JPH09133655A - Photo-acoustic spectroscopy and spectrometer - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent the sensitivity from lowering due to the phase difference or interference caused by the difference between the irradiating position of exciting light and each point at the sensitive part of a sensor by irradiating a sample with an exciting light while scanning at a rate higher than the sound velocity. SOLUTION: A sample 4 is irradiated intermittently with a light of such wavelength as being absorbed by an object emitted from a light source 1. A beam splitter 2 introduces a part thereof to an optical scanner 3 which then irradiates the sample 4 with an exciting light while scanning at a rate higher than the sound velocity. Consequently, a substance in the sample 4 absorbs the light and excited. When the absorbed energy is discharged, displacement takes place through thermal expansion thus generating a photo-acoustic wave. It is detected by a piezoelectric sensor 5 having a planar sensitive part touching the sample 4 and converted into an electric signal. The electric signal is amplified through an amplifier 6 and subjected to analysis and determination by a metric controller 8 thus producing a signal proportional to the quantity of substance to be measured in the sample 4.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an analysis device and an analysis method for analyzing a chemical substance by a photoacoustic method, and is particularly suitable for non-invasive blood component analysis for analyzing components in blood without collecting blood. The present invention relates to a photoacoustic spectroscopy analyzer and analysis method that can be used.

[0002]

2. Description of the Related Art A conventional photoacoustic spectroscopic analyzer is, for example,
KM Quan et al., Phys. Med. Biol., 38, (1993), 1911-
As described in 1922, the position of irradiating the sample with a pulsed excitation light beam is fixed, and a piezoelectric sensor having a flat sensitive portion is provided in contact with the sample in a direction perpendicular to the optical axis of the excitation light,
It was common to measure photoacoustic signals. On the other hand, JP-A-63-2476 by Elizabeth May Dowling
Japanese Unexamined Patent Publication No. 52-52 discloses a method of obtaining the concentration of a substance in a biological sample by a photoacoustic spectroscopic device using a plurality of light sources and a plurality of piezoelectric sensors.

[0003]

However, since the photoacoustic signal is generated concentrically around the optical axis of the excitation light, a piezoelectric sensor having a planar sensitive portion is used in the above-mentioned Phys. Med.
ol., 38, (1993), 1911-1922, the time at which the photoacoustic wave reaches the sensor-sensitive part varies depending on the parts of the sensor-sensitive part. At a specific time,
There is a problem that it is difficult to detect with high sensitivity because the phase of the photoacoustic signal is different in each part of the sensor sensitive part and the outputs of each part of the sensor interfere with each other. In particular, when it is necessary to measure a weak signal such as non-invasive blood component analysis, it is preferable to shorten the distance between the optical axis and the piezoelectric sensor, and it is preferable to increase the area of the sensor sensitive section. . However, if this is done, the curvature of the wavefront of the photoacoustic wave in the sensor sensitive section becomes large and the arrival time difference of the photoacoustic wave becomes large. Conversely, the phase difference and the interference of the photoacoustic signal become conspicuous, so high sensitivity can be achieved. could not.

Further, Japanese Patent Application Laid-Open No. 63-247652 discloses a method of using a plurality of light sources and a plurality of piezoelectric sensors, for example, arranging a row of these light sources and the piezoelectric sensors around a measurement sample for measurement. Has been done. However, the plurality of light sources are for generating lights of different wavelengths (page 7, upper right line 8), and are the plurality of piezoelectric sensors provided in a one-to-one correspondence with each light source (FIG. 3, FIG. 4 or 5), or the output sides are connected to each other (page 3, lower right line, FIG. 7) 1
It is used as one sensor. Therefore, considering the photoacoustic wave incident on each piezoelectric sensor, there is only one light source from which the photoacoustic wave is generated, and the irradiation position of the excitation light is also fixed. In other words, if we consider the combination of individual light sources and piezoelectric sensors, in principle Phy
s. Med. Biol., 38, (1993), 1911-1922, and has the same problem as above.

It is an object of the present invention to perform sensitivity in photoacoustic spectroscopic analysis using a sensor having a planar sensitive section due to phase difference and interference caused by a distance difference between the irradiation position of excitation light and each section of the sensor sensitive section. Is to detect the photoacoustic signal with high sensitivity.

[0006]

The above object is to irradiate a sample while exciting light is scanned at a speed equal to or higher than the speed of sound in the sample, and to generate a linear composite wave formed at the tip of the wavefront of the photoacoustic wave into a planar shape. It is achieved by generating the sensor in parallel with the sensor-sensitive part and simultaneously detecting by one sensor. That is,
The present invention, in a photoacoustic spectroscopic analyzer comprising a means for irradiating a sample with excitation light and a sensor for detecting a photoacoustic wave emitted from the sample, while scanning the excitation light at a speed equal to or higher than the speed of sound in the sample. It is characterized by irradiation.

The sound velocity in the sample is c and the scanning speed of the excitation light is v
In this case, the scanning direction of the excitation light is set so as to form an angle a represented by the following formula with respect to the flat sensitive portion of the sensor. sina = c / v At this time, when the length of the sensitive portion of the sensor is L and the scanning time of the excitation light is Tn, the following equation holds. ^{L = Tn (v 2 -c 2} ) 1/2

Further, according to the present invention, the excitation light is emitted while scanning toward the sensor at a speed equal to the speed of sound in the sample. Alternatively, a plurality of excitation lights are simultaneously emitted from one sensor at positions equidistant from each other. In order to improve the reproducibility of the measurement, it is preferable to guide the excitation light to the sample by an optical fiber bundle and use a sensor head to which the optical fiber bundle and the sensor are fixed. The optical fiber bundle is an optical fiber bundle for image transmission in which a light pattern incident on one end is output to the other end as it is, and it is preferable to provide a unit capable of arbitrarily adjusting the optical scanning pattern.

The present invention also provides a photoacoustic spectroscopic analysis method for detecting a photoacoustic wave emitted from a sample by irradiating the sample with excitation light, wherein the photoacoustic wave is generated at a plurality of positions in the sample, It is characterized in that the wavefront tips of a plurality of photoacoustic waves are simultaneously detected by one sensor. In the analysis, the excitation light is irradiated individually to each position in the sample, the photoacoustic wave from each irradiation position is detected by the sensor, and at least one of the irradiation position of the excitation light and the scanning speed of the excitation light is determined by its propagation time. Is preferably corrected.

The first absorption by the substance to be measured as excitation light
By using the excitation light of the wavelength and the excitation light of the second wavelength absorbed by the medium in the sample and comparing the measurement results of both, the concentration of the substance to be measured in the medium can be obtained. The photoacoustic spectroscopic analyzer of the present invention can be used for non-invasive biochemical component analysis for non-invasively measuring biochemical components in a living body. At that time, in the preliminary measurement, the excitation light is individually irradiated to each position in the sample, the photoacoustic wave from each irradiation position is detected by the sensor, and the deviation of the sound velocity in each part of the sample from the propagation time of the photoacoustic wave is detected. Once obtained, the measurement can be performed by correcting the sound velocity deviation by correcting each irradiation position of the excitation light according to the deviation in the main measurement. When analyzing biochemical components in blood, the sample is pre-scanned by using the wavelength of the excitation light as the absorption wavelength of hemoglobin to determine the region where blood vessels exist, and photoacoustic spectroscopy analysis is performed in that region. You can also

[0011]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to the drawings. [First Embodiment] FIG. 1 is a schematic configuration diagram of a first embodiment of a photoacoustic spectroscopy analyzer according to the present invention. 1 is a light source, 2 is a beam splitter, 3 is an optical scanning device, 4 is a sample, 5
Is a piezoelectric sensor, 6 is an amplifier, 7 is a reference light detector, and 8 is a measurement control device.

The light source 1 intermittently emits light (excitation light) having a wavelength absorbed by the substance to be measured in the sample 4. The beam splitter 2 guides a part thereof to the optical scanning device 3, and the optical scanning device 3 changes or scans the direction of the light beam with time. When the sample 4 is irradiated with the excitation light, the substance to be measured in the sample absorbs this light and is excited. Then, when the absorbed energy is released by a non-radiative process, a displacement due to thermal expansion, that is, a photoacoustic wave is generated. A photoacoustic wave intermittently generated in response to the intermittent excitation light is detected by a piezoelectric sensor 5 provided with a flat sensitive portion in contact with the sample and converted into an electric signal.
This is amplified by the amplifier 6 and analyzed and quantified by the measurement control device 8. Since the generated photoacoustic wave is proportional to the absorbance of the measurement target substance, a signal proportional to the amount of the measurement target substance in the sample is obtained as a result. On the other hand, the beam splitter 2
The other light split by is detected by the reference light detector 7 and is used for signal processing in the measurement control device 8 as a reference signal of the light source intensity and the irradiation time.

As the light source 1, a pulse laser-excited dye laser, a pulse-driven semiconductor laser, or the like can be used. The wavelength of the light source 1 can increase the intensity of the photoacoustic signal when the absorbance of the substance to be measured is large, but other wavelengths can be used if the wavelength of the substance to be measured is greater than that of impurities or matrix. But it doesn't matter.
Here, bilirubin, which is one of blood components, was used as a measurement target substance, and a living body phantom was used as a sample. Therefore, Coumarin 450 was used as the dye of the dye laser, and laser light having a maximum absorption wavelength of bilirubin of 450 nm was obtained. The duration of pulsed light is about 5 ns.

The beam splitter 2 used was aluminum vapor-deposited on quartz with a transmittance (toward the sample) of 95% and a reflectance (toward the reference photodetector) of 5%. Although a rotary polygon mirror is used as the optical scanning device 3, it may be based on other principles such as a galvano mirror and a photoacoustic deflector as long as the optical path can be temporally changed and scanned. I don't mind. In addition, if a plurality of polygon mirrors are built in the optical scanning device, and two or more axes of freedom are provided, a two-dimensional scanning pattern can be obtained.

As the piezoelectric sensor 5, a piezoelectric element using a composite piezoelectric material composed of piezoelectric ceramics and an acoustic matching layer of epoxy was used. Of course, if the vibration in the time domain of several microseconds can be detected accurately and with high sensitivity, PVDF
It is also possible to use a polymer piezoelectric element made of, for example. In order to improve the reproducibility of measurement, it is preferable to define the relative positions of the excitation light from the light source, the sample, and the piezoelectric sensor. For this purpose, it is possible to use, for example, a jig for guiding the excitation light to the sample by means of an optical fiber bundle and fixing the optical fiber bundle and the piezoelectric sensor in a mutually adjustable manner. By integrating these as a sensor head, the irradiation position of the excitation light and the installation position of the sensor can be easily defined, and highly reproducible measurement can be performed.

Next, scanning of the excitation light will be described with reference to FIG. FIG. 2 is a cross-sectional view of a surface of the sample 4 including the piezoelectric sensor 5, which is perpendicular to the optical axis of the excitation light. FIG.
As shown in, the starting point is a point A in the direction perpendicular to the sensor surface from one end of the piezoelectric sensor 5, and the ending point is a point B in the direction perpendicular to the sensor surface from the other end of the piezoelectric sensor 5. Excitation light is emitted while scanning a line segment AB connecting the two.

A series of scans of the excitation light, at time 0,
The line segment AB starts from the end point A farther from the piezoelectric sensor 5 and continues at a constant speed v until it ends at the other end point B at time Tn. That is, the scanning speed v of the excitation light on the sample is a quotient obtained by dividing the distance of the line segment AB by the scanning time Tn. Here, as the simplest example, the constant time interval dT
The case of irradiating the excitation light pulse every time will be described.
When Tn is an integral multiple of dT, the excitation light is irradiated in the interval of the line segment AB a total of [(Tn / dT) +1] times at equal intervals. In FIG. 2, each irradiation point in the case of Tn / dT = 8 is indicated by a black circle. The irradiation to the point A is counted as the 0th shot, and the irradiation of the i-th shot is the point C on the line segment AB at the time (dT · i).
Is irradiated. Point C represents the line segment AB as i: [(Tn / d
T) -i]. The photoacoustic waves induced by the excitation light irradiation propagate in the sample concentrically around each irradiation point, but unlike the conventional case where the position of the irradiation point is fixed, each photoacoustic wave Since the centers of are different, the wave energy density becomes spatially asymmetric.

Here, the relationship between the scanning speed v and the sound speed c in the sample will be described with reference to FIG. In FIG. 3, T
In the case of n / dT = 8, the tip of the wavefront of each photoacoustic wave at time Tn is indicated by a circle. Scanning speed v
Is set to be larger than the sound velocity c in the sample 4. In this case, a part of the wavefront tip of the composite wave of each photoacoustic wave is aligned linearly (section DB and D'B), and the phase of the photoacoustic wave is also aligned in this section, so the density of the wave energy of this part is equal. Will be higher than others. The sound velocity c in sample 4 is 15 in the figure.
00m / s, scanning speed v is 8620m / s, AB is 10
It is a schematic diagram when mm, Tn is 1.16 microseconds, and dT is 0.14 microseconds.

Next, the relationship between the scanning section, the scanning direction and the position of the piezoelectric sensor will be described with reference to FIGS. Piezoelectric sensor 5
As the material, a material having a flat sensitive portion, which has good characteristics and can be obtained at low cost, was used. As shown in FIG. 3, the photoacoustic wave generated at time 0 has propagated to the region indicated by the circle at the left end at time c by time Tn, and during this time, the excitation light is transmitted from point A to point B. Up to the speed v. Therefore, (distance AD) :( distance AB) is c:
The following relationship (1) is established for the angle a formed by the line segment DB and the line segment AB. sina = c / v (1)

That is, the section DB in which the wavefront tips of the above-described photoacoustic wave are aligned linearly form an angle a defined by the above equation (1) with respect to the scanning direction AB. In the example above, this angle is approximately 10 degrees. This relationship is similarly established at another time. For example, the tip of the wavefront of the photoacoustic wave at the time Tx after a specific time has elapsed from the time point in FIG. 3 is indicated by a circle in FIG. Between time Tn (FIG. 3) and time Tx (FIG. 4), each photoacoustic wave propagates by the same distance {c · (Tx−Tn)}, so that even at time Tx, one of the tips of the wavefront of the composite wave is propagated. The parts are aligned in a line, and the section is parallel to the line segment DB (or D′ B) in FIG. Therefore, as shown in FIG. 4, by setting the angle formed by the surface of the sensor 5 and the scanning section AB to be the angle a determined by the equation (1), the tip end of the wave front of the linearly aligned composite wave is set to the sensor sensitive section. Can be introduced simultaneously. By doing so, a plurality of ([(Tn / dT) +1} = 9 times in the above example) excitation light irradiation ends of a plurality of photoacoustic waves simultaneously enter the sensor surface in the same phase.

If the angle a is not necessarily large, it may be difficult to precisely set the scanning direction for the sensor 5. In such a case, the excitation light is individually radiated to each irradiation planned position in advance, the time until the wavefront tip of the photoacoustic wave is detected by the sensor 5 is measured, and each irradiation position is measured from this time and the sound velocity. And the sensor distance can be obtained. Although the actual measurement value of the angle a can be obtained based on these data, by comparing this with the assumed value, the correction value representing the deviation of the angle a can be obtained. In the actual measurement, the correction direction is used to adjust the scanning direction and the scanning speed, so that the front end of the wavefront of the composite wave of the photoacoustic waves can be simultaneously incident on the sensor surface in the same phase.

Comparing this embodiment with the conventional example, none of the above-mentioned conventional examples scans the excitation light, and only irradiates a specific point with the excitation light. Only one photoacoustic wave generated by one irradiation of the excitation light is incident on. The wave energy at the time of incidence is [(Tn / dT) +1] in the present invention as compared with the conventional example.
It is twice as large and can be detected with high sensitivity. Since Tn / dT = 8 is set here, it is possible to detect with 9 times higher sensitivity than the conventional example. Of course, it is possible to further increase the sensitivity by further increasing the number of times of excitation light irradiation.

Further, in the conventional example, the shape of the tip of the wavefront of the photoacoustic wave is circular, so that when a flat sensor is used to detect the photoacoustic wave, the time at which the photoacoustic wave is incident differs for each part of the sensor sensitive section. . At a specific time, the photoacoustic wave segments with different phases are incident on each part of the sensor sensitive part, and these interfere with each other, resulting in the signal strength detected by the sensor as a whole. There is a problem that it will decrease. On the other hand, in the embodiment described here, since the shape of the tip of the wavefront of the composite wave of the photoacoustic waves to be detected is linear, even when the detection is performed using a planar sensor, the light is not transmitted to the sensor sensitive section. Waves at the tip of the wavefront of an acoustic wave can be made incident at the same phase at the same time. Therefore, the problem of interference as in the conventional example does not occur with respect to the front end of the wavefront, so that there is no inconvenience that the signal intensity detected by the piezoelectric sensor decreases. When this effect is taken into consideration, this embodiment achieves 9 times or more higher sensitivity than the conventional example.

As is apparent from FIG. 4, the relationship of the following equation (2) is established between the length L of the sensitive portion of the piezoelectric sensor 5 and the duration Tn of a series of scans. However, the starting point A and the ending point B of the scanning are defined as shown in the above description and FIG. In the above example, L is 9.
It is 85 mm. ^{L = Tn (v 2 -c 2} ) 1/2 (2)

The number of times the excitation light is scanned is not limited to one. The accuracy can be further improved by repeating a series of scans and integrating the data. Further, in the above, only the specific surface perpendicular to the irradiation light has been described. However, since the same argument holds for other surfaces that are perpendicular to the irradiation light and include the piezoelectric sensor, it is understood that the same effect can be obtained even if the three-dimensional expansion is performed.

Since the simplest example has been described above, the irradiation of the excitation light is performed regularly, but of course, this need not be the case. It will be understood that if the scanning speed is constant, the same effect can be obtained regardless of the irradiation position in the scanning section. Other parameters are not limited to the above specific numerical values. According to this embodiment, intermittent light, which is excitation light, is irradiated at a plurality of positions in the sample while scanning at a speed equal to or higher than the speed of sound in the sample while maintaining a specific angle with respect to the piezoelectric sensor. Since the photoacoustic waves generated from the same can be received simultaneously in the same phase on the surface of one piezoelectric sensor, there is an effect that highly sensitive measurement can be performed with a simple configuration.

[Second Embodiment] Next, a second embodiment of the present invention will be described with reference to FIG. The second embodiment is almost the same as the first embodiment, but the scanning speed v and the sound speed c in the sample are equal, and accordingly, the relationship between the scanning direction and the position of the piezoelectric sensor is slightly different. FIG. 5 shows sample 4
FIG. 3 is a schematic view of a cross section of a plane perpendicular to the optical axis of excitation light in a cross section including a piezoelectric sensor 5. As shown in FIG. 5, a point A in a direction perpendicular to the sensor surface is set as a start point, and a point B on the perpendicular line and a point B between the piezoelectric sensor are set as end points.
A plurality of excitation lights are irradiated while scanning the line segment AB. Similar to the first embodiment, a series of scanning with the excitation light is performed at time 0.
Constant speed v from point A at point B to point B at time Tn
In this embodiment, this velocity is equal to the sound velocity c in the sample.

In this case, of the photoacoustic waves generated by each irradiation, the irradiation from the next time onward overlaps the tip of the wavefront traveling in the direction A to B. Therefore, the photoacoustic waves due to the respective irradiations are all superposed on the tip of the wavefront traveling in the direction A to B. In FIG. 5, as in the first embodiment, the pulsed excitation light is irradiated to the positions shown by black circles in the figure at constant time intervals dT. Here, the case where Tn / dT = 8 is shown. This photoacoustic wave is incident on the sensitive part of the piezoelectric sensor 5 at a time Tx after a lapse of a certain period of time from the time Tn when a series of irradiation is completed, and the wavefront tip of each photoacoustic wave at this moment is indicated by a circle in FIG. Indicated by. As can be seen from the figure, multiple [(Tn / dT) + 1 = 9 times]
A plurality of photoacoustic waves generated by the irradiation of the exciting light are simultaneously incident on the sensor 5. Comparing this with the conventional example, since the conventional example does not scan the excitation light, only a single photoacoustic wave generated by the irradiation of the excitation light once can be detected. Therefore, in the example of FIG. 5, there is an effect that detection can be performed with a sensitivity 9 times higher than that of the conventional example.

Comparing the second embodiment and the first embodiment, it is common that the excitation light is scanned by both, but is the scanning speed v higher than the sound speed c? There is a difference of equality. The angle formed by the piezoelectric sensor and the scanning section is the angle a defined by the equation (1) in the first embodiment, whereas it is a right angle in the second embodiment. However, when v = c is substituted into the equation (1), a becomes a right angle, so the second embodiment can be regarded as one special example of the first embodiment.

The second embodiment is easy to implement because the scanning direction of the excitation light is simple. However, the shape of the tip of the wavefront of the composite wave of photoacoustic waves is not a straight line,
When the length L of the sensitive portion of the sensor is larger than the distance between the sensor and the irradiation position, there is a possibility that the phase of the detected photoacoustic wave may be slightly different for each portion of the sensitive portion of the sensor. There is. Therefore, in this embodiment, it is particularly effective to make L smaller than the distance between the irradiation section and the sensor.

[Third Embodiment] Next, a third embodiment of the present invention will be described with reference to FIG. The third embodiment is almost the same as the first embodiment, except for the following points. That is, in the third embodiment, instead of scanning the excitation light, a plurality of prepared light sources are simultaneously driven, or a light beam from one light source is divided into a plurality of light beams by using a half mirror or the like. Then, the excitation light is simultaneously incident on a plurality of positions of the sample, and a linear synthetic wave formed at the tip of the wavefront of the photoacoustic wave generated by each excitation light is generated in parallel with the planar sensor sensitive section. , Sensor detects simultaneously.

FIG. 6 is a schematic view of a cross section of the sample 4 including the piezoelectric sensor 5, which is perpendicular to the optical axis of the excitation light. As shown in FIG. 6, a plurality of excitation lights are irradiated onto the line segment AB parallel to the sensitive portion of the piezoelectric sensor 5. In this example,
Excitation light was irradiated at equal intervals on nine points indicated by black circles in the figure. However, irradiation was performed all at once at time 0.
At time Tx when a certain time has elapsed from this point, each photoacoustic wave enters the sensitive section of the piezoelectric sensor 5. The wavefront tip of each photoacoustic wave at this moment is shown by a circle in FIG.

As can be seen from the figure, the wavefront tips of a plurality of photoacoustic waves generated by irradiation of excitation light at a plurality of points (in this case, 9 points) are incident on the sensor 5 at the same time. Comparing this with the conventional example, the case of FIG.
The effect is that detection can be performed with double high sensitivity. This third
Comparing the second embodiment with the first embodiment, the third embodiment is different from the first embodiment in that the excitation light is not scanned in the third embodiment. Further, the scanning speed v is not defined in the third embodiment, and the angle formed by the piezoelectric sensor and the scanning section cannot be directly compared. However, if the third embodiment in which a plurality of positions are simultaneously irradiated with excitation light is regarded as a special example in which the scanning speed v is infinite in the first embodiment, the following similarities can be found. That is, the angle formed by the piezoelectric sensor and the scanning section is the angle a defined by the equation (1) in the first embodiment, whereas in the third embodiment (the scanning section is the irradiation section). Parallel (if considered AB), that is, 0 degrees.
Here, if infinity is substituted for v in the equation (1), a becomes 0 degree, which is consistent with the third embodiment. That is, the third embodiment can be regarded as one special example (in the limit of v = ∞) of the first embodiment.

In this embodiment, it is not necessary to scan the excitation light, and it is sufficient to drive a plurality of independent light sources at the same time or to split the light beam from one light source, so that the structure is simple. . Further, the excitation light only needs to be incident on a position parallel to the sensitive portion of the sensor, so that the angle can be easily set. In the above description, a plurality of discrete (having a dot-shaped cross section) linear excitation light is irradiated onto the line segment AB, but one planar excitation light (having a linear cross section) is used as a line. Minute AB
The same effect can be obtained by irradiating it on top.

[Fourth Embodiment] Next, a fourth embodiment of the present invention will be described with reference to FIG. The fourth embodiment is almost the same as the first embodiment, except that the light having the absorption wavelength of the medium in the sample is used as the excitation light in addition to the light having the absorption wavelength of the substance to be measured. , Different from the first embodiment.

In FIG. 7, 1a is a first light source, 1b is a second light source, and 9 is a beam combiner. The same components as those in FIG. 1 are assigned the same numbers as those in FIG. 1 and detailed description thereof will be omitted. A dye laser having a wavelength of 450 nm is used as the first light source 1a, a pulse-driven semiconductor laser having a wavelength of 1450 nm is used as the second light source 1b, and a transmittance of 5 is used as the beam integrator 9.
A 0% half mirror was used.

Next, the operation of the apparatus shown in FIG. 7 will be described. Under the control of the measurement control device 8, first, the first light source 1a is operated and the second light source 1b is stopped. The beam combiner acts to combine the light from these two sources into one optical path, in which case the beam combiner emits pulsed light from the first source. After that, the photoacoustic signal proportional to the amount of the substance to be measured in the sample 4 corresponding to the first light source 1a is observed by the measurement control device 8 by the same process as in the device of the first embodiment.

When a series of scanning is completed, the measurement control device 8 suspends the first light source 1a and operates the second light source 1b. Then, the second light source 1b is emitted from the beam integrator.
The pulsed light from passes through and emerges. After that, by the same process as above, the measurement control device 8 observes a photoacoustic signal proportional to the amount of water in the medium corresponding to the second light source, which is the wavelength of 1450 nm in the sample. The measurement controller 8 calculates the ratio of these two signals,
It is displayed and output as the abundance ratio of the measurement target substance and the medium, that is, the concentration of the measurement target substance in the medium.

According to this embodiment, in addition to the effect of the first embodiment, there is an effect that the concentration of the substance to be measured in the medium can be obtained. In addition, even if the detection position of the photoacoustic signal due to the measurement target substance fluctuates due to the fluctuation of the excitation light irradiation position or the sensor installation position, the detection of the photoacoustic signal by the medium against these fluctuations of the measurement conditions. Since the efficiency also changes in proportion, these error factors can be removed by obtaining the ratio of the two, and more accurate measurement can be performed.

In this example, since the absorbance of the substance to be measured at the wavelength of the first light source is sufficiently larger than that of the medium, the concentration of the substance to be measured can be obtained by the above method. If the absorbance of the substance to be measured at the wavelength of is not sufficiently large compared to that of the medium, the measurement result using the second light source is subtracted from the measurement result using the first light source, It is also possible to obtain a measurement result corresponding to the amount of substance.

[Fifth Embodiment] Next, a fifth embodiment of the present invention will be described with reference to FIGS. FIG.
Is a schematic view showing the arrangement of the sensors near the measurement site, FIG. 9 is a view showing a state in which the sensor head is attached to the arm, FIG. 10 is a view of the sensor head seen from above, and FIG. FIG. 12 is a schematic view of the light incident end side of the optical fiber bundle,
FIG. 13 is a schematic diagram of the display unit.

The fifth embodiment is almost the same as the fourth embodiment, but a living body is used as a sample, and a blood vessel (vein) near the body surface of the upper arm wrist is used as a measurement site.
By selecting a blood vessel having a short distance from the body surface and a large diameter, it is possible to increase the irradiation light intensity to the blood and the photoacoustic signal is increased, so that high sensitivity is obtained.
If the distance from the body surface is sufficiently short and the thickness is sufficiently thick, a vein or artery at another site may be used.

The piezoelectric sensor 5 was installed along the blood vessel 12 parallel to the body surface of the upper arm wrist 11. In addition, excitation light was made incident through the optical fiber bundle 10 from a direction perpendicular to the sensor 5 when viewed from the blood vessel 12. The optical fiber bundle 10 is an optical fiber having a diameter of about 0.2 mm and a length of 2 to 5 mm and a width of 5 to 5.
It is an optical fiber bundle for image transmission, which is bundled so as to have a length of 10 mm, and the light pattern incident on one end is directly output to the other end. Therefore, the optical fiber bundle 1 on the light source side
By scanning the irradiation light for 0 in a two-dimensional manner, it is possible to realize a two-dimensional complicated spatial scanning pattern for the light beam emitted at the end portion on the sample side. As in the first embodiment, the excitation light is incident along the blood vessel from a point far from the piezoelectric sensor 5 toward a point near the piezoelectric sensor 5.

In order to realize the sensor arrangement shown in FIG. 8, the sensor head 20 fixed to the arm 11 by the belt 21 is used as shown in FIG. Sensor head 20
Is a movable member 23, 2 movable in a vertical direction and an in-plane direction (hereinafter referred to as a horizontal direction) with respect to the plane of the frame body 22.
4 and 25 are provided. A shallow groove 24 is formed on the bottom surface of the movable member 24.
f is provided, and the blood vessel is positioned in the groove 24f for measurement. The piezoelectric sensor 5 is fixed to the bottom of the groove 24f with its long side parallel to the direction of the groove. Further, the light emitting portion of the optical fiber bundle 10 is arranged at a constant interval with respect to the piezoelectric sensor 5.

The movable member 23 cannot move in the vertical direction with respect to the frame body 22 but can move in the horizontal direction by sliding the horizontal protrusion 23a in the groove formed in the frame body 22. ing. The movable member 24 is the movable member 2
It has vertical protrusions 24a to 24d that slide in the vertical grooves provided in the reference numerals 3 and 25, and are movable in the vertical direction. The movable member 25 has a rack 25a that meshes with the worm gear 27, as shown in the sectional view of FIG. The movable portion 25 has a concave portion 25b on the side facing the adjacent movable portion 24, and the movable portion 24 is in the concave portion 25b.
The tongue piece 24e is inserted. The tongue piece 24e is threaded and meshes with the adjusting screw 26 whose movement in the vertical direction is restricted.

Therefore, by rotating the worm gear 27 provided on the sensor head 20, the piezoelectric sensor 5
Also, the position of the light emitting portion of the optical fiber bundle 10 can be moved in the horizontal direction, and by turning the adjusting screw 26, the piezoelectric sensor 5 and the light emitting portion of the optical fiber bundle can be moved in the vertical direction to press the skin. You can adjust the degree. By integrating the piezoelectric sensor 5 and the optical fiber bundle 10 as a sensor head, the irradiation position of the excitation light and the installation position of the sensor can be easily defined, and highly reproducible measurement can be performed.

Here, the sample was blood flowing through a blood vessel of a living body, and the substance to be measured was glucose. Since the main component of blood is water, the concentration of water is measured in addition to glucose,
By taking the ratio of both signals, the glucose concentration in the blood can be obtained as described in the fourth embodiment. Generally, it is effective to increase the intensity of excitation light in order to increase the measurement sensitivity, but if too much light energy is applied to the living body, the risk of adverse effects such as temperature rise, photochemical reaction, and tissue destruction also increases. I will end up. Therefore, when the measurement is performed with the irradiation position of the excitation light fixed as in the conventional case, the incident light energy is limited from the viewpoint of safety for the living body. On the other hand, when the excitation light is emitted while being scanned as in the present invention, this risk can be dispersed to a plurality of irradiation positions to enhance safety.
In other words, when the light energy absorbed per unit volume of the biological sample is constant, photoacoustic waves that are as many as the irradiation positions (9 in this case) can be generated, so high sensitivity is maintained while maintaining safety. Can be achieved.

The position of the blood vessel is confirmed by means such as visual inspection,
Although a sensor head can be installed there, here, preliminary scanning is performed two-dimensionally using excitation light having an absorption wavelength of hemoglobin contained in blood, for example, 550 nm, and the obtained photoacoustic signal is analyzed. By doing so, the area where blood vessels with a large blood volume are present is automatically obtained, and the main measurement is performed within that area.

As shown in FIG. 12, the laser beam 31 emitted from the laser light source 30 is reflected by the mirrors 33 and 34 and enters the light incident end of the optical fiber bundle 10. The mirrors 33 and 34 are rotatable about axes orthogonal to each other by motors 35 and 36 controlled by a controller 37, respectively. Motor 35,36
By controlling the rotation of the mirrors 33 and 34 by controlling the laser beam 31, the laser beam 31 can scan the light incident end of the optical fiber bundle 10 in an arbitrary pattern.
The scanning pattern is reproduced at the light emitting end of the optical fiber bundle 10 fixed to 0.

FIG. 13 shows a two-dimensional display of a photoacoustic signal obtained by performing a two-dimensional preliminary scanning with excitation light having an absorption wavelength of hemoglobin in synchronism with the scanning signal. In the figure, the hatched region represents a region where the photoacoustic signal intensity is large, that is, a region where blood vessels exist. Therefore, in the main measurement for measuring the glucose concentration, the control unit 37 performs excitation light scanning so that the scanning speed, the scanning direction, and the like satisfy the above-mentioned relationships in the region where the blood vessel exists.

Also, the signal due to hemoglobin is small,
When it is difficult to find an area with a large blood volume in the two-dimensional area covered by the optical fiber bundle 10, the measurement control device 8 notifies the operator of the fact and prompts the operator to change the position of the sensor head, and again performs the preliminary scanning. It is possible to reach the optimum measurement site by repeating the above procedure. When measuring a sample that does not necessarily have high homogeneity, such as a living body, the sound velocity may be slightly different depending on the site. In this case, the transmission time of the photoacoustic wave from the irradiation position of the excitation light to the sensor varies depending on the size of the sound velocity, and even if the excitation light is irradiated at the theoretical position, the wavefront tip of the photoacoustic wave does not necessarily exist. May not enter the sensitive part of the sensor at the same time.

In such a case, the excitation light is individually radiated to each irradiation planned position in advance, the time until the wavefront tip of the photoacoustic wave is detected by the sensor is measured, and this time is compared with the theoretical value. By doing so, the correction coefficient representing the sound velocity distribution of the sample can be obtained for each point. In actual measurement, the correction position is used to shift the irradiation position to adjust the distance from the sensor so that the front end of the wavefront of the photoacoustic wave can be made incident on the sensitive portion of the sensor at the same time.

[Sixth Embodiment] Finally, a sixth embodiment of the present invention will be described. This embodiment is almost the same as the fifth embodiment, except that the photoacoustic wave due to the photoacoustic effect is not used for detection, and the transmitted light of the living body is simply measured by one optical sensor to determine the intensity of the incident light. The difference is that the absorbance is obtained from the ratio and the absorption spectroscopic analysis is performed. The measurement site is a site through which light easily passes, such as a fingertip or an earlobe, and the measurement target is glucose, bilirubin, oxygen saturation, or the like.

In this embodiment, since the signal to be detected is light, the time difference according to the distance to the sensor is extremely small. Therefore, scanning the excitation light from the light source does not directly lead to higher sensitivity. However, by dispersing the light irradiation positions, it is possible to reduce the risk of irradiating the living body with light. Further, when the safety is similar, the measurement using a larger exposure amount can be performed, and as a result, the measurement with high sensitivity and high accuracy can be performed.

[0055]

According to the present invention, high sensitivity can be obtained in proportion to the number of irradiations. In addition, the risk to the living body due to light irradiation is reduced, and the analysis can be performed safely.

[Brief description of the drawings]

FIG. 1 is a schematic configuration diagram of a photoacoustic spectroscopy analyzer according to a first embodiment.

FIG. 2 is a sectional view illustrating a method of scanning excitation light.

FIG. 3 is a schematic diagram illustrating the relationship between scanning speed and sound velocity in a sample.

FIG. 4 is a schematic diagram illustrating a relationship between a scanning direction and an angle of a piezoelectric sensor.

FIG. 5 is a schematic diagram illustrating a method of scanning excitation light according to the second embodiment.

FIG. 6 is a schematic diagram illustrating an excitation light irradiation method according to a third embodiment.

FIG. 7 is a schematic configuration diagram of a photoacoustic spectroscopic analysis device according to a fourth embodiment.

FIG. 8 is a schematic diagram showing an arrangement in the vicinity of a measurement site of a biological sample according to a fifth embodiment.

FIG. 9 is a diagram showing a state in which the sensor head is attached to an arm.

FIG. 10 is a view of the sensor head as seen from above.

11 is a cross-sectional view taken along the line AA of FIG.

FIG. 12 is a schematic view of a light incident end side of an optical fiber bundle.

FIG. 13 is a schematic diagram of a display unit.

[Explanation of symbols]

DESCRIPTION OF SYMBOLS 1 ... Light source, 2 ... Beam splitter, 3 ... Optical scanning device, 4 ... Sample, 5 ... Piezoelectric sensor, 6 ... Amplifier, 7 ... Reference photodetector,
8 ... Measurement control device, 9 ... Beam integrator, 10 ... Optical fiber bundle, 11 ... Biological sample, 12 ... Blood vessel, 20 ... Sensor head, 21 ... Band, 22 ... Frame body, 23, 24, 25 ...
Movable member, 24f ... Groove, 26 ... Adjusting screw, 27 ... Worm gear, 30 ... Laser light source, 31 ... Laser beam, 33,
34 ... Mirror, 35, 36 ... Motor, 37 ... Control unit

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takeshi Sonehara 1-280 Higashi Koigakubo, Kokubunji, Tokyo Inside Central Research Laboratory, Hitachi, Ltd. (72) Inventor Masao Kan, 1-280, Higashi Koigakubo, Kokubunji, Tokyo, Hitachi, Ltd. Central Research Laboratory (72) Inventor, Yuji Miyahara, 1-280, Higashi Koigakubo, Kokubunji, Tokyo Hitachi, Ltd.

Claims (13)

[Claims] 1. A photoacoustic spectroscopic analyzer comprising means for irradiating a sample with excitation light and a sensor for detecting a photoacoustic wave emitted from the sample, wherein the excitation light is scanned at a speed equal to or higher than the speed of sound in the sample. A photoacoustic spectroscopic analyzer characterized by irradiating while. 2. When the speed of sound in the sample is c and the scanning speed of the excitation light is v, the scanning direction of the excitation light forms an angle a represented by the following formula with respect to the flat sensitive portion of the sensor. The photoacoustic spectroscopic analyzer according to claim 1. sina = c / v 3. The speed of sound in the sample is c, the scanning speed of the excitation light is v, the length of the sensitive portion of the sensor is L, and the scanning time of the excitation light is T.
The photoacoustic spectroscopic analyzer according to claim 1, wherein when n is satisfied, the following relationship is satisfied. ^{L = Tn (v 2 -c 2} ) 1/2 4. A photoacoustic spectroscopic analyzer comprising means for irradiating a sample with excitation light and a sensor for detecting a photoacoustic wave emitted from the sample, wherein the excitation light has a sensor direction at a speed equal to the speed of sound in the sample. A method for photoacoustic spectroscopy, which comprises irradiating while scanning. 5. A photoacoustic spectroscopic analyzer comprising means for irradiating a sample with excitation light and a sensor for detecting a photoacoustic wave emitted from the sample, wherein a plurality of excitation lights are equidistant from one sensor. A photoacoustic spectroscopic analyzer characterized by irradiating the same at the same time. 6. An optical fiber bundle for guiding the excitation light to the sample and a sensor are fixed to the sensor head, and a means for adjusting a pattern of light scanning emitted from the optical fiber bundle is provided. 2. The photoacoustic spectroscopic analyzer according to item 1. 7. A photoacoustic spectroscopic analysis method for detecting a photoacoustic wave emitted from a sample by irradiating the sample with excitation light, wherein the photoacoustic wave is generated at a plurality of positions in the sample, and a plurality of photoacoustic waves are generated. A photoacoustic spectroscopic analysis method characterized in that the tip of the wavefront of a wave is detected simultaneously by one sensor. 8. In the preliminary measurement, each position in the sample is irradiated with excitation light independently, a photoacoustic wave from each irradiation position is detected by a sensor, and the irradiation position of the excitation light and scanning of the excitation light are determined by the propagation time thereof. 8. The photoacoustic spectroscopic analysis method according to claim 7, wherein at least one of the speeds is corrected. 9. The measurement is performed by irradiating the excitation light of the first wavelength absorbed by the substance to be measured and the excitation light of the second wavelength absorbed by the medium in the sample, and comparing the measurement results of both. 9. The photoacoustic spectroscopic analysis method according to claim 7, wherein the concentration of the substance to be measured in the medium is obtained by this. 10. A non-invasive biochemical component analysis, characterized by non-invasively measuring a biochemical component in a living body using the photoacoustic spectroscopic analyzer according to claim 1. Method. 11. In a preliminary measurement, excitation light is individually radiated to each position in a sample, a photoacoustic wave from each irradiation position is detected by a sensor, and a sound velocity of each portion of the sample is detected from a propagation time of the photoacoustic wave. 11. The non-invasive biochemistry according to claim 10, wherein the deviation is obtained in advance, and in this measurement, the irradiation position of the excitation light is corrected according to the deviation to correct the deviation of the sound velocity to perform the measurement. Component analysis method. 12. The method according to claim 10, wherein the sample is pre-scanned by using the wavelength of the excitation light as the absorption wavelength of hemoglobin to determine the region where the blood vessel exists, and the photoacoustic spectroscopic analysis is performed in that region. The method for analyzing non-invasive biochemical components according to item 1. 13. A non-invasive biochemical component analysis method based on a spectroscopic analysis method, in which light from a light source is scanned to perform spectroscopic analysis at a plurality of sites to reduce the risk of light to a living body and to analyze safely. A non-invasive biochemical component analysis method characterized by being able to perform.