JP2019015685A - Constituent concentration measuring apparatus and analyzing method - Google Patents

Abstract

To provide a high-precision constituent concentration measuring apparatus and measuring method that reduce temporal variation in intensity of light irradiating a sample to be measured during measurement by an OPBS method and an influence of noise in measurement of a photoacoustic wave.SOLUTION: Lights A, B are multiplexed at a frequency ω in mutually opposite-phase relation and made to irradiate a body to be measured (S111). While the light B has its light intensity held at P'=P+δP, the light A has its light intensity swept, and light intensity dependency of S' associated with the body to be measured is measured (S112). After Fourier transformation of time variation of S', light intensity dependency of respective spectrum intensities of S'(ω) of frequency ω and S'(2ω) of double waves is calculated (S113). Then PA'=P+δPof the light A when a magnitude R=S'(2ω)/SA'(ω) of SA'(2ω) to SA'(ω) has a maximum value is acquired (S114). A concentration of a specific component is derived using values of obtained δα, δα, P, P, δP, and δP(S115).SELECTED DRAWING: Figure 14

Description

  The present invention relates to a component concentration measuring apparatus and analysis method for measuring the concentration of a dispersed or dissolved component in a medium in which light and an acoustic signal propagate together, such as water.

  In order to prevent diabetes, it is important to continuously monitor the blood glucose level of diabetic patients. In monitoring blood glucose levels, it is necessary to accurately measure the glucose concentration present in blood. As a measuring method, there is a photoacoustic method. According to the measurement by the photoacoustic method, it is possible to continuously monitor the glucose concentration in the blood. In addition, the photoacoustic measurement is painless for diabetic patients, does not require a blood sample, and does not cause discomfort to the diabetic patient. Also, in the photoacoustic method measurement, compared to other optical measurement methods, efficiency is not deteriorated due to the scattering media, and high sensitivity characteristics can be obtained by combining optics and acoustics.

  There are two photoacoustic methods, a pulse method and a continuous-wave (CW) method. However, in the conventional pulse method and CW method, during the measurement of the glucose concentration in plasma several times, there is a high possibility that other plasma parameters other than the glucose concentration (for example, body temperature, concentration of other components, etc.) will also change. Therefore, there is a problem that the glucose selectivity is poor and it is difficult to obtain an accurate glucose concentration.

  Therefore, an optical power balance shift (OPPBS) method has been developed in which component concentration is measured by a continuous rectangular wave having a phase difference of π (180 °) between two wavelengths (Patent Documents 1-5). reference).

  Specifically, the two intensity-modulated lights having the phase difference π of the wavelengths λ1 and λ2 are combined and output to the object to be measured. Then, a sound wave generated by being absorbed by the component of the object to be measured is detected, and the concentration of the measurement target component in the object to be measured is measured from the magnitude of the sound wave.

Here, for example, the wavelength λ _A and the wavelength λ _B are set so that the absorbance by water, which is the background component in the object to be measured, is equal to each other. The wavelength λ _A is set so that the absorbance due to glucose, which is a measurement target component in the object to be measured, is maximized.

When light of such two different wavelengths is emitted, the light of wavelength λ _A is absorbed by both glucose and water, and the sound wave generated from the object to be measured and the light of wavelength λ _B are absorbed by water. Since the sound wave generated from the measurement object has the same frequency and opposite phase, it is superimposed inside the measurement object, and only the magnitude of the sound wave generated from the measurement object as glucose is absorbed as glucose difference. Will remain.

That is, the size S of the detected acoustic wave is equivalent to the difference between the magnitude of the acoustic wave was measured using only the light of the size and the wavelength lambda _B of the waves measured by using only the light of wavelength lambda _A, to be measured The size is based only on the absorption of a specific component (here, glucose) in the object.

[OPBS measurement method]
Here, the measurement principle of the conventional OPBS method will be briefly described. In the conventional OPBS method, in order to search for a point where no ultrasonic wave is generated from the object to be measured, that is, a point where the intensity S of the photoacoustic signal is 0, the power of the two wavelengths of light is adjusted.

For example, even if the intensity S of the photoacoustic signal is not 0 but is a constant S ₀ , there is no problem as long as it is a known constant. However, for the sake of simplification of explanation, it is assumed that the constant S ₀ is 0.

When the intensity S of the photoacoustic signal is S = 0, the following theoretical formula is established.
α _A P _A −α _B P _B = 0 (1)

Here, P _A and P _B are the powers of the two wavelengths of light A and B, and α _A and α _B are the light absorption coefficients of the object to be measured for the light powers of P _A and P _B , respectively.

At this time, since the sound waves generated from the two wavelengths of light have the same frequency and opposite phases, the intensity S = 0 of the photoacoustic signal cancels inside the object to be measured (or the minimum value: S ₀ ). It can be. In other words, at this time, it can be said that the intensity balance of the sound waves of the light of two wavelengths is balanced.

Here, when the concentration of the component to be measured changes, for example, it is assumed that the glucose concentration has changed by Cg as the component of the object to be measured. When the light absorption coefficients α _A and α _B change by δα _A and δα _B , respectively, due to this change in concentration, the state changes from the state in which equation (1) holds to the state in equation (2).
(Α _A + δα _A C _g ) P _A − (α _B + δα _B C _g ) P _B ≠ 0 (2)

Here, the light absorption coefficient change rates δα _A and δα _B are light absorption coefficients per unit concentration at the light wavelengths λ _A and λ _B of light A and B relating to glucose as a component of the object to be measured. It is a value that can be separately detected by light absorption spectrum measurement using a single reagent solution.

In order to return to the state of S = 0, for example, when the light intensity PA of the light _A is changed, the following equation is established.
(Α _A + δα _A C _g ) (P _A + δP _A ) − (α _B + δα _B C _g ) P _B = 0 (3)

Subsequently, when the light intensity P _B of the other light B is changed at the same time, the following equation is established as in the equation (3).
(Α _A + δα _A Cg) (P _A + δP _A ) − (α _B + δα _B Cg) (P _B + δP _B ) = 0 (4)

In formulas (3) and (4), δP _A and δP _B are the amounts of change in the light intensities P _A and P _B of the light _A and _B , respectively.

  At this time, the following equation is obtained from equation (4).

From formulas (1), (3), and (4), unknown light absorption coefficients α _A and α _B are obtained, and it can be seen from formula (5) that the glucose concentration C _g can be measured.

  Subsequently, the measurement procedure of the OPBS method will be specifically described with reference to a chart.

In the OPBS method disclosed in Patent Documents 1-5, as shown in FIG. 1, two rectangular continuous waveforms of light A and light B having different light wavelengths and having a phase difference of π are identical to the object to be measured. Irradiate from the light output port. At this time, the photoacoustic wave signal S generated from the object to be measured is represented by the following equation where the light absorption coefficient of the object to be measured is α and the light intensity of a certain intensity is P, and the time of each irradiation light in FIG. It becomes the area of a rectangular continuous waveform that is a change.
S = α × P (6)

The OPBS method searches for an inflection point of the phase where the amplitude of the photoacoustic signal is minimum while increasing or decreasing the light intensities P _A and P _B of these two wavelengths of light A and B. This is a method for obtaining the concentration of a dissolved object to be measured.

More specifically, as shown in FIGS. 2A to 2C, first, the light intensity P _B of one of the two lights A and B having different wavelengths is made constant, and the other continue to measure the photoacoustic signal intensity S while changing the light intensity P _a light a. At this time, a curve change in which the photoacoustic signal intensity S takes a minimum value as shown in FIG. In particular, at the position shown in FIG. 2B, the photoacoustic signal intensity S shows a minimum value. This is a state in which the intensity balance of sound waves caused by the two wavelengths of light A and B is balanced. It is a state that holds.

Thereafter, when the light absorption coefficient α _B caused by the increase or decrease in the concentration of a specific component (for example, glucose) in the object to be measured changes, the curve of the photoacoustic signal intensity S shifts as indicated by the broken line in FIG. When the photoacoustic signal intensity takes the minimum value at the same position as in FIG. 2B, the state of Expression (3) is obtained, and the light intensity PA of the light _A also changes (broken line in FIG. 2D). Furthermore, since the state of the equation (4) can be reproduced by changing the light intensity P B of the light _{B in the} same manner, from the equations (1) and (3) to (5), allows evaluation of the concentration C _g of the specific component (e.g. glucose).

However, in practice, the light wavelength of one light _A can be selected so that the light absorption coefficient change rate δα _A of a specific component (for example, glucose) in the object to be measured is so small that it can be ignored (δα _A ≈0). Yes, since the measurement can be evaluated by the change in the light intensity of only the light A and the expressions (1) and (3), that is, by changing only the light intensity P _{B at} which the photoacoustic signal intensity is minimum, It is possible to accurately measure the concentration of a specific component (for example, glucose).

That is, the concentration C = C intensity P _B (C ₀₎ of light B which takes a minimum value of the solid line shown in FIG. 2 (d) when the ₀ in the formula (1) of a specific component in the measuring object (e.g. glucose), Further, the intensity P _{B of the} light B taking the minimum value of the broken line in FIG. 2D when the concentration C ₁ = C ₀ + ΔC when the concentration of the specific component (for example, glucose) in the object to be measured is increased by ΔC. From (C ₁ = C ₀ + ΔC) and equation (3), a concentration increase ΔC of a specific component (for example, glucose) in the object to be measured is obtained.

Japanese Patent Laid-Open No. 2006-154585 JP2015-31670A JP 2014-50563 A JP 2013-106874 A JP 2012-179212 A

In the conventional OPBS method, the optical powers P _A and P _B change even when the driving current of the laser diode is constant, due to the case where the output stability of the light source is not good or the environmental temperature varies. For example, in the formula (1), the optical power P _A is changed by epsilon, expressed by the following equation.
α _A (P _A + ε) −α _B P _B ≠ 0 (7)

In the state of Expression (7), even if the glucose concentration is constant, one of the light intensities (for example, P _A ) must be adjusted in order to make S = 0.
α _A ((P _A + δP _A ) + ε) −α _B P _B = 0 (8)

Therefore, the effect of changes in impact and glucose concentration change in the output of the light source has on the intensity of the photoacoustic signal S is supplied to the intensity S of photoacoustic signal is the same, to distinguish these changes from [delta] P _A measurement result Therefore, it is difficult to accurately measure the glucose concentration when there is a change in the output of the light source. That is, in the conventional OPBS method, it is necessary to always measure the output power of the light source and keep the output of the light source constant.

That is, in the conventional OPBS method, in order to search for the point where the intensity of the photoacoustic signal is the lowest, the intensity of the photoacoustic signal is measured while finely changing the power P _B while keeping the light intensity P _A constant. There is a need to do.

Therefore, the laser diode light intensity, P _A , and P _B stability are required, and long-term stability for short-term stability and measurement reproducibility within one cycle of measurement time for obtaining the minimum value of the photoacoustic signal. Both sexes are required.

  However, in practice, even if injection current control with a feedback circuit is performed, the temporal change stability of the light intensity of LD (laser diode) light is not so high. Intensity fluctuations will occur. Therefore, when the above measurement is actually performed, there is a problem that light intensity noise of several percent is included in the time for measuring the minimum value, which causes a measurement error of the OPBS method that is difficult to improve.

  In addition, when measuring the concentration of components in an actual living body, unlike the standard cell in the laboratory that shuts off external signals and sound sources, the heart beat, blood and fluid flow sounds, muscle movement, etc. There are many noises such as vibrations from various external sound wave sources and external environmental sounds. Due to the influence of noise noise, when detecting the minimum value of the photoacoustic signal, the signal of the minimum value is buried in noise noise, and the light intensity of the minimum value of the photoacoustic signal becomes unclear. there were.

  The present invention has been made to solve the above-described problems, and has reduced the influence of temporal fluctuations in the intensity of irradiated light on a sample to be measured during measurement using the OPBS method and noise noise during measurement of photoacoustic waves. An object of the present invention is to provide a highly accurate component concentration analyzer and analysis method.

  In order to solve the above-mentioned problems, the present invention is a component concentration analyzer, and a light output means for outputting two lights of different wavelengths, which are intensity-modulated by signals having opposite phases at the same frequency, and Optical combining means for combining the two lights, light intensity measuring means for measuring the light intensity of the two lights, and light irradiation means for irradiating the object to be measured with the combined light or only one of the lights And a sound wave detecting means for detecting a sound wave generated inside the object to be measured by the irradiation, and a photoacoustic signal based on the magnitude of the detected sound wave, to calculate the concentration of the measurement target component in the object to be measured. Component concentration calculating means for calculating the frequency spectrum by Fourier transforming the temporal change of the intensity of the photoacoustic signal, and performing the intensity sweeping of one of the two lights. Light at one light frequency Calculating a frequency spectrum intensity ratio that is a magnitude of photoacoustic signal intensity at a frequency twice the frequency of the two lights with respect to an echo signal intensity, and the light of the two lights having the maximum frequency spectrum intensity ratio The concentration of the measurement target component is calculated based on the intensity, the amount of change in the light intensity of the two lights, the light absorption coefficient, and the light absorption coefficient change rate.

  According to a second aspect of the present invention, in the component concentration analyzer according to the first aspect, a modulated signal waveform of light of two different wavelengths, which is intensity-modulated by signals having opposite phases at the same frequency, has a trapezoidal waveform or It is a triangular waveform.

  According to a third aspect of the present invention, in the component concentration analyzer according to the first aspect, the modulated signal waveforms of the light of two different wavelengths that are intensity-modulated by the signals having the opposite phases at the same frequency are sinusoidal waveforms. It is characterized by being.

  The invention according to claim 4 is a component concentration analysis method, wherein an optical output step of outputting two lights of different wavelengths, which are intensity-modulated by signals having opposite phases at the same frequency, respectively, and the two lights A light combining step for combining the two lights, a light intensity measuring step for measuring the light intensity of the two lights, a light irradiation step for irradiating the object to be measured with the combined light or only one light, and the irradiation A sound wave detecting step for detecting a sound wave generated inside the object to be measured by means of, and a component concentration calculation for calculating the concentration of the measurement target component in the object to be measured using a photoacoustic signal based on the magnitude of the detected sound wave And the component concentration calculating step calculates a frequency spectrum by Fourier-transforming a temporal change in the intensity of the photoacoustic signal, and sweeps the intensity of one of the two lights while scanning the two lights. The frequency spectrum intensity ratio, which is the magnitude of the photoacoustic signal intensity at a frequency twice the frequency of the two lights with respect to the photoacoustic signal intensity at the frequency, is calculated, and the frequency spectrum intensity ratio becomes the maximum 2 And calculating the concentration of the measurement target component based on the light intensity of one light, the amount of change in the light intensity of the two lights, the light absorption coefficient, and the light absorption coefficient change rate.

  According to a fifth aspect of the present invention, in the component concentration analysis method according to the fourth aspect, the modulated signal waveforms of light of two different wavelengths whose intensity is modulated by signals having opposite phases at the same frequency are trapezoidal waveforms or It is a triangular waveform.

  According to a sixth aspect of the present invention, in the component concentration analysis method according to the fourth aspect, the modulated signal waveforms of the light of two different wavelengths that are intensity-modulated by signals of opposite phases at the same frequency are sinusoidal waveforms. It is characterized by being.

  The invention according to claim 7 is the component concentration analysis method according to any one of claims 4 to 6, wherein the component concentration calculation step includes a standard in which the concentration of the measurement target component and the light absorption coefficient of the solvent are known. The method includes a step of deriving the rate of change of the light absorption coefficient of the two lights using a sample.

  The invention according to claim 8 is the component concentration analysis method according to any one of claims 4 to 7, wherein the component concentration calculation step is configured to reduce the intensity of the two lights so that the photoacoustic signal intensity becomes a minimum value. After adjusting the light intensity, the concentration of the measurement target component is increased / decreased, and the amount of change in the light intensity of the two lights at which the photoacoustic signal intensity becomes a minimum value after the increase / decrease of the concentration of the measurement target component, the light absorption coefficient It includes the step of measuring the rate of change.

It is a figure which shows the time change of the light intensity at the time of irradiating light A and B by the conventional OPBS method alternately. It is a figure which shows the light intensity dependence of the photoacoustic signal strength S in the conventional OPBS method. It is the schematic which shows the influence of the noise noise with respect to the conventional OPBS method. It is the schematic which shows the time change of the light absorption amount when the light absorption amount of the light A is larger than the light absorption amount of the light B. It is the schematic which shows the time change of the light absorption amount when the light absorption amount of the light A is smaller than the light absorption amount of the light B. It is a figure which shows the frequency spectrum of the photoacoustic signal strength S in case the difference of the light absorption amount of the light A and the light B is large. It is the schematic which shows the time change of the light absorption amount when the light absorption amount of the light A and the light absorption amount of the light B are substantially equal. It is a figure which shows the frequency spectrum of the photoacoustic signal strength S in case the difference of the light absorption amount of the light A and the light B is small. It is the schematic which shows the time change of the light absorption amount in case the time change of the light absorption amount of the light A and the light B is a trapezoid waveform. It is a figure which shows the optical intensity dependence of the magnitude | size R of the photoacoustic signal strength S (2 (omega)) of a 2nd harmonic with respect to the photoacoustic signal strength S ((omega)) of a fundamental wave. It is the schematic which shows the time change of the light absorption amount in case the time change of the light absorption amount of the light A and the light B is a triangular waveform. It is the schematic which shows the time change of the light absorption amount in case the time change of the light absorption amount of the light A and the light B is a sine waveform. It is a schematic block diagram of the component concentration measuring apparatus which concerns on the 1st Embodiment of this invention. It is a processing flow figure of the component concentration analysis method concerning a 1st embodiment of the present invention.

(Noise reduction by ratio of fundamental frequency and second harmonic)
The cause of the measurement error by the conventional OPBS method will be described in detail with reference to the drawings.

FIG. 3 shows a change in the photoacoustic signal intensity S with respect to the light intensity P of the irradiation light by the conventional OPBS method. While the conventional OPBS methods for the photoacoustic signal intensity S is to search the lowest point (minimum value), constantly measures the power P _A of one of the light beam, maintaining the power P _A constant intensity, the other The photoacoustic signal intensity S was measured while finely changing the power P _B of the light beam. In this case, it is a precondition that the power P _A is always kept constant, and the power fluctuation width ΔP _A when it fluctuates during measurement is the point (minimum value) where the photoacoustic signal intensity S is the lowest. It was a cause of error when seeking.

That is, the change of the photoacoustic signal intensity S against the light intensity P in Figure 3, by the power variation width [Delta] P _A is applied, so that the position of the light intensity P of the photoacoustic signal intensity S is the minimum value fluctuates . For this reason, it becomes impossible to detect the light intensity P at which the accurate photoacoustic signal intensity S is a minimum value.

  Further, considering the case where noise noise of various acoustic waves from the outside is added to the intensity of the photoacoustic signal, the hatched noise noise in FIG. 3 is added to the measurement result of the photoacoustic signal intensity S. For this reason, the minimum value of the change in the photoacoustic signal intensity S relative to the light intensity is buried in noise noise, and the position of the light intensity P at which the photoacoustic signal intensity S becomes the minimum value and the photoacoustic signal intensity S is unclear. End up.

  That is, in the environment where the light intensity fluctuation of the irradiation light and the noise noise of various acoustic waves are generated, the influence of the fluctuation and noise is large, and there is a problem in the detection of the minimum value of the photoacoustic signal intensity S itself.

Therefore constituent concentration measuring apparatus of the present invention, in order to photoacoustic signal intensity S as in the conventional OPBS method searches for a minimum point, constantly measuring the light intensity P _A of one of the light A, the light intensity P _A When measuring the intensity of the photoacoustic signal while finely changing the light intensity P _B of the light B while maintaining a constant intensity, the photoacoustic signal intensity S itself is measured, and the light intensity P _B is changed to change the photoacoustic signal. Rather than searching for a position where the signal intensity S is a minimum value, the photoacoustic signal itself is subjected to Fourier transform, and the photoacoustic signal is analyzed on the frequency spectrum.

When combining intensity-modulated light beams A and B in the form of a rectangular wave having two phase differences π (180 °) of periodic wavelengths λ _A and λ _{B at} a frequency ω in the conventional OPBS method and emitting them to the object to be measured 4 shows the time change of the light absorption amount αP when the light absorption amount α _A P _A of the light _A is sufficiently larger than the light absorption amount α _B P _B of the light B, and conversely, the light intensity P _B of the light _B FIG. 5 shows the temporal change of the light absorption amount αP when is sufficiently larger than the light intensity PA of the light _A.

When the difference between the light absorption amount α _A P _A of light _A and the light absorption amount α _B P _B of light B is large as shown in FIG. 4 or FIG. 5, the photoacoustic signal generated by the difference between the light absorption amounts Most of the frequency spectrum components are components of the frequency ω. FIG. 6 shows a frequency spectrum obtained by Fourier transforming the time change of the photoacoustic signal at this time. The peak at the frequency 3ω is a harmonic component generated by the change in the amount of light absorption repeated at the frequency ω.

  At this time, the frequency ratio of the rectangular wave having the duty ratio equal to the time interval of ON (high level) and OFF (low level) being 1 and the frequency ω is (2n + 1) ω because of the symmetry within the time change. (N is 0 and a positive integer). That is, when the difference in the amount of light absorption between the light A and B is large, the frequency spectrum of the photoacoustic signal has a large spectrum intensity at the frequency ω as shown in FIG. The strength is reduced.

  On the other hand, as shown in FIG. 7, when the light A and B are close to a balanced state as in the equations (1) and (3), the light absorption difference between the light A and B becomes very small. . At this time, the frequency spectrum obtained by Fourier transforming the time change of the photoacoustic signal intensity S is as shown in FIG. That is, in the photoacoustic signal intensity S, the fundamental wave S (ω) at the frequency ω is very small, and compared with that, the double wave S (2ω) at the frequency 2ω is relatively large. Come.

The reason why the photoacoustic signal intensity S (2ω) of the second harmonic wave becomes large is that the light absorption amount α _A P _A of the light _A and the light absorption amount α _B P _B of the light B are originally in an accurate rectangular wave signal shape. If the light absorption amount α _A P _A and the light absorption amount α _B P _B have the same magnitude, in principle, the light absorption amount will continue to maintain a constant intensity, and S ( Components such as ω), S (2ω), and S (3ω) are not generated.

However, in practice, it is difficult to generate the light absorption amount α _A P _A and the light absorption amount α _B P _B with an accurate rectangular wave signal shape, and light at the start and end of light irradiation is difficult. Since a slight relaxation time for energy conversion is required for the rise and fall of the absorption amount, a trapezoidal signal shape (trapezoid waveform) is actually obtained as shown in FIG. In this case, the photoacoustic signal intensity S (2ω) of the second harmonic is always generated, and the intensity is the smaller of the light absorption amount α _A P _A and the light absorption amount α _B P _B in FIG. Will be reflected. Therefore, when the light absorption amount α _A P _A and the light absorption amount α _B P _B have the same value and the difference is small, the photoacoustic signal intensity S (2ω) of the second harmonic wave is the light of the fundamental wave. The value is larger than the acoustic signal intensity S (ω).

That is, when the magnitude R of S (2ω) with respect to the photoacoustic signal intensity S (ω) is maximized, the expressions (1) and (3) hold, and the photoacoustic signal intensity S shows a minimum value. The change is schematically shown in FIG.
R = S (2ω) / S (ω) (9)

From the above results, the present invention obtains the light intensity P _A and the light intensity P _B of the light A and the light B when the value of the above expression (9) becomes maximum, and the expressions (1), (4) to (5) ), The concentration of the specific component in the object to be measured can be obtained.

  In this method, since the magnitude of the photoacoustic signal intensity S (2ω) of the double wave relative to the photoacoustic signal intensity S (ω) of the fundamental wave is calculated, the acoustic noise noise as shown in FIG. For example, in the case of white noise having no frequency dependency, the noise noise itself can be neglected in calculation, so that the noise noise can be ignored. Also, in the case of noise noise having frequency dependence, the noise noise intensity is set so that the frequency ω and the double frequency 2ω have the same noise noise intensity or both have a small frequency ω, 2ω on the frequency spectrum. Can be reduced.

In addition, as shown in FIG. 11, the light absorption amount α _A P _A of the light _A and the light absorption amount α _B P _B of the light _B are generated in a triangular waveform, and the light absorption amount is equal. Since the frequency spectrum has only a component of frequency (2n + 1) ω (n is 0 and a positive integer) due to symmetry within the time change, theoretically, the photoacoustic signal intensity S (2ω of frequency 2ω is used. ) Becomes zero.

Therefore, as in the case of the trapezoidal waveform, the maximum value of the magnitude R of the double-wave photoacoustic signal intensity S (2ω) with respect to the fundamental photoacoustic signal intensity S (ω) of Equation (9) is measured. . By obtaining the light intensity P _A and light intensity P _B of the light A and the light B when the value of R is maximized, the identification in the object to be measured is obtained from the expressions (1), (4) to (5). The concentration of the component can be determined.

Further, when the light absorption amount α _A P _A of light _A and the light absorption amount α _B P _B of light B are sinusoidal and the light absorption amounts are equal as shown in FIG. The frequency spectrum after the Fourier transform has a component that is an integral multiple of the frequency ω, but the component that is an even multiple of the frequency ω is larger than the component that is an odd multiple, and the size of the component of the frequency 2ω is another even multiple. Larger than the ingredients. For this reason, even if various noises such as the above-mentioned noise noise are detected, a bandpass filter that deletes signals other than those near the frequency ω and 2ω of the photoacoustic signal S (ω) is used as shown in FIG. The position where the magnitude R of S (2ω) with respect to the photoacoustic signal S (ω) is maximum can be detected with high sensitivity, and is less susceptible to various noises.

Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings.
(First embodiment)
FIG. 13 is a diagram showing a basic configuration of the component concentration analyzer 1 according to the first embodiment. This component concentration analyzer includes an oscillator 101, a first drive circuit 102, a first light source 103, a 180 ° phase shifter 104, a second drive circuit 105, and a second light source 106. Also, an optical multiplexer 107 that combines the output light from the first light source 103 and the second light source 106, an optical demultiplexer 108 that demultiplexes the combined light, and the light intensity at which the demultiplexed light is incident. A measuring instrument 109 and a device cell 110 to be measured are provided. In addition, a sound wave detector 111, an amplifier 112, a waveform observer 113, and a recording / calculating device 114 are provided in the device under test cell 110.

  The oscillator 101 outputs a modulation signal for intensity-modulating each light output from the first light source 103 and the second light source 106. The 180 ° phase shifter 104 inverts one of the modulation signals from the oscillator 101 and outputs the result.

  The first drive circuit 102 drives the first light source 103 based on the modulation signal from the oscillator 101. The second drive circuit 105 drives the second light source 106 based on the modulation signal inverted by the 180 ° phase shifter 104.

The first light source 103 modulates the intensity of the light of wavelength λ _A by the signal from the first drive circuit 102 and outputs the light. The second light source 106 modulates the intensity of the light having the wavelength λ _{B with} the signal from the second drive circuit 105 and outputs the light. As a result, it is possible to output light having two different wavelengths that are electrically intensity-modulated with signals of the opposite phase at the same frequency ω.

Here, it is desirable that the wavelength λ _A and the wavelength λ _B are set so that the absorption exhibited by the background component (non-measurement target component) constituting the object to be measured is equal to each other. For example, when the object to be measured is a living body and the measurement target component is glucose or cholesterol, the absorbance by water indicating most of the object to be measured is the same wavelength.

Further, it is desirable that the wavelength λ _A is set so that the absorption exhibited by the measurement target component is maximized. For example, the wavelength λ _A is preferably 1600 nm or 2100 nm, which is the wavelength that is best absorbed by glucose or cholesterol.

  The first light source 103 and the second light source 106 may be any light source that can change the wavelength and can output light whose intensity is continuously modulated. For example, a DFB (Distributed Feedback) semiconductor laser can be used. When using a wavelength tunable laser, there are a method of changing the oscillation frequency by adjusting the temperature, a method of using an external resonator, and the like. In addition, a gas laser or a solid-state laser can also be used, and a predetermined wavelength may be extracted using a dispersion element such as a prism or a diffraction grating.

  The optical multiplexer 107 combines the measurement light from the first light source 103 and the reference light from the second light source 106, and guides only the combined light or one of the light that is not combined. Irradiate the measurement object cell 110. A right-angle prism, an optical fiber collimator, a filler, or the like may be bonded to the light emitting end in accordance with the surface shape of the measured object cell 110.

  The optical demultiplexer 108 demultiplexes a part of the light emitted from the optical multiplexer 107 toward the device cell 110 to be measured, and guides it to the optical intensity measuring device 109 for measurement. Based on the branching ratio of the vessel 108, the light intensity applied to the measurement object in the measurement object cell 110 is calculated.

  The sound wave detector 111 is disposed at a fixed distance from the light emitting end of the optical multiplexer 107, detects sound waves generated inside the measured object cell 110 by the light emitted from the optical multiplexer 107, and It is converted into an electrical signal proportional to the magnitude (amplitude) of the sound wave and output as a photoacoustic signal. For example, a microphone or a piezoelectric element can be used.

  The amplifier 112 amplifies the photoacoustic signal output from the sound wave detector 111. The waveform observer 113 measures the amplitude and phase of the amplified photoacoustic signal. In addition to the waveform observer 113, the amplitude and phase of the photoacoustic signal may be measured by detection and amplification by a phase detection amplifier (not shown).

  The recording / computing device 114 performs a Fourier transform on the time change of the photoacoustic signal intensity measured by the waveform observer 113 and records a time-varying signal as a frequency spectrum, a bandpass filter for noise removal, It has photoacoustic signal intensities S (ω) and S (2ω) peak intensity extraction, recording, and calculation functions at a wave frequency ω and a double wave frequency 2ω. For example, a computer equipped with a memory and a CPU can be used.

Further, when the recording / calculation device 114 detects the fundamental frequency ω and the double frequency 2ω in the photoacoustic signal, the respective photoacoustic signal intensities S _LD1 detected from the two LD lights LD1 and LD2 are detected. And S _LD2 can also be detected by lock-in detection based on the light intensity fluctuation waveforms (sine waves) of LD1 and _LD2 , respectively. Thereby, measurement with higher sensitivity can be performed, and the phase shift amount φ between the photoacoustic signal intensities S _LD1 and S _LD2 can be detected. Since the phase shift amount φ detected at this time is a phase shift specific to the photoacoustic signal generated by the LD 2 in the sample to be measured, an energy conversion process into a photoacoustic signal specific to the LD 2 is detected. Using this, photoacoustic spectrum analysis can be performed on the sample to be measured.

Hereinafter, the component concentration analysis method according to the present embodiment will be described with reference to FIG. First, the light intensity change rate δα of the light absorption coefficient of the specific component in the object to be measured is measured with respect to the light intensity changes of the light wavelengths λ _A and λ _B having different light wavelengths.

First, in order to obtain the light intensity change rate δα _A of the light absorption coefficient of the specific component in the object to be measured with respect to the light intensity change of the light A, a standard sample having a known concentration of the specific component and a light absorption coefficient of the solvent is prepared. The light A is irradiated (step S101). Then, the light intensity of the light A is swept, and the light intensity dependence of the photoacoustic signal intensity _SAG of the specific component of the light A is measured (step S102). From this measurement result, the light intensity change rate δα _A of the light absorption coefficient of the light _A is calculated from the photoacoustic signal intensity S _AG of the specific component of the light _A (step S103).

Subsequently, in order to obtain the light intensity change rate δα _B of the light absorption coefficient of the specific component in the object to be measured with respect to the light intensity change of the light B, a standard sample whose concentration of the specific component and the light absorption coefficient of the solvent are known is prepared. Then, the light B is irradiated (step S104). Then, the light intensity of the light B is swept, and the light intensity dependency of the photoacoustic signal intensity _SBG of the specific component of the light B is measured (step S105). From this measurement result, the light intensity change rate δα _B of the light absorption coefficient of the light _B is calculated from the photoacoustic signal intensity S _BG of the specific component of the light _B (step S106).

  Next, the process proceeds to measurement of an object to be measured. For example, using a component concentration measuring apparatus as shown in FIG. 13, the light to be measured is alternately irradiated with two light A and light B having a phase difference of 180 ° at the frequency ω (step S107). At this time, since the frequency ω is the frequency of the photoacoustic signal intensity S, it is desirable that the frequency ω be a frequency band that can be detected by the sonic electric transducer 111 such as a microphone or a piezoelectric element. Specifically, it is desirable that it is 20 KHz or less.

First, while adjusting one light B so as to have a constant light intensity P _B , the light intensity of the light A is swept to measure the light intensity dependency of the photoacoustic signal intensity S _A of the object to be measured (step). S108). From this measurement result, after the time variation of the photoacoustic signal intensity S _A Fourier transform photoacoustic signal intensity of the frequency omega S _A (omega) and the second harmonic frequency 2 [omega of the photoacoustic signal intensity S _A of (2 [omega) The light intensity dependency of each spectrum intensity is calculated (step S109). Then, the photoacoustic signal intensity S _A and intensity swept searches the maximum value of S _A (2 [omega) of size _{R = S A (2ω) /} S A (ω) with respect to S _A (omega), the light at that time A light intensity PA of _A is acquired (step S110).

Subsequently, the measurement is returned to the initial state, and the two light A and light B are combined in the opposite phase with each other at the frequency ω, and irradiated on the object to be measured (step S111). The light intensity of the photoacoustic signal intensity S _A 'relating to the object to be measured is changed by sweeping the light intensity of the light A while keeping the light intensity of the light B constant while increasing the light intensity to P _B ' = P _B + δP _B. Measure (Step S112). From this measurement result, the time change of the photoacoustic signal intensity S _A ′ is Fourier transformed, and then the fundamental wave photoacoustic signal intensity S _A ′ (ω) and the double wave photoacoustic signal intensity S _A ′ (2ω) are obtained. The light intensity dependency of each spectrum intensity is calculated (step S113). Then, the intensity of the photoacoustic signal intensity S _A ′ is swept, and the magnitude of S _A ′ (2ω) relative to S _A ′ (ω) R = S _A ′ (2ω) / S _A ′ (ω) The maximum value is searched, and the light intensity P _A ′ = P _A + δP _A of the light A at that time is acquired (step S114).

Finally, using the values of δα _A , δα _B , P _A , P _B , δP _A , and δP _B obtained so far, the concentration of the specific component in the object to be measured is derived (step S115).

DESCRIPTION OF SYMBOLS 101 Oscillator 102, 105 Drive circuit 103, 106 Light source 107 Optical multiplexer 108 Optical demultiplexer 109 Optical intensity measuring device 110 Device under test 111 Sound wave detector 112 Amplifier 113 Waveform observation device 114 Recording / calculation device

Claims (8)

Light output means for outputting two lights of different wavelengths, each of which is intensity-modulated by signals having opposite phases at the same frequency, and
Optical multiplexing means for multiplexing the two lights;
A light intensity measuring means for measuring the light intensity of the two lights;
A light irradiation means for irradiating the object to be measured with the combined light or only one light;
Sound wave detecting means for detecting sound waves generated inside the object to be measured by the irradiation;
Component concentration calculating means for calculating the concentration of the component to be measured in the object to be measured using a photoacoustic signal based on the magnitude of the detected sound wave;
The component concentration calculation means calculates a frequency spectrum by Fourier transforming the temporal change of the intensity of the photoacoustic signal, and scans the light at the frequency of the two lights while sweeping the intensity of one of the two lights. A frequency spectrum intensity ratio, which is the magnitude of the photoacoustic signal intensity at a frequency twice the frequency of the two lights with respect to the acoustic signal intensity, is calculated, and the light of the two lights having the maximum frequency spectrum intensity ratio A component concentration analyzer that calculates the concentration of the measurement target component based on intensity, a change amount of light intensity of the two lights, a light absorption coefficient, and a light absorption coefficient change rate.   2. The component concentration analyzer according to claim 1, wherein the modulated signal waveforms of light of two different wavelengths, which are intensity-modulated by signals having opposite phases at the same frequency, are trapezoidal waveforms or triangular waveforms.   2. The component concentration analyzer according to claim 1, wherein the modulated signal waveforms of light of two different wavelengths whose intensity is modulated by signals having opposite phases at the same frequency are sinusoidal waveforms. An optical output step for outputting two lights of different wavelengths, which are intensity-modulated by signals having opposite phases at the same frequency, and
A light combining step for combining the two lights;
A light intensity measurement step for measuring the light intensity of the two lights;
A light irradiation step of irradiating the object to be measured with the combined light or only one light; and
A sound wave detection step for detecting sound waves generated inside the object to be measured by the irradiation;
A component concentration calculating step for calculating the concentration of the component to be measured in the object to be measured using a photoacoustic signal based on the magnitude of the detected sound wave;
And the component concentration calculating step calculates a frequency spectrum by Fourier-transforming the time change of the intensity of the photoacoustic signal, and sweeps one of the two lights at an intensity at the frequency of the two lights. A frequency spectrum intensity ratio that is the magnitude of the photoacoustic signal intensity at a frequency twice the frequency of the two lights with respect to the photoacoustic signal intensity is calculated, and the two light beams having the maximum frequency spectrum intensity ratio are calculated. A component concentration analysis method comprising calculating a concentration of the measurement target component based on light intensity, a change amount of light intensity of the two lights, a light absorption coefficient, and a light absorption coefficient change rate.   5. The component concentration analysis method according to claim 4, wherein the modulated signal waveforms of light of two different wavelengths whose intensity is modulated by signals having opposite phases at the same frequency are trapezoidal waveforms or triangular waveforms.   5. The component concentration analysis method according to claim 4, wherein the modulated signal waveforms of light of two different wavelengths whose intensity is modulated by signals having opposite phases at the same frequency are sinusoidal waveforms.   The component concentration calculation step includes a step of deriving the light absorption coefficient change rate of the two lights using a standard sample whose concentration of the measurement target component and the light absorption coefficient of the solvent are known. The component concentration analysis method according to any one of claims 4 to 6.   In the component concentration calculation step, after adjusting the light intensity of the two lights so that the photoacoustic signal intensity becomes a minimum value, the concentration of the measurement target component is increased or decreased, and after the increase or decrease of the concentration of the measurement target component The component concentration according to any one of claims 4 to 7, further comprising a step of measuring a change amount of light intensity and a light absorption coefficient change rate of the two lights at which the photoacoustic signal intensity is a minimum value. Analysis method.

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