JP5336438B2 - Component concentration measuring method and apparatus - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To attain exact measurement of constituent concentration without being affected by a boundary state. <P>SOLUTION: A laser diode 1 irradiates an object 11 to be measured with light. An acoustic sensor 5 detects an optical acoustic signal to be generated from the object 11 to be measured. An information processor 10 measures a phase using a signal of a reference frequency whose amplitude becomes maximum as a measurement signal among electric signals obtained at first time, and measures the phase using the signal of the reference frequency after elapse of arbitrary time as the measurement signal. The information processor 10 searches for a frequency of the measurement signal so that the phase to be measured after the elapse of the arbitrary time becomes equal to the phase measured at the first time, and derives constituent concentration of a measuring object after the elapse of the arbitrary time from variation of the searched frequency and the reference frequency. <P>COPYRIGHT: (C)2012,JPO&amp;INPIT

Description

  The present invention relates to a component concentration measuring method and apparatus for continuously monitoring the concentration of components such as blood glucose contained in a measurement object. More specifically, the amount of change in the frequency of the measurement signal is obtained based on the phase information of the measurement signal, and the amount of change in the sound speed is substantially obtained, thereby removing the strong bias of the measurement signal inherent to the CW measurement system, and CW The present invention relates to a technique for eliminating the main problem of a measurement system.

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).

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

  The main problem when adopting the CW method is that the measurement sensitivity depends on the boundary conditions. Here, the boundary means a surface on which elastic waves are reflected in the human body. Such reflection of elastic waves occurs every time the wave propagates through an interface between the acoustic impedance Z1 and the acoustic impedance Z2 different from the acoustic impedance Z1 (for example, an interface between meat and bone, an interface between liquid and air). In the CW method, when such a boundary exists, a local resonance cavity is formed, and as a result, a standing wave is generated in the vicinity of the region irradiated with light. Furthermore, this standing wave or mode of resonance strongly depends on the size of the resonant cavity and its characteristics.

Accurate and reproducible control of boundary conditions is difficult. This is because the dimensions change from patient to patient, and it is easy for the detection part of the acoustic sensor to move several millimeters.
As described above, in the conventional CW method, when monitoring the blood glucose level of the human body, the photoacoustic wave is multiple-reflected on the surface of the human body, so the reflection state changes due to the impedance and shape change of the human body during measurement. As a result of the bias in the measurement signal, there is a problem that an error occurs in the calculated blood glucose level.

  Because of these problems, almost all publications dealing with the photoacoustic method disclose the mechanism of the pulse method. As mentioned above, the pulse method must use high optical power to obtain high sensitivity. Therefore, there was a possibility that it would be a safety problem for the human body.

  The present invention has been made to solve the above-described problems, and realizes component concentration measurement that is accurate and not affected by the boundary state while maintaining the advantage of the CW measurement system that it is not necessary to use high optical power. It is an object of the present invention to provide a component concentration measuring method and apparatus capable of performing the same.

  The component concentration measuring method of the present invention includes a first light irradiation step for irradiating light to a measured object whose concentration of a component to be measured is known, and the first light irradiation step generates the measured object from the measured object. A first photoacoustic signal detecting step for detecting a photoacoustic signal to be output and outputting an electric signal, and a signal having a reference frequency having a maximum amplitude among the electric signals obtained in the first photoacoustic signal detecting step. As a measurement signal, a first phase measurement step for measuring the phase of the measurement signal, a second light irradiation step for irradiating light on the object to be measured after an arbitrary time has elapsed, and this second light irradiation A second photoacoustic signal detecting step for detecting a photoacoustic signal generated from the object to be measured in a step and outputting an electric signal; and the reference among the electric signals obtained in the second photoacoustic signal detecting step. Frequency A second phase measurement step for measuring the phase of the measurement signal, and 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 frequency search step for searching for the frequency of the signal, and a concentration derivation step for deriving the concentration of the component to be measured after the elapse of the arbitrary time from the amount of change between the frequency searched in the frequency search step and the reference frequency. It is characterized by.

In one configuration example of the component concentration measurement method of the present invention, the first and second phase measurement steps and the frequency search step include a function generator that generates a reference signal and a lock that receives the reference signal as an input. By using an in-amplifier, a measurement signal having a desired frequency is detected from the electrical signal obtained in the first and second photoacoustic signal detection steps.
In one configuration example of the component concentration measurement method of the present invention, the concentration derivation step calculates a frequency change rate from the frequency searched in the frequency search step and the reference frequency, and the frequency change rate and the measurement target The component concentration of the measurement target after the arbitrary time elapses is derived from the known frequency change rate when the component concentration changes by a unit amount.

In addition, in one configuration example of the component concentration measurement method of the present invention, a signal having a reference frequency with the maximum amplitude among the electrical signals obtained in the first photoacoustic signal detection step is used as a measurement signal. The second photoacoustic signal detection when the phase measured in the first amplitude measuring step for measuring the amplitude of the signal and the phase measured in the first phase measuring step are equal to the phase measured in the first phase measuring step. A second amplitude measurement step of measuring the amplitude of the measurement signal using the signal of the reference frequency among the electrical signals obtained in the step, and the amplitude measured in the second amplitude measurement step are the first amplitude measurement step. If the amplitude is different from the amplitude measured in the amplitude measurement step, the peak of the amplitude closest to the reference frequency is searched for, and the frequency of the searched peak is the new reference frequency. It is characterized in further comprising a shift calibration means.
Moreover, one configuration example of the component concentration measurement method of the present invention further includes a phase offset adjustment step of adding an offset to the phase so that the phase measured in the first phase measurement step becomes zero. Is.

  The component concentration measuring apparatus according to the present invention includes a light irradiating means for irradiating light to the object to be measured, and light for detecting a photoacoustic signal generated from the object to be measured by this light irradiation and outputting an electric signal. An acoustic signal detection means; a phase measurement means for measuring the phase of the measurement signal included in the electrical signal; a frequency search means for searching for the frequency of the measurement signal after an arbitrary time; and Concentration derivation means for deriving the concentration of a component to be measured from the amount of change in the frequency of the measurement signal, and the light irradiating means for the object to be measured whose component concentration of the measurement object is known at a first time. The phase measuring means irradiates the measured object with light after an arbitrary time, and the phase measuring means has a reference frequency at which the amplitude is maximum among the electrical signals obtained at the first time. Measure signal And measuring the phase of the measurement signal, measuring the phase of the measurement signal using the signal of the reference frequency among the electrical signals after the lapse of any time as a measurement signal, and the frequency search means Searching for the frequency of the measurement signal in which the phase measured after the lapse of an arbitrary time is equal to the phase measured at the first time, and the concentration derivation means includes the frequency searched by the frequency search means and the reference frequency The component concentration of the measurement target after the lapse of the arbitrary time is derived from the amount of change in.

Further, one configuration example of the component concentration measuring apparatus of the present invention further includes a function generator that generates a reference signal, and a lock-in amplifier that receives the reference signal and detects a measurement signal having a desired frequency from the electrical signal. Are provided.
Further, in one configuration example of the component concentration measuring apparatus of the present invention, the concentration derivation unit calculates a frequency change rate from the frequency searched by the frequency search unit and the reference frequency, and the frequency change rate and the measurement target are calculated. The component concentration of the measurement target after the arbitrary time elapses is derived from the known frequency change rate when the component concentration changes by a unit amount.

Further, one configuration example of the component concentration measuring apparatus of the present invention further includes an amplitude measuring unit that measures the amplitude of the measurement signal included in the electrical signal, and a frequency shift calibration unit that calibrates the frequency shift of the measurement signal. The amplitude measuring means measures the amplitude of the measurement signal using a signal of a reference frequency having the maximum amplitude among the electrical signals obtained at the first time as the measurement signal; When the phase measured later is equal to the phase measured at the first time, the amplitude of the measurement signal is measured using the signal of the reference frequency among the electrical signals after the arbitrary time has passed as the measurement signal. The frequency shift calibrating means is configured to provide a frequency closest to the reference frequency when the amplitude measured after the lapse of the arbitrary time is different from the amplitude measured at the first time. Searches the peak in the number of amplitude, is characterized in that the frequency of the searched peak and the new reference frequency.
In addition, one configuration example of the component concentration measuring apparatus of the present invention further includes a phase offset adjusting means for adding an offset to the phase so that the phase measured at the first time becomes zero. is there.

  According to the present invention, a frequency change amount of the measurement signal is obtained based on the phase information of the measurement signal, and the component concentration of the measurement target is derived from the change amount of the frequency, whereby the frequency unique to the measurement system of the CW method is obtained. It is possible to eliminate the bias of shift and realize an accurate measurement that is not affected by the boundary state while maintaining the advantage of the CW measurement system that it is not necessary to use high optical power. In the present invention, it is possible to cope with any boundary state in the object to be measured. In the present invention, the component concentration can be continuously measured, and can be used at several different frequencies in the case of multivariate analysis using a plurality of light wavelengths. In the present invention, robustness can be improved, for example, when non-invasive and continuous measurement of blood glucose concentration is performed.

  Further, in the present invention, by using a function generator and a lock-in amplifier, high frequency accuracy can be obtained, and component concentration measurement that is accurate and not affected by the boundary state can be realized.

  Further, in the present invention, by calculating the frequency change rate from the frequency searched in the frequency search step and the reference frequency, this frequency change rate and the known frequency change rate when the component concentration of the measurement target changes by a unit amount From this, it is possible to derive the concentration of the component to be measured after an arbitrary time has elapsed.

  In the present invention, when the amplitude measured in the second amplitude measurement step is different from the amplitude measured in the first amplitude measurement step, the peak of the amplitude closest to the reference frequency is searched for and searched. By setting the peak frequency as a new reference frequency, it is possible to calibrate the frequency shift of the measurement signal caused by an effect other than the change in the component concentration of the measurement target.

  Further, in the present invention, the processing of the frequency search step can be facilitated by adding an offset to the phase so that the phase measured in the first phase measurement step becomes zero.

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 figure which shows an example of the experimental result by the component concentration measuring apparatus which concerns on embodiment of this invention.

[Principle of the Invention]
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 present invention 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 component concentration measuring method of the present invention, 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 procedure for measuring the component concentration of the present invention 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. 5,1981,19 (GHThomas et al., “Method and apparatus for non-invasive monitoring of blood glucose”, 1992), the concentration of plasma components other than glucose changes slowly. 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 (1)

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 (2)

From the formulas (1) and (2), the following formula is obtained.
f = (nv _ac ) / 2L (3)
From equation (3), 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 Equation (5), J _m is an mth 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 (6)

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 (6), it can be seen that the change in the glucose concentration linearly leads to the change in the frequency of the acoustic signal. .
As described above, in the present invention, 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 a laser diode 1 serving as a light irradiation unit that emits laser light, an LD driver 2 that drives the laser diode 1, an optical fiber 3 that guides the laser light emitted from the laser diode 1, and an optical fiber. 3 is fixed, an optical fiber holder 4 that irradiates a human body or a device under test 11 that is a part of the human body with a laser beam, and a photoacoustic signal generated from the device under test 11 due to the photoacoustic effect are detected, Of the acoustic sensor 5 serving as a photoacoustic signal detecting means for converting the electrical signal proportional to the signal, an amplifier 6 for amplifying the electrical signal output from the acoustic sensor 5, a function generator 7 for generating a reference signal, A lock-in amplifier 8 for detecting a measurement signal of a desired frequency from the output signal of the amplifier 6 by using the output signal and the reference signal output from the function generator 7 as input, and an LD driver A voltage-current converter 9 that supplies a drive current to the bar 2, a function generator 7 and a lock-in amplifier 8, and a computer that processes a measurement signal detected by the lock-in amplifier 8 to derive a blood glucose concentration. And the information processing apparatus 10. An example of the acoustic sensor 5 is a microphone.

  FIG. 4 is a block diagram illustrating a configuration of the information processing apparatus 10. The information processing apparatus 10 includes a function generator control unit 20 that controls the function generator 7, an amplitude measurement unit 21 that measures the amplitude of the measurement signal, a phase measurement unit 22 that measures the phase of the measurement signal, and a phase offset A phase offset adjusting unit 23 for adjusting the amplitude, phase and frequency information of the measurement signal, a glucose concentration deriving unit 25 for deriving a blood glucose concentration from a change in the frequency of the measurement signal, and a measurement A frequency shift calibration unit 26 that calibrates the frequency shift of the signal and a storage unit 27 for storing information are provided. The function generator control unit 20 constitutes frequency search means.

Hereinafter, the operation of the component concentration measuring apparatus of the present embodiment will be described. FIG. 5 is a flowchart showing the operation of the component concentration measuring apparatus.
First, when a drive current is supplied from the LD driver 2, the laser diode 1 emits laser light. Similar to the conventional CW method, the laser light emitted from the laser diode 1 is a continuous wave. This laser beam is guided by the optical fiber 3 and irradiated onto the object to be measured 11 (step S1 in FIG. 5). The acoustic sensor 5 detects a photoacoustic signal generated from the device under test 11, and the amplifier 6 amplifies the electrical signal output from the acoustic sensor 5. The lock-in amplifier 8 detects a measurement signal having a frequency determined by the reference signal output from the function generator 7 among the signals included in the output of the amplifier 6.

  The function generator control unit 20 of the information processing apparatus 10 performs frequency sweep that gradually changes the frequency of the measurement signal detected by the lock-in amplifier 8 by changing the frequency of the reference signal generated by the function generator 7 ( FIG. 5 step S2). 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 21 of the information processing apparatus 10 measures the amplitude A ₀ of the measurement signal at the frequency of this peak (reference frequency f ₀ ) (step in FIG. 5). S4) The phase measurement unit 22 measures the phase P ₀ of the measurement signal at the reference frequency f ₀ (step S5).

Prior to such measurement, the phase offset adjustment unit 23 of the information processing apparatus 10 controls the voltage-current converter 9 through the lock-in amplifier 8 to change the phase of the drive current supplied from the LD driver 2 to the laser diode 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 11 to be measured (step S3 in FIG. 5).

The information recording unit 24 stores the amplitude A ₀ measured by the amplitude measurement unit 21, the phase P ₀ (P ₀ = 0) measured by the phase measurement unit 22, and the peak frequency (reference frequency f ₀ ). (Step S6 in FIG. 5).
Next, a standard blood glucose measurement method is performed on the device under test 11 to obtain a reference concentration X (g / dl) (step S7 in FIG. 5). Thus, the amplitude A ₀ and the phase P ₀ (P ₀ = 0) at the reference frequency f ₀ are obtained with the reference concentration X (g / dl). To perform a standard blood glucose measurement method, insert a glucose sensor into the body of the blood glucose meter, set the needle on a dedicated machine (or body), collect blood from a finger, etc., and absorb the blood into the glucose sensor. Let A standard blood glucose measurement method uses a known concentration of glucose solution as a standard calibration solution for machine operation confirmation. It is used to check whether the machine is operating normally during initial operation, or to check whether the blood glucose level is abnormal (ie, whether the machine is operating normally).

  Here, when a plurality of laser diodes 1 having different oscillation wavelengths are used, the processes in steps S2 to S6 may be performed for each wavelength.

  Next, measurement at time t after an arbitrary time has elapsed from the first measurement in steps S1 to S6 will be described. As in the case of the first measurement, the device under test 11 is irradiated with laser light (step S8 in FIG. 5). Here, by making the phase of the drive current supplied from the LD driver 2 to the laser diode 1 the same as in step S3, the phase of the laser beam irradiated to the object to be measured 11 is made the same as in step S3. Yes.

The function generator control unit 20 of the information processing apparatus 10 causes the lock-in amplifier 8 to detect the measurement signal having the reference frequency f ₀ by changing the frequency of the reference signal generated by the function generator 7. The phase measurement unit 22 of the information processing apparatus 10 measures the phase P ₁ of the measurement signal at the reference frequency f ₀ (step S9 in FIG. 5). 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 reference concentration X (g / dl).

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 20 of the information processing apparatus 10 changes the frequency of the reference signal generated by the function generator 7. 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 S10 in FIG. 5). 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 21 of the information processing apparatus 10 measures the amplitude A ₁ of the measurement signal at the frequency f ₁ (step S11 in FIG. 5).
Then, the information recording unit 24 stores the amplitude A ₁ measured by the amplitude measuring unit 21, the phase P ₁ (P ₁ = P ₀ = 0) of the measurement signal, and the frequency f ₁ in the storage unit 27 (see FIG. 5 step S12).

  The storage unit 27 of the information processing apparatus 10 stores in advance the frequency change rate of the measurement signal when the blood glucose concentration changes by a unit amount (1 (g / dl)). Such frequency change rate data can be obtained in advance by performing a standard blood glucose measurement method. In the present embodiment, the frequency change rate stored in the storage unit 27 is 0.18 (% / g / dl).

The glucose concentration deriving unit 25 of the information processing apparatus 10 derives the blood glucose concentration Y (g / dl) at time t (step S13 in FIG. 5). First, the glucose concentration deriving unit 25 calculates the frequency change rate (f ₁ −f ₀ ) / f ₀ × 100 of the measurement signal. Then, the glucose concentration deriving unit 25 calculates the blood glucose concentration Y (g / dl) at time t by the following equation.
Y = ((f ₁ −f ₀ ) / f ₀ × 100) /0.18+X (7)

That is, by dividing the frequency change rate obtained from the measurement signal by the frequency change rate 0.18 (% / g / dl) stored in the storage unit 27, the amount of change in blood glucose concentration can be obtained. By adding the amount of change to the reference concentration X (g / dl), the blood glucose concentration Y at time t can be calculated.
This is the end of the processing of the component concentration measuring apparatus of the present embodiment. If the processes in steps S8 to S13 in FIG. 5 are repeated, the blood glucose concentration can be continuously monitored. Note that the processing order of steps S1 to S13 is one example, and is not limited to the example of FIG.

In the present embodiment, 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 S9 There are cases where it is equal to (P ₀ = 0). In this case, the amplitude measurement unit 21 of the information processing apparatus 10 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 26 of the information processing apparatus 10 by the function generator 7 changes the frequency of the reference signal generated, performs frequency sweep lock-in amplifier 8 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 26 finds the amplitude peak of the measurement signal, the frequency shift calibration unit 26 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 S1 to S7 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.

6 (A) and 6 (B) are diagrams showing an example of an experimental result by the component concentration measuring apparatus of the present embodiment.
First, processing of steps S1 to S6 in FIG. 5 was performed using pure water as the DUT 11. Here, the DUT 11 was enclosed in a cylindrical glass cell. Needless to say, the blood glucose concentration of water is 0 (g / dl). The measurement result at this time is shown in FIG. 6A shows the phase of the measurement signal when 600 is pure water. Here, as described in step S2, in order to search for the resonance peak of the measurement signal, a frequency sweep that changes the frequency of the measurement signal was performed. A peak at 481 kHz was selected as one peak.

  Subsequently, processing in steps S8 and S9 in FIG. 5 was performed using glucose in the aqueous solution having a blood glucose concentration of 2 (g / dl) as the measurement object 11. As in the case of the pure water described above, the DUT 11 was sealed in a cylindrical glass cell. Here, the resolution of the frequency of the measurement signal is 1 kHz. Even if the function generator 7 shown in FIG. 3 is not provided, an experimental result can be obtained, but when the function generator 7 is not provided, a high frequency accuracy of 1 kHz cannot be obtained. 6A shows the phase of the measurement signal when 601 is 2 (g / dl) glucose in water.

  As can be seen from FIG. 6 (A), in the case of 2 (g / dl) glucose in water with respect to pure water, the frequency of the phase information of the measurement signal despite the cylinder cell dimensions kept constant. The shift is obvious. Although not shown in FIG. 6A, the amplitude information of the measurement signal is also shifted in frequency.

By the processing in step S10, the measurement frequency f ₁ is searched for in which the phase P ₁ of the measurement signal in the case of 2 (g / dl) glucose in water is equal to the phase P ₀ of the measurement signal in the case of pure water. In FIG. 6A, reference numeral 602 denotes the phase of the measurement signal of glucose in water (2 (g / dl)) when the frequency is shifted so as to overlap with the phase P ₀ of the measurement signal in the case of pure water. ing.
If the frequency f ₁ is determined, the blood glucose concentration can be derived by the process of step S13 in FIG.

  Next, FIG. 6B shows the result of measuring the frequency change rate of the measurement signal at different blood glucose concentrations, different optical wavelengths, and different cylindrical glass cell dimensions. In FIG. 6B, reference numeral 603 denotes the frequency change rate of the measurement signal when the optical wavelength is 1610 nm and the length of the cylindrical glass cell in which the DUT 11 is measured is 15.7 mm, and 604 is the optical wavelength is 1380 nm. The frequency change rate of the measurement signal when the glass cell length is 7 mm is shown, and 605 shows the frequency change rate of the measurement signal when the optical wavelength is 1610 nm and the glass cell length is 7 mm.

  The blood glucose concentration could be measured from 65 (mg / dl) to 2 (g / dl) with a frequency accuracy of 1 kHz. The reason for choosing the two optical wavelengths 1610 nm and 1380 nm is that water exhibits equal light absorption for the two optical wavelengths and glucose exhibits different light absorption for the two optical wavelengths.

  6B in FIG. 6B is a straight line obtained from linear regression of the measurement results of 603 to 605, and the slope of this straight line was 0.18. The value 0.18 (% / g / dl) of the frequency change rate stored in the storage unit 27 of the information processing apparatus 10 is obtained in advance by the experiment as described above. The value of the frequency change rate is almost the same as the value reported in the literature (0.15-0.28 (% / g / dl)).

  As described above, in the present embodiment, 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 derived from the amount of change in the frequency, so that high optical power is not used. Thus, it is possible to realize an accurate measurement that is not affected by the boundary state while maintaining the advantage of the CW measurement system.

  In the present embodiment, blood glucose has been described as an example of a component to be measured. However, the present invention is not limited to this, and the present invention can be widely applied to component analysis contained in a measurement object. is there.

  The information processing apparatus 10 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.

  DESCRIPTION OF SYMBOLS 1 ... Laser diode, 2 ... LD driver, 3 ... Optical fiber, 4 ... Optical fiber holder, 5 ... Acoustic sensor, 6 ... Amplifier, 7 ... Function generator, 8 ... Lock-in amplifier, 9 ... Voltage-current converter, 10 DESCRIPTION OF SYMBOLS Information processing apparatus, 20 Function generator control unit, 21 Amplitude measuring unit, 22 Phase measuring unit, 23 Phase offset adjusting unit, 24 Information recording unit, 25 Glucose concentration deriving unit, 26 Frequency shift calibration Part, 27... Storage part.

Claims (10)

A first light irradiation step of irradiating light to a measured object whose concentration of a component to be measured is known;
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 concentration derivation step for deriving a component concentration of a measurement target after the arbitrary time elapses from a change amount between the frequency searched in the frequency search step and the reference frequency. In the component concentration measuring method according to claim 1,
The first and second phase measurement steps and the frequency search step use a function generator for generating a reference signal and a lock-in amplifier having the reference signal as an input, whereby the first and second phase measurement steps are performed. A component concentration measurement method, comprising: detecting a measurement signal having a desired frequency from an electrical signal obtained in the photoacoustic signal detection step. In the component concentration measuring method according to claim 1 or 2,
The concentration derivation step calculates a frequency change rate from the frequency searched in the frequency search step and the reference frequency, and the frequency change rate and a known frequency change rate when the component concentration of the measurement target changes by a unit amount The component concentration measurement method is characterized in that the component concentration of the measurement target after the arbitrary time elapses is derived. In the component concentration measuring method according to any one of claims 1 to 3,
Further, a first amplitude measurement step for measuring the amplitude of the measurement signal using a signal having a reference frequency that maximizes the amplitude among the electrical signals obtained in the first photoacoustic signal detection step,
When the phase measured in the second phase measurement step is equal to the phase measured in the first phase measurement step, the signal of the reference frequency among the electrical signals obtained in the second photoacoustic signal detection step As a measurement signal, a second amplitude measurement step for measuring the amplitude of the measurement signal;
When the amplitude measured in the second amplitude measurement step is different from the amplitude measured in the first amplitude measurement step, the peak of the amplitude having the frequency closest to the reference frequency is searched, and the frequency of the searched peak And a frequency shift calibrating means using a new reference frequency as a reference frequency. In the component concentration measuring method according to any one of claims 1 to 4,
The component concentration measurement method further comprises a phase offset adjustment step of adding an offset to the phase so that the phase measured in the first phase measurement step becomes zero. A light irradiating means for irradiating the object to be measured;
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
Phase measuring means for measuring the phase of the 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;
Concentration deriving means for deriving the concentration of the component to be measured from the amount of change in the frequency of the measurement signal after the arbitrary time has elapsed,
The light irradiating means irradiates the measured object whose component concentration to be measured is known at a first time, and irradiates the measured object with light after an arbitrary time,
The phase measuring means measures the 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 after the elapse of the arbitrary time. Of the electrical signal, the signal of the reference frequency is used as a measurement signal, and the phase of the 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 concentration derivation device derives the component concentration of the measurement target after the arbitrary time elapses from the amount of change between the frequency searched by the frequency search unit and the reference frequency. In the component concentration measuring apparatus according to claim 6,
A function generator for generating a reference signal;
A component concentration measuring apparatus comprising: a lock-in amplifier that receives the reference signal and detects a measurement signal having a desired frequency from the electrical signal. The component concentration measuring apparatus according to claim 6 or 7,
The concentration derivation unit calculates a frequency change rate from the frequency searched by the frequency search unit and the reference frequency, and the frequency change rate and a known frequency change rate when the component concentration of the measurement target changes by a unit amount The component concentration measuring device, wherein the component concentration of the measurement target after the arbitrary time elapses is derived. In the component concentration measuring apparatus according to any one of claims 6 to 8,
Further, amplitude measuring means for measuring the amplitude of the measurement signal included in the electrical signal,
Frequency shift calibration means for calibrating the frequency shift of the measurement signal,
The amplitude measuring means measures the amplitude of the measurement signal using a reference frequency signal having the maximum amplitude among the electrical signals obtained at the first time, and measures the measured signal after an arbitrary time has elapsed. When the measured phase is equal to the phase measured at the first time, the amplitude of the measurement signal is measured using the signal of the reference frequency as a measurement signal among the electrical signals after the lapse of any time,
The frequency shift calibration means searches for the peak of the amplitude of the frequency closest to the reference frequency when the amplitude measured after the arbitrary time is different from the amplitude measured at the first time, A component concentration measuring apparatus characterized in that the searched peak frequency is set as a new reference frequency. In the component concentration measuring apparatus according to any one of claims 6 to 9,
The component concentration measuring apparatus further comprises phase offset adjusting means for adding an offset to the phase so that the phase measured at the first time becomes zero.

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