JP2016188778A - Component concentration analysis device and component concentration analysis method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To find the concentration of a sample to be measured, the measurement of which is difficult.SOLUTION: Provided is a component concentration analysis device comprising: a database 1 for holding a regression coefficient spectrum regarding the concentration of a desired sample to be measured; an irradiator 21 for irradiating the sample to be measured with an infrared ray; an optical detector 22 for receiving an infrared ray having passed through the sample to be measured; a radiator 23 for radiating a millimeter wave/terahertz (THz) wave to the sample to be measured; a radio wave detector 24 for detecting a millimeter wave/terahertz (THz) wave having passed through the sample to be measured; a dielectric measurement probe 25 of coaxial type having the functions of a radiator for radiating a millimeter wave/terahertz (THz) wave to the sample to be measured and a radio wave detector for detecting a millimeter wave/terahertz (THz) wave having passed through the sample to be measured; and an arithmetic unit 3 for finding the concentration of the sample to be measured by fitting the spectra obtained from the optical detector 22, the radio wave detector 24, and the dielectric measurement probe 25 to the regression coefficient spectrum held in the database 1.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a component concentration analyzer and a component concentration analysis method for determining the concentration of a sample to be measured.

  In recent years, with the aging of society, dealing with adult diseases is becoming a major issue. In blood glucose level and other tests, blood collection is necessary, which places a heavy burden on the patient. Therefore, a non-invasive component concentration measurement apparatus that does not collect blood has attracted attention.

  Spectroscopy has been proposed as a noninvasive component concentration measuring apparatus. Conventional non-invasive measurement methods have been attempted in various frequency bands. Diffuse reflection method and photoacoustic method have been tried in near infrared spectroscopy, and total reflection attenuation method has been tried in mid infrared spectroscopy. (See Non-Patent Documents 1, 2, and 3).

  In the spectroscopic method, an electromagnetic wave is irradiated into the skin, and the electromagnetic wave is absorbed and the amplitude of the electromagnetic wave is observed in accordance with the interaction between blood components to be measured, for example, glucose molecules and water. However, the interaction between glucose and electromagnetic waves is small, and there is a limit to the intensity of electromagnetic waves that can be safely irradiated to a living body.

  In the infrared region, there are various absorptions related to biological components. However, in noninvasive measurement methods, the background absorption of water, which is the main component of the living body, and the light scattering of living tissue (skin, blood cells, etc.) are large errors. It is known to be a factor. For example, the background absorption of water is 1000 times the absorption of glucose, so the influence of environmental temperature and humidity and changes in tissue moisture due to sweating become prominent as error factors. In addition, since the water spectrum shifts with temperature in the glucose absorption band, the influence of heat generation cannot be ignored as an error factor. It is known that the light scattering coefficient of skin is difficult to model because the skin structure is a multi-layered structure of keratin and dermis, and there are individual differences.

  The living body is a multicomponent system, and chemometrics techniques such as multivariate analysis such as principal component analysis and PLS regression analysis are generally used for quantification of biological components.

  In the near-infrared region, an unknown spectrum is created using a diffuse reflection method that utilizes light scattering from the skin, blood components such as glucose, albumin, and cholesterol, water, and biological light scattering coefficients that are modeled by light scattering simulation. Analyze (see Non-Patent Document 1). However, since there is a correlation between the variables having the absorption spectrum of the component in the multicomponent system as a variable, it is difficult to obtain sufficient regression accuracy in the regression analysis.

  FIG. 12 shows a conventional infrared spectroscopy system.

  The infrared spectrometer 101 includes a continuous wave light source that generates light having a wavelength in a broad near-infrared region, and an irradiation unit 103 and a detection unit 104 are connected via a multi-core fiber 102. The irradiation unit 103 irradiates the subject T with light, and the detection unit 104 detects light diffusely reflected by in vivo scattering. (Refer nonpatent literature 1).

  Then, a multivariate calibration model is constructed from albumin, glucose, cholesterol, etc., and noninvasive measurement of glucose as a target molecule is performed with high accuracy by the Partial Least Squares regression method.

  In the near-infrared region, a diffusion reflection method using light scattering of the skin, blood components such as glucose, albumin, cholesterol and the like, water, and a biological light scattering coefficient modeled by light scattering simulation are used as the database 105, and a calibration model is created. The calculation unit 106 analyzes the unknown spectrum and displays it on the display unit 107 (see Non-Patent Document 1).

  In order to reduce the influence of light scattering in a living body, there is an example that has been tried using a photoacoustic method in which light is converted into sound waves by photothermal conversion. In order to make a difference in background absorption, it is configured to irradiate the skin with light of two wavelengths modulated in opposite phases and detect a generated sound wave (see Patent Document 1). A continuously modulated light source is used. The first light source generates measurement light having a wavelength λ1. The second light source generates reference light having a wavelength λ2. The oscillator outputs a modulation signal for intensity-modulating light output from the first light source and the second light source. The 180 ° phase shifter inverts and outputs one of the modulation signals from the oscillator. The drive circuit drives the first light source.

  The drive circuit drives the second light source based on the modulation signal inverted by the 180 ° phase shifter. The first light source modulates the intensity of the measurement light having the wavelength λ1 with a signal from the driving circuit and outputs the measurement light. The second light source modulates the intensity of the reference light having the wavelength λ2 with a signal from the driving circuit and outputs the reference light. As a result, each of the two different wavelengths λ1 and λ2 is electrically intensity-modulated with a signal having the same frequency and opposite phase, and then output.

  Here, the two wavelengths λ1 and λ2 are wavelengths in which the difference in absorption exhibited by the target component is greater than the difference in absorption exhibited by the background component. The wavelength λ1 is set to a wavelength at which the target component exhibits characteristic absorption. The wavelengths λ1 and λ2 may be two wavelengths in which the difference in absorption exhibited by the target component is greater than the difference in absorption exhibited by the other components. Thereby, the influence of absorption by components other than water and the component to be measured can be reduced, and the measurement accuracy of the component concentration measuring apparatus can be improved. A photoacoustic signal is generated inside the object to be measured by light of two wavelengths λ1 and λ2, and these photoacoustic signals are detected by an acoustic sensor and converted into an electric signal proportional to sound pressure, and a phase detection amplifier Observed by. The difference in the intensity of the photoacoustic signal corresponding to the two wavelengths is measured as an electrical signal corresponding to the amount of glucose contained in the blood. Although the influence of light scattering can be reduced as compared with the diffuse reflection method, the measurement accuracy is similarly limited by fluctuations in the background absorption of water.

  Although the influence of light scattering is reduced by the longer wavelength in the mid-infrared region, the absorption of water is very large, so non-invasive measurement was attempted by the total reflection attenuation method. The problem is that the depth of penetration into the skin does not reach the dermis layer and the amount of permeation is small, and sufficient sensitivity is not obtained (see Non-Patent Document 2).

  Although there is water absorption, there is a frequency band from microwave to millimeter wave as a frequency band in which the wavelength is very long and light scattering can be ignored. As a conventional measurement method, there is dielectric spectroscopy measurement by reflection type measurement using a coaxial probe connected to a vector network analyzer (hereinafter referred to as VNA) in a microwave to millimeter wave band (see Non-Patent Document 3). ).

  FIG. 13 shows a conventional microwave / millimeter-wave dielectric spectroscopy measurement system. FIG. 1 is a configuration example showing a component concentration measuring apparatus using dielectric spectroscopy.

  Here, the concentration of the target component in the solution in which the background component and the target component are mixed is measured. As described in Non-Patent Document 3, a method of measuring a complex dielectric constant using a coaxial probe 201 is common. Reference numeral G denotes a ground, and reference numeral S denotes a signal line. The coaxial line at the open end is suitable for the liquid measurement sample 202. From the open end, the complex permittivity is calculated from the reflected signal on the premise of an infinite boundary. That is, an electric field is applied to the measurement sample 202, and the reflection coefficient and phase are measured in the frequency domain by VNA. In addition, there is a method in which a step-like voltage that rises quickly is applied to the measurement sample 202 and the complex dielectric constant is obtained from the time change of the reflected waveform. In this case, the transmission coefficient may be measured instead of the reflection coefficient. This method is called a time domain reflection (or transmission) measurement method. In the frequency domain measurement, the frequency of the applied electric field is swept to obtain the reflection coefficient / phase spectrum. The complex dielectric constant can be calculated from the measured spectrum as follows.

ここで、ε*は未知サンプルの複素誘電率、ε_i ^*(i=A,B,C)は較正サンプルＡ，Ｂ，Ｃの複素誘電率である。また、ρ^*は複素反射係数で、測定で得られた反射係数をΓ_i、位相をφ_iとするとき、

Here, ε * is the complex dielectric constant of the unknown sample, and ε _i ^* (i = A, B, C) is the complex dielectric constant of the calibration samples A, B, and C. In addition, ρ ^* is a complex reflection coefficient. When the reflection coefficient obtained by measurement is Γ _i and the phase is φ _i ,

と表される。ρ_iはそれぞれ較正サンプルの測定結果に対応し、ρ^*は未知サンプルの測定結果を表す。

It is expressed. ρ _i corresponds to the measurement result of the calibration sample, and ρ ^* represents the measurement result of the unknown sample.

  In a general measurement using an open end coaxial probe, a calibration sample A is an open end in air, a calibration sample B is a short circuit with a metal plate, a calibration sample C is a solution such as pure water having a known dielectric constant. Use a sample. In addition to the reflective coaxial probe, there is a method for measuring the dielectric constant of a measurement sample by measuring the transmission / reflection characteristics of a transmission line.

  In the microwave to millimeter wave, modeling considering the influence of the solute is possible from the dielectric relaxation spectrum of the aqueous solution by linear combination of the Debye relaxation model (see Non-Patent Document 4). Component analysis is also possible by obtaining the dielectric constant and dielectric relaxation time of each solute by least square fitting of the dielectric relaxation spectrum.

  In addition to the reflective coaxial probe, there is a method for measuring the dielectric constant of a measurement sample by measuring the transmission / reflection characteristics of a transmission line. Non-Patent Document 5 discloses a method of measuring the dielectric constant of a measurement sample by changing the transmission characteristics of a transmission line operating from several G to 40 GHz, and calculating the concentration of a biological component in blood using a calibration model.

  FIG. 14 shows a conventional millimeter waveband / terahertz wave dielectric spectroscopy measurement system. FIG. 14 shows a homodyne detection electromagnetic wave spectroscopy measurement system using a continuously oscillating light source.

  The system includes a first continuous wave light source 1a and a second continuous wave light source 1b, a first splitter 2a and a second splitter 2b, a first coupler 3a and a second coupler 3b, an optical phase modulator 4, and a first It is mainly composed of a photomixer 5a, a first photomixer 5a, and a third photomixer 5c in which both functions of the THz mixer are integrated (see Patent Document 2 and Non-Patent Document 6). Reference numeral 100 denotes a measurement sample, and reference numeral 8 denotes a lens.

  In the conventional dielectric spectroscopic apparatus, when homodyne detection of electromagnetic waves, it is necessary that the two optical path length differences at the time of mixing in the third photomixer 5c match. Therefore, the propagation length of the THz wave propagating in space, the length of the fiber through which light propagates, and the like are adjusted. In the terahertz wave band, it is common to measure the complex dielectric constant of the object to be measured by the free space method using a pseudo optical system using a lens or a parabolic mirror. The free space method is also used in the millimeter wave band as described in Non-Patent Document 3.

  As described above, the dielectric relaxation spectrum is calculated from the amplitude and phase of the signal corresponding to the frequency of the observed radio wave. Generally, it is expressed as a linear combination of relaxation curves based on the Cole-Cole equation, and the complex permittivity is calculated. In the measurement of biological components, for example, the amount of blood components such as glucose and cholesterol contained in blood has a complex dielectric constant, and is measured as an electrical signal (amplitude, phase) corresponding to the change. A multivariate calibration model is constructed by measuring in advance the phase between the complex dielectric constant change and the component concentration of a plurality of components contained, and the component concentration is calibrated from the measured change in the dielectric relaxation spectrum.

  The characteristics in the microwave to terahertz wave band are summarized. Although microwaves cause a change in dielectric constant based on the relaxation spectrum of the interaction between the biological component and water, an absorption spectrum unique to the biological component useful for multivariate analysis does not occur. In the millimeter wave band, there is a maximum absorption peak of water, and the relaxation spectrum of water changes with the concentration of biological components. Terahertz waves are observed as changes in the relaxation spectrum of water due to biological components, and no direct absorption of biological components occurs. Microwave to terahertz waves have temperature-dependent absorption of water, but have the advantage of not causing fluctuations in light scattering of the skin. difficult.

JP 2007-89662 A JP 2013-32933 A

Katsuhiko Maruo, Mitsuhiro Tsurugi, Mamoru Tamura, and Yukihiro Ozaki, "In Vivo Noninvasive Measurement of Blood Glucose by Near-Infrared Diffuse-Reflectance Spectroscopy," Appl. Spectrosc. 57, pp.1236-1244 (2003) H. M. Heise, Ralf Marbach, Gunter Janatsch and J. D. Kruse-Jarres "Multivariate Determination of Glucose in Whole Blood by Attenuated Total Reflection Infrared Spectroscopy", Anal. Chem. 1989, 61, pp.2009-2015. Andrew P. Gregory, and Robert N. Clarke, “A Review of RF and Microwave Techniques for Dielectric Measurements on Polar Liquids”, IEEE Transactions on Dielectrics and Electrical Insulation Vol.13, No.4 Aug. 2006. Keiichiro Shiraga, Yuichi Ogawa, Tetsuhito Suzuki, Naoshi Kondo, Akiyoshi Irisawa and Motoki Imamura "Characterization of Dielectric Responses of Human Cancer Cells in the Terahertz Region", J Infrared Milli Terahz Waves, (2014), 35: pp.493-502. Maximilian Hofmann, Georg Fischer, Robert Weigel, and Dietmar Kissinger, "Microwave-Based Noninvasive Concentration Measurements for Biomedical Applications", IEEE TRANSACTIONS ON MICROWAVE THEORY AND TECHNIQUES, VOL. 61, NO. 5, pp.2195-2204, MAY 2013. J.-Y. Kim H.-J. Song, K. Ajito, M. Yaita, and N. Kukutsu, “Continuous-Wave THz Homodyne Spectroscopy and Imaging System With Electro-Optical Phase Modulation for High Dynamic Range,” IEEE Trans THz Sci. Tech., 3, pp.158-164 (2013). S. Jones, JY Kim, T. Yamada, N. Koshoubu, H. Togo, "Ultra-Wideband Tunable Dual Mode Laser for Continuous Wave THz Generation", Journal of Lightwave Technology, (Volume: PP, Issue: 99), 2014 .

  However, conventionally, when non-invasive measurement of a biological component in the frequency region of radio waves and light is performed, the influence of biological scattering is large on light, whereas an absorption spectrum specific to the biological component is not generated on microwaves to terahertz waves. Therefore, there is a problem that it is difficult to separate the components to be measured and the quantification accuracy of the component concentration is not sufficient.

  An object of this invention is to provide the technique which calculates | requires the density | concentration of the to-be-measured sample which was difficult to measure.

  In order to solve the above problems, the component concentration analyzer of the first aspect of the present invention is a database that holds a regression coefficient spectrum for the concentration of a predetermined sample to be measured (T) in a frequency band that combines infrared light and electromagnetic waves. (1), an irradiator (21) for irradiating the sample to be measured (T) with the infrared light, and a photodetector (22) for receiving the infrared light reflected or transmitted through the sample to be measured (T). ), Radiation means (23, 25, 251) for radiating the electromagnetic wave to the measured sample (T), and electromagnetic wave detection means (24, 25) for detecting the electromagnetic wave reflected or transmitted through the measured sample (T) 25, 271, 239), and the spectrum obtained from the photodetector (22) and the electromagnetic wave detection means (24, 25, 271, 239) to the regression coefficient spectrum held in the database (1). By coating, characterized in that the and a computing unit for determining the concentration of the sample to be measured (T) (3).

The component concentration analysis method of the second aspect of the present invention is a component concentration analysis using a database (1) that holds a regression coefficient spectrum for the concentration of a predetermined sample (T) to be measured in a frequency band that combines infrared light and electromagnetic waves. A method, wherein an irradiator (21) irradiates the sample to be measured (T) with the infrared light,
A photodetector (22) receives the infrared light reflected or transmitted through the sample to be measured (T), and a radiation means (23, 25, 251) radiates the electromagnetic wave to the measurement sample (T). The electromagnetic wave detecting means (24, 25, 271, 239) detects the electromagnetic wave reflected or transmitted through the sample to be measured (T), and the computing unit (3) is configured to detect the photodetector (22) and the Fitting the spectrum obtained from the electromagnetic wave detection means (24, 25, 271, 239) to the regression coefficient spectrum held in the database (1), the concentration of the measured sample (T) is obtained. To do.

  According to the present invention, it is possible to obtain the concentration of a sample to be measured such as a biological component that has been difficult to measure.

The example of the component concentration analyzer which concerns on 1st Embodiment is shown. An example of the electromagnetic wave and infrared spectrum which passed through glucose aqueous solution is shown. An example of an infrared spectrum that has passed through an aqueous ionic solution is shown. An example of the spectrum of the electromagnetic waves and infrared rays which passed through the albumin aqueous solution is shown. The example of the component concentration analyzer which concerns on 2nd Embodiment is shown. The detailed structure of the location of the code | symbol 250 in FIG. 5 is shown. The example of the component concentration analyzer which concerns on 3rd Embodiment is shown. The example of the component concentration analyzer which concerns on 4th Embodiment is shown. It is the result of having performed the multivariate analysis of glucose aqueous solution using the spectrum of micro wave-millimeter wave. This is the result of concentration calibration of glucose and albumin in a multicomponent aqueous solution by multivariate analysis. The example of the component concentration analyzer which concerns on 5th Embodiment is shown. 1 shows a conventional infrared spectroscopy system. A conventional microwave / millimeter-wave dielectric spectroscopy system is shown. A conventional millimeter-wave and terahertz-wave dielectric spectroscopy system is shown.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings.

[First Embodiment]
FIG. 1 shows an example of a component concentration analyzer according to the first embodiment.

  The component concentration analyzer includes a database 1 that holds a regression coefficient spectrum for the concentration of a desired sample to be measured, an irradiator 21 that irradiates the sample to be measured with infrared light, and infrared light that has passed through the sample to be measured. A photodetector 22 for receiving, a radiator 23 for radiating a millimeter wave / terahertz (THz) wave to the sample to be measured, an electromagnetic wave detector 24 for detecting a millimeter wave / terahertz (THz) wave transmitted through the sample to be measured; A coaxial dielectric measurement probe 25 having a function of a radiator that radiates microwaves / millimeter waves to a sample to be measured and an electromagnetic wave detector that detects microwaves / millimeter waves transmitted through the sample to be measured; By fitting the spectrum obtained from the electromagnetic wave detector 24 and the dielectric measurement probe 25 to the regression coefficient spectrum held in the database 1, the concentration of the sample to be measured is determined. And a Mel calculator 3.

  A liquid sample containing the sample to be measured (desired component) flows through the flow cells 201 and 202 and is stored in the container 210.

  The millimeter wave / terahertz (THz) wave radiated from the radiator 23 is reflected by the parabolic mirror 221, transmitted through the sample in the flow cell 201, reflected by the parabolic mirror 221, and received by the electromagnetic wave detector 24. Is done. That is, the measurement is performed by a free space method using a pseudo optical system using a parabolic mirror or a lens (not shown).

  The millimeter wave / THz wave spectrometer 222 obtains the amplitude and phase spectrum (frequency spectrum) of the received millimeter wave / terahertz (THz) wave. The complex dielectric constant is also obtained.

  The dielectric measurement probe 25 immersed in the sample in the container 210 emits a microwave / millimeter wave, and the microwave / millimeter wave forms an electric field in the sample in the container 210, and the dielectric measurement probe 25 has an electric field (micrometer). Wave / millimeter wave).

  The microwave / millimeter wave measurement device 225 obtains the spectrum (frequency spectrum) of the amplitude and phase of the received electric field (microwave / millimeter wave). The complex dielectric constant is also obtained.

  The irradiator 21 is, for example, a lamp that generates broadband infrared light, and the generated infrared light passes through the sample in the flow cell 202 and is received by the photodetector 22. A material having sensitivity according to the reception frequency band is used for the photodetector 22. Infrared rays may be collimated using a lens.

  The infrared spectroscopic device 227 obtains the spectrum (frequency spectrum) of the received infrared amplitude and phase. Since the spectrum reflects the absorbance of the sample, it is also called an absorbance spectrum.

  The millimeter wave / THz wave spectrometer 222 and the microwave / millimeter wave measurement device 225 include a vector network analyzer having a broadband oscillator inside, a time-resolved spectrometer that generates radio waves using an optical pulse light source, or a continuous wave light source. Any of the continuous wave spectrometers that generate radio waves using the.

  The database 1 holds a regression coefficient spectrum for each concentration so that a plurality of samples (components) to be measured can be quantified simultaneously. That is, the database 1 holds a regression coefficient spectrum for the concentration of the sample to be measured in a frequency band that combines infrared light and electromagnetic waves (microwave / millimeter wave / terahertz (THz) wave).

  The computing unit 3 executes a chemometric processing method such as principal component analysis or PLS method, measures the concentration of the target sample (component) to be measured, and displays it on the display unit 4.

  For example, when targeting in vivo molecules, absorption of water, ions, albumin, triglyceride (neutral fat), cholesterol and other components is also observed in the vicinity of 1600 nm in the near infrared region where glucose exhibits absorption. Accordingly, an error factor corresponding to the concentration of water, ions, albumin, triglyceride (neutral fat), cholesterol and the like other than glucose is generated in the measured value. In addition, the influence of the temperature dependence on the quantitative accuracy cannot be ignored. Furthermore, in the living body, the influence of living body scattering affects the accuracy. It is required to eliminate these effects and selectively detect the glucose concentration. Since the detected glucose concentration is low, the regression level decreases when the noise level is high and the wave number / wavelength region is used.

  In the present embodiment, the dielectric relaxation phenomenon of water, which is the main component and polar molecule in the living body, and the change thereof, or the interaction between water and the solute are measured in microwaves, millimeter waves, and terahertz waves. In the infrared region, molecular vibrations of biomolecules in the living body are measured.

  FIG. 2 shows an example of the spectrum of electromagnetic waves and infrared rays that have passed through an aqueous glucose solution.

  FIG. 2A shows the imaginary part (lm [ε]) of the complex dielectric constant in the gigahertz band, and the numerical value for each line type indicates the concentration of the glucose aqueous solution. At a certain frequency, the higher the concentration, the higher the lm [ε]. This is called absorption increase.

  FIG. 2B shows the amplitude in the near infrared region, and the numerical value for each line type indicates the concentration of the glucose aqueous solution. At a certain frequency, the higher the concentration, the lower the amplitude. This is called absorption increase.

  FIG. 2C shows the transmission intensity in the terahertz band, and the numerical value for each line type indicates the concentration of the glucose aqueous solution. At a certain frequency, the higher the concentration, the higher the transmission intensity. This is called absorption reduction.

  FIG. 3 shows an example of an infrared spectrum that has passed through an aqueous ionic solution.

  FIG. 3 shows the amplitude in the near-infrared region, and the numerical value for each line type indicates the concentration of the ion aqueous solution. At a certain frequency, the higher the concentration, the higher the amplitude. This is called absorption reduction.

  FIG. 4 shows an example of the spectrum of electromagnetic waves and infrared rays that have passed through an albumin aqueous solution.

  FIG. 4A shows the imaginary part (lm [ε]) of the complex dielectric constant in the gigahertz band, and the numerical value for each line type indicates the concentration of the albumin aqueous solution. At a certain frequency, the higher the concentration, the higher the lm [ε]. This is called absorption increase.

  FIG. 4B shows the absorbance in the near infrared region, and the numerical value for each line type indicates the concentration of the albumin aqueous solution. At a certain frequency, the higher the concentration, the lower the absorbance. This is called absorption reduction.

  In the microwave, it is known that the relaxation peak in the low frequency band due to ions is prominent, and can be used for analysis of ions. On the other hand, in the millimeter wave band of 20 GHz or more and terahertz waves, the influence is slight. In microwave to millimeter wave, the Debye relaxation peak corresponding to the molecular weight can be observed depending on the hydration state of the solute and water. In a glucose aqueous solution, a Debye relaxation peak exists at about 20 GHz, and a shift of glucose can be observed in a millimeter wave. Even in the terahertz band, changes in the spectrum can be measured by changing the volume fraction of water. Moreover, since albumin has a very large molecular weight, it exhibits a relaxation peak at a low frequency in the microwave band (for example, 500 MHz or less). Therefore, there is a possibility of selective quantitative analysis between macromolecules and glucose. In the near-infrared spectrum, the absorption changes in any component due to a change in the volume fraction of water or an absorption spectrum derived from a substance.

  The microwave to terahertz wave has a wavelength of about 1000 times the near-infrared wavelength and can hardly ignore the in-vivo scattering, and thus can be measured by ignoring the in-vivo scattering. In addition, since there is no solute absorption in the terahertz band, the volume fraction of water in the living body can be measured independently of other components. It is possible to correct the change in volume fraction of water and the temperature dependence, which are problems in the conventional infrared, without being affected by biological scattering. The importance of this correction is apparent from the fact that, for example, at 1600 nm in the infrared region, water absorption is 1000 times the physiological glucose concentration, which is equivalent to a spectral shift due to a temperature change of 0.1 ° C.

  The spectral data of the regression coefficient spectrum stored in the database 1 includes, for example, data at different concentrations and temperatures of aqueous solutions of ions, albumin, triglycerides (neutral fats), cholesterol and the like, and data of a mixture thereof. Use.

  That is, before the computing unit 3 executes the spectral quantitative analysis technique, the physical property values (temperature, concentration, pH, etc.) of the substances measured in advance are made into a database as a reference list, and a calibration curve is created from each spectrum. And since a measurement spectrum is expressed by the linear combination of the component spectrum in each physical property value, the regression coefficient spectrum of each component is obtained and stored in advance as the database 1. As a method for creating a calibration curve, Principal Component Regression (PCR) or Partial Least Squares regression (PLS) may be used.

  The computing unit 3 calculates the concentration of each component by fitting the measured spectrum using the created regression coefficient spectrum.

[Second Embodiment]
FIG. 5 shows an example of a component concentration analyzer according to the second embodiment.

  The component concentration analyzer includes a database 1 that holds a regression coefficient spectrum for a desired sample concentration, an irradiator 21 that irradiates the sample T with infrared light, and an infrared that passes through the sample T. A photodetector 22 that receives light, a radiator 23 that radiates electromagnetic waves to the sample T to be measured, an electromagnetic wave detector 24 that detects electromagnetic waves that have passed through the sample T to be measured, and a light source that generates light of a predetermined wavelength 231, an amplitude modulator 233 that amplitude-modulates light from the light source 231, an optical splitter 235 that splits the light after amplitude modulation by the amplitude modulator 233, and a coaxial line 237 connected to the radiator 23. The coplanar line (not shown in FIG. 5), the amplifier 239 connected to the coaxial line 237, the output signal of the photodetector 22, the output signal of the electromagnetic wave detector 24, and the output signal of the amplifier 239 are locked. It received via a down-amp 243, by fitting the spectra obtained by the signal to regression coefficient spectrum held in the database 1, and a computing unit 3 for determining the concentration of the sample. The calculator 3 displays the concentration on the display 4, for example.

  The irradiator 21 includes, for example, a lens, and generates infrared light from one light branched by the optical splitter 235. The radiator 23 is a photomixer, for example, and generates electromagnetic waves from the other light branched by the optical splitter 235. The radiator 23 is a photomixer using UTC-PD, and its bias may be modulated, and the terahertz (THz) wave radiated from the radiator 23 may be amplitude-modulated with a chopper or the like.

  The controller 241 shifts the wavelength of the light source 231 under the control of the computing unit 3. The lock-in amplifier 243 controls the oscillation frequency w of the oscillator 245 with a voltage, and controls the amplitude modulator 233 with the oscillation frequency w. The amplitude modulator 233 is, for example, a Mach-Zehnder type amplitude modulator using an electro-optic crystal that can be electrically amplitude-modulated by a control signal.

  Microwave signal generation is more suitable for generating low frequencies when the spectral line width of the light source is narrow. In general, the spectral line width of a DFB laser is about 500 kHz, and a signal of several hundred MHz can be generated.

  The radiator 23 generates radio waves having the beat frequency of two lights, for example, radio waves from several GHz to several THz.

  The light source 231 generates light of at least two different frequencies. The wavelength of one light is variable under the control of the controller 241.

  By changing the wavelength linearly, one of the two lights branched from the optical splitter 235 linearly sweeps (sweeps) the frequency of the difference frequency beat signal of F2-F1 in the radiator 23.

  For example, a signal having a single frequency f (for example, 100 kHz) from the oscillator 245 is applied to the amplitude modulator 233. Thereby, the amplitude modulator 233 performs amplitude modulation.

  The electromagnetic wave detector 24 is, for example, an SBD with an antenna (Schottky barrier diode). In SBD, an electric signal having a frequency f is output by envelope detection. The electric signal is synchronously detected, and the lock-in amplifier 243 detects the amplitude.

  FIG. 6 shows a detailed structure of a portion denoted by reference numeral 250 in FIG.

  The coplanar line 251 is disposed at the position of the sample T to be measured by the cell 253 and is connected to the coaxial line 237 via the connector 255. The coplanar line 251 is connected to the amplifier 239 in FIG. 5 via another connector 255 and a coaxial line 237. For example, an electromagnetic wave (microwave / millimeter wave) of 1 MHz to 50 GHz is introduced into the coaxial line 237, passes through the sample T to be measured at the location of the coplanar line 251, passes through the coaxial line 237, and is received by the amplifier 239.

  Microwave to millimeter wave have a long wavelength, and the system size becomes large for spatial propagation. The coaxial line 237 is connected to the connector 255 on the board 256 and propagates through the coplanar line 251. A flow path is formed on the coplanar line 251, and the sample T to be measured is branched and passes. By measuring the pass characteristic of the coplanar line 251, the dielectric constant of the sample T to be measured can be measured.

  The substrate 256 is disposed so as to be thermally connected to the cell 253. A material having high thermal conductivity such as silicon or ceramics may be used as the material of the substrate 256, and a paste material having good thermal conductivity may be applied between the substrate 256 and the cell 253. With such an arrangement, since one sample T can be measured simultaneously, the accuracy of temperature control of the sample T to be measured can be increased, and the accuracy is improved.

  Reference numeral 257 indicates infrared rays emitted from the irradiator 21 and electromagnetic waves emitted from the radiator 23 to the space. The radiator 23 emits, for example, a millimeter wave / terahertz wave of 50 GHz to 10 THz. Is done. Infrared rays and electromagnetic waves pass through an opening called a window of the cell 253, pass through the sample T to be measured, and are received by the photodetector 22 and the electromagnetic wave detector 24.

  As described above, by adopting a configuration in which a single sample T to be measured is irradiated with infrared rays, microwaves / millimeter waves, and millimeter waves / terahertz waves at the same time, the size and accuracy of the apparatus can be reduced.

[Third Embodiment]
FIG. 7 shows an example of a component concentration analyzer according to the third embodiment. The component concentration analyzer according to the third embodiment has a device configuration for homodyne detection. The database 1 and the calculator 3 are not shown.

  The component concentration analyzer includes a continuous wave light source 261 that generates light of a predetermined wavelength, an optical splitter 262 that bifurcates light having a frequency F1 generated from the continuous wave light source 261, and a frequency F2 generated from the continuous wave light source 261. Optical splitter 263 that splits light into two, coupler 264 that combines one light split by optical splitter 262 and one light split by optical splitter 263, and the phase of the other light split by optical splitter 263 The optical phase modulator 265 to be coupled, the other light branched by the optical splitter 262 and the coupler 267 that combines the light after phase modulation by the optical phase modulator 265, and the light that splits the light multiplexed by the coupler 264 into two. A splitter 268.

  The irradiator 21 generates infrared light from the light branched by the optical splitter 268. Although not shown, the infrared light passes through the sample T to be measured and is received by the photodetector 22.

  The radiator 23 generates an electromagnetic wave from another light branched by the optical splitter 268. The electromagnetic wave is radiated from the radiator 23, reflected by the parabolic mirror 221 and the like, and transmitted through the sample T to be measured.

  The photodiode 269 generates an electromagnetic wave from another light branched by the optical splitter 268 and introduces the electromagnetic wave into the coaxial line 237.

  In the third embodiment, similarly to FIG. 6, the cell 253 is used, the infrared rays from the irradiator 21 and the electromagnetic waves from the radiator 23 are passed through one measured sample T, and the coplanar line 251 is passed through. The electromagnetic wave of another frequency is passed through the sample T to be measured.

  The amplifier 239 outputs the received electromagnetic wave to the lock-in amplifier 243 via the coaxial line 237.

  The electromagnetic wave detector 271 integrates both functions of the photomixer and the photomixer and the THz mixer, and performs homodyne detection of the electromagnetic wave that has passed through the sample T to be measured. The lock-in amplifier 243 controls the oscillation frequency w of the oscillator 245 with a voltage based on the signal from the electromagnetic wave detector 271 and controls the optical phase modulator 265 with the oscillation frequency w.

  In the third embodiment, in order to perform homodyne detection of electromagnetic waves, for example, phase modulation is performed by an optical phase modulator 265 using an electro-optic effect. The optical phase modulator 265 is a phase modulator using an electro-optic crystal that can be electrically phase-modulated by a control signal. The optical phase modulator 265 applies a signal having a single frequency f (for example, 40 kHz) from the oscillator 245 to generate serrodyne. Phase modulation is performed, and a frequency shift equivalent to the modulation frequency f is generated in the light. Note that the frequency that can be swept is limited by the modulation band of the phase modulator 265.

  As described above, the continuous wave light source 261 generates light of at least two different frequencies F1 and F2, and one frequency F2 is variable.

  The optical splitters 262 and 263 have a function of branching the optical power of the input light into two at a predetermined ratio and outputting it.

  For example, the center frequency of the operating band is 193.15 THz, and the optical power ratio is 50:50.

  The controller 241 receives the signal from the lock-in amplifier 243 via the monitor 272 and controls the continuous wave light source 261.

  The controller 241 linearly changes 193.125 THz to F1 = 193.225 THz or less and F2 = 194.125 THz or more, and outputs it from the continuous wave light source 261.

  The coupler 264 linearly sweeps the F2-F1 difference frequency beat signal.

  For example, in order to set the difference frequency to 0.6 THz, F1 = 193.125 THz and F2 = 193.725 THz.

  The coupler 267 outputs light of frequency F1 and frequency F2 + w. That is, by shifting the frequency F2 by the frequency w, the frequency of the difference frequency beat signal can be changed and a continuous spectrum can be obtained.

  Further, an optical splitter 268 is provided, for example, by setting F1 = 193.125 THz and F2 = 193.135 THz, a high frequency signal of 10 GHz is generated in the photodiode 269, and the high frequency is transmitted by the coaxial line 237 connected to the photodiode 269. Propagates electromagnetic waves. As the amplifier 239, a low noise amplifier is used according to the signal amount. In this way, a continuous microwave to millimeter wave spectrum can be obtained by changing the frequency of the difference frequency beat signal.

  The optical splitter 268 may be switched as a switch. The coaxial line 237 is connected to a connector (not shown) on the board, and propagates electromagnetic waves through the coplanar line. A flow path is formed on the coplanar line, and the sample to be measured is branched and passes. By measuring the pass characteristic of the coplanar line, the dielectric constant of the sample to be measured can be measured.

  The lights having two different light wavelengths are combined by the couplers 264 and 267 and then input to the radiator 23 and the electromagnetic wave detector 271, respectively. A difference frequency beat signal (electromagnetic wave) is radiated from the radiator 23, the electromagnetic wave is irradiated to the sample T to be measured by the parabolic mirror 221, and the electromagnetic wave transmitted through the sample T to be measured later enters the electromagnetic wave detector 271. . The electromagnetic wave detector 271 performs homodyne detection using two different lights having a frequency difference similar to the electromagnetic wave.

  The electromagnetic wave detector 271 outputs an electric signal having a frequency f by homodyne detection. The electric signal is synchronously detected, and the lock-in amplifier 243 detects the amplitude and phase.

  When homodyne detection of electromagnetic waves, the length of the optical fiber that propagates the light is adjusted in advance so that the two optical path length differences during mixing of the electromagnetic wave detector 271 match.

  In this way, the electrical signal is synchronously detected, and the lock-in amplifier 243 detects the amplitude and phase. With such a configuration, homodyne detection having a high S / N ratio can be performed.

  As the radiator 23, for example, a single traveling carrier photodiode (UTC-PD: Uni-Travelling-Carrier Photodiode) can be used.

  The electromagnetic wave detector 271 mounts an optical fiber and a THz mixer composed of an SBD (Schottky barrier diode) with an antenna and a photomixer composed of an UTC-PD with an antenna in the same package. This can be achieved. The electromagnetic wave detector 271 may be a photoconductive antenna (PCA).

[Fourth Embodiment]
FIG. 8 shows an example of a component concentration analyzer according to the fourth embodiment. The database 1 and the calculator 3 are not shown.

  In the fourth embodiment, a transmission type is arranged in the measurement system of the dielectric spectroscopic sensor, and the amplitude and phase of the transmission signal are measured. The figure exemplifies a measurement example when a sample to be measured is contained in a liquid such as an aqueous solution or oil. The sample to be measured may be a solid.

  An electromagnetic wave (THz wave or the like) is radiated from the radiator 23 to the sample to be measured held in the dielectric constant measurement cell 281 through a lens or the like, and the electromagnetic wave transmitted through the sample to be measured is detected through the lens or the like. This is detected by the device 24. A signal from the electromagnetic wave detector 24 is received by the lock-in amplifier 243 via the low noise amplifier 281.

  Although not shown, the sample to be measured is irradiated with infrared light using the irradiator 21 as in FIG. Moreover, the infrared light which permeate | transmitted the to-be-measured sample is received using the photodetector 22. FIG.

  The computing unit (not shown) receives the output signal of the photodetector and the output signal of the electromagnetic wave detector 24 via the lock-in amplifier 243, and the regression coefficient stored in the database is the spectrum obtained from the signal. By fitting to the spectrum, the concentration of the sample to be measured is obtained.

  FIG. 9 shows the results of multivariate analysis of an aqueous glucose solution using a spectrum of μ wave to millimeter wave. FIG. 10 shows the concentration calibration of glucose and albumin in a multi-component aqueous solution by multivariate analysis. It is the result of having gone. In both cases, the root mean square error (RMSECV) in cross validation was 100 mg / dL or less. Similarly, it is possible to improve the accuracy of multivariate analysis by including the spectrum in the terahertz wave band or the infrared region in the database.

  The size of the dielectric constant measurement cell 281 is, for example, several millimeters × several millimeters or more as the beam size or more, and the thickness depends on the transmittance of the sample, but it is about 0.1 mm in pure water. The fixing jig (window material) for fixing the sample to be measured may be a high resistance Si, Z cut crystal, HDPE, TPX, Tsurupica, etc. that transmits electromagnetic waves well, and has a high transmittance depending on the measurement frequency. Select. The liquid dielectric constant measurement cell 281 may have a flow cell configuration including an inlet and an outlet.

[Fifth Embodiment]
FIG. 11 shows an example of a component concentration analyzer according to the fifth embodiment. The database 1 and the calculator 3 are not shown.

  In FIG. 11, a component that is a sample to be measured exists in an irradiation region 291 of a human finger 291. Here, it is assumed that the sample to be measured absorbs a lot of electromagnetic waves.

  In this case, as shown in FIG. 11, a dielectric constant measurement cell is arranged on an ATR prism 293 made of silicon, and the reflected signal is measured spectroscopically.

  That is, an electromagnetic wave (THz wave or the like) is radiated from the radiator 23 to the irradiation region 291 via the lens and the ATR prism 293, and the electromagnetic wave reflected by the irradiation region 291 is reflected to the electromagnetic wave detector via the ATR prism 293 and the lens. 24. A signal from the electromagnetic wave detector 24 is received by the lock-in amplifier 243 via the low noise amplifier 281.

  In addition, the infrared light generated by the infrared light source 295 is irradiated to the irradiation region 291 through the ATR prism 293 using the irradiator 21. Further, infrared light reflected by the irradiation region 291 is received using a photodetector (not shown).

  That is, the fourth embodiment is an embodiment in which an electromagnetic wave and infrared light are irradiated to the position (the same position) of the sample to be measured.

  The computing unit (not shown) receives the output signal of the photodetector and the output signal of the electromagnetic wave detector 24 via the lock-in amplifier 243, and the regression coefficient stored in the database is the spectrum obtained from the signal. By fitting to the spectrum, the concentration of the sample to be measured is obtained.

  The material of the ATR prism 293 may be appropriately selected depending on the dielectric constant of the sample to be measured. For example, in addition to high resistance Si, polymer or quartz may be used. By providing a frame on the ATR prism 293 and placing a human finger 291, it can be applied to component analysis in human blood or interstitial fluid.

  Infrared light can be considered to reach the skin tissue about 1 mm at a wavelength with an absorption coefficient of 10 cm −1 and receive absorption of interstitial fluid and blood in the path. The electromagnetic wave has a wavelength of about 1 mm at 300 GHz, for example, and is about the same as the depth under the skin. Accordingly, information in the same region can be selectively obtained by selecting a frequency at which the penetration depth of the ATR prism 293 by the evanescent wave is considered to be approximately the same.

  As described above, according to the component concentration analyzer according to each embodiment of the present invention, it is possible to non-invasively quantify biological components necessary for a health check by dielectric spectroscopy analysis in a band from microwave to infrared. it can.

DESCRIPTION OF SYMBOLS 1 Database 3 Calculator 21 Irradiator 22 Photodetector 23 Radiator 24,271 Electromagnetic wave detector 25 Dielectric measurement probe 231 Light source 233 Amplitude modulator 235, 262, 263, 268 Optical splitter 237 Coaxial line 239 Amplifier 261 Continuous wave light source 264 267 Coupler 265 Optical phase modulator 269 Photodiode

Claims (7)

A database (1) holding a regression coefficient spectrum for the concentration of a predetermined sample to be measured (T) in a frequency band combining infrared light and electromagnetic waves;
An irradiator (21) for irradiating the sample to be measured (T) with the infrared light;
A photodetector (22) that receives the infrared light reflected or transmitted through the sample to be measured (T);
Radiation means (23, 25, 251) for radiating the electromagnetic wave to the sample to be measured (T);
Electromagnetic wave detection means (24, 25, 271, 239) for detecting the electromagnetic wave reflected or transmitted through the sample to be measured (T);
By fitting the spectrum obtained from the photodetector (22) and the electromagnetic wave detection means (24, 25, 271, 239) to the regression coefficient spectrum held in the database (1), the sample to be measured (T And a computing unit (3) for obtaining the concentration of component). The radiating means (23, 25, 251)
First radiation means (23) for generating electromagnetic waves in a first frequency band;
Second radiating means (25, 251) for generating electromagnetic waves in a second frequency band,
The electromagnetic wave detection means (24, 25, 271, 239)
First electromagnetic wave detection means (24) for detecting electromagnetic waves in the first frequency band;
The component concentration analyzer according to claim 1, further comprising second electromagnetic wave detection means (25, 239) for detecting electromagnetic waves in the second frequency band. A light source (231);
An amplitude modulator (233) for amplitude-modulating light from the light source (231);
An optical splitter (235) for bifurcating the light after amplitude modulation by the amplitude modulator (233),
The irradiator (21) generates infrared light from one light branched by the optical splitter (235),
The component concentration analyzer according to claim 1, wherein the radiating means (23, 25, 251) includes a radiator (23) that generates an electromagnetic wave from the other light branched by the optical splitter (235). . The radiating means (23, 25, 251) is arranged at the position of the sample to be measured (T), and a coaxial line (237) for introducing an electromagnetic wave generated from the other light branched by the optical splitter (235). Including a coplanar line (251) connected via
The component concentration analyzer according to claim 3, wherein the electromagnetic wave detection means (24, 25, 271, 239) includes an amplifier (239) connected to the coplanar line (251) via a coaxial line. . A continuous wave light source (261);
A first optical splitter (262) that splits the light of the first frequency (F1) generated from the continuous wave light source (261) into two;
A second optical splitter (263) for bifurcating light of the second frequency (F2) generated from the continuous wave light source (261);
A first coupler (264) for combining one light branched by the first optical splitter (262) and one light branched by the second optical splitter (263);
An optical phase modulator (265) for modulating the phase of the other light branched by the second optical splitter (263);
A second coupler (267) for combining the other light branched by the first optical splitter (262) and the light after phase modulation by the optical phase modulator (265);
A third optical splitter (268) for branching the light combined by the first coupler (264),
The irradiator (21) generates infrared light from the light branched by the third optical splitter (268),
The radiating means (23, 25, 251) includes a radiator (23) that generates electromagnetic waves from other light branched by the third optical splitter (268),
The electromagnetic wave detection means (24, 25, 271, 239) includes an electromagnetic wave detector (271) that performs homodyne detection of the electromagnetic wave using the light combined by the second coupler (267). The component concentration analyzer according to claim 1. The radiating means (23, 25, 251) is disposed at the position of the sample to be measured (T), and is a coaxial line for introducing an electromagnetic wave generated from the other light branched by the third optical splitter (268). 237) including a coplanar line (251),
6. The component concentration analyzer according to claim 5, wherein the electromagnetic wave detection means (24, 25, 271, 239) includes an amplifier (239) connected to the coplanar line via a coaxial line (237). . A component concentration analysis method using a database (1) that holds a regression coefficient spectrum for the concentration of a predetermined sample to be measured (T) in a frequency band that combines infrared light and electromagnetic waves,
An irradiator (21) irradiates the sample to be measured (T) with the infrared light,
A photodetector (22) receives the infrared light reflected or transmitted through the sample to be measured (T);
Radiation means (23, 25, 251) radiates the electromagnetic wave to the measurement sample (T),
An electromagnetic wave detection means (24, 25, 271, 239) detects the electromagnetic wave reflected or transmitted through the measured sample (T),
The computing unit (3) fits the spectrum obtained from the photodetector (22) and the electromagnetic wave detection means (24, 25, 271, 239) to the regression coefficient spectrum held in the database (1). A concentration analysis method for determining the concentration of the sample to be measured (T).

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