WO2014045762A1 - Capteur de lumière fluorescente et système de détection - Google Patents

Capteur de lumière fluorescente et système de détection Download PDF

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Publication number
WO2014045762A1
WO2014045762A1 PCT/JP2013/071793 JP2013071793W WO2014045762A1 WO 2014045762 A1 WO2014045762 A1 WO 2014045762A1 JP 2013071793 W JP2013071793 W JP 2013071793W WO 2014045762 A1 WO2014045762 A1 WO 2014045762A1
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Prior art keywords
recess
sensor
light
photoelectric conversion
conversion element
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PCT/JP2013/071793
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English (en)
Japanese (ja)
Inventor
亮 太田
松本　淳
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テルモ株式会社
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Publication of WO2014045762A1 publication Critical patent/WO2014045762A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Definitions

  • the present invention relates to a fluorescence sensor for measuring the concentration of an analyte in a liquid and a sensor system including the fluorescence sensor, and in particular, a fluorescence sensor that is a microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology, and the above-described sensor
  • the present invention relates to a sensor system including a fluorescent sensor.
  • a fluorometer that measures an analyte concentration by injecting a fluorescent dye and a solution to be measured containing an analyte into a transparent container, irradiating excitation light, and measuring the fluorescence intensity from the fluorescent dye is known.
  • Fluorescent dyes change their properties due to the presence of analyte, and when they receive excitation light, they generate fluorescence with an intensity corresponding to the analyte concentration. have.
  • the excitation light from a light source is irradiated to the indicator in which the analyte in a to-be-measured solution can go in and out, and the photodetector receives the fluorescence which an indicator produces.
  • the photodetector is a photoelectric conversion element and outputs an electrical signal corresponding to the received light intensity.
  • the analyte concentration in the solution is calculated based on the electrical signal from the photodetector.
  • microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology.
  • the microfluorometer is referred to as “fluorescence sensor”.
  • the fluorescent sensor 104 shown in FIGS. 1 and 2 is disclosed in International Publication No. 2010/119916.
  • the sensor unit 110 which is a main functional unit of the fluorescence sensor 104 includes a silicon substrate 111 on which a photoelectric conversion element 112 is formed, a transparent intermediate layer 113, a filter layer 114, a light emitting element 115, a transparent protective layer 116, An indicator 117 and a light shielding layer 118 are provided.
  • the analyte 9 passes through the light shielding layer 118 and enters the indicator 117.
  • the filter layer 114 of the fluorescence sensor 104 blocks excitation light and transmits fluorescence. Further, the light emitting element 115 transmits fluorescence.
  • the indicator 117 In the fluorescence sensor 104, when the excitation light generated by the light emitting element 115 enters the indicator 117, the indicator 117 generates fluorescence corresponding to the analyte concentration.
  • the fluorescent sensor 104 has a simple configuration and can be easily downsized.
  • the fluorescent sensor 104 since the fluorescent sensor 104 has the light emitting element 115 and the photoelectric conversion element 112 disposed inside the frame portion that holds the indicator 117, the fluorescent sensor 104 is not easy to manufacture.
  • An object of the embodiment of the present invention is to provide a fluorescent sensor that is easy to manufacture and a sensor system with high detection sensitivity.
  • the fluorescent sensor of one embodiment of the present invention includes an SOI substrate in which an active layer is disposed on a substrate layer via an oxide film, and the active layer constituting the first main surface is a through via. 1 recess is formed, the substrate layer constituting the second main surface is formed with a second recess that is a through via having a size including a region facing the first recess, Furthermore, the substrate part on which a photoelectric conversion element for converting fluorescence into an electric signal is formed, a filter covering the photoelectric conversion element, blocking excitation light, and the second recess, When the excitation light is received, the indicator that generates the fluorescence having an intensity corresponding to the concentration of the analyte and the outside light entering the indicator that covers the opening of the second recess are blocked, but the analyte passes.
  • the light shielding layer to be It covers the region comprises a light-emitting element for generating the excitation light.
  • the sensor system includes an SOI substrate in which an active layer is disposed on a substrate layer via an oxide film, and penetrates through the active layer constituting the first main surface.
  • a first concave portion that is a via is formed, and a second concave portion that is a through via having a size including a region facing the first concave portion is formed in the substrate layer constituting the second main surface.
  • a substrate part on which a photoelectric conversion element for converting fluorescence into an electric signal is formed, a filter covering the photoelectric conversion element and blocking excitation light, and the second recess are provided.
  • the analyte passes through the light-shielding layer, and the first It covers the region immediately below the opening of the part comprises a fluorescent sensor comprising a light emitting element for generating the excitation light, and a main body portion having a computing unit for correcting the electrical signal.
  • a compact fluorescent sensor with high detection sensitivity and a sensor system with high detection sensitivity can be provided.
  • the fluorescence sensor 4 and the sensor system 1 according to the first embodiment of the present invention will be described.
  • the sensor system 1 includes a fluorescent sensor 4, a main body 2, and a receiver 3 that receives and stores a signal from the main body 2. Transmission / reception of signals between the main body 2 and the receiver 3 is performed wirelessly or by wire.
  • the fluorescent sensor 4 includes a needle portion 7 that is punctured by a subject and a connector portion 8 that is joined to the rear end portion of the needle portion 7.
  • the needle part 7 has an elongated needle body part 6 and a needle tip part 5 including a sensor part 10 which is a main function part. Needle tip 5, needle body 6, and connector 8 may be integrally formed of the same material, or may be separately produced and joined.
  • the connector part 8 is detachably fitted to the fitting part 2A of the main body part 2.
  • the plurality of wirings 60 extending from the sensor unit 10 of the fluorescent sensor 4 are electrically connected to the main body unit 2 when the connector unit 8 is mechanically fitted to the fitting unit 2A of the main body unit 2. .
  • the fluorescent sensor 4 is a needle type sensor that can continuously measure the analyte concentration for a predetermined period, for example, one week after the sensor unit 10 is inserted into the body. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.
  • the main body unit 2 includes a control unit 2B that performs driving and control of the sensor unit 10, and a calculation unit 2C that processes a signal output from the sensor unit 10. Note that at least one of the control unit 2B and the calculation unit 2C may be disposed on the connector unit 8 of the fluorescent sensor 4 or the receiver 3.
  • the main body 2 further includes a radio antenna for transmitting and receiving radio signals to and from the receiver 3, a battery, and the like.
  • the main body 2 has a signal line instead of a wireless antenna.
  • the receiver 3 may not be provided when the main body 2 includes a memory unit having a necessary capacity.
  • the fluorescent sensor 4 includes a substrate unit 20, a filter 14, an indicator 17, a light shielding layer 18, and a light emitting element 15 as main functional elements.
  • the substrate unit 20 and the light emitting element 15 are bonded via the bonding layer 13.
  • the substrate unit 20 includes an SOI (Silicon on Insulator) in which an active layer (SOI layer) 21 is disposed on a support substrate layer (substrate layer) 22 via a buried silicon oxide film (Buried Oxide: BOX layer) 23. ) It consists of a substrate.
  • SOI Silicon on Insulator
  • the thickness of the active layer 21 is several ⁇ m to 100 ⁇ m
  • the thickness of the BOX layer 23 having a high light transmittance is 1 ⁇ m to several tens of ⁇ m
  • the thickness of the substrate layer 22 is 10 ⁇ m to several hundreds of ⁇ m.
  • the active layer 21 made of silicon constituting the first main surface 20SA of the substrate part 20 is formed with a recess 24 as a first through via, and the substrate layer made of silicon constituting the second main surface 20SB. 22 is formed with a recess 25 which is a second through via. That is, the recess 24 penetrates the active layer 21, the recess 25 penetrates the substrate layer 22, the bottom surface 24B and the bottom surface 25B are both the BOX layer 23, and the recess 25 and the recess 24 define the BOX layer 23. Is touching through.
  • FIG. 4B is a plan view for explaining an arrangement state of some components of the fluorescence sensor 4.
  • the recesses 24 and 25 are formed in the same region in the XY plane of the substrate unit 20, and the planar view size of the bottom surface 24 ⁇ / b> B of the recess 24 is smaller than the bottom surface 25 ⁇ / b> B of the recess 25. That is, the bottom surface 25B is formed so as to completely cover the bottom surface 24B.
  • the region where the recess 24 is formed includes a region facing the recess 25.
  • a light receiving portion 12T of a photodiode (Photo-Diode: PD) element 12 which is a photoelectric conversion element that converts fluorescence into an electric signal is formed. That is, the PD element 12 is disposed so as to surround the opening of the recess 24 so that the light receiving surface faces the indicator 17 disposed inside the recess 25.
  • the light receiving unit 12T is referred to as a PD element 12.
  • the planar view shape of the concave portion 24 may be a shape obtained by reducing the planar shape of the PD element 12 in order to be arranged inside the PD element 12, but a polygon, a circle, an ellipse, or the like that is different from the shape of the PD element 12. But you can.
  • the filter 14 is disposed so as to cover the wall surface of the PD element 12 and the recess 24 formed on the first main surface 20SA. That is, the filter 14 is not disposed on the bottom surface 24 ⁇ / b> B of the recess 24. Note that a transparent protective film such as silicon oxide may be formed before the filter 14 is formed.
  • the filter 14 blocks excitation light having a wavelength of 375 nm, for example, and blocks the excitation light from entering the active layer 21 including the PD element 12.
  • the filter 14 may be a light shielding layer that blocks light having a wavelength other than the excitation light.
  • the filter in the region covering the PD element 12 on the wall surface of the recess 24 preferably transmits fluorescence from the viewpoint of improving detection sensitivity. Since the PD element 12 has a small signal output due to excitation light that becomes noise, the filter 14 can realize a sensor with a high S / N ratio.
  • a wiring layer 50 including detection signal wirings 51 and 52 and drive signal wirings 53 and 54 is disposed on the first main surface 20SA via the filter 14.
  • the detection signal wirings 51 and 52 output detection signals from the PD element 12.
  • the detection signal wiring 51 is connected to the light receiving portion 12T of the PD element, and the detection signal wiring 52 is connected to the low resistance region 12H of the same semiconductor impurity type as the active layer 21.
  • the drive signal wirings 53 and 54 supply a drive signal to the drive signal electrode 15T of the light emitting element 15. That is, each wiring of the wiring layer 50 is connected to a plurality of wirings 60 that pass through the needle body 6.
  • the bonding layer 13 bonds the substrate unit 20 and the LED and protects the wall surfaces of the PD element 12 and the recess 24.
  • the bonding layer 13 may also be filled in the recess 24. Conversely, the bonding layer 13 may not be formed in the region immediately below the opening of the recess 24.
  • the bonding layer 13 is selected from adhesive materials having characteristics such as electrical insulation, moisture barrier properties, and good transmittance for excitation light.
  • an epoxy resin, a silicone resin, an organic resin such as a transparent amorphous fluororesin, a transparent inorganic material such as a silicon oxide film or a silicon nitride film, or a composite laminated film thereof can be used. .
  • the indicator 17 filled in the recess 25 generates fluorescence due to the interaction with the entering analyte 9 and excitation light.
  • the thickness of the indicator 17 is the same as the depth of the recess 25, that is, the thickness of the substrate layer 22, and is 10 ⁇ m to several hundred ⁇ m.
  • the indicator 17 is made of a base material containing a fluorescent dye that generates fluorescence having an intensity corresponding to the amount of the analyte 9 that has entered the inside, that is, the concentration of the analyte in the solution to be measured.
  • the light shielding layer 18 covering the opening 25A of the recess 25 has a thickness of about several tens of ⁇ m.
  • the light shielding layer 18 prevents excitation light and fluorescence from leaking to the outside, and at the same time, prevents outside light from entering the inside.
  • the light shielding layer 18 also has analyte permeability that does not hinder the passage of the analyte 9.
  • the light leakage prevention layer 19 disposed so as to cover the bottom surface (the surface facing the light emitting surface) and the wall surface of the light emitting element 15 is reflected by the excitation light emitted from the bottom surface and the wall surface and the surface of the active layer 21.
  • the excitation light is prevented from leaking outside. That is, the light leakage prevention layer 19 has a function similar to that of the light shielding layer 18, but does not require analyte permeability.
  • FIGS. 6A to 6F are partial cross-sectional views of the region of the sensor unit 10 of one fluorescent sensor 4.
  • the sensor unit 10 of a large number of fluorescent sensors 4 is collectively included as a wafer process.
  • a sensor substrate is fabricated.
  • the PD element 12 which is a photoelectric conversion element is formed on the active layer 21 of the first main surface 20SA of the SOI wafer 20W using a normal semiconductor process.
  • the planar shape and size of the light receiving portion 12T are preferably elongated, for example, 150 ⁇ m in length and 500 ⁇ m in width because the location where the sensor unit 10 is disposed is the needle tip 5.
  • the light receiving portion 12T is formed by introducing a semiconductor impurity type impurity opposite to that of the active layer 21.
  • the low resistance region 12H is formed by introducing impurities of the same semiconductor impurity type as the active layer 21.
  • the active layer 21 is an N-type semiconductor
  • a P-type semiconductor diffusion layer is formed in the light receiving portion 12T by boron diffusion, and phosphorus, arsenic, or the like is introduced into the low resistance region 12H.
  • the photoelectric conversion element may be a photoconductor (photoconductor) element or a phototransistor element.
  • photo-etching is performed on the active layer 21 of the first main surface 20SA to form a recess 24.
  • Various known methods can be used for etching.
  • the recess 24 is disposed inside the planar region of the PD element 12.
  • the recess 24 is a through via that penetrates the active layer 21, and the BOX layer 23 is exposed on the bottom surface.
  • the filter 14 is formed on the wall surface of the active layer 21 and the recess 24 of the first main surface 20SA.
  • the filter 14 is not formed on the bottom surface 24 ⁇ / b> B of the recess 24 by using film formation by CVD and anisotropic dry etching.
  • a transparent protective film such as a silicon oxide film may be formed before forming the filter 14.
  • the filter 14 may be a multiple interference type such as a dielectric multilayer film, but is preferably an absorption type, for example, a single layer made of silicon, silicon carbide, silicon oxide, silicon nitride, or an organic material, or the single layer. It is a multilayer layer in which layer layers are laminated.
  • the transmittance of the silicon layer and the silicon carbide layer is 10 ⁇ 5 % or less at the excitation light wavelength of 375 nm, whereas the transmittance is 10% or more at the fluorescence wavelength of 460 nm (the transmittance of the excitation light wavelength). (Transmittance of fluorescence wavelength) and the transmittance selectivity of 6 digits or more.
  • detection signal wirings 51 and 52 for outputting a detection signal from the PD element 12 and drive signal wirings 53 and 54 for supplying a driving signal to the light emitting element 15 are formed by sputtering. Alternatively, they are disposed by patterning such as wiring metal film formation and photolithography / etching by vapor deposition or the like.
  • the detection signal wirings 51 and 52 are connected to the light receiving unit 12T and the low resistance region 12H of the PD element through contact holes (not shown) of the filter 14, respectively.
  • the material of the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54 Al, Cu, Au, Pt, W, Mo or the like, which is a metal material, or low resistance polysilicon containing impurities at a high concentration is used. .
  • the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54 are disposed in one wiring layer 50, but a multilayer wiring may be used.
  • a multilayer wiring may be used as the material of the interlayer insulating layer of the multilayer wiring.
  • an inorganic insulating material such as a silicon oxide film or a silicon nitride film, or an organic insulating material such as polyimide is used.
  • At least one of the detection signal wirings 51 and 52 and the drive signal wirings 53 and 54 is widened. You may arrange in.
  • the light emitting element 15 is bonded to the first main surface 20SA of the SOI wafer 20W via the bonding layer 13 so as to cover the opening of the recess 24.
  • the refractive index of the bonding layer 13 filling the concave portion 24 is substantially equal to the refractive index of the BOX layer 23.
  • the light emitting element 15 is selected from a chip on which a light emitting element such as an organic EL element, an inorganic EL element, or a laser diode element is formed.
  • the light-emitting element 15 is a light-emitting diode (LED) from the viewpoints of light generation efficiency, wide wavelength selectivity of excitation light, and generation of light having a wavelength other than excitation light. Is preferred.
  • the bonding layer 13 is manufactured by applying a resin and performing a curing process.
  • a transparent SiO 2 layer or silicon nitride layer or the like may be disposed in advance on the surface to which the resin is applied by a CVD method or the like.
  • a conductive adhesive or flip chip bonding is used for electrical connection between the drive signal electrode 15T of the light emitting element 15 and the drive signal wirings 53 and 54.
  • the drive signal electrode 15T of the light emitting element 15 is electrically connected to the drive signal wirings 53 and 54 at the same time. Since the light emitting element 15 and the substrate portion are electrically bonded simultaneously with the physical bonding, the fluorescent sensor 4 can be easily manufactured.
  • the bonding layer 13 also has a function of a sealing member that seals the electrical connection portion.
  • the light leakage prevention layer 19 is disposed on the lower surface and the wall surface of the light emitting element 15.
  • the light leakage prevention layer 19 may be the same material as the light shielding layer 18, or may be an organic resin mixed with carbon black, a metal, or a multilayer film or a composite film made of these materials. Note that the light emitting element 15 in which the light leakage prevention layer 19 is disposed in advance may be bonded to the substrate unit 20.
  • the excitation light emitted from the bottom surface and the wall surface of the light emitting element 15 is reflected upward, that is, as a reflection film that reflects in the direction of the indicator 17. It is also possible to give this function.
  • the light leakage prevention layer 19 may be disposed on the outer surface of the sensor unit 10 such as the entire lower surface of the substrate unit 20, the wall surface, and the upper surface not covered with the light shielding layer 18.
  • the silicon wafer 20 ⁇ / b> W is turned upside down to form a recess 25 that is a through via in the substrate layer 22 of the second main surface 20 ⁇ / b> SB.
  • a known method can be used for etching the substrate layer 22.
  • the BOX layer 23 is exposed on the bottom surface 25 ⁇ / b> B of the recess 25, and the recess 25 and the recess 24 are in contact with each other via the BOX layer 23.
  • the indicator 17 is filled in the recess 25.
  • the indicator 17 is made of a hydrogel containing a fluorescent dye or a hydrogel combined with a fluorescent dye.
  • the fluorescent dye is selected according to the type of the analyte 9, and any fluorescent dye whose intensity of fluorescence generated according to the amount of the analyte 9 changes reversibly can be used.
  • the fluorescent sensor 4 uses a ruthenium organic complex, a fluorescent phenylboronic acid derivative, a substance that reversibly binds to glucose, such as fluorescein bound to a protein, or the like.
  • Hydrogel components that easily contain water include acrylate hydrogels prepared by polymerizing polysaccharides such as methylcellulose or dextran, monomers such as (meth) acrylamide, methylacrylamide, or hydroxyethyl acrylate, or polyethylene glycol and diisocyanate. Urethane-based hydrogel prepared from the above can be used.
  • the indicator 17 may be bonded to the wall surface of the recess 25, the light shielding layer 18 on the upper surface, the bottom surface 25B of the recess 25, or the like via an adhesive layer such as a silane coupling agent.
  • the indicator 17 may be manufactured by filling the concave portion 25 with an indicator containing a gel skeleton-forming material before polymerization and covering the opening with the light shielding layer 18 and then polymerizing the indicator 17. For example, when a phosphate buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator is placed in the recess 24 and left in a nitrogen atmosphere for 1 hour, the indicator 17 is produced.
  • fluorescent dye 9,10-bis [N- [2- (5,5-dimethylborinan-2-yl) benzyl] -N- [6 ′-[(acryloylpolyethyleneglycol-3400) carbonylamino]- n-hexylamino] methyl] -2-acetylanthracene (F-PEG-AAm), acrylamide as the gel skeleton-forming material, sodium peroxodisulfate and N, N, N ′, N as the polymerization initiator '-Tetramethylethylenediamine is used.
  • the light shielding layer 18 is disposed so as to cover the opening of the concave portion 25 of the second main surface 20SB.
  • the light shielding layer 18 has a submicron pore structure, an inorganic thin film such as metal or ceramic, or a composite structure with hydrogels in which carbon black is mixed in a base material of an organic polymer such as polyimide or polyurethane, or Furthermore, a resin in which carbon black is mixed into an analyte-permeable polymer such as celluloses or polyacrylamide, or a resin obtained by laminating them can be used.
  • the sensor substrate 10W having the SOI wafer 20W as a base material is separated into individual pieces, so that a large number of sensor units 10 are manufactured at once.
  • the fluorescence sensor 4 is completed by joining the sensor part 10 with the front-end
  • the manufacturing method of the fluorescent sensor is not limited to this.
  • the silicon wafer 20W in the state shown in FIG. 6C may be separated into pieces, and the light emitting elements 15 and the like may be bonded to the respective substrate portions 20.
  • the silicon wafer 20 ⁇ / b> W may be processed and joined to the connector portion 8 so that the extended portion of the substrate portion 20 constitutes the needle body portion 6 of the needle portion 7.
  • the fluorescent sensor 4 is easy to manufacture and can be mass-produced by a wafer process. For this reason, the fluorescence sensor 4 can provide stable quality at low cost.
  • the light emitting element 15 emits pulsed excitation light having a center wavelength of around 375 nm at an interval of once every 30 seconds, for example.
  • the pulse current to the light emitting element 15 is 1 mA to 100 mA
  • the pulse width of light emission is 1 ms to 100 ms.
  • the excitation light generated by the light emitting element 15 is transmitted through the BOX layer 23 constituting the bottom surface 24 ⁇ / b> B of the recess 24 and enters the indicator 17.
  • the indicator 17 emits fluorescence having an intensity corresponding to the concentration of the analyte 9.
  • the analyte 9 passes through the light shielding layer 18 and enters the indicator 17.
  • the fluorescent dye of the indicator 17 generates fluorescence having a longer wavelength, for example, 460 nm, for example, with respect to excitation light having a wavelength of 375 nm.
  • the fluorescence generated by the indicator 17 passes through the BOX layer 23 and the thin active layer 21 on the BOX layer 23 side of the light receiving unit 12T and enters the light receiving unit 12T of the PD element 12. That is, as already described, the light receiving portion 12T is a diffusion layer in which impurities are introduced from the surface of the active layer 21, and the thin active layer 21 remains on the BOX layer 23 side. Since the fluorescence transmittance of the active layer 21 is not high, the thickness of the active layer 21 remaining on the BOX layer 23 side is preferably 10 ⁇ m or less, particularly preferably 3 ⁇ m or less. The fluorescence is photoelectrically converted by the light receiving unit 12T, and the generated photogenerated charge is output as a detection signal.
  • the calculation unit 2C of the main body unit 2 performs calculation processing based on the detection signal, that is, the current caused by the photogenerated charge from the PD element 12 or the voltage caused by the accumulated photogenerated charge. Calculate the amount of light.
  • the fluorescent sensor 4 Since the fluorescent sensor 4 is manufactured using an SOI substrate, it is easy to manufacture, and further detects the fluorescence from the indicator 17 via the BOX layer 23 having a high transmittance. For this reason, the fluorescence sensor 4 has high detection sensitivity while being small. Similarly, the sensor system 1 including the fluorescent sensor 4 has high detection sensitivity. Furthermore, since a large number of fluorescent sensors can be manufactured at once by processing in a wafer state, the manufacturing process of the fluorescent sensor 4 is easy and the cost is low.
  • the fluorescence sensor 4 there is one concave portion 24 that is a light guide path through which the excitation light from the light emitting element 15 enters the indicator 17.
  • the intensity of the excitation light generated by the light emitting element 15 and incident on the indicator 17 has an in-plane distribution. That is, since the high-intensity excitation light is irradiated to the indicator 17 in the region immediately above the bottom surface 24B of the recess 24, the fluorescence intensity emitted from the indicator 17 in that region is high. However, when high-intensity excitation light is irradiated, deterioration of the indicator 17 may be promoted.
  • the intensity of the excitation light incident on the indicator 17 decreases, and the intensity of the fluorescence emitted by the indicator 17 in that region also decreases. That is, if the intensity of the excitation light incident on the indicator 17 has a large in-plane distribution, the detection sensitivity of the fluorescent sensor may be reduced, or deterioration with time may be accelerated.
  • the active layer 21 has a plurality of recesses 24A.
  • Forming a plurality of recesses 24A in the active layer 21 means forming a plurality of light guides.
  • the indicator 17 in the vicinity of the region immediately above each recess 24A is irradiated with relatively strong excitation light. For this reason, in the fluorescence sensor 4A, the excitation light having a more uniform intensity distribution is incident on the indicator 17, so that there is no possibility that the detection sensitivity is lowered or the deterioration with time is accelerated.
  • the fluorescent sensor 4A has the effect of the fluorescent sensor 4, and further has high detection sensitivity, and the deterioration of the indicator 17 is unlikely to proceed.
  • the planar shape and arrangement of the recesses 24 can take various forms as shown in FIGS. 7A to 7C.
  • the planar shape of the recess 24A is a quadrangle in the fluorescent sensor 4A shown in FIG. 7A, but may be a polygon or an ellipse such as a hexagon as in the fluorescent sensor 4A1 shown in FIG. 7B, or a combination thereof. The shape may be different. Moreover, you may combine the recessed part 24A from which magnitude
  • the size of the planar dimension of the recess 24, for example, the length of the side is 1 ⁇ m to several hundred ⁇ m.
  • the distribution is corrected by the opening area, shape, arrangement, and the like of the plurality of recesses 24, and the intensity distribution of the excitation light incident on the indicator 17 is further increased. Can be averaged.
  • the excitation light distribution suitable for the planar view shape of the indicator 17, that is, the shape of the bottom surface 25 ⁇ / b> B of the recess 25 can be realized by the same method.
  • the fluorescent sensor 4A and the like according to the modified example 1 have the effect of the fluorescent sensor 4, and further, since the intensity distribution of the excitation light incident on the indicator 17 is averaged, the detection is performed while being small. High sensitivity.
  • the sensor system 1A including the fluorescent sensor 4A has high detection sensitivity. Furthermore, the sensitivity reduction phenomenon due to the temporal deterioration peculiar to the fluorescent sensor having the indicator 17 is small.
  • the excitation light is directly incident on the region directly above the recess 24, which is the light guide, so that the intensity of the excitation light is high. However, the intensity of the excitation light decreases with increasing distance from the region directly above.
  • the sensor unit 10B of the fluorescent sensor 4B according to the modified example 2 includes a light scattering layer 26 serving as a light scattering unit on the bottom surface 24B of the recess 24.
  • the light scattering layer 26 is made of, for example, a transparent material in which metal particles are dispersed.
  • metal particles metals with a high particle reflectance such as Al and Ag having a particle size of ⁇ m are suitable, and as transparent materials, resins such as silicone resins or inorganic glasses such as SOG (Spin-On-Glass) are suitable. Is suitable.
  • the light scattering layer 26 is disposed in the recess 24 by a printing method, a photolithography process, or the like. In the fluorescent sensor 4B shown in FIG. 8, the light scattering layer 26 is disposed on the bottom surface 24B of the recess 24, but may be disposed so as to fill the recess 24.
  • the refractive index of the light scattering layer 26 is substantially equal to the refractive index of the BOX layer 23.
  • the excitation light from the light emitting element 15 is scattered by the light scattering layer 26, and the intensity distribution of the excitation light incident on the indicator 17 is averaged. That is, the intensity of the excitation light in the indicator 17 increases in the region away from the bottom surface 24B of the recess 24, the fluorescence intensity emitted from the indicator in that region also increases, and the excitation light in the region immediately below the bottom surface 24B of the recess 24. The strength is weakened.
  • the sensor unit 10B1 of the fluorescence sensor 4B1 of Modification 2 shown in FIG. 9 has a concave lens 26A as light scattering means.
  • the concave lens can be formed by utilizing the meniscus phenomenon due to the surface tension with the wall surface of the recess 24 when the transparent resin such as liquid silicone or the inorganic glass such as SOG is disposed inside the recess 24.
  • a concave surface can be formed in the bonding layer 13 of the recess 24 by performing an etch back process by RIE or the like.
  • a light scattering part 26B which is a light scattering means, is formed in the BOX layer 23.
  • the light scattering portion 26B only needs to be formed on at least one of the bottom surface 24B and the bottom surface 25B.
  • the light scattering portion 26B is a diffraction structure formed with regular irregularities formed in the BOX layer 23, or a light scattering structure with irregular irregularities.
  • the structure is processed on the BOX layer 23 of the Si wafer on which the BOX layer 23 is formed, and then the active layer 21 is formed on the BOX layer 23, whereby the light scattering portion 26B. Is formed.
  • a metal scattering film 26C as a light scattering means is disposed on the BOX layer 23 on the bottom surface of the recess 25.
  • the metal scattering film 26C is formed by lift-off of a fine metal pattern or photolithography.
  • a light scattering layer 26D in which metal particles as light scattering means are dispersed is disposed in the BOX layer 23 on the bottom surface 25B of the recess 25.
  • the metal scattering film 26 ⁇ / b> C and the light scattering layer 26 ⁇ / b> D may be disposed on the entire bottom surface 25 ⁇ / b> B of the recess 25.
  • Fluorescence sensor 4B equipped with a light scattering means that averages the in-plane distribution of the excitation light intensity has higher detection sensitivity and less sensitivity reduction due to deterioration with time, in addition to the effects of fluorescence sensor 4 and the like.
  • the sensor system 1C and the fluorescence sensor 4C of the second embodiment will be described. Since the fluorescent sensor 4C and the like are similar to the fluorescent sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the light emitting element 15 is generated in addition to the PD element 12 which is the first photoelectric conversion element for detecting the fluorescence generated by the indicator 17.
  • a PD element 12B which is a second photoelectric conversion element that detects excitation light to be emitted, is formed.
  • the PD element 12 and the PD element 12B are PD elements having the same semiconductor structure, and the PD element 12B is disposed in a region outside the PD element 12.
  • the light emitting element 15L covers not only the area directly under the opening of the recess 24 but also the area directly under the second PD element 12B. That is, the dimension in plan view of the light emitting element 15 is a size that covers a region immediately below the opening of the recess 24 and also covers a region directly below the PD element 12B.
  • the filter 14 is not disposed on the surface of the PD element 12B. Therefore, the PD element 12B outputs an electrical signal (detection signal) corresponding to the intensity of the excitation light generated by the light emitting element 15L.
  • the manufacturing method of the fluorescent sensor 4C is similar to the manufacturing method of the fluorescent sensor 4.
  • the PD element (light receiving part) 12B is formed simultaneously with the formation of the light receiving part 12T and the low resistance region 12H of the PD element by the impurity implantation process.
  • the diffusion layer (light receiving portion) of the PD element 12B that detects the excitation light of the LED may be a diffusion layer having the same structure (concentration and diffusion depth) as the PD element 12T, but it matches the excitation light wavelength and the fluorescence wavelength.
  • the structure of the diffusion layer may be different.
  • the first main surface 20SA of the substrate unit 20 is also provided with a detection signal wiring (not shown) that transmits a detection signal output from the PD element 12B.
  • the detection signal wiring 52 connected to the low resistance region 12H serves as a common wiring for the PD element 12 and the PD element 12B.
  • the intensity of the fluorescence generated by the indicator 17 increases or decreases depending on not only the amount of analyte but also the intensity of excitation light.
  • the calculation unit 2C that processes the electrical signal (detection signal) output from the fluorescence sensor 4C converts the electrical signal (detection signal) from the first PD element 12 to the second PD element 12B. Correct based on the electrical signal.
  • the fluorescence sensor 4C and the sensor system 1C have the effects of the fluorescence sensor 4 and the sensor system 1 and the like, and the intensity of excitation light changes due to variations in the light emission efficiency of the light emitting element 15L or excitation light amount drift during operation. However, highly accurate measurement is possible.
  • the PD element 12 ⁇ / b> T is formed in the active layer 21 similarly to the sensor unit 10 of the fluorescence sensor 4, and the second recess 25 of the substrate layer 22 is further formed.
  • a PD element 12D is also formed on the wall surface.
  • the PD element 12D covered with the filter 14D may be formed on at least one of the four wall surfaces.
  • the PD elements 12D and 12 (12T) are connected to the respective wiring layers 50 through the through wiring 58, and the low resistance regions 12HD1 and 12HD2 through the through wiring 59.
  • the substrate portion 20 is an SOI substrate, the recesses 24 and 25 can be easily formed. Furthermore, since the PD element 12D is formed on the wall surface surrounding the indicator 17, the sensitivity is high.
  • PD elements may be formed on the active layer 21 in addition to the wall surface and bottom surface of the second recess 25 of the substrate layer 22. That is, in the fluorescence sensor in which the fluorescence sensor 4 and the fluorescence sensor 4D are combined, photoelectric conversion elements are formed on the area surrounding the first recess 24 of the active layer 21 and the wall surface of the second recess 25 of the substrate layer 22. Yes.
  • the fluorescent sensor has high sensitivity because it has a large light receiving area.
  • a plurality of concave portions 24 may be formed as in the fluorescence sensor 4A, or a light diffusion portion may be provided as in the fluorescence sensor 4B.
  • the fluorescent sensor 4 that detects saccharides such as glucose has been described as an example.
  • the fluorescent dye corresponds to various uses such as an enzyme sensor, a pH sensor, an immune sensor, or a microorganism sensor. be able to.
  • an enzyme sensor e.g., a hydroxypyrenetrisulfonic acid derivative or the like
  • a phenylboronic acid derivative having a fluorescent residue is used when measuring a saccharide.
  • a potassium ion e.g., a crown ether derivative having a fluorescent residue is used.

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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

Cette invention concerne un capteur de lumière fluorescente (4) comprenant : une partie substrat (20) comprenant un substrat SOI portant une couche active (21) agencée sur une couche de substrat (22) par l'intermédiaire d'une couche BOX (23) et contenant un élément PD (12), ladite partie substrat comportant une première partie évidée (24), qui est un trou débouchant, formée sur la couche active (21) et une seconde partie évidée (25), qui est un trou débouchant d'une taille englobant une zone en regard de la première partie évidée (24), formée dans la couche de substrat (22) ; un filtre (14) qui protège contre la lumière d'excitation couvrant l'élément PD (12) ; un indicateur (17) placé dans la seconde partie évidée (25) ; une couche de protection contre la lumière (18) couvrant l'ouverture de la seconde partie évidée (28) ;; et un élément électroluminescent (15) qui génère la lumière d'excitation.
PCT/JP2013/071793 2012-09-21 2013-08-12 Capteur de lumière fluorescente et système de détection WO2014045762A1 (fr)

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JP2012-207771 2012-09-21

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62261036A (ja) * 1986-04-23 1987-11-13 ア−・フアウ・エル　ア−・ゲ− 物質濃度を測定するためのセンサ素子
JP2003525432A (ja) * 2000-03-02 2003-08-26 マイクロチップス・インコーポレーテッド 化学物質およびデバイスを格納し、選択的に露出させるための微細加工されたデバイス
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ
JP2012520087A (ja) * 2009-04-13 2012-09-06 オリンパス株式会社 蛍光センサ、針型蛍光センサ、およびアナライトの計測方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62261036A (ja) * 1986-04-23 1987-11-13 ア−・フアウ・エル　ア−・ゲ− 物質濃度を測定するためのセンサ素子
JP2003525432A (ja) * 2000-03-02 2003-08-26 マイクロチップス・インコーポレーテッド 化学物質およびデバイスを格納し、選択的に露出させるための微細加工されたデバイス
JP2012520087A (ja) * 2009-04-13 2012-09-06 オリンパス株式会社 蛍光センサ、針型蛍光センサ、およびアナライトの計測方法
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ

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