WO2023157164A1 - 非侵襲物質分析装置 - Google Patents

非侵襲物質分析装置 Download PDF

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Publication number
WO2023157164A1
WO2023157164A1 PCT/JP2022/006342 JP2022006342W WO2023157164A1 WO 2023157164 A1 WO2023157164 A1 WO 2023157164A1 JP 2022006342 W JP2022006342 W JP 2022006342W WO 2023157164 A1 WO2023157164 A1 WO 2023157164A1
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WIPO (PCT)
Prior art keywords
sample
temperature
temperature sensor
substance
excitation light
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Ceased
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PCT/JP2022/006342
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English (en)
French (fr)
Japanese (ja)
Inventor
祐樹 津田
周作 林
浩一 秋山
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Mitsubishi Electric Corp
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Mitsubishi Electric Corp
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Application filed by Mitsubishi Electric Corp filed Critical Mitsubishi Electric Corp
Priority to JP2022542213A priority Critical patent/JP7205002B1/ja
Priority to PCT/JP2022/006342 priority patent/WO2023157164A1/ja
Priority to US18/834,630 priority patent/US12292400B2/en
Priority to CN202280091478.2A priority patent/CN118679381B/zh
Priority to DE112022005931.1T priority patent/DE112022005931B4/de
Publication of WO2023157164A1 publication Critical patent/WO2023157164A1/ja
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed 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 or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration or pH-value ; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid or cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7203—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal
    • A61B5/7207—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal of noise induced by motion artifacts
    • A61B5/721—Signal processing specially adapted for physiological signals or for diagnostic purposes for noise prevention, reduction or removal of noise induced by motion artifacts using a separate sensor to detect motion or using motion information derived from signals other than the physiological signal to be measured
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N25/00—Investigating or analyzing materials by the use of thermal means
    • G01N25/20—Investigating or analyzing materials by the use of thermal means by investigating the development of heat, i.e. calorimetry, e.g. by measuring specific heat, by measuring thermal conductivity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/02—Details of sensors specially adapted for in-vivo measurements
    • A61B2562/0271—Thermal or temperature sensors

Definitions

  • This disclosure relates to a non-invasive substance analyzer.
  • Patent Document 1 discloses a noninvasive analysis system that includes an optical medium, an infrared light source, a probe light source, and a photodiode. Specifically, a biological sample is placed on the optical medium. An infrared light source emits infrared light. Infrared light illuminates the biological sample through an optical medium. The infrared light is absorbed by the biological sample and the biological sample heats up. The degree of heat absorption of a biological sample depends on the amount or concentration of the biological component in or on the surface of the sample.
  • the probe light source radiates probe light, which is visible light, toward an optical medium.
  • the probe light is totally internally reflected at the interface between the optical medium and the biological sample and exits the optical medium.
  • the absorbed heat of the biological sample is transferred to the optical medium and changes the refractive index of the optical medium.
  • a change in the refractive index of the optical medium affects total internal reflection of the probe light at the interface between the optical medium and the biological sample, and changes the traveling direction of the probe light emitted from the optical medium.
  • the photodiode functions as an optical position sensor to detect changes in the traveling direction of the probe light.
  • the amount or concentration of the biological component is measured from the change in the traveling direction of the probe light detected by the photodiode. For example, if the sample is a patient's skin, the patient's blood glucose level is measured as the biological component.
  • a non-invasive substance analysis device of the present disclosure includes a sample support plate, an excitation light source, and a temperature sensor.
  • the sample support plate has a first major surface including a sample placement area and a second major surface opposite the first major surface.
  • An excitation light source emits excitation light toward a sample placed on the sample placement area.
  • a temperature sensor is provided on the first main surface.
  • a through hole is provided in the sample support plate extending from the sample placement area to the second major surface. The excitation light is applied to the sample through the through-hole.
  • the sample support plate is provided with a through-hole through which the excitation light passes. Therefore, the excitation light reaches the sample with stronger light intensity without being absorbed by the sample support plate. The heat of absorption of the sample increases. In addition, it becomes difficult for the heat absorbed by the sample to escape in the thickness direction of the sample support plate (the direction in which the first main surface and the second main surface are opposed to each other).
  • the temperature signal output from the temperature sensor increases when the sample is irradiated with the excitation light. Therefore, substances in the sample or on the surface of the sample can be analyzed more accurately.
  • FIG. 1 is a schematic plan view of the noninvasive substance analyzer of Embodiment 1.
  • FIG. FIG. 2 is a schematic cross-sectional view of the noninvasive substance analyzer of Embodiment 1 taken along the cross-sectional line II-II shown in FIG. 1;
  • 1 is a schematic partial enlarged cross-sectional view of the noninvasive substance analyzer of Embodiment 1;
  • FIG. 1 is a circuit diagram of a lock-in amplifier;
  • FIG. 1 is a diagram showing a flowchart of a noninvasive substance analysis method according to Embodiment 1;
  • FIG. FIG. 10 is a diagram showing simulation results of normalized temperature variation widths of Example 1 and Comparative Examples 1-1 and 1-2;
  • FIG. 3 is a schematic cross-sectional view of a noninvasive substance analyzer of a modification of Embodiment 1;
  • FIG. 10 is a schematic cross-sectional view of a noninvasive substance analyzer according to Embodiment 2;
  • FIG. 10 is a diagram showing simulation results of normalized temperature variation widths of Example 2 and Comparative Examples 2-1 and 2-2;
  • FIG. 11 is a schematic plan view of a noninvasive substance analyzer according to Embodiment 3;
  • FIG. 11 is a schematic cross-sectional view of the noninvasive substance analyzer of Embodiment 3 taken along the cross-sectional line XI-XI shown in FIG. 10;
  • FIG. 11 is a schematic plan view of a noninvasive substance analyzer according to Embodiment 4;
  • FIG. 13 is a schematic cross-sectional view of the noninvasive substance analyzer of Embodiment 4 taken along the cross-sectional line XIII-XIII shown in FIG. 12;
  • FIG. 11 is a schematic plan view of a noninvasive substance analyzer according to Embodiment 5;
  • FIG. 15 is a schematic cross-sectional view of the noninvasive substance analyzer of Embodiment 5 taken along the cross-sectional line XV-XV shown in FIG. 14;
  • FIG. 11 is a schematic plan view of a noninvasive substance analyzer according to Embodiment 6;
  • FIG. 17 is a schematic cross-sectional view of the noninvasive substance analyzer of Embodiment 6 taken along the cross-sectional line XVII-XVII shown in FIG. 16;
  • Embodiment 1 A noninvasive substance analyzer 1 according to a first embodiment will be described with reference to FIGS. 1 to 4.
  • FIG. 1 and 2 the noninvasive substance analyzer 1 includes a sample support plate 10, an excitation light source 20, an optical chopper 22, temperature sensors 25 and 26, a lock-in amplifier 34, and a signal processor. 37 and a substance analysis unit 38 .
  • the sample support plate 10 has a principal surface 10a and a principal surface 10b opposite to the principal surface 10a.
  • the major surface 10a includes a sample placement area 12 on which a sample 15 is placed.
  • Sample 15 is, for example, a biological sample such as a patient's finger, wrist, arm, earlobe or lip.
  • the sample support plate 10 is composed of a substrate 11 .
  • the substrate 11 is made of a material that is opaque to the excitation light 21 .
  • the substrate 11 is made of, for example, plastic such as polyethylene, polycarbonate, polyurethane or acrylic resin, or glass.
  • the sample support plate 10 is provided with a through hole 13 extending from the sample placement area 12 to the main surface 10b.
  • the size of the sample 15 is larger than the size of the through-hole 13 in plan view of the main surface 10a.
  • the excitation light source 20 emits excitation light 21 toward the sample 15 placed on the sample placement area 12 .
  • the wavelength of excitation light 21 is determined according to the absorption wavelengths of substances in sample 15 or on the surface of sample 15 .
  • the excitation light 21 is, for example, mid-infrared light.
  • the wavelength of the excitation light 21 is, for example, 6.0 ⁇ m or longer.
  • the wavelength of the excitation light 21 may be 8.0 ⁇ m or longer.
  • the wavelength of the excitation light 21 is, for example, 13.0 ⁇ m or less.
  • the wavelength of the excitation light 21 may be 11.0 ⁇ m or less.
  • the excitation light 21 may be light having multiple wavelengths.
  • the wavelength range of the excitation light 21 is a wavelength range including the wavelength of the fingerprint spectrum of sugar (for example, a wavelength range of 8.5 ⁇ m or more and 10 ⁇ m or less).
  • the excitation light source 20 is, for example, a quantum cascade laser capable of emitting broadband mid-infrared light. Reference light that is not absorbed by material in the sample 15 or on the surface of the sample 15 may be applied to the sample 15 along with the excitation light 21 .
  • the optical chopper 22 periodically intensity-modulates the excitation light 21 .
  • the optical chopper 22 includes, for example, multiple rotating blades. A plurality of rotating blades are made of a material that is opaque to the excitation light 21 .
  • the sample 15 is not illuminated by the excitation light 21 when the excitation light 21 is blocked by one of the plurality of rotating vanes.
  • the sample 15 is irradiated with the excitation light 21 when the excitation light 21 passes through between a pair of rotor blades adjacent to each other among the plurality of rotor blades.
  • the optical chopper 22 intensity-modulates the excitation light 21 emitted from the excitation light source 20 .
  • the optical chopper 22 transmits a reference signal having the same frequency as the intensity modulation frequency of the intensity-modulated excitation light 21 to the lock-in amplifier 34 through the electrical wiring 30 .
  • the excitation light 21 intensity-modulated by the optical chopper 22 enters the sample support plate 10 from the main surface 10b side.
  • the excitation light 21 passes through the through-hole 13 and irradiates the sample 15 .
  • the excitation light 21 travels along the central axis 13c of the through hole 13, for example.
  • the excitation light 21 impinges on the sample 15 .
  • the excitation light 21 is absorbed by substances in the sample 15 or on the surface of the sample 15 . Absorption of excitation light 21 by materials in sample 15 or on the surface of sample 15 generates heat of absorption in sample 15 .
  • the excitation light 21 when the excitation light 21 is blocked by the optical chopper 22 , the excitation light 21 does not irradiate the sample 15 and the sample 15 does not generate absorption heat. Therefore, the temperature of the sample 15 fluctuates with the intensity-modulated frequency of the excitation light 21 .
  • a substance in the sample 15 or on the surface of the sample 15 is, for example, a biological component.
  • the substance analyzed by the noninvasive substance analyzer 1 is sugar present in the interstitial fluid in the patient's epidermis.
  • the temperature sensors 25, 26 are provided on the main surface 10a. Temperature sensors 25 and 26 are provided in the sample placement area 12 . When the sample 15 is placed on the sample placement area 12 , the temperature sensors 25 and 26 come into contact with the sample 15 and detect the temperature of the sample 15 . Temperature sensors 25 and 26 detect the temperature of sample 15 and output a temperature signal corresponding to the temperature to lock-in amplifier 34 . Specifically, the temperature sensor 25 detects the temperature of the portion of the sample 15 in contact with the temperature sensor 25 and outputs a temperature signal corresponding to the temperature to the lock-in amplifier 34 . The temperature sensor 26 detects the temperature of the portion of the sample 15 in contact with the temperature sensor 26 and outputs a temperature signal corresponding to the temperature to the lock-in amplifier 34 .
  • the temperature signals output from the temperature sensors 25 and 26 also fluctuate with the intensity-modulated frequency of the excitation light 21 .
  • the temperature sensors 25 and 26 output the minimum value of the temperature signal when the sample 15 is not irradiated with the excitation light 21, and output the maximum value of the temperature signal when the sample 15 is irradiated with the excitation light 21.
  • the difference between the maximum and minimum values of the temperature signal is the amplitude of the temperature signal.
  • the amplitude of the temperature signals of the temperature sensors 25,26 corresponds to the temperature variation of the sample 15 as measured by the temperature sensors 25,26 during the sample 15 analysis.
  • the analysis of the sample 15 means the time when the sample 15 is irradiated with the intensity-modulated excitation light 21 .
  • Temperature sensors 25 and 26 are arranged near through hole 13 .
  • the distance d1 between each of the temperature sensors 25 and 26 and the through hole 13 is 50 ⁇ m or less.
  • the distance d1 may be 20 ⁇ m or less, or may be 10 ⁇ m or less.
  • Distance d1 is 10% or less of the size of through-hole 13 (eg, the diameter of through-hole 13).
  • the distance d 1 may be 5% or less of the size of the through hole 13 .
  • the temperature sensors 25 and 26 are rotationally symmetrical with respect to the central axis 13c of the through-hole 13 in plan view of the main surface 10a.
  • temperature sensors 25 and 26 include temperature sensor bodies 27 . Temperature sensors 25 and 26 may further include protective film 28 .
  • the temperature sensor body 27 is, for example, a thermocouple, thermopile, thermistor or diode.
  • the thermocouple measures the temperature of the sample 15 by bringing two dissimilar material pieces into contact with each other and from the thermoelectromotive force generated at the contact portion of the two dissimilar material pieces.
  • the two pieces of material that make up the thermocouple are, for example, iron, copper-nickel alloy, copper, nickel-chromium alloy, nickel-aluminum alloy, nickel-silicon alloy, nickel-chromium-silicon alloy, platinum, platinum-rhodium alloy, bismuth, antimony, or A combination of these.
  • the two pieces of material that make up the thermocouple may be formed by p-type polysilicon and n-type polysilicon.
  • a thermopile is formed by connecting multiple thermocouples.
  • the electrical resistance of the thermistor changes with the temperature of the thermistor.
  • the temperature of the sample 15 is detected from the electrical resistance of the thermistor.
  • the thermistor is preferably made of a material with a large temperature coefficient of resistance.
  • Thermistors are formed, for example, by vanadium oxide, NiMoCo oxide, Ti, polycrystalline silicon, amorphous silicon, amorphous silicon germanium, MnO3 or YBaCuO.
  • the forward voltage of the diode changes according to the temperature of the diode.
  • the temperature of the sample 15 is detected from the forward voltage of the diode.
  • the diode is, for example, a Si diode.
  • the protective film 28 covers the temperature sensor main body 27.
  • Protective film 28 prevents sample 15 from contacting temperature sensor body 27 .
  • the protective film 28 preferably has a low thermal conductivity (for example, a thermal conductivity of 0.5 W/(m ⁇ K) or less) and a thin thickness (for example, a thickness of 10 ⁇ m or less). Since the thermal conductivity of the protective film 28 is low, it becomes difficult for the heat absorbed by the sample 15 to rapidly spread over the entire sample support plate 10 . Since the protective film 28 is thin, even if the thermal conductivity of the protective film 28 is low, the heat absorbed by the sample 15 is efficiently conducted to the temperature sensor main body 27 .
  • lock-in amplifier 34 is connected to optical chopper 22 by electrical wiring 30 .
  • a lock-in amplifier 34 receives from the optical chopper 22 a reference signal having the same frequency as the intensity modulation frequency of the intensity-modulated excitation light 21 . 1 and 2, lock-in amplifier 34 is connected to temperature sensors 25 and 26 by electrical wiring 32 .
  • Lock-in amplifier 34 receives temperature signals corresponding to the temperature of sample 15 from temperature sensors 25 , 26 . Specifically, the lock-in amplifier 34 receives from the temperature sensor 25 a temperature signal corresponding to the temperature of the portion of the sample 15 with which the temperature sensor 25 is in contact. Lock-in amplifier 34 receives from temperature sensor 26 a temperature signal corresponding to the temperature of the portion of sample 15 in contact with temperature sensor 26 .
  • the lock-in amplifier 34 synchronously detects the temperature signals received from the temperature sensors 25 and 26 with the reference signal received from the optical chopper 22 .
  • the lock-in amplifier 34 outputs the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 .
  • the temperature swing signal of temperature sensor 25 is the temperature swing signal corresponding to the temperature swing of sample 15 as measured by temperature sensor 25 during analysis of sample 15 .
  • the temperature swing signal of temperature sensor 26 is the temperature swing signal corresponding to the temperature swing of sample 15 as measured by temperature sensor 26 during analysis of sample 15 .
  • Lock-in amplifier 34 includes multiplier 35 and low-pass filter 36 .
  • a multiplier 35 multiplies the temperature signal from the temperature sensor 25 and the reference signal.
  • the multiplier 35 outputs a DC component proportional to the amplitude of the temperature signal from the temperature sensor 25 and an AC component varying at twice the frequency of the intensity modulation frequency of the excitation light 21 .
  • a low-pass filter 36 removes the AC component and passes the DC component.
  • lock-in amplifier 34 outputs a DC component proportional to the amplitude of the temperature signal from temperature sensor 25 .
  • the amplitude of the temperature signal of temperature sensor 25 corresponds to the temperature fluctuation width of the portion of sample 15 in contact with temperature sensor 25 during analysis of sample 15 . Therefore, the DC component is the temperature fluctuation width signal of the temperature sensor 25 .
  • the lock-in amplifier 34 outputs a DC component proportional to the amplitude of the temperature signal from the temperature sensor 26.
  • the DC component is the temperature fluctuation width signal of the temperature sensor 26 .
  • the signal processing section 37 is connected to the lock-in amplifier 34 .
  • the signal processing unit 37 receives the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 from the lock-in amplifier 34 .
  • the signal processing unit 37 calculates the average of the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 .
  • the signal processing unit 37 outputs an average temperature fluctuation width signal corresponding to the average of the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 .
  • the signal processing unit 37 is, for example, a microcomputer including a processor and a storage device.
  • the signal processing section 37 operates by the processor executing a program stored in the storage device.
  • the substance analysis unit 38 is connected to the signal processing unit 37.
  • the substance analysis unit 38 receives the average temperature fluctuation width signal from the signal processing unit 37 .
  • a material analysis unit 38 analyzes the material in the sample 15 or on the surface of the sample 15 based on the average temperature fluctuation width signal.
  • the material analysis unit 38 has a data table in which the wavelength of the excitation light 21 and the type of material are associated, and a data table in which the magnitude of the average temperature fluctuation width signal and the amount or concentration of the material are associated. to identify the type of substance in the sample 15 or on the surface of the sample 15 and to calculate the amount or concentration of the substance.
  • the substance analysis unit 38 is, for example, a microcomputer including a processor and a storage device. These data tables are stored in a storage device.
  • the substance analysis section 38 operates by the processor executing a program stored in the storage device.
  • the thermal conductivity of the substrate 11 may be, for example, 5 W/(mK) or less, 2 W/(mK) or less, or 1 W/(mK) or less. It may be 0.3 W/(m ⁇ K) or less. Therefore, the absorption heat generated in the sample 15 by irradiating the sample 15 with the excitation light 21 does not spread rapidly over the entire substrate 11, and the temperature fluctuation width signals of the temperature sensors 25 and 26 increase. Substances in the sample 15 or on the surface of the sample 15 can be analyzed with greater accuracy.
  • the thermal conductivity of the substrate 11 is preferably smaller than that of the sample 15.
  • the thermal conductivity of the sample 15 is approximately 0.5 W/(m ⁇ K).
  • the thermal conductivity of the substrate 11 is 0.1 W/(m ⁇ K) or more and 0.3 W/(m ⁇ K) or less. Therefore, the absorption heat generated in the sample 15 by irradiating the sample 15 with the excitation light 21 does not spread rapidly over the entire substrate 11, and the temperature fluctuation width signals of the temperature sensors 25 and 26 increase. Substances in the sample 15 or on the surface of the sample 15 can be analyzed with greater accuracy.
  • the thermal diffusion length L of the absorbed heat of sample 15 is given by equation (1).
  • f is the frequency of absorption heat of the sample 15 (the intensity modulation frequency of the excitation light 21), and ⁇ is the thermal diffusion coefficient of the sample 15.
  • the frequency (Intensity modulation frequency of excitation light 21) is set to, for example, 5 Hz or more and 100 Hz or less.
  • the noninvasive substance analysis method of the present embodiment comprises placing the sample 15 on the sample placement area 12 (S1). Heat transfer between the sample support plate 10 and the sample 15 occurs when there is a difference between the temperature of the sample support plate 10 and the sample 15 . This heat transfer makes the detection of the temperature swing signal difficult and the analysis of substances in or on the surface of the sample 15 difficult. Therefore, step S2, which will be described later, is not performed until a state of thermal equilibrium is achieved between the sample support plate 10 and the sample 15. FIG. Achieving a state of thermal equilibrium between the sample support plate 10 and the sample 15 can be detected by temperature sensors 25 , 26 .
  • step S2 is performed.
  • the noninvasive substance analysis method of the present embodiment comprises irradiating the sample 15 with the excitation light 21 intensity-modulated by the optical chopper 22 (S2).
  • the optical chopper 22 transmits a reference signal having the same frequency as the intensity-modulated frequency of the pumping light 21 through the electrical wiring 30 to the lock-in amplifier 34 .
  • the non-invasive substance analysis method of the present embodiment comprises obtaining the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 (S3).
  • the lock-in amplifier 34 receives the reference signal from the optical chopper 22 and the temperature signal from the temperature sensor 25 .
  • Lock-in amplifier 34 includes multiplier 35 and low-pass filter 36 .
  • a multiplier 35 multiplies the temperature signal from the temperature sensor 25 and the reference signal.
  • the multiplier 35 outputs a DC component proportional to the amplitude of the temperature signal from the temperature sensor 25 and an AC component varying at twice the frequency of the intensity modulation frequency of the excitation light 21 .
  • a low-pass filter 36 removes the AC component and passes the DC component.
  • lock-in amplifier 34 outputs a DC component proportional to the amplitude of the temperature signal from temperature sensor 25 .
  • a DC component is a temperature fluctuation width signal of the temperature sensor 25 .
  • the lock-in amplifier 34 outputs a DC component proportional to the amplitude of the temperature signal from the temperature sensor 26.
  • the DC component is the temperature fluctuation width signal of the temperature sensor 26 .
  • the noninvasive substance analysis method of the present embodiment comprises obtaining an average of the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 as an average temperature fluctuation width signal (S4).
  • the signal processing unit 37 receives the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 from the lock-in amplifier 34 .
  • the signal processing unit 37 calculates the average of the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 as an average temperature fluctuation width signal.
  • the signal processing section 37 outputs the average temperature variation width signal to the material analysis section 38 .
  • the non-invasive material analysis method of the present embodiment comprises analyzing the material in the sample 15 or on the surface of the sample 15 based on the average temperature fluctuation width signal (S5).
  • the substance analysis unit 38 receives the average temperature fluctuation width signal from the signal processing unit 37 .
  • the material analysis unit 38 has a data table in which the wavelength of the excitation light 21 and the type of material are associated, and a data table in which the magnitude of the average temperature fluctuation width signal and the amount or concentration of the material are associated. to identify the type of substance in the sample 15 or on the surface of the sample 15 and to calculate the amount or concentration of the substance.
  • Example 1 of the present embodiment By comparing Example 1 of the present embodiment with Comparative Examples 1-1 and 1-2 with reference to FIG. 6, the action of the noninvasive substance analyzer 1 of the present embodiment will be described.
  • Example 1 the substrate 11 is made of a material that does not transmit the excitation light 21 (for example, plastic or glass). Further, in Example 1, the diameter of the through-hole 13 is 36 ⁇ m, and the diameter of the light irradiation region 21b of the excitation light 21 is 30 ⁇ m. Comparative Example 1-1 is the same as Example 1, but the through hole 13 is not formed in the substrate 11 . Comparative Example 1-2 is similar to Comparative Example 1-1, except that in Comparative Example 1-2, the transmittance of substrate 11 to excitation light 21 is assumed to be 100%.
  • the normalized temperature fluctuation width in FIG. 6 is normalized by the temperature fluctuation width of the edge of the through-hole 13 in the main surface 10a of Example 1, Comparative Example 1-1, and Comparative Example 1-2.
  • the width of temperature fluctuation at each point on the main surface 10a is the temperature at each point on the main surface 10a when the sample 15 is not irradiated with the excitation light 21 and the temperature at each point on the main surface 10a when the sample 15 is irradiated with the excitation light 21. given by the difference between the temperature
  • Example 1 through holes 13 are provided in the sample support plate 10 . Therefore, the excitation light 21 reaches the sample 15 with stronger light intensity without being absorbed by the sample support plate 10 . The heat of absorption of sample 15 increases. Also, the thermal conductivity of the air in the through-hole 13 (0.024 W/(mK)) is the same as the thermal conductivity of the substrate 11 (for example, the thermal conductivity of plastic: about 0.1 W/(mK). about 0.3 W/(m ⁇ K), glass thermal conductivity: about 0.5 W/(m ⁇ K) or more and less than about 0.7 W/(m ⁇ K)).
  • the heat absorbed by the sample 15 is less likely to escape in the thickness direction of the sample support plate 10 (the direction in which the main surface 10a and the main surface 10b face each other).
  • the temperature fluctuation width of the main surface 10a during the analysis of the sample 15 increases.
  • substances in or on the surface of sample 15 can be analyzed more accurately.
  • Comparative Example 1-1 the substrate 11 is made of a material that does not allow the excitation light 21 to pass therethrough. Therefore, the excitation light 21 does not reach the sample 15, and no absorption heat of the sample 15 is generated. The temperature fluctuation width of the main surface 10a during the analysis of the sample 15 is zero. In Comparative Example 1-1, the substances in sample 15 or on the surface of sample 15 cannot be analyzed accurately.
  • Comparative Example 1-2 it is assumed that the transmittance of the substrate 11 with respect to the excitation light 21 is 100%, and the excitation light 21 reaches the sample 15. Therefore, the temperature fluctuation width of the main surface 10a during the analysis of the sample 15 is not zero. However, in Comparative Example 1-2, the through hole 13 is not provided in the substrate 11 . Therefore, in Comparative Example 1-2, the heat absorbed by the sample 15 diffuses more quickly than in Example 1 in the thickness direction of the sample support plate 10 (the direction in which the main surfaces 10a and 10b face each other). The temperature fluctuation width of the main surface 10a in Comparative Example 1-2 is smaller than the temperature fluctuation width of the main surface 10a in the first embodiment. Comparative Examples 1-2 do not allow accurate analysis of substances in or on the surface of sample 15 .
  • the sample support plate 10 (substrate 11 ) may be made of a material transparent to the excitation light 21 .
  • the number of temperature sensors 25, 26 may be three or more.
  • the temperature sensor 26 may be omitted, and the number of temperature sensors 25 may be one. In this case, the signal processing section 37 is omitted.
  • the substance analysis unit 38 receives the temperature fluctuation width signal of the temperature sensor 25 from the lock-in amplifier 34 .
  • the material analysis unit 38 analyzes the material in the sample 15 or on the surface of the sample 15 based on the temperature fluctuation width signal of the temperature sensor 25 . In step S3, the temperature fluctuation width signal of the temperature sensor 25 is obtained, step S4 is omitted, and in step S5, the substance in the sample 15 or on the surface of the sample 15 is to analyze.
  • the noninvasive substance analyzer 1 may further include a beam splitter 23 and a photodetector 24.
  • the excitation light 21 intensity-modulated by the optical chopper 22 enters the beam splitter 23 .
  • a beam splitter 23 splits the excitation light 21 into excitation light 21 towards the sample 15 and excitation light 21 towards the photodetector 24 .
  • the beam splitter 23 causes a portion of the excitation light 21 intensity-modulated by the optical chopper 22 to enter the photodetector 24 .
  • a photodetector 24 detects the intensity of the intensity-modulated excitation light 21 .
  • Photodetector 24 is, for example, a photodiode.
  • Photodetector 24 is connected to lock-in amplifier 34 by electrical wiring 30 .
  • the photodetector 24 outputs a reference signal corresponding to the intensity of the intensity-modulated excitation light 21 to the lock-in amplifier 34 .
  • the influence of fluctuations in the intensity of the excitation light 21 can be removed from the temperature fluctuation width signals of the temperature sensors 25 and 26 . Even if the intensity of the excitation light 21 varies, the substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the non-invasive substance analyzer 1 of this embodiment includes a sample support plate 10, an excitation light source 20, and at least one temperature sensor (for example, temperature sensors 25 and 26).
  • the sample support plate 10 has a first main surface (main surface 10a) including the sample mounting area 12 and a second main surface (main surface 10b) opposite to the first main surface.
  • the excitation light source 20 emits excitation light 21 toward the sample 15 placed on the sample placement area 12 .
  • At least one temperature sensor is provided on the first major surface.
  • a through hole 13 is provided in the sample support plate 10 extending from the sample placement area 12 to the second main surface. The excitation light 21 passes through the through-hole 13 and irradiates the sample 15 .
  • the sample support plate 10 is provided with a through-hole 13 through which the excitation light 21 passes. Therefore, the excitation light 21 reaches the sample 15 with stronger light intensity without being absorbed by the sample support plate 10 .
  • the heat of absorption of sample 15 increases. Also, the heat absorbed by the sample 15 is less likely to escape in the thickness direction of the sample support plate 10 (the direction in which the first main surface (main surface 10a) and the second main surface (main surface 10b) face each other).
  • the temperature signal output from at least one temperature sensor for example, the temperature sensors 25 and 26
  • substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the non-invasive substance analyzer 1 it is possible to use a material opaque to the excitation light 21 as the sample support plate 10 (substrate 11).
  • the choice of materials for the sample support plate 10 (substrate 11) is expanded.
  • a material for example, plastic or glass
  • the excitation light 21 is applied to the sample 15.
  • the temperature signal output from at least one temperature sensor e.g., temperature sensors 25 and 26
  • At least one temperature sensor (for example, temperature sensors 25 and 26) is provided in the sample placement area 12 and contacts the sample 15.
  • the heat absorbed by the sample 15 is efficiently conducted to at least one temperature sensor (for example, the temperature sensors 25 and 26).
  • the temperature signal output from at least one temperature sensor increases when the sample 15 is irradiated with the excitation light 21 . Substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the noninvasive substance analyzer 1 of the present embodiment further includes a substance analysis section 38.
  • the material analysis unit 38 analyzes the material in the sample 15 or on the surface of the sample 15 based on the temperature fluctuation range signal of at least one temperature sensor (for example, the temperature sensors 25 and 26).
  • the temperature swing signal of the at least one temperature sensor corresponds to the temperature swing of the sample 15 measured by the at least one temperature sensor during analysis of the sample 15 .
  • the temperature fluctuation width signal noise included in the temperature signal output from at least one temperature sensor (for example, temperature sensors 25 and 26) is removed. Substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the noninvasive material analyzer 1 of the present embodiment further includes a signal processing section 37 and a material analysis section 38.
  • the at least one temperature sensor is a plurality of temperature sensors 25,26.
  • the signal processing unit 37 outputs an average of a plurality of temperature fluctuation width signals.
  • the plurality of temperature swing signals each correspond to a temperature swing of sample 15 measured by a corresponding one of the plurality of temperature sensors 25, 26 during sample 15 analysis.
  • a material analysis unit 38 analyzes the material in or on the surface of the sample 15 based on the average of the multiple temperature range signals.
  • the noise included in the temperature signals output from the temperature sensors 25 and 26 is removed from the temperature fluctuation width signal. Also, the averaging of the multiple temperature swing signals reduces the variation between the multiple temperature swing signals. Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • At least one temperature sensor (for example, temperature sensors 25 and 26) includes a temperature sensor main body 27.
  • the temperature sensor body 27 is a thermocouple, thermopile, thermistor or diode.
  • the non-invasive substance analyzer 1 can be miniaturized.
  • At least one temperature sensor (for example, the temperature sensors 25 and 26) further includes a protective film 28 covering the temperature sensor body 27.
  • the protective film 28 prevents the sample 15 from contacting the temperature sensor main body 27. Therefore, the life of the temperature sensor main body 27 is extended.
  • a noninvasive substance analyzer 1b according to the second embodiment will be described with reference to FIG.
  • a noninvasive substance analyzer 1b of the present embodiment has the same configuration as the noninvasive substance analyzer 1 of Embodiment 1, but differs mainly in the following points.
  • the sample support plate 10 includes the low thermal conductive film 14 in addition to the substrate 11.
  • the substrate 11 of the present embodiment has higher thermal conductivity than the substrate 11 of the first embodiment.
  • substrate 11 may have a greater thermal conductivity than sample 15 .
  • the substrate 11 is formed of a semiconductor substrate such as silicon (thermal conductivity: about 160 W/(m ⁇ K)). Since the substrate 11 is made of a semiconductor material, the through holes 13 having a small size (for example, a diameter of several tens of ⁇ m) can be easily formed using a semiconductor microfabrication process.
  • the low heat conductive film 14 is provided on the substrate 11 .
  • the low thermal conductive film 14 has thermal conductivity lower than that of the substrate 11 .
  • the thermal conductivity of the low thermal conductive film 14 is, for example, 20% or less of the thermal conductivity of the substrate 11 .
  • the thermal conductivity of the low thermal conductive film 14 may be 10% or less of the thermal conductivity of the substrate 11, may be 5% or less of the thermal conductivity of the substrate 11, or may be 2% of the thermal conductivity of the substrate 11. % or less, or 1% or less of the thermal conductivity of the substrate 11 .
  • the low thermal conductive film 14 is made of, for example, silicon dioxide (thermal conductivity: 1.4 W/(m ⁇ K)).
  • the main surface 10a is formed of a low thermal conductive film 14. A portion of the main surface 10a may be formed by the low heat conductive film 14 .
  • the sample mounting area 12 is formed of a low heat conductive film 14 .
  • Temperature sensors 25 and 26 are provided on the low thermal conductive film 14 .
  • Through holes 13 are provided in both the substrate 11 and the low thermal conductive film 14 .
  • Example 2 of the present embodiment By comparing Example 2 of the present embodiment with Comparative Examples 2-1 and 2-2 with reference to FIG. 9, the action of the noninvasive substance analyzer 1b of the present embodiment will be described.
  • Example 2 the substrate 11 is made of silicon, and the low thermal conductive film 14 is made of silicon dioxide. Further, in Example 2, the diameter of the through-hole 13 is 36 ⁇ m, and the diameter of the light irradiation region 21b of the excitation light 21 is 30 ⁇ m. Comparative Example 2-1 is the same as Example 2, but the through hole 13 is not formed in the substrate 11 . Comparative Example 2-2 is similar to Comparative Example 2-1, except that in Comparative Example 2-2, the transmittance of substrate 11 to excitation light 21 is assumed to be 100%.
  • the normalized temperature fluctuation width in FIG. 9 is normalized by the temperature fluctuation width of the edge of the through hole 13 in the main surface 10a of Example 2, Comparative Example 2-1, and Comparative Example 2-2.
  • the width of temperature fluctuation at each point on the main surface 10a is the temperature at each point on the main surface 10a when the sample 15 is not irradiated with the excitation light 21 and the temperature at each point on the main surface 10a when the sample 15 is irradiated with the excitation light 21. given by the difference between the temperature
  • Example 2 through holes 13 are provided in the sample support plate 10 . Therefore, the excitation light 21 reaches the sample 15 with stronger light intensity without being absorbed by the sample support plate 10 .
  • the heat of absorption of sample 15 increases.
  • the thermal conductivity of the air in the through-hole 13 (0.024 W/(mK)) is higher than the thermal conductivity of the substrate 11 (for example, the thermal conductivity of silicon: about 160 W/(mK)). is also low. Therefore, the heat absorbed by the sample 15 is less likely to escape in the thickness direction of the sample support plate 10 (the direction in which the main surface 10a and the main surface 10b face each other).
  • the temperature fluctuation width of the main surface 10a during the analysis of the sample 15 increases.
  • substances in or on the surface of sample 15 can be analyzed more accurately.
  • Comparative Example 2-1 the through-holes 13 are not provided in the sample support plate 10, but the substrate 11 is made of silicon and allows the excitation light 21 to pass therethrough. Therefore, the excitation light 21 reaches the sample 15, and the temperature variation width of the main surface 10a is not zero. However, in Comparative Example 2-1, part of the excitation light 21 is reflected by the main surface 10b or absorbed by the substrate 11. FIG. Therefore, the intensity of the excitation light 21 reaching the sample 15 in Comparative Example 2-1 is less than the intensity of the excitation light 21 reaching the sample 15 in Example 2. FIG.
  • Comparative Example 2-1 the heat absorbed by the sample 15 diffuses more quickly than in Example 2 in the thickness direction of the sample support plate 10 (the direction in which the main surface 10a and the main surface 10b face each other). As a result, the temperature variation width of the main surface 10a in Comparative Example 2-1 is smaller than the temperature variation width of the main surface 10a in Example 2.
  • FIG. 2-1 the substance in sample 15 or on the surface of sample 15 cannot be accurately analyzed.
  • Comparative Example 2-2 the substrate 11 is not provided with the through holes 13 . Therefore, in Comparative Example 2-2, the heat absorbed by the sample 15 diffuses more quickly than in Example 2 in the thickness direction of the sample support plate 10 (the direction in which the main surface 10a and the main surface 10b face each other).
  • the temperature variation width of the main surface 10a in Comparative Example 2-2 is smaller than the temperature variation width of the main surface 10a in Example 2.
  • FIG. 2-2 the substances in sample 15 or on the surface of sample 15 cannot be accurately analyzed.
  • the noninvasive substance analyzer 1b of the present embodiment further exhibits the following effects.
  • the sample support plate 10 includes a substrate 11 and a low thermal conductive film 14.
  • the low thermal conductive film 14 is provided on the substrate 11 and has a thermal conductivity lower than that of the substrate 11 .
  • At least part of the first main surface (main surface 10 a ) is formed of the low thermal conductive film 14 .
  • At least one temperature sensor (for example, temperature sensors 25 and 26) is provided on the low thermal conductive film 14. As shown in FIG.
  • the low heat conductive film 14 makes it difficult for the heat absorbed by the sample 15 to escape in the thickness direction of the sample support plate 10 (the direction in which the main surface 10a and the main surface 10b face each other).
  • the temperature signal output from at least one temperature sensor increases. Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • Embodiment 3 A noninvasive substance analyzer 1c according to Embodiment 3 will be described with reference to FIGS. 10 and 11.
  • FIG. A noninvasive substance analyzer 1c of the present embodiment has the same configuration as the noninvasive substance analyzer 1 of Embodiment 1, but differs mainly in the following points.
  • the noninvasive substance analyzer 1c further includes reference temperature sensors 40 and 41.
  • the reference temperature sensors 40, 41 are constructed similarly to the temperature sensors 25, 26.
  • FIG. Specifically, the reference temperature sensors 40, 41 include a temperature sensor body 27 (see FIG. 3).
  • the reference temperature sensors 40 , 41 may further include a protective film 28 (see FIG. 3) covering the temperature sensor body 27 .
  • the reference temperature sensors 40, 41 are provided on the main surface 10a. Reference temperature sensors 40 , 41 are provided in the sample placement area 12 and contact the sample 15 . Reference temperature sensors 40 and 41 output reference temperature signals corresponding to the temperature of sample 15 to lock-in amplifier 34 . Specifically, the reference temperature sensor 40 outputs a reference temperature signal corresponding to the temperature of the portion of the sample 15 with which the reference temperature sensor 40 is in contact. The reference temperature sensor 41 outputs a reference temperature signal corresponding to the temperature of the portion of the sample 15 with which the reference temperature sensor 41 is in contact.
  • the sample 15 is a living organism, thermal fluctuations of the sample 15 (e.g., body temperature fluctuations, etc.) or movements of the sample 15 (e.g., during the analysis of substances in or on the surface of the sample 15) contraction or relaxation of the muscles contained in the sample 15, or variations in the position of the sample 15, etc.) may occur.
  • the reference temperature sensors 40 , 41 detect temperature fluctuations due to thermal fluctuations or movement of the sample 15 without being affected by the absorption heat of the sample 15 . Therefore, in a plan view of the main surface 10a, the distance d2 between each of the reference temperature sensors 40 and 41 and the through hole 13 is greater than the distance d1 between each of the temperature sensors 25 and 26 and the through hole 13 . big.
  • the distance d2 is, for example, 10 times or more the distance d1 .
  • the distance d2 may be 20 times or more the distance d1 . In one example, distance d1 is 5 ⁇ m and distance d2 is 200 ⁇ m.
  • the reference temperature sensors 40 and 41 are arranged rotationally symmetrically with respect to the central axis 13c of the through hole 13 in a plan view of the main surface 10a. Therefore, temperature fluctuations due to thermal fluctuations or movement of the sample 15 can be detected more accurately.
  • the reference temperature sensor 40 is arranged in the same direction as the temperature sensor 25 with respect to the central axis 13c of the through hole 13 in a plan view of the main surface 10a. Therefore, variations in the reference temperature signal of the reference temperature sensor 40 due to thermal variations or motion of the sample 15 during analysis of the sample 15 are reflected in the temperature sensor 25 signals due to thermal variations or motion of the sample 15 during analysis of the sample 15 . is similar to the variation of the temperature signal in The reference temperature sensor 40 more accurately detects variations in the temperature signal of the temperature sensor 25 due to thermal variations or movement of the sample 15 during analysis of the sample 15 without being affected by the absorption heat of the sample 15. can be done.
  • the reference temperature sensor 41 is arranged in the same direction as the temperature sensor 26 with respect to the central axis 13c of the through hole 13. Therefore, variations in the temperature signal of the reference temperature sensor 41 due to thermal variations or movements of the sample 15 during analysis of the sample 15 are reflected in the temperature of the temperature sensor 26 due to thermal variations or movements of the sample 15 during analysis of the sample 15. Similar to signal fluctuations.
  • the reference temperature sensor 41 more accurately detects fluctuations in the temperature signal of the temperature sensor 26 due to thermal fluctuations or movement of the sample 15 during analysis of the sample 15 without being affected by the absorption heat of the sample 15. can be done.
  • the lock-in amplifier 34 outputs the temperature fluctuation width signal of the temperature sensor 25 and the temperature fluctuation width signal of the temperature sensor 26 to the signal processing section 37 as in the first embodiment.
  • the temperature swing signal of the temperature sensor 25 and the temperature swing signal of the temperature sensor 26 are the effects of heat absorption of the sample 15, as well as fluctuations in the temperature signal due to thermal fluctuations or movement of the sample 15 during analysis of the sample 15. affected by
  • the temperature range signal of temperature sensor 25 and the temperature range signal of temperature sensor 26 can be used to determine the temperature range of sample 15 during analysis of sample 15. It is necessary to remove the effects of variations in the temperature signal due to fluctuations or motion.
  • the signal processing unit 37 receives the reference temperature signal from the reference temperature sensor 40 and the reference temperature signal from the reference temperature sensor 41 .
  • the signal processing unit 37 calculates the fluctuation width of the reference temperature signal of the reference temperature sensor 40 during analysis of the sample 15 as the reference temperature fluctuation width signal of the reference temperature sensor 40 .
  • the signal processing unit 37 calculates the fluctuation width of the reference temperature signal of the reference temperature sensor 41 during analysis of the sample 15 as the reference temperature fluctuation width signal of the reference temperature sensor 41 .
  • the signal processing unit 37 calculates the difference between the temperature fluctuation width signal of the temperature sensor 25 and the reference temperature fluctuation width signal of the reference temperature sensor 40 as the calibrated temperature fluctuation width signal of the temperature sensor 25 .
  • the calibrated temperature swing signal of the temperature sensor 25 is the temperature sensor 25 attributed to the heat absorption of the sample 15, with the effects of variations in the temperature signal due to thermal variations or motion of the sample 15 during analysis of the sample 15 removed. is a temperature fluctuation width signal of .
  • the signal processing unit 37 calculates the difference between the temperature fluctuation width signal of the temperature sensor 26 and the reference temperature fluctuation width signal of the reference temperature sensor 41 as the calibrated temperature fluctuation width signal of the temperature sensor 26 .
  • the calibrated temperature swing signal of the temperature sensor 26 is the temperature sensor 26 attributed to the heat absorption of the sample 15, with the effects of variations in the temperature signal due to thermal variations or motion of the sample 15 during analysis of the sample 15 removed. is a temperature fluctuation width signal of .
  • the signal processing unit 37 calculates the average of the calibrated temperature fluctuation width signal of the temperature sensor 25 and the calibrated temperature fluctuation width signal of the temperature sensor 26 as an average calibrated temperature fluctuation width signal.
  • a material analyzer 38 analyzes the material in or on the surface of the sample 15 based on the average calibrated temperature swing signal.
  • the temperature sensor 26 may be omitted, and the number of temperature sensors 25 may be one.
  • the signal processing section 37 outputs the calibrated temperature fluctuation range signal of the temperature sensor 25 to the substance analysis section 38 .
  • the material analysis unit 38 analyzes the material in the sample 15 or on the surface of the sample 15 based on the calibrated temperature range signal of the temperature sensor 25 .
  • the noninvasive substance analyzer 1c of the present embodiment further exhibits the following effects.
  • the noninvasive substance analyzer 1c of the present embodiment further includes reference temperature sensors 40 and 41 provided on the first main surface (main surface 10a).
  • Reference temperature sensors 40 , 41 are provided in the sample placement area 12 and contact the sample 15 .
  • the second distance (distance d 2 ) between the reference temperature sensors 40 and 41 and the through hole 13 is the first distance (distance d 2 ) between the temperature sensors 25 and 26 and the through hole 13 It is 10 times or more the distance d 1 ).
  • the reference temperature sensors 40 and 41 detect temperature fluctuations during the analysis of the sample 15 without being affected by the absorption heat of the sample 15. Therefore, temperature fluctuations due to the heat absorption of the sample 15 can be detected more accurately without being affected by temperature signal fluctuations due to thermal fluctuations or movement of the sample 15 during analysis of the sample 15 . Substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the signal processing unit 37 converts the temperature fluctuation width signal of at least one temperature sensor (for example, the temperature sensors 25 and 26) into the reference temperature fluctuation width of the reference temperature sensors 40 and 41.
  • a calibrated temperature swing signal of the at least one temperature sensor is calculated by calibrating with the signal.
  • a material analysis unit 38 analyzes the material in or on the surface of the sample 15 based on the calibrated temperature range signal of at least one temperature sensor.
  • the thermal variation or Temperature fluctuations due to heat absorption of the sample 15 can be detected more accurately without being affected by temperature signal fluctuations caused by movement. Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • Embodiment 4 A non-invasive substance analyzer 1d according to Embodiment 4 will be described with reference to FIGS. 12 and 13.
  • FIG. A noninvasive substance analyzer 1d of the present embodiment has the same configuration as the noninvasive substance analyzer 1 of Embodiment 1, but differs mainly in the following points.
  • the noninvasive substance analyzer 1d further includes an optical medium 45.
  • the optical medium 45 transmits the excitation light 21 .
  • the transmittance of the optical medium 45 to the excitation light 21 is greater than the transmittance of the sample support plate 10 (substrate 11 ) to the excitation light 21 .
  • the optical medium 45 is made of chalcogenide glass (SSbSnGe), for example.
  • the optical medium 45 blocks the through hole 13 .
  • a portion of the sample mounting area 12 is formed by an optical medium 45 .
  • the entire sample mounting area 12 may be formed by the optical medium 45 .
  • Sample 15 may be mounted on optical medium 45 .
  • a part of the through hole 13 is filled with an optical medium 45 .
  • a portion of the through-hole 13 that is closer to the main surface 10 b than the optical medium 45 is a cavity that is not filled with the optical medium 45 .
  • the excitation light 21 illuminates the sample 15 through the optical medium 45 and the cavity.
  • the entire through hole 13 may be filled with the optical medium 45 .
  • the thermal conductivity of the optical medium 45 is lower than that of the substrate 11 .
  • the thermal conductivity of the optical medium 45 may be 10% or less of the thermal conductivity of the substrate 11, may be 5% or less of the thermal conductivity of the substrate 11, or may be 2% of the thermal conductivity of the substrate 11. It may be below.
  • the substrate 11 is made of silicon (thermal conductivity: about 160 W/(m ⁇ K))
  • the optical medium 45 is made of chalcogenide glass (thermal conductivity: 0.36 W/(m ⁇ K)). ing.
  • the thermal conductivity of the air in the cavity (0.024 W/(m ⁇ K)) is lower than that of the substrate 11 .
  • the noninvasive substance analyzer 1d of the present embodiment has the following effects similar to those of the noninvasive substance analyzer 1 of the first embodiment.
  • the noninvasive substance analyzer 1d of the present embodiment further includes an optical medium 45 that transmits the excitation light 21.
  • the optical medium 45 closes the through hole 13 .
  • At least part of the sample mounting area 12 is formed by an optical medium 45 .
  • the excitation light 21 irradiates the sample 15 through the optical medium 45 .
  • the excitation light 21 reaches the sample 15 with stronger light intensity without being absorbed by the sample support plate 10 .
  • the heat of absorption of sample 15 increases. Also, the heat absorbed by the sample 15 is less likely to escape in the thickness direction of the sample support plate 10 (the direction in which the first main surface (main surface 10a) and the second main surface (main surface 10b) face each other).
  • the temperature signals output from the temperature sensors 25 and 26 are increased. Substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • the sample 15 can be placed on the optical medium 45 . Therefore, even if the size of the sample 15 is smaller than the size of the through-hole 13, or even if the sample 15 is liquid, the substance in the sample 15 or on the surface of the sample 15 can be analyzed.
  • the optical medium 45 transparent to the excitation light 21 such as mid-infrared light is more expensive and has lower mechanical strength than the sample support plate 10 (substrate 11). Since the optical medium 45 is provided in the through hole 13 of the sample support plate 10 (substrate 11), the amount of the optical medium 45 used is less than when the entire sample support plate 10 (substrate 11) is formed of the optical medium 45. Decrease. Therefore, the mechanical strength of the noninvasive substance analyzer 1d can be improved, and the cost of the noninvasive substance analyzer 1d can be reduced.
  • the sample support plate 10 includes the substrate 11 in the noninvasive substance analyzer 1d of the present embodiment.
  • Optical medium 45 has a lower thermal conductivity than substrate 11 .
  • the sample 15 is irradiated with the excitation light 21, the temperature signals output from the temperature sensors 25 and 26 are increased. Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • Embodiment 5 A noninvasive substance analyzer 1e according to Embodiment 5 will be described with reference to FIGS. 14 and 15.
  • FIG. A noninvasive substance analyzer 1e of the present embodiment has the same configuration as the noninvasive substance analyzer 1d of Embodiment 4, but differs mainly in the following points.
  • the size of through-hole 13 of the present embodiment is larger than the size of through-hole 13 of the fourth embodiment, and the size of optical medium 45 of the present embodiment is the same as that of the fourth embodiment. larger than the size of the optical medium 45;
  • the diameter of the through-hole 13 and the diameter of the optical medium 45 of the present embodiment are each 200 ⁇ m.
  • temperature sensors 25 and 26 are arranged on optical medium 45 .
  • the thermal conductivity of the optical medium 45 is lower than that of the substrate 11 .
  • the temperature sensors 25 and 26 are arranged outside the light irradiation region 21b of the excitation light 21 in a plan view of the main surface 10a.
  • the noninvasive substance analyzer 1e of the present embodiment has the following effects in addition to the effects of the noninvasive substance analyzer 1d of the fourth embodiment.
  • At least one temperature sensor (for example, temperature sensors 25 and 26) is arranged on an optical medium 45 having a thermal conductivity lower than that of the substrate 11.
  • the heat absorbed by the sample 15 It becomes difficult to escape in the direction in which the surface extends.
  • the temperature signal output from at least one temperature sensor increases. Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • Embodiment 6 A non-invasive substance analyzer 1f according to Embodiment 6 will be described with reference to FIGS. 16 and 17.
  • FIG. The noninvasive substance analyzer 1f of the present embodiment has the same configuration as the noninvasive substance analyzer 1 of the first embodiment, but differs mainly in the following points.
  • the noninvasive substance analyzer 1f includes a temperature sensor 50 instead of the temperature sensors 25, 26 (see FIGS. 1 and 2).
  • the temperature sensor 50 includes a first optical waveguide 51 , a waveguide ring resonator 52 , a second optical waveguide 53 and a clad layer 54 .
  • Temperature sensor 50 may further include terminations 55 , 56 .
  • the substrate 11 supports the first optical waveguide 51, the waveguide ring resonator 52, the second optical waveguide 53, and the clad layer .
  • Substrate 11 has main surface 10b.
  • the substrate 11 is, for example, a silicon substrate.
  • the probe light emitted from the probe light source 58 is incident on the first optical waveguide 51 .
  • the wavelength of the probe light may be shorter than the wavelength of the excitation light 21 .
  • the probe light source 58 is a laser diode for optical communication, and the wavelength of the probe light is 1100 nm or more and 1700 nm or less.
  • the first optical waveguide 51 includes an end 51a into which probe light is incident and an end 51b opposite to the end 51a.
  • the first optical waveguide 51 has a higher refractive index than the clad layer 54 .
  • the probe light propagates through the first optical waveguide 51 .
  • the first optical waveguide 51 is, for example, a silicon waveguide.
  • the waveguide ring resonator 52 is optically coupled to the first optical waveguide 51 .
  • the waveguide ring resonator 52 has a higher refractive index than the clad layer 54 .
  • the probe light propagates through the waveguide ring resonator 52 .
  • the waveguide ring resonator 52 has a thermo-optic effect.
  • the waveguide ring resonator 52 is, for example, a silicon waveguide.
  • the thermo-optic coefficient of silicon is 2.3 ⁇ 10 ⁇ 4 (K ⁇ 1 ). Silicon has a relatively large thermo-optic coefficient among optical materials for optical waveguides.
  • the through hole 13 is formed inside the waveguide ring resonator 52 .
  • the second optical waveguide 53 is optically coupled to the waveguide ring resonator 52 .
  • the second optical waveguide 53 has a higher refractive index than the clad layer 54 .
  • the probe light propagates through the second optical waveguide 53 .
  • the second optical waveguide 53 is arranged symmetrically with the first optical waveguide 51 with respect to the waveguide ring resonator 52 in a plan view of the main surface 10a.
  • the second optical waveguide 53 includes an end 53a optically coupled to the light intensity detector 59 and an end 53b opposite the end 53a.
  • the ends 51 a and 53 a are on the same side with respect to the waveguide ring resonator 52 .
  • the ends 51 b and 53 b are on the same side with respect to the waveguide ring resonator 52 .
  • the cladding layer 54 separates the first optical waveguide 51 , the waveguide ring resonator 52 and the second optical waveguide 53 from the substrate 11 .
  • the clad layer 54 covers the first optical waveguide 51 , the waveguide ring resonator 52 and the second optical waveguide 53 .
  • Cladding layer 54 has main surface 10a.
  • the thermal conductivity of the clad layer 54 is smaller than that of the substrate 11 .
  • the cladding layer 54 is made of silica-based glass, for example.
  • the terminating portion 55 is provided at the end 51b of the first optical waveguide 51 .
  • the termination portion 56 is provided at the end 53 b of the second optical waveguide 53 .
  • Terminations 55 and 56 scatter or absorb the probe light to reduce return light of the probe light traveling to waveguide ring resonator 52 , probe light source 58 and light intensity detector 59 .
  • the terminal portions 55 and 56 are formed of, for example, a tapered waveguide that tends to scatter outside the waveguide and an electrode (for example, a metal electrode) that absorbs the scattered light.
  • Absorption heat is generated in the sample 15 by absorption of the excitation light 21 by substances in the sample 15 or on the surface of the sample 15 .
  • the heat absorbed by the sample 15 is conducted to the waveguide ring resonator 52, and the temperature of the waveguide ring resonator 52 changes.
  • the waveguide ring resonator 52 has a thermo-optic effect. Therefore, when the temperature of the waveguide ring resonator 52 changes, the refractive index of the waveguide ring resonator 52 changes, and the first optical waveguide 51 passes through the waveguide ring resonator 52 to the second optical waveguide.
  • the coupling rate of probe light to 53 changes.
  • the light intensity detector 59 is, for example, a photodiode.
  • the light intensity detector 59 detects the light intensity of the probe light from the first optical waveguide 51 to the second optical waveguide 53 via the waveguide ring resonator 52 .
  • Light intensity detector 59 is connected to lock-in amplifier 34 .
  • the light intensity detector 59 outputs the light intensity signal of the probe light to the lock-in amplifier 34 .
  • the lock-in amplifier 34 synchronously detects the light intensity signal of the probe light received from the light intensity detector 59 with the excitation light intensity signal received from the photodetector 24 .
  • Lock-in amplifier 34 outputs a DC component proportional to the amplitude of the light intensity signal from light intensity detector 59 .
  • the DC component corresponds to the temperature fluctuation width of the sample 15 during analysis of the sample 15 and is the temperature fluctuation width signal of the temperature sensor 50 .
  • the lock-in amplifier 34 outputs the temperature fluctuation width signal of the temperature sensor 50 to the material analysis section 38 .
  • the substance analysis unit 38 receives the temperature fluctuation width signal of the temperature sensor 50 from the lock-in amplifier 34 .
  • the material analysis section 38 analyzes the material in the sample 15 or on the surface of the sample 15 based on the temperature fluctuation width signal of the temperature sensor 50 .
  • the noninvasive substance analyzer 1f of the present embodiment has the following effects similar to those of the noninvasive substance analyzer 1 of the first embodiment.
  • the temperature sensor 50 includes a first optical waveguide 51 into which probe light is incident, and a waveguide ring resonator 52 optically coupled to the first optical waveguide 51. , a second optical waveguide 53 optically coupled to a waveguide ring resonator 52 and an optical intensity detector 59 for detecting the intensity of the probe light.
  • the sample support plate 10 is provided with a through hole 13 through which the excitation light 21 passes. Therefore, the excitation light 21 reaches the sample 15 with stronger light intensity without being absorbed by the sample support plate 10 .
  • the heat of absorption of sample 15 increases. Also, the heat absorbed by the sample 15 is less likely to escape in the thickness direction of the sample support plate 10 (the direction in which the first main surface (main surface 10a) and the second main surface (main surface 10b) face each other).
  • the temperature signal output from the temperature sensor 50 increases when the sample 15 is irradiated with the excitation light 21 . Therefore, substances in the sample 15 or on the surface of the sample 15 can be analyzed more accurately.
  • Embodiments 1 to 6 disclosed this time should be considered as examples in all respects and not restrictive. As long as there is no contradiction, at least two of Embodiments 1 to 6 disclosed this time may be combined.
  • the scope of the present disclosure is indicated by the scope of claims rather than the above description, and is intended to include all changes within the meaning and scope of equivalence to the scope of claims.

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  • Measurement Of The Respiration, Hearing Ability, Form, And Blood Characteristics Of Living Organisms (AREA)
  • Measuring And Recording Apparatus For Diagnosis (AREA)
PCT/JP2022/006342 2022-02-17 2022-02-17 非侵襲物質分析装置 Ceased WO2023157164A1 (ja)

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PCT/JP2022/006342 WO2023157164A1 (ja) 2022-02-17 2022-02-17 非侵襲物質分析装置
US18/834,630 US12292400B2 (en) 2022-02-17 2022-02-17 Non-invasive substance analysis apparatus
CN202280091478.2A CN118679381B (zh) 2022-02-17 2022-02-17 非侵入式物质分析装置
DE112022005931.1T DE112022005931B4 (de) 2022-02-17 2022-02-17 Vorrichtung zur nichtinvasiven substanzanalyse

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DE112022005931B4 (de) 2026-01-15
JP7205002B1 (ja) 2023-01-16
CN118679381A (zh) 2024-09-20
CN118679381B (zh) 2025-03-11

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