WO2014045387A1 - Fluorescent sensor - Google Patents
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- WO2014045387A1 WO2014045387A1 PCT/JP2012/074178 JP2012074178W WO2014045387A1 WO 2014045387 A1 WO2014045387 A1 WO 2014045387A1 JP 2012074178 W JP2012074178 W JP 2012074178W WO 2014045387 A1 WO2014045387 A1 WO 2014045387A1
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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"
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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
- G01N21/645—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 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 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.
- An object of the present invention is to provide a fluorescent sensor with high detection sensitivity.
- the fluorescent sensor of one embodiment of the present invention includes a substrate portion having a hole, an indicator that is disposed inside the hole and receives excitation light and generates fluorescence having an intensity according to the concentration of the analyte, A cover portion made of a semiconductor material formed with a light emitting element that generates excitation light, a through-hole through which the analyte passes, covering the opening of the hole, and a photoelectric conversion element that converts the fluorescence into an electrical signal;
- FIG. 5 is an exploded cross-sectional view taken along the line VV of FIG. 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 fluorescence sensor 4 of the first embodiment detects glucose in the body fluid of the subject.
- the sensor unit 10 includes a bonded substrate unit 30 in which the frame-shaped substrate unit 40 having the through hole 40X and the wiring substrate unit 20 are bonded, and an indicator disposed in the through hole 40X. 17 and the light emitting element 15, a cover portion 18 that covers the opening on the upper surface of the through hole 40 ⁇ / b> X, and a light shielding layer 19 that covers the cover portion 18.
- the cover portion 18 is made of a semiconductor material through which the analyte 9 passes, in which a photodiode element (hereinafter referred to as “PD element”) 12 that is a photoelectric conversion element that converts the fluorescence F into an electrical signal is formed.
- PD element photodiode element
- the cover portion 18 is made of, for example, a silicon substrate having a minute through hole 18X, and the light receiving portion 12T of the PD element 12 is formed on one surface.
- the PD element 12 includes a light receiving portion 12T and a low resistance region 12H having a high conductivity in which impurities are partially introduced.
- the light receiving portion 12T may be referred to as a PD element 12.
- the minute through hole 18 ⁇ / b> X of the cover part 18 is an entry path through which the body fluid including the analyte 9 enters the indicator 17. That is, the body part can pass through the cover part 18.
- the size, shape, position, and formation density of the minute through holes 18X of the cover portion 18 are appropriately selected according to the specifications.
- the minute through holes 18X do not need to be arranged in an orderly manner as shown in FIG.
- 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 cover portion 18 in which the minute through hole 18X is formed is produced by patterning the minute through hole 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.
- the cover portion 18 may be made of a porous semiconductor through which an analyte-containing solution can pass.
- 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 part 18 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 light shielding layer 19 prevents the excitation light E and the fluorescence F from leaking to the outside, and at the same time, prevents the external light G from entering the indicator 17.
- the light shielding layer 19 has, for example, a submicron pore structure that does not prevent the analyte 9 from passing through the inside thereof and reaching the indicator 17.
- the light shielding layer 19 is made of 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 a cellulose or polyacrylamide.
- a resin in which carbon black is mixed into an analyte-permeable polymer or a resin in which these are laminated is used.
- the frame-like substrate portion 40 and the wiring substrate portion 20 are 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. Use.
- the same silicon as the material of the cover portion 18A is particularly preferable.
- the through hole 40X in which the indicator 17 and the light emitting element 15 are housed is a wiring board portion 20 on the lower surface, the cover portion 18 on the upper surface, and a concave portion of the frame-like substrate portion 40 on the side surface.
- the shape of the through hole 40X is a rectangular parallelepiped (quadrangular columnar shape), but may be a columnar shape, a polygonal columnar shape, or the like.
- the side surface of the through hole 40X may be inclined with respect to the main surface.
- a reflective film that reflects fluorescence 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.
- a wiring 61 for transmitting a signal of the PD element 12 among the wiring 60 is formed in the cover portion 18.
- the wirings 51 and 61 are a part of the plurality of wirings 60.
- a filter that transmits the fluorescence F and blocks the excitation light E is disposed on the light receiving surface of the PD element 12, that is, the lower surface of the cover portion 18. May be.
- 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.
- the light emitting element 15 may be sealed with a transparent intermediate layer up to the upper surface. The resin-sealed light emitting element 15 is not easily affected by the moisture of the indicator 17.
- the indicator 17 is made of a hydrogel having a fluorescent dye that generates fluorescence F having a wavelength longer than that of the excitation light E by the analyte 9 and the excitation light E. That is, the indicator 17 is composed of a hydrogel that contains the fluorescent dye that generates the fluorescent light F with a light amount corresponding to the analyte concentration in the sample and that allows the excitation light E and the fluorescent light F to pass therethrough satisfactorily.
- the indicator 17 may be the analyte 9 itself in which the fluorescent dye that does not include the fluorescent dye and generates the fluorescence F exists in the solution.
- Hydrogel is water such as acrylic hydrogel produced by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel produced from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.
- the hydrogel has a size that does not leave the sensor through the cover 18 and the light shielding layer 19. For this reason, it is preferable that the hydrogel has a molecular weight of 1,000,000 or more, or is in the form of particles having a diameter equal to or larger than the pore diameter of the cover portion 18, for example, 50 nm or larger, or is in a form in which it does not flow.
- phenylboronic acid derivatives having a fluorescent residue are suitable as fluorescent dyes.
- the fluorescent dye is prevented from detaching from the sensor by using a high molecular weight material or chemically fixing to a hydrogel.
- 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 transmits the fluorescence F 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.
- 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 by the indicator 17 enters the PD element 12 on the upper surface of the indicator 17. For this reason, the fluorescence sensor 4 is more sensitive than the conventional fluorescence sensor 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 fluorescence sensor 4A is the same as the fluorescence sensor 4 in that the PD element 12 is formed on the cover portion 18A, but differs in that the light shielding layer 19 is not provided.
- the cover portion 18A has the function of the light shielding layer 19, that is, the function of preventing the entry of the external light G and the leakage of the excitation light E and the fluorescence F.
- the size D of the minute through hole 18X of the cover portion 18A is equal to or less than the wavelength of the excitation light E, light leakage can be prevented.
- the lower limit value of the size D of the minute through hole 18X is equal to or larger than the size through which the analyte 9 can pass. Therefore, the size D of the minute through hole 18X is preferably 1 nm to 350 nm, more preferably 10 nm to 350 nm, and still more preferably 100 nm to 300 nm when the analyte 9 is glucose, for example.
- the size D of the minute through hole 18X is the maximum length of the opening, and is the diameter when the opening is circular, and is an average value calculated from an electron micrograph.
- the cover portion 18A1 of the fluorescent sensor 4A1 in the modification of the second embodiment, the cover portion 18a and the cover portion 18b are arranged so that the minute through holes 18X1 and 18X2 are alternately arranged. Are stacked via a predetermined gap 18c.
- cover part 18A1 has laminated
- a porous material through which a body fluid can pass may be used.
- the sizes D1 and D2 of the minute through holes 18X1 and 18X2 of the cover portion 18A1 may exceed the wavelength of the excitation light E unlike the cover portion 18A. This is because even a cover portion having a small opening with a large opening has good light-shielding properties if the minute through-holes are alternately laminated.
- the cover portion having a laminated structure in which the thickness T of the gap 18c is smaller than the wavelength of the excitation light and larger than the size of the analyte 9 allows the analyte 9 to pass therethrough and has a very good light shielding property.
- Fluorescent sensor 4A and fluorescent sensor 4A1 have the effect of fluorescent sensor 4 and have a simple structure.
- the fluorescence sensor 4B of the third embodiment will be described. Since the fluorescence sensor 4B is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals, and description thereof is omitted.
- the fluorescence sensor 4B is the same as the fluorescence sensor 4A in that the PD element 12 is formed on the cover portion 18A.
- the fluorescent sensor 4B is a second photoelectric conversion element on at least one side surface (wall surface) of the bottomed recess 30X that is a hole filled with the indicator 17, that is, on at least one side surface side of the indicator 17.
- the PD element 12B is formed, and the light emitting element 15 is disposed on the bottom surface of the recess 30X.
- the PD element 12B which is the second photoelectric conversion element, is formed on the four wall surfaces of the concave portion 30X having a rectangular opening formed in the substrate portion 30B made of a semiconductor such as silicon, and the light emitting element is formed on the bottom surface of the concave portion 30X. 15 is disposed. Note that the opening surface of the recess 30X is wider than the bottom surface, and the side surface is inclined at a predetermined angle ⁇ rather than perpendicular (90 degrees) to the bottom surface.
- a plurality of through wirings are formed on the bottom surface of the recess 30X of the substrate part 30B, and a drive signal is transmitted to the light emitting element 15 and a signal of the PD element 12B is transmitted through the through wiring. .
- the fluorescence sensor 4B will be briefly described. In addition, although it may manufacture for every one fluorescence sensor 4B, it is preferable to manufacture many sensors collectively as a wafer process.
- a mask layer having a plurality of openings is manufactured on the first main surface of a silicon wafer having an area where a plurality of elements can be manufactured. Then, a plurality of concave portions 30X having a bottom surface parallel to the first main surface is formed by an etching method.
- etching method a wet etching method using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution, or the like is preferable, but dry etching such as reactive ion etching (RIE) or chemical dry etching (CDE) is used.
- TMAH tetramethylammonium hydroxide
- KOH potassium hydroxide
- CDE chemical dry etching
- PD elements 12B are formed on the four side surfaces of the respective recesses 30X by a known semiconductor process.
- the concave portion 30X whose side surface is inclined not only has a larger area in which the PD element 12 can be formed, but also the PD element 12D can be easily formed on the side surface than the concave portion whose vertical side surface is vertical. If the inclination angle ⁇ of the side surface is 30 to 70 degrees, the above effect is remarkable.
- the light emitting elements 15 are respectively disposed on the bottom surfaces of the plurality of recesses 30X. Furthermore, the indicator 17 is filled in the concave portion, and the cover portion 18 on which the PD element 12 is formed is joined so as to close the opening of the concave portion 30X. Then, the silicon wafer on which the plurality of sensors are formed is separated into pieces, and the fluorescent sensor 4B is completed.
- the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61.
- the fluorescent light F2 emitted from the indicator 17 to the lateral side is received by the PD element 12B, and a signal is transmitted through the wiring 62 (60).
- the fluorescence sensor 4B has the same effect as the fluorescence sensor 4A and the like, and further, the PD element 12B as the second photoelectric conversion element is also formed on the side surface side of the indicator 17, so that the sensitivity is higher.
- the fluorescent sensor 4C shown in FIG. 12 is a second photoelectric conversion element on the side where the PD element 12 is formed in the cover portion 18A and the hole filled with the indicator 17. This is the same in that the PD element 12B is formed.
- the hole is a through hole 30X1 formed in the substrate portion 30C, and the light emitting element 15 is disposed so as to cover the opening on the lower surface of the through hole 30X1.
- the substrate portion 30C is made of silicon
- the through hole 30X1 is formed by etching
- the PD element 12B is formed by a known semiconductor process.
- the substrate portion 30C is not a semiconductor, a silicon film is formed on the wall surface after the through hole is formed, for example, by a CVD method.
- an electrode pad for mounting the light emitting element 15 is disposed on the bottom surface 30SB of the substrate portion 30C, and the electrode pad is connected to the wiring 51 disposed on the bottom surface 30SB.
- a wiring 62 for transmitting a signal from the PD element 12B is also provided on the bottom surface 30SB.
- the fluorescence sensor 4C has higher sensitivity because the PD element 12B, which is the second photoelectric conversion element, is formed on the side surface of the indicator 17 as well as the fluorescence sensor 4B. Furthermore, since it is not necessary to form a through wiring, the manufacturing is easier than the fluorescent sensor 4B.
- the fluorescence sensor 4D of the fifth embodiment will be described. Since the fluorescence sensor 4D is similar to the fluorescence sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.
- the substrate part 30D of the fluorescence sensor 4D is made of a semiconductor such as silicon on which the frame-like substrate part 40D in which the second through hole 40X serving as a hole is formed and the PD element 12D which is the third photoelectric conversion element is formed. This is a bonded substrate portion to which the detection substrate portion 20D made of is bonded. And the light emitting element 15 is mounted in the detection board
- the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61.
- the fluorescent light F3 emitted downward from the indicator 17 is received by the PD element 12D, and a signal is transmitted through the wiring 63 (60).
- the fluorescence sensor 4D has the effect of the fluorescence sensor 4, and further has a higher sensitivity because the PD element 12D, which is the third photoelectric conversion element, is also formed on the bottom surface side of the through hole 40X.
- Fluorescent sensors 4E to 4H are all the same as fluorescent sensor 4 and the like in that each has a cover portion on which a PD element is formed.
- one large through hole 18XE is formed in the approximate center of the cover portion 18E. That is, as already described, in the case where the light shielding layer 19 is present, the size and number of through holes in the cover portion are not limited.
- a through hole 12X is formed in the approximate center of the PD element 12F, which is a third light receiving portion disposed below the indicator 17.
- the light emitting element 15 is arrange
- the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, and the fluorescence F2 emitted downward is detected by the PD element 12F.
- the excitation light E from the light emitting element 15 enters the indicator 17 through the through hole 12X.
- a plurality of through holes 12X may be formed in the PD element 12F.
- the fluorescent sensor 4F has an SOI (active layer (SOI layer)) that is disposed on a support substrate layer (substrate layer) via a buried silicon oxide film (Buried Oxide: BOX layer). It can be easily manufactured by using a silicon on insulator substrate. That is, the indicator 17 is disposed in the through via formed in the substrate layer of the SOI substrate, the through via 12X is formed in the active layer, and the PD element 12F is formed so as to surround the through via 12X.
- SOI active layer
- BOX layer buried silicon oxide film
- the fluorescence sensor 4G of the eighth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4D shown in FIG. 15 are combined.
- the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12
- the fluorescence F2 emitted horizontally is detected by the PD element 12B
- the fluorescence F2 emitted downward is the PD element. Detected by 12D.
- the fluorescence sensor 4H of the ninth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4F shown in FIG. 17 are combined.
- the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12
- the fluorescence F2 emitted horizontally is detected by the PD element 12B
- the fluorescence F2 emitted downward is the PD element. It is detected by 12F.
- Each of the fluorescence sensors 4E to 4H has the effect of the fluorescence sensor 4, and further emits in another direction in addition to the PD element formed on the cover portion that receives the fluorescence emitted upward. Since it has a PD element that receives fluorescence, it has higher sensitivity.
- 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 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) having: a substrate section (30) comprising a hole (40X); an indicator (17) arranged inside the hole (40X) and which receives excitation light (E) and generates fluorescent light (F) having an intensity corresponding to the concentration of an analyte (9); a light-emitting element (15) that generates the excitation light (E); and a cover section (18) covering the hole (40X) and comprising a semiconductor material having formed therein a through-hole (18X) through which the analyte (9) passes and a PD element (12) that converts the fluorescent light (F) to an electric signal.
Description
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。
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。 Various analyzers for measuring the concentration of an analyte in a solution, that is, a substance to be measured have been developed. For example, 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. Yes. 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. And 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.
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。 Various analyzers for measuring the concentration of an analyte in a solution, that is, a substance to be measured have been developed. For example, 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. Yes. 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. And 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.
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)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.
本発明は、検出感度が高い蛍光センサを提供することを目的とする。
An object of the present invention is to provide a fluorescent sensor with high detection sensitivity.
本発明の一態様の蛍光センサは、穴のある基板部と、前記穴の内部に配設された、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インジケータと、前記励起光を発生する発光素子と、前記穴の開口を覆う、前記アナライトが通過する貫通孔と、前記蛍光を電気信号に変換する光電変換素子とが形成された半導体材料からなるカバー部と、を有する。
The fluorescent sensor of one embodiment of the present invention includes a substrate portion having a hole, an indicator that is disposed inside the hole and receives excitation light and generates fluorescence having an intensity according to the concentration of the analyte, A cover portion made of a semiconductor material formed with a light emitting element that generates excitation light, a through-hole through which the analyte passes, covering the opening of the hole, and a photoelectric conversion element that converts the fluorescence into an electrical signal; Have
<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>
Thefluorescence 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.
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
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7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軸方向を上方向という。 <Structure of sensor part>
Next, the structure of thesensor 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.
次に、図4~図7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軸方向を上方向という。 <Structure of sensor part>
Next, the structure of the
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のある枠状基板部40と配線基板部20とが接合された接合基板部30と、貫通孔40Xに配設されたインジケータ17及び発光素子15と、貫通孔40Xの上面の開口を覆うカバー部18と、カバー部18を覆う遮光層19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 a bonded substrate unit 30 in which the frame-shaped substrate unit 40 having the through hole 40X and the wiring substrate unit 20 are bonded, and an indicator disposed in the through hole 40X. 17 and the light emitting element 15, a cover portion 18 that covers the opening on the upper surface of the through hole 40 </ b> X, and a light shielding layer 19 that covers the cover portion 18.
蛍光センサ4では、カバー部18が、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イオード素子(以下「PD素子」という)12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。すなわち、図7に示すように、カバー部18は微少貫通孔18Xのある、例えばシリコン基板からなり、片面にPD素子12の受光部12Tが形成されている。なお、PD素子12は受光部12Tと部分的に不純物を導入した導電率の高い低抵抗領域12Hとから構成されているが、以下、受光部12Tを、PD素子12ということがある。
In the fluorescence sensor 4, the cover portion 18 is made of a semiconductor material through which the analyte 9 passes, in which a photodiode element (hereinafter referred to as “PD element”) 12 that is a photoelectric conversion element that converts the fluorescence F into an electrical signal is formed. . That is, as shown in FIG. 7, the cover portion 18 is made of, for example, a silicon substrate having a minute through hole 18X, and the light receiving portion 12T of the PD element 12 is formed on one surface. The PD element 12 includes a light receiving portion 12T and a low resistance region 12H having a high conductivity in which impurities are partially introduced. Hereinafter, the light receiving portion 12T may be referred to as a PD element 12.
カバー部18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17に進入する進入経路である。すなわち、カバー部18は体液が通過可能である。
The minute through hole 18 </ b> X of the cover part 18 is an entry path through which the body fluid including the analyte 9 enters the indicator 17. That is, the body part can pass through the cover part 18.
カバー部18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は図7に示すように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 portion 18 are appropriately selected according to the specifications. For example, the minute through holes 18X do not need to be arranged in an orderly manner as shown in FIG. 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が形成されたカバー部18は、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 cover portion 18 in which the minute through hole 18X is formed is produced by patterning the minute through hole 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18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, the cover portion 18 may be made of a porous semiconductor through which an analyte-containing solution can pass. 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18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 part 18 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.
遮光層19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 light shielding layer 19 prevents the excitation light E and the fluorescence F from leaking to the outside, and at the same time, prevents the external light G from entering the indicator 17.
遮光層19は、アナライト9が、その内部を通過してインジケータ17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19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 light shielding layer 19 has, for example, a submicron pore structure that does not prevent the analyte 9 from passing through the inside thereof and reaching the indicator 17. The light shielding layer 19 is made of 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 a cellulose or polyacrylamide. A resin in which carbon black is mixed into an analyte-permeable polymer or a resin in which these are laminated is used.
枠状基板部40及び配線基板部20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。
The frame-like substrate portion 40 and the wiring substrate portion 20 are 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. Use. The same silicon as the material of the cover portion 18A is particularly preferable.
インジケータ17及び発光素子15が内部に収容されている貫通孔40Xは、下面が配線基板部20であり、上面がカバー部18であり、側面が枠状基板部40の凹部である。貫通孔40Xの形状は直方体(四角柱状)であるが、円柱状、または多角柱状等であってもよい。
The through hole 40X in which the indicator 17 and the light emitting element 15 are housed is a wiring board portion 20 on the lower surface, the cover portion 18 on the upper surface, and a concave portion of the frame-like substrate portion 40 on the side surface. The shape of the through hole 40X is a rectangular parallelepiped (quadrangular columnar shape), but may be a columnar shape, a polygonal columnar shape, or the like.
なお、後述するように貫通孔40Xの側面は主面に対して傾斜していてもよい。また、側面に蛍光を反射する反射膜が配設されていてもよい。
As will be described later, the side surface of the through hole 40X may be inclined with respect to the main surface. In addition, a reflective film that reflects fluorescence 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18には、配線60のうちPD素子12の信号を伝送する配線61が形成されている。配線51、61は複数の配線60の一部である。
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. A wiring 61 for transmitting a signal of the PD element 12 among the wiring 60 is formed in the cover portion 18. The wirings 51 and 61 are a part of the plurality of wirings 60.
なお、PD素子12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12の受光面、すなわち、カバー部18の下面に配設してもよい。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が上面まで透明中間層で封止されていてもよい。樹脂封止されている発光素子15は、インジケータ17の水分の影響を受けにくい。
In order to prevent the excitation light E from entering the PD element 12, a filter that transmits the fluorescence F and blocks the excitation light E is disposed on the light receiving surface of the PD element 12, that is, the lower surface of the cover portion 18. May be. 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 with a transparent intermediate layer up to the upper surface. The resin-sealed light emitting element 15 is not easily affected by the moisture of the indicator 17.
インジケータ17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。すなわちインジケータ17は、試料中のアナライト濃度に応じた光量の蛍光Fを発生する蛍光色素が含まれる、励起光E及び蛍光Fが良好に透過するハイドロゲルから構成されている。なお、インジケータ17が蛍光色素を含まず、蛍光Fを発生する蛍光色素が溶液中に存在するアナライト9そのものでもよい。
The indicator 17 is made of a hydrogel having a fluorescent dye that generates fluorescence F having a wavelength longer than that of the excitation light E by the analyte 9 and the excitation light E. That is, the indicator 17 is composed of a hydrogel that contains the fluorescent dye that generates the fluorescent light F with a light amount corresponding to the analyte concentration in the sample and that allows the excitation light E and the fluorescent light F to pass therethrough satisfactorily. The indicator 17 may be the analyte 9 itself in which the fluorescent dye that does not include the fluorescent dye and generates the fluorescence F exists in the solution.
ハイドロゲルは、メチルセルロースもしくはデキストラン等の多糖類、アクリルアミド、メチロールアクリルアミド、ヒドロキシエチルアクリレート等のモノマーを重合して作製するアクリル系ハイドロゲル、またはポリエチレングリコールとジイソシアネートから作製するウレタン系ハイドロゲル等の水を含みやすい材料に蛍光色素を内包することにより形成されている。
Hydrogel is water such as acrylic hydrogel produced by polymerizing monomers such as polysaccharides such as methylcellulose or dextran, acrylamide, methylolacrylamide, hydroxyethyl acrylate, or urethane hydrogel produced from polyethylene glycol and diisocyanate. It is formed by encapsulating a fluorescent dye in a material that is easy to contain.
ハイドロゲルは、カバー部18及び遮光層19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18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 leave the sensor through the cover 18 and the light shielding layer 19. For this reason, it is preferable that the hydrogel has a molecular weight of 1,000,000 or more, or is in the form of particles having a diameter equal to or larger than the pore diameter of the cover portion 18, for example, 50 nm or larger, or is in a form in which it does not flow.
一方、蛍光色素としては、グルコース等の糖類を測定する場合には、蛍光残基を有するフェニルボロン酸誘導体等が適している。蛍光色素は、高分子量材料としたり、または、ハイドロゲルに化学的に固定したりすることにより、センサ外に離脱することが防止されている。
On the other hand, when measuring sugars such as glucose, phenylboronic acid derivatives having a fluorescent residue are suitable as fluorescent dyes. The fluorescent dye is prevented from detaching from the sensor by using a high molecular weight material or chemically fixing to a hydrogel.
蛍光色素と、ゲル骨格形成材と、重合開始剤と、を含むリン酸緩衝液を、窒素雰囲気下で1時間放置し、重合することにより、インジケータは作製される。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、蛍光Fを透過する素子が選択される。
As the light emitting element 15, an element that transmits the fluorescence F 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.
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.
図6に示すように、蛍光センサ4では、インジケータ17が発生した蛍光Fは、インジケータ17の上面のPD素子12に入射する。このため、蛍光センサ4は従来の蛍光センサ104よりも高感度である。
As shown in FIG. 6, in the fluorescence sensor 4, the fluorescence F generated by the indicator 17 enters the PD element 12 on the upper surface of the indicator 17. For this reason, the fluorescence sensor 4 is more sensitive than the conventional fluorescence sensor 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, thefluorescence 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.
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
図8に示すように蛍光センサ4Aは、蛍光センサ4と比較すると、カバー部18AにPD素子12が形成されている点では同じであるが、遮光層19を有していない点で異なっている。そして、蛍光センサ4Aでは、カバー部18Aが遮光層19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。
As shown in FIG. 8, the fluorescence sensor 4A is the same as the fluorescence sensor 4 in that the PD element 12 is formed on the cover portion 18A, but differs in that the light shielding layer 19 is not provided. . In the fluorescence sensor 4A, the cover portion 18A has the function of the light shielding layer 19, that is, the function of preventing the entry of the external light G and the leakage of the excitation light E and the fluorescence F.
図9Aに示すように、蛍光センサ4Aでは、カバー部18Aの微少貫通孔18Xの大きさDが励起光Eの波長以下であるために、漏光を防止できる。なお微少貫通孔18Xの大きさDの下限値は、アナライト9が通過できる大きさ以上である。このため、微少貫通孔18Xの大きさDは、例えばアナライト9がグルコースの場合には、1nm~350nmが好ましく、より好ましくは10nm~350nm、さらに好ましくは100nm~300nmである。なお、微少貫通孔18Xの大きさDとは開口の最大長であり、開口が円形の場合は直径であり、電子顕微鏡写真から算出した平均値である。
As shown in FIG. 9A, in the fluorescence sensor 4A, since the size D of the minute through hole 18X of the cover portion 18A is equal to or less than the wavelength of the excitation light E, light leakage can be prevented. The lower limit value of the size D of the minute through hole 18X is equal to or larger than the size through which the analyte 9 can pass. Therefore, the size D of the minute through hole 18X is preferably 1 nm to 350 nm, more preferably 10 nm to 350 nm, and still more preferably 100 nm to 300 nm when the analyte 9 is glucose, for example. The size D of the minute through hole 18X is the maximum length of the opening, and is the diameter when the opening is circular, and is an average value calculated from an electron micrograph.
また、図9Bに示すように第2実施形態の変形例の蛍光センサ4A1のカバー部18A1では、カバー部18aとカバー部18bとが、それぞれの微少貫通孔18X1、18X2が互い違いに配置されるように、所定の空隙18cを介して積層されている。微少貫通孔が互い違いの積層構造のカバー部18A1は、外光G、励起光E及び蛍光Fを効率的に遮るとともに、体液が通過可能である。なお、カバー部18A1は、カバー部18aとカバー部18bを積層しているが、3層以上のカバー部を積層してもよい。また空隙18cに替えて、体液が通過可能な、例えば多孔質等を用いてもよい。
9B, in the cover portion 18A1 of the fluorescent sensor 4A1 according to the modification of the second embodiment, the cover portion 18a and the cover portion 18b are arranged so that the minute through holes 18X1 and 18X2 are alternately arranged. Are stacked via a predetermined gap 18c. The cover portion 18A1 having a laminated structure in which minute through-holes are staggered effectively blocks external light G, excitation light E, and fluorescence F, and allows body fluid to pass through. In addition, although cover part 18A1 has laminated | stacked the cover part 18a and the cover part 18b, you may laminate | stack three or more cover parts. Further, instead of the gap 18c, for example, a porous material through which a body fluid can pass may be used.
カバー部18A1の微少貫通孔18X1、18X2の大きさD1、D2は、カバー部18Aと異なり励起光Eの波長を超えてもよい。大きな開口の微少貫通孔のあるカバー部であっても、微少貫通孔が互い違いの積層構造であれば、良好な遮光性を有するからである。特に、空隙18cの厚さTが励起光の波長より小さく、かつアナライト9の大きさより大きい積層構造のカバー部は、アナライト9が通過可能で、かつ、非常に良好な遮光性を有する。
The sizes D1 and D2 of the minute through holes 18X1 and 18X2 of the cover portion 18A1 may exceed the wavelength of the excitation light E unlike the cover portion 18A. This is because even a cover portion having a small opening with a large opening has good light-shielding properties if the minute through-holes are alternately laminated. In particular, the cover portion having a laminated structure in which the thickness T of the gap 18c is smaller than the wavelength of the excitation light and larger than the size of the analyte 9 allows the analyte 9 to pass therethrough and has a very good light shielding property.
蛍光センサ4A及び蛍光センサ4A1は、蛍光センサ4の効果を有し、さらに構造が簡単である。
Fluorescent sensor 4A and fluorescent sensor 4A1 have the effect of fluorescent sensor 4 and have a simple structure.
<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, thefluorescence sensor 4B of the third embodiment will be described. Since the fluorescence sensor 4B is similar to the fluorescence sensor 4, the same components are denoted by the same reference numerals, and description thereof is omitted.
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
図10に示すように蛍光センサ4Bは、蛍光センサ4Aと比較すると、カバー部18AにPD素子12が形成されている点では同じである。しかし、蛍光センサ4Bには、インジケータ17が充填された穴である有底の凹部30Xの少なくとも一の側面(壁面)、すなわち、インジケータ17の少なくとも一の側面側に第2の光電変換素子であるPD素子12Bが形成されており、凹部30Xの底面に発光素子15が配設されている。
As shown in FIG. 10, the fluorescence sensor 4B is the same as the fluorescence sensor 4A in that the PD element 12 is formed on the cover portion 18A. However, the fluorescent sensor 4B is a second photoelectric conversion element on at least one side surface (wall surface) of the bottomed recess 30X that is a hole filled with the indicator 17, that is, on at least one side surface side of the indicator 17. The PD element 12B is formed, and the light emitting element 15 is disposed on the bottom surface of the recess 30X.
すなわち、シリコン等の半導体からなる基板部30Bに形成された、開口部が矩形の凹部30Xの4つの壁面に第2の光電変換素子であるPD素子12Bが形成され、凹部30Xの底面に発光素子15が配設されている。なお、凹部30Xの開口面は底面よりも広く、側面は、底面に対して垂直(90度)ではなく所定の角度θで傾斜している。
That is, the PD element 12B, which is the second photoelectric conversion element, is formed on the four wall surfaces of the concave portion 30X having a rectangular opening formed in the substrate portion 30B made of a semiconductor such as silicon, and the light emitting element is formed on the bottom surface of the concave portion 30X. 15 is disposed. Note that the opening surface of the recess 30X is wider than the bottom surface, and the side surface is inclined at a predetermined angle θ rather than perpendicular (90 degrees) to the bottom surface.
なお、図示しないが、基板部30Bの凹部30Xの底面には複数の貫通配線が形成されており、貫通配線を介して発光素子15に駆動信号を伝送するとともに、PD素子12Bの信号を伝送する。
Although not shown, a plurality of through wirings are formed on the bottom surface of the recess 30X of the substrate part 30B, and a drive signal is transmitted to the light emitting element 15 and a signal of the PD element 12B is transmitted through the through wiring. .
次に、蛍光センサ4Bの製造方法について簡単に説明する。なお、1個の蛍光センサ4B毎に製造してもよいが、ウエハプロセスとして一括して多数のセンサを製造することが好ましい。
Next, a method for manufacturing the fluorescence sensor 4B will be briefly described. In addition, although it may manufacture for every one fluorescence sensor 4B, it is preferable to manufacture many sensors collectively as a wafer process.
最初に、複数の素子が作製可能な面積を有するシリコンウエハの第1の主面に複数の開口を有するマスク層が作製される。そして、エッチング法により、第1の主面と平行な底面のある複数の凹部30Xが形成される。
First, a mask layer having a plurality of openings is manufactured on the first main surface of a silicon wafer having an area where a plurality of elements can be manufactured. Then, a plurality of concave portions 30X having a bottom surface parallel to the first main surface is formed by an etching method.
エッチング法としては、水酸化テトラメチルアンモニウム(TMAH)水溶液、水酸化カリウム(KOH)水溶液などを用いるウエットエッチング法が望ましいが、反応性イオンエッチング(RIE)、ケミカルドライエッチング(CDE)などのドライエッチング法も用いてもよい
例えば、シリコンウエハとしてシリコン(100)面を用いた場合には、(111)面のエッチング速度が(100)面に比べて遅い異方性エッチングとなるため、凹部の側面は(111)面となり、(100)面(底面)との角度は、54.7度となる。 As an etching method, a wet etching method using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution, or the like is preferable, but dry etching such as reactive ion etching (RIE) or chemical dry etching (CDE) is used. For example, when a silicon (100) plane is used as a silicon wafer, the etching speed of the (111) plane is anisotropic etching compared to the (100) plane, so the side surface of the recess Becomes the (111) plane, and the angle with the (100) plane (bottom surface) is 54.7 degrees.
例えば、シリコンウエハとしてシリコン(100)面を用いた場合には、(111)面のエッチング速度が(100)面に比べて遅い異方性エッチングとなるため、凹部の側面は(111)面となり、(100)面(底面)との角度は、54.7度となる。 As an etching method, a wet etching method using a tetramethylammonium hydroxide (TMAH) aqueous solution, a potassium hydroxide (KOH) aqueous solution, or the like is preferable, but dry etching such as reactive ion etching (RIE) or chemical dry etching (CDE) is used. For example, when a silicon (100) plane is used as a silicon wafer, the etching speed of the (111) plane is anisotropic etching compared to the (100) plane, so the side surface of the recess Becomes the (111) plane, and the angle with the (100) plane (bottom surface) is 54.7 degrees.
次に、それぞれの凹部30Xの4側面にPD素子12Bが公知の半導体プロセスにより形成される。側面が傾斜している凹部30Xは、側面が垂直な凹部に比べてPD素子12を形成できる面積が広いだけでなく、側面へのPD素子12Dの形成が容易である。なお側面の傾斜角度θが30~70度であれば、上記効果が顕著である。
Next, PD elements 12B are formed on the four side surfaces of the respective recesses 30X by a known semiconductor process. The concave portion 30X whose side surface is inclined not only has a larger area in which the PD element 12 can be formed, but also the PD element 12D can be easily formed on the side surface than the concave portion whose vertical side surface is vertical. If the inclination angle θ of the side surface is 30 to 70 degrees, the above effect is remarkable.
複数の凹部30Xの底面に、それぞれ発光素子15が配設される。さらに、凹部内にインジケータ17が充填され、凹部30Xの開口を塞ぐように、PD素子12が形成されたカバー部18が接合される。そして複数のセンサが形成されたシリコンウエハが個片化され蛍光センサ4Bが完成する。
The light emitting elements 15 are respectively disposed on the bottom surfaces of the plurality of recesses 30X. Furthermore, the indicator 17 is filled in the concave portion, and the cover portion 18 on which the PD element 12 is formed is joined so as to close the opening of the concave portion 30X. Then, the silicon wafer on which the plurality of sensors are formed is separated into pieces, and the fluorescent sensor 4B is completed.
図11に示すように蛍光センサ4Bでは、インジケータ17から上側に出射される蛍光F1はPD素子12により受光され信号が配線61を介して伝送される。また、インジケータ17から横側に出射される蛍光F2はPD素子12Bにより受光され信号が、配線62(60)を介して伝送される。
As shown in FIG. 11, in the fluorescence sensor 4B, the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61. The fluorescent light F2 emitted from the indicator 17 to the lateral side is received by the PD element 12B, and a signal is transmitted through the wiring 62 (60).
蛍光センサ4Bは蛍光センサ4A等と同様の効果を有し、さらにインジケータ17の側面側にも第2の光電変換素子であるPD素子12Bが、形成されているため、より高感度である。
The fluorescence sensor 4B has the same effect as the fluorescence sensor 4A and the like, and further, the PD element 12B as the second photoelectric conversion element is also formed on the side surface side of the indicator 17, so that the sensitivity is higher.
<第4実施形態>
次に、第4実施形態の蛍光センサ4Cについて説明する。蛍光センサ4Cは蛍光センサ4B等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, thefluorescence sensor 4C of the fourth embodiment will be described. Since the fluorescence sensor 4C 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.
次に、第4実施形態の蛍光センサ4Cについて説明する。蛍光センサ4Cは蛍光センサ4B等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
図12に示す蛍光センサ4Cは、蛍光センサ4Bと比較すると、カバー部18AにPD素子12が形成されている点、及び、インジケータ17が充填された穴の側面に第2の光電変換素子であるPD素子12Bが形成されている点で同じである。
Compared with the fluorescent sensor 4B, the fluorescent sensor 4C shown in FIG. 12 is a second photoelectric conversion element on the side where the PD element 12 is formed in the cover portion 18A and the hole filled with the indicator 17. This is the same in that the PD element 12B is formed.
しかし、蛍光センサ4Cでは、穴は基板部30Cに形成された貫通孔30X1であり、貫通孔30X1の下面の開口を覆うように発光素子15が配設されている。基板部30Cがシリコンからなる場合には、貫通孔30X1はエッチングにより形成され、PD素子12Bは公知の半導体プロセスにより形成される。基板部30Cが半導体でない場合には、貫通孔形成後に壁面に、例えばCVD法によりシリコン膜が形成される。
However, in the fluorescence sensor 4C, the hole is a through hole 30X1 formed in the substrate portion 30C, and the light emitting element 15 is disposed so as to cover the opening on the lower surface of the through hole 30X1. When the substrate portion 30C is made of silicon, the through hole 30X1 is formed by etching, and the PD element 12B is formed by a known semiconductor process. When the substrate portion 30C is not a semiconductor, a silicon film is formed on the wall surface after the through hole is formed, for example, by a CVD method.
図示しないが、基板部30Cの底面30SBには発光素子15を実装する電極パッドが配設されており、電極パッドは底面30SBに配設された配線51と接続されている。また、底面30SBにはPD素子12Bの信号を伝送する配線62も配設されている。
Although not shown, an electrode pad for mounting the light emitting element 15 is disposed on the bottom surface 30SB of the substrate portion 30C, and the electrode pad is connected to the wiring 51 disposed on the bottom surface 30SB. A wiring 62 for transmitting a signal from the PD element 12B is also provided on the bottom surface 30SB.
図13に示すように蛍光センサ4Cは、蛍光センサ4Bと同様にインジケータ17の側面側にも第2の光電変換素子であるPD素子12Bが形成されているため、より高感度である。さらに、貫通配線を形成する必要がないため、蛍光センサ4Bよりも製造が容易である。
As shown in FIG. 13, the fluorescence sensor 4C has higher sensitivity because the PD element 12B, which is the second photoelectric conversion element, is formed on the side surface of the indicator 17 as well as the fluorescence sensor 4B. Furthermore, since it is not necessary to form a through wiring, the manufacturing is easier than the fluorescent sensor 4B.
<第5実施形態>
次に、第5実施形態の蛍光センサ4Dについて説明する。蛍光センサ4Dは蛍光センサ4等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, thefluorescence sensor 4D of the fifth embodiment will be described. Since the fluorescence sensor 4D is similar to the fluorescence sensor 4 and the like, the same components are denoted by the same reference numerals and description thereof is omitted.
次に、第5実施形態の蛍光センサ4Dについて説明する。蛍光センサ4Dは蛍光センサ4等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
図14に示す蛍光センサ4Dは、蛍光センサ4Aと比較すると、カバー部18AにPD素子12が形成されている点では同じである。しかし、蛍光センサ4Dの基板部30Dは、穴となる第2の貫通孔40Xの形成された枠状基板部40Dと、第3の光電変換素子であるPD素子12Dが形成されたシリコン等の半導体からなる検出基板部20Dと、が接合された接合基板部である。そして、貫通孔40Xの底面を構成する検出基板部20Dに発光素子15が実装されている。
14 is the same as the fluorescence sensor 4A in that the PD element 12 is formed in the cover portion 18A as compared with the fluorescence sensor 4A. However, the substrate part 30D of the fluorescence sensor 4D is made of a semiconductor such as silicon on which the frame-like substrate part 40D in which the second through hole 40X serving as a hole is formed and the PD element 12D which is the third photoelectric conversion element is formed. This is a bonded substrate portion to which the detection substrate portion 20D made of is bonded. And the light emitting element 15 is mounted in the detection board | substrate part 20D which comprises the bottom face of the through-hole 40X.
図15に示すように、蛍光センサ4Dでは、インジケータ17から上側に出射される蛍光F1はPD素子12により受光され信号が配線61を介して伝送される。また、インジケータ17から下側に出射される蛍光F3はPD素子12Dにより受光され信号が配線63(60)を介して伝送される。
As shown in FIG. 15, in the fluorescence sensor 4D, the fluorescence F1 emitted upward from the indicator 17 is received by the PD element 12 and a signal is transmitted via the wiring 61. The fluorescent light F3 emitted downward from the indicator 17 is received by the PD element 12D, and a signal is transmitted through the wiring 63 (60).
蛍光センサ4Dは蛍光センサ4の効果を有し、さらに貫通孔40Xの底面側にも第3の光電変換素子であるPD素子12Dが、形成されているため、より高感度である。
The fluorescence sensor 4D has the effect of the fluorescence sensor 4, and further has a higher sensitivity because the PD element 12D, which is the third photoelectric conversion element, is also formed on the bottom surface side of the through hole 40X.
<第6実施形態~第9実施形態>
次に、第6実施形態の蛍光センサ4E~第9実施形態の蛍光センサ4Hについて説明する。蛍光センサ4E~4Hは蛍光センサ4等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。 <Sixth to ninth embodiments>
Next, thefluorescence sensor 4E of the sixth embodiment to the fluorescence sensor 4H of the ninth embodiment will be described. Since the fluorescence sensors 4E to 4H 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.
次に、第6実施形態の蛍光センサ4E~第9実施形態の蛍光センサ4Hについて説明する。蛍光センサ4E~4Hは蛍光センサ4等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。 <Sixth to ninth embodiments>
Next, the
蛍光センサ4E~4Hは、いずれもPD素子が形成されたカバー部を有する点で蛍光センサ4等と同じである。
Fluorescent sensors 4E to 4H are all the same as fluorescent sensor 4 and the like in that each has a cover portion on which a PD element is formed.
図16に示すように第6実施形態の蛍光センサ4Eは、カバー部18Eの略中央に1つの大きな貫通孔18XEが形成されている。すなわち、すでに説明したように、遮光層19がある場合には、カバー部の貫通孔の大きさ及び数に制限はない。
As shown in FIG. 16, in the fluorescent sensor 4E of the sixth embodiment, one large through hole 18XE is formed in the approximate center of the cover portion 18E. That is, as already described, in the case where the light shielding layer 19 is present, the size and number of through holes in the cover portion are not limited.
図17に示すように第7実施形態の蛍光センサ4Fは、インジケータ17の下側に配設された第3の受光部であるPD素子12Fの略中央に貫通孔12Xが形成されている。そして、PD素子12Fの下側に発光素子15が配設されている。
As shown in FIG. 17, in the fluorescence sensor 4F according to the seventh embodiment, a through hole 12X is formed in the approximate center of the PD element 12F, which is a third light receiving portion disposed below the indicator 17. And the light emitting element 15 is arrange | positioned under PD element 12F.
蛍光センサ4Fでは、インジケータ17から上方向に出射する蛍光F1はPD素子12により検出され、下方向に出射する蛍光F2はPD素子12Fにより検出される。
In the fluorescence sensor 4F, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, and the fluorescence F2 emitted downward is detected by the PD element 12F.
発光素子15からの励起光Eは、貫通孔12Xを介してインジケータ17に入射する。なお、PD素子12Fに複数の貫通孔12Xが形成されていてもよい。
The excitation light E from the light emitting element 15 enters the indicator 17 through the through hole 12X. A plurality of through holes 12X may be formed in the PD element 12F.
詳細は説明しないが、蛍光センサ4Fは、活性層(SOI層)が、埋め込みシリコン酸化膜(Buried Oxide:BOX層)を介して、支持基板層(基板層)上に配設されているSOI(Silicon on Insulator)基板を用いることで容易に作製できる。すなわち、SOI基板の基板層に形成した貫通ビアにインジケータ17を配設し、活性層に貫通ビア12Xを形成するとともに貫通ビア12Xを取り囲むようにPD素子12Fが形成される。
Although not described in detail, the fluorescent sensor 4F has an SOI (active layer (SOI layer)) that is disposed on a support substrate layer (substrate layer) via a buried silicon oxide film (Buried Oxide: BOX layer). It can be easily manufactured by using a silicon on insulator substrate. That is, the indicator 17 is disposed in the through via formed in the substrate layer of the SOI substrate, the through via 12X is formed in the active layer, and the PD element 12F is formed so as to surround the through via 12X.
図18に示すように第8実施形態の蛍光センサ4Gは、図13に示した蛍光センサ4Cと、図15に示した蛍光センサ4Dと、を組み合わせた構造である。
As shown in FIG. 18, the fluorescence sensor 4G of the eighth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4D shown in FIG. 15 are combined.
すなわち、蛍光センサ4Gでは、インジケータ17から上方向に出射する蛍光F1はPD素子12により検出され、横方向に出射する蛍光F2はPD素子12Bにより検出され、下方向に出射する蛍光F2はPD素子12Dにより検出される。
That is, in the fluorescence sensor 4G, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, the fluorescence F2 emitted horizontally is detected by the PD element 12B, and the fluorescence F2 emitted downward is the PD element. Detected by 12D.
図19に示すように第9実施形態の蛍光センサ4Hは、図13に示した蛍光センサ4Cと、図17に示した蛍光センサ4Fと、を組み合わせた構造である。
As shown in FIG. 19, the fluorescence sensor 4H of the ninth embodiment has a structure in which the fluorescence sensor 4C shown in FIG. 13 and the fluorescence sensor 4F shown in FIG. 17 are combined.
すなわち、蛍光センサ4Hでは、インジケータ17から上方向に出射する蛍光F1はPD素子12により検出され、横方向に出射する蛍光F2はPD素子12Bにより検出され、下方向に出射する蛍光F2はPD素子12Fにより検出される。
That is, in the fluorescence sensor 4H, the fluorescence F1 emitted upward from the indicator 17 is detected by the PD element 12, the fluorescence F2 emitted horizontally is detected by the PD element 12B, and the fluorescence F2 emitted downward is the PD element. It is detected by 12F.
蛍光センサ4E~4Hは、いずれも蛍光センサ4の効果を有し、さらに上方向に出射される蛍光を受光する、カバー部に形成されたPD素子に加えて、さらに別の方向に出射される蛍光を受光するPD素子を有しているため、より高感度である。
Each of the fluorescence sensors 4E to 4H has the effect of the fluorescence sensor 4, and further emits in another direction in addition to the PD element formed on the cover portion that receives the fluorescence emitted upward. Since it has a PD element that receives fluorescence, it has higher sensitivity.
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.
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 (7)
- 穴のある基板部と、
前記穴の内部に配設された、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インジケータと、
前記励起光を発生する発光素子と、
前記穴の開口を覆う、前記アナライトが通過する貫通孔と、前記蛍光を電気信号に変換する光電変換素子とが形成された半導体材料からなるカバー部と、を有することを特徴とする蛍光センサ。 A substrate part with holes,
An indicator disposed inside the hole for receiving excitation light and generating fluorescence having an intensity corresponding to the concentration of the analyte;
A light emitting element for generating the excitation light;
A fluorescence sensor comprising: a through-hole through which the analyte passes covering the opening of the hole; and a cover portion made of a semiconductor material on which a photoelectric conversion element for converting the fluorescence into an electric signal is formed. . - 前記カバー部を覆う、前記アナライトが通過する遮光層を有することを特徴とする請求項1に記載の蛍光センサ。 The fluorescent sensor according to claim 1, further comprising a light-shielding layer that covers the cover portion and through which the analyte passes.
- 前記カバー部に、前記励起光の波長以下の大きさの複数の微少貫通孔が形成さ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 fluorescent sensor according to claim 1, wherein a plurality of minute through holes having a size equal to or smaller than the wavelength of the excitation light are formed in the cover part.
- 前記穴の側面に第2の光電変換素子が形成さ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 fluorescent sensor according to claim 1, wherein a second photoelectric conversion element is formed on a side surface of the hole.
- 前記基板部の前記穴が凹部であり、前記凹部の底面に前記発光素子が配設されていることを特徴とする請求項4に記載の蛍光センサ。 The fluorescent sensor according to claim 4, wherein the hole of the substrate portion is a recess, and the light emitting element is disposed on a bottom surface of the recess.
- 前記基板部の前記穴が貫通孔であり、前記穴の下面の開口を覆うように前記発光素子が配設されていることを特徴とする請求項4に記載の蛍光センサ。 The fluorescent sensor according to claim 4, wherein the hole of the substrate portion is a through hole, and the light emitting element is disposed so as to cover an opening on a lower surface of the hole.
- 前記基板部が、前記穴となる第2の貫通孔の形成された枠状基板部と、第3の光電変換素子が形成された検出基板部と、が接合された接合基板部であり、
前記穴の底面に前記発光素子が配設さ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 substrate portion is a bonded substrate portion in which a frame-shaped substrate portion in which a second through hole serving as the hole is formed and a detection substrate portion in which a third photoelectric conversion element is formed are bonded,
The fluorescent sensor according to claim 1, wherein the light emitting element is disposed on a bottom surface of the hole.
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AT524748A1 (en) * | 2021-02-19 | 2022-09-15 | Johannes Krottmaier Dr | Optical unit for measuring fluorescent light |
Citations (6)
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 |
WO2004071291A2 (en) * | 2003-02-13 | 2004-08-26 | Medtronic, Inc. | Implantable chemical sensor |
JP2012093128A (en) * | 2010-10-25 | 2012-05-17 | Olympus Corp | Fluorescence sensor |
-
2012
- 2012-09-21 WO PCT/JP2012/074178 patent/WO2014045387A1/en active Application Filing
Patent Citations (6)
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 |
WO2004071291A2 (en) * | 2003-02-13 | 2004-08-26 | Medtronic, Inc. | Implantable chemical sensor |
JP2012093128A (en) * | 2010-10-25 | 2012-05-17 | Olympus Corp | Fluorescence sensor |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AT524748A1 (en) * | 2021-02-19 | 2022-09-15 | Johannes Krottmaier Dr | Optical unit for measuring fluorescent light |
AT524748B1 (en) * | 2021-02-19 | 2023-03-15 | Johannes Krottmaier Dr | Optical unit for measuring fluorescent light |
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