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WO2014045386A1 - Capteur de lumière fluorescente - Google Patents

Capteur de lumière fluorescente Download PDF

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Publication number
WO2014045386A1
WO2014045386A1 PCT/JP2012/074177 JP2012074177W WO2014045386A1 WO 2014045386 A1 WO2014045386 A1 WO 2014045386A1 JP 2012074177 W JP2012074177 W JP 2012074177W WO 2014045386 A1 WO2014045386 A1 WO 2014045386A1
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WO
WIPO (PCT)
Prior art keywords
sensor
fluorescence
indicator
light
fluorescent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2012/074177
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English (en)
Japanese (ja)
Inventor
亮 太田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Terumo Corp
Original Assignee
Terumo Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Terumo Corp filed Critical Terumo Corp
Priority to PCT/JP2012/074177 priority Critical patent/WO2014045386A1/fr
Publication of WO2014045386A1 publication Critical patent/WO2014045386A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0071—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by measuring fluorescence emission
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter
    • A61B5/14735—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter comprising an immobilised reagent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
    • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
    • A61B5/6848—Needles
    • 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 the 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.
  • the fluorescent dye changes its property due to the presence of the analyte, and generates fluorescence having an intensity corresponding to the analyte concentration when receiving excitation light.
  • a small-sized fluorometer has a light source, a photodetector, and an indicator containing a fluorescent dye.
  • the excitation light from a light source is irradiated to the indicator in which the analyte in a to-be-measured solution can go in and out, and the photodetector receives the fluorescence which an indicator produces.
  • the photodetector is a photoelectric conversion element and outputs an electrical signal corresponding to the received light intensity.
  • the analyte concentration in the solution is calculated based on the electrical signal from the photodetector.
  • microfluorometer manufactured using semiconductor manufacturing technology and MEMS technology.
  • the microfluorometer is referred to as “fluorescence sensor”.
  • the fluorescent sensor 104 shown in FIGS. 1 and 2 is disclosed in International Publication No. 2010/119916.
  • the sensor unit 110 which is a main functional unit of the fluorescence sensor 104 includes a silicon substrate 111 on which a photoelectric conversion element 112 is formed, a transparent intermediate layer 113, a filter layer 114, a light emitting element 115, a transparent protective layer 116, An indicator 117 and a light shielding layer 118 are provided.
  • the analyte 9 passes through the light shielding layer 118 and enters the indicator 117.
  • the filter layer 114 of the fluorescence sensor 104 blocks excitation light and transmits fluorescence. Further, the light emitting element 115 transmits fluorescence.
  • the indicator 117 In the fluorescence sensor 104, when the excitation light E generated by the light emitting element 115 enters the indicator 117, the indicator 117 generates fluorescence F corresponding to the analyte concentration.
  • a part of the fluorescence F generated by the indicator 117 passes through only the light emitting element 115 and the filter layer 114 or 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.
  • An object of the present invention is to provide a fluorescent sensor with high detection sensitivity.
  • the fluorescent sensor of the embodiment receives an excitation light and generates an intensity of fluorescence according to the concentration of the analyte, and converts the fluorescence disposed below and on the side of the indicator into an electrical signal.
  • a photoelectric conversion element having an opening; a light emitting element that is disposed below the photoelectric conversion element and irradiates the indicator with the excitation light through the opening; and a light shielding layer that covers an upper surface of the indicator .
  • FIG. 5 is a cross-sectional view of the sensor portion of the fluorescent sensor according to the first embodiment, taken along line VV in FIG. 4. It is a top view of the recessed part of the fluorescence sensor of 1st Embodiment. It is sectional drawing of the sensor part for demonstrating the manufacturing method of the fluorescence sensor of 1st Embodiment.
  • the sensor system 1 includes a fluorescent sensor 4, a main body 2, and a receiver 3 that receives and stores a signal from the main body 2. Transmission / reception of signals between the main body 2 and the receiver 3 is performed wirelessly or by wire.
  • the fluorescent sensor 4 includes a needle portion 7 that is punctured by a subject and a connector portion 8 that is joined to the rear end portion of the needle portion 7.
  • the needle part 7 has an elongated needle body part 6 and a needle tip part 5 including a sensor part 10 which is a main function part. Needle tip 5, needle body 6, and connector 8 may be integrally formed of the same material, or may be separately produced and joined.
  • the connector part 8 is detachably fitted to the fitting part 2A of the main body part 2.
  • the plurality of wirings 60 extending from the sensor unit 10 of the fluorescent sensor 4 are electrically connected to the main body unit 2 when the connector unit 8 is mechanically fitted to the fitting unit 2A of the main body unit 2. .
  • the fluorescent sensor 4 is a needle type sensor that can continuously measure the analyte concentration for a predetermined period, for example, one week after the sensor unit 10 is inserted into the body. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.
  • the main body unit 2 includes a control unit 2B that performs driving and control of the sensor unit 10, and a calculation unit 2C that processes a signal output from the sensor unit 10. Note that at least one of the control unit 2B and the calculation unit 2C may be disposed on the connector unit 8 of the fluorescent sensor 4 or the receiver 3.
  • the main body 2 further includes a wireless antenna for transmitting / receiving a wireless signal to / 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 fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject.
  • the sensor unit 10 includes a substrate unit 40, an indicator 17, a light emitting element 15, a light shielding layer 18, and a light leakage prevention unit 19.
  • the indicator 17 When the indicator 17 receives the excitation light from the light emitting element 15, the indicator 17 generates fluorescence having an intensity corresponding to the concentration of the analyte that has entered through the light shielding layer 18.
  • a bottomed recess 40XA is formed in the first main surface 40SA of the substrate portion 40, and a through hole 40XB is formed on the bottom surface of the recess 40XA so as to be inserted into the second main surface 40SB.
  • the substrate portion 40 is formed with a recess 40XA having a part of the through hole 40XB.
  • the indicator 17 is disposed in the recess 40XA.
  • the light emitting element 15 is mounted on the second main surface 40SB so as to cover a region immediately below the opening of the through hole 40XB.
  • the light shielding layer 18 is disposed so as to cover the opening of the recess 40XA of the first main surface 40SA.
  • the light leakage prevention unit 19 is disposed so as to cover the light emitting element 15.
  • the light receiving part 12T of the PD element 12 which is a photoelectric conversion element for converting fluorescence into an electric signal is disposed below and on the side of the indicator 17, in other words, on the wall surface and bottom surface of the recess 40XA.
  • the PD element 12 includes a light receiving part 12T and a low-resistance region 12H having a high conductivity in which impurities are partially introduced.
  • the light receiving part 12T is referred to as a PD element 12.
  • the PD element 12 (12T) has an opening 12X because the PD element 12 (12T) is not disposed in the opening on the bottom surface of the recess 40XA, that is, the through hole 40XB.
  • the light emitting element 15 is disposed below the PD element 12 and irradiates the indicator 17 with excitation light through the opening 12X of the PD element 12.
  • a filter 14 that transmits fluorescence and blocks excitation light covers the wall surfaces of the PD element 12 and the through hole 40XB.
  • the filter 14 also covers a region irradiated with excitation light on the second main surface 40SB of the substrate unit 40.
  • the filter 14 blocks excitation light having a wavelength of 375 nm, for example, but transmits fluorescence having a wavelength of 460 nm.
  • the second main surface 40SB of the substrate unit 40 includes a wiring 51 for supplying a driving signal, which is connected to the external electrode 15T of the light emitting element 15, and wirings 61 and 62 for transmitting a detection signal of the PD element 12.
  • a wiring 60 is provided.
  • the electrical connection portion between the wiring 51 and the external electrode 15T of the light emitting element 15 is sealed with the resin 13.
  • a transparent resin 13 such as a silicone resin or a transparent amorphous fluororesin is also filled in the through hole 40XB.
  • the indicator 17 is made of a hydrogel having a fluorescent dye that generates fluorescence having a wavelength longer than that of the excitation light by the analyte 9 and the excitation light. That is, the indicator 17 is composed of a hydrogel that contains a fluorescent dye that emits light of a light amount corresponding to the analyte concentration in the sample and that allows good transmission of excitation light and fluorescence.
  • the indicator 17 may be the analyte 9 itself that does not contain a fluorescent dye and the fluorescent dye that generates fluorescence exists in the solution.
  • Hydrogel is water such as acrylic hydrogel prepared by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel prepared from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.
  • 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.
  • an indicator is produced by polymerizing a phosphoric acid buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator in a nitrogen atmosphere for 1 hour and polymerizing.
  • 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.
  • an element that transmits fluorescence is selected from light emitting elements that emit desired excitation light, such as an LED element, an organic EL element, an inorganic EL element, or a laser diode element.
  • the light-emitting element 15 is preferably an LED element from the viewpoints of fluorescence transmittance, light generation efficiency, wide wavelength selectivity of excitation light, and generation of a small amount of light other than the wavelength having excitation action. . Furthermore, among LED elements, an ultraviolet LED element made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
  • the light shielding layer 18 prevents the excitation light E and the fluorescence F from leaking to the outside of the sensor unit 10, and at the same time prevents outside light from entering the inside of the sensor unit 10. Further, the light shielding layer 18 has biocompatibility and is hydrophilic so as not to prevent passage of body fluid containing the analyte 9.
  • a composite material is used in which hydrogel used for the indicator 17 is mixed with fine particles that do not transmit light such as carbon black or carbon nanotubes.
  • the substrate portion 40 is made of a resin material such as silicon, glass or metal having a Young's modulus of several tens to several hundreds of GPa, or polypropylene or polystyrene having a Young's modulus of about 1 GPa to 5 GPa.
  • the light leakage prevention unit 19 has a function similar to that of the light shielding layer 18, but does not need analyte permeability.
  • Fluorescent sensors 4 may be manufactured one by one, but it is preferable to manufacture a large number of sensors in a batch as a wafer process.
  • a silicon wafer 40W having an area capable of producing a plurality of elements is prepared.
  • a low resistance region 12H having high conductivity is formed by partially introducing impurities at a predetermined position of the second main surface 40SB of the silicon wafer 40W, and a connection portion 12L to be connected to the light receiving portion 12T later is formed. Is done.
  • insulating layers 41 (41A, 41B) made of, for example, silicon oxide are formed on the first main surface 40SA and the second main surface 40SB.
  • a rectangular opening 41XA is formed in the insulating layer 41A of the first main surface 40SA, and a rectangular opening 41XB is formed in the insulating layer 41B of the second main surface 40SB.
  • the recess 40XA is formed using the insulating layer 41A (opening 41XA) of the first main surface 40SA as an etching mask.
  • a wet etching method using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution or the like, or a dry method such as reactive ion etching (RIE) or chemical dry etching (CDE) is used.
  • TMAH tetramethylammonium hydroxide
  • KOH potassium hydroxide
  • CDE chemical dry etching
  • the PD element 12 (light receiving portion 12D) is formed on the wall surface and bottom surface of the recess 40XA. That is, impurity implantation is performed.
  • impurity implantation is performed after the silicon layer is formed on the wall surface and bottom surface of the recess 40XA.
  • the through hole 40XB is formed using the insulating layer 41B of the second main surface 40SB as an etching mask. Etching is performed in the same manner as the formation of the recess 40XA.
  • the shapes of the openings 41XA and 41XB that is, the opening shape of the recess 40XA and the opening shape of the through hole 40XB may be circular, elliptical, or polygonal.
  • the filter 14 is formed so as to cover the PD element 12 and the second main surface 40SB.
  • the filter 14 may be a multiple interference filter, but is preferably a light absorption filter, for example, a single layer made of silicon, silicon carbide, silicon oxide, silicon nitride, or an organic material, or the single layer It is a multilayer layer formed by laminating.
  • wiring 60 (51, 61, 62) is disposed on the second main surface 40SB.
  • the low resistance region 12H and the connection portion 12L of the PD element 12 are connected to the wirings 61 and 62 through contact holes formed in the insulating layer 41B and the filter 14.
  • the resin 13 is filled in the through hole 40XB, and the electrode 15T of the light emitting element 15 is connected to the wiring 51, whereby the light emitting element 15 is mounted on the second main surface 40SB.
  • the indicator 17 is arrange
  • a phosphoric acid buffer containing a fluorescent dye, a gel skeleton-forming material, and a polymerization initiator is filled in the recess 40XA, the opening of the recess 40XA is covered with the light shielding layer 18, and then the polymerization reaction is advanced to produce the indicator 17. May be. Moreover, you may arrange
  • the resin 13 only seals the connection portion of the light emitting element 15, and the inside of the through hole 40XB may be hollow. In this case, the resin 13 does not need to be transparent.
  • the light leakage prevention unit 19 may be the same material as the light shielding layer 18, or may be an organic resin mixed with carbon black, a metal, or a multilayer film or a composite film made of these materials.
  • the reflection light that reflects the excitation light emitted from the bottom surface and the wall surface of the light emitting element 15 upward, that is, toward the indicator 17 is used. It is also possible to give this function.
  • the light leakage prevention unit 19 may be disposed on the outer surface of the sensor unit 10 such as the entire lower surface of the substrate unit 40, the wall surface, and the upper surface not covered with the light shielding layer 18.
  • 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.
  • the excitation light E generated by the light emitting element 15 to which the drive signal is supplied via the wiring 51 enters the indicator 17 through the through hole 40XB and the opening 12X of the PD element 12.
  • the indicator 17 generates fluorescence F having a longer wavelength, for example, a wavelength of 460 nm with respect to the excitation light E having a wavelength of 375 nm.
  • the fluorescence F1 emitted downward from the indicator 17 is received by the PD element 12 on the bottom surface of the recess 40XA, and the fluorescence F2 emitted laterally from the indicator 17 is received by the PD element 12 on the wall surface of the recess 40XA and detected.
  • a signal is transmitted via the wiring 61.
  • the calculation unit 2C of the main body unit 2 performs calculation processing based on the detection signal, that is, the current caused by the photogenerated charge from the PD element 12 or the voltage caused by the accumulated photogenerated charge. Calculate the amount of light.
  • Fluorescence sensor 4 has high fluorescence light receiving efficiency and high detection sensitivity because PD element 12 receives fluorescence F1 and fluorescence F2.
  • the fluorescent sensor 4 is formed with a PD element that detects a background detection signal that is not affected by the excitation light E and the fluorescence F, a PD element that detects the intensity of the excitation light E is formed, and the temperature is detected.
  • An element to be formed may be formed.
  • the fluorescence sensor 4A of the second embodiment will be described. Since the fluorescence sensor 4A is similar to the fluorescence sensor 4B and the like, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the transparent layer 23 becomes a recess (via hole) on the bottom surface.
  • the transparent layer 23 made of silicon oxide is disposed on the PD element 12 using the CVD method or the like after the formation of the recess 40XA and before the formation of the through hole 40XB.
  • the material of the transparent layer 23 may be, for example, silicon nitride as long as it has a high excitation light transmittance.
  • the BOX layer can be the transparent layer 23. That is, the through via formed in the substrate layer can be the recess 40XA, and the through via formed in the SOI layer can be the through hole 40XB.
  • the resin 13 only seals the connection portion of the light emitting element 15, and the through hole 40XB is hollow.
  • Body fluid enters the recess 40XA in which the indicator 17 is disposed.
  • the bottom surface of the recess 40XA is sealed with the transparent layer 23. For this reason, there is no possibility that the body fluid or the like affects the electric components such as the wiring 60 disposed on the second main surface 40SB.
  • Fluorescent sensor 4A has the effect of fluorescent sensor 4 and is more reliable.
  • fluorescent sensors 4B and 4C according to modified examples of the embodiment will be described. Since the fluorescence sensors 4B and 4C are similar to the fluorescence sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.
  • FIG. 10 shows the arrangement of the through holes 40XB formed in the bottom surface of the recess 40XA, as in FIG. That is, in the fluorescent sensor 4B of the first modification, a plurality of through holes 40XB1 to 40XB3 are formed on the bottom surface. A plurality of openings 12X1 to 12X3 are formed in the PD element corresponding to the through holes 40XB1 to 40XB3.
  • the indicator 17 in the vicinity of the region directly above the through hole is irradiated with relatively strong excitation light.
  • excitation light with a more uniform intensity distribution is incident on the indicator 17, so that there is a possibility that the detection sensitivity may be lowered or deterioration with time may be accelerated. Absent.
  • the planar shape of the through holes 40XB1 to 40XB3 is not limited to a quadrangle, and may be a polygon such as a hexagon or an ellipse, or a shape such as a combination thereof. . Moreover, you may combine the through-hole from which a magnitude
  • the LED 15 has an in-plane distribution of emission intensity
  • the distribution is corrected by the opening area, shape and arrangement of the plurality of through holes, and the intensity distribution of the excitation light incident on the indicator 17 is further averaged. it can.
  • the fluorescence sensor 4 ⁇ / b> C according to the second modification includes a light scattering unit 26 that scatters excitation light irradiated on the indicator 17.
  • the light scattering portion 26 disposed in the through hole 40XB has a concave lens shape.
  • the light scattering portion 26 can be formed by utilizing a meniscus phenomenon due to surface tension with the wall surface of the through hole 40XB when a transparent resin such as liquid silicone or an inorganic glass such as SOG is disposed inside the through hole 40XB.
  • Excitation light from the LED 15 is scattered by the light scattering unit 26, and the intensity distribution of the excitation light incident on the indicator 17 is averaged. That is, the intensity of the excitation light in the indicator 17 increases in the region away from the opening 12X, the fluorescence intensity emitted from the indicator in that region increases, and the excitation light intensity in the region immediately above the opening 12X decreases.
  • a light scattering layer made of a transparent material in which metal particles are dispersed may be disposed in the opening 12X.
  • the fluorescence sensor 4C having the light scattering part 26 that averages the in-plane distribution of the excitation light intensity has higher detection sensitivity and less sensitivity reduction due to deterioration with time, in addition to the effects of the fluorescence sensor 4 and the like.
  • a sensor that detects saccharides such as glucose has been described as an example.
  • a fluorescent sensor can be used in various applications such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye. Yes.

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PCT/JP2012/074177 2012-09-21 2012-09-21 Capteur de lumière fluorescente Ceased WO2014045386A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008039655A (ja) * 2006-08-09 2008-02-21 National Institute Of Advanced Industrial & Technology 微小対象物放出光検出装置
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte
JP2012075750A (ja) * 2010-10-04 2012-04-19 Olympus Corp 生体成分測定装置
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008039655A (ja) * 2006-08-09 2008-02-21 National Institute Of Advanced Industrial & Technology 微小対象物放出光検出装置
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte
JP2012075750A (ja) * 2010-10-04 2012-04-19 Olympus Corp 生体成分測定装置
JP2012093128A (ja) * 2010-10-25 2012-05-17 Olympus Corp 蛍光センサ

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