WO2014045384A1 - Capteur de lumière fluorescente - Google Patents

Capteur de lumière fluorescente 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
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PCT/JP2012/074175
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English (en)
Japanese (ja)
Inventor
亮 太田
憲治 宮田
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テルモ株式会社
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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/fr
Publication of WO2014045384A1 publication Critical patent/WO2014045384A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—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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  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Physics & Mathematics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Optics & Photonics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)

Abstract

Cette invention concerne un capteur de lumière fluorescente (4) comprenant : une partie substrat (20) ; deux indicateurs (17A, 17B) placés de façon à prendre la partie substrat (20) en sandwich, qui reçoivent la lumière d'excitation (E), génèrent une lumière fluorescente (F) d'une intensité correspondant à la concentration d'un analyte (9), et ayant un extérieur partiellement cylindrique ; un élément électroluminescent (15) fixé sur la partie substrat (20) et qui génère la lumière d'excitation (E) ; et un élément de conversion photoélectrique (12) qui convertit la lumière fluorescente (F) en signal électrique.
PCT/JP2012/074175 2012-09-21 2012-09-21 Capteur de lumière fluorescente WO2014045384A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019074451A (ja) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 光計測装置

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2768913A1 (fr) * 1998-08-26 2000-03-09 Sensors For Medicine And Science, Inc. Dispositifs de detection optique
JP2004529352A (ja) * 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 参照通路を備えたエレクトロオプティカルセンサ装置
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ
JP2012520087A (ja) * 2009-04-13 2012-09-06 オリンパス株式会社 蛍光センサ、針型蛍光センサ、およびアナライトの計測方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2768913A1 (fr) * 1998-08-26 2000-03-09 Sensors For Medicine And Science, Inc. Dispositifs de detection optique
JP2002523774A (ja) * 1998-08-26 2002-07-30 センサーズ・フォー・メデセン・アンド・サイエンス・インコーポレーテッド 光学式検知装置
JP2004529352A (ja) * 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 参照通路を備えたエレクトロオプティカルセンサ装置
JP2012520087A (ja) * 2009-04-13 2012-09-06 オリンパス株式会社 蛍光センサ、針型蛍光センサ、およびアナライトの計測方法
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019074451A (ja) * 2017-10-18 2019-05-16 浜松ホトニクス株式会社 光計測装置

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