JP5647092B2 - Component concentration measuring method and apparatus - Google Patents

Description

  The present invention relates to a method and an apparatus for measuring a concentration of a component by a photoacoustic method, which can be applied to the measurement of the concentration of glucose present in blood plasma or the concentration of other components present in plasma.

In order to prevent diabetes, it is necessary to accurately measure the glucose concentration present in plasma. There is a photoacoustic method as a method for continuously monitoring the blood glucose level of a diabetic patient, which is summarized as follows.
(A) The photoacoustic method provides continuous blood glucose monitoring.
(B) It is painless for a diabetic patient, does not require a blood sample, and does not cause discomfort to the diabetic patient.
(C) Compared with other optical technologies, there is no deterioration in efficiency due to scattering media.
(D) High sensitivity characteristics can be obtained by combining optics and acoustics.

  There are two types of photoacoustic methods: a pulse method and a continuous-wave (hereinafter referred to as CW) method. The pulse method has a drawback that high optical power must be used to obtain high sensitivity. On the other hand, the CW method has a drawback that the signal intensity changes when the characteristic at the reflection surface changes, that is, there is no reproducibility. However, since high optical power may cause a problem in terms of safety for the human body, it is preferable to adopt the CW method (see Patent Document 1, Patent Document 2, and Patent Document 3). In the pulse method and the CW method, the component concentration is quantified by utilizing the fact that the amplitude of the acoustic wave is proportional to the component concentration.

JP 2008-125542 A JP 2008-125543 A JP 2008-145262 A

  In the conventional pulse method and CW method, during the measurement of glucose concentration in plasma several times, it is highly possible that other plasma parameters other than the glucose concentration (for example, body temperature, concentration of other components, etc.) will also change. There was a problem that glucose selectivity was poor and it was difficult to obtain an accurate glucose concentration.

  The present invention has been made to solve the above problems, and an object of the present invention is to provide a component concentration measuring method and apparatus capable of measuring a component concentration such as blood glucose concentration with high accuracy.

The component concentration measuring method of the present invention includes M (M is an integer of 2 or more) unknown parameters consisting of (M-1) component concentrations Ca, Cb, Cc,. Light is irradiated to the object to be measured using one light irradiation means among n light irradiation means (n is an integer satisfying (n (n-1) / 2 + 1)> = M) having different wavelengths. The first measurement step for obtaining the measurement result by the frequency shift (FS) method and all the combinations of two light irradiation means that can be selected from the n light irradiation means are used for the object to be measured. The second measurement step of irradiating the light and obtaining a measurement result by an optical power balance shift (OPPBS) method, the measurement result of the first measurement step, and the measurement result of the second measurement step, Concentration derivation that determines the concentration of the component in the measurement object The concentration derivation step includes FS (λ1) as the measurement result of the first measurement step, OPBS (λ1, λ2), OPBS (λ1, λ3) as the measurement result of the second measurement step, When OPBS (λ1, λ4),..., OPBS (λn-1, λn) (λ1, λ2, λ3, λ4,..., Λn-1, λn are emitted from n light irradiation means. Wavelength), an expression FS (λ1) = KaCa + KbCb + KcCc +... + KtT expressing the measurement result of the first measurement step, and an expression OPBS (λ1, λ2) expressing the measurement result of the second measurement step. _{= Qa λ1, λ2 Ca + Qb} λ1, λ2 Cb + Qc λ1, λ2 Cc + ··· + Qt λ1, λ2 T, OPBS (λ1, λ3) = Qa λ1, λ3 Ca + Qb λ1, λ3 Cb + Qc λ1, λ3 Cc + ··· + Qt λ1, λ3 T, OPBS _{λ1, λ4) = Qa λ1,} λ4 Ca + Qb λ1, λ4 Cb + Qc λ1, λ4 Cc + ··· + Qt λ1, λ4 T, ··· OPBS (λn-1, λn) = Qa λn-1, λn Ca + Qb λn-1, _{λn Cb + Qc λn-1,} λn Cc + ··· + Qt λn-1, simultaneous equations (Ka consisting of _{λn T, Kb, Kc, ···} , Kt, Qa λi, λj, Qb λi, λj, Qc λi, λj ,..., Qt _{λi, λj} (where i, j = 1 to n, i ≠ j) is a predetermined coefficient), the concentrations of components Ca, Cb, Cc,. The step of determining the concentration Ca is a blood glucose concentration .

  Further, in one configuration example of the component concentration measurement method of the present invention, the first measurement step includes a first light irradiation step of irradiating light to the object to be measured, and the first light irradiation step. A first photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured and outputting an electric signal, and an amplitude of the electric signal obtained in the first photoacoustic signal detection step is maximum. A first phase measurement step for measuring the phase of the measurement signal, and a second light irradiation step for irradiating the object to be measured after an arbitrary time; Obtained by a second photoacoustic signal detection step of detecting a photoacoustic signal generated from the object to be measured by the second light irradiation step and outputting an electric signal, and the second photoacoustic signal detection step Telegraph Of the reference frequency as a measurement signal, the second phase measurement step for measuring the phase of the measurement signal, and the phase measured at the second phase measurement step were measured at the first phase measurement step. A frequency search step for searching for the frequency of the measurement signal equal to the phase, and a frequency change derivation step for obtaining a change amount between the frequency searched in the frequency search step and the reference frequency as a measurement result of the first measurement step; It is characterized by including.

In one configuration example of the component concentration measurement method of the present invention, the second measurement step includes a third light irradiation step of irradiating the object to be measured with intensity-modulated light, and the third light irradiation. A third photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured in a step and outputting an electric signal; and an amplitude of the electric signal obtained in the third photoacoustic signal detection step is maximum. A first frequency measurement step for measuring the modulation frequency as a first frequency, a third phase measurement step for measuring the phase of the electrical signal when the amplitude is maximum as a reference phase, Wave light is intensity-modulated with signals having the first frequency and different phases, and the object to be measured is irradiated, and the optical power of at least one of the two intensity-modulated lights is gradually changed. And a fourth photoacoustic signal detecting step for detecting a photoacoustic signal generated from the object to be measured by the fourth light irradiating step and outputting an electrical signal. A fourth phase measurement step for searching for a first inflection point where the phase of the electrical signal obtained in the photoacoustic signal detection step is 0; and optical powers of the two intensity-modulated lights at the first inflection point A first light power measuring step for measuring the difference between the first and second objects, a fifth light irradiating step for irradiating the measured object with intensity-modulated light after a lapse of an arbitrary time, and the fifth light irradiating step. A fifth photoacoustic signal detection step for detecting a photoacoustic signal generated from the measurement object and outputting an electric signal, and the phase of the electric signal obtained in the fifth photoacoustic signal detection step becomes the reference phase. Modulation frequency is 2nd A second frequency measurement step for searching as a frequency, and two light beams having different wavelengths are intensity-modulated by signals of the second frequency and different phases, respectively, and irradiated on the object to be measured; A sixth light irradiation step for gradually changing the optical power of at least one of the light intensity-modulated light, and a photoacoustic signal generated from the object to be measured by this sixth light irradiation step to output an electrical signal A sixth photoacoustic signal detecting step, a fifth phase measuring step for searching for a second inflection point where the phase of the electrical signal obtained in the sixth photoacoustic signal detecting step is 0, A second optical power measurement step for measuring the optical power difference between the two intensity-modulated lights at the second inflection point; the optical power difference measured in the second optical power measurement step; and the first light power An optical power change deriving step that obtains the amount of change from the difference in optical power measured in the measuring step as a measurement result of the second measuring step, and can be selected from the n light irradiation means For each combination of light irradiation means, the third light irradiation step, the third photoacoustic signal detection step, the first frequency measurement step, the third phase measurement step, and the fourth light irradiation step, The fourth photoacoustic signal detection step, the fourth phase measurement step, the first optical power measurement step, the fifth light irradiation step, the fifth photoacoustic signal detection step, and the second frequency Measurement step, sixth light irradiation step, sixth photoacoustic signal detection step, fifth phase measurement step, second optical power measurement step, and optical power change derivation A step conducted, is characterized in that to obtain a measurement result of the second measurement step for each combination of the two light irradiation means.
In one configuration example of the component concentration measuring method of the present invention, n in the n light irradiation means is an integer satisfying (n (n−1) / 2 + 1)> M.

In addition, the component concentration measuring apparatus according to the present invention has M (M is an integer of 2 or more) unknown parameters including (M-1) component concentrations Ca, Cb, Cc,. A light irradiating means for irradiating the object to be measured with light; a photoacoustic signal detecting means for detecting a photoacoustic signal generated from the object to be measured by the light irradiation and outputting an electrical signal; and the object to be measured. On the other hand, light is emitted from one of the light irradiating means among n (n is an integer satisfying (n (n-1) / 2 + 1)> = M) having different wavelengths, and the frequency The first measurement means that obtains a measurement result based on the electrical signal by the shift (FS) method and all combinations of two light irradiation means that can be selected from the n light irradiation means. Light is irradiated to the measurement object, and the optical power balance shift (O A second measurement means for obtaining a measurement result based on the electric signal by the BS) method; a measurement object in the object to be measured from the measurement result of the first measurement means and the measurement result of the second measurement means; Concentration derivation means for determining the concentration of the components of the first measurement means, the concentration derivation means FS (λ1) as the measurement result of the first measurement means, and OPBS (λ1, λ2) as the measurement result of the second measurement means. ), OPBS (λ1, λ3), OPBS (λ1, λ4),..., OPBS (λn-1, λn) (λ1, λ2, λ3, λ4,..., Λn-1, λn are (wavelength of light emitted from n light irradiation means), the expression FS (λ1) = KaCa + KbCb + KcCc +... + KtT expressing the measurement result of the first measurement means, and the measurement result of the second measurement means Expression OPBS (λ1, λ2) = Qa _{λ1, λ2 Ca + Qb λ1, λ2 Cb +} Qc λ1, λ2 Cc + ··· + Qt λ1, λ2 T, OPBS (λ1, λ3) = Qa λ1, λ3 Ca + Qb λ1, λ3 Cb + Qc λ1, λ3 Cc + ··· + Qt λ1, λ3 T, OPBS (λ1 _{, λ4) = Qa λ1, λ4} Ca + Qb λ1, λ4 Cb + Qc λ1, λ4 Cc + ··· + Qt λ1, λ4 T, ··· OPBS (λn-1, λn) = Qa λn-1, λn Ca + Qb λn-1, λn Cb + Qc _{λn-1, λn} Cc +... + Qt _{λn-1, λn} T and simultaneous equations (Ka, Kb, Kc,..., Kt, Qa _{λi, λj} , Qb _{λi, λj} , Qc _{λi, λj} , _.. , Qt _{λi, λj} (i, j = 1 to n, i ≠ j) is a predetermined coefficient), the concentrations of the components in the object to be measured are Ca, Cb, Cc,. The concentration Ca is a blood glucose concentration .

  Further, in one configuration example of the component concentration measuring apparatus according to the present invention, the first measuring unit includes a first phase measuring unit that measures the phase of the measurement signal included in the electrical signal, and an arbitrary time elapsed. A frequency search means for searching for a frequency of the measurement signal; and a frequency change deriving means for obtaining a change amount of the frequency of the measurement signal after elapse of an arbitrary time as a measurement result of the first measurement means, One light irradiating means among the n light irradiating means irradiates light to the object to be measured at a first time, and irradiates light to the object to be measured after an arbitrary time has elapsed. The first phase measuring means measures a phase of the measurement signal using a signal of a reference frequency having the maximum amplitude among the electrical signals obtained at the first time, and measures the phase of the arbitrary signal. Electricity after time The signal of the reference frequency of the signal is used as a measurement signal, and the phase of the measurement signal is measured. The frequency search means is configured such that the phase measured after the lapse of the arbitrary time is the phase measured at the first time. Searching for equal frequency of the measurement signal, the frequency change deriving means obtains a change amount between the frequency searched by the frequency searching means and the reference frequency as a measurement result of the first measuring means. To do.

  Further, in one configuration example of the component concentration measuring apparatus of the present invention, the second measuring means includes an optical power control means for controlling optical power, a frequency measuring means for measuring the frequency of the electric signal, and the electric signal. A second phase measuring means for measuring the phase of the optical power, an optical power measuring means for measuring the difference between the optical powers of the two intensity-modulated lights, and a change amount of the optical power after an arbitrary time elapses. Optical power change deriving means obtained as a measurement result of the means, wherein the light irradiating means irradiates the device under test with intensity-modulated light at a first time, and has two different wavelengths at a second time. Wave light is intensity-modulated by signals having a first frequency and different phases, and the object to be measured is irradiated to the object to be measured, and the object to be measured is irradiated with intensity-modulated light at a third time. Different from each other in time The two light waves having the wavelengths are intensity-modulated with signals of the second frequency and different phases, respectively, and irradiate the object to be measured, and the optical power control means has two intensities at the second and fourth times. The optical power of at least one intensity-modulated light of the modulated light is gradually changed, and the frequency measuring means uses the modulation frequency that maximizes the amplitude of the electrical signal obtained at the first time as the first frequency. The second frequency measurement means is obtained at the first time by measuring and searching for the modulation frequency at which the phase of the electrical signal obtained at the third time becomes a reference phase as the second frequency. Measuring the phase of the electrical signal when the amplitude of the electrical signal is maximum as the reference phase, searching for a first inflection point where the phase of the electrical signal obtained at the second time is 0, and At the fourth time The second inflection point at which the phase of the electrical signal obtained in this way becomes 0 is searched, and the optical power measurement means is configured to detect the light of the two intensity-modulated lights at the first inflection point at the second time. A power difference is measured, a difference in optical power between the two intensity-modulated lights at the second inflection point is measured at the fourth time, and the optical power change deriving means is measured at the fourth time. The amount of change between the measured optical power difference and the optical power difference measured at the second time is obtained as a measurement result of the second measuring means, and is selected from the n light irradiation means. A measurement result is obtained by performing measurement for each combination of two obtained light irradiation means.

  According to the present invention, the first measurement step for obtaining the measurement result by the frequency shift (FS) method and the second measurement step for obtaining the measurement result by the optical power balance shift (OPPBS) method are performed, and the first measurement step is performed. By determining the concentration of the component of the measurement target in the measurement object from the measurement result of the measurement step and the measurement result of the second measurement step, the selectivity of the measurement target can be improved, and a plurality of different substances can be obtained. It is possible to measure the concentration of a component to be measured, such as glucose, with high accuracy in a multi-component measurement object. In the OPBS method, by appropriately selecting the wavelengths of the two intensity-modulated lights, it is possible to cause a difference between different substances in the gradient of the relationship between the concentration and the optical power. Therefore, the selectivity of the measurement target can be improved by appropriately selecting the light wavelength so that the sensor response to the specific measurement target is maximized.

  In the present invention, the calculation accuracy and convergence of the simultaneous equations are improved when (n (n-1) / 2 + 1)> M rather than (n (n-1) / 2 + 1) = M.

It is a figure which shows the relationship between the amplitude of the measurement signal output from an acoustic sensor, and blood glucose concentration. FIG. 6 shows the change in measurement signal at two different blood glucose concentrations. It is a block diagram which shows the structure of the component concentration measuring apparatus which concerns on embodiment of this invention. It is a block diagram which shows the structure of the information processing apparatus of the component concentration measuring apparatus which concerns on embodiment of this invention. It is a flowchart which shows operation | movement of the component concentration measuring apparatus which concerns on embodiment of this invention. It is a flowchart which shows the operation | movement at the time of the measurement by the FS method of the component concentration measuring apparatus which concerns on embodiment of this invention. It is a figure explaining a mode that an acoustic wave is generated by two light of a different wavelength. It is a figure which shows the amplitude and phase of a photoacoustic signal when optical power is changed when the blood glucose concentration of a to-be-measured object is a reference blood glucose concentration. It is a figure which shows the amplitude and phase of a photoacoustic signal when optical power is changed when the blood glucose concentration and albumin concentration of a to-be-measured object change. It is a flowchart which shows the operation | movement at the time of the measurement by the OPBS method of the component concentration measuring apparatus which concerns on embodiment of this invention. It is a figure which shows an optical power balance-phase characteristic.

[Principle of the Invention]
In the present invention, in order to accurately measure blood glucose concentration, light is a new component concentration measuring method that improves glucose selectivity according to the light wavelength by utilizing the principle that the amplitude of the photoacoustic signal depends on the light absorption coefficient. A power balance shift (Optical Power Balance Shift, hereinafter abbreviated as OPBS) method will be described first.

The OPBS method searches for the inflection point of the phase where the amplitude of the photoacoustic signal is minimal while increasing or decreasing the power of two light beams with different optical wavelengths and a phase difference of π, and dissolves it in the blood from the result. It is a method to measure the concentration of molecules. This method can be expanded to detect not only glucose components in plasma but also other plasma components (such as albumin and cholesterol).
The following theoretical formula is used to explain the concept of the detection method. The photoacoustic signal intensity S can be expressed as:

Here, K is a constant, β is a coefficient of thermal expansion of the object to be measured, v is a sound velocity, n is an experimental system parameter depending on the setup, C _p is a specific heat of the object to be measured, α is a light absorption coefficient of the object to be measured, P is the optical power.
Further, when two differential signal settings are used, the photoacoustic signal intensity S can be expressed by the following equation.

In Equation (2), P ₁ and P ₂ are optical powers, and α ₁ and α ₂ are optical absorption coefficients of the object to be measured for light having optical powers P ₁ and P ₂ , respectively.
The problem is that parameters such as constant K, thermal expansion coefficient β, sound velocity v, and specific heat C _p depend on temperature or the concentration of the mixture, so that the photoacoustic signal intensity S cannot be used directly for the calculation of blood glucose concentration. It is. In order to suppress such dependency, in the measurement method disclosed in Patent Document 1, normalization is performed with a signal of one wavelength.

On the other hand, in the OPBS method, the optical power P ₁ with the lowest photoacoustic signal intensity S is searched for while changing the power (for example, P ₁ ) of one of the two optical beams. Theoretically, the minimum value of the photoacoustic signal intensity S is 0. However, since there is noise experimentally, it does not become 0. The photoacoustic signal intensity S at this time is approximately 100 times smaller than the photoacoustic signal intensity when a one-wavelength light beam is used. For the sake of simple explanation, here, the noise is ignored and the photoacoustic signal intensity S is set to zero. When S = 0, a new theoretical formula can be written as
α ₁ P ₁ −α ₂ P ₂ = 0 (3)

When the concentration of the component to be measured is changed, for example, the blood glucose concentration is changed by C _{g, and the} light absorption coefficients α ₁ and α ₂ are changed by δα ₁ and δα ₂ due to the change in concentration, respectively, Equation (3) is It changes from the established state to the state of Equation (4).
(Α ₁ + δα ₁ C _g ) P ₁ − (α ₂ + δα ₂ C _g ) P ₂ ≠ 0 (4)

When the power (for example, P ₁ ) of _one light beam is changed to return to the state of S = 0, the following equation is established.
(Α ₁ + δα ₁ C _g ) (P ₁ + δP ₁ ) − (α ₂ + δα ₂ C _g ) P ₂ = 0 (5)
The following equation is obtained from equation (5).

In equations (5) and (6), δP ₁ is the amount of change in the optical power P ₁ . From equation (6), it can be seen that in the present invention, the blood glucose concentration can be measured from the optical power variation δP ₁ , the known optical absorption coefficients α ₁ and α _2, and the optical absorption coefficient variations δα ₁ and δα _2. . The above is the principle of the OPBS method.

  However, unless it is assumed that all parameters other than glucose, such as temperature and albumin concentration, are maintained at a constant level during the measurement, the correct glucose concentration cannot be measured only by the two-wavelength OPBS method. However, in continuous glucose concentration monitoring, this assumption changes in a short time. Therefore, the two-wavelength OPBS method needs to increase the number of wavelengths or be combined with another method having a specific response to the mixed substance. Therefore, in the present invention, a frequency shift (Frequency Shift, hereinafter abbreviated as FS) method based on a change in sound speed due to the component concentration is combined with the OPBS method. The response of the OPBS method depends on the two light wavelengths used. Therefore, the signal response is measured by the FS method, and further, the signal response of the OPBS method is measured by using several pairs of optical wavelengths.

  Hereinafter, the FS method will be described. FIG. 1 shows the relationship between the amplitude of the measurement signal output from the acoustic sensor and the blood glucose concentration. Here, when a human body or an object to be measured that is a part of the human body is irradiated with light, the photoacoustic signal generated from the object to be measured by the photoacoustic effect is detected by the acoustic sensor, and the electrical signal output from the acoustic sensor (Measurement signal) is obtained. In FIG. 1, reference numerals 100, 101, 102, and 103 denote characteristics when the frequency of the measurement signal is 479 kHz, 480 kHz, 481 kHz, and 482 kHz, respectively.

  In the case where a measurement signal having an arbitrary fixed frequency is used for measurement of blood glucose concentration as in the prior art, as shown in FIG. 1, measurement sensitivity of blood glucose concentration and measurement signal amplitude-blood glucose concentration characteristics The linearity of depends strongly on the frequency of the measurement signal. That is, the response of the acoustic sensor is strongly different depending on the selected frequency of the measurement signal. Although the result of FIG. 1 is a result obtained with only one light wavelength, the same phenomenon always appears when the CW method is adopted.

  The FS method is characterized in that a function generator is newly used as means for adjusting the frequency of the measurement signal. The function generator preferably generates a reference signal with a frequency of up to 1 MHz and has a high frequency accuracy on the order of mHz.

  Next, when the blood glucose concentration changes with time, the measurement signal changes as follows. FIGS. 2A and 2B show changes in measurement signals at two different blood glucose concentrations Ow and Og. 2A and 2B, reference numeral 200 indicates the characteristic of the measurement signal in the case of the blood glucose concentration Ow, and reference numeral 201 indicates the characteristic of the measurement signal in the case of the blood glucose concentration Og.

  Regarding the amplitude information of the measurement signal, the amplitude peak frequency shifts by Δf and the amplitude peak value shifts by ΔV in accordance with the change in blood glucose concentration. When the blood glucose concentration increases with time, the peak frequency shifts to the high frequency side, and when the blood glucose concentration decreases, the peak frequency shifts to the low frequency side. Δf depends on the optical wavelength.

  On the other hand, the phase information of the measurement signal shifts along the frequency axis according to the change in blood glucose concentration. When the blood glucose concentration decreases with the passage of time, the phase information shifts to the low frequency side, and when the blood glucose concentration increases, the phase information shifts to the high frequency side.

Thus, the change in glucose concentration has the effect of causing two shifts. That is, there is an effect of shifting along the X axis (frequency) appearing in both the amplitude and phase, and an effect of shifting along the Y axis (amplitude) appearing only in the amplitude. While it is difficult to distinguish between the two shifts in the amplitude information, the phase information undergoes only a frequency shift.
Therefore, in the FS method, the amount of change in the frequency of the measurement signal is obtained based on the phase information of the measurement signal, and the blood glucose concentration is accurately measured from the amount of change in the frequency.

  Next, the measurement procedure of the FS method will be described. First, in the first measurement, when a laser beam is irradiated on the object to be measured and a photoacoustic signal generated from the object to be measured is detected by the photoacoustic effect by the acoustic sensor, a wide frequency measurement span of the acoustic sensor (for example, 200 The photoacoustic signal is measured in the range of -600 kHz.

Due to multiple reflection of the photoacoustic signal, a plurality of peaks appear in the amplitude information of the measurement signal output from the acoustic sensor. One of these peaks is selected to determine the frequency of the reference signal generated from the function generator near the frequency of the selected peak. This peak frequency is called a reference frequency f ₀ . Here, important parameter is the phase P ₀ of the measurement signal in the amplitude A ₀ and the reference frequency f ₀ of the measurement signal at the reference frequency f _0. At this time, in order to set the phase P _{0 of the} measurement signal to 0, it is preferable to add an offset to the phase of the laser light applied to the object to be measured as described later. Then, the amplitude A ₀ , the phase P ₀ (P ₀ = 0), and the frequency f ₀ are recorded.

Here, since the true glucose concentration value is not known, at the same time, a standard measurement is performed to confirm the blood glucose concentration to obtain a reference concentration G ₀ (g / dl). Thus, the amplitude A ₀ and the phase P ₀ (P ₀ = 0) at the reference frequency f ₀ are obtained at the reference density G ₀ (g / dl).

Next, measurement at the reference frequency f ₀ is performed at time t after an arbitrary time has elapsed. Since the phase of the measurement signal is set to 0 at the reference frequency f ₀ , the phase P ₁ of the measurement signal at the reference frequency f ₀ is not 0 if the glucose concentration changes to G ₁ (g / dl) at time t. . Here, when the phase P ₀ phase P ₁ is large means that it should increase the frequency of the measurement signal, when the phase P ₁ with respect to the phase P ₀ is small should reduce the frequency of the measurement signal It means that. Therefore, the measurement frequency is changed by the function generator so that the phase P ₁ of the measurement signal at time t becomes equal to P ₀ (here, 0). Let f ₁ be the frequency at which phase P ₁ is equal to P ₀ . Then, the amplitude A ₁ and phase P ₁ (P ₁ = P ₀ = 0) of the measurement signal at the frequency f ₁ are recorded.

The frequency change rate Δf / f = (f ₁ −f ₀ ) / f ₀ of the measurement signal accompanying the change of the glucose concentration is the rate of change of the sound velocity Δv / v = (v (G ₁ ) −v (G ₀ )) / v (G ₀ ). Here, v (G ₀ ) is the speed of sound at the glucose concentration G ₀ (g / dl), and v (G ₁ ) is the speed of sound at the glucose concentration G ₁ (g / dl). As described later, the blood glucose concentration can be estimated from the frequency change rate Δf / f of the measurement signal.

  When the blood glucose concentration is estimated using the speed of sound, this estimation process is not affected by the size of the resonance cavity or the resonance mode. Although the optical wavelength is related to the size of the resonance cavity and the resonance mode, the optical wavelength can be freely selected for some specific purpose.

  The selection of the optical wavelength will be described. Measurement of blood glucose concentration using the speed of sound is an effective measurement method, but a change in plasma components is likely to lead to a change in sound speed. In the technique disclosed in US Pat. No. 5,191,819 (GHThomas et al., “Method and apparatus for non-invasive monitoring of blood glucose”, 1992), the concentration of plasma components other than glucose slowly changes. During this period, it is assumed that the other components are at a constant concentration level. This assumption may be valid for short-time measurements. However, when the blood glucose concentration is continuously monitored as in the present invention, the drift (the frequency of the measurement signal caused by other influences other than the glucose concentration change) is considered. (Shift) is likely to occur. The present invention proposes the following two approaches for solving this drift problem.

(A) In order to correct the drift, the blood glucose concentration is measured periodically (every several hours) by a standard measurement method, and the component concentration measuring device is readjusted according to the new value of the blood component.
(B) Carefully select the optical wavelength to use the amplitude signal and simultaneously detect plasma components.

  In the present invention, calibration measurement is periodically required. However, since this calibration is not required several times per day, the method (B) is preferable. The method of (B) is similar to the technique disclosed in US Pat. No. 4,506,543 (AJKamp et al., “Analysis of salt concentrations”, 1985). Measurements can be made simultaneously.

In the method described above, only phase information such as P ₁ and P ₀ is considered. However, the amplitude A ₀ of the measurement signal the blood glucose concentration at the frequency f ₀ when the known, the comparison between the amplitude A ₁ of the measurement signal at the frequency f _1, the difference in signal intensity due to the change of the main absorption of light The concentration can be measured from

  For example, let us consider the case of an object to be measured in which two compounds a and b are mixed. Compounds a and b affect the sound speed parameter. However, if an optical wavelength is selected in which the two compounds a and b exhibit different light absorption ratios, two equations having two unknown parameters of the concentrations of the compounds a and b can be obtained. One equation is the difference in sound speed between the first time and the second time, and the other equation is the difference in signal amplitude between the first time and the second time. It is an equation. Assuming that all other compounds are at a constant concentration, the concentrations of compounds a and b can be clearly determined.

  In the case of an object to be measured in which three compounds a, b, and c are mixed, two different optical wavelengths are required. Measuring the phase gives the same result as yielding only one equation when using two optical wavelengths. However, two more equations can be obtained by choosing two optical wavelengths where the three compounds a, b and c exhibit different light absorption ratios.

  Thus, if n optical wavelengths are used, the concentration of (n + 1) compounds can be measured. However, this measurement is limited to when the measurement time is short enough to guarantee a constant concentration of all compounds.

Next, it will be described that the change in frequency of the measurement signal associated with the change in glucose concentration is related to the change in sound speed of the photoacoustic signal associated with the change in glucose concentration. A plurality of peaks appear in the electrical signal obtained by the acoustic sensor when the object to be measured is irradiated with light. This peak is due to confinement of photoacoustic energy in a small space. The resonance mode is formed by a plurality of reflections. First, as a model of a space in which photoacoustic energy is confined, two planes parallel to each other and infinitely long are used. The distance between the two planes is L. Under this simple condition, the following equation holds.
L = (nλ) / 2 (7)

Here, n is a positive integer and λ is the wavelength of the acoustic signal. When the velocity of the acoustic signal is v _ac and the resonance frequency of the nth mode is f, the wavelength λ of the acoustic signal is expressed by the following equation.
λ = v _ac / f (8)

From the equations (7) and (8), the following equation is obtained.
f = (nv _ac ) / 2L (9)
From Equation (9), it can be seen that the resonance frequency f is proportional to the velocity v _{ac of the} acoustic signal.

When the lateral confinement is introduced, the resonance frequency f _j can be expressed as follows only when the space in which the photoacoustic energy is confined is a cylindrical cavity.

Here, j = (nmq), and n, m, and q are the radial azimuth, azimuth, and longitudinal mode numbers, respectively. R is the radius of the cylinder and L is the length of the cylinder. α _mn is the (n + 1) th root of the equation.

In Expression (11), J _m is an m-th order Bessel function. When m = n = 0, f _00q is the resonance frequency of the qth longitudinal mode. The important fact is that the resonance frequency f of the acoustic signal depends linearly on the velocity v _{ac of the} acoustic signal. That is, as a result of the change in the velocity v _ac of the acoustic signal, a change occurs in the resonance frequency f of the acoustic signal, so that the following relationship is obtained.
Δf / f = Δv _ac / v _ac (12)

The velocity v _{ac of the} acoustic signal and the glucose concentration are in a linear relationship. Further, since the change in the velocity v _ac of the acoustic signal and the change in the resonance frequency f have the relationship shown in the equation (12), it can be seen that the change in the glucose concentration linearly leads to the change in the frequency of the acoustic signal. . Thus, in the FS method, the glucose concentration is derived from the change in the frequency of the measurement signal.

[Embodiment]
Hereinafter, embodiments of the present invention will be described with reference to the drawings. FIG. 3 is a block diagram showing the configuration of the component concentration measuring apparatus according to the embodiment of the present invention.
The component concentration measuring apparatus includes laser diodes 1-1, 1-2, 1-3, 1-4,..., 1-n and laser diodes 1-1 and 1 serving as light irradiation means for irradiating laser light. .., 1-n, and laser diodes 1-1, 1-2, 1-3, 1-4,. , 3-n for guiding laser light emitted from n, and laser diodes 1-1, 1-2, 1-3, 1-4,..., 1-n, an optical coupler 4 for combining the laser light, an optical fiber 5 for guiding the laser light combined by the optical coupler 4, and an object to be measured 13 (solvent). Generated from the object to be measured 13 due to the photoacoustic effect. A photoacoustic signal is detected and converted into an electrical signal proportional to sound pressure, an acoustic sensor 8 serving as a photoacoustic signal detection means, an amplifier 9 for amplifying the electrical signal output from the acoustic sensor 8, and a reference signal are generated. A function generator 10, a lock-in amplifier 11 for receiving a measurement signal of a desired frequency from the output signal of the amplifier 9 with the output signal of the amplifier 9 and the reference signal output from the function generator 10 as inputs, and a function From the information processing apparatus 12 including a computer that controls the generator 10 and the lock-in amplifier 11 and processes the measurement signal detected by the lock-in amplifier 11 to determine the concentration of the component to be measured in the DUT 13. Composed.

  Examples of the laser diodes 1-1, 1-2, 1-3, 1-4,..., 1-n include, for example, a distributed feedback semiconductor laser (DFB-LD). The wavelengths of light emitted from the laser diodes 1-1, 1-2, 1-3, 1-4,. An example of the acoustic sensor 8 is a microphone.

  FIG. 4 is a block diagram showing the configuration of the information processing apparatus 12. The information processing apparatus 12 includes a function generator control unit 120 that controls the function generator 10, an amplitude measurement unit 121 that measures the amplitude of the measurement signal, a phase measurement unit 122 that measures the phase of the measurement signal, and a phase offset A phase offset adjustment unit 123 that adjusts the amplitude, phase and frequency information of the measurement signal, or an information recording unit 124 that records frequency and phase information of the measurement signal, and a frequency shift calibration unit that calibrates the frequency shift of the measurement signal 125, a frequency change rate deriving unit 126 for deriving a frequency change rate of the measurement signal, a frequency measuring unit 127 for measuring the frequency of the measurement signal, an optical power control unit 128 for controlling the optical power, and two intensity modulations An optical power measurement unit 129 for measuring the difference in optical power of light, an optical power change amount deriving unit 130 for deriving a change amount of the optical power, a measurement result by the FS method, Having a concentration derivation section 131 for determining the component concentration of the measurement object from the measurement result by PBS method, and a storage unit 132 for information storage. The function generator control unit 120 constitutes frequency search means.

Hereinafter, the operation of the component concentration measuring apparatus according to the present embodiment will be described. FIG. 5 is a flowchart showing the operation of the component concentration measuring apparatus.
The component concentration measuring apparatus first performs measurement by the FS method (step S1 in FIG. 5), then performs measurement by the OPBS method (step S2), and determines the measurement target from the measurement result by the FS method and the measurement result by the OPBS method. The component concentration is determined (step S3).

  Hereinafter, the measurement by the FS method will be described in detail. FIG. 6 is a flowchart showing an operation at the time of measurement by the FS method of the component concentration measuring apparatus. Since measurement is performed at one wavelength in the FS method, only one laser diode is used. Here, the laser diode 1-1 is used.

  The device under test 13 is introduced into the photoacoustic cell 6. When a drive current is supplied from the laser driver 2, the laser diode 1-1 emits laser light. Similar to the conventional CW method, the laser light emitted from the laser diode 1-1 is a continuous wave. This laser light is guided by the optical fiber 3-1, passes through the optical coupler 4, is further guided by the optical fiber 5, and irradiates the object to be measured 13 in the photoacoustic cell 6 through the optical window 7 ( FIG. 6 step S100).

  The acoustic sensor 8 detects a photoacoustic signal generated from the device under test 13, and the amplifier 9 amplifies the electrical signal output from the acoustic sensor 8. The lock-in amplifier 11 detects a measurement signal having a frequency determined by the reference signal output from the function generator 10 among the signals included in the output of the amplifier 9.

  The function generator control unit 120 of the information processing apparatus 12 performs frequency sweep that gradually changes the frequency of the measurement signal detected by the lock-in amplifier 11 by changing the frequency of the reference signal generated by the function generator 10 ( FIG. 6 step S101). In this way, the resonance peak of the measurement signal is searched.

Next, when the amplitude peak of the measurement signal is found, the amplitude measurement unit 121 of the information processing apparatus 12 measures the amplitude A ₀ of the measurement signal at the frequency of this peak (reference frequency f ₀ ) (step in FIG. 6). (S103), the phase measurement unit 122 measures the phase P ₀ of the measurement signal at the reference frequency f ₀ (step S104).

Prior to such measurement, the phase offset adjustment unit 123 of the information processing apparatus 12 controls the laser driver 2 through the lock-in amplifier 11, and changes the phase of the drive current supplied from the laser driver 2 to the laser diode 1-1. It is preferable to set the phase P ₀ of the measurement signal to 0 by changing the phase of the laser beam irradiated to the object 13 to be measured (step S102 in FIG. 6).

The information recording unit 124 stores the amplitude A ₀ measured by the amplitude measuring unit 121, the phase P ₀ (P ₀ = 0) measured by the phase measuring unit 122, and the peak frequency (reference frequency f ₀ ). (Step S105 in FIG. 6).

  Next, measurement at time t after an arbitrary time has elapsed from the first measurement in steps S100 to S105 will be described. As in the case of the first measurement, the device under test 13 is irradiated with laser light (step S106 in FIG. 6). Here, by making the phase of the drive current supplied from the laser driver 2 to the laser diode 1-1 the same as in step S102, the phase of the laser light irradiated to the object to be measured 13 is the same as in step S102. I have to.

The function generator control unit 120 of the information processing apparatus 12 causes the lock-in amplifier 11 to detect the measurement signal having the reference frequency f ₀ by changing the frequency of the reference signal generated by the function generator 10. The phase measurement unit 122 of the information processing device 12 measures the phase P ₁ of the measurement signal at the reference frequency f ₀ (step S107 in FIG. 6). When the phase P _{1 of the} measurement signal is equal to the phase P ₀ (P ₀ = 0), the blood glucose concentration at time t is the same as the blood glucose concentration at the time of the first measurement in steps S100 to S105.

On the other hand, when the phase P _{1 of the} measurement signal is different from the phase P ₀ (P ₀ = 0), the function generator control unit 120 of the information processing device 12 changes the frequency of the reference signal generated by the function generator 10. Thus, the frequency of the measurement signal is searched for (the phase P ₁ is 0 in this case) where the phase P ₁ of the measurement signal is equal to P ₀ (step S108 in FIG. 6). Let f ₁ be the frequency at which phase P ₁ is equal to P ₀ .

When the frequency f ₁ is found, the amplitude measuring unit 121 of the information processing apparatus 12 measures the amplitude A ₁ of the measurement signal at the frequency f ₁ (step S109 in FIG. 6).
Then, the information recording unit 124 stores the amplitude A ₁ measured by the amplitude measuring unit 121, the phase P ₁ (P ₁ = P ₀ = 0) of the measurement signal, and the frequency f ₁ in the storage unit 132 (see FIG. 6 step S110).

The frequency change rate deriving unit 126 of the information processing device 12 calculates the frequency change rate (f ₁ −f ₀ ) / f ₀ × 100 of the measurement signal (step S111 in FIG. 6). The wavelength of light emitted from the laser diode 1-1 is λ1, and the signal response (frequency change rate calculated by the frequency change rate deriving unit 126) as a measurement result is expressed as FS (λ1). The operation at the time of measurement by the FS method of the component concentration measuring device is thus completed.

In the measurement by the FS method, it is not necessary to measure the amplitude of the measurement signal. However, in the case where there is no change in the blood glucose concentration, the frequency shift of the measurement signal caused by the influence other than the glucose concentration change can be calibrated by using the amplitude A ₀ and the amplitude A ₁ . The frequency shift calibration will be described below.

In cases where other components besides glucose concentration change are mixed, canceled the phase variation of the measurement signal due to glucose concentration change, the phase P ₁ is a phase P ₀ when measuring the phase P ₁ of the measurement signal in step S107 There are cases where it is equal to (P ₀ = 0). In this case, the amplitude measurement unit 121 of the information processing device 12 measures the amplitude A ₁ of the measurement signal at the reference frequency f ₀ . When the amplitude A ₁ of the measurement signal is different from the amplitude A ₀ , a component other than glucose, for example, a component such as albumin can be estimated from the amplitude A _{1 of the} measurement signal.

When the components other than the glucose concentration change are mixed and the phase P ₁ and the phase P ₀ (P ₀ = 0) of the measurement signal are different, the frequency shift calibration unit 125 of the information processing device 12 by the function generator 10 changes the frequency of the reference signal generated, performs frequency sweeping the lock-in amplifier 11 to gradually change the frequency of the measurement signal detected, searches for a peak closest to the reference frequency f _0.

When the frequency shift calibration unit 125 finds the peak of the amplitude of the measurement signal, the frequency shift calibration unit 125 sets the frequency of this peak as a new reference frequency f ₀ . In this way, the reference frequency f ₀ can be updated, and the frequency shift of the measurement signal caused by effects other than the glucose concentration change can be calibrated.

Since the calibration cannot be performed if the blood glucose concentration changes, the processing of steps S100 to S105 is performed periodically (for example, every several hours), and the amplitude A ₀ , the phase P _0, and the reference frequency f ₀ are appropriately set. Update it.

  Next, measurement by the OPBS method will be described in detail. The OPBS method takes advantage of the advantages defined in the prior art (see Patent Document 1) using light of two wavelengths. Two rectangular laser beams with different wavelengths are intensity-modulated by signals of the same frequency and opposite phase, respectively, to generate a rectangular wave beam, and the rectangular wave beam is combined and irradiated on a measurement object (for example, plasma). Then, the two laser beams are absorbed by the measurement object with their respective light absorption coefficients. As a result, an acoustic wave is generated by a photoacoustic effect (an effect in which the optical energy absorbed by the object to be measured is changed into thermal energy and an acoustic wave is generated by volume expansion due to the thermal energy) (FIG. 7). In FIG. 7, 60 indicates a photoacoustic signal by a rectangular wave beam emitted from the laser diode 1-1, and 61 indicates a photoacoustic signal by a rectangular wave beam emitted by the laser diode 1-2. The acoustic wave is proportional to a difference in intensity between two signals αP (α is a light absorption coefficient of the object to be measured and P is an optical power) by each of the two laser beams.

  In the OPBS method, first, the level (signal amplitude) of a reference photoacoustic signal is determined based on a known reference blood glucose concentration. When the blood glucose concentration changes from the reference blood glucose concentration, the amplitude of the photoacoustic signal from the two lights varies with the light wavelength and the light absorption coefficient. The power of the two lights is changed to balance the light absorption effect due to the change in blood glucose concentration, and the amplitude of the photoacoustic signal is returned to the level of the reference photoacoustic signal determined at the reference blood glucose concentration.

When one light is irradiated on the object to be measured, the intensity S (signal amplitude) of the generated photoacoustic signal can be expressed as in the above equation (1). In addition, when two light beams having different wavelengths are intensity-modulated with signals having the same frequency and opposite phases, and the object to be measured is irradiated, the intensity S of the generated photoacoustic signal is expressed by the above equation (2). Can be represented. However, since the parameters such as the constant K, the thermal expansion coefficient β, the sound velocity v, and the specific heat C _p depend on the temperature or the concentration of the mixture as described above, the photoacoustic signal intensity S is directly used for calculating the blood glucose concentration. It is not possible. In order to suppress such dependency, in the measurement method disclosed in Patent Document 1, standardization is performed using a signal of one wavelength.

In the OPBS method of the present embodiment, the optical power P ₁ or P ₂ that minimizes the photoacoustic signal intensity S is searched for by (α ₁ P ₁ −α ₂ P ₂ ) in Expression (2). The minimum value of the photoacoustic signal intensity S is determined within the noise range. In practice, in order to change the optical power output, the range of adjustment of the laser voltage in FIG. 3 is taken into consideration, so that two wavelengths (λ ₁ , λ ₂ ) and two light absorption coefficients (α ₁ , α ₂ ) are obtained. On the other hand, the optical power is determined as (P ₁ , P ₂ ).

FIG. 8 is a diagram showing the amplitude and phase of the photoacoustic signal when the optical powers P ₁ and P ₂ are changed when the blood glucose concentration of the object to be measured is the reference blood glucose concentration of 0 g / dL. In FIG. 8, the horizontal axis represents the optical power balance, and the vertical axis represents the amplitude and phase of the photoacoustic signal. In FIG. 8, 70 indicates the amplitude of the photoacoustic signal, and 71 indicates the phase of the photoacoustic signal. In the optical power balance, the relationship between the powers of two lights is expressed by a laser voltage, and a point where αP in each of the two laser lights is equal is zero. In the optical power balance is smaller than zero region becomes lower in the optical power P ₂ than the light power P _1, whereas, in a large area from the optical power balance is zero, the optical power than the optical power P ₁ P ₂ Is higher.

  As is clear from FIG. 8, at the point where the optical power balance is 0, that is, at the point where αP is equal in each of the two laser beams, the amplitude of the photoacoustic signal shows a minimum value, and the phase of the photoacoustic signal is inflected. Indicates a point. Theoretically, the amplitude of the photoacoustic signal at the point where the optical power balance is zero should be zero, but it is experimentally a minimum value including noise and does not become zero.

  Changing the power of one of the two lights changes the amplitude and phase of the photoacoustic signal. The amplitude of the photoacoustic signal increases on both sides of the point where the optical power balance is zero. That is, when the power of one light is reduced, the difference in intensity between the two signals αP is increased, and the amplitude of the photoacoustic signal is increased. Also, when the power of one light is reduced, the phase of the photoacoustic signal approaches the phase of the photoacoustic signal when excited by the other light alone. That is, it approaches a state excited by only one light.

In summary, when one of the two light powers P ₂ is reduced or the light power P ₁ is raised to make the light power balance smaller than 0, the amplitude of the photoacoustic signal increases. The phase differs by -90 degrees between the two phases. That is, the phase of the photoacoustic signal at this time is the same as the phase of the photoacoustic signal (that is, −90 degrees) when excited by the light alone having the optical power P ₁ . Further, when the optical power P ₂ is increased or the optical power P ₁ is decreased to make the optical power balance larger than 0, the amplitude of the photoacoustic signal increases, and the phase of the photoacoustic signal is equal to that of the optical power P ₂ . The phase is the same as the phase of the photoacoustic signal when excited by light alone (ie, +90 degrees).

  Here, there are two important characteristics in that the optical power balance is zero. First, since the photoacoustic signals of two wavelengths are phase shifted by ± 90 degrees, the point where the optical power balance is 0 coincides with the phase 0 point which is the inflection point. In addition, on both sides of the inflection point, the phase of the photoacoustic signal has a clear positive or negative value, and the relationship between the phase and the optical power is linear, so the phase can be measured quickly and the measurement is simple. Yes, it is possible to measure accurately, and the position of the inflection point 0 can be obtained with good accuracy from the positive and negative values of the phase. From these two features, blood glucose concentration can be measured with high accuracy by phase measurement.

  Here we focus on the amplitude signal, not the phase, to provide an easy-to-understand explanation. The phase point at which the amplitude of the photoacoustic signal is the minimum and becomes the inflection point of the phase of the photoacoustic signal is located at a point where αP in each of the two lights is equal. When the blood glucose concentration of the object to be measured is the reference blood glucose concentration of 0 g / dL, the above equation (3) is established at this phase point.

Experimentally, since noise exists, it is difficult to make the amplitude of the photoacoustic signal zero. However, the minimum value of the amplitude of the photoacoustic signal is a value two orders of magnitude lower than the amplitude of the photoacoustic signal when light of one wavelength is used. Then, conceptually, the amplitude of the photoacoustic signal can be reduced to a level at which the noise level can be completely ignored. Next, the component concentration of the object to be measured is changed. For example, the blood glucose concentration is changed from 0 to C _g [g / dL].

FIG. 9A is a diagram showing the amplitude and phase of the photoacoustic signal when the optical powers P ₁ and P ₂ are changed when the blood glucose concentration of the object to be measured changes by C _g [g / dL]. FIG. 9B is a diagram showing the amplitude and phase of the photoacoustic signal when the optical powers P ₁ and P ₂ are changed when the albumin concentration of the object to be measured is changed. 9A and 9B, the horizontal axis represents the optical power balance, and the vertical axis represents the amplitude and phase of the photoacoustic signal.

  In FIG. 9A, 80 indicates the amplitude of the photoacoustic signal when the blood glucose concentration changes, 81 indicates the phase of the photoacoustic signal when the blood glucose concentration changes, and 82 indicates the blood glucose concentration changes. The amplitude of the previous photoacoustic signal is shown, and 83 shows the phase of the photoacoustic signal before the blood glucose concentration changes. In FIG. 9B, 84 indicates the amplitude of the photoacoustic signal when the albumin concentration changes, 85 indicates the phase of the photoacoustic signal when the albumin concentration changes, and 86 indicates before the albumin concentration changes. , 87 indicates the phase of the photoacoustic signal before the albumin concentration changes.

When the blood glucose concentration or albumin concentration changes, the amplitude and phase of the photoacoustic signal change according to the change in αP. For example, when the blood glucose concentration changes by C _{g and the} light absorption coefficients α ₁ and α ₂ change by δα ₁ and δα ₂ due to the concentration change, the above equation (4) is established. There are two methods for detecting the component concentration (blood glucose concentration, albumin concentration, etc.). Either a method of searching for an optical power balance at which the amplitude of the photoacoustic signal is minimum, or a method of searching for an optical power balance at the inflection point of the phase of the photoacoustic signal.

Around the point where the optical power balance is 0, the relationship between the phase of the photoacoustic signal and the optical power is close to linear, so that the position of the phase 0 can be accurately evaluated. The optical power difference for moving the phase of the photoacoustic signal to a new inflection point after the component concentration change can be obtained by measurement. 9A and 9B, a new inflection point (amplitude 80 of the photoacoustic signal after the change in the component concentration) is obtained by increasing the optical power P ₂ or decreasing the optical power P _1. , 84 can be shifted to the minimum).

In the OPBS method of the present embodiment, the optical power is changed in order to search for a point where the phase of the photoacoustic signal is zero. More specifically, in order to change the optical power, the drive voltages of the laser diodes 1-1 and 1-2 are changed. When the phase of the photoacoustic signal is 0, the above equations (5) and (6) are established. As apparent from the equation (6), the blood glucose concentration C _g can be obtained from a new light power balance shift value δP ₁ unique to glucose and relative light absorption coefficients δα ₁ and δα ₂ . When the component concentration to be measured is the albumin concentration, it can be obtained in the same manner. The light absorption coefficients α ₁ and α ₂ and the light absorption coefficient change amounts δα ₁ and δα ₂ can be obtained from light absorption spectrum measurement.

  The OPBS method of the present embodiment is an efficient method for non-invasively measuring the components of a solution based on photoacoustic measurement. This measurement method can optimize a very selective approach to one specific composition by choosing two optical wavelengths. Obviously, many solutes can be detected in different solvents given the various optical wavelengths available. In addition, it is possible to measure any difference in absorption coefficient (density) by adjusting the corresponding optical power and obtaining the power balance.

The choice of optical wavelength is not limited by the absorption coefficient. If α ₁ = 2α ₂ , P ₁ = 0.5P ₂ and equation (3) is still valid. Furthermore, measurement methods based on phase 0 inflection points converge quickly and provide very accurate measurements. In order to measure the phase of the photoacoustic signal, it is necessary to store several measurement points. If the noise is completely ignored, it is possible to determine the linear slope from the 2-point measurement data, whereas the parabola (second-order polynomial) requires 3-point measurement data. From this point of view, the linear characteristic of the photoacoustic signal can obtain an inflection point with a phase of 0 earlier.

  However, based on the dependency between noise and the required measurement accuracy, the number of measurement points should be drastically increased. If the change of the photoacoustic signal is linear, the position of phase 0 can be obtained with very accurate accuracy from the measurement data of two points, and the position can be searched within a small range. On the other hand, when the change in the photoacoustic signal is parabolic, the binary search algorithm (binary search) is the best method. However, the time required to obtain the position where the phase is 0 is very long. From an experimental perspective, it is difficult to estimate the quantitative increase in measurement time in relation to the sensor response time. However, if the linear behavior of the phase of the photoacoustic signal is used, it can be measured more quickly and an accurate component concentration value can be provided.

Next, the measurement by the OPBS method will be described in more detail. FIG. 10 is a flowchart showing the operation at the time of measurement by the OPBS method of the component concentration measuring apparatus.
First, only the laser diode 1-1 is operated to determine the reference level in the initial state at time t0. The device under test 13 is introduced into the photoacoustic cell 6. When a drive current is supplied from the laser driver 2, the laser diode 1-1 emits laser light. At this time, when a rectangular-wave drive current is supplied from the laser driver 2, the laser diode 1-1 emits intensity-modulated light. The wavelength of light is, for example, 1384 nm. This intensity-modulated light is guided by the optical fiber 3-1, passes through the optical coupler 4, is further guided by the optical fiber 5, and irradiates the object to be measured 13 in the photoacoustic cell 6 through the optical window 7. (FIG. 10, step S200).

  The acoustic sensor 8 detects a photoacoustic signal generated from the device under test 13, and the amplifier 9 amplifies the electrical signal output from the acoustic sensor 8. The lock-in amplifier 11 detects a measurement signal having a frequency determined by the reference signal output from the function generator 10 among the signals included in the output of the amplifier 9.

  The function generator control unit 120 of the information processing device 12 changes the frequency of the drive current supplied from the laser driver 2 to the laser diode 1-1 by changing the frequency of the reference signal generated by the function generator 10. The optical modulation frequency sweep is performed to gradually change the optical modulation frequency and to gradually change the frequency of the measurement signal detected by the lock-in amplifier 11 (the same frequency as the optical modulation frequency) (step S201 in FIG. 10). Thus, the acoustic resonance peak is searched.

Next, when the maximum amplitude of the measurement signal is found, the frequency measurement unit 127 of the information processing apparatus 12 measures the frequency of the measurement signal at the maximum amplitude (reference frequency F0), and the phase measurement unit 122 The phase of the measurement signal at the time of amplitude (reference phase P0) is measured (step S202 in FIG. 10).
The information recording unit 124 of the information processing apparatus 12 stores the reference frequency F0 measured by the frequency measuring unit 127 and the reference phase P0 measured by the phase measuring unit 122 in the storage unit 132 (step S203 in FIG. 10).

  Next, the two laser diodes 1-1 and 1-2 are operated, and the two lights are combined to perform measurement. When a drive current is supplied from the laser driver 2, the laser diodes 1-1 and 1-2 emit laser light. At this time, the laser driver 2 supplies the light emitted from the laser diodes 1-1 and 1-2 by supplying a rectangular-wave drive current having the same frequency and an opposite phase to the laser diodes 1-1 and 1-2. Intensity modulation is performed using signals of the same frequency and opposite phase. At this time, the wavelength of the light emitted from the laser diode 1-1 is, for example, 1384 nm, and the wavelength of the light emitted from the laser diode 1-2 is, for example, 1610 nm. The power of the two lights is the same. The intensity-modulated lights emitted from the laser diodes 1-1 and 1-2 are respectively guided by the optical fibers 3-1 and 3-2, combined by the optical coupler 4, and further guided by the optical fiber 5, and the optical window. 7 to irradiate the object 13 to be measured in the photoacoustic cell 6 (step S204 in FIG. 10).

  Subsequently, the function generator control unit 120 of the information processing apparatus 12 supplies the laser diodes 1-1 and 1-2 from the laser driver 2 by changing the frequency of the reference signal generated by the function generator 10. The frequency of the drive current is changed, the optical modulation frequency is set to the reference frequency F0, and the frequency of the measurement signal detected by the lock-in amplifier 11 is set to the reference frequency F0. The optical power control unit 128 of the information processing apparatus 12 gradually changes the power of the light emitted from the laser diode 1-1 by changing the magnitude of the drive current supplied from the laser driver 2 to the laser diode 1-1. The changing optical power sweep is performed (step S205 in FIG. 10).

The phase measuring unit 122 of the information processing apparatus 12 searches for an inflection point of the phase of the measurement signal, that is, a point where the phase becomes 0 (step S206 in FIG. 10). When the inflection point of the phase is found, the optical power measurement unit 129 of the information processing apparatus 12 measures the difference between the optical powers of the two lights at the inflection point (step S207 in FIG. 10). The optical power measurement unit 129 measures a reference drive voltage difference V _OPBS0 that is a difference between a drive voltage supplied to the laser diode 1-1 and a drive voltage supplied to the laser diode 1-2 as a difference in optical power.

  Since the two optical powers at the time of step S204 are the same, when only the power of one of the two lights is changed, the initial optical power and the inflection point at the time of step S204 for this one light. The difference (drive voltage difference) from the optical power at may be obtained. In the optical power sweep in step S205, the power of light emitted from the two laser diodes 1-1 and 1-2 may be changed.

  Next, measurement at time t after an arbitrary time has elapsed from time t0 will be described. First, only one laser diode 1-1 is operated to perform measurement using only one light. The intensity-modulated light emitted from the laser diode 1-1 is guided by the optical fiber 3-1, passes through the optical coupler 4, is further guided by the optical fiber 5, passes through the optical window 7, and passes through the optical acoustic cell 6. The measurement object 13 is irradiated (step S208 in FIG. 10).

The function generator control unit 120 of the information processing device 12 changes the frequency of the drive current supplied from the laser driver 2 to the laser diode 1-1 by changing the frequency of the reference signal generated by the function generator 10. The optical modulation frequency is set to the reference frequency F0. Further, the function generator control unit 120 changes the optical modulation frequency from the reference frequency F0 by changing the frequency of the reference signal generated by the function generator 10.
The phase measurement unit 122 of the information processing device 12 searches for a point where the phase of the measurement signal becomes the reference phase P0, and the frequency measurement unit 127 of the information processing device 12 measures the frequency F1 at this point. In this way, the frequency F1 corresponding to the reference phase P0 is searched (step S209 in FIG. 10). The frequency F1 is located in the vicinity of the reference frequency F0.

  Next, the two laser diodes 1-1 and 1-2 are operated, and the two lights are combined to perform measurement. The laser driver 2 supplies a rectangular-wave drive current having the same frequency and an opposite phase to the laser diodes 1-1 and 1-2, thereby allowing the light emitted from the laser diodes 1-1 and 1-2 to be the same frequency. Intensity modulation is performed using signals of opposite phase. Similarly to the above, the wavelength of light emitted from the laser diode 1-1 is, for example, 1384 nm, and the wavelength of light emitted from the laser diode 1-2 is, for example, 1610 nm. The power of the two lights is the same. The intensity-modulated lights emitted from the laser diodes 1-1 and 1-2 are respectively guided by the optical fibers 3-1 and 3-2, combined by the optical coupler 4, and further guided by the optical fiber 5, and the optical window. 7 to irradiate the object 13 to be measured (step S210 in FIG. 10).

  Subsequently, the function generator control unit 120 of the information processing apparatus 12 supplies the laser diodes 1-1 and 1-2 from the laser driver 2 by changing the frequency of the reference signal generated by the function generator 10. The frequency of the drive current is changed, the optical modulation frequency is set to the frequency F1, and the frequency of the measurement signal detected by the lock-in amplifier 11 is set to the frequency F1. The optical power control unit 128 of the information processing apparatus 12 gradually changes the power of the light emitted from the laser diode 1-1 by changing the magnitude of the drive current supplied from the laser driver 2 to the laser diode 1-1. The optical power sweep to be changed is performed (step S211 in FIG. 10).

The phase measurement unit 122 of the information processing apparatus 12 searches for an inflection point of the phase of the measurement signal, that is, a point where the phase becomes 0 (step S212 in FIG. 10). When the inflection point of the phase is found, the optical power measurement unit 129 of the information processing apparatus 12 measures the difference between the optical powers of the two lights at the inflection point (step S213 in FIG. 10). The optical power measurement unit 129 measures a drive voltage difference V _OPBS1 that is a difference between a drive voltage supplied to the laser diode 1-1 and a drive voltage supplied to the laser diode 1-2 as a difference in optical power.

  Since the two optical powers at the time of step S210 are the same, when only the power of one of the two lights is changed, the initial optical power and the inflection point at the time of step S210 for this one light. The difference (drive voltage difference) from the optical power at may be obtained. Further, in the optical power sweep in step S211, the power of light emitted from the two laser diodes 1-1 and 1-2 may be changed.

The storage unit 132 of the information processing apparatus 12 stores in advance calibration data indicating a relationship between the difference between the drive voltage difference V _OPBS1 and the reference drive voltage difference V _OPBS0 (V _OPBS1 −V _OPBS0 ) and the optical power change amount _δP . It is remembered. Such calibration data can be obtained by actually measuring in advance. The optical power change amount deriving unit 130 of the information processing apparatus 12 refers to the storage unit 132 and acquires the optical power change amount _δP corresponding to the drive voltage difference (V _OPBS1 −V _OPBS0 ) (step S214 in FIG. 10). The wavelength of the light emitted from the laser diode 1-1 is λ1, the wavelength of the light emitted from the laser diode 1-2 is λ2, and the signal response as the measurement result (the optical power obtained by the optical power variation deriving unit 130) (Change amount) is expressed as OPBS (λ1, λ2). This completes the measurement using the laser diodes 1-1 and 1-2.

  Next, returning to step S200, the measurements in steps S200 to S214 are performed using a combination of laser diodes 1-1 and 1-3 different from laser diodes 1-1 and 1-2. Thus, the measurement in steps S200 to S214 is performed for all combinations of two laser diodes that can be selected from the laser diodes 1-1, 1-2, 1-3, 1-4,. To do. For example, when the wavelength of light emitted from the laser diode 1-3 is λ3 and the wavelength of light emitted from the laser diode 1-4 is λ4, the combination of the laser diodes 1-1 and 1-3 is used. The signal response (the optical power change amount obtained by the optical power change amount deriving unit 130), which is a measurement result, is expressed as OPBS (λ1, λ3), and is measured when a combination of laser diodes 1-1 and 1-4 is used. The resulting signal response is expressed as OPBS (λ1, λ4).

  When measurement in steps S200 to S214 is completed for all combinations of two laser diodes that can be selected (YES in step S215 in FIG. 10), the operation of the component concentration measurement apparatus during measurement by the OPBS method is completed.

In the OPBS method of the present embodiment, the intensity of the two lights is modulated with a signal having the same frequency and opposite phase, but the intensity of the light may be modulated with a signal having a phase difference other than 180 °.
The phase of the signal for intensity-modulating the two lights was manually changed to obtain the optical power balance-phase characteristic shown in FIG. The horizontal axis in FIG. 11 is the optical power balance, and the vertical axis is the phase of the photoacoustic signal. Here, light having a wavelength of 1438 nm and light having a wavelength of 1610 nm are used. The optical power balance is expressed by a laser driving voltage of a laser diode that generates light of 1438 nm. The laser drive voltage of the laser diode that generates light of 1610 nm is 1.4V. In FIG. 11, 400 is a characteristic when the phase difference of each signal that modulates the intensity of two lights is 180 °, 401 is a characteristic when the phase difference is 180.1 °, and 402 is a phase difference of 180.3 °. 403 is a characteristic when the phase difference is 180.8 °, 404 is a characteristic when the phase difference is 185.8 °, 405 is a characteristic when the phase difference is 195.8 °, and 406 is a phase difference. Shows the characteristics when the angle is 178.8 °.

  When the phase difference between the signals for intensity-modulating the two lights is 180 °, the phase of the photoacoustic signal remains −90 ° when the drive voltage of one laser diode is changed. Since the signal intensity is low at around 0.51 V, the characteristics are distorted by the influence of the phase noise of the photoacoustic signal. Immediately after that, a 180 ° phase shift suddenly occurs in the photoacoustic signal and becomes discontinuous. As in the case before the phase shift, distortion due to noise occurs, and the phase of the photoacoustic signal is stabilized at 90 °.

  When the phase difference between the signals for intensity-modulating the two lights is around 180 ° (180.1 °, 180.8 °, 180.3 °), the phase of the photoacoustic signal is at the discontinuous point of the phase change described above. It is changing continuously. There is a region where the phase of the photoacoustic signal is stable at ± 90 ° in the voltages before and after the discontinuity. When the phase difference between the signals for intensity-modulating the two lights is not 180 ° (185.8, 195.8), the phase of the photoacoustic signal is ± only in the continuous transition region of the photoacoustic signal phase at all voltages. There is no region that is stable at 90 °. As described above, the measurement was performed by increasing the phase difference of the signal from 180 °. However, when the phase difference of the signal was decreased to 178.8 °, a symmetrical tendency was obtained. That is, the slope of the phase change from the phase 90 ° to the phase −90 ° with respect to the drive voltage is reversed. In conclusion, for accurate and appropriate solution component concentration measurement, the phase difference between the signals for intensity modulation of the two lights can be about 180 ° ± 30 °.

  Practically, it is not appropriate to use 180 ° as the phase difference between the signals for intensity-modulating the two lights because the influence of noise is large in the phase transition region of the photoacoustic signal. Also, since the slope of the phase change of the photoacoustic signal is steep, the bisection method is the only approach for determining the point where the phase of the photoacoustic signal is 0, and it takes time to measure and the convergence is poor. . In order to increase the measurement speed, a linear transition region is most appropriate. That is, this is a method for estimating the position of phase 0 relatively from a plurality (2, 3) of measurement points around the phase 0 point of the photoacoustic signal. In such a method, measurement accuracy can be improved more reliably by repeating measurement and estimation.

  When the phase difference between the signals for intensity-modulating the two lights is close to 180 °, a linear transition region around the phase 0 point of the photoacoustic signal is obtained. Since the slope of the phase change of the photoacoustic signal is relatively steep, the phase changes greatly even in a small component concentration range, and appropriate measurement accuracy can be obtained. On the other hand, as the phase difference between the signals for intensity-modulating the two lights increases from 180 °, the slope of the phase change of the photoacoustic signal becomes gentle. In such a case, even in a large component concentration range, the concentration can be quantified because there is a phase 0 point in the phase transition region. Therefore, the phase difference between the signals for intensity-modulating the two lights is appropriately set according to a desired density range in order to determine measurement accuracy and dynamic range.

  When the phase difference between the signals for intensity-modulating the two lights is greatly different from 180 °, for example, when 180 ° is different from 10 °, 20 ° or 30 °, the linear transition region of the phase of the photoacoustic signal is wide. The measurement range can be used, and measurement of a wide concentration range can be supported. Therefore, for a large density range, the phase difference between the signals for intensity-modulating the two lights may be set to 190 °, 200 ° or 210 °, for example. However, since the gradient of the phase change of the photoacoustic signal becomes gentle and the measurement accuracy decreases, the concentration range and the measurement accuracy are in a trade-off relationship.

Next, the concentration deriving unit 131 of the information processing apparatus 12 determines the concentration of the component to be measured from the measurement result by the FS method and the measurement result by the OPBS method (step S3 in FIG. 5).
In human tissue, many kinds of molecules exist at a certain concentration level and change with time. In order to accurately monitor one composition (here glucose), it is therefore necessary to remove some ubiquitous biases (compositions and parameters whose changes affect glucose concentration measurements). Furthermore, due to noise and measurement uncertainty, in order to estimate the consistency and accuracy of the results, more measurements are required than are necessary to obtain the measurement values.

  When the OPBS method using two wavelengths is expanded to the OPBS method using n wavelengths, a combination of n (n-1) / 2 can be taken. Also, frequency shifts must be evaluated and corrected before performing measurements with the OPBS method. However, this frequency shift also leads to FS measurements. Since this protocol does not depend on the optical wavelength, it can be implemented at any optical wavelength and only needs to be performed once. The FS method is highly sensitive but has low glucose selectivity. Furthermore, the frequency shift response is constant regardless of the wavelength or acoustic mode.

  As a result, an equation of (n (n-1) / 2 + 1) can be obtained from n light wavelengths. Here, a system having M (M is an integer of 2 or more) unknown parameters, for example, Ca, Cb, Cc,. Ca, Cb, Cc,... Are the concentrations of certain components in the object to be measured, and T is the temperature of the object to be measured. An example of the concentration Ca is blood glucose concentration. An example of the concentration Cb is albumin concentration. Even if we focus on one of the M unknown parameters, the entire system must be analyzed to obtain at least M equations. However, since (n (n−1) / 2 + 1) equations can be obtained from n laser diodes, n needs to be an integer satisfying (n (n−1) / 2 + 1)> = M. .

Once n is determined, the following equations can be obtained for each wavelength combination.
The signal response FS (λ1) that is a measurement result by the FS method can be expressed as the following equation.
FS (λ1) = KaCa + KbCb + KcCc +... + KtT (13)
Here, Ka, Kb, Kc,..., Kt are proportional coefficients.

Signal responses OPBS (λ1, λ2), OPBS (λ1, λ3), OPBS (λ1, λ4),..., OPBS (λn-1, λn), which are measurement results by the OPBS method, are expressed as follows: it can. Since there are n (n-1) / 2 combinations of two laser diodes that can be selected from n laser diodes, the signal response obtained by the OPBS method is also n (n-1) / 2. It becomes.
OPBS (λ1, λ2) = Qa _{λ1, λ2} Ca + Qb _{λ1, λ2} Cb + Qc _{λ1, λ2} Cc
+ ... + Qt _{λ1, λ2} T
OPBS (λ1, λ3) = Qa _{λ1, λ3} Ca + Qb _{λ1, λ3} Cb + Qc _{λ1, λ3} Cc
+ ... + Qt _{λ1, λ3} T
OPBS (λ1, λ4) = Qa _{λ1, λ4} Ca + Qb _{λ1, λ4} Cb + Qc _{λ1, λ4} Cc
+ ... + Qt _{λ1, λ4} T
...
OPBS (λn-1, λn) = Qa _{λn-1, λn} Ca + Qb _{λn-1, λn} Cb + Qc _{λn-1, λn} Cc +... + Qt _{λn-1, λn} T (14)

Here, Qa _{λi, λj} , Qb _{λi, λj} , Qc _{λi, λj} ,..., Qt _{λi, λj} (i, j = 1 to n, i ≠ j) are proportional coefficients. Expressions (13) and (14) are described as a matrix as follows.

The central matrix, that is, the coefficient matrix, includes coefficients Ka, Kb, Kc,..., Kt and Qa _{λi, λj} , Qb _{λi, λj} , Qc _{λi, λj} , ..., Qt _{λi, λj.} Yes. The coefficients Ka, Kb, Kc, · · ·, Kt and _{Qa λi, λj, Qb λi,} λj, Qc λi, λj, ···, Qt λi, the value of _{lambda] j} are each composition envisioned (glucose And albumin, other blood components, etc.) have been experimentally obtained beforehand by calibration measurement. Therefore, the concentration deriving unit 131 of the information processing apparatus 12 determines M unknown parameters Ca, Cb, Cc,..., T by solving the simultaneous equations of Expressions (13) and (14). (Step S3 in FIG. 5).

  If the coefficient matrix is a square matrix, there is one solution for unknown parameters Ca, Cb, Cc,. Since there are multiple solutions if the coefficient matrix has more rows than columns, several mathematical processes are required to determine the most probable Ca, Cb, Cc,. Although the solution cannot be uniquely determined, it is possible to check which is the optimal solution among a plurality of solutions. Considering instability and noise, the second approach with (n (n−1) / 2 + 1)> M is more than the first approach with (n (n−1) / 2 + 1) = M. There is no doubt that it is more stable.

  Even if measurement accuracy is important, the number of light sources may not be increased indefinitely. This is because an increase in the number of light sources leads to an increase in the cost and size of the apparatus and the measurement time. Logically, the approach of this embodiment is not limited by the number of unknown parameters. However, reducing the number of variables by using the FS method that can be implemented in the configuration of the OPBS method is useful for simplifying the actual system.

  In the present embodiment, the composition matrix is evaluated by an experiment in a laboratory environment. However, in an experiment in a patient's living body, the coefficient varies slightly among individuals. Thus, in order to set the starting value of the glucose concentration before starting a continuous measurement, at least one measurement value based on standard methods is required. By comparing the measurement result according to the present embodiment with the measurement result by the standard method, the matrix coefficient can be adjusted to the patient.

  The information processing apparatus 12 according to the present embodiment can be realized by, for example, a computer including a CPU, a storage device, and an interface, and a program that controls these hardware resources. A program for operating such a computer is provided in a state of being recorded on a recording medium such as a flexible disk, a CD-ROM, a DVD-ROM, or a memory card. The CPU writes the read program into the storage device, and executes the processing described in this embodiment in accordance with this program.

  The present invention can be applied to a technique for continuously monitoring the concentration of components such as blood glucose. The present invention can also be applied to the measurement of the concentration of glucose present in the body of a living body, the concentration of glucose present in blood plasma, or the concentration of other components present in plasma.

  1-1, 1-2, 1-3, 1-4,..., 1-n laser diode, 2 laser driver, 3-1, 3-2, 3-3, 3-4,. .., 3-n, 5 ... optical fiber, 4 ... optical coupler, 6 ... photoacoustic cell, 7 ... optical window, 8 ... acoustic sensor, 9 ... amplifier, 10 ... function generator, 11 ... lock-in amplifier, 12 ... Information processing device, 13 ... object to be measured, 120 ... function generator control unit, 121 ... amplitude measurement unit, 122 ... phase measurement unit, 123 ... phase offset adjustment unit, 124 ... information recording unit, 125 ... frequency shift calibration unit, 126 ... Frequency change rate deriving unit, 127 ... Frequency measuring unit, 128 ... Optical power control unit, 129 ... Optical power measuring unit, 130 ... Optical power change amount deriving unit, 131 ... Concentration deriving unit, 132 ... Storage unit.

Claims (8)

(M-1) Wavelengths of the measured objects having M (M is an integer of 2 or more) unknown parameters having concentrations Ca, Cb, Cc,... Light irradiation is performed using one of the different light irradiation units (n is an integer satisfying (n (n-1) / 2 + 1)> = M), and is performed by a frequency shift (FS) method. A first measurement step for obtaining a measurement result;
The measurement object is irradiated with light using all combinations of two light irradiation means that can be selected from the n light irradiation means, and a measurement result is obtained by an optical power balance shift (OPBS) method. A second measurement step;
A concentration derivation step for determining a concentration of a component to be measured in the object to be measured from the measurement result of the first measurement step and the measurement result of the second measurement step;
The concentration derivation step includes:
The measurement result of the first measurement step is FS (λ1), the measurement result of the second measurement step is OPBS (λ1, λ2), OPBS (λ1, λ3), OPBS (λ1, λ4),. When OPBS (λn-1, λn) (λ1, λ2, λ3, λ4,..., Λn-1, λn are wavelengths of light emitted from n light irradiation means),
Expression FS (λ1) = KaCa + KbCb + KcCc +... + KtT expressing the measurement result of the first measurement step;
Expression expressing the measurement result of the second measurement step OPBS (λ1, λ2) = Qa _{λ1, λ2} Ca + Qb _{λ1, λ2} Cb + Qc _{λ1, λ2} Cc
+ ... + Qt _{λ1, λ2} T,
OPBS (λ1, λ3) = Qa _{λ1, λ3} Ca + Qb _{λ1, λ3} Cb + Qc _{λ1, λ3} Cc
+ ... + Qt _{λ1, λ3} T,
OPBS (λ1, λ4) = Qa _{λ1, λ4} Ca + Qb _{λ1, λ4} Cb + Qc _{λ1, λ4} Cc
+ ... + Qt _{λ1, λ4} T,
...
OPBS (λn-1, λn) = Qa _{λn-1, λn} Ca + Qb _{λn-1, λn} Cb + Qc _{λn-1, λn} Cc
+ ... + Qt _{λn-1, λn} T
, Kt, Qa _{λi, λj} , Qb _{λi, λj} , Qc _{λi, λj} ,..., Qt _{λi, λj} (i, j = 1 to n , I ≠ j) includes determining a concentration Ca, Cb, Cc,... Of the component in the object to be measured by solving a predetermined coefficient) ,
The component concentration measuring method, wherein the concentration Ca is a blood glucose concentration . In the component concentration measuring method according to claim 1,
The first measuring step includes
A first light irradiation step of irradiating the object to be measured with light;
A first photoacoustic signal detection step for detecting a photoacoustic signal generated from the measurement object by the first light irradiation step and outputting an electric signal;
A first phase measurement step for measuring a phase of the measurement signal using a signal having a reference frequency having a maximum amplitude among the electrical signals obtained in the first photoacoustic signal detection step;
A second light irradiation step of irradiating the object to be measured with light after an arbitrary period of time;
A second photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured by the second light irradiation step and outputting an electric signal;
A second phase measurement step for measuring the phase of the measurement signal using the signal of the reference frequency as a measurement signal among the electrical signals obtained in the second photoacoustic signal detection step;
A frequency search step for searching for a frequency of a measurement signal in which the phase measured in the second phase measurement step is equal to the phase measured in the first phase measurement step;
A component concentration measurement method comprising: a frequency change deriving step for obtaining a change amount between the frequency searched in the frequency search step and the reference frequency as a measurement result of the first measurement step. In the component concentration measuring method according to claim 1 or 2,
The second measuring step includes
A third light irradiation step of irradiating the object to be measured with intensity-modulated light;
A third photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured by the third light irradiation step and outputting an electric signal;
A first frequency measurement step of measuring, as the first frequency, the modulation frequency at which the amplitude of the electrical signal obtained in the third photoacoustic signal detection step is maximum;
A third phase measuring step for measuring the phase of the electric signal when the amplitude is maximum as a reference phase;
Two waves of different wavelengths are intensity-modulated by signals of the first frequency and different phases, respectively, and irradiated on the object to be measured, and the optical power of at least one of the two intensity-modulated lights A fourth light irradiation step for gradually changing
A fourth photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured by the fourth light irradiation step and outputting an electric signal;
A fourth phase measurement step for searching for a first inflection point at which the phase of the electrical signal obtained in the fourth photoacoustic signal detection step is 0;
A first optical power measurement step for measuring a difference in optical power between two intensity-modulated lights at the first inflection point;
A fifth light irradiation step of irradiating the object to be measured with intensity-modulated light after an arbitrary period of time;
A fifth photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured by the fifth light irradiation step and outputting an electric signal;
A second frequency measurement step for searching for a modulation frequency at which the phase of the electrical signal obtained in the fifth photoacoustic signal detection step is the reference phase as a second frequency;
Two waves of different wavelengths are intensity-modulated with signals of the second frequency and different phases, respectively, and irradiated on the object to be measured, and the optical power of at least one of the two intensity-modulated lights A sixth light irradiation step for gradually changing
A sixth photoacoustic signal detection step for detecting a photoacoustic signal generated from the object to be measured by the sixth light irradiation step and outputting an electric signal;
A fifth phase measurement step for searching for a second inflection point where the phase of the electrical signal obtained in the sixth photoacoustic signal detection step is 0;
A second optical power measurement step for measuring a difference in optical power between the two intensity-modulated lights at the second inflection point;
Optical power for obtaining the amount of change between the difference in optical power measured in the second optical power measurement step and the difference in optical power measured in the first optical power measurement step as a measurement result in the second measurement step A change derivation step,
For each combination of two light irradiation means that can be selected from the n light irradiation means, the third light irradiation step, the third photoacoustic signal detection step, the first frequency measurement step, and the A third phase measurement step, the fourth light irradiation step, the fourth photoacoustic signal detection step, the fourth phase measurement step, the first light power measurement step, and the fifth light irradiation step; The fifth photoacoustic signal detection step, the second frequency measurement step, the sixth light irradiation step, the sixth photoacoustic signal detection step, the fifth phase measurement step, and the second optical power. A component concentration measuring method, wherein the measuring step and the optical power change deriving step are performed, and the measurement result of the second measuring step is obtained for each combination of the two light irradiation means. In the component concentration measuring method according to any one of claims 1 to 3,
N in the n light irradiation means is an integer satisfying (n (n-1) / 2 + 1)> M. (M-1) Irradiate light to an object to be measured having M (M is an integer of 2 or more) unknown parameters having concentrations Ca, Cb, Cc,... Light irradiation means;
Photoacoustic signal detection means for detecting a photoacoustic signal generated from the object to be measured by this light irradiation and outputting an electrical signal; and
Light is emitted from one light irradiation means among the n light irradiation means (n is an integer satisfying (n (n-1) / 2 + 1)> = M) with respect to the object to be measured. First measuring means for irradiating and obtaining a measurement result based on the electrical signal by a frequency shift (FS) method;
The measurement object is irradiated with light using all combinations of two light irradiation means that can be selected from the n light irradiation means, and the electric signal is converted into an electric signal by an optical power balance shift (OPPBS) method. A second measuring means for obtaining a measurement result based on the measurement result;
A concentration deriving unit for determining a concentration of a component to be measured in the measurement object from the measurement result of the first measurement unit and the measurement result of the second measurement unit;
The concentration deriving means includes
The measurement result of the first measurement means is FS (λ1), the measurement result of the second measurement means is OPBS (λ1, λ2), OPBS (λ1, λ3), OPBS (λ1, λ4),. When OPBS (λn-1, λn) (λ1, λ2, λ3, λ4,..., Λn-1, λn are wavelengths of light emitted from n light irradiation means),
Expression FS (λ1) = KaCa + KbCb + KcCc +... + KtT expressing the measurement result of the first measuring means,
Expression expressing the measurement result of the second measuring means OPBS (λ1, λ2) = Qa _{λ1, λ2} Ca + Qb _{λ1, λ2} Cb + Qc _{λ1, λ2} Cc
+ ... + Qt _{λ1, λ2} T,
OPBS (λ1, λ3) = Qa _{λ1, λ3} Ca + Qb _{λ1, λ3} Cb + Qc _{λ1, λ3} Cc
+ ... + Qt _{λ1, λ3} T,
OPBS (λ1, λ4) = Qa _{λ1, λ4} Ca + Qb _{λ1, λ4} Cb + Qc _{λ1, λ4} Cc
+ ... + Qt _{λ1, λ4} T,
...
OPBS (λn-1, λn) = Qa _{λn-1, λn} Ca + Qb _{λn-1, λn} Cb + Qc _{λn-1, λn} Cc
+ ... + Qt _{λn-1, λn} T
, Kt, Qa _{λi, λj} , Qb _{λi, λj} , Qc _{λi, λj} ,..., Qt _{λi, λj} (i, j = 1 to n , I ≠ j) determines the concentrations Ca, Cb, Cc,... Of the components in the measured object by solving a predetermined coefficient) ,
2. The component concentration measuring apparatus according to claim 1, wherein the concentration Ca is a blood glucose concentration . In the component concentration measuring apparatus according to claim 5,
The first measuring means includes
First phase measuring means for measuring a phase of a measurement signal included in the electrical signal;
A frequency search means for searching for the frequency of the measurement signal after an arbitrary period of time;
A frequency change deriving unit that obtains the amount of change in the frequency of the measurement signal after elapse of the arbitrary time as a measurement result of the first measurement unit;
One light irradiating means among the n light irradiating means irradiates light to the object to be measured at a first time, and irradiates light to the object to be measured after an arbitrary time has elapsed. And
The first phase measuring means measures a phase of the measurement signal using a signal of a reference frequency having a maximum amplitude among the electrical signals obtained at the first time, and measures the phase of the arbitrary time. Of the electrical signal after the lapse of time, the signal of the reference frequency as a measurement signal, the phase of this measurement signal is measured,
The frequency search means searches for a frequency of a measurement signal in which a phase measured after the arbitrary time has elapsed is equal to a phase measured at the first time,
The component concentration measuring device, wherein the frequency change deriving unit obtains a change amount between the frequency searched by the frequency searching unit and the reference frequency as a measurement result of the first measuring unit. In the component concentration measuring apparatus according to claim 5 or 6,
The second measuring means includes
Optical power control means for controlling optical power;
Frequency measuring means for measuring the frequency of the electrical signal;
Second phase measuring means for measuring the phase of the electrical signal;
Optical power measuring means for measuring the difference between the optical powers of the two intensity-modulated lights; and
An optical power change deriving unit that obtains a change amount of the optical power after an arbitrary time as a measurement result of the second measuring unit;
The light irradiating means irradiates the object to be measured with intensity-modulated light at a first time, and outputs two light beams having different wavelengths at a first time with signals having different phases at a second time. Intensity modulation is performed to irradiate the object to be measured, and the object to be measured is irradiated with intensity-modulated light at the third time, and two light beams having different wavelengths are applied to the second frequency at the fourth time. And irradiating the object to be measured with intensity modulation by signals of different phases,
The optical power control means gradually changes the optical power of at least one of the two intensity-modulated lights at the second and fourth times,
The frequency measuring means measures, as the first frequency, a modulation frequency at which the amplitude of the electric signal obtained at the first time becomes maximum, and the phase of the electric signal obtained at the third time is referred to Search for a modulation frequency to be a phase as the second frequency,
The second phase measuring means measures the phase of the electric signal when the amplitude of the electric signal obtained at the first time is maximum as the reference phase, and the electric signal obtained at the second time. Searching for a first inflection point where the phase of the electric signal becomes 0, searching for a second inflection point where the phase of the electrical signal obtained at the fourth time becomes 0,
The optical power measuring means measures a difference in optical power between two intensity-modulated lights at the first inflection point at the second time, and 2 at the second inflection point at the fourth time. Measure the difference in optical power of the two intensity-modulated lights,
The optical power change deriving means calculates the change amount between the optical power difference measured at the fourth time and the optical power difference measured at the second time as a measurement result of the second measuring means. As sought
A component concentration measuring apparatus, wherein a measurement result is obtained by performing measurement for each combination of two light irradiation means that can be selected from the n light irradiation means. In the component concentration measuring apparatus according to any one of claims 5 to 7,
N in the n light irradiation means is an integer satisfying (n (n-1) / 2 + 1)> M.

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