WO2023075465A1 - System and method for measuring glucose concentration by using photothermal modulation laser speckle imaging, and recording medium having recorded thereon computer-readable program for executing the method - Google Patents

System and method for measuring glucose concentration by using photothermal modulation laser speckle imaging, and recording medium having recorded thereon computer-readable program for executing the method Download PDF

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WO2023075465A1
WO2023075465A1 PCT/KR2022/016609 KR2022016609W WO2023075465A1 WO 2023075465 A1 WO2023075465 A1 WO 2023075465A1 KR 2022016609 W KR2022016609 W KR 2022016609W WO 2023075465 A1 WO2023075465 A1 WO 2023075465A1
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glucose
glucose concentration
coenzyme
laser speckle
sensing unit
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김종진
이원주
김철
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한국전기연구원
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0075—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence by spectroscopy, i.e. measuring spectra, e.g. Raman spectroscopy, infrared absorption spectroscopy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1486—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using enzyme electrodes, e.g. with immobilised oxidase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/155—Devices specially adapted for continuous or multiple sampling, e.g. at predetermined intervals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/157—Devices characterised by integrated means for measuring characteristics of blood

Definitions

  • the present invention relates to biocomponent measurement technology, and more particularly, to a system and method for measuring a change in sugar concentration in a body fluid by irradiating light and using a detected optical signal.
  • the change in glucose concentration in the body is generally based on blood sampling, and the electrochemical reaction between the enzyme applied to the electrode surface and the glucose in the blood is measured by using the electrode. quantified through
  • an electrochemical measurement method is influenced by external factors such as electrode material, electron transport material, applied voltage, measurement environment, and correction factor, and thus has limitations in sensitivity and accuracy.
  • the electrochemical measurement method has limitations in measuring the rapidly changing glucose concentration change due to the slow diffusion of electrons generated by glucose oxidase and glucose reaction, and it is technically necessary to detect the real-time change in glucose concentration. It contains limitations.
  • the present invention has been made to solve the above-mentioned conventional problems, and provides a blood glucose measurement system and method that can accurately detect real-time changes in glucose concentration without a blood sampling process and without being affected by external factors. aims to
  • the glucose concentration measuring system includes a glucose sensing unit, a photothermal light irradiation unit, and a glucose concentration calculating unit.
  • the glucose sensing unit has a plate layer on which a scatterer for laser speckle image is fixed is formed on the bottom, and a photothermal light irradiation unit emits light in a predetermined absorption wavelength band of glucose oxidase and coenzyme in a solution of coenzyme dissolution located on the plate layer.
  • the glucose concentration calculation unit calculates the concentration of glucose applied to the glucose sensing unit from the temperature change in the glucose sensing unit.
  • the speckle pattern is changed only according to the change in refractive index, so that the concentration of glucose can be more accurately measured.
  • the scatter may be metal nanoparticles of a preset wavelength band in which the absorption wavelength band of the coenzyme overlaps with the absorption wavelength band. According to this configuration, a photothermal effect occurs not only in the coenzyme but also in the scatter, so that the refractive index change can be amplified.
  • the glucose concentration calculation unit may calculate the concentration of glucose by measuring a change in the refractive index of the sensing unit according to a slight thermal change induced by an oxidation-reduction reaction of the glucose oxidase and the coenzyme of the glucose sensing unit. According to this configuration, a change in the degree of oxidation-reduction according to the glucose concentration of the coenzyme causes a change in the absorption of the coenzyme, and the resulting temperature change in the glucose sensing unit can be more easily measured.
  • the laser speckle image generation unit may further include a laser light source unit irradiating laser light to the glucose sensing unit and a laser speckle image generation unit generating a laser speckle image from light incident from the glucose sensing unit, and the glucose concentration calculator further generates the laser speckle image. It can be used to calculate the concentration of glucose. According to this configuration, it is possible to more precisely measure the minute temperature change and the corresponding refractive index change in the glucose sensing unit using the laser speckle image.
  • it may further include a frequency modulator for modulating the frequency of photothermal light.
  • a frequency modulator for modulating the frequency of photothermal light.
  • an image output unit for outputting a laser speckle image may be further included. According to this configuration, it is possible to directly check the laser speckle image calculated by the system with the naked eye.
  • the glucose concentration measurement method according to the present invention is a glucose concentration measurement method performed by a glucose concentration measurement system, and a dissolution solution of glucose oxidase and coenzyme located on a plate layer on which a scatter for laser speckle image is fixed is used as a coenzyme
  • the present invention it is possible to more accurately detect a change in glucose concentration without being affected by external factors, without a blood sampling process or the addition of a separate conductive polymer or chromophore.
  • the speckle pattern is changed only according to the change in refractive index, so that the concentration of glucose can be more accurately measured.
  • a change in the degree of oxidation-reduction according to the glucose concentration of the coenzyme causes a change in the absorption of the coenzyme, and thus a temperature change in the glucose sensing unit can be more easily measured.
  • FIG. 1 is a schematic block diagram of a glucose concentration measurement system according to an embodiment of the present invention.
  • FIG. 2 is a diagram showing the concept of an actual implementation example of the glucose concentration measuring device of FIG. 1;
  • Figure 3 is a diagram showing the flow of the glucose concentration measurement method.
  • FIG. 4 is a view showing changes in light absorption characteristics of a specific band (450 nm) according to the degree of oxidation-reduction of coenzymes.
  • FIG. 5 is a diagram showing a PT-LSI measurement algorithm
  • FIG. 1 is a schematic block diagram of a glucose concentration measuring system according to the present invention
  • FIG. 2 is a diagram showing the concept of an actual embodiment of the glucose concentration measuring device of FIG. 1
  • FIG. 3 is a flow diagram of the glucose concentration measuring method it is a drawing
  • the glucose concentration measuring system includes a glucose sensing unit 110, a photothermal light irradiation unit 120, a glucose concentration calculating unit 130, a frequency modulating unit 140, a laser light source unit 150, and a laser speckle image generating unit. 160, and an image output unit 170, and the glucose sensing unit 110 again includes a scatter fixing plate 112.
  • the glucose sensing unit 110 includes a glucose oxidase and a coenzyme located on the metal nanoparticle plate 112 at the bottom of the sensing chamber. Blood glucose is measured in an optical manner using the glucose sensing unit 110, and blood sugar can be sensed only by changing the self-optical characteristics of the coenzyme without adding an additional chromogen or luminous body.
  • the coenzyme (Flavin Adenine Dinucleotide, FAD) is reduced by reacting with Hydrogen Peroxide, and the change in optical properties of the reduced coenzyme (FADH 2 ) can be observed to quantify glucose. .
  • FIG. 4 is a diagram showing changes in light absorption characteristics of a specific band (450 nm) according to the degree of oxidation-reduction of FAD.
  • the photothermal light irradiation unit 120 irradiates light of a preset absorption wavelength band of the coenzyme to the glucose sensing unit 110 .
  • the frequency modulator 140 modulates the frequency of the photothermal light.
  • irradiating light of a specific frequency-modulated band enables selective photothermal modulation of the oxidized or reduced coenzyme, and the periodic photothermal effect around the coenzyme changes the periodic refractive index of the medium.
  • oxidized or reduced coenzyme components can be quantified with high selectivity, and high-precision glucose quantification can be performed using this.
  • the laser light source unit 150 radiates laser light to the glucose sensing unit 110 .
  • a laser light source generating a laser speckle pattern is continuously irradiated to the glucose sensing unit 110 .
  • the laser speckle image generator 160 generates a laser speckle image from light incident from the glucose sensor 110 . To observe in real time the degree of endothermic change that changes according to the frequency of the heat light source during the glucose response on the glucose sensing unit 110 and the refractive index change that changes accordingly and the laser speckle pattern that varies according to the refractive index change using an image sensor will be.
  • the image output unit 170 outputs a laser speckle image. Accordingly, it is possible to continuously monitor and display changes in blood sugar in bodily fluid in real time.
  • FIG. 5 is a diagram illustrating a measurement algorithm of photothermal modulation-laser speckle pattern.
  • the intensity fluctuation value of each pixel of the measured image sequence is extracted, analyzed through Fourier transform on the frequency domain, and the enhanced fluctuation frequency by PT of the scatter is derived.
  • the normalized magnitude value obtained after performing the above process for each pixel on the 2D image is finally implemented as a photothermal modulation-laser speckle pattern image through 1:1 mapping to the corresponding pixel position.
  • the glucose concentration calculation unit 130 calculates the concentration of glucose applied to the glucose sensing unit 110 from the temperature change in the glucose sensing unit 110 .
  • the glucose concentration calculation unit 130 may calculate the glucose concentration using the change in refractive index of the glucose sensing unit 110 .
  • the highest value of the frequency matching the photothermal modulation frequency is recorded and analyzed through frequency analysis of the laser speckle image stored in real time.
  • a blood glucose value suitable for a specific signal value may be quantified by correcting the analyzed signal value according to a change in blood glucose value.
  • the present invention proposes a technique for measuring glucose degrading enzyme and coenzyme without a separate staining process.
  • the degree of refractive index change occurring during thermal conduction relaxation after photothermal stimulation of glucose degrading enzyme and coenzyme is observed with a laser speckle detection device to measure the sugar concentration in body fluid in an optical manner.
  • the light absorption characteristics of the coenzyme that vary according to the change in the sugar concentration in the body fluid and the change in the degree of refractive index appearing during thermal conduction relaxation after the photothermal reaction are measured in the laser specification. It is measured by the change of the large signal and optically measures the change in sugar concentration through an algorithm that quantifies it.
  • the glucose oxidase and the metal nanoparticles having the same light absorption band located at the bottom of the coenzyme solution container are irradiated on top of the solution, and the light remaining after being absorbed according to the light absorbance of the coenzyme is transmitted to the metal nanoparticles. causes a photothermal reaction.
  • the laser speckle shape is realized by the scattering of the metal nanoparticles, and the change in the local laser light refractive index around the metal nanoparticles according to the photothermal reaction is observed.
  • the laser speckle image change corresponding to the photothermal can be observed.
  • the degree of coenzyme reduction can be calculated in proportion to the glucose concentration in the solution, and the glucose concentration in the solution can be quantified.
  • the glucose concentration can be observed with high sensitivity, and the glucose concentration in the body can be estimated and calculated in saliva, tears, sweat, etc., which are lower than the glucose concentration dissolved in blood.

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Abstract

Disclosed are a system and a method for measuring glucose concentration by using photothermal modulation laser speckle imaging, and a recording medium having recorded thereon a computer-readable program for executing the method. The system for measuring glucose concentration comprises a glucose sensing unit, a photothermal light radiation unit, and a glucose concentration calculation unit. The glucose sensing unit has formed, on the base, a plate layer to which a scatter for laser speckle imaging is fixed, the photothermal light radiation unit radiates light having a predetermined absorption wavelength band of a coenzyme in a glucose oxidase and coenzyme dissolved solution located on the plate layer, and the glucose concentration calculation unit calculates the glucose concentration applied to the glucose sensing unit from changes in temperature in the glucose sensing unit.

Description

광열 모듈레이션 레이저 스펙클 영상을 이용한 포도당 농도 측정 시스템, 방법, 및 상기 방법을 실행시키기 위한 컴퓨터 판독 가능한 프로그램을 기록한 기록 매체 Glucose concentration measurement system using photothermal modulation laser speckle image, method, and recording medium recording a computer readable program for executing the method
본 발명은 생체 성분 측정 기술에 관한 것으로서, 더욱 상세하게는 광을 조사하고 검출된 광신호를 사용하여 체액 내의 당 농도 변화를 측정하기 위한 시스템 및 방법에 관한 것이다.The present invention relates to biocomponent measurement technology, and more particularly, to a system and method for measuring a change in sugar concentration in a body fluid by irradiating light and using a detected optical signal.
현재, 제1형 및 2형 당뇨환자에게서 일상적으로 시행되고 있는 혈당측정 방법에서, 체내 글루코스 농도 변화는 일반적으로 혈액 채취를 기반으로 전극면에 도포된 효소와 혈액내의 글루코스의 전기화학적 반응을 전극을 통해 정량화하고 있다. 그런데, 이와 같은 전기화학적 측정 방식은 전극의 소재, 전자 전달 물질, 인가전압, 측정 환경 및 보정 팩터 등 외부적인 요소에 영향을 받아 민감도 및 정확도의 한계를 가진다. Currently, in the blood glucose measurement method routinely performed in type 1 and type 2 diabetic patients, the change in glucose concentration in the body is generally based on blood sampling, and the electrochemical reaction between the enzyme applied to the electrode surface and the glucose in the blood is measured by using the electrode. quantified through However, such an electrochemical measurement method is influenced by external factors such as electrode material, electron transport material, applied voltage, measurement environment, and correction factor, and thus has limitations in sensitivity and accuracy.
또한, 연속 글루코스 측정과 관련하여서는, 전기화학적 측정방식은 글루코스 산화효소와 글루코스 반응으로 발생된 전자의 느린 확산으로 인해 빠르게 변하는 글루코스 농도 변화를 측정하는데 제약이 따르고, 글루코스 농도의 실시간 변화를 감지하는데 기술적 한계점을 내포하고 있다. In addition, with respect to continuous glucose measurement, the electrochemical measurement method has limitations in measuring the rapidly changing glucose concentration change due to the slow diffusion of electrons generated by glucose oxidase and glucose reaction, and it is technically necessary to detect the real-time change in glucose concentration. It contains limitations.
또한, 채혈을 통한 측정 대신 침이나 눈물 등 타액을 통해 체내 글루코스 농도의 변화를 비침습적으로 측정하는 글루코스 측정 장치의 개발도 진행되고 있지만, 타액 분비물 내에 잔존하는 미량의 글루코스 농도(혈액 대비 10분의 1 수준)를 현재의 전기화학 측정방식이나 비색측정 방식으로는 정확히 정량화하는데 한계가 있다. In addition, although the development of a glucose measurement device that non-invasively measures the change in glucose concentration in the body through saliva, such as saliva or tears, instead of measurement through blood sampling is in progress, the trace amount of glucose concentration remaining in saliva secretion (10 minutes compared to blood) is being developed. 1 level) has limitations in accurately quantifying it with the current electrochemical measurement method or colorimetric method.
본 발명은 상술한 종래의 문제점을 해결하기 위해 안출된 것으로서, 채혈 과정 없이, 외부적인 요소에 영향을 받지 않고 정확하게, 글루코스 농도의 실시간 변화를 감지할 수 있도록 해 주는 혈당 측정 시스템 및 방법을 제공하는 것을 목적으로 한다.The present invention has been made to solve the above-mentioned conventional problems, and provides a blood glucose measurement system and method that can accurately detect real-time changes in glucose concentration without a blood sampling process and without being affected by external factors. aims to
상기 목적을 달성하기 위해 본 발명에 따른 포도당 농도 측정 시스템은 포도당 센싱부, 광열 광 조사부, 및 포도당 농도 산출부를 포함한다. 포도당 센싱부는 레이저 스펙클 영상을 위한 스캐터가 고정된 플레이트층이 바닥에 형성되고, 광열 광 조사부는 플레이트층 상에 위치하는 글루코스 산화효소 및 조효소 용해 용액 중 조효소의 미리 설정된 흡수 파장 대역의 광을 조사하며, 포도당 농도 산출부는 포도당 센싱부에서의 온도 변화로부터 포도당 센싱부에 인가된 포도당의 농도를 산출한다.To achieve the above object, the glucose concentration measuring system according to the present invention includes a glucose sensing unit, a photothermal light irradiation unit, and a glucose concentration calculating unit. The glucose sensing unit has a plate layer on which a scatterer for laser speckle image is fixed is formed on the bottom, and a photothermal light irradiation unit emits light in a predetermined absorption wavelength band of glucose oxidase and coenzyme in a solution of coenzyme dissolution located on the plate layer. and the glucose concentration calculation unit calculates the concentration of glucose applied to the glucose sensing unit from the temperature change in the glucose sensing unit.
이와 같은 구성에 의하면, 채혈 과정이나 별도의 전도성 고분자나 발색체의 첨가 없이, 외부적인 요소에 영향을 받지 않고 보다 정확하게 글루코스 농도의 변화를 감지할 수 있게 된다. According to this configuration, it is possible to more accurately detect a change in glucose concentration without being affected by external factors, without a blood collection process or the addition of a separate conductive polymer or chromogen.
특히, 레이저 스펙클 영상을 위한 스캐터를 센서에 고정시킴으로써, 굴절률의 변화에 따라서만 스펙클 패턴이 달라져 더욱 정확한 글루코스의 농도를 측정할 수 있게 된다.In particular, by fixing the scatterer for the laser speckle image to the sensor, the speckle pattern is changed only according to the change in refractive index, so that the concentration of glucose can be more accurately measured.
이때, 스캐터는 조효소의 흡수 파장 대역과 흡수 파장 대역이 중복되는 미리 설정된 파장 대역의 금속 나노 입자일 수 있다. 이와 같은 구성에 의하면, 광열 효과가 조효소뿐만 아니라 스캐터에서도 발생해 굴절률 변화의 증폭이 가능해 진다.In this case, the scatter may be metal nanoparticles of a preset wavelength band in which the absorption wavelength band of the coenzyme overlaps with the absorption wavelength band. According to this configuration, a photothermal effect occurs not only in the coenzyme but also in the scatter, so that the refractive index change can be amplified.
또한, 포도당 농도 산출부는 포도당 센싱부의 포도당 산화효소 및 조효소의 산화 환원 반응으로 유도된 미세 열변화에 따른 센싱부의 굴절률 변화를 측정하여 포도당의 농도를 산출할 수 있다. 이와 같은 구성에 의하면, 조효소의 포도당 농도에 따른 산화 환원 정도의 변화가 조효소의 흡광 변화를 야기하고 이로 인한 포도당 센싱부에서의 온도 변화를 보다 용이하게 측정할 수 있게 된다.In addition, the glucose concentration calculation unit may calculate the concentration of glucose by measuring a change in the refractive index of the sensing unit according to a slight thermal change induced by an oxidation-reduction reaction of the glucose oxidase and the coenzyme of the glucose sensing unit. According to this configuration, a change in the degree of oxidation-reduction according to the glucose concentration of the coenzyme causes a change in the absorption of the coenzyme, and the resulting temperature change in the glucose sensing unit can be more easily measured.
또한, 포도당 센싱부에 레이저 광을 조사하는 레이저 광원부, 및 포도당 센싱부로부터 입사된 광으로부터 레이저 스펙클 영상을 생성하는 레이저 스펙클 영상 생성부를 더 포함하고, 포도당 농도 산출부는 레이저 스펙클 영상을 더 이용하여 포도당의 농도를 산출할 수 있다. 이와 같은 구성에 의하면, 레이저 스펙클 영상을 이용하여 포도당 센싱부에서의 미세 온도 변화와 이에 따른 굴절률 변화를 보다 정밀하게 측정할 수 있게 된다.The laser speckle image generation unit may further include a laser light source unit irradiating laser light to the glucose sensing unit and a laser speckle image generation unit generating a laser speckle image from light incident from the glucose sensing unit, and the glucose concentration calculator further generates the laser speckle image. It can be used to calculate the concentration of glucose. According to this configuration, it is possible to more precisely measure the minute temperature change and the corresponding refractive index change in the glucose sensing unit using the laser speckle image.
또한, 광열 광의 주파수를 변조하는 주파수 변조부를 더 포함할 수 있다. 이와 같은 구성에 의하면, 주파수의 변조를 통해 잡음과 같은 외부 요인으로 인한 영향을 배제할 수 있게 된다.In addition, it may further include a frequency modulator for modulating the frequency of photothermal light. According to this configuration, it is possible to exclude influences due to external factors such as noise through frequency modulation.
또한, 레이저 스펙클 영상을 출력하는 영상 출력부를 더 포함할 수 있다. 이와 같은 구성에 의하면, 시스템에 의해 산출되는 레이저 스펙클 영상을 직접 육안으로 확인할 수 있게 된다.In addition, an image output unit for outputting a laser speckle image may be further included. According to this configuration, it is possible to directly check the laser speckle image calculated by the system with the naked eye.
또한, 본 발명에 따른 포도당 농도 측정 방법은 포도당 농도 측정 시스템이 수행하는 포도당 농도 측정 방법으로서, 레이저 스펙클 영상을 위한 스캐터가 고정된 플레이트층상에 위치하는 글루코스 산화효소 및 조효소의 용해 용액으로 조효소의 미리 설정된 흡수 파장 대역의 광을 조사하는 광열 광 조사 단계, 용해 용액으로부터 입사된 광을 검출하는 센싱 단계, 및 용해 용액에서의 온도 변화로부터 용해 용액체에서의 포도당의 농도를 산출하는 포도당 농도 산출 단계를 포함한다.In addition, the glucose concentration measurement method according to the present invention is a glucose concentration measurement method performed by a glucose concentration measurement system, and a dissolution solution of glucose oxidase and coenzyme located on a plate layer on which a scatter for laser speckle image is fixed is used as a coenzyme A photothermal light irradiation step of irradiating light of a preset absorption wavelength band, a sensing step of detecting light incident from the dissolution solution, and glucose concentration calculation of calculating the concentration of glucose in the dissolution solution from the temperature change in the dissolution solution. Include steps.
아울러, 상기 방법을 실행시키기 위한 컴퓨터 판독 가능한 프로그램을 기록한 기록 매체가 함께 개시된다.In addition, a recording medium recording a computer readable program for executing the method is disclosed together.
본 발명에 의하면, 채혈 과정이나 별도의 전도성 고분자나 발색체의 첨가 없이, 외부적인 요소에 영향을 받지 않고 보다 정확하게 글루코스 농도의 변화를 감지할 수 있게 된다. According to the present invention, it is possible to more accurately detect a change in glucose concentration without being affected by external factors, without a blood sampling process or the addition of a separate conductive polymer or chromophore.
또한, 레이저 스펙클 영상을 위한 스캐터를 센서에 고정시킴으로써, 굴절률의 변화에 따라서만 스펙클 패턴이 달라져 더욱 정확한 글루코스의 농도를 측정할 수 있게 된다.In addition, by fixing the scatterer for the laser speckle image to the sensor, the speckle pattern is changed only according to the change in refractive index, so that the concentration of glucose can be more accurately measured.
또한, 광열 효과가 조효소뿐만 아니라 스캐터에서도 발생해 굴절률 변화의 증폭이 가능해 진다.In addition, a photothermal effect occurs not only in the coenzyme but also in the scatter, so that the refractive index change can be amplified.
또한, 조효소의 포도당 농도에 따른 산화 환원 정도의 변화가 조효소의 흡광 변화를 야기하고 이로 인한 포도당 센싱부에서의 온도 변화를 보다 용이하게 측정할 수 있게 된다.In addition, a change in the degree of oxidation-reduction according to the glucose concentration of the coenzyme causes a change in the absorption of the coenzyme, and thus a temperature change in the glucose sensing unit can be more easily measured.
또한, 레이저 스펙클 영상을 이용하여 포도당 센싱부에서의 미세 온도 변화와 이에 따른 굴절률 변화를 보다 정밀하게 측정할 수 있게 된다.In addition, by using the laser speckle image, it is possible to more precisely measure the minute temperature change in the glucose sensing unit and the refractive index change accordingly.
또한, 주파수의 변조를 통해 잡음과 같은 외부 요인으로 인한 영향을 배제할 수 있게 된다.In addition, it is possible to exclude influences due to external factors such as noise through frequency modulation.
또한, 시스템에 의해 산출되는 레이저 스펙클 영상을 직접 육안으로 확인할 수 있게 된다.In addition, it is possible to visually check the laser speckle image produced by the system.
도 1은 본 발명의 일 실시예에 따른 포도당 농도 측정 시스템의 개략적인 블록도.1 is a schematic block diagram of a glucose concentration measurement system according to an embodiment of the present invention.
도 2는 도 1의 포도당 농도 측정 장치 실제 구현 예의 개념을 도시한 도면.2 is a diagram showing the concept of an actual implementation example of the glucose concentration measuring device of FIG. 1;
도 3은 포도당 농도측정 방법의 흐름을 도시한 도면.Figure 3 is a diagram showing the flow of the glucose concentration measurement method.
도 4는 조효소의 산화-환원 정도에 따른 특정 대역(450nm)의 흡광특성 변화를 도시한 도면.4 is a view showing changes in light absorption characteristics of a specific band (450 nm) according to the degree of oxidation-reduction of coenzymes.
도 5는 PT-LSI의 측정 알고리즘을 도시한 도면.5 is a diagram showing a PT-LSI measurement algorithm;
이하, 첨부된 도면을 참조하여 본 발명의 바람직한 실시예를 설명한다.Hereinafter, preferred embodiments of the present invention will be described with reference to the accompanying drawings.
도 1은 본 발명에 따른 포도당 농도 측정 시스템의 개략적인 블록도이고, 도 2는 도 1의 포도당 농도 측정 장치 실제 구현 예의 개념을 도시한 도면이며, 도 3은 포도당 농도측정 방법의 흐름을 도시한 도면이다. 1 is a schematic block diagram of a glucose concentration measuring system according to the present invention, FIG. 2 is a diagram showing the concept of an actual embodiment of the glucose concentration measuring device of FIG. 1, and FIG. 3 is a flow diagram of the glucose concentration measuring method it is a drawing
도 1에서, 포도당 농도 측정 시스템은 포도당 센싱부(110), 광열 광 조사부(120), 포도당 농도 산출부(130), 주파수 변조부(140), 레이저 광원부(150), 레이저 스펙클 영상 생성부(160), 및 영상 출력부(170)를 포함하며, 포도당 센싱부(110)는 다시 스캐터 고정 플레이트(112)를 포함한다. 1, the glucose concentration measuring system includes a glucose sensing unit 110, a photothermal light irradiation unit 120, a glucose concentration calculating unit 130, a frequency modulating unit 140, a laser light source unit 150, and a laser speckle image generating unit. 160, and an image output unit 170, and the glucose sensing unit 110 again includes a scatter fixing plate 112.
도 2에서, 포도당 센싱부(110)는 센싱 챔버 바닥의 금속나노입자 플레이트(112) 상에 위치하는 글루코스 산화효소 및 조효소를 포함한다. 포도당 센싱부(110)를 이용하여 광학 방식으로 혈당을 측정하며, 추가 발색체나 발광체의 첨가 없이 조효소의 자가 광학특성 변화만으로 혈당을 센싱할 수 있다.In FIG. 2 , the glucose sensing unit 110 includes a glucose oxidase and a coenzyme located on the metal nanoparticle plate 112 at the bottom of the sensing chamber. Blood glucose is measured in an optical manner using the glucose sensing unit 110, and blood sugar can be sensed only by changing the self-optical characteristics of the coenzyme without adding an additional chromogen or luminous body.
체액 상의 글루코스가 용해된 글루코스 산화효소와 반응시, 조효소(Flavin Adenine Dinucleotide, FAD)는 Hydrogen Peroxide와 반응하여 환원되고, 환원된 조효소(FADH2)의 광학 특성 변화를 관측하여 글루코스를 정량화할 수 있다. When glucose in the body fluid reacts with dissolved glucose oxidase, the coenzyme (Flavin Adenine Dinucleotide, FAD) is reduced by reacting with Hydrogen Peroxide, and the change in optical properties of the reduced coenzyme (FADH 2 ) can be observed to quantify glucose. .
FADH2의 비율이 증가할수록 450nm의 흡광성이 선형적으로 감소하기 때문에, 이를 통해 Label-Free하게 체액상의 글루코스 농도를 생체삽입이 가능한 고분자 복합체를 활용하여 광학적으로 정량화할 수 있다. 도 4는 FAD의 산화-환원 정도에 따른 특정 대역(450nm)의 흡광특성 변화를 도시한 도면이다.Since the absorbance at 450 nm decreases linearly as the ratio of FADH 2 increases, it is possible to optically quantify the glucose concentration in the body fluid in a label-free manner using a polymer complex that can be inserted into the body. 4 is a diagram showing changes in light absorption characteristics of a specific band (450 nm) according to the degree of oxidation-reduction of FAD.
광열 광 조사부(120)는 조효소의 미리 설정된 흡수 파장 대역의 광을 포도당 센싱부(110)로 조사한다. 이때, 주파수 변조부(140)는 광열 광의 주파수를 변조한다. The photothermal light irradiation unit 120 irradiates light of a preset absorption wavelength band of the coenzyme to the glucose sensing unit 110 . At this time, the frequency modulator 140 modulates the frequency of the photothermal light.
광열모듈레이션을 활용하여 용해 용액상에서 글루코스 농도에 따라 발생하는 자가흡광변화를 증폭 검출하여, 전극없이 글루코스 변화를 측정하기 위한 구성이다.It is a configuration for measuring glucose change without an electrode by amplifying and detecting the change in self-absorption that occurs according to the concentration of glucose in the dissolution solution using photothermal modulation.
조효소의 흡광 특성 변화를 고려하여, 주파수 변조된 특정 대역대의 빛을 조사하면 산화 또는 환원된 조효소의 선별적 광열모듈레이션이 가능하고, 조효소 주변의 주기적 광열효과는 매질의 주기적 굴절률을 달리하게 된다. Considering the change in the absorption characteristics of the coenzyme, irradiating light of a specific frequency-modulated band enables selective photothermal modulation of the oxidized or reduced coenzyme, and the periodic photothermal effect around the coenzyme changes the periodic refractive index of the medium.
이를 Laser-Speckle로 영상화하여 분석하면 높은 선택성을 가지고 산화 또는 환원된 조효소 성분을 정량화할 수 있고, 이를 활용하여 고정밀 글루코스 정량화를 수행할 수 있다.If this is imaged and analyzed with a Laser-Speckle, oxidized or reduced coenzyme components can be quantified with high selectivity, and high-precision glucose quantification can be performed using this.
레이저 광원부(150)는 포도당 센싱부(110)에 레이저 광을 조사한다. 용해 용액에서의 굴절률 변화를 레이저 스펙클 영상을 통해서 측정하기 위해, 레이저 스펙클 패턴을 생성하는 레이저 광원을 연속적으로 포도당 센싱부(110)에 조사하는 것이다.The laser light source unit 150 radiates laser light to the glucose sensing unit 110 . In order to measure the refractive index change in the dissolution solution through a laser speckle image, a laser light source generating a laser speckle pattern is continuously irradiated to the glucose sensing unit 110 .
레이저 광원을 연속적으로 조사하면서 레이저 스펙클 패턴을 만들고, 혈당과 반응하여 변화하는 흡광 정도를 조효소의 흡수대역인 450나노미터 파장을 갖는 LED 및 레이저 주파수 모듈레이션을 통해 특정 파장대의 흡광을 유발한다.While irradiating the laser light source continuously, a laser speckle pattern is created, and the degree of light absorption that changes in response to blood sugar is induced through an LED having a wavelength of 450 nanometers, which is the absorption band of the coenzyme, and laser frequency modulation to induce light absorption in a specific wavelength range.
레이저 스펙클 영상 생성부(160)는 포도당 센싱부(110)로부터 입사된 광으로부터 레이저 스펙클 영상을 생성한다. 이미지 센서를 활용하여 포도당 센싱부(110)상의 혈당 반응시 열광원의 주파수에 따라 변화하는 흡열 변화의 정도 및 이에 따라 변화하는 굴절률 변화와 굴절률 변화에 따라 달라지는 레이저 스펙클 패턴을 실시간으로 관측하기 위한 것이다.The laser speckle image generator 160 generates a laser speckle image from light incident from the glucose sensor 110 . To observe in real time the degree of endothermic change that changes according to the frequency of the heat light source during the glucose response on the glucose sensing unit 110 and the refractive index change that changes accordingly and the laser speckle pattern that varies according to the refractive index change using an image sensor will be.
영상 출력부(170)는 레이저 스펙클 영상을 출력한다. 이에 따라, 체액 내의 혈당의 변화를 연속적으로 실시간 모니터링 및 디스플레이 할 수 있게 된다.The image output unit 170 outputs a laser speckle image. Accordingly, it is possible to continuously monitor and display changes in blood sugar in bodily fluid in real time.
도 5는 광열모듈레이션-레이저스펙클 패턴의 측정 알고리즘을 도시한 도면이다. 측정된 이미지 시퀀스의 각 픽셀에서의 intensity fluctuation(강도 변동)값을 추출하고, 이를 주파수 도메인 상에서 푸리에 변환을 통해 분석하여, scatter의 PT에 의한 enhanced fluctuation frequency 도출한다. 5 is a diagram illustrating a measurement algorithm of photothermal modulation-laser speckle pattern. The intensity fluctuation value of each pixel of the measured image sequence is extracted, analyzed through Fourier transform on the frequency domain, and the enhanced fluctuation frequency by PT of the scatter is derived.
이어서, 2D 이미지상의 각 픽셀에 대하여 위 과정을 수행 후 얻어진 정규화 된 magnitude값을 해당 픽셀 위치에 1:1 매핑을 통해 최종적으로 광열모듈레이션-레이저스펙클 패턴 이미지를 구현한다. Then, the normalized magnitude value obtained after performing the above process for each pixel on the 2D image is finally implemented as a photothermal modulation-laser speckle pattern image through 1:1 mapping to the corresponding pixel position.
광열모듈레이션-레이저스펙클 패턴 결과로써, 분석 물질의 소량의 변화도 fluctuation signals의 주파수 도메인 상에서의 magnitude값으로 해석하는 경우, 반응 전후의 미세 신호가 증폭될 수 있다. As a result of the photothermal modulation-laser speckle pattern, when even a small amount of change in an analyte is interpreted as a magnitude value in the frequency domain of fluctuation signals, minute signals before and after the reaction can be amplified.
포도당 농도 산출부(130)는 포도당 센싱부(110)에서의 온도 변화로부터 포도당 센싱부(110)에 인가된 포도당의 농도를 산출한다. 이때, 포도당 농도 산출부(130)는 포도당 센싱부(110)의 굴절률 변화를 이용하여 포도당의 농도를 산출할 수 있다. The glucose concentration calculation unit 130 calculates the concentration of glucose applied to the glucose sensing unit 110 from the temperature change in the glucose sensing unit 110 . In this case, the glucose concentration calculation unit 130 may calculate the glucose concentration using the change in refractive index of the glucose sensing unit 110 .
이를 위해, 실시간으로 저장된 레이저 스펙클 영상의 주파수 분석을 통해 광열 모듈레이션 주파수와 일치하는 주파수의 최고값을 기록하고 분석한다. 분석된 신호값을 혈당값의 변화에 맞게 보정하여 특정 신호값에 맞는 혈당 값을 정량화할 수 있다.To this end, the highest value of the frequency matching the photothermal modulation frequency is recorded and analyzed through frequency analysis of the laser speckle image stored in real time. A blood glucose value suitable for a specific signal value may be quantified by correcting the analyzed signal value according to a change in blood glucose value.
정리하면, 본 발명은 포도당 분해 효소, 조효소를 활용하여 별도의 염색 과정 없이 측정하기 위한 기술을 제시한다. 본 발명에서는, 포도당 분해 효소 및 조효소의 광열 자극 후 열전도 이완시 나타나는 굴절률 변화 정도를 레이저 스펙클 검출 장치로 관측하여 체액 내의 당농도를 광학방식으로 측정한다.In summary, the present invention proposes a technique for measuring glucose degrading enzyme and coenzyme without a separate staining process. In the present invention, the degree of refractive index change occurring during thermal conduction relaxation after photothermal stimulation of glucose degrading enzyme and coenzyme is observed with a laser speckle detection device to measure the sugar concentration in body fluid in an optical manner.
보다 구체적으로, 본 발명에서는, 복수개의 레이저 광원부와 고속 영상 센서를 포함하는 검출 장치를 통해 체액 내의 당농도 변화에 따라 달라지는 조효소의 흡광 특성과 광열 반응 후 열전도 이완시 나타나는 굴절률 정도의 변화를 레이저 스펙클 신호의 변화로 측정하고, 이를 정량화하는 알고리즘을 통해 광학적으로 당농도의 변화를 측정한다.More specifically, in the present invention, through a detection device including a plurality of laser light source units and a high-speed image sensor, the light absorption characteristics of the coenzyme that vary according to the change in the sugar concentration in the body fluid and the change in the degree of refractive index appearing during thermal conduction relaxation after the photothermal reaction are measured in the laser specification. It is measured by the change of the large signal and optically measures the change in sugar concentration through an algorithm that quantifies it.
정량화 알고리즘 적용을 통해, 체액 내의 당농도 변화를 측정하고 저장할 수 있으며, 디스플레이부에서 측정되는 체액 내 당 수치 값에 따른 정량화 값을 표시할 수 있다. Through the application of a quantification algorithm, it is possible to measure and store changes in sugar concentration in bodily fluids, and display quantified values according to numerical values of sugar in bodily fluids measured on the display unit.
한편, 포도당산화효소가 포도당과 산화 반응시 조효소는 연쇄 환원반응이 일어나고 환원된 조효소는 특정 광파장에 대한 흡광성이 변화하게 되지만, 조효소는 특정파장에 대한 흡광성은 뛰어나나 주변 매질로의 열조도에 따라 국소적 영역에서 광열반응은 낮다. On the other hand, when glucose oxidase is oxidized with glucose, the coenzyme undergoes a chain reduction reaction, and the reduced coenzyme changes its absorbance for a specific wavelength. Accordingly, the photothermal response in the local area is low.
본 발명에서는, 포도당산화효소 및 조효소 용액 용기의 바닥에 위치한 동일한 흡광대역을 갖는 극소적 광열효율이 높은 금속나노입자에 용액 위에서 조사되어 조효소의 흡광성에 따라 흡수되고 남은 빛이 전달되어 금속나노입자의 광열반응을 일으키게된다. In the present invention, the glucose oxidase and the metal nanoparticles having the same light absorption band located at the bottom of the coenzyme solution container are irradiated on top of the solution, and the light remaining after being absorbed according to the light absorbance of the coenzyme is transmitted to the metal nanoparticles. causes a photothermal reaction.
금속나노입자의 광열반응시 금속나노입자에 결맞음 레이저를 조사해 주면, 금속나노입자의 산란에 의해 레이저스펙클 형상을 구현하게 되고, 광열반응에 따라 금속나노입자 주변의 국소적 레이저 빛 굴절률의 변화를 초래하여 광열에 대응하는 레이저 스펙클 영상 변화를 관측할 수 있다.When coherent laser is irradiated on the metal nanoparticles during the photothermal reaction of the metal nanoparticles, the laser speckle shape is realized by the scattering of the metal nanoparticles, and the change in the local laser light refractive index around the metal nanoparticles according to the photothermal reaction is observed. As a result, the laser speckle image change corresponding to the photothermal can be observed.
이와 같은 광열 레이저 스펙클 영상 변화를 통해 용액내의 포도당 농도에 비례하여 조효소환원정도를 계산할 수 있고, 용액의 포도당 농도를 정량화할 수 있다. Through such a photothermal laser speckle image change, the degree of coenzyme reduction can be calculated in proportion to the glucose concentration in the solution, and the glucose concentration in the solution can be quantified.
본 발명의 구현을 통해 고민감도로 포도당 농도를 관측할 수 있고, 혈액에 녹아 있는 포도당 농도보다 낮은 침 눈물 땀 등에서 체내 포도당 농도를 예상 계산할 수 있다. Through the implementation of the present invention, the glucose concentration can be observed with high sensitivity, and the glucose concentration in the body can be estimated and calculated in saliva, tears, sweat, etc., which are lower than the glucose concentration dissolved in blood.
본 발명이 비록 일부 바람직한 실시예에 의해 설명되었지만, 본 발명의 범위는 이에 의해 제한되어서는 아니 되고, 특허청구범위에 의해 뒷받침되는 상기 실시예의 변형이나 개량에도 미쳐야할 것이다.Although the present invention has been described by some preferred embodiments, the scope of the present invention should not be limited thereto, but should also extend to modifications or improvements of the above embodiments supported by the claims.

Claims (9)

  1. 레이저 스펙클 영상을 위한 스캐터가 고정된 플레이트층이 바닥에 형성된 포도당 센싱부;a glucose sensing unit on the bottom of which is a plate layer to which a scatterer for laser speckle image is fixed;
    상기 플레이트층 상에 위치하는 글루코스 산화효소 및 조효소 용해 용액 중 조효소의 미리 설정된 흡수 파장 대역의 광을 조사하는 광열 광 조사부; 및a photothermal light irradiation unit for irradiating light of a predetermined absorption wavelength band of the coenzyme in the glucose oxidase and coenzyme dissolution solution located on the plate layer; and
    상기 포도당 센싱부에서의 온도 변화로부터 상기 포도당 센싱부에 인가된 포도당의 농도를 산출하는 포도당 농도 산출부를 포함하는 것을 특징으로 하는 포도당 농도 측정 시스템.A glucose concentration measuring system comprising a glucose concentration calculation unit for calculating the concentration of glucose applied to the glucose sensing unit from a temperature change in the glucose sensing unit.
  2. 청구항 1에 있어서,The method of claim 1,
    상기 스캐터는 상기 조효소의 흡수 파장 대역과 흡수 파장 대역이 중복되는 미리 설정된 파장 대역의 금속 나노 입자인 것을 특징으로 하는 포도당 농도 측정 시스템.The scatterer is a glucose concentration measuring system, characterized in that the metal nanoparticles of a preset wavelength band in which the absorption wavelength band and the absorption wavelength band of the coenzyme overlap.
  3. 청구항 2에 있어서,The method of claim 2,
    상기 포도당 농도 산출부는 상기 포도당 센싱부에서의 굴절률 변화를 이용하여 상기 포도당의 농도를 산출하는 것을 특징으로 하는 포도당 농도 측정 시스템.The glucose concentration measuring system, characterized in that the glucose concentration calculation unit calculates the concentration of the glucose using a refractive index change in the glucose sensing unit.
  4. 청구항 3에 있어서,The method of claim 3,
    상기 포도당 센싱부에 레이저 광을 조사하는 레이저 광원부; 및a laser light source unit irradiating laser light to the glucose sensing unit; and
    상기 포도당 센싱부로부터 입사된 광으로부터 레이저 스펙클 영상을 생성하는 레이저 스펙클 영상 생성부를 더 포함하고,Further comprising a laser speckle image generator for generating a laser speckle image from light incident from the glucose sensor,
    상기 포도당 농도 산출부는 상기 레이저 스펙클 영상을 이용하여 상기 포도당의 농도를 산출하는 것을 특징으로 하는 포도당 농도 측정 시스템.Wherein the glucose concentration calculation unit calculates the concentration of the glucose using the laser speckle image.
  5. 청구항 4에 있어서,The method of claim 4,
    상기 광열 광의 주파수를 변조하는 주파수 변조부를 더 포함하는 것을 특징으로 하는 포도당 농도 측정 시스템.Glucose concentration measuring system characterized in that it further comprises a frequency modulator for modulating the frequency of the photothermal light.
  6. 청구항 5에 있어서,The method of claim 5,
    상기 포도당 센싱부는 상기 플레이트층 상측에 상기 글루코스 산화효소 및 조효소 용해 용액의 수용 공간이 형성된 것을 특징으로 하는 포도당 농도 측정 시스템. The glucose sensing unit glucose concentration measuring system, characterized in that the receiving space for the glucose oxidase and the coenzyme dissolution solution is formed on the upper side of the plate layer.
  7. 청구항 6에 있어서,The method of claim 6,
    상기 레이저 스펙클 영상을 출력하는 영상 출력부를 더 포함하는 것을 특징으로 하는 포도당 농도 측정 시스템.Glucose concentration measurement system further comprising an image output unit for outputting the laser speckle image.
  8. 포도당 농도 측정 시스템이 수행하는 포도당 농도 측정 방법으로서,A glucose concentration measurement method performed by a glucose concentration measurement system,
    레이저 스펙클 영상을 위한 스캐터가 고정된 플레이트층상에 위치하는 글루코스 산화효소 및 조효소의 용해 용액으로 상기 조효소의 미리 설정된 흡수 파장 대역의 광을 조사하는 광열 광 조사 단계; A photothermal light irradiation step of irradiating light of a predetermined absorption wavelength band of the coenzyme into a dissolution solution of glucose oxidase and coenzyme located on a plate layer to which a scatterer for a laser speckle image is fixed;
    상기 용해 용액으로부터 입사된 광을 검출하는 센싱 단계; 및a sensing step of detecting light incident from the dissolution solution; and
    상기 용해 용액에서의 온도 변화로부터 상기 용해 용액체에서의 포도당의 농도를 산출하는 포도당 농도 산출 단계를 포함하는 것을 특징으로 하는 포도당 농도 측정 방법.A glucose concentration measuring method comprising a glucose concentration calculation step of calculating the concentration of glucose in the dissolution solution from a temperature change in the dissolution solution.
  9. 청구항 8의 방법을 실행시키기 위한 컴퓨터 판독 가능한 프로그램을 기록한 기록 매체.A recording medium recording a computer readable program for executing the method of claim 8.
PCT/KR2022/016609 2021-10-27 2022-10-27 System and method for measuring glucose concentration by using photothermal modulation laser speckle imaging, and recording medium having recorded thereon computer-readable program for executing the method WO2023075465A1 (en)

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