second joining member 22 has the same configuration and can be formed in the same manner.
  • the two first IDT electrodes 11 are covered with one first bonding member 21, but the two first IDT electrodes 11 may be covered with separate first bonding members 21.
  • the two first IDT electrodes 11 may be covered with one first joining member 21 and a partition may be provided between the two first IDT electrodes 11.
  • the two second IDT electrodes 12 may be covered with separate second joining members 22, or between the two second IDT electrodes 12 using one second joining member 22. A partition may be provided.
  • a mechanism for detecting a target material using the detection element 3 using SAW will be described.
  • a predetermined voltage is applied to the first IDT electrode 11 from an external measuring instrument via the wiring 7, the first extraction electrode 19, and the like.
  • the surface of the substrate 10 is excited in the formation region of the first IDT electrode 11, and SAW having a predetermined frequency is generated.
  • a part of the generated SAW propagates toward the detection unit 13, passes through the detection unit 13, and then reaches the second IDT electrode 12.
  • the detection unit 13 when the first substance is included in the sample solution, a change caused by the substance having a higher molecular weight than the first substance is caused on the substrate surface. Occur. As a result, characteristics such as the phase of the SAW passing under the detection unit 13 change. When the SAW whose characteristics have changed in this way reaches the second IDT electrode 12, a voltage corresponding to the SAW is generated in the second IDT electrode 12. This voltage is output to the outside through the second extraction electrode 20, the wiring 7, etc., and the properties and components of the sample solution can be examined by reading it with an external measuring instrument.
  • the sensor 100 uses a capillary phenomenon. Specifically, since the second cover member 2 is joined to the first cover member 1, the groove portion 15 formed on the lower surface of the second cover member 2 becomes an elongated tube. Taking into account the material of the first cover member 1 and the second cover member 2, by setting the width or diameter of the groove portion 15 to a predetermined value, a capillary phenomenon is caused in the elongated tube formed by the groove portion 15. Can do.
  • the width (dimension in the y direction) of the groove 15 is, for example, 0.5 mm to 3 mm, and the depth (dimension in the z direction) is, for example, 0.1 mm to 0.5 mm.
  • the groove part 15 has the extension part 15e which is a part extended beyond the detection part 13, and the 3rd through-hole 18 connected with the extension part 15e is formed in the 2nd cover member 2. As shown in FIG. When the sample solution enters the flow path 15, the air present in the flow path 15 is released to the outside from the third through hole 18.
  • the sample solution By forming a tube that generates such a capillary phenomenon in a cover member made up of the first cover member 1 and the second cover member 2, if the sample solution is brought into contact with the inflow port 14, the sample solution will form the groove portion 15. It is sucked into the cover member as a flow path. Therefore, according to the sensor 100, since the sample solution itself includes the sample solution suction mechanism, the sample solution can be sucked without using an instrument such as a pipette. Moreover, since the part with the inflow port 14 is roundish and the inflow port 14 is formed at the apex, the inflow port 14 is easily discriminated.
  • the channel 15 of the sample solution formed by the groove 15 has a depth of about 0.3 mm, while the detection element 3 has a thickness of about 0.3 mm.
  • the thickness of 3 is almost equal. Therefore, if the detection element 3 is placed on the flow channel 15 as it is, the flow channel 15 is blocked. Therefore, in the sensor 100, as shown in FIG. 4, a recess 5 is provided in the first cover member 1 on which the detection element 3 is mounted, and the detection element 3 is accommodated in the recess 5, thereby The flow path 15 is not blocked. That is, the flow path 15 formed by the groove 15 can be secured by setting the depth of the recess 5 to be approximately equal to the thickness of the detection element 3 and mounting the detection element 3 in the recess 5.
  • FIG. 3 is a perspective view of the second cover member 2 in a state where the fourth base 2b is removed. Since the sample solution channel 15 is secured, the sample solution that has flowed into the channel 15 by capillary action is shown. Can be smoothly guided to the detection unit 13.
  • the height from the bottom surface of the concave portion 5 on the upper surface of the substrate 10 is equal to or greater than the depth of the concave portion 5 from the viewpoint of sufficiently securing the sample solution flow path 15. Keep it small. For example, if the height of the upper surface of the base 10 from the bottom surface of the recess 5 is the same as the depth of the recess 5, the bottom surface of the flow path 15 and the detection unit 13 can be obtained when the inside of the groove portion 15 is viewed from the inlet 14. Can be approximately the same height.
  • the thickness of the base 10 is made smaller than the depth of the recess 5, and the height from the bottom surface of the recess 5 of the first bonding member 21 and the second bonding member 22 is substantially the same as the depth of the recess 5. I have to.
  • the first partition portion 25 and the second partition portion 26 of the third base 2a are replaced with other portions.
  • it is necessary to perform such processing by making the height of the first and second joining members 21 and 22 from the bottom surface of the recess 5 substantially the same as the depth of the recess 5. The production efficiency is improved.
  • the planar shape of the recess 5 is, for example, a shape similar to the planar shape of the substrate 10, and the recess 5 is slightly larger than the substrate 10. More specifically, the recess 5 is sized so that a gap of about 100 ⁇ m is formed between the side surface of the substrate 10 and the inner wall of the recess 5 when the substrate 10 is mounted in the recess 5.
  • the detection element 3 is fixed to the bottom surface of the recess 5 with a die bond material mainly composed of epoxy resin, polyimide resin, silicon resin, or the like.
  • the end 19e of the first extraction electrode 19 and the wiring 7 are electrically connected by a metal thin wire 27 (see FIG. 4A) made of, for example, Au.
  • the connection between the end 20e of the second extraction electrode 20 and the wiring 7 is the same.
  • the connection between the first extraction electrode 19 and the second extraction electrode 20 and the wiring 7 is not limited to the metal thin wire 27, and may be a conductive adhesive such as Ag paste, for example.
  • a gap is provided in the connection portion between the first extraction electrode 19 and the second extraction electrode 20 and the wiring 7. Therefore, when the 2nd cover member 2 is bonded together to the 1st cover member 1, damage to the metal fine wire 27 is suppressed.
  • This void can be easily formed by providing the first through hole 16 and the second through hole 17 in the third base 2a.
  • the presence of the first partition portion 25 between the first through hole 16 and the groove portion 15 prevents the sample solution flowing through the groove portion 15 from flowing into the gap formed by the first through hole 16. it can. Thereby, it is possible to suppress occurrence of a short circuit due to the sample solution between the plurality of first extraction electrodes 19.
  • the presence of the second partition portion 26 between the second through hole 17 and the groove portion 15 suppresses the sample solution flowing through the groove portion 15 from flowing into the gap formed by the second through hole 17. Can do. Thereby, it is possible to suppress occurrence of a short circuit due to the sample solution between the plurality of second extraction electrodes 20.
  • the first partition portion 25 is located on the first joining member 21, and the second partition portion 26 is located on the second joining member 22. Therefore, more strictly speaking, the flow path 15 of the specimen solution is defined not only by the groove 15 but also by the side wall on the groove 15 side of the first bonding member 21 and the side wall on the groove 15 side of the second bonding member 22.
  • the first partition portion 25 is on the upper surface of the first bonding member 21, and the second partition portion 26 is Although it is better to contact the upper surface of the second joining member 22, in the sensor 100, between the lower surface of the first partition part 25 and the upper surface of the first joining member 21 and the lower surface of the second partition part 26.
  • a gap is provided between the second bonding member 22 and the upper surface. This gap is, for example, 10 ⁇ m to 60 ⁇ m.
  • the sample solution usually has a certain degree of viscoelasticity, the sample solution becomes difficult to enter the gap by setting the gap to 10 ⁇ m to 60 ⁇ m, and the sample solution is formed by the first through hole 16 and the second through hole 17. It is also possible to suppress leakage into the gap.
  • the width of the first partition portion 25 is wider than the width of the first vibration space 23.
  • the side wall of the first partition portion 25 is positioned on the frame of the first joining member 21.
  • the first extraction electrode 19, the second extraction electrode 20, the thin metal wire 27 and the wiring 7, which are located in the gap formed by the first through hole 16 and the second through hole 17, are made of an insulating member 28 (FIG. 3, FIG. 4A). Thereby, corrosion of these electrodes and the like can be suppressed. Further, by providing the insulating member 28, the sample solution enters the gap between the first partition portion 25 and the first bonding member 21 or the gap between the second partition portion 26 and the second bonding member 22. Even in this case, the sample solution is blocked by the insulating member 28. Therefore, a short circuit between the extraction electrodes due to leakage of the sample solution can be suppressed.
  • the detection element 3 since the detection element 3 is accommodated in the concave portion 5 of the first cover member 1, a flow path 15 of the sample solution from the inlet 14 to the detection unit 13 can be secured, and a capillary phenomenon or the like can be obtained.
  • the sample solution sucked from the inlet can be made to flow to the detection unit 13. That is, it is possible to provide the sensor 100 having the suction mechanism itself while using the thick detection element 3.
  • the flow path 15 may have a groove provided on at least one surface of the first cover member 1 and the second cover member 2.
  • the flow path 15 may be provided by forming a groove provided on at least one surface of the first cover member 1 and the second cover member 2.
  • FIG. 7 is a cross-sectional view illustrating a modified example of the sensor 100.
  • This cross-sectional view corresponds to the cross section shown in FIG. 4A.
  • the position where the terminal 6 is formed is changed.
  • the terminal 6 is formed at the other end in the longitudinal direction of the second base 1b.
  • it is formed on the upper surface of the fourth base 2b.
  • the terminal 6 and the wiring 7 are electrically connected by a through conductor 29 that penetrates the second cover member 2.
  • the through conductor 29 is made of, for example, Ag paste or plating.
  • the terminal 6 can also be formed on the lower surface side of the first cover member 1. Therefore, the terminal 6 can be formed at an arbitrary position on the surface of the first cover member 1 and the second cover member 2, and the position thereof can be determined according to the measuring instrument to be used.
  • FIG. 8 is a cross-sectional view showing another modification of the sensor 100.
  • This sectional view corresponds to the section shown in FIG. 4B.
  • an absorbing material 30 that absorbs the sample solution at a predetermined speed is provided at the end of the flow path 15 formed by the groove 15.
  • the absorbent material 30 is made of, for example, a porous material capable of absorbing a liquid such as a sponge.
  • the detection element 3 is composed of a surface acoustic wave element.
  • the detection element 3 in which an optical waveguide or the like is formed so that surface plasmon resonance occurs may be used.
  • a change in the refractive index of light in the detection unit 13 is read.
  • the detection element 3 in which a vibrator is formed on a piezoelectric substrate such as quartz can be used. In this case, for example, a change in the oscillation frequency of the vibrator is read.
  • the first cover member 1 is formed by the first base body 1a and the second base body 1b
  • the second cover member 2 is formed by the third base body 2a and the fourth base body 2b.
  • the present invention is not limited thereto, and a cover member in which the bases are integrated, for example, the first cover member 1 in which the first base 1a and the second base 1b are integrated may be used.
  • a recess 5 may be provided for each detection element 3 or a long recess 5 that can accommodate all the detection elements 3 may be formed.
  • the groove 15 may be provided in either the first cover member 1 or the second cover member 2 or may be provided in both. That is, the flow path 15 may be formed by providing a groove in both the first cover member 1 and the second cover member 2, and a groove is provided in one of the first cover member 1 or the second cover member 2. Alternatively, the flow path 15 may be formed.
  • FIGS. 9 to 10, FIG. 11A, and FIG. 11B are diagrams showing a configuration in which the cover member 45 is directly joined to the base 10.
  • the case where the base body 10 is provided on the first cover member 1 and the first cover member 1 and the second cover member 2 are joined has been described as an example. is not.
  • the flow path 15 may be formed by bonding a cover member directly to the base 10. Details will be described below.
  • the flow path 15 is formed by providing a groove in the cover member 45 joined to the base body 10A.
  • the channel 15 may be formed by providing a groove on both the cover member 45 and the base 10A provided on the upper surface of the base 10A, and the base 10A may be provided with a groove.
  • the flow path 15 may be formed.
  • FIG. 9 is a perspective view showing an example of a sensor when a cover member is joined to a base.
  • the sensor 100 ⁇ / b> A includes a base body 10 ⁇ / b> A and a cover member 45.
  • the cover member 45 includes an inflow port 14A that is an inflow port for the sample solution, and a third through hole 18A that is an air hole or an outflow port for the sample solution.
  • the case where the inlet 14 ⁇ / b> A is provided on the upper surface of the cover member 45 is shown as an example, but the present invention is not limited to this.
  • the inflow port 14 ⁇ / b> A may be provided on the side surface of the cover member 45, similarly to the sensor 100.
  • the cover member 45 has a pad 44.
  • the pad 44 corresponds to the end 19 e of the first extraction electrode 19 and the end 20 e of the second extraction electrode 20 of the sensor 100.
  • FIG. 10 is a perspective view showing an example of a sensor when one half of one side of the cover member is removed.
  • a perspective view of the sensor 100A when one half of the cover member 45 is removed is shown.
  • a space 40 serving as a sample flow path for the sample solution is formed inside the cover member 45.
  • the inflow port 14 ⁇ / b> A is connected to the space 40. That is, the sample solution that has entered from the inflow port 14 ⁇ / b> A flows into the space 40.
  • the space 40 in the sensor 100A corresponds to the flow path 15 in the sensor 100.
  • FIG. 11A and FIG. 11B are cross-sectional views showing an example of a sensor when a cover member is joined to a base.
  • 11A is a cross-sectional view taken along the line IVa-IVa in FIG. 9, and
  • FIG. 11B is a cross-sectional view taken along the line IVb-IVb in FIG.
  • the first IDT electrode 11 and the second IDT electrode 12, the short-circuit electrode 42a, the short-circuit electrode 42b, and the like are provided on the upper surface of the base 10A. Further, the first IDT electrode 11 and the second IDT electrode 12, the short-circuit electrode 42 a, the short-circuit electrode 42 b, and the like are covered with a protective film 41.
  • the protective film 41 contributes to preventing oxidation of each electrode and wiring.
  • the protective film 41 is made of, for example, silicon oxide, aluminum oxide, zinc oxide, titanium oxide, silicon nitride, or silicon.
  • the protective film 41 is silicon dioxide (SiO 2 ).
  • the protective film 41 is laminated on the base body 10A so as to cover the base body 10A, the first IDT electrode 11, and the second IDT electrode 12.
  • the protective film 41 is formed over the entire top surface of the base 10A so as to expose the pads 44 (see FIG. 9). Since the first IDT electrode 11 and the second IDT electrode 12 are covered with the protective film 41, the IDT electrode can be prevented from corroding.
  • the thickness of the protective film 41 is, for example, 100 nm to 10 ⁇ m. Furthermore, 100 nm to 2 ⁇ m is preferable.
  • the protective film 41 is not necessarily formed over the entire top surface of the base body 10A. For example, only the vicinity of the center of the top surface of the base body 10A is exposed so that the region along the outer periphery of the top surface of the base body 10A including the pads 44 is exposed. You may form so that it may coat
  • the short-circuit electrode 42a and the short-circuit electrode 42b are for electrically short-circuiting the portion of the upper surface of the base 10A that becomes the SAW propagation path.
  • the SAW loss can be reduced depending on the type of SAW.
  • the short-circuit electrode 42 a and the short-circuit electrode 42 b are, for example, rectangular shapes extending along the SAW propagation path from the first IDT electrode 11 to the second IDT electrode 12.
  • the width of the short-circuit electrode 42a and the short-circuit electrode 42b in the direction orthogonal to the SAW propagation direction (x-direction) is, for example, the same as the intersection width of the electrode fingers of the first IDT electrode 11.
  • the end of the first IDT electrode 11 in the direction parallel to the SAW propagation direction of the short-circuit electrode 42a and the short-circuit electrode 42b (y-direction) is SAW from the center of the electrode finger located at the end of the first IDT electrode 11. It is located at a distance of half a wavelength.
  • the end of the short-circuit electrode 42a and the short-circuit electrode 42b on the second IDT electrode 12 side in the y direction is away from the center of the electrode finger located at the end of the second IDT electrode 12 by a half wavelength of SAW. To position.
  • the frequency characteristics using parameters such as the number of electrode fingers between the first IDT electrode 11 and the second IDT electrode 12, the distance between adjacent electrode fingers, and the intersection width of the electrode fingers.
  • the SAW excited by the IDT electrode include a Rayleigh wave, a love wave, and a leaky wave.
  • An elastic member for suppressing SAW reflection may be provided in a region outside the first IDT electrode 11 in the SAW propagation direction.
  • the SAW frequency can be set, for example, within a range of several megahertz (MHz) to several gigahertz (GHz). In particular, when the frequency is set from several hundred MHz to 2 GHz, it is practical, and it is possible to reduce the size of the base 10A and thus the size of the sensor 100A.
  • the short-circuit electrode 42a and the short-circuit electrode 42b may be in an electrically floating state, or may be provided with a ground potential pad 44 and connected thereto to be a ground potential.
  • the short-circuit electrode 42a and the short-circuit electrode 42b are set to the ground potential, propagation of direct waves due to electromagnetic coupling between the first IDT electrode 11 and the second IDT electrode 12 can be suppressed.
  • the short-circuit electrode 42a and the short-circuit electrode 42b are made of, for example, aluminum, an alloy of aluminum and copper, gold, or the like. These electrodes may have a multilayer structure. In the case of a multilayer structure, for example, the first layer is made of titanium or chromium, and the second layer is made of aluminum, an aluminum alloy, or gold.
  • the plate-like body 43 (see FIG. 10) has a concave portion for forming the first vibration space 23 and the second vibration space 24, and is joined to the base body 10A, whereby the first vibration space 23 and the second vibration space. 24 is formed.
  • the plate-like body 43 is formed using, for example, a photosensitive resist.
  • the plate-like body 43 corresponds to the first joining member 21 and the second joining member 22 in the sensor 100.
  • a through portion is formed. This through portion is provided to form the fixed film 200 on the SAW propagation path.
  • a detection unit 13 is provided.
  • a process for preventing a substance detected by the detection unit 13 from adhering to the fixed film for the reference unit may be performed.
  • the nucleic acid such as DNA is mistakenly attached to the fixed membrane of the reference portion by charging the fixed membrane of the reference portion negatively by any method. Can be prevented.
  • gold may be formed of a substance other than gold as a fixed film for the reference portion, taking into account that nucleic acids such as DNA tend to adhere to gold.
  • FIG.12 and FIG.13 is sectional drawing which shows an example of the modification of the sensor which concerns on embodiment of this invention.
  • the specimen may be brought into contact with the detection unit 13 by dropping from above. That is, as shown in FIGS. 12 and 13, the sensor 100 ⁇ / b> B may expose the detection unit 13 without having a cover member that covers the detection unit 13 or forms a flow path.
  • the sensor 100B is placed in the detection device 500, and the sample is brought into contact with the detection unit 13 by the user pouring the sample onto the detection unit 13 of the sensor 100B using the pipette 51 or the like.
  • the case where the sensor 100B has the protective film 41 is shown as an example.
  • the present invention is not limited to this, and the sensor 100B does not have to have the protective film 41 as shown in FIG. good.
  • the configuration of the detection device 500 in the example shown in FIG. 13, the case where the electrode 502 that contacts the various electrodes 19e or 20e of the sensor 100B is provided on the upper cover 501 of the detection device 500 is shown as an example.
  • the present invention is not limited to this, and may be provided on the base 503 of the detection apparatus 500 as shown in FIG.
  • FIG. 14 is a diagram showing 8-OHdG. (1) in FIG. 14 shows deoxyguanosine. When active oxygen acts on deoxyguanosine and DNA is damaged, that is, when subjected to oxidative stress, as shown in (2) of FIG. 14, 8-OHdG and Become. 8-OHdG can be used as a chemically stable traditional oxidative stress marker. Further, 8-OHdG increases in proportion to the active oxygen that causes dullness and itching of the skin. The molecular weight of 8-OHdG is 283.
  • a SAW chip as a high-sensitivity transducer as a disposable sensor
  • a light, thin and short sensor suitable for disposable can be obtained, and a small and simple sensor can be realized.
  • the SAW propagation path that is an action part with a biological substance and the IDT electrode that is a conversion part to an electric signal can be finely manufactured on one substrate.
  • the sensor itself can be made very small, can be mass-produced by a wafer process or the like, and a disposable sensor chip can be easily realized.
  • the SAW detection circuit is similar to the circuit configuration adopted in many wireless terminals and communication devices in tablet terminals, and the sensor detection circuit described above is used in electronic devices such as wireless terminals and tablet terminals. It is also possible to connect easily.
  • the detection unit 13 with which the specimen is brought into contact will be described in detail.
  • the specimen is, for example, a specimen obtained by crushing urine, saliva, skin keratin in the liquid, or a specimen obtained by crushing somatic tissue in the liquid, and more preferably, for example, urine.
  • the detection unit 13 includes, for example, a fixed film 200 and a coupling unit 203 (see FIG. 15A) fixed on the fixed film 200.
  • the present invention is not limited to this, and the fixing film 200 may not be provided.
  • the fixed film 200 as a material for forming the fixed film 200, for example, Au (gold), Ti, Cu or the like can be used, and Au is preferable.
  • the detection unit 13 is provided in a propagation path of an elastic wave propagating from the first IDT electrode 11 to the second IDT electrode 12, and is a binding unit capable of binding to a specific binding substance 210 (see FIG. 18) capable of binding to 8-OHdG. 203.
  • the specific binding substance 210 capable of binding to 8-OHdG is a substance capable of selectively binding to 8-OHdG.
  • the specific binding substance 210 a substance having a higher molecular weight than 8-OHdG may be used.
  • the specific binding substance 210 include an anti-8-OHdG antibody, an artificial antibody, and a DNA repair enzyme.
  • the anti-8-OHdG antibodies it is preferable to use an anti-8-OHdG monoclonal antibody.
  • the specific binding substance 210 is a substance that can bind to 8-OHdG and can also bind to 8-OHdG203b for detection (see FIG. 15A) provided in the detection unit 13.
  • One specific binding substance 210 includes one or a plurality of 8-OHdG contained in the specimen and a detection substance provided in the detection unit 13 when the specimen contains 8-OHdG. It will bind to any one of 8-OHdG203b.
  • the detection unit 13 includes, for example, 8-OHdG 203b for detection in the coupling unit 203.
  • the detection 8-OHdG203b may have an arbitrary structure capable of selectively binding to the specific binding substance 210.
  • a linker molecule is bonded to the 3 ′ position, the 5 ′ position, or other carbon positions. May be.
  • the linker molecule preferably binds to 8-OHdG203b for detection in a form that retains as much as possible the molecular structure of 8-OHdG203b for detection, which is a binding target, for example, the 3 ′ position of 8-OHdG203b for detection. It is preferable to bond to a position as far as possible from the 8'-position hydroxy group.
  • TEG Tetraethylene Glycol
  • the detection unit 13 preferably includes a chain substance (substance having a chain molecular structure) 201, and 8-OHdG 203b for detection is bound to the fixed film 200 by the chain substance 201.
  • the chain substance 201 is, for example, alkane, polyethylene glycol, or a complex molecule of alkane and polyethylene glycol, and alkane that is a linear molecule is preferable.
  • FIG. 15A and FIG. 15B are diagrams for illustrating an example of the detection unit according to the embodiment of the present invention.
  • the detection unit 13 includes, for example, a fixed film 200, a chain substance 201 having an arbitrary length, a protein (streptavidin, SA) 202, and 8-OHdG 203b for detection in order from the substrate 10 side.
  • the end of detection 8-OHdG 203b is modified with biotin 203a that binds to streptavidin 202 via a linker molecule.
  • a chain substance 201 whose one end is fixed to the fixed film 200, and a streptavidin 202 are bound to the end side of the chain substance 201 opposite to the base body 10 through the biotin 203a. 8-OHdG203b for detection is bound.
  • a linear substance or a substance having one or a plurality of branches can be used. From the viewpoint of securing the height of 8-OHdG 203b for detection from the surface of the substrate 10, the linear substance is used. It is preferable to use a substance in the form of a solid.
  • a fixing method for fixing the detection 8-OHdG 203b to the substrate surface will be described.
  • an immobilization method for example, strong affinity between streptavidin 202 and biotin 203a may be used.
  • streptavidin 202 is immobilized on the immobilization film 200 in advance.
  • a self-assembled film SAM, Self-Assembled Monolayer
  • alkylthiol or the like is strept on the substrate 10 previously formed by thiol bonding so that the streptavidin 202 covers the surface of the fixed film 200 as much as possible.
  • Avidin 202 is immobilized.
  • biotin 203a is preliminarily bound to the end of the substance having an 8-OHdG structure, and the 8-OHdG structure is bound to streptavidin 202 via biotin 203a by contacting with streptavidin 202.
  • 8-OHdG203b can be fixed to streptavidin 202.
  • the detection unit 13 may be washed with an arbitrary solvent for the purpose of removing a substance having an 8-OHdG structure remaining without being bound to the streptavidin 202.
  • the solvent used for washing is, for example, NaOH.
  • BSA bovine serum albumin
  • the protein 202 and the detection 8-OHdG 203b may be bonded to each other without using an intervening substance such as a linker molecule or biotin 203a.
  • FIG. 16 is a diagram illustrating an example of a technique for producing a detection unit of a sensor according to an embodiment of the present invention. As shown in (1) and (2) of FIG.
  • the chain substance 201 is formed on the base body 10 on the surface of which the fixed film 200 or the like is formed.
  • a SAM having an arbitrary film thickness may be formed.
  • DTDP (3,3′-dithiodipropionic acid) or 16MHDA (16-mercaptohexadecaonic acid)
  • FIG. 16 shows an example in which DTDP is used.
  • streptavidin 202 is bound to the end of the SAM opposite to the substrate 10.
  • streptavidin 202 can be bound by using NHS (N-Hydroxysuccinimide) and EDC (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide). Then, as shown in FIG. 16 (4), 8-OHdG 203 b for detection is bound to streptavidin 202.
  • 8-OHdG 203b for detection modified with biotin 203a as the binding unit 203 and binding biotin 203a of the binding unit 203 to streptavidin 202, the detection unit 13 is provided with 8-OHdG 203b for detection. Can do.
  • FIG. 17A is a diagram for explaining a model of a part of the detection unit of the sensor according to the embodiment of the present invention.
  • a case where the fixed film 200, the chain substance 201, the protein 202, and the detection unit 13 are sequentially bonded to the upper surface of the substrate 10 will be described as an example. As shown in FIG.
  • the length of the chain substance 201 can be calculated as follows based on the uneven shape of the surface of the fixed film 200 and the size of the protein 202. That is, when a model as shown in FIG. 17A is assumed, the distance from the bottom of the unevenness of the fixed film 200 to the center of the protein 202 should be longer than the length derived by the following equation (1). Become.
  • the length of the chain substance 201 is equal to or longer than the length derived by the following formula (2). Based on this, the size (length) of the chain substance 201, the protein 202, and the binding portion 203 formed on the fixed film 200 is determined in relation to the uneven shape on the surface of the fixed film 200. Can do.
  • the protein 202 can be effectively immobilized on the immobilization film 200 via the chain substance 201 even when the surface of the immobilization film 200 is uneven.
  • the binding part 203 can be effectively bound to the protein 202, high detection accuracy by the detection part 13 can be ensured.
  • FIG. 17B is a diagram for describing a part of the detection unit of the sensor according to the embodiment of the present invention as a model.
  • an Au film is used as the fixed film 200
  • an SAM having an alkyl group is used as the chain substance 201
  • the streptavidin 202 is bonded to the end of the chain substance 201.
  • the radius of the streptavidin 202 is about 2.5 nm and the inclination angle of the surface irregularities of the Au film is 45 degrees, as shown in FIG.
  • the length of the chain substance 201 is preferably equal to or longer than the length calculated based on the uneven shape of the surface of the fixed film 200 and the size of the streptavidin 202.
  • the surface roughness of the Au film is RMS (Root Mean Square) 2.7 nm, and the inclination angle of the unevenness on the surface of the Au film is 45 degrees. Since the radius of streptavidin 202 is about 2.5 nm, when the end of the chain substance 201 on the substrate 10 side is bonded to the bottom of the irregularities on the surface of the Au film, It is sufficient that the length is equal to or longer than the length derived by the following formula (3).
  • the length per one C—C bond (carbon-carbon bond) is 0.133 nm.
  • the number of C—C bonds which is the length of the chain site of SAM, is preferably 8 or more.
  • FIG. 18 and 19 are diagrams for explaining a process of binding a specific binding substance to the detection unit of the sensor according to the embodiment of the present invention.
  • the specimen is brought into contact with a specific binding substance 210 having a molecular weight larger than that of 8-OHdG and capable of binding to 8-OHdG, and the specific binding substance 210 remaining without binding to 8-OHdG220 in the specimen is
  • the detection unit 13 As shown in FIG. 18, it is possible to combine with the 8-OHdG 203b for detection of the detection unit 13.
  • the detection unit 13 is in the state shown in (1) of FIG. 19 (in FIG. 19 (1) and (2), the horizontal line indicates the fixed film 200)
  • the specific binding substance 210 mixed in contact with the detection unit 13.
  • the specific binding substance 210 in the mixed solution with the specimen and the 8-OHdG203b for detection bind.
  • the mass of the substance existing in the vicinity of the surface of the base body 10 increases, so that the surface state of the base body 10 changes and the surface acoustic wave changes.
  • 8-OHdG220 when 8-OHdG220 is present in the sample, when the specific binding substance 210 binds to 8-OHdG220 in the sample, 8-OHdG203b for detection is detected. It becomes difficult to combine.
  • the smaller the 8-OHdG220 in the sample the more specific binding substances 210 that can be bound to the 8-OHdG203b for detection of the detection unit 13.
  • the more 8-OHdG220 in the sample the more the specific binding substance 210 binds to the 8-OHdG203b for detection as a result of the binding between the specific binding substance 210 and the 8-OHdG220 in the specimen.
  • the specific binding substance 210 may be attached to the flow path 15 of the sensor 100 in advance so that the specimen and the specific binding substance 210 come into contact with each other.
  • the specific binding substance 210 is attached to or bonded to the side surface of the flow path 15 of the sensor 100 closer to the inlet than the detection unit 13 before reaching the detection unit 13.
  • the specific binding substance 210 and the specimen may be surely contacted.
  • FIG. 20 is a plan view showing a modification of the detection element of the sensor according to the embodiment of the present invention.
  • the detection element 3 ⁇ / b> A further includes a configuration for grasping the timing at which the specimen contacts.
  • the configuration and function of the detection element 3A shown in FIG. 20 are the same as the configuration and function of the detection element 3 shown in FIG.
  • the detection element 3A includes a pair of electrodes 60a and 60b and a pair of conductors 61a and 61b that are connected to the electrodes 60a and 60b and are spaced apart from each other on the upper surface.
  • the detection element 3A a direct current or a minute AC voltage is applied to the pair of conductors 61a and 61b via the electrode 60a and the electrode 60b.
  • the pair of conductors 61a and 61b can be electrically connected to each other through the sample. Therefore, by detecting a resistance change accompanying the conduction, the sample is detected. It is possible to detect the timing at which is dropped.
  • the specimen is, for example, urine, and it is preferable that ions with a high concentration exist in the liquid from the viewpoint of obtaining conduction. In FIG.
  • the electrodes 60 a and 60 b and the pair of conductors 61 a and 61 b are disposed so as to be sandwiched between two sets of the first IDT electrode 11, the second IDT electrode 12, and the detection unit 13.
  • positions electrode 60a, 60b can be determined arbitrarily.
  • FIG. 21 is a diagram illustrating an example of a detection method according to the embodiment of the present invention.
  • a portion of the surface of the substrate that is located in a propagation path of an elastic wave that propagates from a first IDT (InterDigital Transducer) electrode that generates an elastic wave to a second IDT electrode that receives the elastic wave that propagates from the first IDT electrode In addition, a preparatory step of preparing a sensor including a detection unit having a binding part capable of binding to the specific binding substance 210 capable of binding to 8-OHdG is performed. For example, as described above, the sensor 100 is prepared by creating the sensor 100.
  • a contact process is performed in which the specimen that has contacted the specific binding substance 210, that is, the specimen that has been pretreated, is brought into contact with the detection unit 13 of the sensor 100 described above.
  • a urine sample is collected.
  • the specific binding substance 210 and the specimen 52 are brought into contact with each other by mixing a predetermined amount of the specimen with the predetermined amount of the specific binding substance 210 using the pipette 51.
  • a predetermined amount of the specimen 52 and a predetermined amount of the specific binding substance 210 can be brought into contact with each other.
  • the sample 52 is allowed to stand for a predetermined time so that the 8-OHdG contained in the sample 52 and the specific binding substance 210 are bound to each other, thereby pretreating the sample 52.
  • the mixed solution 211 of the specific binding substance 210 and the specimen 52 after the pretreatment is dropped onto the sensor 100B and brought into contact with the detection unit 13 of the sensor 100B.
  • the mixed liquid 211 is dropped from the upper part of the detection unit 13 using the pipette 51, thereby directly contacting the sample 52 and the detection unit 13 without using the flow path. Can be made.
  • a detection step is performed to detect whether 8-OHdG is contained in the specimen by detecting the binding between the specific binding substance 210 and the binding portion 203 generated in the contact step. That is, by detecting a change in the state of the surface of the substrate 10 in contact, it is detected how much 8-OHdG is contained in the specimen before the pretreatment.
  • the detection unit 13 detects a change in the surface acoustic wave generated from the first IDT electrode 11 of the sensor 100 and propagated to the second IDT electrode 12 using a detection device. It is possible to detect a change in state.
  • a calibration curve indicating the relationship between the amount of 8-OHdG contained in the specimen and the change in the surface acoustic wave is created in advance, and the detection unit 13 detects the calibration curve based on the calibration curve.
  • the amount of 8-OHdG contained in the specimen can be determined from the state change.
  • a method for creating a calibration curve will be described.
  • variation in measurement timing can be suppressed by utilizing a configuration for grasping the timing at which the pre-processed specimen 52 contacts the detection element 3.
  • the detection element 3A according to the modification shown in FIG. 20 can be used. For example, when the specimen 52 is dropped on the detection element 3, it may take a predetermined time until the components of the solution are completely mixed and stabilized.
  • the measurement may be started after a predetermined time has elapsed from when the previously detected liquid sample was dropped. Based on the calibration curve created using these measurement conditions, the 8-OHdG concentration contained in the sample to be measured can be calculated.
  • measurement is started when a predetermined time has elapsed after the pretreated specimen has contacted the detection element, and from the time when the specimen is dropped based on the change in the detection signal at the time when this measurement is started.
  • the total signal change amount may be obtained by estimating (extrapolating) the signal change until the measurement start time. This method is effective, for example, when the difference between the detection unit 13 and the reference unit at the start of measurement is set to “0” and subsequent changes with time are acquired.
  • any method may be used as a method for bringing the sample into contact with the detection unit 13.
  • the specimen may be brought into contact by being guided from the inlet 14 to the detector 13 via the groove 15 or as shown in FIG.
  • the specimen may be contacted by dropping it directly from the upper part of the detection unit 13.
  • the sensor 100 is a measurement cell of an SPR device or a QCM quartz sensor
  • the sample solution is manually brought into contact with the detection unit 13 of the biocell, or the sample solution is injected into the flow cell of the SPR device or the QCM measurement device. You may make it contact by.
  • the change in the state of the surface of the substrate 10 means a change in mass or a change in dielectric constant, a change in viscoelasticity, a change in propagation characteristics caused by the binding of the 8-OHdG 203b for detection of the detection unit 13 to the specific binding substance 210.
  • resonance frequency change For example, when measurement is performed using an SPR device, when the 8-OHdG 203b for detection of the detection unit 13 and the specific binding substance 210 bind to each other, the mass and dielectric constant of the substrate surface change, resulting from this change. SPR angle change is generated.
  • the change in the state of the surface of the substrate is a change in mass or a change in dielectric constant caused by the binding between the 8-OHdG 203b for detection of the detection unit 13 and the specific binding substance 210, and a change in the SPR angle is detected.
  • a change in state of the substrate surface is detected.
  • the SAW sensor when used, a propagation characteristic change due to a mass change or viscoelastic change on the substrate surface occurs.
  • the change in the state of the substrate surface is a change in mass or viscoelasticity caused by the binding between the 8-OHdG 203b for detection of the detection unit 13 and the specific binding substance 210, and a change in propagation characteristics is detected.
  • a change in state of the substrate surface is detected.
  • the state change of the substrate surface is a change in mass caused by the binding between the 8-OHdG 203b for detection of the detection unit 13 and the specific binding substance 210, and the state of the substrate surface is detected by detecting the change in the resonance frequency. A change is detected.
  • the change in the substrate surface is caused by the binding between the 8-OHdG 203b for detection of the detection unit 13 and the specific binding substance 210. Therefore, the more 8-OHdG is contained in the specimen, the smaller the number of specific binding substances 210 by binding to 8-OHdG220 in the specimen in the above-described pretreatment. There is a tendency that the number of bonds between 8-OHdG203b and the specific binding substance 210 for the detection of ⁇ is decreased.
  • the specific binding substance 210 has a molecular weight larger than that of 8-OHdG.
  • the method for detecting the change in the substrate surface due to the binding between the specific binding substance 210 and the substrate surface compared with the method for detecting the change in the substrate surface due to the binding between 8-OHdG and the substrate surface.
  • the mass change, dielectric constant change, and viscoelastic change on the substrate surface become large, and the detection sensitivity can be improved.
  • small molecules that could not be measured by the conventional method of detecting by fixing small molecules on the substrate surface can be detected with high sensitivity.
  • the detection system is configured such that 8-OHdG in the specimen is located on a portion of the surface of the substrate positioned in the propagation path of the elastic wave propagating to the second IDT electrode that receives the elastic wave propagating from the first IDT electrode that generates the elastic wave.
  • a sensor having a detection part having a binding part capable of binding to a specific binding substance capable of binding to the sensor is configured such that 8-OHdG in the specimen is located on a portion of the surface of the substrate positioned in the propagation path of the elastic wave propagating to the second IDT electrode that receives the elastic wave propagating from the first IDT electrode that generates the elastic wave.
  • a sensor having a detection part having a binding part capable of binding to a specific binding substance capable of binding to the sensor.
  • the detection apparatus makes the specimen contain 8-OHdG by contacting the specimen brought into contact with the specific binding substance with the detection part of the sensor and detecting the binding between the specific binding substance and the binding part. Is detected. That is, when the binding part of the sensor comes into contact with the specific binding substance, the detection device detects whether 8-OHdG is contained in the specimen by detecting the binding between the specific binding substance and the binding part.
  • the detection device is a device that executes an arbitrary detection process using the sensor described above.
  • Examples of the detection device include an SPR device, a SAW sensor control device, and a QCM measurement device.
  • the detection device is preferably a SAW sensor control device.
  • the detection apparatus may execute a conversion process for converting the detection result obtained from the specific binding substance 210 into a detection result for 8-OHdG.
  • the detection apparatus may execute a conversion process for converting the detection result obtained from the specific binding substance 210 into a detection result for 8-OHdG.
  • the detection apparatus may execute a conversion process for converting the detection result obtained from the specific binding substance 210 into a detection result for 8-OHdG.
  • the molecular weight of the specific binding substance 210 and the molecular weight of 8-OHdG are known, the result that “specific binding substance 210 is present in“ x ”grams (or mol)” is obtained.
  • Such a result can be converted into a result that “8-OHdG is present in“ y ”grams (or mol)”.
  • a SAW chip was fabricated, and then a sensor was fabricated by providing 8-OHdG for detection in the detection section of the SAW chip. Then, after creating a detection line, 8-OHdG was detected by a sensor using urine as a specimen.
  • the detection process performed using urine as a sample will be described after the manufacture of the SAW chip, the application of 8-OHdG for detection to the detection unit of the SAW chip, and the generation of the detection line are described.
  • a photoresist pattern of comb-like electrodes is formed on a quartz substrate as a base by using a photolithography method, a Ti / Au electrode thin film is formed by an electron beam evaporation method, and then lift-off is performed.
  • Comb electrodes (IDT electrodes) and wiring electrodes were formed.
  • a silicon oxide thin film having a thickness of about 1 ⁇ m was formed on the pair of IDT electrodes by using a plasma CVD method using TEOS (Tetra Ethyl Ortho Silicate) and oxygen as raw materials.
  • TEOS Tetra Ethyl Ortho Silicate
  • oxygen oxygen
  • a resist pattern was formed on the silicon oxide film formed on the entire surface, and etching was performed by immersing in a buffer hydrofluoric acid solution to form a contact window.
  • a thin film of Ti / Au is formed by electron beam evaporation, and lift-off is performed, whereby the Au film and the wire bonding pad are formed. Formed.
  • the pad was designed to cover the silicon oxide contact window and was electrically connected to the lower wiring electrode.
  • the pair of IDT electrodes were arranged opposite to each other so that one had the function of a transmitter and the other had the function of a receiver.
  • the IDT electrode line and space (L / S) were about 1 ⁇ m.
  • An Au film of about 1 mm was sandwiched between a pair of IDT electrodes.
  • two sets of a pair of IDT electrodes and an Au film were formed on one sensor, and one was used as the “detection side” and the other was used as the “reference side”.
  • the quartz substrate was diced and cut into a predetermined size.
  • the chip obtained by cutting was fixed on the back side with an epoxy adhesive on a glass epoxy mounting substrate (hereinafter referred to as a mounting substrate) on which wiring was previously formed. Then, a pad electrode on the chip and a bonding pad portion on the mounting substrate were electrically connected by Au thin wires.
  • the SAW chip mounted on the mounting substrate is so-called piranha cleaned, and the entire substrate including the substrate is immersed in a 1 mM 16-MHDA ethanol solution for 16 hours, followed by running water cleaning and nitrogen blow drying, and the 16-MHDA SAM is Au It formed in the surface layer of the film
  • EDC aqueous solution 0.4M EDC aqueous solution and 0.1M NHS aqueous solution are mixed in equal amounts, dropped onto each Au film on the detection side and the reference side, and left at room temperature for 20 minutes, at the end of the SAM.
  • the located carboxy group was activated. After activation, unnecessary EDC and NHS were removed, and then washed with pure water.
  • biotin-modified 8-OHdG was dissolved in the HBS-N buffer solution, dropped onto the Au film on the detection side and allowed to stand at room temperature for 10 minutes to immobilize biotin-modified 8-OHdG in SA. Washing was performed by replacing with phosphate buffer.
  • the entire substrate was placed in a freezer, the solution on the Au film was frozen, and then lyophilized in vacuum.
  • Anti-8-OHdG antibody was dissolved in a phosphate buffer to prepare a 50 ⁇ g / mL antibody solution, and 10 ⁇ L of the solution was dispensed into a microtube and freeze-dried.
  • 8-OHdG reagent was dissolved in 20 ⁇ L PBS (Phosphate Buffered Saline) so as to have different concentrations from 0.5 ng / mL to 200 ng / mL, and a plurality of standard reagents were prepared.
  • PBS Phosphate Buffered Saline
  • a standard reagent was added to the lyophilized microtube, and the sample was left to stand at room temperature for 15 minutes, and the sample was pretreated by reacting the antibody with 8-OHdG in the standard reagent.
  • Example 1 to Example 4 urine was collected from the same person, and 20 ⁇ l of the collected urine was added to a freeze-dried microtube and left at room temperature for 15 minutes. The urine used in Examples 1 to 4 has a different collection time.
  • the preparation method for the freeze-dried microtube is the same as the preparation method for preparing the calibration curve.
  • Comparative Examples 1 to 4 In Comparative Examples 1 to 4, the same urine as in Examples 1 to 4 (urine collected from the same person at the same time) was used, and 8-OHdG was determined by a known ELISA (Enzyme-Linked ImmunoSorbent Assay) method. Concentration was calculated.
  • FIG. 22 is a diagram showing the results of Examples 1 to 4 and Comparative Examples 1 to 4.
  • Examples 1 to 4 are No. 1 to 4 and Comparative Examples 1 to 4 5-8.
  • the concentration calculated using the sensor according to the embodiment of the present invention was the same value as the concentration calculated using a known ELISA method.
  • the sensor according to the embodiment of the present invention in addition to obtaining the same result as in the case of using the ELISA method, it is possible to reduce the time required to measure the 8-OHdG concentration. I was able to. That is, according to the known ELISA method, it may take from half a day to one day to measure the 8-OHdG concentration in the specimen. In contrast, according to the sensor according to the embodiment of the present invention, it is only a few minutes to measure the phase difference between the detection unit 13 and the reference unit, that is, the concentration of 8-OHdG in the sample. 8-OHdG could be measured accurately in a short time.

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Abstract

　L'invention porte sur un capteur destiné à déterminer si 8-OHdG est compris dans un échantillon, le capteur comprenant : un substrat ; une première électrode IDT destinée à générer une onde élastique, la première électrode IDT étant positionnée sur une surface d'un substrat ; une seconde électrode IDT destinée à recevoir une onde élastique propagée depuis la première électrode IDT, la seconde électrode IDT étant positionnée sur la surface du substrat ; et une unité de détection positionnée dans un trajet de propagation dans lequel se propage l'onde élastique, et ayant une partie de liaison pouvant être liée à une substance de liaison spécifique pouvant être liée à 8-OHdG dans un échantillon.
PCT/JP2014/076134 2013-09-30 2014-09-30 Capteur, procédé de détection, système de détection et dispositif de détection WO2015046577A1 (fr)

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WO2016194879A1 (fr) * 2015-05-29 2016-12-08 京セラ株式会社 Procédé de détection et dispositif de détection
JP2017020861A (ja) * 2015-07-09 2017-01-26 国立大学法人九州工業大学 センシング装置
CN108982616A (zh) * 2018-07-27 2018-12-11 上海健康医学院 基于石墨烯及壳聚糖的生物传感器及其制备方法
EP4130750A4 (fr) * 2020-03-27 2024-03-20 Kyocera Corporation Système d'inspection, cartouche, procédé d'inspection et dispositif d'inspection

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WO2016194879A1 (fr) * 2015-05-29 2016-12-08 京セラ株式会社 Procédé de détection et dispositif de détection
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CN108982616A (zh) * 2018-07-27 2018-12-11 上海健康医学院 基于石墨烯及壳聚糖的生物传感器及其制备方法
EP4130750A4 (fr) * 2020-03-27 2024-03-20 Kyocera Corporation Système d'inspection, cartouche, procédé d'inspection et dispositif d'inspection

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