KR900000843B1 - Tissue metabolism measuring apparatus - Google Patents

Abstract

A device to measure the state of biological metabolism comprises: a light source to generate ultrashort light pulses of two or more wavelengths; a light dividing means to divide the ultrashort light pulse generated by the light source into a reference light pulse and a sample light pulse; a reference light pass to guide the reference light pulse divided by the light dividing means; a sample light pass to guide the divided sample light pulse to a living body; a delay means to delay the reference light pulse; a converging means to converge the reference light pulse; a nonlinear optical crystal to generate second harmonic; a muliplier phototube to obtain the ave. of the counted values.

Description

Metabolic Dynamic Measurement Device

1 shows the principle of one embodiment of the invention;

FIG. 2 is a view showing an example of ultra-short optical pulses applied to the apparatus for measuring metabolic dynamics shown in FIG.

3 is a waveform diagram showing reference light pulses, biotransmission light pulses, and second harmonics of these pulses.

4 is a waveform diagram for explaining measurement of a curve S (?) With respect to a delay time of a second harmonic.

FIG. 5 is a waveform diagram for explaining an operation of obtaining S (τ) by the photon counting device shown in FIG.

6 is a diagram showing the configuration of an embodiment of the present invention.

7 is a diagram showing the configuration of a device for measuring metabolism in a conventional organ.

8 and 9 are diagrams showing optical paths of light detected in a conventional apparatus.

* Explanation of symbols for main parts of the drawings

11, 35, 36: half mirror

12, 14, 15, 19, 20, 34, 48, 49: mirror

16, 37, 40, 42, 44: lens 16, 45: crystal

18, 46: filter 21, 50: delayed light

22, 51: photomultiplier tube 23, 52: photon counting device

31, 32, 33: optical pulse generator 38, 39, 43: optical fiber

53: controller 54: printer

55: display device

The present invention relates to a biometabolometer measuring device, in particular, changes in the oxygenation state and blood volume of hemoglobin in the organs or other parts of the human body or animal body, and changes in the redox effect of cytoplasmic cytochromes. The present invention relates to a device for measuring metabolic dynamics, such as measurement.

FIG. 7 is a diagram showing the configuration of a device for measuring metabolism in a conventional body organ, and FIGS. 8 and 9 are diagrams showing an optical path of light detected in a conventional measuring device. The apparatus shown in FIG. 7 is described in Japanese Patent Laid-Open No. 57-115232. In the example shown in FIG. 7, the near infrared light source 1 alternately emits near infrared light of different wavelengths. This near-infrared light passes through the head 3 of the human body via the optical fiber 2, and the detection system 4 measures its intensity. The adjusting device 5 adjusts the speed and order of the monochromatic flash and demodulates the detected optical signal. The feedback adjustment system 6 keeps the optical signal detected at one wavelength constant by the negative electric feedback adjustment of the detection sensitivity, and corrects the change in the transmittance caused by the change of the blood volume in the sensitizing organ during the perspective time. . The output adjustment circuit 7 outputs the feedback voltage blood volume indicating signal simultaneously with the received reference and measurement signals.

In the apparatus shown in FIG. 7, the light in the range of 700 nm to 1300 nm is incident from the head 3 to change the oxygenation state of hemoglobin in the brain, blood volume, and the redox effect of cytoplasmic cytochrome. It can envelop by detecting transmitted light. At this time, 805 nm, which is the equivalent absorption point of hemoglobin, is used as the reference wavelength, and deoxygenated hemoglobin has a small peak at about 760 nm and an oxygen-dependent absorber of cytochrome aa 3 in the wavelength range of 700 nm to 1300 nm.

Also in Japanese Patent Application Laid-Open No. 60-72542, in the same manner as described above, the binding of the protein to oxygen that can bind to oxygen molecules such as hemoglobin and myoglobin in the living body using light and absorption characteristics in the wavelength band Optical CT device that can observe the state quantitatively in two-dimensional distribution and can observe oxygen concentration of cytochondria in two-dimensional distribution from the oxidation and reduction states of cytochromes, constituents of respiratory chain Is proposed.

However, even if the light of 700 nm to 1300 nm has higher biotransmittance than the visible light region, when irradiated to the living body and detected the transmitted light, the incident light has a shorter wavelength compared to the size of hemoglobin, so Upon scattering and absorption, the detected light entails the components of the diffused light. This is described, for example, in C. C. Johnson, Optical Diffusion in Blood IEEE TRANSACTION ONBIO-MEDICAL ENGINEERING Vol. BME-17 No. 2, 1970 pp 129-133.

That is, as shown in FIG. 8, when the detector 9 is configured to detect light incident on the living body, the light detected by the detector 9 is an optical path that is a straight line connecting the incident light and the detector 9. In addition to light that has passed through 10a, scattered and diffused light includes light that has passed through optical paths 10b and 10c other than the optical path 10a. In this way, when the transmitted light is always detected, it is not possible to limit which path in the living body the detection light passes through. In the case of the apparatus as shown in FIG. As shown in FIG. 9, only information on an optical path (a diagonal line in FIG. 9) that is much wider than the optical path 10a connecting the incident light and the detector 9 can be enveloped. In the case of clinically diagnosing organ disorders such as blood circulation disorder and the extent thereof, the position of the disorder becomes a problem, so it is not meaningful as such a wide range of information in the raw vegetable. Therefore, the main object of the present invention is to provide a biometabolism measuring apparatus capable of detecting only the light of the linear component connecting the incident light and the detection unit, and observing ecological metabolism such as blood behavior or respiratory behavior at the correct position. will be.

According to the present invention, there is provided an apparatus for measuring metabolic dynamics, comprising: a light source for generating a plurality of high repetitive ultrashort pulses of wavelengths; A guiding reference optical path, a sample optical path that guides the branched sample optical pulses to the living body, and guides the sample optical pulses that have passed through the living body; and a delay for delaying either optical pulses of the reference optical path and the sample optical path. Means for condensing the reference light pulse that has guided the reference optical path and the sample light pulse that has passed through the sample optical path at a predetermined angle, a crystal for generating a second harmonic on the basis of the focused optical pulses, and Photon multiplier for detecting the second harmonic and photons of the output of the photomultiplier tube are counted, averaged by the predetermined number of counted values, and averaged, and delayed based on the averaged value. Photons of the value of the second harmonic photon counted when the delay amount of the means is changed and the delay amount of the reference light pulse and the sample light pulse passed through the living body is zero based on the delay time and the average value within the delay time. Measurement calculation means for outputting an average value, and control means for controlling the light source and the measurement calculation means to store photon average values at a plurality of wavelengths, and to calculate and output metabolic dynamics in vivo based on the photon average values of the respective wavelengths. .

In the apparatus for measuring metabolic dynamics according to the present invention, the average value of counting photons of the second harmonic generated from the crystal when the delay amount of the sample light pulse and the reference light pulse passed through the living body is determined to be obtained, thereby causing the bioluminescence. Since the scattering component in the body can be removed and only the component traveling straight in the body can be detected, the positional information becomes clearer when detecting the information in the living body using the transmitted light.

Hereinafter, an embodiment of the present invention will be described in detail with reference to the accompanying drawings.

FIG. 1 is a view for explaining the principle of the present invention, FIG. 2 is a view showing an example of ultra-short light pulses applied to the apparatus for measuring metabolic dynamics shown in FIG. 1, and FIG. 3 is a reference light pulse and biotransmitted light. Fig. 4 is a waveform diagram showing pulses and their second harmonics, and Fig. 4 is a waveform diagram illustrating the measurement of the curve S (?) With respect to the delay time of the second harmonic. Where τ is the delay time.

First, the principle of this invention is demonstrated with reference to FIGS. In this invention, a high repetition ultra-short pulse of light is used. Such high repetition ultra-short optical pulses, for example, using a semiconductor laser can obtain optical pulses having a half width of several to several P sec (P sec = 10 ^-12 sec) at a repetition frequency of 1 GHz. For example, the ultra-short light pulses shown in FIG. 2 have a light pulse interval of 10 ⁻⁹ sec, and generate 10 ⁹ pulses in one second. Such optical pulses are not limited to semiconductor lasers, but can also be realized in dye lasers and the like.

This ultra-short optical pulse is branched by the half mirror 11 into a sample light pulse traveling in a direction perpendicular to the reference light pulse traveling in a straight direction. Among these, the sample light pulses are irradiated to the living body 13 as a target by the mirror 12. The light pulse which has passed through the living body is reflected by the mirrors 14 and 15 and guided to the lens 16. Hereinafter, this light pulse is referred to as a living passage light pulse. On the other hand, the reference light pulses are reflected by the mirror 19, guided to the delayed light path 21, and reflected by the mirror 20, and guided to the lens 16 in the same manner as the living light pulses. Here, as the delayed optical path 21, two mirrors may be combined as shown in FIG. 1, and the same thing as a prism or a tetrahedron may be used. The operation of the delayed light path 21 will be described later. The lens 7 collects the biological passing light pulse and the reference light pulse and enters the nonlinear optical crystal 17.

Here, the reference pulses and the biological passage pulses have waveforms as shown in FIG. 3 before they become the nonlinear optical crystals 17, respectively. That is, the reference light pulses are slightly lower in power than the ultra-short light pulses shown in FIG. The pulse width does not change. However, the biological passage light pulses are extremely reduced in power when passing through the living body 13, and, as described in FIG. 8, the optical paths 10b and (other than the straight optical path 10a) ( Since the intensity of light passed through 10c) is detected, the pulse width of the ultra-short light pulse shown in FIG. 2 cannot be maintained, and the tail is pulled back. By the way, it can be confirmed that the start portion of the biological passage pulse reflects only the components of the light passing through the straight optical path 10a shown in FIG. This originates in reaching the detector 9 at the earliest because the straight path 10a is the shortest distance in the optical path of the living body 13. In this way, only the straight component can be selected and detected by using a pulse having a fast start time such as ultra-short pulse.

In order to detect only this straight component, the nonlinear optical crystal 17 is used. This crystal 17 is a crystal such as LiIO ₃ or KDP, and generates a second harmonic by injecting the reference light pulse and the bio-pass light pulse. The power S of this second harmonic is a function of the delay time τ which is substantial for the distance of the delayed optical path 21 of FIG. 1, and when the reference light pulse is Ir and the biological light pulse is Is,

Is displayed as: Therefore, S (τ) is proportional to the integral value of the product of Is (t) and Ir (t-τ).

Here, it is important to note that although the biological light pulses are attenuated largely in the living body 13 (actual measurements have shown that they have been attenuated to 10 ^-9 of the incident light power in the head of the rat), the biological light pulses are weak. Even if the second harmonic output S is a small integral of the living passage pulse and the reference light pulse, and the intensity of the reference light pulse is large, the second harmonic output S can be sufficiently detected.

Τ in the above formula (1) is a delay time corresponding to the distance of the delayed light path 21 shown in FIG. 1 as described above. In other words, it is the time obtained by dividing the optical path difference between the reference light pulse from the half mirror 11 to the crystal 17 by the light flux. As shown in FIG. 4, τ is set to 0 when the reference light pulse and the biological passage light pulse reach the crystal 17 at the same time, and the sample light pulse is changed by changing the delay light path 21. The reference light pulse is delayed. That is, S is a function of τ, and by changing the delayed light path 21, the waveform can be observed as shown in FIG. 3C. At this time, when tau = 0, since the start portion of the sample light pulse reflects the straight component, the value of S (0) becomes a signal of only the straight component, and when detected, the scattered light of the living body as shown in FIG. The components 10b and 10c can be removed and only the linear light component 10a can be detected.

The second harmonic output from the crystal 17 is radiated in the direction of the center line of the incident angles of the reference light pulse and the biological passage light pulse, as indicated by the dotted lines in FIG. The wavelength of the second harmonic is 1/2 of the wavelength of the ultra short pulse pulse shown in FIG. This second harmonic passes through the filter 18 and is applied to the photomultiplier tube 22. The filter 18 transmits only the wavelength of the second harmonic, so that the photomultiplier tube detects only the second harmonic component and outputs photons.

FIG. 5 is a waveform diagram for explaining an operation of obtaining S (?) By the photon counting device shown in FIG.

Next, referring to Fig. 5, the operation of the photon counting device shown in Fig. 1 will be described. The photon counting device 23 detects S (?) By performing the operation as shown in FIG. 5 so as to obtain a stable output. That is, the photon counting device 23 first sets the delayed light path 21 at a predetermined position, and counts the photons output from the photomultiplier pipe 22 at photon count intervals as shown in FIG. 5B. . In this case, for example, as shown in FIG. 5A, photons are counted while five ultrashort pulses of light pass through the living body 13. The number of light pulses set at intervals is related to the sensitivity for detecting S (?), And the larger the number, the better the sensitivity.

At this time, the transition of the photon coefficient is as shown in Fig. 5c, and when the photon count output is sampled by the sample holder signal as shown in Fig. 5d, the sample output as shown in Fig. 5e is obtained. Can be. This is an output corresponding to the photon coefficient within the photon coefficient interval. This time axis is enlarged and displayed in FIG. 5f. In order to detect stable S (τ), for example, an average of five times of this sample holder output is set to S (τ) at a certain τ. Of course, this five times average may be several times, and is determined by the stability and sensitivity of an apparatus.

Next, by changing the delayed light path 21 of FIG. 1, changing the delay time of the reference light pulse, and similarly obtaining S (?), An output as shown in FIG. 5g can be obtained. And this S (0) value is detected as a linear light component. Although such a process is considered to require a lot of time, since a high repetitive ultra-short pulse of light is used, for example, a light pulse of 1 GHz or 10 P sec, an S (τ) for a certain τ is obtained. If 10 ⁻⁹ sec × 5 × 5 = 2.5 × 10 ^-8 sec = 25n sec, and 50 floats S (τ) are obtained,

50 × 25n sec = 1.25μ sec

S (?) Is obtained.

In principle, it is possible to detect at this speed, but in practice, it is limited by the count rate of the photomultiplier tube 22 for photon counting or the band of the preamplifier subsequent thereto, or the delay optical path 21 is mechanically Because it takes time to set up, it takes about 1m sec.

6 is a diagram showing one embodiment of the present invention. The example shown in FIG. 6 shows an example of non-invasive measurement of the metabolism of oxygen in vivo. The example shown in FIG. 6 is the same as that of FIG. 1 in principle, or in place of the half mirrors 11, mirrors 12, 14, and 15 in FIG. 38), (39) and (43) are used. In this embodiment, the pulse generators 31, 32, and 33, which generate high repetitive ultra-short pulses of wavelengths lambda 1, lambda 2, and lambda 3, are mounted so that the ultra-short pulses generated from the pulse generator 31 are mirrored. The light is incident on the lens 37 via the 34, half mirror 35, and half mirror 36.

The ultra-tour pulse generated from the pulse generator 32 is incident on the lens 37 via the half mirrors 35 and 36. In addition, the ultra-short optical pulse generated by the pulse generator 33 is incident on the lens 37 via the half mirror 36. Ultrashort pulses of wavelengths λ1, λ2, and λ3 incident on the lens 37 are branched at the optical fibers 38 and 39, and the ultrashort pulses branched at the optical fiber 38 pass through the lens 40 to generate a living body. Incident on (41). The biological passing light pulses having passed through the living body 41 are collected by the lens 44 via the lens 42 and the optical fiber 43 and are incident on the crystal 45.

On the other hand, the reference light pulses branched to the optical fiber 39 are delayed in the delayed light path 50 via the lens 47 and the mirror 48, are reflected by the mirror 49, and are incident on the lens 44. The reference light pulses and the bio-pass light pulses collected by the lens 44 are incident on the crystal 45, and the second harmonic is generated by the crystal 45. This second harmonic is incident on the photomultiplier tube 51 via the filter 46. The photon counting device 52 then counts the photons that are the outputs of the photomultiplier tube 51 as in the first diagram above. In addition, the controller 53 controls the optical pulse generators 31, 32, and 33, and obtains the above-mentioned S (0) value based on the output of the photon counting device 52, and the living body 41 The amount of hemoglobin, oxygenation degree of hemoglobin, and redox degree of Cytaa 3 are calculated, printed by the printer 54 and displayed on the display device 55. In the embodiment shown in FIG. 6, three wavelengths? 1,? 2 and? 3 are generated as the optical pulse generator 31, respectively, but may be three or more wavelengths. Of course, these wavelengths [lambda] 1, [lambda] 2, and [lambda] 3 have good biopermeability of 700 to 1300 nm and are wavelengths capable of encouraging the dynamics of hemoglobin and Cytaa3.

As described above, according to the present invention, since the photon of the second harmonic is counted when the delay amount of the reference light pulse passed through the living body and the delayed sample light pulse is equal to each other, the photon average value is calculated. The scattering component can be removed, and only the straight component on the incident optical axis can be detected. As a result, it is possible to monitor the metabolic dynamics on a particular axis in the body. In addition, since the high repetition ultra-short light pulse is used, it is also possible to sufficiently improve the detection sensitivity of the amount of transmitted light, and the operability is good because the sensitivity can be easily changed.

Claims (5)

A light source for generating a plurality of high repetitive ultra-short optical pulses of a plurality of wavelengths, optical branching means for splitting the ultra-short optical pulses generated from the light source into a reference light pulse and a sample light pulse, and a reference optical path for guiding a reference light pulse branched by the optical branching means; A sample path for guiding the sample light pulses branched by the optical branch means to the living body and guiding the sample light pulses passing through the living body, the delay means for delaying any one of the reference light beams and the sample light path; A crystal for generating a second harmonic on the basis of the light collecting means for condensing the reference light pulse that has guided the reference light path and the sample light pulse that has passed through the sample light at a predetermined angle, and the light pulse condensed by the light converging means; A photomultiplier tube for detecting the second harmonic generated from the photomultiplier and a photon of the output of the photomultiplier tube, and counting The average value is obtained by equalizing, and the delay means changes the delay amount of either the sample light pulse or the reference light pulse on the basis of the average value, and based on the delay time and the average value within the delay time, Measurement operation means for outputting a photon average value of a value obtained by counting photons of the second harmonic when the delayed amount of the reference light pulse and the delayed sample light pulse is zero, and controlling the light source and the measurement operation means And a control means for storing the photon average value at the wavelength of and calculating and outputting the metabolism in the living body based on the photon average value at each wavelength. The apparatus according to claim 1, wherein a filter for passing only a second harmonic generated from the crystal is installed between the crystal and the photomultiplier tube. The apparatus for measuring metabolic dynamics according to claim 1, wherein said control means calculates oxygen saturation, hemoglobin amount, and redox degree of Cytaa 3 as hemoglobin in said metabolism in vivo. 4. The apparatus for measuring metabolic dynamics according to claim 3, further comprising display means for displaying metabolism in the living body calculated by the control means. 4. The apparatus for measuring metabolic dynamics according to claim 3, comprising recording means for recording metabolism in said living body calculated by said control means.

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