WO2013084975A1 - Fluorescence sensor and method for manufacturing fluorescence sensor - Google Patents

Fluorescence sensor and method for manufacturing fluorescence sensor Download PDF

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Publication number
WO2013084975A1
WO2013084975A1 PCT/JP2012/081606 JP2012081606W WO2013084975A1 WO 2013084975 A1 WO2013084975 A1 WO 2013084975A1 JP 2012081606 W JP2012081606 W JP 2012081606W WO 2013084975 A1 WO2013084975 A1 WO 2013084975A1
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WIPO (PCT)
Prior art keywords
photoelectric conversion
fluorescence
conversion element
sensor
excitation light
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PCT/JP2012/081606
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French (fr)
Japanese (ja)
Inventor
広呂紀 畠
松本　淳
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オリンパス株式会社
テルモ株式会社
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Publication of WO2013084975A1 publication Critical patent/WO2013084975A1/en

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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"
    • G01N21/643—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" non-biological material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
    • 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
    • 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
    • G01N2021/6482—Sample cells, cuvettes

Definitions

  • the present invention relates to a fluorescent sensor for measuring the concentration of an analyte in an aqueous solution and a method for manufacturing the fluorescent sensor, and in particular, an indicator made of a hydrogel that generates fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light.
  • the present invention relates to a fluorescent sensor and a method for manufacturing the fluorescent sensor.
  • the fluorescence sensor includes a light emitting unit that generates excitation light, an indicator unit that generates fluorescence having an intensity corresponding to the analyte concentration, and a photoelectric conversion element unit that detects fluorescence from the indicator.
  • the sensor system 101 includes a fluorescent sensor 130, a main body 140, and a receiver 145 having a storage unit that receives and stores a signal from the main body 140. Transmission / reception of signals between the main body 140 and the receiver 145 is performed wirelessly or by wire.
  • the fluorescent sensor 130 has an elongated needle body 33 having the sensor part 110 at the distal end 32 and a connector 35 integrated with the needle rear end 34 of the needle body 33.
  • the connector part 35 is detachably fitted to the fitting part 41 of the main body part 140.
  • the fluorescent sensor 130 is electrically connected to the main body portion 140 by mechanically fitting the connector portion 35 with the fitting portion 41 of the main body portion 140.
  • the main body 140 includes a wireless antenna for wirelessly transmitting and receiving signals to and from the receiver 145, a power source such as a battery, and various circuits for driving and controlling the sensor unit 110.
  • the sensor unit 110 of the fluorescence sensor 130 includes a photoelectric conversion element 112 that converts the fluorescence F formed on the base 111 into an electrical signal, a transparent protective layer 113, and a filter that covers the photoelectric conversion element 112.
  • the light emitting element 115 that transmits the fluorescence F and generates the excitation light E
  • the transparent protective layer 116 that covers the light emission element 115
  • the analyte 2 to interact with the analyte 2 to generate the fluorescence F.
  • An indicator 117 and a light-shielding cover layer 118 are included.
  • the filter 114 transmits the fluorescence F but does not transmit the excitation light E.
  • the excitation light E generated by the light emitting element 115 is applied to the indicator 117 through the protective layer 116.
  • Fluorescence F is generated by the interaction between the excitation light E and the analyte 2 that has entered the indicator 117. Part of the generated fluorescence F passes through the light emitting element 115 and enters the photoelectric conversion element 112, and the photoelectric conversion element 112 generates an output signal such as current or voltage corresponding to the fluorescence intensity, that is, the concentration of the analyte 2. .
  • the fluorescence sensor 130 cannot detect the fluorescence F emitted in other directions other than the lower side. That is, the conventional fluorescence sensor 130 has a low detection efficiency of the fluorescence F, and thus it cannot be said that the detection sensitivity is high.
  • An object of the embodiment of the present invention is to provide a highly sensitive fluorescent sensor and a method of manufacturing a highly sensitive fluorescent sensor.
  • the fluorescent sensor includes a cylindrical base portion, a photoelectric conversion element portion that converts fluorescent light into an electrical signal, covering the inner peripheral surface of the base portion, and covering the photoelectric conversion element portion.
  • a filter that transmits the excitation light and blocks the excitation light, a light-emitting portion that generates excitation light disposed on the inner peripheral side of the base portion with respect to the filter, and the excitation light filled in the base portion.
  • An indicator that receives the light and generates the fluorescence having an intensity according to the analyte concentration; and a cover that covers the opening of the base body and allows the analyte to pass therethrough and blocks the excitation light and the fluorescence.
  • a method for manufacturing a fluorescence sensor comprising: a step of disposing a photoelectric conversion element unit that converts fluorescence into an electric signal on a flat substrate; and covering the photoelectric conversion element unit with the fluorescence.
  • the fluorescence sensor 30 is used as the sensor system 1 in combination with the main body 40 and the receiver 45 in the same manner as the conventional fluorescence sensor 130 described above.
  • the fluorescence sensor 30 is a glucose sensor that detects glucose, which is an analyte in the body fluid of the subject.
  • the fluorescence sensor 30 can measure the analyte concentration continuously for a predetermined period, for example, one week after the sensor unit 10 is inserted into the body.
  • the collected bodily fluid or the bodily fluid that circulates through the body via a flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the fluorescence sensor 30 into the body.
  • the photoelectric conversion element layer 12 (see FIG. 5) and the light emitting element 15 (see FIG. 5) of the sensor unit 10 of the distal end portion 32 are electrically connected to the connector unit 35 through a plurality of wires 19 that pass through the needle body 33. Has been.
  • the drive power from the main body 40 is transmitted to the light emitting element 15 via the wiring 19, and the sensor signal from the photoelectric conversion element layer 12 is transmitted to the main body 40 via the other wiring 19.
  • the sensor unit 10 of the fluorescence sensor 30 constitutes a tip 32 extending from the needle body 33.
  • the external appearance of the sensor unit 10 includes a cylindrical base part 21 and a cover part 18 that closes the opening on the front end side of the base part 21.
  • the base portion 21 has a diameter of 10 ⁇ m to 1 mm and a length of 100 ⁇ m to 10 mm. “ ⁇ ” means “above and below”.
  • the base portion 21 in which the flat base 21X is rolled and joined in a cylindrical state has a straight joint 22 in the longitudinal direction. That is, although the base
  • the cover portion 18 has a function of preventing the indicator 17 disposed inside the cylindrical base portion 21 from being emitted to the outside, and further has a light shielding function of blocking the excitation light E and the fluorescence F. That is, the cover unit 18 prevents the excitation light E and the fluorescence F generated inside the sensor unit 10 from leaking to the outside. Further, the cover portion 18 prevents external light from entering the inside of the base portion 21.
  • the cover portion 18 is made of a material that allows the analyte 2 to pass through the inside thereof and reach the inside of the sensor portion 10. That is, the analyte 2 can freely enter and leave the indicator 17 inside the base portion 21 via the cover portion 18.
  • FIG. 5 is a structural diagram of a cross section perpendicular to the longitudinal direction of the sensor unit 10 of the fluorescence sensor 30.
  • the outer wall of the sensor unit 10 is composed of the cylindrical base body 21.
  • the inner peripheral surface of the base portion 21 is covered with a photoelectric conversion element layer 12 that is a photoelectric conversion element portion.
  • the inner peripheral side of the photoelectric conversion element layer 12 is covered with a filter 14.
  • the light emitting element 15, which is a light emitting unit that generates the excitation light E, is mounted on the inner peripheral side with respect to the filter 14.
  • An indicator 17 that receives excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration is accommodated inside the base portion 21 via a protective layer 16 that covers the light emitting element 15 and the filter 14. That is, the indicator 17 is substantially cylindrical.
  • the base part 21 in which the indicator 17 or the like is accommodated needs to have a light shielding property like the cover part 18.
  • a composite material in which a light-shielding cover layer is laminated on a flexible sheet for example, a polyimide sheet on which aluminum or gold is vapor-deposited, for the base 21X.
  • a composite material in which a light-shielding metal foil such as stainless steel and a flexible sheet are bonded together may be used.
  • the flexible sheet various flexible materials other than polyimide, for example, plastic materials such as PET (polyethylene terephthalate), or rubber materials such as PDMS (polydimethylsiloxane) can be used.
  • the thickness of the flexible sheet may be several ⁇ m to several tens of ⁇ m, but is preferably 10 ⁇ m to 20 ⁇ m in consideration of flexibility and mechanical strength.
  • the thickness of the light-shielding cover layer may be from several ⁇ m to several tens of ⁇ m, but 1 to 5 ⁇ m is preferable in order to achieve both flexibility and light-shielding properties.
  • the thin metal plate provided with flexibility and light-shielding property as the base
  • the photoelectric conversion element layer 12 converts the fluorescence F into an electric signal.
  • the photoelectric conversion element layer 12 is preferably a photodiode (PD), but is not limited to this, and is selected from various photoelectric conversion elements such as a photoconductor or a phototransistor.
  • the photoelectric conversion element layer 12 of the fluorescent sensor 30 has flexibility.
  • An inorganic semiconductor material such as silicon can be used for the photoelectric conversion element layer 12, but an organic semiconductor material may also be used.
  • the flexibility of the photoelectric conversion layer is easily obtained, and the production of the fluorescence sensor is facilitated as will be described later.
  • organic semiconductor materials include polycyclic aromatic hydrocarbons such as pentacene, anthracene, or rubrene, low-molecular compounds such as tetracyanoquinodimethane (TCNQ), or polyacetylene or poly-3-hexylthiophene (P3HT).
  • TCNQ tetracyanoquinodimethane
  • P3HT poly-3-hexylthiophene
  • a polymer such as polyparaphenylene vinylene (PPV) can be used.
  • the thickness of the photoelectric conversion element layer 12 is several nm to several ⁇ m, but for example, it is 10 to 100 nm when formed by vapor deposition.
  • the photoelectric conversion element layer 12 covers 100% of the surface of the base 21X without a gap, and at least the coverage is 30% or more, preferably 40% or more, particularly preferably 70% or more.
  • the fluorescence sensor 30 is highly sensitive.
  • the filter 14 blocks the excitation light E generated by the light emitting element 15, for example, having a wavelength of 375 nm, and transmits the fluorescence F generated by the indicator 17, for example, having a wavelength of 460 nm.
  • the filter 14 may be a multiple interference filter, but is preferably a light absorption filter, 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 formed by laminating.
  • the transmittance of a silicon layer and a silicon carbide layer is 10 ⁇ 5 % or less at a wavelength of 375 nm, whereas the transmittance is 10% or more at a wavelength of 460 nm (transmittance of excitation light wavelength / transmission of fluorescence wavelength).
  • the transmittance selectivity is 6 digits or more.
  • an element that transmits fluorescence F is selected from various types of light emitting elements such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element. From the viewpoints of light generation efficiency, broadness of wavelength selectivity of excitation light, generation of only light having a wavelength other than ultraviolet rays serving as excitation light E, and high transmittance of fluorescence F, inorganic LEDs are used.
  • An element chip is preferred.
  • an ultraviolet light-emitting LED element chip made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
  • the light emitting element 15 emits pulses.
  • the pulse width of light emission is 10 ms to 100 ms
  • the pulse current is about 1 mA to 100 mA
  • the center wavelength of the excitation light E is around 375 nm.
  • the fluorescent sensor 30 in which the light emitting element 15 emits pulses at intervals of once every 30 seconds measures the analyte concentration every 30 seconds.
  • the indicator 17 receives the excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration.
  • the indicator 17 interacts with the analyte 2 that has entered from the outside of the sensor unit 10 through the cover unit 18, and when receiving the excitation light E, generates an amount of fluorescence F corresponding to the analyte concentration.
  • the indicator 17 is made of a base material containing a fluorescent dye that generates fluorescence F having an intensity corresponding to the analyte concentration.
  • the fluorescent dye is selected according to the type of the analyte 2, and a fluorescent dye that reversibly changes the intensity of the fluorescence generated according to the amount of the analyte 2 can be used.
  • the indicator 17 uses, as a fluorescent dye, a ruthenium organic complex, a fluorescent phenylboronic acid derivative, or a substance that reversibly binds to glucose, such as fluorescein bound to a protein.
  • the base material of the indicator 17 is preferably transparent so that excitation light from the light emitting part and fluorescence from the fluorescent dye in the indicator 17 can be transmitted satisfactorily.
  • the base material is preferably a hydrogel that easily contains water, a urethane hydrogel prepared by polymerizing a polysaccharide such as methylcellulose or dextran, a monomer such as (meth) acrylamide, methylolacrylamide, or hydroxyethyl acrylate, or A urethane hydrogel prepared from polyethylene glycol and diisocyanate is used.
  • the protective layer 16 is made of a transparent material that protects the photoelectric conversion element layer 12 and the light emitting element 15.
  • a silicon oxide layer, a silicon nitride layer, a composite laminated layer composed of a silicon oxide layer and a silicon nitride layer, a silicone resin layer, or a transparent amorphous fluororesin layer can be used. Then, it is a silicon oxide layer.
  • a transparent protective layer similar to the protective layer 16 may be disposed between the photoelectric conversion element layer 12 and the filter 14.
  • the photoelectric conversion element layer 12 is disposed on the base 21X. That is, a light absorption layer that is an inorganic semiconductor or an organic semiconductor and electrodes that serve as an anode and a cathode of the light absorption layer are formed. After masking is performed using a printing method or a photolithography method, when an impurity is partially implanted into the pentacene film by an ion implantation method, a p-type ion implantation layer and an n ion implantation layer are formed, and a photodiode is formed. Is formed.
  • a polycrystalline silicon layer is formed as a filter 14 by, for example, a CVD method so as to cover the photoelectric conversion element layer 12. This process can also be realized by adhering a film-like filter.
  • a separately manufactured LED element as a light emitting element 15 is mounted on the filter 14 by a flip chip bonding method or the like.
  • a plurality of light emitting elements 15 may be mounted according to the length of the base portion 21.
  • a plurality of wirings 19 each connected to the photoelectric conversion element layer 12 or the light emitting element 15 are formed by depositing a conductive metal such as aluminum and patterning by a photolithography method.
  • the protective layer 16 is formed by, for example, the CVD method so as to cover the filter 14 and the light emitting element 15, and the sensor base 21Y is completed.
  • the sensor base 21Y may be manufactured one by one, it is preferable to manufacture a plurality of sensor bases 21Y simultaneously. That is, a large polyimide sheet (base 21X) is bonded to a support base, and the constituent elements are sequentially disposed thereon, and then cut and separated into a large number of sensor bases 21Y.
  • a sensor substrate 21Y having a width of 1.57 mm (500 ⁇ m ⁇ ⁇ ) and an area of 1 mm in length is obtained using a 4-inch ⁇ base 21X. More than 5000 pieces can be manufactured at once.
  • the areas of the individual bases 21X may be determined before dividing into individual pieces. That is, in the sensor base 21Y illustrated in FIG. 6, the coverage of the photoelectric conversion element layer 12 disposed on the base 21X is approximately 100%, but in order to increase the manufacturing yield, the photoelectric conversion element The layer 12 may also be patterned after placement to reduce the coverage.
  • the sensor base 21Y (base 21X) is joined by an adhesive or the like through the joint 22 in a state where the surface on which the photoelectric conversion element layer 12 is disposed is curved to form a cylindrical base 21.
  • the cuts (slits) 23 such as the protective layer 16 inside the base portion 21 may also be joined by an adhesive or the like.
  • a shape memory alloy may be used as the material of the base 21X, and the substrate 21X may be formed into a cylindrical shape by heat treatment due to the shape memory effect.
  • the joining portion 22 may be joined to the end surface with an adhesive or may be joined via a joining member disposed on the outer surface.
  • the curved sensor base 21Y may be inserted and held in a cylindrical inflexible holding cylinder.
  • the indicator 17 is filled into the inside from the opening at the front end.
  • a phosphate buffer solution containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator is placed in the base portion 21 and left for 1 hour in a nitrogen atmosphere.
  • fluorescent dye 9,10-bis [N- [2- (5,5-dimethylborinan-2-yl) benzyl] -N- [6 ′-[(acryloyl polyethylene glycol-3400) carbonylamino ] -N-hexylamino] methyl] -2-acetylanthracene (F-PEG-AAm), acrylamide as the gel skeleton-forming material, sodium peroxodisulfate and N, N, N ′ as the polymerization initiator N'-tetramethylethylenediamine is used.
  • a water-containing indicator or a dry indicator prepared in advance may be put into the base portion 21.
  • the cover 18 is made of, for example, a porous metal or ceramic, or a composite material in which fine particles that do not transmit light such as carbon black or carbon nanotubes are mixed with hydrogel.
  • the light transmittance of the cover 18 is about 1 ⁇ 10 ⁇ 3 % to 1 ⁇ 10 ⁇ 5 % at the excitation light wavelength and the visible light wavelength.
  • the main structure of the fluorescence sensor 30 including the needle main body 33, the needle base end, and the connector 35 is separately manufactured by processing a silicon wafer or the like. And the sensor part 10 produced by the said process is arrange
  • the fluorescence sensor 30 includes the cylindrical base portion 21, the photoelectric conversion element layer 12 that covers the inner peripheral surface of the base portion 21, the filter 14 that covers the photoelectric conversion element layer 12, and the filter 14.
  • the light emitting element 15 disposed on the inner peripheral side, and the indicator 17 filled in the base portion 21 are provided.
  • the photoelectric conversion element layer 12 receives most of the fluorescence F emitted from the indicator 17 in various directions. For this reason, the fluorescence sensor 30 has high fluorescence detection sensitivity. Moreover, according to the manufacturing method of the fluorescence sensor 30, a highly sensitive fluorescence sensor can be manufactured.
  • the base portion 21 in which the sensor base 21Y in which the flexible photoelectric conversion element layer 12 and the flexible filter 14 are stacked on the flexible base 21X is rounded and processed into a cylindrical shape is formed in the longitudinal direction.
  • the photoelectric conversion element layer 12 and the filter 14 on the inner peripheral side of the joint portion 22 have a cut (slit) 23.
  • the fluorescence sensor 30 having the above-described structure can be regarded as being produced by rounding the plate-like substrate 31X.
  • the base body 21X needs to be flexible in order to be rounded into a cylindrical shape, but the base part 21 in the cylindrical shape does not need flexibility. For this reason, as already described, a cylindrical inflexible holding cylinder may be used, or the outer peripheral portion of the cylindrical base portion 21 may be coated with a highly biocompatible resin or metal.
  • the fluorescence sensor 30A of the second embodiment and the method for manufacturing the fluorescence sensor 30A will be described. Since the manufacturing method of the fluorescent sensor 30A and the fluorescent sensor 30A is similar to the manufacturing method of the fluorescent sensor 30 and the fluorescent sensor 30, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the fluorescence sensor 30 ⁇ / b> A includes a plurality of photoelectric conversion elements 12 ⁇ / b> A in which the photoelectric conversion element part of the sensor part 10 ⁇ / b> A is divided in the longitudinal direction of the base part 21.
  • Each photoelectric conversion element 12A is, for example, a PD element formed on a single crystal silicon substrate.
  • the photoelectric conversion element 12A obtained by thinning the silicon substrate from the back side can be bent slightly. However, it is not easy to bend the photoelectric conversion element 12 ⁇ / b> A along the inner surface of the base portion 21 like the photoelectric conversion element layer 12 made of an organic semiconductor. For this reason, as shown in FIG. 8, in the manufacturing method of the fluorescence sensor 30A, the photoelectric conversion element substrate including a plurality of photoelectric conversion elements is joined to the base 21X and then divided into the plurality of photoelectric conversion elements 12A.
  • the division into the plurality of photoelectric conversion elements 12A does not need to be completely separated, and it is only necessary to make cuts as shown in FIG. Further, instead of bonding the silicon substrate on which the plurality of photoelectric conversion elements 12A are formed to the base 21X, the lower side of the silicon substrate may be used as the base. In this case, the base 21X is unnecessary.
  • strip-like photoelectric conversion elements 12A may be arranged and joined on the base 21X.
  • the coverage of the photoelectric conversion element 12A on the base 21X is 30% or more, preferably 40% or more.
  • the upper limit of the coverage of the photoelectric conversion element 12A is, for example, 90% because of the structure.
  • the fluorescent sensor 30A has the effects of the fluorescent sensor 30, and can be manufactured at low cost because a silicon semiconductor that is easy to manufacture and inexpensive can be used as the PD element.
  • the manufacturing method of the fluorescent sensor 30A is easy to manufacture and can manufacture an inexpensive fluorescent sensor.
  • the fluorescence sensor 30B of the third embodiment and the method for manufacturing the fluorescence sensor 30B will be described. Since the manufacturing method of the fluorescent sensor 30B and the fluorescent sensor 30B is similar to the manufacturing method of the fluorescent sensor 30 and the fluorescent sensor 30, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the photoelectric conversion element layer 12 ⁇ / b> B As shown in FIG. 9, in the fluorescence sensor 30 ⁇ / b> B, half of the organic semiconductor layer disposed on the inner surface of the base portion 21 of the sensor unit 10 ⁇ / b> B is the photoelectric conversion element layer 12 ⁇ / b> B made of the same PD element as the fluorescence sensor 30.
  • the photoelectric conversion element layer 12B is covered with a filter 14B.
  • the remaining half of the organic semiconductor layer is a light emitting layer 15B made of an organic light emitting diode (OLED).
  • the filter 14B and the light emitting layer 15B are covered with a protective layer 16.
  • half of the organic semiconductor layer formed on the substrate 21X is a photoelectric conversion element layer 12B that converts fluorescence F into an electrical signal, and the other half is light emission that generates excitation light E by changing the material of the organic semiconductor.
  • the layer 15B is used.
  • changing the material of the organic semiconductor includes changing the kind and concentration of the same material as the dopan.
  • the fluorescent sensor 30 or the like was the light emitting element 15 made of a non-flexible inorganic LED element in which the light emitting portion emits point light.
  • the light emitting layer 15B of the fluorescence sensor 30B is a flexible surface light emitter.
  • the fluorescent sensor 30B is low in cost because it is not necessary to mount the light emitting element 15 in a chip state separately manufactured like the fluorescent sensor 30 by the flip chip bonding method. In addition, the fluorescent sensor 30B has high reliability because the light emitting layer 15B is laminated on the base 21A, and there is no possibility of failure such as removal of the mounted light emitting element.
  • the indicator 17 can be irradiated with excitation light E having a more uniform intensity than the fluorescent sensor 30. Furthermore, the light emitting layer 15B generates less heat than the light emitting element 15.
  • the fluorescent sensor 30B has the same effect as the fluorescent sensor 30, and the luminous efficiency of the indicator 17 is high because it receives the excitation light E having a uniform intensity. Furthermore, the fluorescence sensor 30B can be used stably for a longer period than the fluorescence sensor 30B because the indicator 17 is less deteriorated by receiving excessive excitation light and heat.
  • the organic semiconductor layer was divided into approximately two equal parts into the light emitting part and the photoelectric conversion element part.
  • the division ratio between the light emitting unit and the photoelectric conversion element unit can be changed according to the specification.
  • the amount of excitation light can be appropriately set by changing the division ratio of the organic semiconductor layer in accordance with the ease of fluorescence emission of the analyte to be detected.
  • the organic semiconductor layer is divided into the light emitting part and the photoelectric conversion element part in the radial direction of the inner periphery.
  • the light emitting unit and the photoelectric conversion element unit may be divided in the longitudinal direction of the sensor unit 10B.
  • the cover portion 18 side may be a light emitting portion
  • the needle main body portion 33 side may be a photoelectric conversion element portion.
  • a light emitting layer 15C made of a flexible surface light emitter is laminated on the filter 14.
  • the light emitting layer 15C is made of the same organic light emitting diode as the light emitting layer 15B already described, but a transparent conductive material is used not only for the upper electrode but also for the lower electrode.
  • the light emitting layer 15C has a high light transmittance at the wavelength of the fluorescence F.
  • the manufacturing method of the fluorescent sensor 30C and the fluorescent sensor 30C is easy to manufacture and low cost because the photoelectric conversion element layer 12C and the light emitting layer 15B have a laminated structure in addition to the effects of the fluorescent sensor 30B and the like.
  • the fluorescence sensor 30 that detects glucose is described as an example.
  • the fluorescence sensor is a detection sensor for other saccharides, an enzyme sensor, a pH sensor, an immune sensor, or a microorganism depending on the selection of a fluorescent dye. It can be used for various applications such as sensors.
  • a fluorescent dye a hydroxypyrenetrisulfonic acid derivative is used when measuring the hydrogen ion concentration or carbon dioxide in a living body, and a phenylboronic acid derivative having a fluorescent residue is used when measuring a saccharide.
  • a crown ether derivative having a fluorescent residue is used.

Abstract

A fluorescence sensor (30) is provided with: a cylindrical base body part (31); a photoelectric conversion element layer (12) for converting a fluorescent light (F) into an electrical signal, the layer covering the inside peripheral surface of the base body part (31); a filter (14) for transmitting the fluorescent light (F) and cutting off an excitation light (E), the filter covering the photoelectric conversion element layer (12); an electroluminescent element (15) for generating the excitation light (E), the electroluminescent element arranged further toward the inside periphery of the base body part (31) relative to the filter (14); an indicator (17) for receiving the excitation light (E) and generating the fluorescent light (F) at an intensity corresponding to the concentration of an analyte, the interior of the base body part (31) being filled with the indicator.

Description

蛍光センサおよび蛍光センサの製造方法Fluorescence sensor and method of manufacturing fluorescence sensor
　本発明は、水溶液中のアナライトの濃度を計測する蛍光センサおよび前記蛍光センサの製造方法に関し、特に、励起光を受光するとアナライト濃度に応じた強度の蛍光を発生するハイドロゲルからなるインジケータを具備する蛍光センサおよび前記蛍光センサの製造方法に関する。 The present invention relates to a fluorescent sensor for measuring the concentration of an analyte in an aqueous solution and a method for manufacturing the fluorescent sensor, and in particular, an indicator made of a hydrogel that generates fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light. The present invention relates to a fluorescent sensor and a method for manufacturing the fluorescent sensor.
　液体中のアナライトすなわち被計測物質の濃度を測定する各種のセンサが開発されている。例えば、蛍光センサは、励起光を発生する発光部と、アナライト濃度に応じた強度の蛍光を発生するインジケータ部と、インジケータからの蛍光を検出する光電変換素子部と、を有している。 Various sensors have been developed to measure the concentration of analytes in liquids, that is, substances to be measured. For example, the fluorescence sensor includes a light emitting unit that generates excitation light, an indicator unit that generates fluorescence having an intensity corresponding to the analyte concentration, and a photoelectric conversion element unit that detects fluorescence from the indicator.
　図１に示すように、国際公開第２０１０／１１９９１６号パンフレットには、本体部１４０およびレシーバー１４５と組み合わせてセンサシステム１０１として使用される蛍光センサ１３０が開示されている。すなわち、センサシステム１０１は、蛍光センサ１３０と、本体部１４０と、本体部１４０からの信号を受信し記憶する記憶部のあるレシーバー１４５と、を有する。本体部１４０とレシーバー１４５との間の信号の送受信は無線または有線で行われる。 As shown in FIG. 1, International Publication No. 2010/119916 pamphlet discloses a fluorescent sensor 130 used as a sensor system 101 in combination with a main body 140 and a receiver 145. That is, the sensor system 101 includes a fluorescent sensor 130, a main body 140, and a receiver 145 having a storage unit that receives and stores a signal from the main body 140. Transmission / reception of signals between the main body 140 and the receiver 145 is performed wirelessly or by wire.
　蛍光センサ１３０は、先端部３２にセンサ部１１０を有する細長い針本体部３３と、針本体部３３の針後端部３４と一体化したコネクタ部３５と、を有する。コネクタ部３５は本体部１４０の嵌合部４１と着脱自在に嵌合する。蛍光センサ１３０はコネクタ部３５が本体部１４０の嵌合部４１と機械的に嵌合することにより、本体部１４０と電気的に接続される。 The fluorescent sensor 130 has an elongated needle body 33 having the sensor part 110 at the distal end 32 and a connector 35 integrated with the needle rear end 34 of the needle body 33. The connector part 35 is detachably fitted to the fitting part 41 of the main body part 140. The fluorescent sensor 130 is electrically connected to the main body portion 140 by mechanically fitting the connector portion 35 with the fitting portion 41 of the main body portion 140.
　本体部１４０は、図示しないがレシーバー１４５との間で、無線により信号を送受信するための無線アンテナと、電池等の電源と、センサ部１１０の駆動および制御などを行う各種回路を有する。 Although not shown, the main body 140 includes a wireless antenna for wirelessly transmitting and receiving signals to and from the receiver 145, a power source such as a battery, and various circuits for driving and controlling the sensor unit 110.
　図２に示すように、蛍光センサ１３０のセンサ部１１０は、基体１１１に形成された蛍光Ｆを電気信号に変換する光電変換素子１１２と、透明な保護層１１３と、光電変換素子１１２を覆うフィルタ１１４と、蛍光Ｆを透過し励起光Ｅを発生する発光素子１１５と、発光素子１１５を覆う透明な保護層１１６と、アナライト２と相互作用することによって励起光を受光すると蛍光Ｆを発生するインジケータ１１７と、遮光性のカバー層１１８とから構成される。フィルタ１１４は、蛍光Ｆを透過するが、励起光Ｅは透過しない。 As shown in FIG. 2, the sensor unit 110 of the fluorescence sensor 130 includes a photoelectric conversion element 112 that converts the fluorescence F formed on the base 111 into an electrical signal, a transparent protective layer 113, and a filter that covers the photoelectric conversion element 112. 114, the light emitting element 115 that transmits the fluorescence F and generates the excitation light E, the transparent protective layer 116 that covers the light emission element 115, and the analyte 2 to interact with the analyte 2 to generate the fluorescence F. An indicator 117 and a light-shielding cover layer 118 are included. The filter 114 transmits the fluorescence F but does not transmit the excitation light E.
　発光素子１１５が発生した励起光Ｅが、保護層１１６を介して、インジケータ１１７に照射される。励起光Ｅとインジケータ１１７の内部に侵入したアナライト２との相互作用により、蛍光Ｆが発生する。発生した蛍光Ｆの一部は発光素子１１５を透過して光電変換素子１１２に入射し、光電変換素子１１２において蛍光強度、つまりアナライト２の濃度に応じた電流または電圧などの出力信号が発生する。 The excitation light E generated by the light emitting element 115 is applied to the indicator 117 through the protective layer 116. Fluorescence F is generated by the interaction between the excitation light E and the analyte 2 that has entered the indicator 117. Part of the generated fluorescence F passes through the light emitting element 115 and enters the photoelectric conversion element 112, and the photoelectric conversion element 112 generates an output signal such as current or voltage corresponding to the fluorescence intensity, that is, the concentration of the analyte 2. .
　しかし、蛍光センサ１３０は、光電変換素子１１２がインジケータ１１７の下方にしかないため、下方以外の他の方向に出射する蛍光Ｆを検出できなかった。すなわち、従来の蛍光センサ１３０は、蛍光Ｆの検出効率が低いため、検出感度が高いとはいえない場合があった。 However, since the photoelectric conversion element 112 is only below the indicator 117, the fluorescence sensor 130 cannot detect the fluorescence F emitted in other directions other than the lower side. That is, the conventional fluorescence sensor 130 has a low detection efficiency of the fluorescence F, and thus it cannot be said that the detection sensitivity is high.
　本発明の実施形態は、感度の高い蛍光センサおよび感度の高い蛍光センサの製造方法を提供することを目的とする。 An object of the embodiment of the present invention is to provide a highly sensitive fluorescent sensor and a method of manufacturing a highly sensitive fluorescent sensor.
　本発明の実施形態の蛍光センサは、筒状の基体部と、前記基体部の内周面を覆う、蛍光を電気信号に変換する光電変換素子部と、前記光電変換素子部を覆う、前記蛍光を透過し励起光を遮断するフィルタと、前記フィルタよりも前記基体部の内周側に配設された励起光を発生する発光部と、前記基体部の内部に充填された、前記励起光を受光してアナライト濃度に応じた強度の前記蛍光を発生するインジケータと、前記基体部の開口を覆う、前記アナライトが通過可能で、前記励起光および前記蛍光を遮断するカバー部と、を具備する。 The fluorescent sensor according to the embodiment of the present invention includes a cylindrical base portion, a photoelectric conversion element portion that converts fluorescent light into an electrical signal, covering the inner peripheral surface of the base portion, and covering the photoelectric conversion element portion. A filter that transmits the excitation light and blocks the excitation light, a light-emitting portion that generates excitation light disposed on the inner peripheral side of the base portion with respect to the filter, and the excitation light filled in the base portion. An indicator that receives the light and generates the fluorescence having an intensity according to the analyte concentration; and a cover that covers the opening of the base body and allows the analyte to pass therethrough and blocks the excitation light and the fluorescence. To do.
　本発明の別の実施形態の蛍光センサの製造方法は、平板状の基体に、蛍光を電気信号に変換する光電変換素子部を配設する工程と、前記光電変換素子部を覆う、前記蛍光を透過し励起光を遮断するフィルタを配設する工程と、前記フィルタの上に、前記励起光を発生する発光部を配設する工程と、前記基体を、前記光電変換素子部配設面が内側となるように湾曲した状態で接合部を介して接合することにより筒状の基体部とする工程と、前記基体部の内部に、前記励起光を受光してアナライト濃度に応じた前記蛍光を発生するインジケータを充填する工程と、前記基体部の開口を、前記アナライトが通過可能で、前記励起光および前記蛍光を遮断するカバー部で覆う工程と、を具備する。 According to another embodiment of the present invention, there is provided a method for manufacturing a fluorescence sensor, comprising: a step of disposing a photoelectric conversion element unit that converts fluorescence into an electric signal on a flat substrate; and covering the photoelectric conversion element unit with the fluorescence. A step of disposing a filter that transmits and blocks excitation light; a step of disposing a light-emitting unit that generates the excitation light on the filter; and a surface on which the photoelectric conversion element portion is disposed And a step of forming a cylindrical base portion by joining through a joint portion in a curved state so that the fluorescence corresponding to the analyte concentration is received inside the base portion by receiving the excitation light. A step of filling the generated indicator, and a step of covering the opening of the base portion with a cover portion through which the analyte can pass and blocks the excitation light and the fluorescence.
従来の蛍光センサシステムの斜視図である。It is a perspective view of the conventional fluorescence sensor system. 従来の蛍光センサのセンサ部の断面図である。It is sectional drawing of the sensor part of the conventional fluorescence sensor. 第１実施形態の蛍光センサシステムの斜視図である。It is a perspective view of the fluorescence sensor system of a 1st embodiment. 第１実施形態の蛍光センサの先端部の斜視図である。It is a perspective view of the front-end | tip part of the fluorescence sensor of 1st Embodiment. 第１実施形態の蛍光センサのセンサ部の断面図である。It is sectional drawing of the sensor part of the fluorescence sensor of 1st Embodiment. 第１実施形態の蛍光センサのセンサ部の製造方法を説明するための斜視図である。It is a perspective view for demonstrating the manufacturing method of the sensor part of the fluorescence sensor of 1st Embodiment. 第２実施形態の蛍光センサのセンサ部の断面図である。It is sectional drawing of the sensor part of the fluorescence sensor of 2nd Embodiment. 第２実施形態の蛍光センサの光電変換素子を説明するための斜視図である。It is a perspective view for demonstrating the photoelectric conversion element of the fluorescence sensor of 2nd Embodiment. 第３実施形態の蛍光センサのセンサ部の断面図である。It is sectional drawing of the sensor part of the fluorescence sensor of 3rd Embodiment. 第４実施形態の蛍光センサのセンサ部の断面図である。It is sectional drawing of the sensor part of the fluorescence sensor of 4th Embodiment.
＜第１実施形態＞
　図３に示すように、本発明の第１実施形態の蛍光センサ３０は、すでに説明した従来の蛍光センサ１３０と同様に、本体部４０およびレシーバー４５と組み合わせてセンサシステム１として使用される。蛍光センサ３０は、被検体の体液中のアナライトであるグルコースを検出するグルコースセンサである。蛍光センサ３０はセンサ部１０を体内に挿入後、所定期間、例えば、１週間、継続してアナライト濃度を測定可能である。しかし、蛍光センサ３０を体内に挿入しないで、採取した体液、または体外の流路を介して体内と循環する体液を、体外においてセンサ部１０と接触させてもよい。 <First Embodiment>
As shown in FIG. 3, the fluorescence sensor 30 according to the first embodiment of the present invention is used as the sensor system 1 in combination with the main body 40 and the receiver 45 in the same manner as the conventional fluorescence sensor 130 described above. The fluorescence sensor 30 is a glucose sensor that detects glucose, which is an analyte in the body fluid of the subject. The fluorescence sensor 30 can measure the analyte concentration continuously for a predetermined period, for example, one week after the sensor unit 10 is inserted into the body. However, the collected bodily fluid or the bodily fluid that circulates through the body via a flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the fluorescence sensor 30 into the body.
　先端部３２のセンサ部１０の光電変換素子層１２（図５参照）および発光素子１５（図５参照）は針本体部３３を挿通する複数の配線１９を介してコネクタ部３５と電気的に接続されている。本体部４０からの駆動電力は配線１９を介して発光素子１５に送電されるとともに、光電変換素子層１２からのセンサ信号は他の配線１９を介して本体部４０に送信される。 The photoelectric conversion element layer 12 (see FIG. 5) and the light emitting element 15 (see FIG. 5) of the sensor unit 10 of the distal end portion 32 are electrically connected to the connector unit 35 through a plurality of wires 19 that pass through the needle body 33. Has been. The drive power from the main body 40 is transmitted to the light emitting element 15 via the wiring 19, and the sensor signal from the photoelectric conversion element layer 12 is transmitted to the main body 40 via the other wiring 19.
　図４に示すように、蛍光センサ３０のセンサ部１０は、針本体部３３から延設された先端部３２を構成している。センサ部１０の外観は、筒状の基体部２１と、基体部２１の先端側の開口を塞ぐカバー部１８と、からなる。基体部２１は、例えば、直径が１０μｍ～１ｍｍであり、長さが１００μｍ～１０ｍｍである。なお、「～」は「以上、以下」を意味する。後述するように、平板状の基体２１Ｘが丸められ筒状状態で接合された基体部２１には、長手方向に直線状の接合部２２がある。すなわち、基体部２１と基体２１Ｘとは同じものであるが、形状が異なるため別の符号を付して説明する。 As shown in FIG. 4, the sensor unit 10 of the fluorescence sensor 30 constitutes a tip 32 extending from the needle body 33. The external appearance of the sensor unit 10 includes a cylindrical base part 21 and a cover part 18 that closes the opening on the front end side of the base part 21. For example, the base portion 21 has a diameter of 10 μm to 1 mm and a length of 100 μm to 10 mm. “˜” means “above and below”. As will be described later, the base portion 21 in which the flat base 21X is rolled and joined in a cylindrical state has a straight joint 22 in the longitudinal direction. That is, although the base | substrate part 21 and the base | substrate 21X are the same, since a shape differs, it attaches | subjects and demonstrates another code | symbol.
　カバー部１８は、筒状の基体部２１の内部に配設されたインジケータ１７が外部に放出されるのを防止する機能を有し、さらに励起光Ｅおよび蛍光Ｆを遮断する遮光機能を有する。すなわち、カバー部１８は、センサ部１０の内部で発生する励起光Ｅおよび蛍光Ｆが、外部へ漏光するのを防止する。さらに、カバー部１８は、外光が基体部２１の内部に進入するのを防止する。また、カバー部１８は、アナライト２が、その内部を通過してセンサ部１０の内部に到達することが可能な材料で構成されている。すなわち、アナライト２は、カバー部１８を介して基体部２１の内部のインジケータ１７に出入り自由である。 The cover portion 18 has a function of preventing the indicator 17 disposed inside the cylindrical base portion 21 from being emitted to the outside, and further has a light shielding function of blocking the excitation light E and the fluorescence F. That is, the cover unit 18 prevents the excitation light E and the fluorescence F generated inside the sensor unit 10 from leaking to the outside. Further, the cover portion 18 prevents external light from entering the inside of the base portion 21. The cover portion 18 is made of a material that allows the analyte 2 to pass through the inside thereof and reach the inside of the sensor portion 10. That is, the analyte 2 can freely enter and leave the indicator 17 inside the base portion 21 via the cover portion 18.
　図５は、蛍光センサ３０のセンサ部１０の長手方向に垂直な断面の構造図である。すでに説明したようにセンサ部１０の外壁は筒状の基体部２１からなる。基体部２１の内周面は光電変換素子部である光電変換素子層１２により覆われている。さらに光電変換素子層１２の内周側はフィルタ１４に覆われている。励起光Ｅを発生する発光部である発光素子１５はフィルタ１４よりも内周側に実装されている。発光素子１５およびフィルタ１４を覆う保護層１６を介して、基体部２１の内部には励起光Ｅを受光してアナライト濃度に応じた強度の蛍光Ｆを発生するインジケータ１７が収容されている。すなわち、インジケータ１７は略円筒状である。 FIG. 5 is a structural diagram of a cross section perpendicular to the longitudinal direction of the sensor unit 10 of the fluorescence sensor 30. As already described, the outer wall of the sensor unit 10 is composed of the cylindrical base body 21. The inner peripheral surface of the base portion 21 is covered with a photoelectric conversion element layer 12 that is a photoelectric conversion element portion. Furthermore, the inner peripheral side of the photoelectric conversion element layer 12 is covered with a filter 14. The light emitting element 15, which is a light emitting unit that generates the excitation light E, is mounted on the inner peripheral side with respect to the filter 14. An indicator 17 that receives excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration is accommodated inside the base portion 21 via a protective layer 16 that covers the light emitting element 15 and the filter 14. That is, the indicator 17 is substantially cylindrical.
　インジケータ１７等が収容されている基体部２１には、カバー部１８と同様に遮光性が必要である。このため、基体２１Ｘにはフレキシブルシートに遮光性のカバー層を積層した複合材料、例えば、アルミニウムまたは金を蒸着したポリイミドシート、を用いることが好ましい。また、ステンレス等の遮光性の金属箔とフレキシブルシートとを貼り合わせた複合材料を用いてもよい。 The base part 21 in which the indicator 17 or the like is accommodated needs to have a light shielding property like the cover part 18. For this reason, it is preferable to use a composite material in which a light-shielding cover layer is laminated on a flexible sheet, for example, a polyimide sheet on which aluminum or gold is vapor-deposited, for the base 21X. Alternatively, a composite material in which a light-shielding metal foil such as stainless steel and a flexible sheet are bonded together may be used.
　フレキシブルシートはポリイミド以外にも様々な可撓性材料、例えば、ＰＥＴ（ポリエチレンテレフタレート）などのプラスティック材料、またはＰＤＭＳ（ポリジメチルシロキサン）などのゴム材料を用いることができる。フレキシブルシートの厚さは数μｍから数十μｍであればよいが、可撓性と機械的強度とを考慮すると１０μｍ～２０μｍが好ましい。 As the flexible sheet, various flexible materials other than polyimide, for example, plastic materials such as PET (polyethylene terephthalate), or rubber materials such as PDMS (polydimethylsiloxane) can be used. The thickness of the flexible sheet may be several μm to several tens of μm, but is preferably 10 μm to 20 μm in consideration of flexibility and mechanical strength.
　一方、遮光性のカバー層の厚さは数μｍから数十μｍであればよいが、可撓性と遮光性との両立からは、１～５μｍが好ましい。 On the other hand, the thickness of the light-shielding cover layer may be from several μm to several tens of μm, but 1 to 5 μm is preferable in order to achieve both flexibility and light-shielding properties.
　なお、基体２１Ｘとして、可撓性と遮光性とを備えた薄い金属板を用いてもよい。フレキシブルシートと貼り合わせる金属箔、または上記金属板として例えばＮｉ-Ｔｉ合金を用いれば、その形状記憶効果を利用することにより、後述する筒状化加工が容易になる。また後述するように、筒状の保持部の内部に平板状の基体２１Ｘを丸めた状態で挿入し保持する基体部２１の場合には、保持部が遮光性を有していれば基体２１Ｘには可撓性のみあればよい。 In addition, you may use the thin metal plate provided with flexibility and light-shielding property as the base | substrate 21X. If, for example, a Ni-Ti alloy is used as the metal foil to be bonded to the flexible sheet or the metal plate, the shape memory effect is used to facilitate the cylindrical processing described later. As will be described later, in the case of the base portion 21 that is inserted and held in a state where the flat plate-like base 21X is rolled inside the cylindrical holding portion, if the holding portion has light shielding properties, Need only be flexible.
　光電変換素子層１２は、蛍光Ｆを電気信号に変換する。光電変換素子層１２には、好ましくは、フォトダイオード（ＰＤ）が用いられるが、これに限るものではなく、フォトコンダクタまたはフォトトランジスタなどの各種光電変換素子から選択される。 The photoelectric conversion element layer 12 converts the fluorescence F into an electric signal. The photoelectric conversion element layer 12 is preferably a photodiode (PD), but is not limited to this, and is selected from various photoelectric conversion elements such as a photoconductor or a phototransistor.
　蛍光センサ３０の光電変換素子層１２は可撓性を有する。光電変換素子層１２にはシリコン等の無機半導体材料を利用できるが、有機半導体材料を用いても良い。この場合には、光電変換層の可撓性が得やすくなり、後述のとおり、蛍光センサの製造が容易になる。 The photoelectric conversion element layer 12 of the fluorescent sensor 30 has flexibility. An inorganic semiconductor material such as silicon can be used for the photoelectric conversion element layer 12, but an organic semiconductor material may also be used. In this case, the flexibility of the photoelectric conversion layer is easily obtained, and the production of the fluorescence sensor is facilitated as will be described later.
　例えば、有機半導体材料には、ペンタセン、アントラセン、もしくはルブレンなどの多環芳香族炭化水素、テトラシアノキノジメタン（ＴＣＮＱ）などの低分子化合物、または、ポリアセチレンやポリ-3-ヘキシルチオフェン（Ｐ３ＨＴ）もしくはポリパラフェニレンビニレン（ＰＰＶ）などのポリマーなどを用いることができる。光電変換素子層１２の厚さは数ｎｍ～数μｍであるが、例えば、蒸着法で形成した場合は１０～１００ｎｍである。 For example, organic semiconductor materials include polycyclic aromatic hydrocarbons such as pentacene, anthracene, or rubrene, low-molecular compounds such as tetracyanoquinodimethane (TCNQ), or polyacetylene or poly-3-hexylthiophene (P3HT). Alternatively, a polymer such as polyparaphenylene vinylene (PPV) can be used. The thickness of the photoelectric conversion element layer 12 is several nm to several μm, but for example, it is 10 to 100 nm when formed by vapor deposition.
　原理的には、光電変換素子層１２の面積が広い程、受光感度は高くなる。しかし、光電変換素子層１２が基体２１Ｘの表面を隙間なく覆っている被覆率１００％である必要はなく、少なくとも被覆率３０％以上、好ましくは４０％以上、特に好ましくは、７０％以上であれば、蛍光センサ３０は高感度である。 In principle, the larger the area of the photoelectric conversion element layer 12, the higher the light receiving sensitivity. However, it is not necessary that the photoelectric conversion element layer 12 covers 100% of the surface of the base 21X without a gap, and at least the coverage is 30% or more, preferably 40% or more, particularly preferably 70% or more. For example, the fluorescence sensor 30 is highly sensitive.
　フィルタ１４は、発光素子１５が発生する、例えば波長３７５ｎｍの励起光Ｅを遮断し、インジケータ１７が発生する、例えば波長４６０ｎｍの蛍光Ｆは透過する。フィルタ１４は、多重干渉型フィルタでもよいが、好ましくは、光吸収型フィルタであり、例えばシリコン、炭化シリコン、酸化シリコン、窒化シリコン、もしくは有機材料等からなる単層層、または、前記単層層を積層してなる多層層である。例えば、シリコン層および炭化シリコン層は、波長３７５ｎｍでは透過率は１０－５％以下であるのに対して、波長４６０ｎｍでは透過率１０％以上と、（励起光波長の透過率／蛍光波長の透過率）の比として６桁以上の透過率選択性を有する。 The filter 14 blocks the excitation light E generated by the light emitting element 15, for example, having a wavelength of 375 nm, and transmits the fluorescence F generated by the indicator 17, for example, having a wavelength of 460 nm. The filter 14 may be a multiple interference filter, but is preferably a light absorption filter, 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 formed by laminating. For example, the transmittance of a silicon layer and a silicon carbide layer is 10 −5 % or less at a wavelength of 375 nm, whereas the transmittance is 10% or more at a wavelength of 460 nm (transmittance of excitation light wavelength / transmission of fluorescence wavelength). As a ratio, the transmittance selectivity is 6 digits or more.
　励起光Ｅを発生する発光素子１５としては、ＬＥＤ素子、有機ＥＬ素子、無機ＥＬ素子、またはレーザーダイオード素子など多様な種類の発光素子の中から、特に蛍光Ｆを透過する素子が選択される。そして、光発生効率、励起光の波長選択性の広さ、および励起光Ｅとなる紫外線以外の波長の光を僅かしか発生しないこと、蛍光Ｆの透過率が高いなどの観点からは、無機ＬＥＤ素子チップが好ましい。さらに、サファイア基体上に形成された窒化ガリウム系化合物半導体よりなる紫外線発光ＬＥＤ素子チップが特に好ましい。 As the light emitting element 15 that generates the excitation light E, an element that transmits fluorescence F is selected from various types of light emitting elements such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element. From the viewpoints of light generation efficiency, broadness of wavelength selectivity of excitation light, generation of only light having a wavelength other than ultraviolet rays serving as excitation light E, and high transmittance of fluorescence F, inorganic LEDs are used. An element chip is preferred. Furthermore, an ultraviolet light-emitting LED element chip made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
　発光素子１５はパルス発光する。例えば、発光のパルス幅は１０ｍｓ～１００ｍｓ、パルス電流は１ｍＡ～１００ｍＡ程度、また、励起光Ｅの中心波長は３７５ｎｍ前後である。例えば発光素子１５が３０秒に１回の間隔でパルス発光する蛍光センサ３０は３０秒毎にアナライト濃度を測定する。 The light emitting element 15 emits pulses. For example, the pulse width of light emission is 10 ms to 100 ms, the pulse current is about 1 mA to 100 mA, and the center wavelength of the excitation light E is around 375 nm. For example, the fluorescent sensor 30 in which the light emitting element 15 emits pulses at intervals of once every 30 seconds measures the analyte concentration every 30 seconds.
　インジケータ１７は、励起光Ｅを受光してアナライト濃度に応じた強度の蛍光Ｆを発生する。インジケータ１７は、センサ部１０の外部よりカバー部１８を通過して進入してきたアナライト２と相互作用し、励起光Ｅを受光すると、アナライト濃度に応じた光量の蛍光Ｆを発生する。インジケータ１７は、アナライト濃度に応じた強度の蛍光Ｆを発生する蛍光色素が含まれたベース材料から構成されている。 The indicator 17 receives the excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration. The indicator 17 interacts with the analyte 2 that has entered from the outside of the sensor unit 10 through the cover unit 18, and when receiving the excitation light E, generates an amount of fluorescence F corresponding to the analyte concentration. The indicator 17 is made of a base material containing a fluorescent dye that generates fluorescence F having an intensity corresponding to the analyte concentration.
　蛍光色素は、アナライト２の種類に応じて選択され、アナライト２の量に応じて発生する蛍光の強度が可逆的に変化する蛍光色素が使用できる。インジケータ１７は、グルコースを測定するため、蛍光色素として、ルテニウム有機錯体、蛍光フェニルボロン酸誘導体、または蛋白と結合したフルオレセイン等のグルコースと可逆結合する物質を用いる。 The fluorescent dye is selected according to the type of the analyte 2, and a fluorescent dye that reversibly changes the intensity of the fluorescence generated according to the amount of the analyte 2 can be used. In order to measure glucose, the indicator 17 uses, as a fluorescent dye, a ruthenium organic complex, a fluorescent phenylboronic acid derivative, or a substance that reversibly binds to glucose, such as fluorescein bound to a protein.
　インジケータ１７のベース材料は発光部からの励起光およびインジケータ１７中の蛍光色素からの蛍光が良好に透過できる透明性をもつことが好ましい。ベース材料としては、含水し易いハイドロゲルが好ましく、メチルセルロースもしくはデキストランなどの多糖類、（メタ）アクリルアミド、メチロールアクリルアミド、もしくはヒドルキシエチルアクリレート等のモノマーを重合して作製するウレタン系ハイドロゲル、またはポリエチレングリコールとジイソシアネートから作製するウレタン系ハイドロゲルなどを用いる。 The base material of the indicator 17 is preferably transparent so that excitation light from the light emitting part and fluorescence from the fluorescent dye in the indicator 17 can be transmitted satisfactorily. The base material is preferably a hydrogel that easily contains water, a urethane hydrogel prepared by polymerizing a polysaccharide such as methylcellulose or dextran, a monomer such as (meth) acrylamide, methylolacrylamide, or hydroxyethyl acrylate, or A urethane hydrogel prepared from polyethylene glycol and diisocyanate is used.
　保護層１６は光電変換素子層１２および発光素子１５を保護する透明材料からなる。保護層１６としては、シリコン酸化層、シリコン窒化層、酸化シリコン層とシリコン窒化層とからなる複合積層層、シリコーン樹脂層、または透明非晶性フッ素樹脂層を用いることができるが、本実施形態ではシリコン酸化層である。 The protective layer 16 is made of a transparent material that protects the photoelectric conversion element layer 12 and the light emitting element 15. As the protective layer 16, a silicon oxide layer, a silicon nitride layer, a composite laminated layer composed of a silicon oxide layer and a silicon nitride layer, a silicone resin layer, or a transparent amorphous fluororesin layer can be used. Then, it is a silicon oxide layer.
　なお、光電変換素子層１２とフィルタ１４の間にも保護層１６と同様の透明な保護層を配設してもよい。 A transparent protective layer similar to the protective layer 16 may be disposed between the photoelectric conversion element layer 12 and the filter 14.
　次に、図６を用いて蛍光センサ３０の製造方法について説明する。 Next, a method for manufacturing the fluorescent sensor 30 will be described with reference to FIG.
＜光電変換素子配設工程＞
　基体２１Ｘに光電変換素子層１２が配設される。すなわち、無機半導体あるいは有機半導体である光吸収層とその光吸収層の陽極および陰極となる電極とが形成される。印刷法またはフォトリソグラフィ法を用いてマスキングが行われた後に、イオン注入法で部分的にペンタセン膜に不純物がインプラントされると、ｐ型イオン注入層とｎイオン注入層とが形成され、フォトダイオードが形成される。 <Photoelectric conversion element arranging step>
The photoelectric conversion element layer 12 is disposed on the base 21X. That is, a light absorption layer that is an inorganic semiconductor or an organic semiconductor and electrodes that serve as an anode and a cathode of the light absorption layer are formed. After masking is performed using a printing method or a photolithography method, when an impurity is partially implanted into the pentacene film by an ion implantation method, a p-type ion implantation layer and an n ion implantation layer are formed, and a photodiode is formed. Is formed.
＜フィルタ配設工程＞
　次に、光電変換素子層１２を覆うように、例えば、ＣＶＤ法により多結晶シリコン層がフィルタ１４として成膜される。この工程はフィルム状のフィルタを接着することでも実現できる。 <Filter placement process>
Next, a polycrystalline silicon layer is formed as a filter 14 by, for example, a CVD method so as to cover the photoelectric conversion element layer 12. This process can also be realized by adhering a film-like filter.
＜発光部配設工程＞
　次に、発光素子１５として、別途作製されたチップ状態のＬＥＤ素子がフリップチップボンディング法などで、フィルタ１４上に実装される。なお、基体部２１の長さに応じて、複数の発光素子１５を実装してもよい。 <Light emitting part arrangement process>
Next, a separately manufactured LED element as a light emitting element 15 is mounted on the filter 14 by a flip chip bonding method or the like. A plurality of light emitting elements 15 may be mounted according to the length of the base portion 21.
　さらに、アルミニウムなどの導電性金属を蒸着し、フォトリソグラフィ法でパターニングすることで、それぞれが光電変換素子層１２または発光素子１５と接続された複数の配線１９が形成される。次に、フィルタ１４および発光素子１５を覆うように、例えばＣＶＤ法により保護層１６が成膜され、センサ基体２１Ｙが完成する。 Furthermore, a plurality of wirings 19 each connected to the photoelectric conversion element layer 12 or the light emitting element 15 are formed by depositing a conductive metal such as aluminum and patterning by a photolithography method. Next, the protective layer 16 is formed by, for example, the CVD method so as to cover the filter 14 and the light emitting element 15, and the sensor base 21Y is completed.
　なお、センサ基体２１Ｙは、１枚ずつ作製してもよいが、複数のセンサ基体２１Ｙを同時に一括して作製することが好ましい。すなわち、大きなポリイミドシート（基体２１Ｘ）を支持基体に接合し、その上に順に前記構成要素を配設した後に、切断し個片化することにより多数のセンサ基体２１Ｙが作製される。 In addition, although the sensor base 21Y may be manufactured one by one, it is preferable to manufacture a plurality of sensor bases 21Y simultaneously. That is, a large polyimide sheet (base 21X) is bonded to a support base, and the constituent elements are sequentially disposed thereon, and then cut and separated into a large number of sensor bases 21Y.
　例えば、センサ部１０の直径が５００μｍ、長さが１ｍｍの場合には、４インチφの基体２１Ｘを用いると、幅１．５７ｍｍ（５００μｍ×π）、長さ１ｍｍの面積のセンサ基体２１Ｙが、５０００個以上、一括して作製できる。 For example, when the sensor unit 10 has a diameter of 500 μm and a length of 1 mm, a sensor substrate 21Y having a width of 1.57 mm (500 μm × π) and an area of 1 mm in length is obtained using a 4-inch φ base 21X. More than 5000 pieces can be manufactured at once.
　なお、それぞれの前記構成要素を順に配設するときに、パターニングを行い、個片化前に、個々の基体２１Ｘの領域が確定していてもよい。すなわち、図６に例示したセンサ基体２１Ｙでは、基体２１Ｘの上に配設された光電変換素子層１２の被覆率が略１００％であるが、製造歩留まりを高くする等のために、光電変換素子層１２も配設後にパターニングし、被覆率を低くしてもよい。 It should be noted that when each of the constituent elements is arranged in order, patterning may be performed, and the areas of the individual bases 21X may be determined before dividing into individual pieces. That is, in the sensor base 21Y illustrated in FIG. 6, the coverage of the photoelectric conversion element layer 12 disposed on the base 21X is approximately 100%, but in order to increase the manufacturing yield, the photoelectric conversion element The layer 12 may also be patterned after placement to reduce the coverage.
＜筒状加工工程＞
　センサ基体２１Ｙ（基体２１Ｘ）が、光電変換素子層１２の配設面が内側となるように湾曲した状態で接合部２２を介して接着剤等により接合され筒状の基体部２１となる。基体部２１の内部の保護層１６等の切れ目（スリット）２３も、接着剤等により接合されていてもよい。 <Cylindrical process>
The sensor base 21Y (base 21X) is joined by an adhesive or the like through the joint 22 in a state where the surface on which the photoelectric conversion element layer 12 is disposed is curved to form a cylindrical base 21. The cuts (slits) 23 such as the protective layer 16 inside the base portion 21 may also be joined by an adhesive or the like.
　なお、基体２１Ｘの材料に形状記憶合金を用いて、形状記憶効果により加熱処理すると筒状となるようにしてもよい。接合部２２は端面を接着剤で接合してもよいし、外面に配設した接合部材を介して接合してもよい。また筒状の非可撓性の保持筒の中に湾曲状態のセンサ基体２１Ｙを挿入して保持してもよい。 It should be noted that a shape memory alloy may be used as the material of the base 21X, and the substrate 21X may be formed into a cylindrical shape by heat treatment due to the shape memory effect. The joining portion 22 may be joined to the end surface with an adhesive or may be joined via a joining member disposed on the outer surface. Alternatively, the curved sensor base 21Y may be inserted and held in a cylindrical inflexible holding cylinder.
＜インジケータ充填工程＞
　筒状の基体部２１の後端部の開口を樹脂で封止した後、先端部の開口から内部にインジケータ１７が充填される。例えば、蛍光色素と、ゲル骨格形成材と、重合開始剤と、を含むリン酸緩衝液を、基体部２１の内部に入れ、窒素雰囲気下で１時間放置される。例えば、蛍光色素としては、９、１０－ビス［Ｎ－［２－（５，５－ジメチルボリナン－２－イル）ベンジル］－Ｎ－［６‘－［（アクリロイルポリエチレングリコール－３４００）カルボニルアミノ］－ｎ－ヘキシルアミノ］メチル］－２－アセチルアントラセン（Ｆ－ＰＥＧ－ＡＡｍ）を、ゲル骨格形成材としては、アクリルアミドを、重合開始剤としては、ペルオキソ二硫酸ナトリウムおよびＮ、Ｎ、Ｎ’、Ｎ‘－テトラメチルエチレンジアミンを用いる。 <Indicator filling process>
After the opening at the rear end of the cylindrical base portion 21 is sealed with resin, the indicator 17 is filled into the inside from the opening at the front end. For example, a phosphate buffer solution containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator is placed in the base portion 21 and left for 1 hour in a nitrogen atmosphere. For example, as a fluorescent dye, 9,10-bis [N- [2- (5,5-dimethylborinan-2-yl) benzyl] -N- [6 ′-[(acryloyl polyethylene glycol-3400) carbonylamino ] -N-hexylamino] methyl] -2-acetylanthracene (F-PEG-AAm), acrylamide as the gel skeleton-forming material, sodium peroxodisulfate and N, N, N ′ as the polymerization initiator N'-tetramethylethylenediamine is used.
　もちろん、予め作製した含水状態のインジケータ、または乾燥状態のインジケータを、基体部２１の内部に投入してもよい。 Of course, a water-containing indicator or a dry indicator prepared in advance may be put into the base portion 21.
＜カバー部配設工程＞
　次に、筒状の基体部２１の先端部の開口がカバー部１８により覆われ、封止される。カバー部１８は、例えば多孔質の金属もしくはセラミックス、またはハイドロゲルにカーボンブラックもしくはカーボンナノチューブなど光を通さない微粒子を混合した複合材料からなる。例えばカーボンブラックを混入した場合には、カバー部１８の光透過率は励起光波長および可視光波長で１×１０－３％～１×１０－５％程度である。 <Cover part placement process>
Next, the opening at the tip of the cylindrical base portion 21 is covered with the cover portion 18 and sealed. The cover 18 is made of, for example, a porous metal or ceramic, or a composite material in which fine particles that do not transmit light such as carbon black or carbon nanotubes are mixed with hydrogel. For example, when carbon black is mixed, the light transmittance of the cover 18 is about 1 × 10 −3 % to 1 × 10 −5 % at the excitation light wavelength and the visible light wavelength.
　針本体部３３、針基端部およびコネクタ部３５からなる蛍光センサ３０の主要構造体は、別途、シリコンウエハ等を加工することにより作製される。そして上記工程により作製されたセンサ部１０が、針本体部３３に配設されることで、蛍光センサ３０が完成する。なお、センサ部１０と針本体部３３との接合箇所は樹脂等で補強されることが好ましい。 The main structure of the fluorescence sensor 30 including the needle main body 33, the needle base end, and the connector 35 is separately manufactured by processing a silicon wafer or the like. And the sensor part 10 produced by the said process is arrange | positioned in the needle | hook main body part 33, and the fluorescence sensor 30 is completed. In addition, it is preferable that the joining location of the sensor part 10 and the needle | hook main-body part 33 is reinforced with resin.
　以上の説明のように、蛍光センサ３０は、筒状の基体部２１と、基体部２１の内周面を覆う光電変換素子層１２と、光電変換素子層１２を覆うフィルタ１４と、フィルタ１４よりも内周側に配設された発光素子１５と、基体部２１の内部に充填されたインジケータ１７と、を具備する。 As described above, the fluorescence sensor 30 includes the cylindrical base portion 21, the photoelectric conversion element layer 12 that covers the inner peripheral surface of the base portion 21, the filter 14 that covers the photoelectric conversion element layer 12, and the filter 14. The light emitting element 15 disposed on the inner peripheral side, and the indicator 17 filled in the base portion 21 are provided.
　このため、インジケータ１７が様々な方向に出射した蛍光Ｆの多くを光電変換素子層１２は受光する。このため、蛍光センサ３０は蛍光検出感度が高い。また蛍光センサ３０の製造方法によれば感度の高い蛍光センサを製造できる。 Therefore, the photoelectric conversion element layer 12 receives most of the fluorescence F emitted from the indicator 17 in various directions. For this reason, the fluorescence sensor 30 has high fluorescence detection sensitivity. Moreover, according to the manufacturing method of the fluorescence sensor 30, a highly sensitive fluorescence sensor can be manufactured.
　そして、可撓性の基体２１Ｘの上に可撓性の光電変換素子層１２および可撓性のフィルタ１４等を積層したセンサ基体２１Ｙを丸めて筒状に加工した基体部２１には、長手方向に板状の基体２１Ｘを湾曲状態で接合した接合部２２がある。さらに、接合部２２の内周側の光電変換素子層１２およびフィルタ１４には切れ目（スリット）２３がある。言い換えれば、上記記載の構造の蛍光センサ３０は、板状の基体３１Ｘを丸めて作製されていると見なすことができる。 The base portion 21 in which the sensor base 21Y in which the flexible photoelectric conversion element layer 12 and the flexible filter 14 are stacked on the flexible base 21X is rounded and processed into a cylindrical shape is formed in the longitudinal direction. There is a joint portion 22 in which the plate-like base 21X is joined in a curved state. Further, the photoelectric conversion element layer 12 and the filter 14 on the inner peripheral side of the joint portion 22 have a cut (slit) 23. In other words, the fluorescence sensor 30 having the above-described structure can be regarded as being produced by rounding the plate-like substrate 31X.
　なお、基体２１Ｘは筒状に丸めるために可撓性が必要であるが、筒状になった基体部２１には可撓性は必要ない。このため、すでに説明したように筒状の非可撓性の保持筒を用いたり、筒状の基体部２１の外周部に生体適合性の高い樹脂または金属等をコーティングしたりしてもよい。 The base body 21X needs to be flexible in order to be rounded into a cylindrical shape, but the base part 21 in the cylindrical shape does not need flexibility. For this reason, as already described, a cylindrical inflexible holding cylinder may be used, or the outer peripheral portion of the cylindrical base portion 21 may be coated with a highly biocompatible resin or metal.
＜第２実施形態＞
　次に、第２実施形態の蛍光センサ３０Ａおよび蛍光センサ３０Ａの製造方法について説明する。蛍光センサ３０Ａおよび蛍光センサ３０Ａの製造方法は、蛍光センサ３０および蛍光センサ３０の製造方法と類似しているため同じ構成要素には同じ符号を付し説明は省略する。 <Second Embodiment>
Next, the fluorescence sensor 30A of the second embodiment and the method for manufacturing the fluorescence sensor 30A will be described. Since the manufacturing method of the fluorescent sensor 30A and the fluorescent sensor 30A is similar to the manufacturing method of the fluorescent sensor 30 and the fluorescent sensor 30, the same components are denoted by the same reference numerals and description thereof is omitted.
　図７に示すように、蛍光センサ３０Ａでは、センサ部１０Ａの光電変換素子部が基体部２１の長手方向に分割された複数の光電変換素子１２Ａからなる。 As shown in FIG. 7, the fluorescence sensor 30 </ b> A includes a plurality of photoelectric conversion elements 12 </ b> A in which the photoelectric conversion element part of the sensor part 10 </ b> A is divided in the longitudinal direction of the base part 21.
　それぞれの光電変換素子１２Ａは、例えば単結晶シリコン基板に形成されたＰＤ素子である。シリコン基板を裏面側から薄層化加工した光電変換素子１２Ａは、少し湾曲できる。しかし、光電変換素子１２Ａは、有機半導体からなる光電変換素子層１２のように、基体部２１の内面に沿って丸く曲げることは容易ではない。このため、図８に示すように、蛍光センサ３０Ａの製造方法では、複数の光電変換素子からなる光電変換素子基板が、基体２１Ｘに接合された後、複数の光電変換素子１２Ａに分割される。 Each photoelectric conversion element 12A is, for example, a PD element formed on a single crystal silicon substrate. The photoelectric conversion element 12A obtained by thinning the silicon substrate from the back side can be bent slightly. However, it is not easy to bend the photoelectric conversion element 12 </ b> A along the inner surface of the base portion 21 like the photoelectric conversion element layer 12 made of an organic semiconductor. For this reason, as shown in FIG. 8, in the manufacturing method of the fluorescence sensor 30A, the photoelectric conversion element substrate including a plurality of photoelectric conversion elements is joined to the base 21X and then divided into the plurality of photoelectric conversion elements 12A.
　なお、複数の光電変換素子１２Ａへの分割は完全に個片化する必要はなく、図８に示すように、切り込みを入れただけよい。また、複数の光電変換素子１２Ａが形成されたシリコン基板を基体２１Ｘに接合するのではなく、シリコン基板の下側を基体として使用してもよい。この場合には、基体２１Ｘは不要である。 It should be noted that the division into the plurality of photoelectric conversion elements 12A does not need to be completely separated, and it is only necessary to make cuts as shown in FIG. Further, instead of bonding the silicon substrate on which the plurality of photoelectric conversion elements 12A are formed to the base 21X, the lower side of the silicon substrate may be used as the base. In this case, the base 21X is unnecessary.
　もちろん、別途作製した個片化された短冊状の光電変換素子１２Ａを基体２１Ｘの上に並べて接合してもよい。 Needless to say, separately produced strip-like photoelectric conversion elements 12A may be arranged and joined on the base 21X.
　すでに説明したように、基体２１Ｘに対する光電変換素子１２Ａの被覆率は３０％以上、好ましくは４０％以上である。蛍光センサ３０Ａでは構造上、光電変換素子１２Ａの被覆率の上限は例えば９０％である。 As already described, the coverage of the photoelectric conversion element 12A on the base 21X is 30% or more, preferably 40% or more. In the fluorescent sensor 30A, the upper limit of the coverage of the photoelectric conversion element 12A is, for example, 90% because of the structure.
　蛍光センサ３０Ａは、蛍光センサ３０が有する効果を有し、さらに製造が容易で安価なシリコン半導体をＰＤ素子として用いることができるため、低コスト化である。蛍光センサ３０Ａの製造方法は、製造が容易で、安価な蛍光センサを製造できる。 The fluorescent sensor 30A has the effects of the fluorescent sensor 30, and can be manufactured at low cost because a silicon semiconductor that is easy to manufacture and inexpensive can be used as the PD element. The manufacturing method of the fluorescent sensor 30A is easy to manufacture and can manufacture an inexpensive fluorescent sensor.
＜第３実施形態＞
　次に、第３実施形態の蛍光センサ３０Ｂおよび蛍光センサ３０Ｂの製造方法について説明する。蛍光センサ３０Ｂおよび蛍光センサ３０Ｂの製造方法は、蛍光センサ３０および蛍光センサ３０の製造方法と類似しているため同じ構成要素には同じ符号を付し説明は省略する。 <Third Embodiment>
Next, the fluorescence sensor 30B of the third embodiment and the method for manufacturing the fluorescence sensor 30B will be described. Since the manufacturing method of the fluorescent sensor 30B and the fluorescent sensor 30B is similar to the manufacturing method of the fluorescent sensor 30 and the fluorescent sensor 30, the same components are denoted by the same reference numerals and description thereof is omitted.
　図９に示すように、蛍光センサ３０Ｂでは、センサ部１０Ｂの基体部２１の内面に配設した有機半導体層の半分が、蛍光センサ３０と同じＰＤ素子からなる光電変換素子層１２Ｂである。光電変換素子層１２Ｂはフィルタ１４Ｂで覆われている。そして、有機半導体層の残りの半分は、有機発光ダイオード（ＯＬＥＤ）からなる発光層１５Ｂである。フィルタ１４Ｂおよび発光層１５Ｂは保護層１６で覆われている。 As shown in FIG. 9, in the fluorescence sensor 30 </ b> B, half of the organic semiconductor layer disposed on the inner surface of the base portion 21 of the sensor unit 10 </ b> B is the photoelectric conversion element layer 12 </ b> B made of the same PD element as the fluorescence sensor 30. The photoelectric conversion element layer 12B is covered with a filter 14B. The remaining half of the organic semiconductor layer is a light emitting layer 15B made of an organic light emitting diode (OLED). The filter 14B and the light emitting layer 15B are covered with a protective layer 16.
　すなわち、基体２１Ｘに成膜した有機半導体層の半分を、蛍光Ｆを電気信号に変換する光電変換素子層１２Ｂとし、残りの半分を、有機半導体の材質を変えることで励起光Ｅを発生する発光層１５Ｂとしている。ここで有機半導体の材質を変えることには、同一材料のドーパンとの種類、濃度を変えることも含まれる。蛍光センサ３０等は発光部が点発光する可撓性のない無機ＬＥＤ素子からなる発光素子１５であった。これに対して蛍光センサ３０Ｂの発光層１５Ｂは可撓性を有する面発光体である。 That is, half of the organic semiconductor layer formed on the substrate 21X is a photoelectric conversion element layer 12B that converts fluorescence F into an electrical signal, and the other half is light emission that generates excitation light E by changing the material of the organic semiconductor. The layer 15B is used. Here, changing the material of the organic semiconductor includes changing the kind and concentration of the same material as the dopan. The fluorescent sensor 30 or the like was the light emitting element 15 made of a non-flexible inorganic LED element in which the light emitting portion emits point light. On the other hand, the light emitting layer 15B of the fluorescence sensor 30B is a flexible surface light emitter.
　蛍光センサ３０Ｂは、蛍光センサ３０のように別途作製されたチップ状態の発光素子１５をフリップチップボンディング法により実装する必要がないため、低コストである。かつ、蛍光センサ３０Ｂは発光層１５Ｂが基体２１Ａの上に積層形成されているため、実装された発光素子が外れるなどの故障のおそれがないため信頼性が高い。 The fluorescent sensor 30B is low in cost because it is not necessary to mount the light emitting element 15 in a chip state separately manufactured like the fluorescent sensor 30 by the flip chip bonding method. In addition, the fluorescent sensor 30B has high reliability because the light emitting layer 15B is laminated on the base 21A, and there is no possibility of failure such as removal of the mounted light emitting element.
　さらに、蛍光センサ３０Ｂの発光部である発光層１５Ｂが面発光体であるため、蛍光センサ３０よりも、均一な強度の励起光Ｅをインジケータ１７に照射できる。さらに、発光層１５Ｂは発光素子１５よりも発熱量が小さい。 Furthermore, since the light emitting layer 15B, which is the light emitting part of the fluorescent sensor 30B, is a surface light emitter, the indicator 17 can be irradiated with excitation light E having a more uniform intensity than the fluorescent sensor 30. Furthermore, the light emitting layer 15B generates less heat than the light emitting element 15.
　蛍光センサ３０Ｂは、蛍光センサ３０と同じ効果を有し、さらに均一な強度の励起光Ｅを受光するためインジケータ１７の発光効率が高い。さらに蛍光センサ３０Ｂは、過剰な励起光の受光および熱によるインジケータ１７の劣化が少ないため、蛍光センサ３０Ｂよりも長期間にわたり安定した使用が可能である。 The fluorescent sensor 30B has the same effect as the fluorescent sensor 30, and the luminous efficiency of the indicator 17 is high because it receives the excitation light E having a uniform intensity. Furthermore, the fluorescence sensor 30B can be used stably for a longer period than the fluorescence sensor 30B because the indicator 17 is less deteriorated by receiving excessive excitation light and heat.
　なお、蛍光センサ３０Ｂは、有機半導体層を発光部と光電変換素子部とに略２等分していた。しかし、発光部と光電変換素子部との分割割合は仕様に応じて変更可能である。例えば、検出するアナライトの蛍光発光し易さに合わせて有機半導体層の分割割合を変更することで、励起光の光量等を適切に設定できる。 In addition, in the fluorescence sensor 30B, the organic semiconductor layer was divided into approximately two equal parts into the light emitting part and the photoelectric conversion element part. However, the division ratio between the light emitting unit and the photoelectric conversion element unit can be changed according to the specification. For example, the amount of excitation light can be appropriately set by changing the division ratio of the organic semiconductor layer in accordance with the ease of fluorescence emission of the analyte to be detected.
　また、蛍光センサ３０Ｂは、有機半導体層を発光部と光電変換素子部とに内周の径方向に分割していた。しかし、発光部と光電変換素子部とはセンサ部１０Ｂの長手方向に分割してもよい。例えばカバー部１８側を発光部とし、針本体部３３側を光電変換素子部としてもよい。 Further, in the fluorescence sensor 30B, the organic semiconductor layer is divided into the light emitting part and the photoelectric conversion element part in the radial direction of the inner periphery. However, the light emitting unit and the photoelectric conversion element unit may be divided in the longitudinal direction of the sensor unit 10B. For example, the cover portion 18 side may be a light emitting portion, and the needle main body portion 33 side may be a photoelectric conversion element portion.
＜第４実施形態＞
　次に、第４実施形態の蛍光センサ３０Ｃおよび蛍光センサ３０Ｃの製造方法について説明する。蛍光センサ３０Ｃおよび蛍光センサ３０Ｃの製造方法は、蛍光センサ３０および蛍光センサ３０の製造方法と類似しているため同じ構成要素には同じ符号を付し説明は省略する。 <Fourth embodiment>
Next, the fluorescence sensor 30C of the fourth embodiment and the method for manufacturing the fluorescence sensor 30C will be described. Since the fluorescent sensor 30C and the manufacturing method of the fluorescent sensor 30C are similar to the fluorescent sensor 30 and the manufacturing method of the fluorescent sensor 30, the same components are denoted by the same reference numerals and description thereof is omitted.
　図１０に示すように、蛍光センサ３０Ｃのセンサ部１０Ｃでは、フィルタ１４の上に可撓性を有する面発光体からなる発光層１５Ｃが積層されている。発光層１５Ｃは、すでに説明した発光層１５Ｂと同じ有機発光ダイオードからなるが、上部電極だけでなく、下部電極にも透明導電材料が用いられている。また、発光層１５Ｃは、蛍光Ｆの波長において高い光透過率を有する。 As shown in FIG. 10, in the sensor unit 10C of the fluorescence sensor 30C, a light emitting layer 15C made of a flexible surface light emitter is laminated on the filter 14. The light emitting layer 15C is made of the same organic light emitting diode as the light emitting layer 15B already described, but a transparent conductive material is used not only for the upper electrode but also for the lower electrode. The light emitting layer 15C has a high light transmittance at the wavelength of the fluorescence F.
　蛍光センサ３０Ｃおよび蛍光センサ３０Ｃの製造方法は、蛍光センサ３０Ｂ等が有する効果に加えて、光電変換素子層１２Ｃと発光層１５Ｂとが積層構造であるため作製が容易で低コスト化である。 The manufacturing method of the fluorescent sensor 30C and the fluorescent sensor 30C is easy to manufacture and low cost because the photoelectric conversion element layer 12C and the light emitting layer 15B have a laminated structure in addition to the effects of the fluorescent sensor 30B and the like.
　なお、以上の説明は、グルコースを検出する蛍光センサ３０等を例に説明したが、蛍光センサは、蛍光色素の選択によって、他の糖類の検出センサ、酵素センサ、ｐＨセンサ、免疫センサ、または微生物センサ等の多様な用途に対応できる。例えば、蛍光色素には、生体内の水素イオン濃度または二酸化炭素を測定する場合には、ヒドロキシピレントリスルホン酸誘導体などを用い、糖類を測定する場合には蛍光残基を有するフェニルボロン酸誘導体などを用い、カリウムイオンを測定する場合には蛍光残基を有するクラウンエーテル誘導体などを用いる。 In the above description, the fluorescence sensor 30 that detects glucose is described as an example. However, the fluorescence sensor is a detection sensor for other saccharides, an enzyme sensor, a pH sensor, an immune sensor, or a microorganism depending on the selection of a fluorescent dye. It can be used for various applications such as sensors. For example, as a fluorescent dye, a hydroxypyrenetrisulfonic acid derivative is used when measuring the hydrogen ion concentration or carbon dioxide in a living body, and a phenylboronic acid derivative having a fluorescent residue is used when measuring a saccharide. When measuring potassium ion, a crown ether derivative having a fluorescent residue is used.
　すなわち、本発明は、上述した実施形態および変形例に限定されるものではなく、本発明の要旨を変えない範囲において、種々の変更、改変等ができる
　本出願は、２０１１年１２月８日に日本国に出願された特願２０１１－２６９２０６号を優先権主張の基礎として出願するものであり、上記の開示内容は、本願明細書、請求の範囲、図面に引用されたものとする。 In other words, the present invention is not limited to the above-described embodiments and modifications, and various changes and modifications can be made without departing from the scope of the present invention. Japanese Patent Application No. 2011-269206 filed in Japan is filed as a basis for claiming priority, and the above disclosure is cited in the present specification, claims and drawings.

Claims (9)

  1. 　筒状の基体部と、
    　前記基体部の内周面を覆う、蛍光を電気信号に変換する光電変換素子部と、
    　前記光電変換素子部を覆う、前記蛍光を透過し励起光を遮断するフィルタと、
    　前記フィルタよりも前記基体部の内周側に配設された励起光を発生する発光部と、
    　前記基体部の内部に充填された、前記励起光を受光してアナライト濃度に応じた強度の前記蛍光を発生するインジケータと、
    　前記基体部の開口を覆う、前記アナライトが通過可能で、前記励起光および前記蛍光を遮断するカバー部と、を具備することを特徴とする蛍光センサ。     A cylindrical base portion;
    A photoelectric conversion element portion that covers the inner peripheral surface of the base portion and converts fluorescence into an electrical signal;
    A filter that covers the photoelectric conversion element part and transmits the fluorescence and blocks excitation light;
    A light emitting part for generating excitation light disposed on the inner peripheral side of the base part from the filter;
    An indicator that fills the inside of the base portion and receives the excitation light and generates the fluorescence having an intensity according to the analyte concentration;
    A fluorescence sensor comprising: a cover portion that covers the opening of the base portion, allows the analyte to pass therethrough, and blocks the excitation light and the fluorescence.
  2. 　前記基体部の長手方向に板状の基体を湾曲状態で接合した接合部があり、
    　前記基体、前記光電変換素子部、および前記フィルタが、可撓性を有し、
    　前記接合部の内周側の前記光電変換素子部および前記フィルタに切れ目があることを特徴とする請求項１に記載の蛍光センサ。     There is a joined portion obtained by joining a plate-like substrate in a curved state in the longitudinal direction of the substrate portion,
    The base, the photoelectric conversion element portion, and the filter have flexibility,
    The fluorescence sensor according to claim 1, wherein the photoelectric conversion element part and the filter on the inner peripheral side of the joint part have a break.
  3. 　前記光電変換素子部が、有機半導体からなることを特徴とする請求項２に記載の蛍光センサ。 The fluorescent sensor according to claim 2, wherein the photoelectric conversion element portion is made of an organic semiconductor.
  4. 　前記発光部が可撓性を有する面発光体からなることを特徴とする請求項３に記載の蛍光センサ。 The fluorescent sensor according to claim 3, wherein the light emitting portion is made of a flexible surface light emitter.
  5. 　前記光電変換素子部が前記基体部の長手方向に分割された複数の光電変換素子からなることを特徴とする請求項２に記載の蛍光センサ。 3. The fluorescence sensor according to claim 2, wherein the photoelectric conversion element portion is composed of a plurality of photoelectric conversion elements divided in the longitudinal direction of the base portion.
  6. 　平板状の基体に、蛍光を電気信号に変換する光電変換素子部を配設する工程と、
    　前記光電変換素子部を覆う、前記蛍光を透過し励起光を遮断するフィルタを配設する工程と、
    　前記フィルタの上に、前記励起光を発生する発光部を配設する工程と、
    　前記基体を、前記光電変換素子部配設面が内側となるように湾曲した状態で接合部を介して接合することにより筒状の基体部とする工程と、
    　前記基体部の内部に、前記励起光を受光してアナライト濃度に応じた前記蛍光を発生するインジケータを充填する工程と、
    　前記基体部の開口を、前記アナライトが通過可能で、前記励起光および前記蛍光を遮断するカバー部で覆う工程と、を具備することを特徴とする蛍光センサの製造方法。     A step of disposing a photoelectric conversion element portion for converting fluorescence into an electric signal on a flat substrate;
    Disposing a filter that covers the photoelectric conversion element and transmits the fluorescence and blocks excitation light; and
    Disposing a light emitting unit for generating the excitation light on the filter;
    A step of joining the base body through a joint portion in a curved state so that the photoelectric conversion element portion disposition surface is on the inside, thereby forming a cylindrical base body portion;
    Filling the inside of the base portion with an indicator that receives the excitation light and generates the fluorescence according to the analyte concentration;
    And a step of covering the opening of the base portion with a cover portion through which the analyte can pass and blocks the excitation light and the fluorescence.
  7. 　前記光電変換素子部が、有機半導体からなることを特徴とする請求項６に記載の蛍光センサの製造方法。 The method for manufacturing a fluorescent sensor according to claim 6, wherein the photoelectric conversion element portion is made of an organic semiconductor.
  8. 　前記発光部が可撓性を有する面発光体からなることを特徴とする請求項７に記載の蛍光センサの製造方法。 The method for manufacturing a fluorescent sensor according to claim 7, wherein the light emitting portion is made of a flexible surface light emitter.
  9. 　前記光電変換素子部が前記基体部の長手方向に分割された複数の光電変換素子からなることを特徴とする請求項６に記載の蛍光センサの製造方法。 The method for manufacturing a fluorescent sensor according to claim 6, wherein the photoelectric conversion element portion is composed of a plurality of photoelectric conversion elements divided in the longitudinal direction of the base portion.
PCT/JP2012/081606 2011-12-08 2012-12-06 Fluorescence sensor and method for manufacturing fluorescence sensor WO2013084975A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
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