WO2013094562A1 - Capteur de fluorescence, système de capteur et procédé de correction de capteur de fluorescence - Google Patents

Capteur de fluorescence, système de capteur et procédé de correction de capteur de fluorescence Download PDF

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Publication number
WO2013094562A1
WO2013094562A1 PCT/JP2012/082664 JP2012082664W WO2013094562A1 WO 2013094562 A1 WO2013094562 A1 WO 2013094562A1 JP 2012082664 W JP2012082664 W JP 2012082664W WO 2013094562 A1 WO2013094562 A1 WO 2013094562A1
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Prior art keywords
indicator
emitting element
light
fluorescence
light emitting
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PCT/JP2012/082664
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English (en)
Japanese (ja)
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悦朗 清水
松本　淳
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オリンパス株式会社
テルモ株式会社
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Publication of WO2013094562A1 publication Critical patent/WO2013094562A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • 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
    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N2021/7769—Measurement method of reaction-produced change in sensor
    • G01N2021/7786—Fluorescence

Definitions

  • the present invention relates to a fluorescence sensor that measures the concentration of an analyte in an aqueous solution, a sensor system that measures the concentration of an analyte in an aqueous solution, and a correction method for the fluorescence sensor.
  • the fluorescence sensor includes a light emitting unit that generates excitation light, an indicator unit that generates fluorescence having an intensity corresponding to the analyte concentration, and a photoelectric conversion element unit that detects fluorescence from the indicator.
  • the sensor system 101 includes a fluorescent sensor 130, a main body 140, and a receiver 145 having a storage unit that receives and stores a signal from the main body 140. Transmission / reception of signals between the main body 140 and the receiver 145 is performed wirelessly or by wire.
  • the fluorescent sensor 130 has an elongated needle body 33 having the sensor part 110 at the distal end 32 and a connector 35 integrated with the needle rear end 34 of the needle body 33.
  • the connector part 35 is detachably fitted to the fitting part 41 of the main body part 140.
  • the fluorescent sensor 130 is electrically connected to the main body portion 140 by mechanically fitting the connector portion 35 with the fitting portion 41 of the main body portion 140.
  • the main body 140 includes a wireless antenna for wirelessly transmitting and receiving signals to and from the receiver 145, a power source such as a battery, and various circuits for driving and controlling the sensor unit 110.
  • the sensor unit 110 of the fluorescence sensor 130 includes a photoelectric conversion element 112 that converts the fluorescence F formed on the base 111 into an electrical signal, a transparent protective layer 113, and a filter that covers the photoelectric conversion element 112.
  • the light emitting element 115 that transmits the fluorescence F and generates the excitation light E
  • the transparent protective layer 116 that covers the light emission element 115
  • the analyte 2 to interact with the analyte 2 to generate the fluorescence F.
  • An indicator 117 and a light-shielding cover layer 118 are included.
  • the filter 114 transmits the fluorescence F but does not transmit the excitation light E.
  • the excitation light E generated by the light emitting element 115 is applied to the indicator 117 through the protective layer 116.
  • Fluorescence F is generated by the interaction between the excitation light E and the analyte 2 that has entered the indicator 117. Part of the generated fluorescence F passes through the light emitting element 115 and enters the photoelectric conversion element 112, and the photoelectric conversion element 112 generates an output signal such as current or voltage corresponding to the fluorescence intensity, that is, the concentration of the analyte 2. .
  • the output from the photoelectric conversion element 112 is reduced even when the analyte concentration is the same, and the measurement accuracy may be lowered.
  • Embodiments of the present invention are intended to provide a fluorescent sensor with high measurement accuracy, a sensor system with high measurement accuracy, and a correction method for a fluorescent sensor with high measurement accuracy.
  • the fluorescent sensor receives the first light emitting element and the second light emitting element that generate excitation light, and the excitation light generated by the first light emitting element, and the intensity according to the analyte concentration.
  • a sensor system receives first and second light emitting elements that generate excitation light, and excitation light generated by the first light emitting element, in accordance with an analyte concentration.
  • a first indicator that emits fluorescent light of a high intensity, and the first indicator receives less excitation light from the second light emitting element than the first light received from the first light emitting element.
  • a second indicator including an analyte having the same concentration as the indicator; and a photoelectric conversion element unit that converts the fluorescence generated by the first indicator and the fluorescence generated by the second indicator into electrical signals, respectively.
  • a fluorescence sensor a control unit that controls light emission timings of the first light emitting element and the second light emitting element, and an intensity of the fluorescence generated by the first indicator. And calculating a degree of deterioration of the first indicator or the second indicator from the intensity of the fluorescence generated by the second indicator, and correcting the electric signal using the degree of deterioration; It has.
  • a correction method for a fluorescence sensor includes a first light emitting element and a second light emitting element that generate excitation light, and excitation light generated by the first light emitting element.
  • a first indicator that generates fluorescence having an intensity corresponding to the analyte concentration, and excitation light that is less than excitation light received by the first indicator from the first light emitting element is received from the second light emitting element.
  • a second indicator including an analyte having the same concentration as the first indicator, and a photoelectric conversion element unit that converts fluorescence generated by the first indicator and the second indicator into an electrical signal.
  • the fluorescence sensor 30 according to the first embodiment of the present invention is used as the sensor system 1 in combination with the main body 40 and the receiver 45 in the same manner as the conventional fluorescence sensor 130 described above. That is, since the sensor system 1 is similar to the sensor system 101, the same components are denoted by the same reference numerals and description thereof is omitted.
  • the fluorescent sensor 30 is a glucose sensor that detects glucose, which is an analyte in the body fluid of the subject.
  • the fluorescence sensor 30 can measure the analyte concentration continuously for a predetermined period, for example, one week after the sensor unit 10 is inserted into the body. However, the collected body fluid or the body fluid circulating through the body via the flow path outside the body may be brought into contact with the sensor unit 10 outside the body without inserting the sensor unit 10 into the body.
  • the main body 40 includes a control unit 42 that drives and controls the sensor unit 10, and a calculation unit 43 that processes an electrical signal output from the sensor unit 10.
  • the control unit 42 and the calculation unit 43 are each composed of a calculation circuit such as a CPU, but may be the same CPU. Note that at least one of the control unit 42 and the calculation unit 43 may be disposed on the connector unit 35 of the fluorescent sensor 30 or the receiver 45.
  • the receiver 45 is not necessary for the sensor system. That is, the sensor system may be composed of the fluorescence sensor 30 and the main body 40.
  • the photodiode element 12 (see FIG. 4) and the light emitting elements 15A and 15B (see FIG. 4) of the sensor unit 10 at the tip 32 are electrically connected to the connector unit 35 via a plurality of wires 19 that pass through the needle body 33. It is connected.
  • the driving power from the main body 40 is transmitted to the light emitting elements 15A and 15B via the wiring 19, and the electric signal output from the photodiode element 12 is transmitted to the main body 40 via the other wiring 19.
  • the sensor unit 10 of the fluorescence sensor 30 includes a light emitting element 15A that is a first light emitting element and a light emitting element 15B that is a second light emitting element, an indicator 17, and a photodiode that is a photoelectric conversion element. And an element (PD element) 12.
  • the indicator 17 can be considered to be functionally divided into an indicator 17A as a first indicator and an indicator 17B as a second indicator.
  • the PD element 12 is formed on the surface of the silicon substrate 11.
  • a temperature sensor 21 having substantially the same structure as the PD element 12 is also formed on the silicon substrate 11.
  • the filter 14 is disposed on a transparent protective layer 13 that covers the PD element 12.
  • An indicator 17 that receives the excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration is disposed on the transparent protective layer 16 that covers the filter 14 and the light emitting elements 15A and 15B.
  • the uppermost light shielding layer 18 is arranged so as to cover the upper surface of the indicator 17. The light shielding layer 18 prevents the excitation light E and the fluorescence F from leaking to the outside of the sensor unit 10, and at the same time, prevents the outside light from entering the sensor unit 10.
  • the sensor unit 10 of the fluorescent sensor 30 is sealed with a light shielding sealing resin 22 except for the light shielding layer 18.
  • the indicator 17 etc. may be accommodated in the sensor frame which consists of silicon
  • the PD element 12 converts fluorescence F into an electrical signal.
  • the photoelectric conversion element is not limited to the PD element 12 and is selected from various photoelectric conversion elements such as a photoconductor or a phototransistor.
  • the PD element 12 has a structure in which a p-type diffusion region is formed in an n-type semiconductor region.
  • Both the protective layer 13 and the protective layer 16 are made of a transparent material.
  • the protective layer 16 electrically insulates the indicator 17 containing moisture from the light emitting elements 15A and 15B.
  • the protective layer 13 and the protective layer 16 may be made of different materials.
  • the filter 14 blocks the excitation light E having a wavelength of 375 nm, for example, generated by the light emitting elements 15A and 15B, and transmits the fluorescence F having a wavelength of 460 nm, for example, generated by the indicator 17.
  • the filter 14 may be a multiple interference filter, but is preferably a light absorption filter, for example, a single layer made of silicon, silicon carbide, silicon oxide, silicon nitride, or an organic material, or the single layer It is a multilayer layer formed by laminating.
  • the transmittance of a silicon layer and a silicon carbide layer is 10 ⁇ 5 % or less at a wavelength of 375 nm, whereas the transmittance is 10% or more at a wavelength of 460 nm (transmittance of excitation light wavelength / transmission of fluorescence wavelength).
  • the transmittance selectivity is 6 digits or more.
  • the light emitting elements 15A and 15B that generate the excitation light E are selected from LED elements, organic EL elements, inorganic EL elements, laser diode elements, and the like. From the viewpoints of light generation efficiency, wide wavelength selectivity of the excitation light E, little light with a wavelength other than the ultraviolet rays used as the excitation light E, high transmittance of the fluorescence F, and the like. LED elements are preferred. Furthermore, an ultraviolet light-emitting LED element made of a gallium nitride compound semiconductor formed on a sapphire substrate is particularly preferable.
  • the indicator 17 receives the excitation light E and generates fluorescence F having an intensity corresponding to the analyte concentration.
  • the indicator 17 interacts with the analyte 2 that has entered through the light-shielding layer 18 from the outside of the sensor unit 10 and receives the excitation light E to generate a fluorescence F having a light amount corresponding to the concentration of the analyte 2.
  • the indicator 17 is composed of a base material containing a fluorescent dye that generates fluorescence F having an intensity corresponding to the amount of the analyte 2, that is, the analyte concentration in the sample.
  • the indicator 17 includes an indicator 17A in a region that receives the excitation light EA from the light emitting element 15A, and an indicator 17B in a region that receives the excitation light EB from the light emitting element 15B.
  • the intensity of the excitation light E attenuates in proportion to the square of the distance from the light emitting part. For this reason, in the vicinity of the boundary between the indicator 17A and the indicator 17B, the deterioration of the indicator 17 due to the excitation light irradiation does not occur remarkably, so that it is not necessary to define the boundary clearly. However, for convenience of explanation, it is assumed that the boundary between the indicator 17A and the indicator 17B is immediately above the intermediate position between the light emitting element 15A and the light emitting element 15B.
  • the fluorescent dye is selected according to the type of the analyte 2, and a fluorescent dye that reversibly changes the intensity of the fluorescence generated according to the amount of the analyte 2 can be used.
  • the indicator 17 uses, as a fluorescent dye, a ruthenium organic complex, a fluorescent phenylboronic acid derivative, or a substance that reversibly binds to glucose, such as fluorescein bound to a protein.
  • the base material of the indicator 17 preferably has a high light transmittance of the excitation light E and fluorescence F from the light emitting part.
  • the base material is preferably a hydrogel that easily contains water, a urethane hydrogel prepared by polymerizing a polysaccharide such as methylcellulose or dextran, a monomer such as (meth) acrylamide, methylolacrylamide, or hydroxyethyl acrylate, or A urethane hydrogel prepared from polyethylene glycol and diisocyanate is used.
  • the light shielding layer 18 is made of a material that does not prevent the analyte 2 from passing through the inside and reaching the indicator 17.
  • the light shielding layer 18 is made of, for example, porous metal or ceramics, or light such as carbon black or carbon nanotubes that passes through the hydrogel used for the indicator 17. A composite material in which fine particles are mixed is preferable.
  • the light shielding layer 18 may cover not only the indicator 17 but the entire sensor unit 10.
  • the output from the PD element 12 is reduced even when the analyte concentration is the same, and the measurement accuracy may be lowered.
  • the inventor has found that the cause of this change with time is deterioration of the indicator 17 due to excitation light irradiation (hereinafter referred to as “light deterioration”), and has completed the present invention.
  • light deterioration due to excitation light irradiation
  • the intensity of the fluorescence generated by the indicator 17 decreases as the usage time increases even at the same analyte concentration.
  • the indicator 17A receives the excitation light EA generated by the light emitting element 15A and generates fluorescent FA having an intensity corresponding to the analyte concentration.
  • the indicator 17B receives the excitation light EB generated by the light emitting element 15B, and generates fluorescence FB having an intensity corresponding to the analyte concentration. Note that the light emitting element 15A and the light emitting element 15B are controlled by the control unit 42 so as not to emit light simultaneously.
  • the excitation light received by the indicator 17B from the light emitting element 15B within a unit time is less than the excitation light received by the indicator 17A from the light emitting element 15A.
  • the energy that the indicator 17B receives from the excitation light within the unit time is less than the energy that the indicator 17A receives from the excitation light. For this reason, the indicator 17B is slower in light deterioration than the indicator 17A.
  • the degradation degree ⁇ A of the indicator 17A is calculated from the intensity of the fluorescent FA generated by the indicator 17A received by the PD element 12 and the intensity of the fluorescent FB generated by the indicator 17B. Then, using the deterioration degree ⁇ A, the intensity of the fluorescent FA received by the PD element 12 is corrected to the intensity when there is no light deterioration.
  • the concentration of the contained analyte is the same between the indicator 17A and the indicator 17B that are arranged close to each other. Therefore, when the intensity of the excitation light EA and the intensity of the excitation light EB are the same, and the deterioration degree of the indicator 17A and the deterioration degree of the indicator 17B are the same, the intensity of the fluorescence FA and the fluorescence FB is the same. is there.
  • the calculation unit 43 performs an operation of reading an electrical signal (output) from the PD element 12 in accordance with the timing of light emission of each of the light emitting elements 15A and 15B under the control of the control unit 42. That is, the calculation unit 43 performs an output read operation for a certain time within the light emission time of each of the light emitting elements 15A and 15B.
  • the output by the fluorescent FA corresponding to the light emission of the light emitting element 15A is referred to as an output IA
  • the output from the fluorescent light FB corresponding to the light emission of the light emitting element 15B is referred to as an output IB.
  • the light emitting element 15A and the light emitting element 15B do not emit light at the same time, it is possible to distinguish whether the output from the PD element 12 is the output IA or the output IB.
  • the light emitting element 15A and the light emitting element 15B may emit light at the same time. The output from the PD element 12 at that time is not used for processing.
  • the output IA indicates the intensity of the fluorescent FA generated by the indicator 17A
  • the output IB indicates the intensity of the fluorescent FB generated by the indicator 17B.
  • Each of the output IA and the output IB is referred to as an output I.
  • the light emitting element 15A and the light emitting element 15B are set so that the light emission intensity and the light emitting time are the same, and the light emitting period of the light emitting element 15B is k times (k> 1) the light emitting period of the light emitting element 15A.
  • the magnification k is, for example, 1.5 to 50, and preferably 2 to 10. If it is in the said range, high measurement accuracy will be ensured.
  • the light emitting elements 15A and 15B are controlled to emit light at a timing when one of the light emitting elements is not emitting light.
  • the light emission interval of the light emitting element 15B that does not emit light simultaneously with the light emitting element 15A is longer than the light emission interval of the light emitting element 15A.
  • the indicator 17B receives from the light emitting element 15B excitation light EB that is less as excitation light within a certain time than the excitation light EA received by the indicator 17A from the light emitting element 15A.
  • the light emitting element 15A emits light with a light emission intensity: WA (watts), a light emission time: ⁇ tA (seconds), and a cycle: ⁇ TA (seconds).
  • the light emitting element 15B emits light with emission intensity: WB (watts), light emission time: ⁇ tB (seconds), and cycle: ⁇ TB (seconds).
  • WA WB
  • ⁇ tA ⁇ tB
  • ⁇ TB k ⁇ ⁇ TA.
  • the light emitting element 15A of the fluorescent sensor 30 starts the first light emission (light emission intensity WA) at time 0 and ends the light emission after ⁇ tA.
  • the light emitting element 15B starts the first light emission (light emission intensity WB) at time t1, and ends the light emission after ⁇ tB.
  • the light emitting element 15A emits light for ⁇ tA time every ⁇ TA time after the first light emission starts.
  • the light emitting element 15B emits light for ⁇ tB time every ⁇ TB time after the first light emission starts.
  • the time tn shown in FIG. 5 is an arbitrary time after the start of use of the fluorescent sensor.
  • the light emitting element 15A emits light (tn / ⁇ TA) times.
  • the light emitting element 15B emits light (tn / ⁇ TB) times by the time (tn + t1).
  • the time tn is sufficiently longer than the time t1, and therefore, tn ⁇ (tn ⁇ t1).
  • the light emitting elements 15A and 15B generate energy of WA ⁇ (tn / ⁇ TA) ⁇ ⁇ tA and WB ⁇ (tn / ⁇ TB) ⁇ ⁇ tB, respectively.
  • Indicators 17A and 17B receive energy proportional to the amount of energy.
  • ⁇ TB k ⁇ ⁇ TA
  • the indicator 17A receives k times larger energy than the indicator 17B.
  • the outputs IA (tn) and IB (tn) of the PD element 12 that have undergone light degradation due to the passage of time tn are the outputs IA (0) and IB (0) at time 0 and the degradation degree ⁇ (0 ⁇ 0) of the indicator 17.
  • IA (tn) IA (0) ⁇ (1 ⁇ A)
  • IB (tn) IB (0) ⁇ (1 ⁇ B)
  • ⁇ A is the deterioration degree of the indicator 17A
  • ⁇ B is the deterioration degree of the indicator 17B.
  • Equation 3 Since the indicator 17A receives k times larger energy than the indicator 17B, (Equation 3) is established.
  • Equation 6 for calculating the deterioration degree ⁇ A of the indicator 17A at time tn from IA (tn) and IB (tn) is derived from (Equation 5).
  • the calculation unit 43 uses the calculated deterioration degree ⁇ A to change the output IA (tn) at time tn to the output IA (0) at time 0, that is, the indicator 17A.
  • the output can be corrected to IA (0) in the case where the light is not deteriorated.
  • the correction method of the fluorescence sensor 30 is such that the light emitting element 15A emits light at any time tn when the light emitting element 15B does not emit light, and the first from the PD element 12 according to the fluorescence intensity FA generated by the indicator 17A.
  • the fluorescence sensor 30 calculates the degradation degree ⁇ B of the second indicator from the intensity of the fluorescence generated by the first indicator and the intensity of the fluorescence generated by the second indicator, and uses the degradation degree ⁇ B to output IB ( tn) may be corrected to the output IB (0).
  • the fluorescence sensor 30 and the sensor system 1 have high measurement accuracy.
  • the correction method of the fluorescence sensor 30 has high measurement accuracy.
  • the calculation unit 43 can perform correction in consideration of the temperature change. That is, the energy that causes photodegradation is represented only by the irradiation energy from the light emitting element, but it may be generated by a mechanism involving other energy. For example, when the light degradation is accelerated when the temperature is high, the temperature measured by the temperature sensor 21 may be added to the correction parameter.
  • the indicator 17 and the indicator 17A and the indicator 17B are clearly divided through the light shielding wall 51.
  • the light shielding wall 51 is arranged so that the excitation light EA from the light emitting element 15A does not enter the indicator 17B and the excitation light EB from the light emitting element 15B does not enter the indicator 17A.
  • Fluorescent sensor 30A has the same effect as fluorescent sensor 30 and has higher measurement accuracy.
  • a dimming unit that reduces the intensity of the excitation light EB generated by the light emitting element 15B on the upper surface of the light emitting element 15B that is the path of the excitation light EB from the light emitting element 15B to the indicator 17.
  • a neutral density filter 52 is provided.
  • the neutral density filter 52 has a transmittance of approximately 100% at the fluorescence wavelength, but (100 / k)% at the excitation light wavelength.
  • the intensity of the excitation light received by the indicator 17B is (1 / k) of the intensity of the excitation light received by the indicator 17A.
  • the indicator 17A receives k times as much energy as the indicator 17B.
  • the fluorescent sensor 30B and the like have the effect of the fluorescent sensor 30 and the like, and the two light emitting elements 15A and 15B of the sensor unit 10B emit light with the same cycle, so that the control is easy.
  • the light emission intensity of the light emitting element 15A: WA (watt) is k times (k> 1) the light emission intensity of the light emitting element 15B: WB (watt).
  • WA k ⁇ WB
  • the indicator 17B receives excitation light having an intensity of (1 / k) of the indicator 17A.
  • the indicator 17A receives k times larger energy from the excitation light than the indicator 17B.
  • the calculation unit 43 can correct the output I by calculating the deterioration degree ⁇ using a method substantially similar to that of the fluorescence sensor 30.
  • the fluorescent sensor 30C and the like have the effect of the fluorescent sensor 30 and the like, and the two light emitting elements 15A and 15B of the sensor unit 10C emit light at the same cycle, and therefore, control is easy.
  • a correction method for the fluorescence sensor 30D, the sensor system 1D, and the fluorescence sensor 30D according to the second embodiment will be described.
  • the correction method of the fluorescence sensor 30D, the sensor system 1D, and the fluorescence sensor 30D is similar to the correction method of the fluorescence sensor 30, the sensor system 1, and the fluorescence sensor 30. Omitted.
  • the indicator 17 is housed inside a substantially rectangular sensor frame 20 made of silicon.
  • the PD element 12D is formed on the four wall surfaces of the inner surface of the sensor frame 20 made of a semiconductor by a known semiconductor process, and the filter 14D is disposed so as to cover the PD element 12D.
  • the fluorescent light FA and FB generated by the indicators 17A and 17B are incident on the PD element 12D disposed so as to surround the indicator 17.
  • Fluorescent sensor 30D has the effect of fluorescent sensor 30 and the like, and further, because the PD element has a large light receiving area, it detects analyte with higher sensitivity.
  • the PD element 12D of the sensor unit 10D of the fluorescence sensor 30D may be formed on a part of the inner surface of the sensor frame 20.
  • the PD element 12E is formed on the four side surfaces of the rectangular concave portion formed on the substrate 11E made of a semiconductor such as silicon, and the light emitting element 15A is formed on the bottom surface of the concave portion. , 15B are disposed.
  • the opening surface of the recess is wider than the bottom surface, and the side surface is not perpendicular to the bottom surface but is inclined at a predetermined angle ⁇ .
  • substrate 11E which has a recessed part may be produced by joining the frame-shaped sensor frame board
  • the indicator 17 is arrange
  • the fluorescence sensor 30E will be described. In addition, although it may manufacture for every one fluorescence sensor 30E, it is preferable to manufacture many fluorescence sensors 30E collectively as a wafer process.
  • a mask layer having a plurality of mask portions on the first main surface of a silicon wafer having an area where a plurality of fluorescent sensors 30E can be manufactured is manufactured. Then, a plurality of recesses 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
  • the PD element 12E is formed on at least a part of the four side surfaces of each recess by a known semiconductor process.
  • the concave portion whose side surface is inclined not only has a larger area for forming the PD element than the concave portion whose vertical side surface is vertical, but also facilitates the formation of the PD element 12E on the side surface. If the inclination angle of the side surface is 30 to 70 degrees, the above effect is remarkable.
  • the filter 14E is disposed on the side PD element 12E.
  • light emitting elements 15A and 15B are disposed on the bottom surfaces of the plurality of recesses, respectively.
  • a buffer solution serving as the indicator 17 is filled in the recess.
  • the light shielding layer 18 is bonded so as to close the opening of the recess. Then, by dividing the silicon wafer on which the plurality of sensor units 10E are formed, a plurality of fluorescent sensors 30E are manufactured at once.
  • the fluorescent sensor 30E has the same effects as the fluorescent sensor 30D and the like, and the substrate 11E also serves as a frame portion, and the side surface of the concave portion that is the PD element forming surface is inclined, so that the manufacturing is easy.
  • the overall shape of the sensor unit such as the fluorescent sensor 30 in the embodiment and the modification described above is a right prism shape
  • the sensor unit has a trapezoidal shape, a curved side surface, or one direction of the sensor side surface.
  • the fluorescent sensor etc. which extended may be sufficient.
  • the fluorescent sensor 30 and the like had two light emitting elements 15A and 15B.
  • the excitation light E emitted from one light emitting element may be split using an optical element such as a beam splitter and irradiated to the first indicator or the second indicator.
  • the fluorescence sensor 30 and the like have detected the fluorescence FA and FB generated by the excitation light EA and EB from the two light emitting elements 15A and 15B that do not emit light simultaneously by one PD element under the control of the control unit.
  • the first PD element that detects the fluorescent FA and the second PD element that detects the fluorescent FB are used and simultaneously generated by the excitation light EA and EB from the two light emitting elements 15A and 15B that emit light simultaneously. Fluorescence FA and FB may be detected.
  • the fluorescent sensor 30 for detecting saccharides such as glucose has been described as an example, various uses such as an enzyme sensor, a pH sensor, an immunosensor, or a microorganism sensor can be handled by selecting a fluorescent dye.
  • a fluorescent dye For example, when measuring in vivo hydrogen ion concentration or carbon dioxide as a fluorescent dye, a hydroxypyrenetrisulfonic acid derivative or the like is used.
  • a phenylboronic acid derivative having a fluorescent residue or the like is used.
  • a potassium ion is used, a crown ether derivative having a fluorescent residue is used.

Abstract

L'invention concerne un capteur de fluorescence (30) comprenant les éléments suivants : un élément d'émission (15A) et un élément d'émission (15B) qui génèrent de la lumière d'excitation (E) ; un indicateur (17A) qui reçoit de la lumière d'excitation (EA) générée par l'élément d'émission (15A) et génère de la fluorescence (FA) ayant une intensité qui est fonction d'une concentration en analyte ; un indicateur (17B) qui reçoit de l'élément d'émission (15B) de la lumière d'excitation (EB) qui est inférieure à la lumière d'excitation (EA) que l'indicateur (17A) reçoit de l'élément d'émission (15A), et qui contient de l'analyte dans la même concentration que l'indicateur (17A) ; et un élément PD (12) pour la conversion de la fluorescence (FA, FB) générée par l'indicateur (17A) et l'indicateur (17B) en un signal électrique.
PCT/JP2012/082664 2011-12-21 2012-12-17 Capteur de fluorescence, système de capteur et procédé de correction de capteur de fluorescence WO2013094562A1 (fr)

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JP2011280121 2011-12-21

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03262945A (ja) * 1990-03-13 1991-11-22 Sankyo Co Ltd 化学発光検出装置
JP2001194302A (ja) * 2000-01-14 2001-07-19 Otsuka Denshi Co Ltd 光学測定装置
JP2004529352A (ja) * 2001-05-04 2004-09-24 センサーズ・フォー・メディシン・アンド・サイエンス インコーポレーテッド 参照通路を備えたエレクトロオプティカルセンサ装置
JP2006126715A (ja) * 2004-11-01 2006-05-18 Terumo Corp 光導波路およびこの光導波路を用いた蛍光センサ
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03262945A (ja) * 1990-03-13 1991-11-22 Sankyo Co Ltd 化学発光検出装置
JP2001194302A (ja) * 2000-01-14 2001-07-19 Otsuka Denshi Co Ltd 光学測定装置
JP2004529352A (ja) * 2001-05-04 2004-09-24 センサーズ・フォー・メディシン・アンド・サイエンス インコーポレーテッド 参照通路を備えたエレクトロオプティカルセンサ装置
JP2006126715A (ja) * 2004-11-01 2006-05-18 Terumo Corp 光導波路およびこの光導波路を用いた蛍光センサ
WO2010119916A1 (fr) * 2009-04-13 2010-10-21 Olympus Corporation Capteur de fluorescence, capteur de fluorescence de type aiguille et procédé pour mesurer un analyte

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