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WO2013084975A1 - Capteur de fluorescence et son procédé de fabrication - Google Patents

Capteur de fluorescence et son procédé de fabrication 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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WO
WIPO (PCT)
Prior art keywords
photoelectric conversion
fluorescence
conversion element
sensor
excitation light
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2012/081606
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English (en)
Japanese (ja)
Inventor
広呂紀 畠
松本　淳
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Terumo Corp
Olympus Corp
Original Assignee
Terumo Corp
Olympus Corp
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Filing date
Publication date
Application filed by Terumo Corp, Olympus Corp filed Critical Terumo Corp
Publication of WO2013084975A1 publication Critical patent/WO2013084975A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or 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.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Optics & Photonics (AREA)
  • Engineering & Computer Science (AREA)
  • Surgery (AREA)
  • Medical Informatics (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • General Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Analytical Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Emergency Medicine (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

La présente invention concerne un capteur de fluorescence (30) équipé d'une partie corps de base cylindrique (31) ; d'une couche d'élément de conversion photoélectrique (12) permettant de convertir une lumière fluorescente (F) en un signal électrique, la couche recouvrant la surface périphérique intérieure de la partie corps de base (31) ; d'un filtre (14) permettant de transmettre la lumière fluorescente (F) et de couper une lumière d'excitation (E), le filtre recouvrant la couche d'élément de conversion photoélectrique (12) ; d'un élément électroluminescent (15) permettant de générer la lumière d'excitation (E), l'élément électroluminescent étant disposé davantage vers la périphérie intérieure de la partie corps de base (31) par rapport au filtre (14) ; d'un indicateur (17) permettant de recevoir la lumière d'excitation (E) et de générer la lumière fluorescente (F) à une intensité correspondant à la concentration d'un analyte, l'intérieur de la partie corps de base (31) étant rempli de l'indicateur.
PCT/JP2012/081606 2011-12-08 2012-12-06 Capteur de fluorescence et son procédé de fabrication Ceased WO2013084975A1 (fr)

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JP2011-269206 2011-12-08
JP2011269206 2011-12-08

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9715727B2 (en) 2012-02-23 2017-07-25 Smith & Nephew, Inc. Video endoscopic system
JP2019511749A (ja) * 2016-03-28 2019-04-25 サウジ アラビアン オイル カンパニー 複合フォトニック構造を構築及び検査するシステム及び方法
JP2019074451A (ja) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 光計測装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08107890A (ja) * 1994-07-18 1996-04-30 Minimed Inc 光グルコースセンサー
JP2002523774A (ja) * 1998-08-26 2002-07-30 センサーズ・フォー・メデセン・アンド・サイエンス・インコーポレーテッド 光学式検知装置
JP2005513426A (ja) * 2001-12-11 2005-05-12 センサーズ・フォー・メディシン・アンド・サイエンス インコーポレーテッド 高性能蛍光光センサー
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08107890A (ja) * 1994-07-18 1996-04-30 Minimed Inc 光グルコースセンサー
JP2002523774A (ja) * 1998-08-26 2002-07-30 センサーズ・フォー・メデセン・アンド・サイエンス・インコーポレーテッド 光学式検知装置
JP2005513426A (ja) * 2001-12-11 2005-05-12 センサーズ・フォー・メディシン・アンド・サイエンス インコーポレーテッド 高性能蛍光光センサー
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9715727B2 (en) 2012-02-23 2017-07-25 Smith & Nephew, Inc. Video endoscopic system
US10783626B2 (en) 2012-02-23 2020-09-22 Smith & Nephew, Inc. Video endoscopic system
JP2019511749A (ja) * 2016-03-28 2019-04-25 サウジ アラビアン オイル カンパニー 複合フォトニック構造を構築及び検査するシステム及び方法
CN112835138A (zh) * 2016-03-28 2021-05-25 沙特阿拉伯石油公司 用于构造和测试复合光子结构的系统和方法
JP2019074451A (ja) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 光計測装置

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