1. Field of the Invention
The present invention relates to an optical measurement device which measures the properties of a test subject by light.
2. Description of the Related Art
In the medical field, an optical measurement device including a light source which irradiates a test subject with light and a photodetector which receives light reflected from the test subject or fluorescence emitted from the test subject is widely used. For example, an optical measurement device, which measures the oxygen saturation of the blood by exploiting the light absorption of hemoglobin, is known (JP5222934B). Furthermore, an optical measurement device, which measures the amount of light emitted from nicotinamide adenine dinucleotide (NADH) in a biological body, is known. The oxygen saturation of the test subject or the amount of a metabolite such as NADH that is measured by the optical measurement device is used in various types of diagnosis.
With the optical measurement device of JP5222934B, the amount of oxygen supplied can be estimated based on the oxygen saturation, but the amount of oxygen used cannot be ascertained. Therefore, the normal tissue 10 in which anaerobic metabolism occurs cannot be differentiated from the cancerous tissue 11 in which anaerobic metabolism occurs at all times.
In addition, the amount of NADH is closely related to the metabolism and increases more in the anaerobic metabolism than in the aerobic metabolism. Consequently, if the amount of light emitted from NADH is measured by the optical measurement device of JP2011-053135A, the amount of oxygen used can be estimated. However, with the optical measurement device of JP2011-053135A, the amount of oxygen supplied cannot be ascertained. As a result, the normal tissue 10 in which anaerobic metabolism occurs cannot be differentiated from the cancerous tissue 11 in which anaerobic metabolism occurs at all times.
That is, each of the optical measurement devices of JP5222934B and JP2011-053135A merely measures either the amount of oxygen supplied or the amount of oxygen used, and does not measure the balance between the oxygen utilization and the oxygen supply. Therefore, with the measurement results obtained by those optical measurement devices, cancer cannot be accurately diagnosed.
An object of the present invention is to provide an optical measurement device which can measure the balance between the oxygen utilization and the oxygen supply in the metabolism of a test subject.
An optical measurement device of the present invention includes a light source which irradiates a test subject with first light for measuring the degree of oxygen supply to a metabolic system and a photodetector which receives reflected light or transmitted light of the first light and second light emitted from the test subject according to the degree of oxygen utilization by the metabolic system.
The photodetector may be constituted with a first photodetector which is for receiving the reflected light of the first light and a second photodetector which is for receiving the second light.
The first light is, for example, light of a wavelength range that is attenuated by being partially absorbed into the test subject by passing through the test subject. Specifically, the first light is light of a wavelength range that is attenuated by being partially absorbed into oxidized hemoglobin or reduced hemoglobin contained in the test subject.
The second light is fluorescence which is emitted from the test subject, phosphorescence, or light which is generated by the Raman effect. The second light is, for example, fluorescence emitted from nicotinamide adenine dinucleotide or flavin adenine dinucleotide.
The second light may be fluorescence emitted from a substance expressed by being fused with a fluorescent protein through genetic manipulation.
A spectral filter which narrows down the wavelength range of the first light may be disposed between the light source and the test subject. Furthermore, a spectral filter which narrows down the wavelength range of the light received by the photodetector may be disposed between the test subject and the photodetector.
The light source may irradiate the test subject with excitation light such that the second light is emitted. In this case, the light source may include a first light source which radiates the first light and a second light source which radiates the excitation light. A spectral filter which narrows down the wavelength range of the excitation light may be disposed between the light source and the test subject.
The light source may irradiate the test subject with the first light and the excitation light at the same time. Furthermore, the light source may irradiate the test subject with the first light and the excitation light at different times.
It is preferable that the optical measurement device includes a signal processing portion which separates a signal generated from a substance as a measurement subject, from a light receiving signal output from the photodetector.
It is preferable that the optical measurement device includes an index value calculation portion which calculates an index value relating to the balance between the oxygen supply to the metabolic system and the oxygen utilization by the metabolic system, based on the amount of the received reflected or transmitted light of the first light and the amount of the received second light.
For example, the index value calculation portion calculates the oxygen saturation of the test subject based on the reflected or transmitted light of the first light, determines the amount of the substance emitting the second light based on the amount of the received second light, and calculates a ratio between the oxygen saturation and the amount of the substance emitting the second light as an index value.
According to the optical measurement device of the present invention, it is possible to measure the balance between the oxygen utilization and the oxygen supply in the metabolism of a test subject.
As shown in
in order to observe the degree oxygen utilization in the metabolic system of the test subject 24, the photodetector 22 receives second light R2 emitted from a light emitting substance in a subject. The amount of the light emitting substance varies depending on the degree of the oxygen utilization in the metabolic system of the subject. Accordingly, the amount of the light emitted and the amount of the light received by the photodetector 22 also depend on the degree of the oxygen utilization. Therefore, the optical measurement device 20 observes the amount of received fluorescent light FL as an index of the oxygen utilization in the metabolic system of the subject. In case the light emitting substance is a fluorescent substance or a phosphorescent substance, the light source 21 radiates excitation light L2 (third light) for exciting the light emitting substance.
The test subject 24 is a biological body, and examples thereof include a portion or the entirety of an animal including a human being, samples cut off from animals, and cells.
The optical measurement device 20 is, for example, a point measurement device (a contact type or a non-contact type), a biological image measurement device, or an endoscope (a soft endoscope or a hard endoscope).
The light source 21 is, for example, a lamp of xenon, halogen, mercury, or metal halide, a light emitting diode (LED), a laser light source, or a combination of these.
The photodetector 22 is, for example, a photoelectric tube, a photomultiplier tube, a charge coupled device (CCD), or a complementary metal oxide semiconductor (CMOS) device.
The light absorbing substance is, for example, oxidized hemoglobin or reduced hemoglobin. As the amount of oxygen in the test subject 24 increases, the amount of the oxidized hemoglobin increases while the amount of the reduced hemoglobin decreases.
In case the light absorbing substance is the oxidized or reduced hemoglobin, the wavelength range of the first light L1 may be narrowed down to a range in which there is a great difference in light absorption between the oxidized hemoglobin and the reduced hemoglobin and a range in which there is a small difference in light absorption therebetween. As shown in
In case a broadband lighting is used as the light source 21, for example, as shown in
The light emitting substance is, for example, an autofluorescent substance which spontaneously exists in a biological body. The amount of nicotinamide adenine dinucleotide (NADH) as one of the autofluorescent substances increases as the oxygen utilization by the metabolic system decreases. In some cases, the amount of flavin adenine dinucleotide (FAD) varies depending on a degree of oxygen utilization by the metabolic system.
The substance whose amount or activity varies in relation to the oxygen utilization by the metabolic system may be artificially caused to emit light. For example, a protein called prolyl hydroxylase domain-containing protein 2 (PHD2), whose amount varies in relation to the oxygen utilization by the metabolic system, may be expressed by being fused with a fluorescent protein by means of manipulating the gene of PHD2.
In order that the light from the light emitting substance as a measurement subject is observed differentially from another light, for example, the spectral filter 32 is preferably disposed between the test subject 24 and the photoreceiver at the time of receiving the second light R2 (see
In case the excitation light is radiated for exciting the light emitting substance, the wavelength range thereof may be narrowed down such that light in a wavelength range that is easily absorbed into the light emitting substance is used, for example. At this time, for example, broadband lighting should be used as the light source 21, and the spectral filter 31 transmitting light of a wavelength range that can be easily absorbed into the light emitting substance should be disposed between the light source 21 and the test subject 24 (see
In case the light source 21 irradiates the test subject 24 with the excitation light L2 in addition to the first light L1 as shown in
In case the light source 21 is constituted with the first light source 21a and the second light source 21b, for example, a xenon lamp can be used as the first light source 21, and LED can be used as the second light source 21b. In this way, different devices can be used as the first light source 21a and the second light source 21b. It goes without saying that a xenon lamp may be used as the first light source 21a, and another xenon lamp may be used as the second light source 21b. Furthermore, for example, the same device is used as the first light source 21a and the second light source 21b. For instance, in case a xenon lamp is used as the first light source 21a, the same xenon lamp as the first light source 21a may be used as the second light source 21b, such that the light source 21 is constituted with two xenon lamps.
The first light L1 and the excitation light L2 (third light) may be radiated at the same time. In this case, the reflected light R1 of the first light L1 and the second light R2 generated by the radiation of the excitation light L2 arrive the photodetector 22 substantially at the same time. Therefore, by the combination of the spectral filter 31 and the spectral filter 32, the reflected light R1 and the second light R2 can be differentially observed.
The time of radiating the first light L1 and receiving the reflected light R1 thereof may be set to be different from the time of radiating the excitation light L2 and receiving the second light R2, such that the reflected light R1 of the first light L1 and the second light R2 are differentially observed. The temporal observation by the time-division manner described above can be realized by, for example, regulating the time during which the spectral filter 31 or 32 (or a combination thereof) functions.
As shown in
Furthermore, the first light L1 and the excitation light L2 may be radiated at different times, such that the reflected light R1 of the first light L1 and the second light R2 arrive the photodetector 22 at different times, and the reflected light R1 of the first light L1 and the second light R2 are differentially observed. At this time, the time of radiating the first light L1 and receiving the reflected light R1 thereof may be set to be different from the time of radiating the excitation light L2 and receiving the second light R2, such that the reflected light R1 of the first light L1 and the second light R2 are easily differentiated and observed.
In case signals which are different from the signal resulting from the light absorption by the light absorbing substance as the measurement subject, for example, signals which result from the light absorption by the light absorbing substance not being a measurement subject or result from the light emission from the light emitting substance are mixed in the light receiving signal resulting from the reflected light R1 of the first light L1 (or in case the aforementioned signals are likely to be mixed in the light receiving signal), it is preferable to separate those signals by a method of multivariate analysis such as multiple regression analysis as shown in
In this case, a storage portion 41 and a signal processing portion 42 should be provided as shown in
The signal processing portion 42 may use a method of multivariate analysis such as non-negative matrix factorization that does not require the storage of data of known optical spectra so as to estimate the signal resulting from light absorption by the light absorbing substance as the measurement subject.
In case signals which are different from the signal resulting from the light emission from the light emitting substance as the subject, for example, signals which result from the light emission from the light emitting substance not being a subject or result from the light absorption by the light absorbing substance are mixed in the light receiving signal of the second light R2 (or in case the aforementioned signals are likely to be mixed in the light receiving signal), it is preferable to separate those signals by a method of multivariate analysis as described above so as to estimate the signals resulting from the light emission by the light emitting substance as the subject. In this case, the storage portion 41 and the signal processing portion 42 should be provided (see
The separation and extraction of the signal generated from the light absorbing substance as the measurement subject and the separation and extraction of the signal generated from the light emitting substance as the measurement subject can be performed during the multivariate analysis conducted once.
In the storage portion 41, for example, data of oxidized hemoglobin, reduced hemoglobin, bilirubin, myoglobin, melanin, lipofuscin, and the like are preferably stored as the data of the absorption spectrum. Furthermore, in the storage portion 41, for example, data of NADH, FAD, collagen, porphyrin, elastin, melanin, lipofuscin, and the like are preferably stored as the data of the emission spectrum. In case the light emitting substance is a fluorescent substance or a phosphorescent substance, and the emission spectrum varies with the wavelength of the excitation light, data corresponding to the wavelength of the illumination light used may be stored in the storage portion 41.
As shown in
For example, the index value calculation portion 51 calculates, as an index value, a ratio or difference between the amount of the received reflected light R1 of the first light L1 and the amount of the received second light R2. Furthermore, a ratio or difference between a value calculated as a function of one variable of the amount of the first light received and a value calculated as a function of one variable of the amount of the second light received may be calculated as an index value. In addition, the index value calculation portion 51 may calculates a plurality of parameter values. For example, an index value calculated based on the amount of the received reflected light R1 of the first light L1 and an index value calculated based on the amount of the received second light R2 may be separately calculated. Herein, the index value calculation portion 51 may output the amount of the received reflected light R1 of the first light L1 and the amount of the received second light R2 as parameter values without particularly performing calculation.
More specifically, it is preferable that the index value calculation portion 51 calculates an index value relating to the balance between the oxygen supply to the metabolic system of the test subject 24 and the oxygen utilization by the metabolic system. For example, the oxygen saturation is calculated based on the amount of the received reflected light R1 of the first light L1, and the amount of NADH in the test subject 24 is calculated based on the amount of the received second light R2. Then, for example, a ratio therebetween (amount of NADH/oxygen saturation) is calculated as an index value. The ratio between the amount of NADH and the oxygen saturation shows the oxygen dependency in energy metabolism. Specifically, the smaller the index value, the higher the oxygen dependency in the energy metabolism. That is, it is understood that the smaller the index value, the more the aerobic metabolism predominant over the anaerobic metabolism. Accordingly, even if the oxygen saturation is low or even if the amount of NADH is great, the measured site of the test subject 24 is highly likely to be the normal tissue 10. Inversely, the greater the index value, the lower the oxygen dependency in the energy metabolism, and the more the anaerobic metabolism predominant over the aerobic metabolism. Accordingly, even if the oxygen saturation is high or even if the amount of NADH is not increasing, as long as the index value is great, the measured site of the test subject 24 is highly likely to be the cancerous tissue 11. Therefore, the ratio between the amount of NADH and the oxygen saturation is an excellent parameter for differentiating the normal tissue 10 from the cancerous tissue 11. Herein, although a ratio of amount of NADH/oxygen saturation is used as an index value, a ratio of oxygen saturation/amount of NADH may also be used as an index value.
It is preferable that the display portion 23 displays the index value output from the index value calculation portion 51 in the form of a numerical value, gray scale, color, a graph, or a combination of these. In case the photodetector 22 is an image sensor such as CCD or CMOS, the display portion 23 may display the index value in the form of an image. In this case, the index value may be displayed in the form of gray scale, color, or the like for each pixel or for each of partial region (a region consisting of a plurality of pixels) of the test subject 24.
In case an image is displayed on the display portion 23 as above, for example, if there is a plurality of parameter values consisting of parameter values relating to each of the reflected light R1 of the first light L1 and the second light R2, when a user designates a place in the image, the index value in the place may be displayed in the form of a numerical value, gray scale, color, or a graph that pops out. Furthermore, the images showing the respective parameter values may be displayed in a line or displayed by being temporally switched with each other. The images may be automatically switched at a predetermined timing or switched based on the instruction from the user.
In case a plurality of parameter values is calculated, a lookup table associating those parameter values with the displayed gray scale or the color in the display may be preset such that display is performed based on the lookup table. For example, the lookup table may be a correspondence table in which the plurality of parameter values is associated with the intensity of channels of red, green, and blue of the display. The correspondence table is, for example, linear correspondence expressed in a matrix.
The display portion 23 may display the history of the index value in the form of a numerical value, gray scale, color, a graph, or a combination of these, Therefore, the display portion 23 may be provided with a device (or a storage portion) which stores the index values of the past.
The optical measurement device 20 can be used for diagnosis of cancer, for example. In addition, for example, in developing a drug, the optical measurement device 20 can be used for evaluating drug efficacy or for obtaining a guideline regarding in what way the compound structure of the drug should be changed. In these cases, for improving the convenience of the user, it is preferable that the display portion 23 displays determination results showing whether or not the test subject 24 has cancer, the probability thereof, a degree of malignancy of cancer, the type of cancer, the prognosis prediction, the potency of drug efficacy, a suggested drug, and the like.
Herein, the optical measurement device 20 measures the amount of a substance correlating to the oxygen utilization in the metabolic system of the test subject 24 based on the amount of the received second light R2 generated by the radiation of the excitation light L2. However, the second light R2 includes not only fluorescence or phosphorescence but also light generated by the Raman effect. That is, the optical measurement device 20 can measure the amount of a substance correlating to the oxygen utilization in the metabolic system of the test subject 24 by the Raman spectroscopy.
Number | Date | Country | Kind |
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2013-202546 | Sep 2013 | JP | national |
This application is a Continuation of PCT International Application No. PCT/JP2014/063848 filed on May 26, 2014, which claims priority under 35 U.S.C §119 (a) to Japanese Patent Application No. 2013-202546 filed on Sep. 27, 2013. Each of the above application(s) is hereby expressly incorporated by reference, in its entirety, into the present application.
Number | Date | Country | |
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Parent | PCT/JP2014/063848 | May 2014 | US |
Child | 15041298 | US |