WO2014045388A1 - Fluorescent sensor - Google Patents

Fluorescent sensor Download PDF

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Publication number
WO2014045388A1
WO2014045388A1 PCT/JP2012/074179 JP2012074179W WO2014045388A1 WO 2014045388 A1 WO2014045388 A1 WO 2014045388A1 JP 2012074179 W JP2012074179 W JP 2012074179W WO 2014045388 A1 WO2014045388 A1 WO 2014045388A1
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WO
WIPO (PCT)
Prior art keywords
fluorescence
light
emitting element
sensor
substrate
Prior art date
Application number
PCT/JP2012/074179
Other languages
French (fr)
Japanese (ja)
Inventor
亮 太田
悦朗 清水
Original Assignee
テルモ株式会社
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.)
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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/JP2012/074179 priority Critical patent/WO2014045388A1/en
Publication of WO2014045388A1 publication Critical patent/WO2014045388A1/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
    • G01N21/645—Specially adapted constructive features of fluorimeters

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 disposed in each of two substrate portions and a hollow portion formed in the two substrate portions, receives excitation light, and emits fluorescence having an intensity corresponding to the concentration of the analyte.
  • the two substrate parts comprising two indicators that generate, a light emitting element substrate part provided with a light emitting element that generates the excitation light, and one or more photoelectric conversion elements that convert the fluorescence into an electrical signal. Is formed so that the light emitting element substrate portion is sandwiched between the two indicators, and the light emitting element is disposed between the two indicators.
  • FIG. 5 is an exploded cross-sectional view taken along line VV in FIG. 4 at the distal end portion of the fluorescent sensor.
  • FIG. 5 is a cross-sectional view taken along line VV in FIG. 4 at the distal end portion of the fluorescent sensor.
  • FIG. 11 is a cross-sectional view taken along the line XI-XI in FIG. 10 at the tip of the fluorescent sensor. It is a cross-sectional schematic diagram for demonstrating operation
  • 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 includes two frame-shaped substrate portions 40A and 40B having a through-hole 40X and a transparent resin interposed between the two frame-shaped substrate portions 40A and 40B.
  • Two indicators 17A and 17B disposed in a bonding substrate portion 30 to which a wiring substrate portion 20 as a light emitting element substrate portion formed of glass or the like is bonded, and through holes 40X of the frame-like substrate portions 40A and 40B.
  • a light emitting element 15 that is disposed on the wiring board portion 20 and emits light in the vertical and horizontal directions, two cover portions 18A and 18B that cover the opening of the upper surface or the lower surface of the through hole 40X, and the cover portions 18A and 18B Two light shielding layers 19A and 19B covering each of them are provided.
  • the first frame substrate portion 40A, the first indicator 17A, 17B, the two cover portions 18A, 18B, and the two light shielding layers 19A, 19B the first frame substrate portion 40A, the first indicator. 17A, the first cover portion 18A and the first light shielding layer 19A are on the upper side, and the second frame-shaped substrate portion 40B, the second indicator 17B, the second cover portion 18B and the second light shielding layer 19B are on the lower side. Are arranged so as to be laminated.
  • the first light shielding layer 19A, the first cover portion 18A, the first frame-like substrate portion 40A provided with the first indicator 17A, and the light emitting element 15 are provided on the upper surface.
  • the wiring board part 20, the second frame-like board part 40B provided with the second indicator 17B, the second cover part 18B, and the second light shielding layer 19B are laminated. That is, the two frame-like substrate portions 40A and 40B are disposed so as to sandwich the wiring substrate portion 20, and the first indicator 17A and the second indicator 17B are stacked so as to sandwich the light emitting element 15.
  • the cover portions 18A and 18B are formed by photodiode elements (hereinafter referred to as “PD elements”) 12A and 12B, which are photoelectric conversion elements that convert the fluorescence F from the light emitting element 15 into an electrical signal.
  • PD elements photodiode elements
  • the upper first cover portion 18A is provided with a first PD element 12A which is a photoelectric conversion element
  • the lower second cover portion 18B is provided with a second PD element 12B. ing.
  • the cover portions 18A and 18B are made of, for example, a silicon substrate having a minute through hole 18X (see FIG. 8), and the light receiving portions 12T of the PD elements 12A and 12B are formed on one side, respectively.
  • the PD elements 12A and 12B have a high conductivity and a low conductivity in which impurities are partially introduced in order to establish electrical connection between the base side of the one-conductivity type light receiving portion and the opposite conductivity type cover portions 18A and 18B.
  • the light receiving portion and the low resistance region may be collectively referred to as PD elements 12A and 12B. That is, the sensor unit 10 of the fluorescent sensor 4 of the present embodiment has a configuration in which two indicators 17A and 17B and PD elements 12A and 12B are provided above and below the light emitting element 15 as a boundary.
  • the minute through holes 18X of the cover portions 18A and 18B are entry paths through which the body fluid including the analyte 9 enters the indicators 17A and 17B. That is, body fluid can pass through the cover portions 18A and 18B.
  • the size, shape, position, and formation density of the minute through holes 18X of the cover portions 18A and 18B are appropriately selected according to the specifications.
  • the minute through holes 18X do not need to be arranged in an orderly manner.
  • the shape of the opening when the minute through hole 18X is observed from the upper surface may be any of a circle, a rectangle, a polygon, and the like.
  • the two cover portions 18A and 18B in which the minute through holes 18X are formed have the same structure as the membrane filter, but are produced by patterning the minute through holes 18X on a silicon plate or a silicon film, for example. .
  • the minute through hole 18X 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 to form the minute through hole 18X.
  • a porous semiconductor that can pass a solution containing an analyte may be used for the cover portions 18A and 18B.
  • 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 cover portions 18A and 18B 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 two light shielding layers 19A and 19B provided on the upper and lower sides prevent the excitation light E and the fluorescence F from leaking to the outside, and at the same time, prevent the external light G from entering the indicator 17.
  • the two light shielding layers 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.
  • a resin in which carbon black is mixed into an analyte-permeable polymer such as, or a resin obtained by laminating them is used.
  • 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 is used. .
  • the same silicon as the material of the cover portion 18A is particularly preferable.
  • the wiring board portion 20 is formed of a transparent resin, glass, or the like so that the excitation light E emitted downward from the light emitting element 15 can be transmitted to the lower indicator 17B side, but the through hole 40X is formed. Only a part may be formed from a transparent member, glass, etc., and may have a light transmittance.
  • the through-hole 40X in which the indicators 17A and 17B and / or the light emitting element 15 are housed is covered with the wiring board portion 20 at the lower surface or the upper surface, and the upper surface or the lower surface is covered with the cover portions 18A and 18B.
  • the side surface constitutes a hollow portion formed by the inner walls of the frame-like substrate portions 40A and 40B.
  • the hollow shape of the through hole 40X here is a rectangular parallelepiped (quadrangular columnar shape), but is not limited to this, and may be a columnar shape, a polygonal columnar shape, or the like. Note that the side surface of the through hole 40X may be inclined with respect to the main surface. Further, a reflective film that reflects the fluorescence F may be disposed on the side surface.
  • the wiring board portion 20 is provided with a wiring 51 that is connected to the external electrode 15T of the light emitting element 15 and supplies a driving signal.
  • wiring 61 for operating the PD elements 12A and 12B of the wiring 60 and transmitting signals is formed in the cover portions 18A and 18B.
  • the wirings 51 and 61 are a part of the plurality of wirings 60.
  • the light emitting element 15 is connected via the through holes 40a and 40b in which the wiring 61 for transmitting the signals of the PD elements 12A and 12B is formed in the frame-like substrate portions 40A and 40B.
  • the detection signal wiring 61 is disposed along with the driving wiring 51 on one main surface (upper surface side) of the wiring substrate section 20 by being guided to the upper surface side of the disposed wiring board section 20.
  • a filter that transmits the fluorescence F and blocks the excitation light E is used as a light receiving surface of the PD elements 12A and 12B, that is, the cover portions 18A and 18B. It is preferable to arrange on the surface facing the indicators 17A and 17B.
  • a filter for example, a light absorption filter that blocks the excitation light E having a wavelength of 375 nm but transmits the fluorescence F having a wavelength of 460 nm is used.
  • a minute through hole through which the analyte can pass is also formed in the filter.
  • the external electrode 15T on the lower surface of the light emitting element 15 is preferably sealed with an insulating resin. Furthermore, the light emitting element 15 may be sealed to the upper surface with a transparent resin or the like. The resin-sealed light emitting element 15 is not easily affected by moisture contained in the indicators 17A and 17B.
  • Indicator 17A, 17B consists of hydrogel which has the fluorescent pigment
  • the indicators 17A and 17B may be the analyte 9 itself in which the fluorescent dye that does not contain the fluorescent dye and the fluorescent dye that 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 separate from the sensor through the cover portions 18A and 18B and the light shielding layers 19A and 19B.
  • the hydrogel may have a molecular weight of 1 million or more, or a particle having a diameter larger than the pore diameter of the cover portions 18A and 18B, for example, a particle having a diameter of 50 nm or more, or a form that is crosslinked and does not flow. preferable.
  • 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.
  • the 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.
  • 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 emits light on both the upper and lower sides is selected from 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. Further, it is preferable to transmit the fluorescence F.
  • 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.
  • the fluorescence F generated from the two indicators 17A and 17B is incident on the PD elements 12A and 12B on the upper surface or the lower surface of the indicators 17A and 17B.
  • the fluorescence F emitted according to the concentration of the analyte 9 is mostly the fluorescence F from the first indicator 17A by the first PD element 12A, and partly by the second PD element 12B.
  • the fluorescence F from the second indicator 17B is mostly detected by the first PD element 12B and partly by the first PD element 12A.
  • the fluorescent sensor 4 can efficiently use the excitation light E from the light emitting element 15 by arranging the indicators 17A and 17B and the PD elements 12A and 12B in the vertical direction with the light emitting element 15 interposed therebetween, so that the conventional fluorescent sensor Higher sensitivity than 104.
  • the fluorescence sensor 4A 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 PD elements 12A and 12B, which are photoelectric conversion elements, are formed in the cover portions 18A and 18B.
  • PD elements 12A and 12B which are photoelectric conversion elements
  • cover portions 18A and 18B are formed in the cover portions 18A and 18B.
  • side opening portions 40S are formed on the side surfaces of the frame-shaped substrate portions 40A and 40B so as to communicate with the through holes 40X of the frame-shaped substrate portions 40A and 40B stacked with the wiring substrate portion 20 interposed therebetween.
  • the cover portions 18A and 18B disposed on the frame-like substrate portions 40A and 40B so as to cover the upper and lower sides of the through holes 40X are the functions of the light shielding layers 19A and 19B, that is, the external light G Has a function of preventing the excitation light E and the fluorescence F from leaking.
  • the two indicators 17A and 17B arranged in the through holes 40X in the frame-shaped substrate portions 40A and 40B are connected to the analytes from the total of the four side surface openings 40S via the light shielding layers 19A and 19B provided on the side surfaces. 9 can enter.
  • the analyte 9 is transmitted from the light shielding layers 19A, 19B provided on the side surfaces to the frame-shaped substrate portions 40A, 40B from the side surface openings 40S of the through holes 40X to the indicators 17A, Enter 17B.
  • the excitation light E emitted from the light emitting element 15 generates the fluorescence F corresponding to the concentration of the analyte 9 from the indicators 17A and 17B, and the fluorescence F1 emitted upward from the first indicator 17A located above is the first.
  • Fluorescence F2 detected by the first PD element 12A of the first cover portion 18A and emitted downward from the second indicator 17B located below is detected by the second PD element 12B of the second cover portion 18B.
  • the fluorescent sensor 4A of the present embodiment has minute through holes in the cover portions 18A and 18B that cover the upper and lower openings of the through holes 40X on the frame-like substrate portions 40A and 40B.
  • 18X does not need to be provided, and as a result, the minute through holes 18X are not formed in the PD elements 12A and 12B.
  • the area of entry of the analyte 9 is increased by the four side surface openings 40S, so that the analyte 9 can easily enter the indicators 17A and 17B, and the response to the concentration change of the analyte 9 is remarkably improved.
  • the side opening 40S communicating with the through-holes 40X of the frame-like substrate portions 40A and 40B is preferably formed on both side surfaces, but is not limited to this, and at least one side surface of the frame-like substrate portions 40A and 40B. It is good also as a structure formed in.
  • the fluorescence sensor 4B of the third embodiment will be described. Since the fluorescence sensor 4B 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 4B shown in FIG. 13 has photoelectric conversion elements on the inner side surfaces of the frame-like substrate portions 40A and 40B that form the through holes 40X in which the indicators 17A and 17B are disposed. Are different in that PD elements 12C and 12D are formed.
  • PD elements 12C and 12D as light receiving portions are provided on the side surfaces of the through holes 40X of the frame-like substrate portions 40A and 40B (only the side surfaces in the front-rear direction are shown in FIG. 13).
  • the light shielding layers 19A and 19B are arranged so as to cover the openings on the upper surface or the lower surface of the through holes 40X of the frame-shaped substrate portions 40A and 40B.
  • Cover portions 18A and 18B including PD elements 12A and 12B may be provided between the light shielding layers 19A and 19B and the indicators 17A and 17B as in the first embodiment.
  • the analyte 9 enters the indicators 17A and 17B from the upper and lower light shielding layers 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 from the light emitting element 15, and the fluorescent light F1 emitted laterally from the first indicator 17A located above is first.
  • Fluorescence F2 detected by one PD element 12C and emitted laterally from the second indicator 17B located below is detected by the second PD element 12D.
  • the fluorescence sensor 4B of the present embodiment does not have the PD elements 12B and 12C on the approach path of the analyte 9, so that the PD elements 12B and 12C are slightly penetrated. It is not necessary to provide the hole 18X, and the PD elements 12C and 12D are formed on the front, back, left and right side surfaces of the indicators 17A and 17B.
  • a PD element 12 ⁇ / b> E that is a photoelectric conversion element is provided between the first indicator 17 ⁇ / b> A and the light emitting element 15. That is, in the fluorescent sensor 4C, the light emitting element 15 is disposed between the PD element 12E and the second indicator 17B.
  • a through hole 12X is formed in the approximate center of the PD element 12E. Then, the excitation light E from the light emitting element 15 enters the second indicator 17B on the lower side and enters the first indicator 17A on the upper side through the through hole 12X. A plurality of through holes 12X may be formed in the PD element 12E.
  • the fluorescence F1 emitted downward from the first indicator 17A and the fluorescence F2 emitted upward from the second indicator 17B are both detected by the PD element 12E.
  • the fluorescence sensor 4D is provided with two PD elements 12EA and 12EB each having a through hole 12X, and these PD elements 12EA and 12EB are arranged vertically so as to sandwich the light emitting element 15. May be.
  • the fluorescence F1 emitted downward from the first indicator 17A is emitted from the first PD element 12EA, and the fluorescence F2 emitted upward from the second indicator 17B is emitted from the second PD element 12EB. Detected.
  • the fluorescence sensors 4C and 4D of the present embodiment have high sensitivity because there is no PD element 12 on the entry path of the analyte 9, and therefore it is not necessary to provide the minute through hole 18X in the PD element 12.
  • the fluorescent sensor 4E here has a structure in which the fluorescent sensor 4B shown in FIG. 13 and the fluorescent sensor 4C shown in FIG. 14 are combined.
  • the fluorescence F1 emitted downward from the first indicator 17A on the upper side is detected by the PD element 12E, and the fluorescence F2 emitted in the lateral direction is detected by the PD element 12C. Further, the fluorescence F3 emitted upward from the second indicator 17B on the lower side is detected by the PD element 12E, and the fluorescence F4 emitted in the lateral direction is detected by the PD element 12D.
  • the fluorescence sensor 4F here may have a structure in which the fluorescence sensor 4B shown in FIG. 13 and the fluorescence sensor 4D shown in FIG. 15 are combined.
  • the fluorescence F1 emitted downward from the first indicator 17A on the upper side is detected by the PD element 12EA, and the fluorescence F2 emitted horizontally is detected by the PD element 12C. Further, the fluorescence F3 emitted upward from the second indicator 17B on the lower side is detected by the PD element 12EB, and the fluorescence F4 emitted in the lateral direction is detected by the PD element 12D.
  • the fluorescence sensors 4E and 4F of the present embodiment have high sensitivity because there is no PD element 12 on the approach path of the analyte 9, and therefore it is not necessary to provide the minute through hole 18X in the PD element 12.
  • the shape of the sensor part of the fluorescence sensor demonstrated in the said several embodiment was a right-angled column shape, trapezoid shape, the shape where the side was curved, or a column shape etc. may be sufficient.
  • the wiring board 20 does not have optical transparency, for example, as shown in FIG. 18, two wiring boards 20A and 20B provided with light emitting elements 15A and 15B are bonded in the vertical direction. It is good.
  • FIG. 19 even if a hole 20a is provided in a part of the wiring substrate 20 facing the light emitting element 15 so that the excitation light E from the light emitting element 15 enters the second indicator 17B side. Good. That is, in the configuration of FIG. 19, the excitation light E that has passed through the hole 20 formed in the wiring board 20 is incident on the second indicator 17B.
  • the fluorescence sensor is compatible with various uses such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye.

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Abstract

A fluorescent sensor (4) comprising: two substrate sections (40A, 40B); two indicators (17A, 17B) arranged, respectively, in hollow sections formed in the two substrate sections (40A, 40B), said indicators receiving excitation light (E) and generating fluorescent light (F) having an intensity corresponding to the concentration of an analyte (9); a light-emitting element substrate section (20) having provided therein a light-emitting element (15) that emits the excitation light (E); and at least one photoelectric conversion element (12) that converts the fluorescent light (F) to an electric signal. The fluorescent sensor (4) is arranged such that: a joined substrate section (30) is formed by the two substrate sections (40A, 40B) being joined so as to sandwich the light-emitting element substrate section (20); and the light-emitting element (15) is sandwiched between the two indicators (17A, 17B).

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、２つの基板部と、前記２つの基板部に形成された中空部にそれぞれ配設され、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する２つのインジケータと、前記励起光を発生する発光素子が設けられた発光素子基板部と、前記蛍光を電気信号に変換する１つ以上の光電変換素子と、を備え、前記２つの基板部によって前記発光素子基板部を挟むように接合された接合基板部が形成され、前記２つのインジケータとの間に前記発光素子が挟まれるように配設されている。 The fluorescence sensor of one embodiment of the present invention is disposed in each of two substrate portions and a hollow portion formed in the two substrate portions, receives excitation light, and emits fluorescence having an intensity corresponding to the concentration of the analyte. The two substrate parts, comprising two indicators that generate, a light emitting element substrate part provided with a light emitting element that generates the excitation light, and one or more photoelectric conversion elements that convert the fluorescence into an electrical signal. Is formed so that the light emitting element substrate portion is sandwiched between the two indicators, and the light emitting element is disposed between the two indicators.
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線に沿った分解断面図である。FIG. 5 is an exploded 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、蛍光センサのカバー部の斜視図である。It is a perspective view of the cover part of a fluorescence sensor. 第２実施形態の蛍光センサの先端部における分解断面図である。It is an exploded sectional view in the tip part of the fluorescence sensor of a 2nd 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１０のＸI－ＸI線に沿った断面図である。FIG. 11 is a cross-sectional view taken along the line XI-XI in FIG. 10 at the tip of 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３実施形態の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 the fluorescence sensor of 3rd Embodiment. 第４実施形態の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 the fluorescence sensor of 4th Embodiment. 同、変形例の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 the fluorescence sensor of a modification similarly. 第５実施形態の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 the fluorescence sensor of 5th Embodiment. 同、変形例の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 the fluorescence sensor of a modification similarly. 蛍光センサの先端部を示し、配線基板構成の一例を示す断面図である。It is sectional drawing which shows the front-end | tip part of a fluorescence sensor and shows an example of a wiring board structure. 蛍光センサの先端部を示し、配線基板構成の他例を示す断面図である。It is sectional drawing which shows the front-end | tip part of a fluorescence sensor, and shows the other example of a wiring board structure.
　＜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及び図５に示すように、センサ部１０は、貫通孔４０Ｘのある２つの枠状基板部４０Ａ，４０Ｂとこれら２つの枠状基板部４０Ａ，４０Ｂの間に介装される透明樹脂、ガラスなどから形成された発光素子基板部としての配線基板部２０とがそれぞれ接合された接合基板部３０と、枠状基板部４０Ａ，４０Ｂの貫通孔４０Ｘに配設される２つのインジケータ１７Ａ，１７Ｂと、配線基板部２０上に配設され、上下左右方向に発光する発光素子１５と、貫通孔４０Ｘの上面または下面の開口を覆う２つのカバー部１８Ａ，１８Ｂと、これらカバー部１８Ａ，１８Ｂのそれぞれを覆う２つの遮光層１９Ａ，１９Ｂと、を有する。 The fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject. As shown in FIGS. 4 and 5, the sensor unit 10 includes two frame-shaped substrate portions 40A and 40B having a through-hole 40X and a transparent resin interposed between the two frame-shaped substrate portions 40A and 40B. Two indicators 17A and 17B disposed in a bonding substrate portion 30 to which a wiring substrate portion 20 as a light emitting element substrate portion formed of glass or the like is bonded, and through holes 40X of the frame- like substrate portions 40A and 40B. A light emitting element 15 that is disposed on the wiring board portion 20 and emits light in the vertical and horizontal directions, two cover portions 18A and 18B that cover the opening of the upper surface or the lower surface of the through hole 40X, and the cover portions 18A and 18B Two light shielding layers 19A and 19B covering each of them are provided.
　なお、２つの枠状基板部４０Ａ，４０Ｂ、２つのインジケータ１７Ａ，１７Ｂ、２つのカバー部１８Ａ，１８Ｂおよび２つの遮光層１９Ａ，１９Ｂのうち、第１の枠状基板部４０Ａ、第１のインジケータ１７Ａ、第１のカバー部１８Ａおよび第１の遮光層１９Ａが上方側、第２の枠状基板部４０Ｂ、第２のインジケータ１７Ｂ、第２のカバー部１８Ｂおよび第２の遮光層１９Ｂが下方側にそれぞれが積層するように配置されている。 Of the two frame substrate portions 40A, 40B, the two indicators 17A, 17B, the two cover portions 18A, 18B, and the two light shielding layers 19A, 19B, the first frame substrate portion 40A, the first indicator. 17A, the first cover portion 18A and the first light shielding layer 19A are on the upper side, and the second frame-shaped substrate portion 40B, the second indicator 17B, the second cover portion 18B and the second light shielding layer 19B are on the lower side. Are arranged so as to be laminated.
　具体的には、上方から順に、第１の遮光層１９Ａ、第１のカバー部１８Ａ、第１のインジケータ１７Ａが設けられた第１の枠状基板部４０Ａ、発光素子１５が上面に設けられた配線基板部２０、第２のインジケータ１７Ｂが設けられた第２の枠状基板部４０Ｂ、第２のカバー部１８Ｂおよび第２の遮光層１９Ｂが積層されている。すなわち、２つの枠状基板部４０Ａ，４０Ｂが配線基板部２０を挟むように配設され、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を挟むように積層される。 Specifically, in order from the top, the first light shielding layer 19A, the first cover portion 18A, the first frame-like substrate portion 40A provided with the first indicator 17A, and the light emitting element 15 are provided on the upper surface. The wiring board part 20, the second frame-like board part 40B provided with the second indicator 17B, the second cover part 18B, and the second light shielding layer 19B are laminated. That is, the two frame- like substrate portions 40A and 40B are disposed so as to sandwich the wiring substrate portion 20, and the first indicator 17A and the second indicator 17B are stacked so as to sandwich the light emitting element 15.
　ここでの蛍光センサ４は、カバー部１８Ａ，１８Ｂが、発光素子１５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）１２Ａ，１２Ｂが形成された、アナライト９が通過する半導体材料からなる。なお、上方側の第１のカバー部１８Ａには、光電変換素子である第１のＰＤ素子１２Ａが設けられ、下方側の第２のカバー部１８Ｂには、第２のＰＤ素子１２Ｂが設けられている。 In this fluorescent sensor 4, the cover portions 18A and 18B are formed by photodiode elements (hereinafter referred to as “PD elements”) 12A and 12B, which are photoelectric conversion elements that convert the fluorescence F from the light emitting element 15 into an electrical signal. Made of a semiconductor material through which the analyte 9 passes. The upper first cover portion 18A is provided with a first PD element 12A which is a photoelectric conversion element, and the lower second cover portion 18B is provided with a second PD element 12B. ing.
　カバー部１８Ａ，１８Ｂは、微少貫通孔１８Ｘ（図８参照）のある、例えばシリコン基板からなり、片面にそれぞれＰＤ素子１２Ａ，１２Ｂの受光部１２Ｔが形成されている。なお、ＰＤ素子１２Ａ，１２Ｂは、一導電型の受光部と、それとは反対導電型のカバー部１８Ａ，１８Ｂの基体側の電気接続をとるために部分的に不純物を導入した導電率の高い低抵抗領域とから構成されているが、以下、受光部と低抵抗領域を合わせて、ＰＤ素子１２Ａ，１２Ｂということがある。すなわち、本実施形態の蛍光センサ４のセンサ部１０には、発光素子１５を境に上下に２つのインジケータ１７Ａ，１７ＢおよびＰＤ素子１２Ａ，１２Ｂが設けられた構成となっている。 The cover portions 18A and 18B are made of, for example, a silicon substrate having a minute through hole 18X (see FIG. 8), and the light receiving portions 12T of the PD elements 12A and 12B are formed on one side, respectively. The PD elements 12A and 12B have a high conductivity and a low conductivity in which impurities are partially introduced in order to establish electrical connection between the base side of the one-conductivity type light receiving portion and the opposite conductivity type cover portions 18A and 18B. In the following description, the light receiving portion and the low resistance region may be collectively referred to as PD elements 12A and 12B. That is, the sensor unit 10 of the fluorescent sensor 4 of the present embodiment has a configuration in which two indicators 17A and 17B and PD elements 12A and 12B are provided above and below the light emitting element 15 as a boundary.
　カバー部１８Ａ，１８Ｂの微少貫通孔１８Ｘ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である。すなわち、カバー部１８Ａ，１８Ｂは、体液が通過可能である。 The minute through holes 18X of the cover portions 18A and 18B are entry paths through which the body fluid including the analyte 9 enters the indicators 17A and 17B. That is, body fluid can pass through the cover portions 18A and 18B.
　カバー部１８Ａ，１８Ｂの微少貫通孔１８Ｘ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１８Ｘ（図８参照）は、整然と配列している必要はない。また、微少貫通孔１８Ｘ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 18X of the cover portions 18A and 18B are appropriately selected according to the specifications. For example, the minute through holes 18X (see FIG. 8) do not need to be arranged in an orderly manner. Further, the shape of the opening when the minute through hole 18X is observed from the upper surface may be any of a circle, a rectangle, a polygon, and the like.
　微少貫通孔１８Ｘが形成された２つのカバー部１８Ａ，１８Ｂは、メンブレンフィルタと同様の構造であるが、例えば、シリコン板またはシリコン膜等に、微少貫通孔１８Ｘ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１８Ｘ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１８Ｘ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 cover portions 18A and 18B in which the minute through holes 18X are formed have the same structure as the membrane filter, but are produced by patterning the minute through holes 18X on a silicon plate or a silicon film, for example. . Specifically, the minute through hole 18X 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 to form the minute through hole 18X.
　また、カバー部１８Ａ，１８Ｂ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 cover portions 18A and 18B. 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.
　カバー部１８Ａ，１８Ｂ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 cover portions 18A and 18B 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.
　上下に設けられた２つの遮光層１９Ａ，１９Ｂは、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がインジケータ１７に進入することを防止する。 The two light shielding layers 19A and 19B provided on the upper and lower sides prevent the excitation light E and the fluorescence F from leaking to the outside, and at the same time, prevent the external light G from entering the indicator 17.
　２つの遮光層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。遮光層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。 The two light shielding layers 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 layers 19A and 19B, a composite composition with an inorganic material such as metal or ceramic, or a hydrogel in which carbon black is mixed in a base material of an organic polymer such as polyimide or polyurethane, or cellulose 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.
　２つの枠状基板部４０Ａ，４０Ｂには、ヤング率が数十ＧＰａから数百ＧＰａのシリコン、ガラスもしくは金属等、または、ヤング率が１ＧＰａ～５ＧＰａの程度の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。カバー部１８Ａの材料と同じシリコンが、特に好ましい。なお、配線基板部２０は、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た励起光Ｅが透過できるように透明樹脂、ガラス等から形成されるが、貫通孔４０Ｘ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。 For the two frame- like substrate portions 40A and 40B, 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 is used. . The same silicon as the material of the cover portion 18A is particularly preferable. The wiring board portion 20 is formed of a transparent resin, glass, or the like so that the excitation light E emitted downward from the light emitting element 15 can be transmitted to the lower indicator 17B side, but the through hole 40X is formed. Only a part may be formed from a transparent member, glass, etc., and may have a light transmittance.
　インジケータ１７Ａ，１７Ｂ及び/または発光素子１５が内部に収容されている貫通孔４０Ｘは、下面または上面が配線基板部２０に覆われており、上面または下面がカバー部１８Ａ，１８Ｂに覆われており、側面が枠状基板部４０Ａ，４０Ｂの内壁により形成された中空部を構成する。ここでの貫通孔４０Ｘの中空形状は、直方体（四角柱状）であるが、これに限定されることなく、円柱状、または多角柱状等であってもよい。なお、貫通孔４０Ｘの側面は、主面に対して傾斜していてもよい。さらに、側面に蛍光Ｆを反射する反射膜が配設されていてもよい。 The through-hole 40X in which the indicators 17A and 17B and / or the light emitting element 15 are housed is covered with the wiring board portion 20 at the lower surface or the upper surface, and the upper surface or the lower surface is covered with the cover portions 18A and 18B. The side surface constitutes a hollow portion formed by the inner walls of the frame- like substrate portions 40A and 40B. The hollow shape of the through hole 40X here is a rectangular parallelepiped (quadrangular columnar shape), but is not limited to this, and may be a columnar shape, a polygonal columnar shape, or the like. Note that the side surface of the through hole 40X may be inclined with respect to the main surface. Further, a reflective film that reflects the fluorescence F may be disposed on the side surface.
　配線基板部２０には、発光素子１５の外部電極１５Ｔと接続され駆動信号を供給する配線５１が配設されている。カバー部１８Ａ，１８Ｂには、配線６０のうちＰＤ素子１２Ａ，１２Ｂを動作させ、信号を伝送する配線６１が形成されている。また、配線５１、６１は複数の配線６０の一部である。なお、図６に示すように、配線６０のうちＰＤ素子１２Ａ，１２Ｂの信号を伝送する配線６１が枠状基板部４０Ａ，４０Ｂに形成されたスルーホール４０ａ，４０ｂを介して、発光素子１５が配設されている配線基板部２０の上面側に導かれて、配線基板部２０の一主面（上面側）にて駆動用の配線５１と共に、検出信号用の配線６１が配置される。 The wiring board portion 20 is provided with a wiring 51 that is connected to the external electrode 15T of the light emitting element 15 and supplies a driving signal. In the cover portions 18A and 18B, wiring 61 for operating the PD elements 12A and 12B of the wiring 60 and transmitting signals is formed. The wirings 51 and 61 are a part of the plurality of wirings 60. As shown in FIG. 6, among the wiring 60, the light emitting element 15 is connected via the through holes 40a and 40b in which the wiring 61 for transmitting the signals of the PD elements 12A and 12B is formed in the frame- like substrate portions 40A and 40B. The detection signal wiring 61 is disposed along with the driving wiring 51 on one main surface (upper surface side) of the wiring substrate section 20 by being guided to the upper surface side of the disposed wiring board section 20.
　なお、ＰＤ素子１２Ａ，１２Ｂに励起光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を遮るフィルタを、ＰＤ素子１２Ａ，１２Ｂの受光面、すなわち、カバー部１８Ａ，１８Ｂのインジケータ１７Ａ，１７Ｂに対向する面に配設するのが好ましい。このようなフィルタには、例えば、波長３７５ｎｍの励起光Ｅを遮断するが、波長４６０ｎｍの蛍光Ｆは透過する光吸収型フィルタを用いる。フィルタを配設する場合には、フィルタにもアナライトが通過可能な微少貫通孔が形成される。また、発光素子１５の下面の外部電極１５Ｔ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が上面まで透明樹脂等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が含有する水分の影響を受けにくい。 In order to prevent the excitation light E from entering the PD elements 12A and 12B, a filter that transmits the fluorescence F and blocks the excitation light E is used as a light receiving surface of the PD elements 12A and 12B, that is, the cover portions 18A and 18B. It is preferable to arrange on the surface facing the indicators 17A and 17B. As such a filter, for example, a light absorption filter that blocks the excitation light E having a wavelength of 375 nm but transmits the fluorescence F having a wavelength of 460 nm is used. When a filter is provided, a minute through hole through which the analyte can pass is also formed in the filter. The external electrode 15T on the lower surface of the light emitting element 15 is preferably sealed with an insulating resin. Furthermore, the light emitting element 15 may be sealed to the upper surface with a transparent resin or the like. The resin-sealed light emitting element 15 is not easily affected by moisture contained in the indicators 17A and 17B.
　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を含み、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１７Ａ，１７Ｂ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 a fluorescent dye that generates a fluorescence F having 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 indicators 17A and 17B may be the analyte 9 itself in which the fluorescent dye that does not contain the fluorescent dye and the fluorescent dye that 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、カバー部１８Ａ，１８Ｂ及び遮光層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、またはカバー部１８Ａ，１８Ｂの孔径以上の例えば径５０ｎｍ以上の粒子状であるか、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 separate from the sensor through the cover portions 18A and 18B and the light shielding layers 19A and 19B. For this reason, the hydrogel may have a molecular weight of 1 million or more, or a particle having a diameter larger than the pore diameter of the cover portions 18A and 18B, for example, a particle having a diameter of 50 nm or more, or a form that is crosslinked and does not flow. preferable.
　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、インジケータは作製される。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。 The 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. 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.
　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、上下両面に発光する素子が選択される。また、蛍光Ｆを透過することが好ましい。 As the light emitting element 15, an element that emits light on both the upper and lower sides is selected from 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. Further, it is preferable to transmit the fluorescence F.
　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.
　本実施形態の蛍光センサ４では、図７に示すように、２つのインジケータ１７Ａ，１７Ｂから発生した蛍光Ｆがインジケータ１７Ａ，１７Ｂの上面または下面のＰＤ素子１２Ａ，１２Ｂ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Ｆは、第１のインジケータ１７Ａからの蛍光Ｆがその大部分は第１のＰＤ素子１２Ａに、一部分は第２のＰＤ素子１２Ｂによって、第２のインジケータ１７Ｂからの蛍光Ｆが大部分は第１のＰＤ素子１２Ｂによって、一部分は第１のＰＤ素子１２Ａ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を挟んで上下方向にインジケータ１７Ａ，１７Ｂ及びＰＤ素子１２Ａ，１２Ｂ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従来の蛍光センサ１０４より高感度となる。 In the fluorescence sensor 4 of the present embodiment, as shown in FIG. 7, the fluorescence F generated from the two indicators 17A and 17B is incident on the PD elements 12A and 12B on the upper surface or the lower surface of the indicators 17A and 17B. At this time, the fluorescence F emitted according to the concentration of the analyte 9 is mostly the fluorescence F from the first indicator 17A by the first PD element 12A, and partly by the second PD element 12B. The fluorescence F from the second indicator 17B is mostly detected by the first PD element 12B and partly by the first PD element 12A. For this reason, the fluorescent sensor 4 can efficiently use the excitation light E from the light emitting element 15 by arranging the indicators 17A and 17B and the PD elements 12A and 12B in the vertical direction with the light emitting element 15 interposed therebetween, so that the conventional fluorescent sensor Higher sensitivity than 104.
＜第２実施形態＞
　次に、第２実施形態の蛍光センサ４Ａ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 sensor 4A 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、カバー部１８Ａ，１８Ｂ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は同じであるが、図９に示すように、配線基板部２０を挟んで積層する枠状基板部４０Ａ，４０Ｂの貫通孔４０Ｘに連通するよう側面開口部４０Ｓを枠状基板部４０Ａ，４０Ｂの側面に形成し、図１０および図１１に示すように、側面開口部４０Ｓを覆うように２つの遮光層１９Ａ，１９Ｂを側面に配置した点で異なっている。そして、ここでの蛍光センサ４Ａでは、枠状基板部４０Ａ，４０Ｂに貫通孔４０Ｘの上下を覆うように配設されるカバー部１８Ａ，１８Ｂが遮光層１９Ａ，１９Ｂの機能、すなわち、外光Ｇの進入を防止し、励起光Ｅ及び蛍光Ｆの漏光を防止する機能、を有する。 Compared with the fluorescent sensor 4 of the first embodiment, the fluorescent sensor 4A of the present embodiment is the same in that PD elements 12A and 12B, which are photoelectric conversion elements, are formed in the cover portions 18A and 18B. As shown in FIG. 9, side opening portions 40S are formed on the side surfaces of the frame-shaped substrate portions 40A and 40B so as to communicate with the through holes 40X of the frame-shaped substrate portions 40A and 40B stacked with the wiring substrate portion 20 interposed therebetween. And as shown in FIG. 11, it is different by the point which has arrange | positioned two light shielding layers 19A and 19B on the side surface so that the side surface opening part 40S may be covered. In the fluorescent sensor 4A here, the cover portions 18A and 18B disposed on the frame- like substrate portions 40A and 40B so as to cover the upper and lower sides of the through holes 40X are the functions of the light shielding layers 19A and 19B, that is, the external light G Has a function of preventing the excitation light E and the fluorescence F from leaking.
　すなわち、枠状基板部４０Ａ，４０Ｂに貫通孔４０Ｘに配置される２つのインジケータ１７Ａ、１７Ｂには、側面に設けられた遮光層１９Ａ，１９Ｂを介して、合計４つの側面開口部４０Ｓからアナライト９が進入可能となる。 In other words, the two indicators 17A and 17B arranged in the through holes 40X in the frame-shaped substrate portions 40A and 40B are connected to the analytes from the total of the four side surface openings 40S via the light shielding layers 19A and 19B provided on the side surfaces. 9 can enter.
　具体的には、図１２に示す、蛍光センサ４Ａでは、側面に設けられた遮光層１９Ａ，１９Ｂからアナライト９が枠状基板部４０Ａ，４０Ｂに貫通孔４０Ｘの側面開口部４０Ｓからインジケータ１７Ａ，１７Ｂに進入する。そして、発光素子１５で発光する励起光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から上方に出射する蛍光Ｆ１が第１のカバー部１８Ａの第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から下方向に出射する蛍光Ｆ２が第２のカバー部１８Ｂの第２のＰＤ素子１２Ｂにより検出される。 Specifically, in the fluorescence sensor 4A shown in FIG. 12, the analyte 9 is transmitted from the light shielding layers 19A, 19B provided on the side surfaces to the frame-shaped substrate portions 40A, 40B from the side surface openings 40S of the through holes 40X to the indicators 17A, Enter 17B. The excitation light E emitted from the light emitting element 15 generates the fluorescence F corresponding to the concentration of the analyte 9 from the indicators 17A and 17B, and the fluorescence F1 emitted upward from the first indicator 17A located above is the first. Fluorescence F2 detected by the first PD element 12A of the first cover portion 18A and emitted downward from the second indicator 17B located below is detected by the second PD element 12B of the second cover portion 18B. The
　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、枠状基板部４０Ａ，４０Ｂに貫通孔４０Ｘの上下の開口を覆うカバー部１８Ａ，１８Ｂに微少貫通孔１８Ｘを設けなくてよく、その結果、ＰＤ素子１２Ａ，１２Ｂにも微少貫通孔１８Ｘが形成されないため、さらに、高感度となる。また、４つの側面開口部４０Ｓによって、アナライト９の進入面積が大きくなることで、インジケータ１７Ａ，１７Ｂにアナライト９が進入し易くなり、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。 From the above, in addition to the effects of the fluorescence sensor 4 of the first embodiment, the fluorescent sensor 4A of the present embodiment has minute through holes in the cover portions 18A and 18B that cover the upper and lower openings of the through holes 40X on the frame- like substrate portions 40A and 40B. 18X does not need to be provided, and as a result, the minute through holes 18X are not formed in the PD elements 12A and 12B. Further, the area of entry of the analyte 9 is increased by the four side surface openings 40S, so that the analyte 9 can easily enter the indicators 17A and 17B, and the response to the concentration change of the analyte 9 is remarkably improved.
　なお、枠状基板部４０Ａ，４０Ｂの貫通孔４０Ｘに連通する側面開口部４０Ｓは、両側面に形成したほうが好ましいが、これに限定されることなく、枠状基板部４０Ａ，４０Ｂの少なくとも一側面に形成する構成としてもよい。 The side opening 40S communicating with the through-holes 40X of the frame- like substrate portions 40A and 40B is preferably formed on both side surfaces, but is not limited to this, and at least one side surface of the frame- like substrate portions 40A and 40B. It is good also as a structure formed in.
＜第３実施形態＞
　次に、第３実施形態の蛍光センサ４Ｂについて説明する。蛍光センサ４Ｂ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 4B of the third embodiment will be described. Since the fluorescence sensor 4B 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１３に示す蛍光センサ４Ｂ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が配設される貫通孔４０Ｘを形成する枠状基板部４０Ａ，４０Ｂの内側面に光電変換素子としてのＰＤ素子１２Ｃ，１２Ｄが形成されている点が異なる。 Compared with the fluorescence sensor 4 of the first embodiment, the fluorescence sensor 4B shown in FIG. 13 has photoelectric conversion elements on the inner side surfaces of the frame- like substrate portions 40A and 40B that form the through holes 40X in which the indicators 17A and 17B are disposed. Are different in that PD elements 12C and 12D are formed.
　具体的には、蛍光センサ４Ｂは、枠状基板部４０Ａ，４０Ｂの貫通孔４０Ｘのそれぞれの側面に受光部としてのＰＤ素子１２Ｃ，１２Ｄが設けられる（なお、図１３では前後方向の側面のみ図示）。また、ここでは、枠状基板部４０Ａ，４０Ｂの貫通孔４０Ｘの上面または下面の開口部を覆うように遮光層１９Ａ，１９Ｂが配設されている。なお、これら遮光層１９Ａ，１９Ｂとインジケータ１７Ａ，１７Ｂの間にも、第１実施形態と同様に、ＰＤ素子１２Ａ，１２Ｂを備えたカバー部１８Ａ，１８Ｂを設けてもよい。 Specifically, in the fluorescence sensor 4B, PD elements 12C and 12D as light receiving portions are provided on the side surfaces of the through holes 40X of the frame- like substrate portions 40A and 40B (only the side surfaces in the front-rear direction are shown in FIG. 13). ). Further, here, the light shielding layers 19A and 19B are arranged so as to cover the openings on the upper surface or the lower surface of the through holes 40X of the frame-shaped substrate portions 40A and 40B. Cover portions 18A and 18B including PD elements 12A and 12B may be provided between the light shielding layers 19A and 19B and the indicators 17A and 17B as in the first embodiment.
　このように構成された蛍光センサ４Ｂは、上下の遮光層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からの励起光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から横方向に出射する蛍光Ｆ１が第１のＰＤ素子１２Ｃにより検出され、下方に位置する第２のインジケータ１７Ｂから横方向に出射する蛍光Ｆ２が第２のＰＤ素子１２Ｄにより検出される。 In the thus configured fluorescent sensor 4B, the analyte 9 enters the indicators 17A and 17B from the upper and lower light shielding layers 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 from the light emitting element 15, and the fluorescent light F1 emitted laterally from the first indicator 17A located above is first. Fluorescence F2 detected by one PD element 12C and emitted laterally from the second indicator 17B located below is detected by the second PD element 12D.
　以上から本実施形態の蛍光センサ４Ｂは、第１実施形態の蛍光センサ４の効果に加え、アナライト９の進入経路上にＰＤ素子１２Ｂ，１２Ｃがないため、これらＰＤ素子１２Ｂ，１２Ｃに微少貫通孔１８Ｘを設けなくてよく、さらに、インジケータ１７Ａ，１７Ｂの前後左右の側面にＰＤ素子１２Ｃ，１２Ｄが形成されているため、より高感度となる。 From the above, in addition to the effects of the fluorescence sensor 4 of the first embodiment, the fluorescence sensor 4B of the present embodiment does not have the PD elements 12B and 12C on the approach path of the analyte 9, so that the PD elements 12B and 12C are slightly penetrated. It is not necessary to provide the hole 18X, and the PD elements 12C and 12D are formed on the front, back, left and right side surfaces of the indicators 17A and 17B.
＜第４実施形態＞
　次に、第４実施形態の蛍光センサ４Ｃ，４Ｄについて説明する。なお、蛍光センサ４Ｃ，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。 <Fourth embodiment>
Next, the fluorescence sensors 4C and 4D of the fourth embodiment will be described. In addition, since the fluorescence sensors 4C and 4D are 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１４に示すように、ここでの蛍光センサ４Ｃは、第１のインジケータ１７Ａと発光素子１５との間に光電変換素子であるＰＤ素子１２Ｅが設けられている。すなわち、蛍光センサ４Ｃは、ＰＤ素子１２Ｅと第２のインジケータ１７Ｂとの間に発光素子１５が配設されている。 As shown in FIG. 14, in the fluorescence sensor 4 </ b> C here, a PD element 12 </ b> E that is a photoelectric conversion element is provided between the first indicator 17 </ b> A and the light emitting element 15. That is, in the fluorescent sensor 4C, the light emitting element 15 is disposed between the PD element 12E and the second indicator 17B.
　ＰＤ素子１２Ｅの略中央には、貫通孔１２Ｘが形成されている。そして、発光素子１５からの励起光Ｅは、下方側の第２のインジケータ１７Ｂに入射すると共に、貫通孔１２Ｘを介して上方側の第１のインジケータ１７Ａに入射する。なお、ＰＤ素子１２Ｅに複数の貫通孔１２Ｘが形成されていてもよい。 A through hole 12X is formed in the approximate center of the PD element 12E. Then, the excitation light E from the light emitting element 15 enters the second indicator 17B on the lower side and enters the first indicator 17A on the upper side through the through hole 12X. A plurality of through holes 12X may be formed in the PD element 12E.
　ここでの蛍光センサ４Ｃでは、第１のインジケータ１７Ａから下方向に出射する蛍光Ｆ１と、第２のインジケータ１７Ｂから上方に出射する蛍光Ｆ２とが、共にＰＤ素子１２Ｅにより検出される。 In the fluorescence sensor 4C here, the fluorescence F1 emitted downward from the first indicator 17A and the fluorescence F2 emitted upward from the second indicator 17B are both detected by the PD element 12E.
　なお、図１５に示すように、蛍光センサ４Ｄは、貫通孔１２Ｘが形成された２つのＰＤ素子１２ＥＡ，１２ＥＢを設けて、これらＰＤ素子１２ＥＡ，１２ＥＢが発光素子１５を挟むように上下に配設してもよい。 As shown in FIG. 15, the fluorescence sensor 4D is provided with two PD elements 12EA and 12EB each having a through hole 12X, and these PD elements 12EA and 12EB are arranged vertically so as to sandwich the light emitting element 15. May be.
　ここでの蛍光センサ４Ｄでは、第１のインジケータ１７Ａから下方向に出射する蛍光Ｆ１が第１のＰＤ素子１２ＥＡに、第２のインジケータ１７Ｂから上方に出射する蛍光Ｆ２が第２のＰＤ素子１２ＥＢにより検出される。 In the fluorescence sensor 4D here, the fluorescence F1 emitted downward from the first indicator 17A is emitted from the first PD element 12EA, and the fluorescence F2 emitted upward from the second indicator 17B is emitted from the second PD element 12EB. Detected.
　以上から本実施形態の蛍光センサ４Ｃ，４Ｄは、いずれもアナライト９の進入経路上にＰＤ素子１２がないため、ＰＤ素子１２に微少貫通孔１８Ｘを設けなくてよいため高感度となる。 From the above, the fluorescence sensors 4C and 4D of the present embodiment have high sensitivity because there is no PD element 12 on the entry path of the analyte 9, and therefore it is not necessary to provide the minute through hole 18X in the PD element 12.
＜第５実施形態＞
　次に、第５実施形態の蛍光センサ４Ｅ，４Ｆについて説明する。なお、蛍光センサ４Ｅ，４Ｆ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。 <Fifth Embodiment>
Next, the fluorescence sensors 4E and 4F of the fifth embodiment will be described. In addition, since the fluorescence sensors 4E and 4F are 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１６に示すように、ここでの蛍光センサ４Ｅは、図１３に示した蛍光センサ４Ｂと、図１４に示した蛍光センサ４Ｃと、を組み合わせた構造である。 As shown in FIG. 16, the fluorescent sensor 4E here has a structure in which the fluorescent sensor 4B shown in FIG. 13 and the fluorescent sensor 4C shown in FIG. 14 are combined.
　すなわち、ここでの蛍光センサ４Ｅでは、上方側の第１のインジケータ１７Ａから下方向に出射する蛍光Ｆ１がＰＤ素子１２Ｅにより検出され、横方向に出射する蛍光Ｆ２がＰＤ素子１２Ｃにより検出される。また、下方側の第２のインジケータ１７Ｂから上方向に出射する蛍光Ｆ３はＰＤ素子１２Ｅにより検出され、横方向に出射する蛍光Ｆ４はＰＤ素子１２Ｄにより検出される。 That is, in the fluorescence sensor 4E here, the fluorescence F1 emitted downward from the first indicator 17A on the upper side is detected by the PD element 12E, and the fluorescence F2 emitted in the lateral direction is detected by the PD element 12C. Further, the fluorescence F3 emitted upward from the second indicator 17B on the lower side is detected by the PD element 12E, and the fluorescence F4 emitted in the lateral direction is detected by the PD element 12D.
　さらに、図１７に示すように、ここでの蛍光センサ４Ｆは、図１３に示した蛍光センサ４Ｂと、図１５に示した蛍光センサ４Ｄと、を組み合わせた構造でもよい。 Further, as shown in FIG. 17, the fluorescence sensor 4F here may have a structure in which the fluorescence sensor 4B shown in FIG. 13 and the fluorescence sensor 4D shown in FIG. 15 are combined.
　すなわち、ここでの蛍光センサ４Ｆでは、上方側の第１のインジケータ１７Ａから下方向に出射する蛍光Ｆ１がＰＤ素子１２ＥＡにより検出され、横方向に出射する蛍光Ｆ２がＰＤ素子１２Ｃにより検出される。また、下方側の第２のインジケータ１７Ｂから上方向に出射する蛍光Ｆ３はＰＤ素子１２ＥＢにより検出され、横方向に出射する蛍光Ｆ４がＰＤ素子１２Ｄにより検出される。 That is, in the fluorescence sensor 4F here, the fluorescence F1 emitted downward from the first indicator 17A on the upper side is detected by the PD element 12EA, and the fluorescence F2 emitted horizontally is detected by the PD element 12C. Further, the fluorescence F3 emitted upward from the second indicator 17B on the lower side is detected by the PD element 12EB, and the fluorescence F4 emitted in the lateral direction is detected by the PD element 12D.
　以上から本実施形態の蛍光センサ４Ｅ，４Ｆは、いずれもアナライト９の進入経路上にＰＤ素子１２がないため、ＰＤ素子１２に微少貫通孔１８Ｘを設けなくてよいため高感度となる。 From the above, the fluorescence sensors 4E and 4F of the present embodiment have high sensitivity because there is no PD element 12 on the approach path of the analyte 9, and therefore it is not necessary to provide the minute through hole 18X in the PD element 12.
　なお、複数の上記実施形態において説明した蛍光センサのセンサ部の形状は直角柱形状であったが、台形形状、側面が湾曲した形状、または円柱状等であってもよい。 In addition, although the shape of the sensor part of the fluorescence sensor demonstrated in the said several embodiment was a right-angled column shape, trapezoid shape, the shape where the side was curved, or a column shape etc. may be sufficient.
　さらに、配線基板２０は、光透過性を有していなくとも、例えば、図１８に示すように、発光素子１５Ａ，１５Ｂが設けられた２つの配線基板２０Ａ，２０Ｂを上下方向に貼り合わせた構成としてもよい。なお、図１９に示すように、発光素子１５からの励起光Ｅが第２のインジケータ１７Ｂ側に入射するよう配線基板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１９の構成においては、配線基板２０に形成された孔部２０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。 Furthermore, even if the wiring board 20 does not have optical transparency, for example, as shown in FIG. 18, two wiring boards 20A and 20B provided with light emitting elements 15A and 15B are bonded in the vertical direction. It is good. In addition, as shown in FIG. 19, even if a hole 20a is provided in a part of the wiring substrate 20 facing the light emitting element 15 so that the excitation light E from the light emitting element 15 enters the second indicator 17B side. Good. That is, in the configuration of FIG. 19, the excitation light E that has passed through the hole 20 formed in the wiring board 20 is incident on the second indicator 17B.
　また、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 addition, although a sensor that detects saccharides such as glucose has been described as an example, the fluorescence sensor is compatible with various uses such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor by selecting a fluorescent dye.
　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. 　２つの基板部と、
    　前記２つの基板部に形成された中空部にそれぞれ配設され、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する２つのインジケータと、
    　前記励起光を発生する発光素子が設けられた発光素子基板部と、
    　前記蛍光を電気信号に変換する１つ以上の光電変換素子と、
    　を備え、
    　前記２つの基板部によって前記発光素子基板部を挟むように接合された接合基板部が形成され、前記２つのインジケータの間に前記発光素子が挟まれるように配設されたことを特徴とする蛍光センサ。     Two substrate sections;
    Two indicators that are respectively disposed in the hollow portions formed in the two substrate portions, receive excitation light, and generate fluorescence having an intensity according to the concentration of the analyte;
    A light emitting element substrate provided with a light emitting element for generating the excitation light;
    One or more photoelectric conversion elements for converting the fluorescence into an electrical signal;
    With
    A fluorescent substrate characterized in that a bonded substrate portion joined so as to sandwich the light emitting element substrate portion between the two substrate portions is formed, and the light emitting element is disposed between the two indicators. Sensor.
  2. 　前記１つ以上の光電変換素子が前記接合基板部の上面および下面に形成される前記中空部の開口に配置され、前記２つのインジケータに対向するように設けられていることを特徴とする請求項１に記載の蛍光センサ。 The one or more photoelectric conversion elements are disposed in openings of the hollow portion formed on an upper surface and a lower surface of the bonding substrate portion, and are provided so as to face the two indicators. The fluorescent sensor according to 1.
  3. 　前記中空部の開口を覆うように配設され、前記アナライトが通過する貫通孔および前記光電変換素子が設けられた半導体材料からなるカバー部を備えてい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 cover part which is arrange | positioned so that the opening of the said hollow part may be covered, and consists of a semiconductor material with which the through-hole through which the said analyte passes, and the said photoelectric conversion element was provided is provided. Item 3. The fluorescent sensor according to Item 2.
  4. 　前記接合基板部の上下面には、前記アナライトが通過する遮光層が設けられていることを特徴とする請求項１から請求項３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 3, wherein a light-shielding layer through which the analyte passes is provided on the upper and lower surfaces of the bonding substrate portion.
  5. 　前記２つの基板部の側部には、前記中空部に連通する側面開口部が形成され、
    　前記側面開口部を覆うように前記アナライトが通過する遮光層が設けられていることを特徴とする請求項１から請求項４のいずれかに記載の蛍光センサ。     A side opening that communicates with the hollow portion is formed on the side of the two substrate portions,
    The fluorescent sensor according to any one of claims 1 to 4, wherein a light-shielding layer through which the analyte passes is provided so as to cover the side opening.
  6. 　前記１つ以上の光電変換素子が前記中空部を形成する前記２つの基板部の内側面に配設されていることを特徴とする請求項１から請求項４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 4, wherein the one or more photoelectric conversion elements are disposed on inner surfaces of the two substrate portions forming the hollow portion.
  7. 　前記１つ以上の光電変換素子の少なくとも１つが前記インジケータと前記発光素子との間に配設されていることを特徴とする請求項１から請求項６のいずれかに記載の蛍光センサ。 The fluorescence sensor according to any one of claims 1 to 6, wherein at least one of the one or more photoelectric conversion elements is disposed between the indicator and the light emitting element.
  8. 　前記１つ以上の光電変換素子が前記２つのインジケータと前記発光素子との間に配設され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 fluorescence sensor according to claim 7, wherein the one or more photoelectric conversion elements are disposed between the two indicators and the light emitting element.
  9. 　前記発光素子基板部は、光透過性を有していることを特徴とする請求項１から請求項８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 8, wherein the light emitting element substrate portion has light permeability.
  10. 　前記発光素子基板部は、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１から請求項８のいずれかに記載の蛍光センサ。 The fluorescence according to any one of claims 1 to 8, wherein the light-emitting element substrate portion has a hole for allowing excitation light to pass through a part where the light-emitting element is provided. Sensor.
PCT/JP2012/074179 2012-09-21 2012-09-21 Fluorescent sensor WO2014045388A1 (en)

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Citations (6)

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JP2001525930A (en) * 1997-05-13 2001-12-11 コルビン，アーサー・イー・ジュニア Improved fluorescence detection device
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JP2012093128A (en) * 2010-10-25 2012-05-17 Olympus Corp Fluorescence sensor

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Publication number Priority date Publication date Assignee Title
US5910661A (en) * 1997-05-13 1999-06-08 Colvin, Jr.; Arthur E. Flourescence sensing device
JP2001525930A (en) * 1997-05-13 2001-12-11 コルビン，アーサー・イー・ジュニア Improved fluorescence detection device
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
JP2003515163A (en) * 1999-11-24 2003-04-22 アイオワ ステイト ユニヴァーシティ リサーチ ファウンデーション インコーポレイテッド Optical sensor and array-containing thin film electroluminescent device
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