WO2014045384A1 - Fluorescent sensor - Google Patents

Fluorescent sensor Download PDF

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Publication number
WO2014045384A1
WO2014045384A1 PCT/JP2012/074175 JP2012074175W WO2014045384A1 WO 2014045384 A1 WO2014045384 A1 WO 2014045384A1 JP 2012074175 W JP2012074175 W JP 2012074175W WO 2014045384 A1 WO2014045384 A1 WO 2014045384A1
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WO
WIPO (PCT)
Prior art keywords
fluorescence
light
sensor
indicators
fluorescent
Prior art date
Application number
PCT/JP2012/074175
Other languages
French (fr)
Japanese (ja)
Inventor
亮 太田
憲治 宮田
Original Assignee
テルモ株式会社
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Publication date
Application filed by テルモ株式会社 filed Critical テルモ株式会社
Priority to PCT/JP2012/074175 priority Critical patent/WO2014045384A1/en
Publication of WO2014045384A1 publication Critical patent/WO2014045384A1/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"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G01N2021/6439—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes" with indicators, stains, dyes, tags, labels, marks

Definitions

  • the present invention relates to a fluorescence sensor for measuring the concentration of an analyte in a solution, and more particularly to a fluorescence sensor having an indicator made of an analyte and a hydrogel that generates fluorescence by excitation light.
  • a fluorometer that measures analyte concentration by injecting a solution to be measured containing a fluorescent dye and an analyte into a transparent container, irradiating excitation light, and measuring the fluorescence intensity from the fluorescent dye is known.
  • Fluorescent dyes change in properties due to the presence of an analyte, and generate fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light.
  • a small fluorometer has a light source, a photodetector, and an indicator containing a fluorescent dye. And the excitation light from a light source is irradiated to the indicator which the analyte in a to-be-measured solution can enter / exit, and the photodetector receives the fluorescence which an indicator generate
  • the photodetector is a photoelectric conversion element and outputs an electrical signal corresponding to the received light intensity. The analyte concentration in the solution is calculated based on the electrical signal from the photodetector.
  • microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology.
  • the microfluorometer is referred to as “fluorescence sensor”.
  • the fluorescent sensor 104 shown in FIGS. 1 and 2 is disclosed in International Publication No. 2010/119916.
  • the sensor unit 110 which is a main functional unit of the fluorescence sensor 104 includes a silicon substrate 111 on which a photoelectric conversion element 112 is formed, a transparent intermediate layer 113, a filter layer 114, a light emitting element 115, a transparent protective layer 116, An indicator 117 and a light shielding layer 118 are provided.
  • the analyte 9 passes through the light shielding layer 118 and enters the indicator 117.
  • the filter layer 114 of the fluorescence sensor 104 blocks the excitation light E and transmits the fluorescence F. Further, the light emitting element 115 transmits the fluorescence F.
  • the indicator 117 In the fluorescence sensor 104, when the excitation light E generated by the light emitting element 115 enters the indicator 117, the indicator 117 generates fluorescence F corresponding to the analyte concentration.
  • the fluorescent sensor 104 has a simple configuration and can be easily downsized.
  • the present invention has been made in view of the above circumstances, and its object is to provide a fluorescent sensor with high detection sensitivity.
  • the fluorescence sensor of one embodiment of the present invention is provided with a substrate portion and the substrate portion interposed therebetween, receives excitation light, generates fluorescence having an intensity according to the concentration of the analyte, and has an outer shape of a partial cylindrical shape.
  • Two indicators to be presented a light emitting element that is mounted on the substrate portion and generates excitation light, and a photoelectric conversion element that converts the fluorescence into an electric signal.
  • FIG. 5 is a cross-sectional view taken along line VV in FIG. 4 at the distal end portion of the fluorescent sensor.
  • FIG. 6 is a cross-sectional view taken along the line VI-VI in FIG. 5 at the tip of the fluorescent sensor.
  • FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor and showing a mold and a light shielding film.
  • FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which a light-shielding film is pressed into a recess of a mold.
  • FIG. 5 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which an indicator is pressed onto a light shielding film in a recess of a mold.
  • FIG. 3 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which a photoelectric conversion element substrate is disposed on an indicator of one mold.
  • FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, showing a mold having a light-shielding film and an indicator embossed in a recess, and a mold having a photoelectric conversion element substrate disposed on the indicator.
  • FIG. 5 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which two molds are overlapped.
  • FIG. 5 is a cross-sectional view illustrating a fluorescent sensor that is completed by removing two molds and explaining a method for manufacturing the fluorescent sensor. It is a cross-sectional schematic diagram for demonstrating operation
  • FIG. 18 is a cross-sectional view of a fluorescent sensor of a modified example different from FIG. It is a perspective view of the front-end
  • FIG. 20 is a cross-sectional view taken along the line XX-XX in FIG. 19 at the tip of the fluorescent sensor. It is a perspective view of the front-end
  • FIG. 22 is a perspective view of a distal end portion of a fluorescent sensor of a modified example different from FIG. It is sectional drawing of the fluorescence sensor of 4th Embodiment. It is sectional drawing of the fluorescence sensor of a modification same as the above.
  • the sensor system 1 includes a fluorescent sensor 4, a main body 2, and a receiver 3 that receives and stores a signal from the main body 2. Transmission / reception of signals between the main body 2 and the receiver 3 is performed wirelessly or by wire.
  • the fluorescent sensor 4 includes a needle portion 7 that is punctured by a subject and a connector portion 8 that is joined to the rear end portion of the needle portion 7.
  • the needle part 7 has an elongated needle body part 6 and a needle tip part 5 including a sensor part 10 which is a main function part. Needle tip 5, needle body 6, and connector 8 may be integrally formed of the same material, or may be separately produced and joined.
  • the connector part 8 is detachably fitted to the fitting part 2A of the main body part 2.
  • the plurality of wirings 60 extending from the sensor unit 10 of the fluorescent sensor 4 are electrically connected to the main body unit 2 when the connector unit 8 is mechanically fitted to the fitting unit 2A of the main body unit 2. .
  • Fluorescent sensor 4 is a needle-type sensor that can continuously measure the analyte concentration of a solution (body fluid) in a living body after inserting sensor unit 10 into the body for a predetermined period, for example, one week. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.
  • the main body unit 2 includes a control unit 2B that performs driving and control of the sensor unit 10, and a calculation unit 2C that processes a signal output from the sensor unit 10. Note that at least one of the control unit 2B and the calculation unit 2C may be disposed in the connector unit 8 of the fluorescent sensor 4 or may be disposed in the receiver 3.
  • the main body 2 further includes a radio antenna for transmitting and receiving radio signals to and from the receiver 3, a battery, and the like.
  • the main body 2 has a signal line instead of a wireless antenna.
  • the receiver 3 may not be provided when the main body 2 includes a memory unit having a necessary capacity.
  • the structure of the sensor unit 10 which is a main functional unit of the fluorescence sensor 4 will be described with reference to FIGS.
  • all the figures are schematic diagrams for explanation, and the vertical and horizontal dimensional ratios and the like are different from actual ones, and some components may not be shown.
  • the Z-axis direction shown in the figure is referred to as an upward direction in the fluorescence sensor 4.
  • the X-axis direction indicates the rear in the front-rear direction of the fluorescent sensor 4
  • the Y-axis direction indicates the left direction in the left-right direction.
  • the fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject.
  • the sensor unit 10 of the present embodiment has a substantially cylindrical shape, a light emitting element 15 that emits light radially in the vertical and horizontal directions, and the light emitting element 15 is mounted on the upper surface.
  • a detection substrate portion 20 formed of a transparent member such as transparent resin or glass, a columnar distal end frame 21 fitted to the distal end portion of the detection substrate portion 20, and a proximal end portion of the detection substrate portion 20.
  • the fitted cylindrical base end frame 22 and the outer shape arranged in the vertical direction so as to sandwich the detection substrate portion 20 have a circular arc cross section, that is, two partial columnar indicators 17A and 17B,
  • the two indicators 17A and 17B are configured to have two light-shielding films 19A and 19B covering the respective domes.
  • the indicators 17A and 17B have a partial cylindrical shape whose outer shape is a circular arc shape as described above.
  • This partial columnar shape is a shape obtained by cutting a column into approximately half.
  • the first indicator 17A and the first light shielding film 19A are on the upper side of the detection substrate unit 20, the second indicator 17B and the second light shielding film 19A.
  • the light shielding film 19 ⁇ / b> B is disposed on the lower side of the detection substrate unit 20.
  • the first light-shielding film 19A, the first indicator 17A, the detection substrate unit 20, the second indicator 17B, and the second light-shielding film 19B are disposed in order from the top. That is, the first indicator 17A and the second indicator 17B are arranged so as to sandwich the detection substrate unit 20 having the light emitting element 15, and the indicators 17A and 17B are covered with the light shielding films 19A and 19B.
  • the light shielding films 19 ⁇ / b> A and 19 ⁇ / b> B are bonded to the edge portions (both end portions) of the detection substrate unit 20.
  • the fluorescence sensor 4 here is a photodiode element (hereinafter referred to as a photoelectric conversion element) that converts the fluorescence F from the indicators 17A and 17B into an electrical signal on the lower surface of the detection substrate portion 20 on which the light emitting element 15 is disposed. (Referred to as “PD element”) 12 is formed.
  • a photoelectric conversion element that converts the fluorescence F from the indicators 17A and 17B into an electrical signal on the lower surface of the detection substrate portion 20 on which the light emitting element 15 is disposed.
  • the detection substrate 20 has the light emitting element 15 mounted on the upper surface and the PD element 12 formed on the lower surface.
  • the detection substrate unit 20 is a transparent substrate made of transparent resin, glass or the like so that the excitation light E emitted from the light emitting element 15 can be transmitted through the indicator 17B on the lower surface side to the excitation light E emitted from the light emitting element 15 downward.
  • the part which forms the hole 12a may be formed of a transparent member, glass or the like and have light transmittance.
  • the PD element 12 is manufactured by forming an organic semiconductor such as pentacene by a vapor deposition method or a coating method and then partially doping impurities.
  • organic semiconductors include polycyclic aromatic hydrocarbons such as pentacene, anthracene, or rubrene, low-molecular compounds such as tetracyanoquinodimethane (TCNQ), polyacetylene, poly-3-hexylthiophene (P3HT), or poly A polymer such as paraphenylene vinylene (PPV) can be used.
  • polycyclic aromatic hydrocarbons such as pentacene, anthracene, or rubrene
  • TCNQ tetracyanoquinodimethane
  • P3HT poly-3-hexylthiophene
  • PV paraphenylene vinylene
  • the PD element 12 has a hole 12a in a part facing the substantially center of the light emitting element 15 so that the excitation light E from the light emitting element 15 is transmitted through the detection substrate part 20 and incident on the second indicator 17B side. Is provided.
  • plastic materials such as PET (polyethylene terephthalate), or rubber materials such as PDMS (polydimethylsiloxane) can be used.
  • PDMS polydimethylsiloxane
  • a thin metal plate may be used.
  • the PD element 12 is manufactured by partially doping impurities after forming the organic semiconductor.
  • the PD element 12 may be formed on the silicon substrate using a silicon substrate.
  • the photoelectric conversion element is not limited to the PD element 12 and is selected from various photoelectric conversion elements such as a photoconductor or a phototransistor.
  • a filter that transmits the fluorescence F and blocks the excitation light E is formed on the surface of the PD element 12 in order to prevent the excitation light E from entering (not shown).
  • the filter for example, it is preferable to use a light absorption filter that blocks excitation light E having a wavelength of 375 nm but transmits fluorescence F having a wavelength of 460 nm.
  • the detection substrate unit 20 on which the PD element 12 is mainly provided is used, but of course, a light emitting element substrate on which the light emitting element 15 is mainly mounted may be used.
  • the detection substrate unit 20 includes the wiring 60 shown in FIG. 3, and a wiring that is connected to the external electrode of the light emitting element 15 and supplies a driving signal and a wiring that transmits the signal of the PD element 12 are formed (whichever (Not shown).
  • the two light shielding films 19A and 19B cover the indicators 17A and 17B to prevent the excitation light E and the fluorescence F from leaking to the outside, and at the same time, the external light G (see FIG. 16) enters the indicators 17A and 17B. To prevent that. Further, the light shielding films 19A and 19B have, for example, a submicron pore structure that does not prevent the analyte 9 from passing through the inside and reaching the adjacent indicators 17A and 17B.
  • an inorganic material such as metal or ceramic, or a composite composition with hydrogels in which carbon black is mixed in a base material of organic polymer such as polyimide or polyurethane, or celluloses or polyacrylamide
  • a resin in which carbon black is mixed into an analyte-permeable polymer such as, or a resin obtained by laminating them is used.
  • the light shielding films 19A and 19B here constitute an entry path through which the body fluid including the analyte 9 enters the indicators 17A and 17B.
  • the light emitting element 15 provided on the detection substrate unit 20 is an element that transmits fluorescence F among light emitting elements that emit desired excitation light E such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element. Is selected.
  • an LED element is used as the light emitting element 15, from the viewpoints of fluorescence transmittance, light generation efficiency, wide wavelength selectivity of the excitation light E, and generation of a light other than a wavelength having an excitation action. preferable.
  • an ultraviolet LED element made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
  • the light emitting element 15 emits pulsed excitation light having a center wavelength of around 375 nm at an interval of once every 30 seconds, for example.
  • the current of the drive signal to the light emitting element 15 is 1 mA to 100 mA
  • the light emission pulse width is 1 ms to 100 ms.
  • Indicator 17A, 17B consists of hydrogel which has the fluorescent pigment
  • the indicator 17 may be the analyte 9 itself in which the fluorescent dye that does not include the fluorescent dye and generates the fluorescence F exists in the solution.
  • Hydrogel is water such as acrylic hydrogel produced by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel produced from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.
  • the hydrogel has a size that does not leave the sensor through the light shielding films 19A and 19B. For this reason, it is preferable that the hydrogel has a molecular weight of 1 million or more, or a form in which the hydrogel is crosslinked and does not flow.
  • phenylboronic acid derivatives having a fluorescent residue are suitable as fluorescent dyes.
  • the fluorescent dye is prevented from detaching from the sensor by using a high molecular weight material or chemically fixing to a hydrogel.
  • Indicators 17A and 17B are produced by allowing a phosphate buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator to stand for 1 hour in a nitrogen atmosphere and polymerize.
  • 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.
  • the external electrode of the light emitting element 15 is preferably sealed with an insulating resin.
  • the light emitting element 15 may be sealed with a transparent intermediate layer up to the upper surface. The resin-sealed light emitting element 15 is not easily affected by the moisture of the indicators 17A and 17B.
  • the distal end frame 21 and the proximal end frame 22 fitted before and after the detection substrate unit 20 are made of silicon, glass, metal, or the like, or a resin material such as polypropylene or polystyrene.
  • the distal end frame 21 and the base end frame 22 may be provided with a plurality of openings communicating with the indicators 17A and 17B, and light shielding films 19A and 19B may be provided so as to cover these openings. Thereby, the analyte 9 can enter the indicators 17A and 17B from the front and rear directions, and the entry area of the analyte 9 to the indicators 17A and 17B can be increased.
  • the manufacturing method of the fluorescence sensor 4 will be briefly described with reference to FIGS.
  • the light shielding films 19 ⁇ / b> A and 19 ⁇ / b> B are embossed on the mold 200 in which the arc-shaped recess 201 is formed.
  • the molds 200A and 200B manufacture one fluorescence sensor 4 as a pair. That is, two indicators 17A and 17B provided in one fluorescent sensor 4 are produced by using two molds 200A and 200B.
  • a predetermined amount of indicators 17A and 17B are embossed on the light shielding films 19A and 19B of the mold 200.
  • the indicators 17A and 17B are in a dry state so as to be easily manufactured.
  • the set amounts of the indicators 17A and 17B are amounts such that the expanded state containing moisture is substantially the same as the capacity of the recess 201 provided with the light shielding films 19A and 19B.
  • the liquid indicators 17A and 17B may be injected onto the light shielding films 19A and 19B of the mold 200. Thus, the indicators 17A and 17B covered with the light shielding films 19A and 19B are completed.
  • the detection substrate portion 20 on which the light emitting element 15 and the PD element 12 are mounted is placed on the second indicator 17 ⁇ / b> B on the lower side here, and the end portion of the detection substrate portion 20 is placed. And the end of the second light shielding film 19B are bonded.
  • the second light shielding film 19B and the second indicator 17B are formed in the first mold 200A in which the first light shielding film 19A and the first indicator 17A are formed.
  • the two second molds 200B are overlapped, and both side edges of the detection substrate 20 in the second mold 200B are bonded to both edges of the first light shielding film 19A.
  • first mold frame 200A and the second mold frame 200B are overlapped so that the detection substrate unit 20 and the first indicator 17A face each other, and both end portions of the detection substrate unit 20 and the light shielding films 19A and 19B are overlapped. Glue both side edges.
  • the order in which the detection substrate unit 20 is placed on the molds 200A and 200B and the procedure for bonding the both side ends of the detection substrate unit 20 and the both side ends of the light shielding films 19A and 19B are not particularly limited.
  • the light shielding films 19A and 19B having a semicircular cross section (arc shape) are covered, and the detection substrate unit 20 is sandwiched between the upper and lower sides. A part of the fluorescent sensor 4 provided with the partial cylindrical indicators 17A and 17B is completed.
  • the distal end portion of the detection substrate portion 20 and the distal end frame 21 are fitted and adhered, and the peripheral end portion of the distal end frame 21 and the arc-shaped distal end portions of the light shielding films 19A and 19B are adhered. Further, the base end portion of the detection substrate portion 20 and the base end frame 22 are fitted and bonded, and the peripheral end portion of the front end frame 21 and the arc-shaped base end portions of the light shielding films 19A and 19B are bonded. Thus, the fluorescence sensor 4 is produced.
  • the fluorescence sensor 4 of this embodiment receives excitation light E from the light emitting element 15 provided at the substantially center, and is generated from the two indicators 17A and 17B according to the concentration of the analyte 9.
  • the fluorescence F thus made enters the PD element 12.
  • the fluorescences F1 and F2 that emit light according to the concentration of the analyte 9 are supplied to the upper surface of the PD element 12 via the detection substrate unit 20 in which the fluorescence F1 from the first indicator 17A has optical transparency.
  • the fluorescent light F2 from the indicator 17B is detected by the lower surface of the PD element 12.
  • the fluorescence sensor 4 is evenly irradiated with the excitation light E from the light emitting element 15 on the two partial cylinder-shaped indicators 17A and 17B, and has higher sensitivity than the conventional fluorescence sensor 104.
  • the fluorescent sensor 4 is provided with indicators 17A and 17B in the vertical direction with the light emitting element 15 interposed therebetween, and the PD element 12 is disposed on the light-transmitting detection substrate unit 20 to thereby remove the light from the light emitting element 15. Since the excitation light E can be used efficiently, the sensitivity becomes high.
  • the fluorescent sensor 4 has a substantially cylindrical shape, and has a partial cylindrical shape (cross-sectional arc shape) in which the respective surfaces of the indicators 17A and 17B are formed in an arc shape, and a light shielding film is formed on the surfaces of the indicators 17A and 17B. It is set as the structure covered with 19A, 19B. Therefore, the fluorescence sensor 4 can take a large area for the analyte 9 to enter the indicators 17A and 17B via the light shielding films 19A and 19B, so that the analyte 9 can easily enter the indicators 17A and 17B. Response to the concentration change of the analyte 9 is remarkably improved.
  • the shape of the indicators 17A and 17B is not limited to the partial cylindrical shape, and may be a polygonal cross-sectional shape such as a dome shape.
  • the fluorescence sensors 4A to 4C of the second embodiment will be described. Since the fluorescence sensor 4A is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the fluorescent sensor 4A of the present embodiment is the same in that indicators 17A and 17B covered with light shielding films 19A and 19B are provided above and below the detection substrate unit 20.
  • the difference is that PD elements 12 ⁇ / b> A and 12 ⁇ / b> B, which are photoelectric conversion elements, are formed on the upper and lower surfaces of the detection substrate unit 20.
  • the first PD element 12A is formed at a position avoiding the light emitting element 15 mounted on the upper surface, and excitation from the light emitting element 15 is performed on the lower surface as in the first embodiment.
  • a second PD element 12B provided with a hole 12a is formed in a portion facing substantially the center of the light emitting element 15 so that the light E is transmitted and incident on the second indicator 17B side.
  • the PD elements 12A and 12B are manufactured by forming an organic semiconductor such as pentacene by a vapor deposition method or a coating method and then partially doping impurities.
  • a filter that transmits the fluorescence F and blocks the excitation light E is formed on the surface of the PD element 12 in order to prevent the excitation light E from entering (not shown).
  • the filter for example, it is preferable to use a light absorption filter that blocks excitation light E having a wavelength of 375 nm but transmits fluorescence F having a wavelength of 460 nm.
  • the analyte 9 enters the indicators 17A and 17B from the upper and lower light shielding films 19A and 19B.
  • the fluorescent light F corresponding to the concentration of the analyte 9 is generated from the indicators 17A and 17B by the excitation light E emitted in the vertical and horizontal directions by the light emitting element 15, and is emitted downward from the first indicator 17A located above.
  • the fluorescence F1 is detected by the first PD element 12A formed on the upper surface of the detection substrate unit 20, and the fluorescence F2 emitted upward from the second indicator 17B located below is formed on the lower surface of the detection substrate unit 20. It is detected by the second PD element 12B.
  • the fluorescence sensor 4A of the present embodiment forms the two PD elements 12A and 12B that individually receive the fluorescence F1 and F2 from the indicators 17A and 17B in addition to the effects of the fluorescence sensor 4 of the first embodiment. With higher sensitivity.
  • the fluorescent sensor 4B here has the light emitting elements 15A and 15B mounted thereon and the light emitting elements 15A and 15B mounted thereon. It is good also as a structure which bonded together two detection board
  • the light emitting element 15 at this time is optimally shaped so that the excitation light E is uniformly irradiated to the indicators 17A and 17B by a lens, sealing resin, or the like according to the partial cylindrical shape of the indicators 17A and 17B.
  • the detection substrate unit 20 a silicon substrate is suitable.
  • the PD elements 12A and 12B have a structure in which a p-type diffusion region is formed in an n-type silicon semiconductor, for example.
  • the PD elements 12A and 12B are manufactured by forming an organic semiconductor on a substrate by a vapor deposition method or a coating method and then partially doping impurities.
  • the fluorescence sensor 4 ⁇ / b> C here is opposed to the detection substrate portion 20 provided with the light emitting element 15 so that the excitation light E from the light emitting element 15 enters the second indicator 17 ⁇ / b> B side.
  • the hole 20a may be provided in a part. That is, in the configuration of FIG. 18, the excitation light E that has passed through the hole 20a formed in the detection substrate 20 is incident on the second indicator 17B.
  • the hole 20a of the detection substrate unit 20 may be filled with a transparent resin. Furthermore, it is good also as a structure which bonded together the two detection board
  • the fluorescence sensor 4D of the third embodiment will be described. Since the fluorescence sensor 4D is similar to the fluorescence sensor 4 of the first embodiment, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the fluorescence sensor 4D of the present embodiment has a partial cylindrical shape (circular arc shape) so as to cover the indicators 17A and 17B as compared with the fluorescence sensor 4 of the first embodiment.
  • the difference is that the frame portions 18A and 18B are provided.
  • the fluorescence sensor 4D here is provided with frame portions 18A and 18B formed in an arc shape so as to cover the indicators 17A and 17B, and the light shielding films 19A and 19B are formed so as to cover these frame portions 18A and 18B. 19B is provided.
  • the frame portions 18A and 18B are formed of stainless steel or flexible material having a thickness of 10 ⁇ m, and a plurality of slits 18a and 18b are provided so that the analyte 9 can enter the indicators 17A and 17B along the longitudinal axis direction of the fluorescent sensor 4D. Is formed.
  • the frame portions 18A and 18B are deformed so that the shapes of the indicators 17A and 17B are each a partial cylindrical shape (a cross-sectional arc shape). Note that the side end portions of the frame portions 18A and 18B are bonded to the upper and lower surfaces of the detection substrate portion 20. Further, the frame portions 18A and 18B may be rigid substrates formed in a circular arc shape in advance.
  • the detection substrate unit 20 and the PD element 12 may have any configuration described in the first or second embodiment.
  • the fluorescence sensor 4D of the present embodiment is provided with the frame portions 18A and 18B as compared with the configuration in which the indicators 17A and 17B are covered only by the light shielding films 19A and 19B. As a result, the strength is remarkably improved.
  • the frame portions 18A and 18B are not limited to the plurality of slits 18a and 18b in the direction along the longitudinal axis direction of the fluorescence sensor 4D.
  • the short axis of the fluorescence sensor 4D is used. It is good also as the slits 18c and 18d along a direction.
  • the plurality of slits formed in the frame portions 18A and 18B may have any shape such as a spiral shape or a lattice shape. Further, the frame portions 18A and 18B may have a mesh structure formed of metal or the like as shown in FIG.
  • fluorescence sensors 4E and 4F of the fourth embodiment will be described. Since the fluorescence sensor 4E is similar to the fluorescence sensors 4 and 4D of the first embodiment and the third embodiment, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the fluorescent sensor 4E of this embodiment shown in FIG. 23 differs from the fluorescent sensors 4 and 4D of the first and third embodiments in that PD elements 12A and 12B are provided in the frame portions 18A and 18B. .
  • a plurality of PD elements 12A and 12B are formed on the inner surface side that faces and contacts the indicators 17A and 17B of the frame portions 18A and 18B. That is, the plurality of PD elements 12A formed on the lower frame portion 18A detect the fluorescence emitted radially from the first indicator 17A located above, and the plurality of PD elements 12B formed on the lower frame portion 18B. Detects the fluorescence emitted radially from the second indicator 17B located below.
  • the frame portions 18A and 18B are bonded to the upper and lower surfaces of the substrate portion 20C formed of a transparent member such as a transparent resin or glass on which the light emitting element 15 is mounted. Further, the frame portions 18A and 18B may be rigid substrates formed in a circular arc shape in advance.
  • the frame portions 18C and 18D in the fluorescent sensor 4F are a plurality of substrate portions 31A and 31B in which PD elements 12A and 12B are formed on a rigid substrate or a flexible substrate formed of silicon or the like. Are connected to each other by flexible substrates 32A and 32B to form a dome shape having a circular arc cross section (semicircular shape). That is, the frame portions 18C and 18D are disposed so as to cover the indicators 17A and 17B so that the indicators 17A and 17B have a partial columnar shape (circular arc shape).
  • the frame portions 18C and 18D are bonded to the upper and lower surfaces of the substrate portion 20C formed from a transparent member such as a transparent resin or glass on which the light emitting element 15 is mounted.
  • the frame portions 18C and 18D are not shown so that the substrate portions 31A and 31B, the PD elements 12A and 12B and the flexible substrates 32A and 32B can enter the body fluid containing the analyte 9 into the indicators 17A and 17B.
  • a through hole is formed. That is, body fluid can pass through the frame portions 18C and 18D.
  • light shielding films 19A and 19B that cover the frame portions 18C and 18D may be provided.
  • the size, shape, position, and formation density of the minute through holes of the frame portions 18C and 18D are appropriately selected according to the specifications.
  • the minute through holes do not need to be arranged in an orderly manner.
  • the shape of the opening when the minute through hole is observed from the upper surface may be any of a circle, a rectangle, a polygon, and the like.
  • the two frame portions 18C and 18D in which the minute through holes are formed in this way are produced by patterning the minute through holes on, for example, a silicon plate or a silicon film.
  • the minute through hole can be formed by dry etching such as ICP-RIE after an etching mask is formed on the surface of a silicon plate or the like by photolithography or a self-assembled film.
  • a machining method using a micro drill or the like may be used.
  • porous semiconductor that can pass a solution containing an analyte may be used for the frame portions 18C and 18D.
  • the porous means a material having voids and pores connected to the outside in the structure. The size, distribution, and shape of the voids / pores need not be regular as long as the solution can pass through.
  • the open porosity of the frame portions 18C and 18D is preferably 5 to 75% by volume, particularly preferably 20 to 50% by volume. If it is more than the said range, a bodily fluid will pass easily, and if it is below the said range, desired mechanical strength will be obtained.
  • the open porosity is a value measured by Archimedes method.
  • the PD elements of the fluorescent sensors 4E and 4F are preferably fabricated on a silicon substrate. However, after forming an organic semiconductor by vapor deposition or coating on a light-shielded transparent substrate, composite material, or metal plate, Alternatively, it may be produced by doping impurities.
  • the light emitting element 15 is mounted only on the upper surface of the substrate portion 20C, it is needless to say that it may be mounted on both surfaces of the substrate portion 20C.
  • the substrate portion 20C may be formed from a non-transparent member instead of a transparent member.
  • the substrate section 20C may have any configuration shown in FIGS. 17 and 18 of the second embodiment.
  • the fluorescence sensors 4E and 4F of the present embodiment individually receive the fluorescence F1 and F2 from the indicators 17A and 17B in addition to the effects of the fluorescence sensors 4 and 4D of the first embodiment and the third embodiment.
  • the plurality of PD elements 12A and 12B in the frame portions 18 and 18A to 18D, higher sensitivity is achieved. Note that the above configuration can also be applied to the frame portions 18A and 18B of the rigid substrate previously formed in an arc shape described in the third embodiment.
  • a sensor that detects saccharides such as glucose has been described as an example.
  • a fluorescent sensor can be used for various applications such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye. ing.

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Abstract

A fluorescent sensor (4) comprising: a substrate section (20); two indicators (17A, 17B) arranged sandwiching the substrate section (20), receiving excitation light (E), generating fluorescent light (F) of an intensity corresponding to the concentration of an analyte (9), and having a partially cylindrical exterior; a light-emitting element (15) attached to the substrate section (20) and which generates the excitation light (E); and a photoelectric conversion element (12) that converts the fluorescent light (F) into an electric signal.

Description

蛍光センサFluorescent sensor
　本発明は、溶液中のアナライトの濃度を計測する蛍光センサに関し、特に、アナライト及び励起光により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に関する。 The present invention relates to a fluorescence sensor for measuring the concentration of an analyte in a solution, and more particularly to a fluorescence sensor having an indicator made of an analyte and a hydrogel that generates fluorescence by excitation light.
　溶液中のアナライトすなわち被計測物質の濃度を測定するための様々な分析装置が開発されている。例えば、蛍光色素とアナライトとを含む被計測溶液とを透明容器に注入し、励起光を照射し蛍光色素からの蛍光強度を計測することによりアナライト濃度を計測する蛍光光度計が知られている。蛍光色素は、アナライトの存在によって性質が変化し励起光を受光するとアナライト濃度に対応した強度の蛍光を発生する。 Various analyzers have been developed for measuring the concentration of analytes in solution, that is, analytes. For example, a fluorometer that measures analyte concentration by injecting a solution to be measured containing a fluorescent dye and an analyte into a transparent container, irradiating excitation light, and measuring the fluorescence intensity from the fluorescent dye is known. Yes. Fluorescent dyes change in properties due to the presence of an analyte, and generate fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light.
　小型の蛍光光度計は、光源と光検出器と蛍光色素を含有したインジケータとを有している。そして、被計測溶液中のアナライトが出入り自在なインジケータに光源からの励起光を照射し、インジケータが発生する蛍光を光検出器が受光する。光検出器は光電変換素子であり、受光強度に応じた電気信号を出力する。光検出器からの電気信号をもとに溶液中のアナライト濃度が算出される。 A small fluorometer has a light source, a photodetector, and an indicator containing a fluorescent dye. And the excitation light from a light source is irradiated to the indicator which the analyte in a to-be-measured solution can enter / exit, and the photodetector receives the fluorescence which an indicator generate | occur | produces. The photodetector is a photoelectric conversion element and outputs an electrical signal corresponding to the received light intensity. The analyte concentration in the solution is calculated based on the electrical signal from the photodetector.
　微量試料中のアナライトを計測するために、半導体製造技術及びＭＥＭＳ技術を用いて作製される微小蛍光光度計が提案されている。以下、微小蛍光光度計のことを「蛍光センサ」という。 In order to measure an analyte in a very small amount of sample, a microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology has been proposed. Hereinafter, the microfluorometer is referred to as “fluorescence sensor”.
　図１及び図２に示す蛍光センサ１０４が国際公開第２０１０／１１９９１６号パンフレットに開示されている。蛍光センサ１０４の主機能部であるセンサ部１１０は、光電変換素子１１２が形成されているシリコン基板１１１と、透明中間層１１３と、フィルタ層１１４と、発光素子１１５と、透明保護層１１６と、インジケータ１１７と、遮光層１１８と、を有する。アナライト９は、遮光層１１８を通過して、インジケータ１１７に進入する。蛍光センサ１０４のフィルタ層１１４は励起光Ｅを遮断し蛍光Ｆを透過する。さらに、発光素子１１５は蛍光Ｆを透過する。 The fluorescent sensor 104 shown in FIGS. 1 and 2 is disclosed in International Publication No. 2010/119916. The sensor unit 110 which is a main functional unit of the fluorescence sensor 104 includes a silicon substrate 111 on which a photoelectric conversion element 112 is formed, a transparent intermediate layer 113, a filter layer 114, a light emitting element 115, a transparent protective layer 116, An indicator 117 and a light shielding layer 118 are provided. The analyte 9 passes through the light shielding layer 118 and enters the indicator 117. The filter layer 114 of the fluorescence sensor 104 blocks the excitation light E and transmits the fluorescence F. Further, the light emitting element 115 transmits the fluorescence F.
　蛍光センサ１０４では、発光素子１１５が発生した励起光Ｅがインジケータ１１７に入射すると、インジケータ１１７はアナライト濃度に応じた蛍光Ｆを発生する。 In the fluorescence sensor 104, when the excitation light E generated by the light emitting element 115 enters the indicator 117, the indicator 117 generates fluorescence F corresponding to the analyte concentration.
　インジケータ１１７が発生した蛍光Ｆの一部は、発光素子１１５とフィルタ層１１４とを通過し、光電変換素子１１２に入射し光電変換される。なお、発光素子１１５が光電変換素子１１２の方向（下方向）に出射した励起光Ｅは、フィルタ層１１４により蛍光強度と比較して計測上問題ないレベルまで減光される。蛍光センサ１０４は、構成が単純で小型化が容易である。 Part of the fluorescence F generated by the indicator 117 passes through the light emitting element 115 and the filter layer 114, enters the photoelectric conversion element 112, and is photoelectrically converted. The excitation light E emitted from the light emitting element 115 in the direction of the photoelectric conversion element 112 (downward) is attenuated by the filter layer 114 to a level that causes no problem in measurement as compared with the fluorescence intensity. The fluorescent sensor 104 has a simple configuration and can be easily downsized.
　しかし、蛍光センサ１０４は光電変換素子１１２が発光素子１１５の下面にあるため、光電変換素子１１２による蛍光Ｆの受光効率が良いとはいえない。このため、より検出感度が高い蛍光センサが求められていた。 However, in the fluorescence sensor 104, since the photoelectric conversion element 112 is on the lower surface of the light emitting element 115, it cannot be said that the light reception efficiency of the fluorescence F by the photoelectric conversion element 112 is good. For this reason, a fluorescence sensor with higher detection sensitivity has been demanded.
　そこで、本発明は、上記事情に鑑みて成されたものであり、その目的とするところは、検出感度が高い蛍光センサを提供することである。 Therefore, the present invention has been made in view of the above circumstances, and its object is to provide a fluorescent sensor with high detection sensitivity.
　本発明の一態様の蛍光センサは、基板部と、前記基板部を挟んで配設され、励起光を受光してアナライトの濃度に応じた強度の蛍光を発生し、外形が部分円柱形状を呈する２つのインジケータと、前記基板部に実装され励起光を発生する発光素子と、前記蛍光を電気信号に変換する光電変換素子と、を備えている。 The fluorescence sensor of one embodiment of the present invention is provided with a substrate portion and the substrate portion interposed therebetween, receives excitation light, generates fluorescence having an intensity according to the concentration of the analyte, and has an outer shape of a partial cylindrical shape. Two indicators to be presented, a light emitting element that is mounted on the substrate portion and generates excitation light, and a photoelectric conversion element that converts the fluorescence into an electric signal.
従来の蛍光センサの断面構造を示した説明図である。It is explanatory drawing which showed the cross-section of the conventional fluorescence sensor. 従来の蛍光センサの構造を示した分解図である。It is the exploded view which showed the structure of the conventional fluorescence sensor. 第１実施形態のセンサシステムの構成図である。It is a block diagram of the sensor system of 1st Embodiment. 同、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 a fluorescence sensor. 同、蛍光センサの先端部における図４のＶ－Ｖ線に沿った断面図である。FIG. 5 is a cross-sectional view taken along line VV in FIG. 4 at the distal end portion of the fluorescent sensor. 同、蛍光センサの先端部における図５のＶＩ－ＶＩ線に沿った断面図である。FIG. 6 is a cross-sectional view taken along the line VI-VI in FIG. 5 at the tip of the fluorescent sensor. 同、蛍光センサの製造方法を説明し、型枠および遮光膜を示す断面図である。FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor and showing a mold and a light shielding film. 同、蛍光センサの製造方法を説明し、型枠の凹部に遮光膜が型押しされた状態の断面図である。FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which a light-shielding film is pressed into a recess of a mold. 同、蛍光センサの製造方法を説明し、型枠の凹部の遮光膜上にインジケータが型押しされた状態の断面図である。FIG. 5 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which an indicator is pressed onto a light shielding film in a recess of a mold. 同、蛍光センサの製造方法を説明し、一方の型枠のインジケータ上に光電変換素子基板が配置された状態の断面図である。FIG. 3 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which a photoelectric conversion element substrate is disposed on an indicator of one mold. 同、蛍光センサの製造方法を説明し、遮光膜、インジケータが凹部に型押しされた型枠とインジケータ上に光電変換素子基板が配置された型枠を示す断面図である。FIG. 4 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, showing a mold having a light-shielding film and an indicator embossed in a recess, and a mold having a photoelectric conversion element substrate disposed on the indicator. 同、蛍光センサの製造方法を説明し、２つの型枠を重ね合わせた状態の断面図である。FIG. 5 is a cross-sectional view illustrating a method for manufacturing a fluorescent sensor, in which two molds are overlapped. 同、蛍光センサの製造方法を説明し、２つの型枠が取り外されて完成される蛍光センサを示す断面図である。FIG. 5 is a cross-sectional view illustrating a fluorescent sensor that is completed by removing two molds and explaining a method for manufacturing the fluorescent sensor. 同、蛍光センサの動作を説明するための断面模式図である。It is a cross-sectional schematic diagram for demonstrating operation | movement of a fluorescence sensor. 第２実施形態の蛍光センサの断面図である。It is sectional drawing of the fluorescence sensor of 2nd Embodiment. 同、蛍光センサの動作を説明するための断面模式図である。It is a cross-sectional schematic diagram for demonstrating operation | movement of a fluorescence sensor. 同、変形例の蛍光センサの断面図である。It is sectional drawing of the fluorescence sensor of a modification same as the above. 同、図１７とは異なる変形例の蛍光センサの断面図である。FIG. 18 is a cross-sectional view of a fluorescent sensor of a modified example different from FIG. 第３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 3rd Embodiment. 同、蛍光センサの先端部における図１９のＸＸ－ＸＸ線に沿った断面図である。FIG. 20 is a cross-sectional view taken along the line XX-XX in FIG. 19 at the tip of the fluorescent sensor. 同、変形例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 a modification similarly. 同、図２１とは異なる変形例の蛍光センサの先端部の斜視図である。FIG. 22 is a perspective view of a distal end portion of a fluorescent sensor of a modified example different from FIG. 第４実施形態の蛍光センサの断面図である。It is sectional drawing of the fluorescence sensor of 4th Embodiment. 同、変形例の蛍光センサの断面図である。It is sectional drawing of the fluorescence sensor of a modification same as the above.
　＜第１実施形態＞
　本発明の第１実施形態の蛍光センサ４及びセンサシステム１について説明する。図３に示すように、センサシステム１は、蛍光センサ４と、本体部２と、本体部２からの信号を受信し記憶するレシーバー３と、を有する。本体部２とレシーバー３との間の信号の送受信は無線または有線で行われる。 <First Embodiment>
The fluorescence sensor 4 and the sensor system 1 according to the first embodiment of the present invention will be described. As shown in FIG. 3, the sensor system 1 includes a fluorescent sensor 4, a main body 2, and a receiver 3 that receives and stores a signal from the main body 2. Transmission / reception of signals between the main body 2 and the receiver 3 is performed wirelessly or by wire.
　蛍光センサ４は、被検体に穿刺される針部７と、針部７の後端部と接合されたコネクタ部８と、からなる。針部７は、細長い針本体部６と、主要機能部であるセンサ部１０を含む針先端部５と、を有する。針先端部５、針本体部６、コネクタ部８は、同一材料により一体形成されていてもよいし、別々に作製され接合されていてもよい。 The fluorescent sensor 4 includes a needle portion 7 that is punctured by a subject and a connector portion 8 that is joined to the rear end portion of the needle portion 7. The needle part 7 has an elongated needle body part 6 and a needle tip part 5 including a sensor part 10 which is a main function part. Needle tip 5, needle body 6, and connector 8 may be integrally formed of the same material, or may be separately produced and joined.
　コネクタ部８は、本体部２の嵌合部２Ａと着脱自在に嵌合する。蛍光センサ４のセンサ部１０から延設された複数の配線６０は、コネクタ部８が本体部２の嵌合部２Ａと機械的に嵌合することにより、本体部２と電気的に接続される。 The connector part 8 is detachably fitted to the fitting part 2A of the main body part 2. The plurality of wirings 60 extending from the sensor unit 10 of the fluorescent sensor 4 are electrically connected to the main body unit 2 when the connector unit 8 is mechanically fitted to the fitting unit 2A of the main body unit 2. .
　蛍光センサ４は、センサ部１０を体内に挿入後、所定期間、例えば、１週間、継続して生体内の溶液（体液）のアナライト濃度を測定可能な針型センサである。しかし、センサ部１０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。 Fluorescent sensor 4 is a needle-type sensor that can continuously measure the analyte concentration of a solution (body fluid) in a living body after inserting sensor unit 10 into the body for a predetermined period, for example, one week. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.
　本体部２は、センサ部１０の駆動及び制御などを行う制御部２Ｂと、センサ部１０から出力された信号を処理する演算部２Ｃと、を有する。なお、制御部２Ｂまたは演算部２Ｃの少なくともいずれかが、蛍光センサ４のコネクタ部８等に配設されていてもよいし、レシーバー３に配設されていてもよい。 The main body unit 2 includes a control unit 2B that performs driving and control of the sensor unit 10, and a calculation unit 2C that processes a signal output from the sensor unit 10. Note that at least one of the control unit 2B and the calculation unit 2C may be disposed in the connector unit 8 of the fluorescent sensor 4 or may be disposed in the receiver 3.
　図示しないが、本体部２は、レシーバー３との間で無線信号を送受信するための無線アンテナと、電池等と、をさらに有する。レシーバー３との間の信号を有線にて送受信する場合には、本体部２は無線アンテナに代えて信号線を有する。なお、本体部２が必要な容量のメモリ部を有する場合にはレシーバー３はなくてもよい。 Although not shown, the main body 2 further includes a radio antenna for transmitting and receiving radio signals to and from the receiver 3, a battery, and the like. When transmitting / receiving a signal to / from the receiver 3 by wire, the main body 2 has a signal line instead of a wireless antenna. Note that the receiver 3 may not be provided when the main body 2 includes a memory unit having a necessary capacity.
＜センサ部の構造＞
　次に、図４～図８を用いて、蛍光センサ４の主要機能部であるセンサ部１０の構造について説明する。なお、図は、いずれも説明のための模式図であり、縦横の寸法比等は実際とは異なっており、一部の構成要素を図示しない場合もある。また、図に示すＺ軸方向を蛍光センサ４における上方向という。さらに、図中、Ｘ軸方向が蛍光センサ４における前後方向の後方を示し、Ｙ軸方向が左右方向の左方向を示している。 <Structure of sensor part>
Next, the structure of the sensor unit 10 which is a main functional unit of the fluorescence sensor 4 will be described with reference to FIGS. In addition, all the figures are schematic diagrams for explanation, and the vertical and horizontal dimensional ratios and the like are different from actual ones, and some components may not be shown. Further, the Z-axis direction shown in the figure is referred to as an upward direction in the fluorescence sensor 4. Further, in the drawing, the X-axis direction indicates the rear in the front-rear direction of the fluorescent sensor 4, and the Y-axis direction indicates the left direction in the left-right direction.
　第１実施形態の蛍光センサ４は、被検体の体液中のグルコースを検出する。図４から図６に示すように、本実施形態のセンサ部１０は、外形略円柱形状をしており、上下左右方向に放射状に発光する発光素子１５と、この発光素子１５が上面に実装された透明樹脂、ガラスなどの透明部材から形成されている検出基板部２０と、この検出基板部２０の先端部分に嵌着された円柱形状の先端枠２１と、検出基板部２０の基端部分に嵌着された円柱形状の基端枠２２と、検出基板部２０を挟むように上下方向に配設された外形が断面円弧状を呈し、すなわち部分円柱形状の２つのインジケータ１７Ａ，１７Ｂと、２つのインジケータ１７Ａ，１７Ｂのそれぞれをドーム状に覆う２つの遮光膜１９Ａ，１９Ｂと、を有して構成されている。ここでのインジケータ１７Ａ，Ｂの形状は、上述したように、外形が断面円弧状として部分円柱形状としている。この部分円柱形状とは、円柱を略半分に切断した形状である。 The fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject. As shown in FIG. 4 to FIG. 6, the sensor unit 10 of the present embodiment has a substantially cylindrical shape, a light emitting element 15 that emits light radially in the vertical and horizontal directions, and the light emitting element 15 is mounted on the upper surface. A detection substrate portion 20 formed of a transparent member such as transparent resin or glass, a columnar distal end frame 21 fitted to the distal end portion of the detection substrate portion 20, and a proximal end portion of the detection substrate portion 20. The fitted cylindrical base end frame 22 and the outer shape arranged in the vertical direction so as to sandwich the detection substrate portion 20 have a circular arc cross section, that is, two partial columnar indicators 17A and 17B, The two indicators 17A and 17B are configured to have two light-shielding films 19A and 19B covering the respective domes. As described above, the indicators 17A and 17B have a partial cylindrical shape whose outer shape is a circular arc shape as described above. This partial columnar shape is a shape obtained by cutting a column into approximately half.
　なお、２つのインジケータ１７Ａ，１７Ｂ、および２つの遮光膜１９Ａ，１９Ｂのうち、第１のインジケータ１７Ａおよび第１の遮光膜１９Ａが検出基板部２０の上方側、第２のインジケータ１７Ｂおよび第２の遮光膜１９Ｂが検出基板部２０の下方側に配置されている。 Of the two indicators 17A and 17B and the two light shielding films 19A and 19B, the first indicator 17A and the first light shielding film 19A are on the upper side of the detection substrate unit 20, the second indicator 17B and the second light shielding film 19A. The light shielding film 19 </ b> B is disposed on the lower side of the detection substrate unit 20.
　具体的には、上方から順に、第１の遮光膜１９Ａ、第１のインジケータ１７Ａ、検出基板部２０、第２のインジケータ１７Ｂおよび第２の遮光膜１９Ｂが配設されている。すなわち、第１のインジケータ１７Ａおよび第２のインジケータ１７Ｂが発光素子１５を有する検出基板部２０を挟むように配設されており、インジケータ１７Ａ，１７Ｂが遮光膜１９Ａ，１９Ｂに覆われている。なお、遮光膜１９Ａ，１９Ｂは、検出基板部２０の縁辺部分（両側端部）に接着されている。 Specifically, the first light-shielding film 19A, the first indicator 17A, the detection substrate unit 20, the second indicator 17B, and the second light-shielding film 19B are disposed in order from the top. That is, the first indicator 17A and the second indicator 17B are arranged so as to sandwich the detection substrate unit 20 having the light emitting element 15, and the indicators 17A and 17B are covered with the light shielding films 19A and 19B. The light shielding films 19 </ b> A and 19 </ b> B are bonded to the edge portions (both end portions) of the detection substrate unit 20.
　ここでの蛍光センサ４は、発光素子１５が上面に配設された検出基板部２０の下面にインジケータ１７Ａ，１７Ｂからの蛍光Ｆを電気信号に変換する光電変換素子であるフォトダーオード素子（以下「ＰＤ素子」という）１２が形成されている。 The fluorescence sensor 4 here is a photodiode element (hereinafter referred to as a photoelectric conversion element) that converts the fluorescence F from the indicators 17A and 17B into an electrical signal on the lower surface of the detection substrate portion 20 on which the light emitting element 15 is disposed. (Referred to as “PD element”) 12 is formed.
　検出基板部２０は、上面に発光素子１５が実装され、下面にＰＤ素子１２が形成されている。 The detection substrate 20 has the light emitting element 15 mounted on the upper surface and the PD element 12 formed on the lower surface.
　なお、検出基板部２０は、発光素子１５からの励起光Ｅを下面側のインジケータ１７Ｂ側へ発光素子１５から下方側へ発光される励起光Ｅが透過できるように透明樹脂、ガラス等の透明基板から形成されるが、孔部１２ａを形成する部分のみが透明部材、ガラス等から形成されて光透過性を有しているものでもよい。 The detection substrate unit 20 is a transparent substrate made of transparent resin, glass or the like so that the excitation light E emitted from the light emitting element 15 can be transmitted through the indicator 17B on the lower surface side to the excitation light E emitted from the light emitting element 15 downward. However, only the part which forms the hole 12a may be formed of a transparent member, glass or the like and have light transmittance.
　検出基板部２０が透明基板の場合、ＰＤ素子１２は、ペンタセン等の有機半導体を蒸着法または塗布法で形成した後、部分的に不純物をドープすることにより作製される。 When the detection substrate unit 20 is a transparent substrate, the PD element 12 is manufactured by forming an organic semiconductor such as pentacene by a vapor deposition method or a coating method and then partially doping impurities.
　例えば、有機半導体には、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。 For example, organic semiconductors include polycyclic aromatic hydrocarbons such as pentacene, anthracene, or rubrene, low-molecular compounds such as tetracyanoquinodimethane (TCNQ), polyacetylene, poly-3-hexylthiophene (P3HT), or poly A polymer such as paraphenylene vinylene (PPV) can be used.
　このとき、ＰＤ素子１２は、発光素子１５からの励起光Ｅが検出基板部２０を透過して第２のインジケータ１７Ｂ側に入射するよう発光素子１５の略中央に対向した一部分に孔部１２ａが設けられている。 At this time, the PD element 12 has a hole 12a in a part facing the substantially center of the light emitting element 15 so that the excitation light E from the light emitting element 15 is transmitted through the detection substrate part 20 and incident on the second indicator 17B side. Is provided.
　一方、ＰＤ素子１２の孔部１２ａに合わせた部分のみが透明部材、ガラス等から形成されて光透過性を有している基板を用いる場合には、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も可能である。また、ステンレス等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。 On the other hand, when using a light-transmitting substrate in which only the portion corresponding to the hole 12a of the PD element 12 is formed from a transparent member, glass, etc., use a polyimide sheet on which aluminum or gold is vapor-deposited. Is also possible. Moreover, you may use the composite material which bonded metal foil, such as stainless steel, and a flexible sheet.
　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。あるいは、薄い金属板を用いてもよい。 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. Alternatively, a thin metal plate may be used.
　このとき、ＰＤ素子１２は、上述したように、有機半導体を形成した後に部分的に不純物をドープすることにより作製される。 At this time, as described above, the PD element 12 is manufactured by partially doping impurities after forming the organic semiconductor.
　また、シリコン基板を用いて、シリコン基板上にＰＤ素子１２を形成してもよいことは勿論である。 Of course, the PD element 12 may be formed on the silicon substrate using a silicon substrate.
　なお、光電変換素子としては、ＰＤ素子１２に限定されることなく、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 is not limited to the PD element 12 and is selected from various photoelectric conversion elements such as a photoconductor or a phototransistor.
　ここで、ＰＤ素子１２表面上には、励起光Ｅが入射するのを防止するために、蛍光Ｆを透過し励起光Ｅを遮るフィルタが形成されていることが好ましい（不図示）。フィルタとしては、例えば、波長３７５ｎｍの励起光Ｅは遮断するが、波長４６０ｎｍの蛍光Ｆは透過する光吸収型フィルタを用いることが好ましい。 Here, it is preferable that a filter that transmits the fluorescence F and blocks the excitation light E is formed on the surface of the PD element 12 in order to prevent the excitation light E from entering (not shown). As the filter, for example, it is preferable to use a light absorption filter that blocks excitation light E having a wavelength of 375 nm but transmits fluorescence F having a wavelength of 460 nm.
　なお、ここでは、ＰＤ素子１２が主体的に設けられる検出基板部２０としているが、勿論、発光素子１５が主体的に実装される発光素子基板としてもよい。 In addition, here, the detection substrate unit 20 on which the PD element 12 is mainly provided is used, but of course, a light emitting element substrate on which the light emitting element 15 is mainly mounted may be used.
　検出基板部２０には、図３に示した配線６０を構成し、発光素子１５の外部電極と接続され駆動信号を供給する配線及びＰＤ素子１２の信号を伝送する配線が形成されている（いずれも不図示）。 The detection substrate unit 20 includes the wiring 60 shown in FIG. 3, and a wiring that is connected to the external electrode of the light emitting element 15 and supplies a driving signal and a wiring that transmits the signal of the PD element 12 are formed (whichever (Not shown).
　２つの遮光膜１９Ａ，１９Ｂは、インジケータ１７Ａ，１７Ｂを覆うことで励起光Ｅ及び蛍光Ｆが外部へ漏光するのを防止すると同時に、外光Ｇ（図１６参照）がインジケータ１７Ａ，１７Ｂに進入することを防止する。また、遮光膜１９Ａ，１９Ｂは、アナライト９が、その内部を通過して近接するインジケータ１７Ａ，１７Ｂに到達するのを妨げない、例えば、サブミクロンサイズのポア構造である。遮光膜１９Ａ，１９Ｂには、金属、セラミック等の無機材料または、ポリイミドもしくはポリウレタン等の有機ポリマーの基材にカーボンブラックが混入されたハイドロゲル類とのコンポジット組成物、または、セルロース類もしくはポリアクリルアミド等のアナライト透過性ポリマーにカーボンブラックを混入した樹脂、または、それらを積層化した樹脂等を用いる。ここでの遮光膜１９Ａ，１９Ｂは、アナライト９を含む体液がインジケータ１７Ａ，１７Ｂに進入する進入経路を構成している。 The two light shielding films 19A and 19B cover the indicators 17A and 17B to prevent the excitation light E and the fluorescence F from leaking to the outside, and at the same time, the external light G (see FIG. 16) enters the indicators 17A and 17B. To prevent that. Further, the light shielding films 19A and 19B have, for example, a submicron pore structure that does not prevent the analyte 9 from passing through the inside and reaching the adjacent indicators 17A and 17B. For the light shielding films 19A and 19B, an inorganic material such as metal or ceramic, or a composite composition with hydrogels in which carbon black is mixed in a base material of organic polymer such as polyimide or polyurethane, or celluloses or polyacrylamide A resin in which carbon black is mixed into an analyte-permeable polymer such as, or a resin obtained by laminating them is used. The light shielding films 19A and 19B here constitute an entry path through which the body fluid including the analyte 9 enters the indicators 17A and 17B.
　検出基板部２０に設けられる発光素子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等の所望の励起光Ｅを発光する発光素子の中から、蛍光Ｆを透過する素子が選択される。 The light emitting element 15 provided on the detection substrate unit 20 is an element that transmits fluorescence F among light emitting elements that emit desired excitation light E such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element. Is selected.
　なお、発光素子１５としては、蛍光透過率、光発生効率、励起光Ｅの波長選択性の広さ、及び励起作用のある波長以外の光を僅かしか発生しないこと等の観点から、ＬＥＤ素子が好ましい。さらにＬＥＤ素子の中でも、サファイア基板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ＬＥＤ素子が、特に好ましい。 In addition, as the light emitting element 15, an LED element is used from the viewpoints of fluorescence transmittance, light generation efficiency, wide wavelength selectivity of the excitation light E, and generation of a light other than a wavelength having an excitation action. preferable. Furthermore, among LED elements, an ultraviolet LED element made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
　発光素子１５は、例えば３０秒に１回の間隔で中心波長が３７５ｎｍ前後の励起光をパルス発光する。例えば、発光素子１５への駆動信号の電流は１ｍＡ～１００ｍＡであり、発光のパルス幅は１ｍｓ～１００ｍｓである。 The light emitting element 15 emits pulsed excitation light having a center wavelength of around 375 nm at an interval of once every 30 seconds, for example. For example, the current of the drive signal to the light emitting element 15 is 1 mA to 100 mA, and the light emission pulse width is 1 ms to 100 ms.
　インジケータ１７Ａ，１７Ｂは、アナライト９及び励起光Ｅにより、励起光Ｅよりも長波長の蛍光Ｆを発生する蛍光色素を有するハイドロゲルからなる。すなわち２つのインジケータ１７Ａ，１７Ｂは、試料中のアナライト濃度に応じた光量の蛍光Ｆを発生する蛍光色素が含まれる、励起光Ｅ及び蛍光Ｆが良好に透過するハイドロゲルから構成されている。なお、インジケータ１７が蛍光色素を含まず、蛍光Ｆを発生する蛍光色素が溶液中に存在するアナライト９そのものでもよい。 Indicator 17A, 17B consists of hydrogel which has the fluorescent pigment | dye which generate | occur | produces the fluorescence F longer wavelength than the excitation light E with the analyte 9 and the excitation light E. FIG. That is, the two indicators 17A and 17B are composed of a hydrogel that contains the fluorescent dye that generates the fluorescence F with a light amount corresponding to the analyte concentration in the sample and that allows the excitation light E and the fluorescence F to pass through well. The indicator 17 may be the analyte 9 itself in which the fluorescent dye that does not include the fluorescent dye and generates the fluorescence F exists in the solution.
　ハイドロゲルは、メチルセルロースもしくはデキストラン等の多糖類、アクリルアミド、メチロールアクリルアミド、ヒドロ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アクリル系ハイドロゲル、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等の水を含みやすい材料に蛍光色素を内包することにより形成されている。 Hydrogel is water such as acrylic hydrogel produced by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel produced from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.
　ハイドロゲルは、遮光膜１９Ａ，１９Ｂを介してセンサ外に離脱することがない大きさであることが好ましい。このため、ハイドロゲルは、構成する分子が分子量１００万以上であるか、または架橋され流動しない形態であることが好ましい。 It is preferable that the hydrogel has a size that does not leave the sensor through the light shielding films 19A and 19B. For this reason, it is preferable that the hydrogel has a molecular weight of 1 million or more, or a form in which the hydrogel is crosslinked and does not flow.
　一方、蛍光色素としては、グルコース等の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等が適している。蛍光色素は、高分子量材料としたり、または、ハイドロゲルに化学的に固定したりすることにより、センサ外に離脱することが防止されている。 On the other hand, when measuring sugars such as glucose, phenylboronic acid derivatives having a fluorescent residue are suitable as fluorescent dyes. The fluorescent dye is prevented from detaching from the sensor by using a high molecular weight material or chemically fixing to a hydrogel.
　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、窒素雰囲気下で１時間放置し、重合することにより、インジケータ１７Ａ，１７Ｂが作製される。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及びＮ、Ｎ、Ｎ’、Ｎ‘－テトラメチルエチレンジアミンを用いる。 Indicators 17A and 17B are produced by allowing a phosphate buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator to stand for 1 hour in a nitrogen atmosphere and polymerize. 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.
　また、発光素子１５の外部電極は、絶縁性樹脂で封止されていることが好ましい。さらに、発光素子１５が上面まで透明中間層で封止されていてもよい。樹脂封止されている発光素子１５は、インジケータ１７Ａ，１７Ｂの水分の影響を受けにくい。 In addition, the external electrode of the light emitting element 15 is preferably sealed with an insulating resin. Furthermore, the light emitting element 15 may be sealed with a transparent intermediate layer up to the upper surface. The resin-sealed light emitting element 15 is not easily affected by the moisture of the indicators 17A and 17B.
　検出基板部２０の前後に嵌合される先端枠２１および基端枠２２は、シリコン、ガラスもしくは金属等、または、ポリプロピレンもしくはポリスチレン等の樹脂材料を用いる。また、これら先端枠２１および基端枠２２は、インジケータ１７Ａ，１７Ｂ側で連通する複数の開口部を設けて、これら開口部を覆うように遮光膜１９Ａ，１９Ｂを設けてもよい。これにより、インジケータ１７Ａ，１７Ｂへ前後方向からもアナライト９が進入でき、インジケータ１７Ａ，１７Ｂへのアナライト９の進入領域を増加させることができる。 The distal end frame 21 and the proximal end frame 22 fitted before and after the detection substrate unit 20 are made of silicon, glass, metal, or the like, or a resin material such as polypropylene or polystyrene. The distal end frame 21 and the base end frame 22 may be provided with a plurality of openings communicating with the indicators 17A and 17B, and light shielding films 19A and 19B may be provided so as to cover these openings. Thereby, the analyte 9 can enter the indicators 17A and 17B from the front and rear directions, and the entry area of the analyte 9 to the indicators 17A and 17B can be increased.
　ここで、図７から図１３を用いて蛍光センサ４の製造方法について簡単に説明する。　
　先ず、図７および図８に示すように、円弧状の凹部２０１が形成された型枠２００に遮光膜１９Ａ，１９Ｂが型押しされる。なお、型枠２００Ａ，２００Ｂは、一対で１つの蛍光センサ４を製造する。すなわち、２つの型枠２００Ａ，２００Ｂを用いることで１つの蛍光センサ４に設けられる２つのインジケータ１７Ａ，１７Ｂが制作される。 Here, the manufacturing method of the fluorescence sensor 4 will be briefly described with reference to FIGS.
First, as shown in FIGS. 7 and 8, the light shielding films 19 </ b> A and 19 </ b> B are embossed on the mold 200 in which the arc-shaped recess 201 is formed. In addition, the molds 200A and 200B manufacture one fluorescence sensor 4 as a pair. That is, two indicators 17A and 17B provided in one fluorescent sensor 4 are produced by using two molds 200A and 200B.
　次に、図９に示すように、予め設定された量のインジケータ１７Ａ，１７Ｂが型枠２００の遮光膜１９Ａ，１９Ｂ上に型押しされる。このときのインジケータ１７Ａ，１７Ｂは、製造し易いように乾燥状態のものが用いられる。インジケータ１７Ａ，１７Ｂの設定量は、水分を含んで膨張した状態が遮光膜１９Ａ，１９Ｂを設けた凹部２０１の容量と略同一となる量である。なお、液状のインジケータ１７Ａ，１７Ｂを型枠２００の遮光膜１９Ａ，１９Ｂ上に注入してもよい。こうして、遮光膜１９Ａ，１９Ｂに覆われたインジケータ１７Ａ，１７Ｂが完成する。 Next, as shown in FIG. 9, a predetermined amount of indicators 17A and 17B are embossed on the light shielding films 19A and 19B of the mold 200. At this time, the indicators 17A and 17B are in a dry state so as to be easily manufactured. The set amounts of the indicators 17A and 17B are amounts such that the expanded state containing moisture is substantially the same as the capacity of the recess 201 provided with the light shielding films 19A and 19B. The liquid indicators 17A and 17B may be injected onto the light shielding films 19A and 19B of the mold 200. Thus, the indicators 17A and 17B covered with the light shielding films 19A and 19B are completed.
　続いて、図１０に示すように、ここでは下方側となる第２のインジケータ１７Ｂ上に発光素子１５およびＰＤ素子１２が実装された検出基板部２０を載置し、検出基板部２０の端部と第２の遮光膜１９Ｂの端部とを接着する。次に、図１１および図１２に示すように、第１の遮光膜１９Ａと第１のインジケータ１７Ａが形成された第１の型枠２００Ａを第２の遮光膜１９Ｂと第２のインジケータ１７Ｂが形成された第２の型枠２００Ｂを重ね合せて、第２の型枠２００Ｂにある検出基板部２０の両側端部と第１の遮光膜１９Ａの両側端部とを接着する。 Subsequently, as shown in FIG. 10, the detection substrate portion 20 on which the light emitting element 15 and the PD element 12 are mounted is placed on the second indicator 17 </ b> B on the lower side here, and the end portion of the detection substrate portion 20 is placed. And the end of the second light shielding film 19B are bonded. Next, as shown in FIGS. 11 and 12, the second light shielding film 19B and the second indicator 17B are formed in the first mold 200A in which the first light shielding film 19A and the first indicator 17A are formed. The two second molds 200B are overlapped, and both side edges of the detection substrate 20 in the second mold 200B are bonded to both edges of the first light shielding film 19A.
　すなわち、検出基板部２０と第１のインジケータ１７Ａが対向するように、第１の型枠２００Ａと第２の型枠２００Ｂが重ね合わせて、検出基板部２０の両側端部と遮光膜１９Ａ，１９Ｂの両側端部を接着する。なお、型枠２００Ａ，２００Ｂに検出基板部２０を載置する順番および検出基板部２０の両側端部と遮光膜１９Ａ，１９Ｂの両側端部を接着する手順は、特に問わないものとする。 That is, the first mold frame 200A and the second mold frame 200B are overlapped so that the detection substrate unit 20 and the first indicator 17A face each other, and both end portions of the detection substrate unit 20 and the light shielding films 19A and 19B are overlapped. Glue both side edges. The order in which the detection substrate unit 20 is placed on the molds 200A and 200B and the procedure for bonding the both side ends of the detection substrate unit 20 and the both side ends of the light shielding films 19A and 19B are not particularly limited.
　こうして、図１３に示すように、型枠２００Ａ，２００Ｂを取り外すことで、断面が半円形状（円弧状）の２つの遮光膜１９Ａ，１９Ｂに覆われ、中央に検出基板部２０を挟んで上下に部分円柱状のインジケータ１７Ａ，１７Ｂが設けられた蛍光センサ４の一部が完成する。 Thus, as shown in FIG. 13, by removing the molds 200A and 200B, the light shielding films 19A and 19B having a semicircular cross section (arc shape) are covered, and the detection substrate unit 20 is sandwiched between the upper and lower sides. A part of the fluorescent sensor 4 provided with the partial cylindrical indicators 17A and 17B is completed.
　そして、検出基板部２０の先端部と先端枠２１を嵌合して接着して、先端枠２１の周端部と遮光膜１９Ａ，１９Ｂの円弧状先端部分を接着する。また、検出基板部２０の基端部と基端枠２２を嵌合して接着して、先端枠２１の周端部と遮光膜１９Ａ，１９Ｂの円弧状基端部分を接着する。こうして、蛍光センサ４が制作される。 Then, the distal end portion of the detection substrate portion 20 and the distal end frame 21 are fitted and adhered, and the peripheral end portion of the distal end frame 21 and the arc-shaped distal end portions of the light shielding films 19A and 19B are adhered. Further, the base end portion of the detection substrate portion 20 and the base end frame 22 are fitted and bonded, and the peripheral end portion of the front end frame 21 and the arc-shaped base end portions of the light shielding films 19A and 19B are bonded. Thus, the fluorescence sensor 4 is produced.
　本実施形態の蛍光センサ４では、図１４に示すように、略中央に設けられた発光素子１５からの励起光Ｅを受けて、２つのインジケータ１７Ａ，１７Ｂからアナライト９の濃度に応じて発生した蛍光ＦがＰＤ素子１２に入射する。このとき、アナライト９の濃度に応じて発光する蛍光Ｆ１，Ｆ２は、第１のインジケータ１７Ａからの蛍光Ｆ１が光透過性を有する検出基板部２０を介してＰＤ素子１２の上面に、第２のインジケータ１７Ｂからの蛍光Ｆ２がＰＤ素子１２の下面によって検出される。そのため、蛍光センサ４は、発光素子１５からの励起光Ｅが部分円柱形状の２つのインジケータ１７Ａ，１７Ｂに均一に照射され、従来の蛍光センサ１０４よりも高感度となる。すなわち、蛍光センサ４は、発光素子１５を挟んで上下方向にインジケータ１７Ａ，１７Ｂを配設して、光透過性を有する検出基板部２０にＰＤ素子１２を配置することで、発光素子１５からの励起光Ｅを効率よく利用できるため高感度となる。 In the fluorescence sensor 4 of this embodiment, as shown in FIG. 14, it receives excitation light E from the light emitting element 15 provided at the substantially center, and is generated from the two indicators 17A and 17B according to the concentration of the analyte 9. The fluorescence F thus made enters the PD element 12. At this time, the fluorescences F1 and F2 that emit light according to the concentration of the analyte 9 are supplied to the upper surface of the PD element 12 via the detection substrate unit 20 in which the fluorescence F1 from the first indicator 17A has optical transparency. The fluorescent light F2 from the indicator 17B is detected by the lower surface of the PD element 12. Therefore, the fluorescence sensor 4 is evenly irradiated with the excitation light E from the light emitting element 15 on the two partial cylinder-shaped indicators 17A and 17B, and has higher sensitivity than the conventional fluorescence sensor 104. In other words, the fluorescent sensor 4 is provided with indicators 17A and 17B in the vertical direction with the light emitting element 15 interposed therebetween, and the PD element 12 is disposed on the light-transmitting detection substrate unit 20 to thereby remove the light from the light emitting element 15. Since the excitation light E can be used efficiently, the sensitivity becomes high.
　さらに、蛍光センサ４は、略円柱形状として、インジケータ１７Ａ，１７Ｂのそれぞれの表面が円弧状に形成された部分円柱形状（断面円弧形状）をしており、これらインジケータ１７Ａ，１７Ｂの表面に遮光膜１９Ａ，１９Ｂで覆った構成としている。そのため、蛍光センサ４は、アナライト９が遮光膜１９Ａ，１９Ｂを介してインジケータ１７Ａ，１７Ｂへの進入する面積を大きくとれるため、インジケータ１７Ａ，１７Ｂにアナライト９が進入し易くなり、その結果、アナライト９の濃度変化に対するレスポンスが格段に向上する。 Further, the fluorescent sensor 4 has a substantially cylindrical shape, and has a partial cylindrical shape (cross-sectional arc shape) in which the respective surfaces of the indicators 17A and 17B are formed in an arc shape, and a light shielding film is formed on the surfaces of the indicators 17A and 17B. It is set as the structure covered with 19A, 19B. Therefore, the fluorescence sensor 4 can take a large area for the analyte 9 to enter the indicators 17A and 17B via the light shielding films 19A and 19B, so that the analyte 9 can easily enter the indicators 17A and 17B. Response to the concentration change of the analyte 9 is remarkably improved.
　なお、インジケータ１７Ａ，１７Ｂの形状は、部分円柱形状に限定されることなく、ドーム状とした断面多角形状などでもよい。 In addition, the shape of the indicators 17A and 17B is not limited to the partial cylindrical shape, and may be a polygonal cross-sectional shape such as a dome shape.
＜第２実施形態＞
　次に、第２実施形態の蛍光センサ４Ａ～４Ｃについて説明する。蛍光センサ４Ａは蛍光センサ４と類似しているので、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 sensors 4A to 4C of the second embodiment will be described. Since the fluorescence sensor 4A is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals and description thereof is omitted.
　本実施形態の蛍光センサ４Ａは、第１実施形態の蛍光センサ４と比較すると、検出基板部２０の上下に遮光膜１９Ａ，１９Ｂで覆われたインジケータ１７Ａ，１７Ｂが設けられている点では同じであるが、図１５に示すように、検出基板部２０の上下面に光電変換素子であるＰＤ素子１２Ａ，１２Ｂが形成されている点で異なっている。 Compared with the fluorescent sensor 4 of the first embodiment, the fluorescent sensor 4A of the present embodiment is the same in that indicators 17A and 17B covered with light shielding films 19A and 19B are provided above and below the detection substrate unit 20. However, as shown in FIG. 15, the difference is that PD elements 12 </ b> A and 12 </ b> B, which are photoelectric conversion elements, are formed on the upper and lower surfaces of the detection substrate unit 20.
　具体的には、検出基板部２０は、上面に実装される発光素子１５を避けた位置に第１のＰＤ素子１２Ａが形成され、下面に第１実施形態と同じように発光素子１５からの励起光Ｅが透過して第２のインジケータ１７Ｂ側に入射するよう発光素子１５の略中央に対向した一部分に孔部１２ａが設けられた第２のＰＤ素子１２Ｂが形成されている。 Specifically, in the detection substrate unit 20, the first PD element 12A is formed at a position avoiding the light emitting element 15 mounted on the upper surface, and excitation from the light emitting element 15 is performed on the lower surface as in the first embodiment. A second PD element 12B provided with a hole 12a is formed in a portion facing substantially the center of the light emitting element 15 so that the light E is transmitted and incident on the second indicator 17B side.
　このとき、ＰＤ素子１２Ａ，１２Ｂは、第１実施形態と同様に、ペンタセン等の有機半導体を蒸着法または塗布法で形成した後、部分的に不純物をドープすることにより作製される。 At this time, as in the first embodiment, the PD elements 12A and 12B are manufactured by forming an organic semiconductor such as pentacene by a vapor deposition method or a coating method and then partially doping impurities.
　ここでも、ＰＤ素子１２表面上には、励起光Ｅが入射するのを防止するために、蛍光Ｆを透過し励起光Ｅを遮るフィルタが形成されている（不図示）。フィルタとしては、例えば、波長３７５ｎｍの励起光Ｅは遮断するが、波長４６０ｎｍの蛍光Ｆは透過する光吸収型フィルタを用いることが好ましい。 Also here, a filter that transmits the fluorescence F and blocks the excitation light E is formed on the surface of the PD element 12 in order to prevent the excitation light E from entering (not shown). As the filter, for example, it is preferable to use a light absorption filter that blocks excitation light E having a wavelength of 375 nm but transmits fluorescence F having a wavelength of 460 nm.
　ここでの蛍光センサ４Ａでは、第１実施形態と同様に、上下の遮光膜１９Ａ，１９Ｂからアナライト９がインジケータ１７Ａ，１７Ｂに進入する。そして、発光素子１５で上下左右方向に発光する励起光Ｅにより、インジケータ１７Ａ，１７Ｂからアナライト９の濃度に応じた蛍光Ｆが発生し、上方に位置する第１のインジケータ１７Ａから下方に出射する蛍光Ｆ１が検出基板部２０の上面に形成された第１のＰＤ素子１２Ａにより検出され、下方に位置する第２のインジケータ１７Ｂから上方に出射する蛍光Ｆ２が検出基板部２０の下面に形成された第２のＰＤ素子１２Ｂにより検出される。 In this fluorescent sensor 4A, as in the first embodiment, the analyte 9 enters the indicators 17A and 17B from the upper and lower light shielding films 19A and 19B. The fluorescent light F corresponding to the concentration of the analyte 9 is generated from the indicators 17A and 17B by the excitation light E emitted in the vertical and horizontal directions by the light emitting element 15, and is emitted downward from the first indicator 17A located above. The fluorescence F1 is detected by the first PD element 12A formed on the upper surface of the detection substrate unit 20, and the fluorescence F2 emitted upward from the second indicator 17B located below is formed on the lower surface of the detection substrate unit 20. It is detected by the second PD element 12B.
　以上から本実施形態の蛍光センサ４Ａは、第１実施形態の蛍光センサ４の効果に加え、インジケータ１７Ａ，１７Ｂからの蛍光Ｆ１，Ｆ２を個別に受光する２つのＰＤ素子１２Ａ，１２Ｂを形成することで、より高感度となる。 From the above, the fluorescence sensor 4A of the present embodiment forms the two PD elements 12A and 12B that individually receive the fluorescence F1 and F2 from the indicators 17A and 17B in addition to the effects of the fluorescence sensor 4 of the first embodiment. With higher sensitivity.
　なお、検出基板部２０が光透過性を有していなくとも、例えば、図１７に示すように、ここでの蛍光センサ４Ｂは、発光素子１５Ａ，１５Ｂが実装され、発光素子１５Ａ，１５Ｂの実装面にＰＤ素子１２Ａ，１２Ｂが形成された２つの検出基板部２０Ａ，２０Ｂを上下方向に貼り合わせた構成としてもよい。なお、このときの発光素子１５は、インジケータ１７Ａ，１７Ｂの部分円柱形状に合わせてレンズ、封止樹脂などにより、インジケータ１７Ａ，１７Ｂに対して励起光Ｅが均一に照射されるように形状を最適化して、例えば、砲弾形状、部分円柱形状としたドーム状、多角形状等とすることが好ましい。 Even if the detection substrate unit 20 does not have optical transparency, for example, as shown in FIG. 17, the fluorescent sensor 4B here has the light emitting elements 15A and 15B mounted thereon and the light emitting elements 15A and 15B mounted thereon. It is good also as a structure which bonded together two detection board | substrate parts 20A and 20B in which PD element 12A, 12B was formed in the surface up and down. Note that the light emitting element 15 at this time is optimally shaped so that the excitation light E is uniformly irradiated to the indicators 17A and 17B by a lens, sealing resin, or the like according to the partial cylindrical shape of the indicators 17A and 17B. For example, it is preferable to form a dome shape, a polygonal shape, or the like having a bullet shape, a partial cylindrical shape, or the like.
　検出基板部２０としては、シリコン基板が好適である。このとき、ＰＤ素子１２Ａ，１２Ｂは、例えば、ｎ型シリコン半導体にｐ型拡散領域を形成した構造からなる。 As the detection substrate unit 20, a silicon substrate is suitable. At this time, the PD elements 12A and 12B have a structure in which a p-type diffusion region is formed in an n-type silicon semiconductor, for example.
　あるいは、透明基板や複合材料もしくは金属板などであってもよい。このとき、ＰＤ素子１２Ａ，１２Ｂは、基板上に有機半導体を蒸着法または塗布法で形成した後、部分的に不純物をドープすることにより作製される。 Alternatively, it may be a transparent substrate, a composite material or a metal plate. At this time, the PD elements 12A and 12B are manufactured by forming an organic semiconductor on a substrate by a vapor deposition method or a coating method and then partially doping impurities.
　さらに、図１８に示すように、ここでの蛍光センサ４Ｃは、発光素子１５からの励起光Ｅが第２のインジケータ１７Ｂ側に入射するよう検出基板部２０の発光素子１５が設けられた対向する一部分に孔部２０ａを設けてもよい。すなわち、図１８の構成においては、検出基板部２０に形成された孔部２０ａを通過した励起光Ｅが第２のインジケータ１７Ｂに入射される。なお、検出基板部２０の孔部２０ａに透明樹脂を充填してもよい。さらに、孔部２０ａが形成された２つの検出基板部２０を図１７に示したように、貼り合わせた構成としてもよい。 Further, as shown in FIG. 18, the fluorescence sensor 4 </ b> C here is opposed to the detection substrate portion 20 provided with the light emitting element 15 so that the excitation light E from the light emitting element 15 enters the second indicator 17 </ b> B side. The hole 20a may be provided in a part. That is, in the configuration of FIG. 18, the excitation light E that has passed through the hole 20a formed in the detection substrate 20 is incident on the second indicator 17B. In addition, the hole 20a of the detection substrate unit 20 may be filled with a transparent resin. Furthermore, it is good also as a structure which bonded together the two detection board | substrate parts 20 in which the hole 20a was formed as shown in FIG.
＜第３実施形態＞
　次に、第３実施形態の蛍光センサ４Ｄについて説明する。蛍光センサ４Ｄは、第１実施形態の蛍光センサ４と類似しているので、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 4D of the third embodiment will be described. Since the fluorescence sensor 4D is similar to the fluorescence sensor 4 of the first embodiment, the same components are denoted by the same reference numerals and description thereof is omitted.
　図１９および図２０に示す、本実施形態の蛍光センサ４Ｄは、第１実施形態の蛍光センサ４と比較すると、インジケータ１７Ａ，１７Ｂを覆うように、それぞれを部分円柱形状（断面円弧状）にする枠部１８Ａ，１８Ｂを設けた点が異なる。 19 and 20, the fluorescence sensor 4D of the present embodiment has a partial cylindrical shape (circular arc shape) so as to cover the indicators 17A and 17B as compared with the fluorescence sensor 4 of the first embodiment. The difference is that the frame portions 18A and 18B are provided.
　具体的には、ここでの蛍光センサ４Ｄは、インジケータ１７Ａ，１７Ｂを覆うように円弧状に形成された枠部１８Ａ，１８Ｂが設けられ、これら枠部１８Ａ，１８Ｂを覆うように遮光膜１９Ａ，１９Ｂが設けられている。枠部１８Ａ，１８Ｂは、１０μｍ厚のステンレス、フレキシブル材などから形成され、蛍光センサ４Ｄにおける長手軸方向に沿って、アナライト９がインジケータ１７Ａ，１７Ｂに進入できるように複数のスリット１８ａ，１８ｂが形成されている。 Specifically, the fluorescence sensor 4D here is provided with frame portions 18A and 18B formed in an arc shape so as to cover the indicators 17A and 17B, and the light shielding films 19A and 19B are formed so as to cover these frame portions 18A and 18B. 19B is provided. The frame portions 18A and 18B are formed of stainless steel or flexible material having a thickness of 10 μm, and a plurality of slits 18a and 18b are provided so that the analyte 9 can enter the indicators 17A and 17B along the longitudinal axis direction of the fluorescent sensor 4D. Is formed.
　枠部１８Ａ，１８Ｂは、インジケータ１７Ａ，１７Ｂの形状がそれぞれを部分円柱形状（断面円弧状）となるように変形される。なお、枠部１８Ａ，１８Ｂの側端部は、検出基板部２０の上下面に接着される。また、枠部１８Ａ，１８Ｂは、予め円弧状に形成したリジット基板でもよい。 The frame portions 18A and 18B are deformed so that the shapes of the indicators 17A and 17B are each a partial cylindrical shape (a cross-sectional arc shape). Note that the side end portions of the frame portions 18A and 18B are bonded to the upper and lower surfaces of the detection substrate portion 20. Further, the frame portions 18A and 18B may be rigid substrates formed in a circular arc shape in advance.
　また、検出基板部２０およびＰＤ素子１２は、第１または第２実施形態に記載のいずれの構成としてもよい。 Moreover, the detection substrate unit 20 and the PD element 12 may have any configuration described in the first or second embodiment.
　以上から本実施形態の蛍光センサ４Ｄは、第１実施形態の蛍光センサ４の効果に加え、遮光膜１９Ａ，１９Ｂのみでインジケータ１７Ａ，１７Ｂを覆う構成に比して、枠部１８Ａ，１８Ｂを設けることで強度が格段に向上する。 From the above, in addition to the effects of the fluorescence sensor 4 of the first embodiment, the fluorescence sensor 4D of the present embodiment is provided with the frame portions 18A and 18B as compared with the configuration in which the indicators 17A and 17B are covered only by the light shielding films 19A and 19B. As a result, the strength is remarkably improved.
　なお、枠部１８Ａ，１８Ｂは、複数のスリット１８ａ，１８ｂを蛍光センサ４Ｄにおける長手軸方向に沿った方向に限定されることなく、例えば、図２１に示すように、蛍光センサ４Ｄにおける短手軸方向に沿ったスリット１８ｃ，１８ｄとしてもよい。また、枠部１８Ａ，１８Ｂに形成される複数のスリットは、螺旋状、格子状など如何なる形状でもよい。さらに、枠部１８Ａ，１８Ｂは、図２２に示すように、金属等から形成されたメッシュ構造としてもよい。 The frame portions 18A and 18B are not limited to the plurality of slits 18a and 18b in the direction along the longitudinal axis direction of the fluorescence sensor 4D. For example, as shown in FIG. 21, the short axis of the fluorescence sensor 4D is used. It is good also as the slits 18c and 18d along a direction. The plurality of slits formed in the frame portions 18A and 18B may have any shape such as a spiral shape or a lattice shape. Further, the frame portions 18A and 18B may have a mesh structure formed of metal or the like as shown in FIG.
＜第４実施形態＞
　次に、第４実施形態の蛍光センサ４Ｅ，４Ｆについて説明する。蛍光センサ４Ｅは、第１実施形態および第３実施形態の蛍光センサ４，４Ｄと類似しているので、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 sensors 4E and 4F of the fourth embodiment will be described. Since the fluorescence sensor 4E is similar to the fluorescence sensors 4 and 4D of the first embodiment and the third embodiment, the same components are denoted by the same reference numerals and description thereof is omitted.
　図２３に示す、本実施形態の蛍光センサ４Ｅは、第１実施形態および第３実施形態の蛍光センサ４，４Ｄと比較すると、ＰＤ素子１２Ａ，１２Ｂを枠部１８Ａ，１８Ｂに設けた点が異なる。 The fluorescent sensor 4E of this embodiment shown in FIG. 23 differs from the fluorescent sensors 4 and 4D of the first and third embodiments in that PD elements 12A and 12B are provided in the frame portions 18A and 18B. .
　具体的には、枠部１８Ａ，１８Ｂのインジケータ１７Ａ，１７Ｂに対向して接触する内面側に複数のＰＤ素子１２Ａ，１２Ｂを形成している。すなわち、上方の枠部１８Ａに形成された複数のＰＤ素子１２Ａが上方に位置する第１のインジケータ１７Ａから放射状に出射する蛍光を検出し、下方の枠部１８Ｂに形成された複数のＰＤ素子１２Ｂが下方に位置する第２のインジケータ１７Ｂから放射状に出射する蛍光を検出する。 More specifically, a plurality of PD elements 12A and 12B are formed on the inner surface side that faces and contacts the indicators 17A and 17B of the frame portions 18A and 18B. That is, the plurality of PD elements 12A formed on the lower frame portion 18A detect the fluorescence emitted radially from the first indicator 17A located above, and the plurality of PD elements 12B formed on the lower frame portion 18B. Detects the fluorescence emitted radially from the second indicator 17B located below.
　枠部１８Ａ，１８Ｂは、発光素子１５が実装された透明樹脂、ガラスなどの透明部材から形成されている基板部２０Ｃの上下面に接着される。また、枠部１８Ａ，１８Ｂは、予め円弧状に形成したリジット基板でもよい。 The frame portions 18A and 18B are bonded to the upper and lower surfaces of the substrate portion 20C formed of a transparent member such as a transparent resin or glass on which the light emitting element 15 is mounted. Further, the frame portions 18A and 18B may be rigid substrates formed in a circular arc shape in advance.
　また、図２４に示すように、蛍光センサ４Ｆにおけるここでの枠部１８Ｃ，１８Ｄは、シリコン等から形成されたリジット基板またはフレキシブル基板にＰＤ素子１２Ａ，１２Ｂを形成した複数の基板部３１Ａ，３１Ｂをフレキシブル基板３２Ａ，３２Ｂで連結して断面円弧状（半円形状）のドーム形状に形成した構成となっている。すなわち、枠部１８Ｃ，１８Ｄは、インジケータ１７Ａ，１７Ｂが部分円柱形状（断面円弧状）となるように、インジケータ１７Ａ，１７Ｂを覆うように配設される。枠部１８Ｃ，１８Ｄは、発光素子１５が実装された透明樹脂、ガラスなどの透明部材から形成されている基板部２０Ｃの上下面に接着される。 Further, as shown in FIG. 24, the frame portions 18C and 18D in the fluorescent sensor 4F are a plurality of substrate portions 31A and 31B in which PD elements 12A and 12B are formed on a rigid substrate or a flexible substrate formed of silicon or the like. Are connected to each other by flexible substrates 32A and 32B to form a dome shape having a circular arc cross section (semicircular shape). That is, the frame portions 18C and 18D are disposed so as to cover the indicators 17A and 17B so that the indicators 17A and 17B have a partial columnar shape (circular arc shape). The frame portions 18C and 18D are bonded to the upper and lower surfaces of the substrate portion 20C formed from a transparent member such as a transparent resin or glass on which the light emitting element 15 is mounted.
　なお、ここでの枠部１８Ｃ，１８Ｄは、基板部３１Ａ，３１Ｂ、ＰＤ素子１２Ａ，１２Ｂおよびフレキシブル基板３２Ａ，３２Ｂがアナライト９を含む体液がインジケータ１７Ａ，１７Ｂに進入できるように、図示しない微少貫通孔が形成されている。すなわち、枠部１８Ｃ，１８Ｄは、体液が通過可能である。また、枠部１８Ｃ，１８Ｄを覆う遮光膜１９Ａ，１９Ｂを設けてもよい。 Here, the frame portions 18C and 18D are not shown so that the substrate portions 31A and 31B, the PD elements 12A and 12B and the flexible substrates 32A and 32B can enter the body fluid containing the analyte 9 into the indicators 17A and 17B. A through hole is formed. That is, body fluid can pass through the frame portions 18C and 18D. Further, light shielding films 19A and 19B that cover the frame portions 18C and 18D may be provided.
　枠部１８Ｃ，１８Ｄの微少貫通孔の大きさ、形状、位置、及び形成密度は、仕様により適宜、選択される。例えば、微少貫通孔は、整然と配列している必要はない。また、微少貫通孔を上面から観察したときの開口部の形状は、円形、矩形、または多角形等のいずれでもよい。 The size, shape, position, and formation density of the minute through holes of the frame portions 18C and 18D are appropriately selected according to the specifications. For example, the minute through holes do not need to be arranged in an orderly manner. Moreover, the shape of the opening when the minute through hole is observed from the upper surface may be any of a circle, a rectangle, a polygon, and the like.
　このように微少貫通孔が形成された２つの枠部１８Ｃ，１８Ｄは、例えば、シリコン板またはシリコン膜等に、微少貫通孔をパターニング形成することにより作製される。具体的には、微少貫通孔は、シリコン板等の表面に、フォトリソグラフィまたは自己組織化膜等によりエッチングマスクを形成した後に、ＩＣＰ－ＲＩＥ等のドライエッチングにより作製できる。微少貫通孔の形成には、マイクロドリル等による機械加工法を用いてもよい。 The two frame portions 18C and 18D in which the minute through holes are formed in this way are produced by patterning the minute through holes on, for example, a silicon plate or a silicon film. Specifically, the minute through hole can be formed by dry etching such as ICP-RIE after an etching mask is formed on the surface of a silicon plate or the like by photolithography or a self-assembled film. For forming the minute through hole, a machining method using a micro drill or the like may be used.
　また、枠部１８Ｃ，１８Ｄには、アナライトを含む溶液が通過可能な多孔質半導体を用いてもよい。なお、多孔質とは構造中に外部と接続された空隙およびと気孔をもつ材料を意味する。空隙／気孔の、大きさ、分布及び形状は、溶液が通過可能であれば、規則性を有している必要はない。 Further, a porous semiconductor that can pass a solution containing an analyte may be used for the frame portions 18C and 18D. The porous means a material having voids and pores connected to the outside in the structure. The size, distribution, and shape of the voids / pores need not be regular as long as the solution can pass through.
　枠部１８Ｃ，１８Ｄの開気孔率は５～７５体積％が好ましく、特に好ましくは２０～５０体積％である。前記範囲以上であれば、体液が通過しやすく、前記範囲以下であれば所望の機械的強度が得られる。なお、開気孔率は、アルキメデス法により測定した値である。 The open porosity of the frame portions 18C and 18D is preferably 5 to 75% by volume, particularly preferably 20 to 50% by volume. If it is more than the said range, a bodily fluid will pass easily, and if it is below the said range, desired mechanical strength will be obtained. The open porosity is a value measured by Archimedes method.
　なお、蛍光センサ４Ｅ，４ＦのＰＤ素子は、シリコン基板上に作製されることが望ましいが、遮光された透明基板や複合材料あるいは金属板に有機半導体を蒸着法または塗布法で形成した後、部分的に不純物をドープすることにより作製されてもよい。 The PD elements of the fluorescent sensors 4E and 4F are preferably fabricated on a silicon substrate. However, after forming an organic semiconductor by vapor deposition or coating on a light-shielded transparent substrate, composite material, or metal plate, Alternatively, it may be produced by doping impurities.
　また、発光素子１５は基板部２０Ｃの上面にのみ実装されているが、基板部２０Ｃの両面に実装されてもよいことは勿論である。この場合、基板部２０Ｃは、透明部材ではなく非透明部材から形成してもよい。 Further, although the light emitting element 15 is mounted only on the upper surface of the substrate portion 20C, it is needless to say that it may be mounted on both surfaces of the substrate portion 20C. In this case, the substrate portion 20C may be formed from a non-transparent member instead of a transparent member.
　さらに、基板部２０Ｃは、第２実施の形態の図１７および図１８に示したいずれの構成としてもよい。　以上から本実施形態の蛍光センサ４Ｅ，４Ｆは、いずれも第１実施形態および第３実施形態の蛍光センサ４，４Ｄの効果に加え、インジケータ１７Ａ，１７Ｂからの蛍光Ｆ１，Ｆ２を個別に受光する複数のＰＤ素子１２Ａ，１２Ｂを枠部１８，１８Ａ～１８Ｄに形成することで、より高感度となる。なお、以上の構成は、第３の実施の形態にて述べた、予め円弧状に形成したリジット基板の枠部１８Ａ，１８Ｂにも適用することができる。 Furthermore, the substrate section 20C may have any configuration shown in FIGS. 17 and 18 of the second embodiment. As described above, the fluorescence sensors 4E and 4F of the present embodiment individually receive the fluorescence F1 and F2 from the indicators 17A and 17B in addition to the effects of the fluorescence sensors 4 and 4D of the first embodiment and the third embodiment. By forming the plurality of PD elements 12A and 12B in the frame portions 18 and 18A to 18D, higher sensitivity is achieved. Note that the above configuration can also be applied to the frame portions 18A and 18B of the rigid substrate previously formed in an arc shape described in the third embodiment.
　以上の説明では、グルコース等の糖類を検出するセンサを例に説明したが、蛍光センサは、蛍光色素の選択によって、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している。 In the above description, a sensor that detects saccharides such as glucose has been described as an example. However, a fluorescent sensor can be used for various applications such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye. ing.
　すなわち、本発明は、上述した実施形態及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。 That is, 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.

Claims (10)

  1. 　基板部と、
    　前記基板部を挟んで配設され、励起光を受光してアナライトの濃度に応じた強度の蛍光を発生し、外形が部分円柱形状を呈する２つのインジケータと、
    　前記基板部に実装され励起光を発生する発光素子と、
    　前記蛍光を電気信号に変換する光電変換素子と、
    　を備えたことを特徴とする蛍光センサ。     A substrate section;
    Two indicators disposed between the substrate portions, receiving excitation light, generating fluorescence having an intensity according to the concentration of the analyte, and having an outer shape of a partial cylindrical shape;
    A light emitting element mounted on the substrate unit for generating excitation light;
    A photoelectric conversion element for converting the fluorescence into an electrical signal;
    A fluorescent sensor comprising:
  2. 　前記２つのインジケータは、前記基板部に接着された前記アナライトが通過する遮光膜に覆われて前記部分円柱形状を呈することを特徴とする請求項１に記載の蛍光センサ。 The fluorescent sensor according to claim 1, wherein the two indicators are covered with a light-shielding film through which the analyte adhered to the substrate portion passes and have the partial cylindrical shape.
  3. 　前記２つのインジケータは、前記基板部に接着された前記アナライトが通過自在な枠部に覆われて前記部分円柱形状を呈することを特徴とする請求項１または請求項２に記載の蛍光センサ。 The fluorescent sensor according to claim 1 or 2, wherein the two indicators are covered with a frame part through which the analyte bonded to the substrate part can pass and have the partial cylindrical shape.
  4. 　前記枠部には、スリットが形成されてい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 a slit is formed in the frame portion.
  5. 　前記枠部は、メッシュ状であることを特徴とする請求項３に記載の蛍光センサ。 4. The fluorescent sensor according to claim 3, wherein the frame portion has a mesh shape.
  6. 　前記光電変換素子が前記２つのインジケータの少なくとも１つに対向して接触するように形成されていることを特徴とする請求項１から請求項５のいずれかに記載の蛍光センサ。 The fluorescent sensor according to any one of claims 1 to 5, wherein the photoelectric conversion element is formed so as to face and contact at least one of the two indicators.
  7. 　前記光電変換素子が前記基板部に形成されていることを特徴とする請求項６に記載の蛍光センサ。 The fluorescence sensor according to claim 6, wherein the photoelectric conversion element is formed on the substrate portion.
  8. 　前記光電変換素子が前記枠部に形成されていることを特徴とする請求項６に記載の蛍光センサ。 The fluorescence sensor according to claim 6, wherein the photoelectric conversion element is formed in the frame portion.
  9. 　前記基板部は、光透過性を有していることを特徴とする請求項７に記載の蛍光センサ。 The fluorescent sensor according to claim 7, wherein the substrate portion has light permeability.
  10. 　前記基板部は、前記発光素子が設けられた一部に励起光が通過するための孔部を有していることを特徴とする請求項７に記載の蛍光センサ。 8. The fluorescent sensor according to claim 7, wherein the substrate part has a hole part through which excitation light passes through a part where the light emitting element is provided.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019074451A (en) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 Light measuring device

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2768913A1 (en) * 1998-08-26 2000-03-09 Sensors For Medicine And Science, Inc. Optical-based sensing devices
JP2004529352A (en) * 2001-05-04 2004-09-24 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 Electro-optical sensor device with reference passage
JP2012093128A (en) * 2010-10-25 2012-05-17 Olympus Corp Fluorescence sensor
JP2012520087A (en) * 2009-04-13 2012-09-06 オリンパス株式会社 Fluorescence sensor, needle-type fluorescence sensor, and analyte measurement method

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2768913A1 (en) * 1998-08-26 2000-03-09 Sensors For Medicine And Science, Inc. Optical-based sensing devices
JP2002523774A (en) * 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 Optical detector
JP2004529352A (en) * 2001-05-04 2004-09-24 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 Electro-optical sensor device with reference passage
JP2012520087A (en) * 2009-04-13 2012-09-06 オリンパス株式会社 Fluorescence sensor, needle-type fluorescence sensor, and analyte measurement method
JP2012093128A (en) * 2010-10-25 2012-05-17 Olympus Corp Fluorescence sensor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019074451A (en) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 Light measuring device

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