JP6754492B2 - Biological tissue analyzer and biological tissue analysis method - Google Patents

Description

The present invention relates to a biological tissue analyzer and a biological tissue analysis method.

A device for non-invasively measuring a biological tissue such as an eyeball by an optical method has been conventionally proposed (for example, Patent Document 1 and the like).

Japanese Unexamined Patent Publication No. 5-261667

However, if the intensity of the light irradiating the living tissue is weak, it is difficult to analyze the depth of the living tissue. On the other hand, if the intensity of the light irradiating the living tissue is too strong, it may cause damage to the living tissue. This risk is particularly remarkable when the living tissue is an eyeball.

As a means for solving this, for example, wavelength sweep type optical coherence tomography (wavelength sweep type OCT or SS-OCT: Swept Source Optical Coherence Tomography) can be considered. However, in wavelength sweep type optical interference tomography, since a plurality of devices must be used for tunable wavelength, the configuration of the devices is complicated and the operation becomes complicated.

Therefore, an object of the present invention is to provide a biological tissue analysis device and a biological tissue analysis method capable of easily analyzing the depths of a biological tissue with a device having a simple configuration.

In order to achieve the above object, the biological tissue analyzer of the present invention includes a light irradiation means, a light separation means, and a spectroscopic means, and the light irradiation means irradiates the biological tissue with light, and the light separation means. The emitted light emitted from the living tissue irradiated with the light is separated according to the position of the space of the living tissue, and the light is dispersed by the spectroscopic means and irradiated to the living tissue. The emitted light emitted from the living tissue irradiated with the light is spectroscopic by the spectroscopic means and by at least one of coherent anti-Stokes Raman spectroscopy (CARS), spontaneous Raman scattering and optical interference tomography (OCT). , The tissue internal structure of the living tissue is analyzed.

The biological tissue analysis method of the present invention includes an irradiation step of irradiating the biological tissue with light, and a light separation step of separating the emitted light emitted from the irradiated biological tissue according to the position of the space of the biological tissue. Coherent Anti-Stokes Raman spectroscopy (CARS), spontaneous Raman scattering, comprising a spectroscopic step of splitting the light irradiating the living tissue or dispersing the emitted light emitted from the irradiated living tissue. And at least one of optical interference spectroscopy (OCT) is used to analyze the tissue internal structure of the living tissue.

According to the present invention, it is possible to provide a biological tissue analyzer and a biological tissue analysis method capable of easily analyzing the depth of a biological tissue with a device having a simple configuration.

FIG. 1 is a diagram showing an example of the configuration of the biological tissue analyzer of the present invention. FIG. 2 is a diagram showing another example of the configuration of the biological tissue analyzer of the present invention. FIG. 3 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 4 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 5 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 6 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 7 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 8 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 9 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 10 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 11 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 12 is a graph showing an example of the function of the wavelength selection filter. FIG. 13 is a diagram showing an example of the configuration of the wavelength selection filter. FIG. 14 is a schematic diagram showing the concept of three-dimensional spectroscopic analysis with varying wavelengths. FIG. 15 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 16 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. FIG. 17 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. FIG. 18 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. FIG. 19 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. FIG. 20 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 21 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 20. FIG. 22 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 20. FIG. 23 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 20. FIG. 24 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 20. FIG. 25 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 20. FIG. 26 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 27 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 26. FIG. 28 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 26. FIG. 29 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 30 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 29. FIG. 31 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 29. FIG. 32 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 29. FIG. 33 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 29. FIG. 34 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 35 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 34. FIG. 36 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 34. FIG. 37 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 34. FIG. 38 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 39 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 38. FIG. 40 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 38. FIG. 41 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 38. FIG. 42 is a diagram showing still another example of the configuration of the biological tissue analyzer of the present invention. FIG. 43 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 42. FIG. 44 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 42. FIG. 45 is a diagram showing an example of a biological tissue analysis method using the biological tissue analyzer of FIG. 42.

Next, the present invention will be described with reference to an example. However, the present invention is not limited by the following description.

In the present invention, the light irradiated to the living tissue may be, for example, monochromatic light or, for example, mixed light containing light of a plurality of wavelengths, for example, broadband light, monochromatic light, or a mixture thereof. It may be light. The monochromatic light may be, for example, laser light. The laser light may be, for example, pulsed laser light or CW (continuous oscillation) laser light. Further, the mixed light containing light having a plurality of wavelengths may be, for example, wideband light or mixed light of a plurality of monochromatic lights. The broadband light may be, for example, white light or super-continue (SC) light.

The biological tissue analyzer of the present invention further includes, for example, an imaging means, in which the spectroscopic emitted light is imaged by the imaging means, and the spectroscopic emitted light is captured by pixels on the image obtained by imaging. May be separated two-dimensionally or three-dimensionally.

The biological tissue analyzer of the present invention further includes, for example, a wavelength tunable filter, and the light emitted from the light irradiating means is fixed to a selected wavelength or the wavelength is fixed by the tunable filter. The emitted light may be separated by a variable filter, and the tissue internal structure of the living tissue may be analyzed by wavelength sweep type optical interference tomography (SS-OCT).

The biological tissue analyzer of the present invention further includes, for example, an interference system or a cofocal optical system, and the interfering system or the cofocal optical system depending on a selected wavelength of the light emitted from the light irradiation means. The position of the system may be adjusted. For example, the following B unit may include the interference system or the confocal optical system.

The biological tissue analyzer of the present invention may include, for example, at least one of the following A unit and B unit.

(A unit)
Including the optical separation means and the spectroscopic means
The spectroscopic means includes a diffraction grating.
The emitted light is two-dimensionally separated by the light separating means.
The two-dimensionally separated emitted light is separated by the diffraction grating.
unit.
(B unit)
Including the optical separation means and the spectroscopic means
The optical separation means includes the imaging means.
The spectroscopic means includes the tunable filter.
The tunable filter disperses the emitted light.
unit.

In the biological tissue analyzer of the present invention, for example, the A unit is a unit for measuring at least one of coherent anti-Stoke Raman spectroscopy (CARS) and spontaneous Raman scattering, and the B unit is optical coherence tomography (OCT). It may be a unit for use.

In the biological tissue analyzer of the present invention, the optical separation means in the A unit may include, for example, a microlens array or a dichroic mirror (also referred to as a multilayer optical function reflecting mirror or a two-color mirror).

The biological tissue analyzer of the present invention may further include, for example, a wavelength tunable filter, and the light emitted from the light irradiating means may be fixed at a selected wavelength by the tunable filter.

The biological tissue analyzer of the present invention further includes, for example, a light irradiation means for coherent anti-Stoke Raman spectroscopy (CARS) in the biological tissue analyzer including the A unit, and the light irradiation means for CARS provides wideband light and The mixed light of the laser light may be irradiated to the living tissue, and the Raman scattered light contained in the emitted light from the living tissue irradiated with the mixed light may be dispersed by the diffraction grating. As a result, for example, a more sensitive analysis can be performed.

In the biological tissue analyzer of the present invention, for example, the light irradiation means for CARS includes a wavelength selection filter, the mixed light is separated by the wavelength selection filter, and only light having a required wavelength is selectively selected for biological tissue. May be irradiated. Further, for example, the wavelength selection filter includes a diffraction grating and a wavelength selection mask, the mixed light is separated by the diffraction grating, and only light having a required wavelength passes through the wavelength selection mask and irradiates a living tissue. May be done.

In the biological tissue analyzer of the present invention, for example, in the A unit and the B unit, the spectroscopic means may further include a narrow band filter, and the spectroscopic emitted light may pass through the narrow band filter. ..

In the biological tissue analyzer of the present invention, for example, in the A unit, the emitted light is three-dimensionally separated by the light separating means, and the three-dimensionally separated emitted light is separated by the diffraction grating. May be done. That is, in the A unit, the emitted light may be separated two-dimensionally or three-dimensionally by the light separating means.

In the biological tissue analyzer of the present invention, for example, in the B unit, the spectroscopic emitted light is imaged by the imaging means, and the spectroscopic emitted light is generated by the pixels on the image obtained by imaging. It may be originally separated. That is, in the B unit, the spectroscopic emitted light may be two-dimensionally separated by the pixels on the image obtained by imaging, or may be three-dimensionally separated.

The biological tissue analyzer of the present invention may further include a light irradiation means for spontaneous Raman scattering in the biological tissue analyzer including the A unit, for example.

The biological tissue analyzer of the present invention may include, for example, the A unit and the B unit, and the A unit and the B unit may share the light irradiation means.

The biological tissue analyzer of the present invention further includes, for example, circularly polarized means, and the light incident on the biological tissue may be circularly polarized by the circularly polarized means. In this case, for example, the biological tissue analyzer of the present invention further includes a circularly polarized light analysis means, and the difference in absorbance (dichroism) of at least a part of the biological tissue with respect to the left and right circularly polarized light by the circularly polarized light analysis means. Sex) may be detected.

The biological tissue analyzer of the present invention may further include, for example, linearly polarized light, and the emitted light emitted from the biological tissue irradiated with the broadband light by the linearly polarized light may be linearly polarized. In this case, for example, the biological tissue analyzer of the present invention further includes a linearly polarized light analyzing means, and the linearly polarized light is analyzed by the linearly polarized light analyzing means, so that at least a part of the living tissue is left and right. Differences in refractive index (optical rotation) with respect to circularly polarized light may be detected.

The biological tissue analyzer of the present invention further includes, for example, a space control mechanism capable of spatially controlling at least one of the intensity and the polarization state of the light irradiated from the light irradiation means, and the space control mechanism At least one of the intensity and the polarized state of the light emitted from the light irradiation means may be controlled and the living tissue may be irradiated.

The biological tissue analyzer of the present invention further includes, for example, an optical filter, in which the spectroscopic emitted light is fixed to a selected wavelength by the optical filter, and a nonlinear optical effect corresponding to the fixed wavelength is obtained. May be measured. Further, in this case, for example, the nonlinear optical effect is at least one selected from the group consisting of second harmonic generation (SHG), third harmonic generation (THG), and two-photon absorption fluorescence (TPF). There may be.

In the biological tissue analyzer and the biological tissue analysis method of the present invention, the biological tissue is not particularly limited, but may be, for example, an eyeball. In this case, the biological tissue may be at least one of the tissues of the eyeball, for example, at least one of the fundus, retina, crystalline lens and cornea. Further, in the present invention, the living tissue may be skin, a tissue of an internal organ of the living body, or the like. Examples of the tissues of the internal organs of the living body include tissues of each organ such as the digestive organs, and are not particularly limited. For example, stomach wall tissue, intestinal wall tissue, gallbladder tissue, liver tissue, pancreatic tissue, and these organs. Examples include cancer tissue. In addition, examples of the biological tissue include tissues of organs related to circulation and the like. Examples of the organs related to circulation include lungs, heart, blood vessels and the like. Examples of the tissue of blood vessels include blood vessel walls and blood. Further, in the biological tissue analyzer and the biological tissue analysis method of the present invention, the biological tissue may be analyzed as it is without being taken out from the living body, or the living tissue may be taken out from the living body and analyzed.

In the present invention, the spectroscopy by the spectroscopic means is not particularly limited, and for example, if the emitted light is Raman scattered light, it is Raman spectroscopy.

Further, in the present invention, "analysis" may be quantitative analysis (measurement) or qualitative analysis unless otherwise specified.

Hereinafter, specific embodiments of the present invention will be described. In the following embodiments 1 to 16, the case where the living tissue is an eyeball will be described. That is, the following embodiments 1 to 16 describe a case where the biological tissue analyzer of the present invention is an eyeball analyzer and an eyeball analysis method using the eyeball analyzer. The following embodiments 1 to 3 are examples of an eyeball analyzer including the A unit. Embodiments 4 to 7 are examples of an eyeball analyzer including the B unit. 8 to 16 are examples of an eyeball analyzer including both the A unit and the B unit. However, the following embodiments are examples, and the present invention is not limited thereto. Further, in each figure, members having the same characteristics are indicated by the same reference numerals.

[Embodiment 1]
FIG. 1 shows an example of the configuration of the eyeball analyzer of the present invention. The figure is an example of an eyeball analyzer including the A unit. As shown in the figure, this eyeball analyzer is composed of a light irradiation means 10 for irradiating an eyeball with broadband light and an A unit 100A. The A unit 100A has an optical separation means 20 that separates emitted light (emitted light) emitted (emitted) from the eyeball 1 irradiated with the broadband light according to the position of the space of the eyeball 1, and wavelengths of the emitted light. It includes a spectroscopic means 31 that disperses each time. Further, the A unit 100A further includes a lens 41 and an imaging means 42.

The light irradiation means 10 is composed of a light source 10A, a lens 11a, a lens 11b, a beam splitter 12, a lens 13, a wavelength variable filter 14, a wavelength selection filter 15, and an interference system. As the light source 10A, for example, a white light source, a super continu (hereinafter sometimes referred to as “SC”) light source, an LED (light emitting diode), or the like can be used. The wavelength selection filter 15 may be, for example, an ND filter (neutral density filter: Neutral Density Filter), a narrow band filter, or the like. Further, the wavelength tunable filter 14 and the wavelength selection filter 15 correspond to spectroscopic means for dispersing the light from the light source 10A. The interference system is arranged in the vicinity of the beam splitter 12 (the region indicated by reference numeral 19 in the drawing) in the light irradiation means 10. A confocal optical system may be arranged instead of the interference system. Further, in the present invention, the beam splitter is not particularly limited, but may be, for example, a beam splitter having a polarization separating ability, or a half mirror having no polarization separating ability when the polarization separating ability is not required.

The light separation means 20 is composed of a microlens array 21, a mask (field mask) 22, and a lens 23. The lens 23 may be, for example, a telecentric lens.

The spectroscopic means 31 is a diffraction grating. The spectroscopic means (diffraction grating) 31 may be, for example, a VPH (Volume Phase Holographic) grating or a grating.

The lens 41 may be, for example, a collimator lens. In FIG. 1, the image pickup means 42 shows a portion of the front surface of the image pickup device in which light displays an image. The imaging means 42 may be, for example, a general camera, a cooled CCD (Charge Coupled Device) camera, a CMOS (Complementary Metal Oxide Semiconductor) camera, or a camera having sensitivity to infrared rays.

In the optical path of the broadband light emitted from the light source 10A, the lens 11a, the wavelength variable filter 14, the wavelength selection filter (bandpass filter) 15, the lens 11b, and the beam splitter 12 are arranged in this order from the irradiation side of the broadband light. It is arranged. Further, in the optical path of the emitted light emitted from the eyeball 1, the lens 13, the beam splitter 12, the microlens array 21, the mask 22, the lens 23, the diffraction grating 31, the lens 41, and the imaging are performed in this order from the emitting side of the emitted light. The means 42 are arranged in this order. Further, the irradiation direction of the broadband light emitted from the light source 10A and the emission direction of the emitted light emitted from the eyeball 1 are perpendicular to each other in FIG. 1, but the angle is not limited to vertical and is arbitrary.

The eyeball analyzer of FIG. 1 can be used, for example, as follows. First, the light irradiation means 10 irradiates the eyeball 1 with light. Specifically, first, broadband light is irradiated from the light source 10A. The broadband light may be, for example, white light or super-continue (SC) light. The broadband light emitted from the light source 10A is converted into parallel light by the lens 11a and dispersed by the tunable filter 14. At this time, the light emitted from the light source 10A can be fixed to the selected wavelength by the wavelength tunable filter 14. Further, the wavelength selection filter 15 selectively transmits light of a specific wavelength, the selectively transmitted light is converged by the lens 11b, then reflected by the beam splitter 12, and further converged by the lens 13. After that, the eyeball 1 is irradiated. Further, the position of the interference system or the cofocal optical system arranged in the region 19 is adjusted according to the wavelength selected by the wavelength variable filter 14 and the wavelength selection filter 15 of the light emitted from the light source 10A. When the fundus of the eyeball 1 is irradiated with light, the light reaches the layer below the fundus, so that the state of the space between the fundus and the layer below the fundus can be analyzed, as will be described later. .. The part of the space between the fundus and the layer below the fundus that can be analyzed by the present invention includes, for example, the fundus, the retina, the fault of the space between the fundus and the layer below the fundus, and the space. Examples include blood vessels. Further, in this embodiment and other embodiments described later, a case where the light irradiated to the eyeball 1 is broadband light will be mainly described. However, in the present invention, the light emitted to the eyeball (for example, the light emitted from the light source 10A) is not limited to the broadband light as described above.

Next, at least a part of the broadband light irradiated to the eyeball 1 is emitted from the eyeball 1 by reflection, fluorescence, scattering, or the like by the eyeball 1. The emitted light emitted from the eyeball 1 is converged by the lens 13 and passes through the beam splitter 12.

The emitted light transmitted through the beam splitter 12 is processed by the A unit 100A as follows. That is, first, the emitted light is incident on the microlens array 21 of the light separation means 20, is separated two-dimensionally, and then is transmitted through the mask 22 to be separated according to the position of the space of the eyeball 1. Further, it is collimated by the lens 23. The emitted light that is two-dimensionally separated and passes through the lens 23 is separated for each wavelength by the spectroscopic means (diffraction grating) 31. In the figure, an example is shown in which the emitted light is separated into each monochromatic light by the diffraction grating 31. Then, the light dispersed by the diffraction grating 31 is converged by the lens 41 and irradiated to the imaging means 42. As a result, an image is formed on the imaging means 42. The image is subjected to, for example, a spectrum analysis means (not shown) to analyze the spectral spectrum of each field of view.

According to the biological tissue analyzer of the present invention, for example, analysis is performed using wavelength sweep type optical coherence tomography (wavelength sweep type OCT or SS-OCT: Swept Source Optical Coherence Tomography; hereinafter referred to as “SS-OCT”). be able to. As a result, even if the intensity of the light irradiating the living tissue is weak, it is possible to analyze the depth of the tissue of the living tissue. Specifically, for example, when analyzing the surface of a living tissue, a short wavelength is used, and when analyzing the inner part (inside) of the living tissue, a long wavelength is used, so that the intensity of light irradiating the living tissue can be increased. Even if it is weak, it is possible to analyze deep inside the tissue of living tissue. Further, according to the biological tissue analyzer of the present invention, the SS-OCT can analyze the internal structure of the biological tissue in the depth direction, and for example, the surface to the depth of the biological tissue can be analyzed by tunable wavelength. Thereby, for example, a minute change in the state of the living tissue can be detected.

However, the measurement method by the biological tissue analyzer of the present invention is not limited to SS-OCT, and as described above, at least one of coherent anti-Stoke Raman spectroscopy (CARS), spontaneous Raman scattering and optical coherence tomography (OCT). It can be analyzed by one. For example, having an A unit allows coherent anti-Stoke Raman spectroscopy (CARS) measurements, and having a B unit allows one or both of spontaneous Raman scattering and optical coherence tomography (OCT). It is not limited to this. SS-OCT is a type of OCT.

Further, as described above, conventionally, in the wavelength sweep type optical interference tomography, since a plurality of devices must be used for wavelength tunable, the configuration of the devices is complicated and the operation is complicated. On the other hand, according to the present invention, it is possible to easily analyze the depth of a living tissue with a device having a simple structure.

Further, according to the eyeball analyzer of FIG. 1, the imaging means 42 is simultaneously irradiated with light of different wavelengths separated for each wavelength by the spectroscopic means (diffraction grating) 31 to form an image. As a result, time simultaneity of analysis can be ensured. Further, for example, in order to widen the field of view of analysis (the range of the space of the eyeball 1 to be analyzed), the eyeball 1 may be analyzed while scanning by a scanning mechanism (not shown). As described above, the eyeball analyzer including the A unit has an advantage that the time simultaneity of the analysis can be ensured. Further, since the A unit can analyze light of different wavelengths at the same time, it is useful for analysis using information of a plurality of wavelengths as a probe, for example. However, the application of the eyeball analyzer including the A unit is not limited to this, and can be used, for example, for analysis using infrared light.

As the spectroscopic means, for example, a prism or the like may be used instead of the diffraction grating 31 to disperse the emitted light for each wavelength. Further, for example, instead of the diffraction grating 31, a wavelength filter may be used to extract only the wavelength of a specific light from the emitted light. Further, the optical separation means 20 may further include at least one such as an image slicer, a slit, an aperture (diaphragm), and a fiber bundle. Further, in the present embodiment, an example in which the optical separation means includes a microlens array is shown, but as described above, the A unit in the present invention is not limited to this. For example, in the A unit 100A, the optical separation means 20 may include a dichroic mirror in addition to or instead of the microlens array 21. The same applies to the A unit of each of the following embodiments.

[Embodiment 2]
FIG. 2 shows another example of the configuration of the eyeball analyzer of the present invention. In the apparatus of FIG. 1, the spectroscopic means was composed of only the diffraction grating 31. However, as shown in the figure, the apparatus of FIG. 2 further includes a narrow band filter 33, and the spectroscopic means 30 is provided by the diffraction grating 31 and the narrow band filter 33. Is configured. The narrow band filter 33 may be an order cut filter instead of the narrow band filter. Further, the narrow band filter 33 is arranged between the diffraction grating 31 and the lens 41 in FIG. However, the position of the narrow band filter 33 is not limited to this, and the same effect can be obtained even if the position of the narrow band filter 33 is arranged between the lens 23 and the diffraction grating 31, for example. As for the emitted light transmitted through the diffraction grating 31, only the light in the required wavelength band selectively passes through the narrow band filter 33 and irradiates the lens 41. Other than these, the eyeball analyzer of FIG. 2 is the same as the eyeball analyzer of FIG. Since the narrow band filter 33 can cut light in an unnecessary wavelength band, for example, the image forming surface (detector surface) of the imaging means 42 can be effectively used. More specifically, for example, a portion of the image forming surface (detector surface) that does not project a spectral spectrum can be used to expand the measurement field of view in the eyeball. This makes this embodiment particularly useful for spectra with high wavelength resolution (analyzing wavelength or more detailed information about it).

[Third Embodiment]
FIG. 3 shows still another example of the configuration of the eyeball analyzer of the present invention. As shown in the figure, in this eyeball analyzer, a polarizing plate 61 is arranged between the lens 11 and the beam splitter 12 in the light irradiation means 10. The polarizing plate 61 may be rotatable about the optical axis, for example. Further, in the A unit 100A, the 1/2 wavelength plate 26 and the polarizing plate 27 are arranged between the lens 23 and the spectroscopic means (diffraction grating) 31 in the above order from the light emitting side. The polarizing plate 27 may be, for example, a polarizing beam splitter instead of the polarizing plate. Other than these, the eyeball analyzer of FIG. 3 is the same as the eyeball analyzer of FIG.

The eyeball analyzer of FIG. 3 can be used, for example, as follows. First, as in FIG. 1, the light source 10A irradiates the broadband light. The broadband light may be, for example, white light or super-continue (SC) light. The broadband light emitted from the light source 10A is converted into parallel light by the lens 11a and dispersed by the tunable filter 14. At this time, the light emitted from the light source 10A can be fixed to the selected wavelength by the wavelength tunable filter 14. Further, light having a specific wavelength is selectively transmitted by the wavelength selection filter 15, the light transmitted selectively is converged by the lens 11b, and then linearly polarized by the polarizing plate 61. The polarized broadband light is processed by the beam splitter 12 and the lens 13 in the same manner as in FIG. 1 and is irradiated to the eyeball 1, and at least a part thereof becomes the light emitted from the eyeball 1 and becomes the lens 13 and the beam. It passes through the splitter 12.

The emitted light transmitted through the beam splitter 12 is processed by the A unit 100A as follows. That is, first, the emitted light is processed by the microlens array 21, the mask 22, and the lens 23 of the light separating means 20 in the same manner as in FIG. 1, and is separated according to the position of the space of the eyeball 1. Next, the emitted light transmitted through the lens 23 is incident on the 1/2 wavelength plate 26. The 1/2 wave plate 26 can be rotated, whereby the direction of linearly polarized light of the emitted light can be changed. The emitted light transmitted through the 1/2 wave plate 26 is selectively emitted with linearly polarized light in a specific direction by the polarizing plate 27, and then separated for each wavelength by a spectroscopic means (diffraction grating 31). The light dispersed for each wavelength by the spectroscopic means (diffraction grating 31) is processed by the lens 41, the imaging means 42, and optionally the spectral analysis means (not shown) in the same manner as in FIG. At this time, the difference in the refractive index (optical rotation) with respect to the left and right circularly polarized light in at least a part of the eyeball 1 may be detected by comparing the spectral spectra of linearly polarized light in different directions by the spectrum analysis means.

In the present invention, the arrangement and usage of the polarizing plate is not limited to the example of FIG. For example, when the data obtained by the eyeball analyzer of the present invention is analyzed by Raman spectroscopy, if a filter that passes only linearly polarized light in a specific direction generated by Raman scattering is used, luminescent light emitted from molecules in the eyeball can be used. Background light (light without linearly polarized light, unpolarized light) can be suppressed. Specifically, for example, when the broadband light emitted from the light source 10A or the light emitted from the eyeball 1 includes background light, it is between the beam splitter 12 and the microlens array 21 (the light incident side of the microlens array 21). ) Or the like, a linear polarizing plate (linear polarization means) is arranged to form a polarizing filter. As a result, it is possible to use only the linearly polarized light required for Raman scattering without transmitting the background light.

Further, for example, instead of the linear polarizing plate, a circularly polarizing plate may be used to circularly polarize the light incident on the eyeball 1 or the light emitted (emitted) from the eyeball 1. When a circularly polarizing plate is used, for example, the 1/2 wave plate 26 is replaced with a rotatable 1/4 wave plate, or the 1/2 wave plate 26 is adjacent to the light incident side or the light emitting side. A rotatable 1/4 wave plate may be used. The circularly polarizing plate (circularly polarized light means) 61 may be capable of switching between left and right in the rotation direction of the circularly polarized light to be transmitted, for example. Further, the circularly polarized light can be converted into linearly polarized light by the 1/4 wave plate. Further, the 1/2 wavelength plate 26 can change the direction of linearly polarized light or the direction of rotation of circularly polarized light. In this way, for example, it is possible to detect the difference in the absorbance of the left and right circularly polarized light in at least a part of the eyeball 1. Thereby, for example, the optical isomer in the eyeball 1 can be detected. Examples of the optical isomer include amino acids or L-forms and D-forms of amino acid residues.

[Embodiment 4]
FIG. 4 shows still another example of the configuration of the eyeball analyzer of the present invention. The figure is an example of an eyeball analyzer including the B unit. As shown in the figure, this eyeball analyzer is composed of a light irradiation means 10 for irradiating an eyeball with broadband light and a B unit 100B.

The light irradiation means 10 includes a light source 10A, a lens 11, a beam splitter 12, and a lens 13. As the light source 10A, for example, a white light source, an SC light source, an LED (light emitting diode), or the like can be used as in FIG. 1 (Embodiment 1). The beam splitter 12 may be the same as that of FIG. 1 (Embodiment 1), for example. The B unit 100B is an optical separation means (imaging means) 20B that separates the emitted light emitted from the eyeball 1 irradiated with the broadband light according to the position of the space of the eyeball 1, and the emitted light is separated for each wavelength. The spectroscopic means (wavelength variable filter) 32 is included. The B unit 100B further includes lenses 25 and 41. As shown in the figure, the components of the B unit 100B are arranged in the order of the lens 25, the spectroscopic means (tunable filter) 32, the lens 41, and the optical separation means (imaging means) 20B from the exit side of the emitted light from the eyeball 1. Has been done.

Further, the eyeball analyzer of FIG. 4 has a wavelength tunable filter 32 as a spectroscopic means instead of the diffraction grating 31 of FIGS. 1 to 3. The tunable filter (tunable filter) 32 may be, for example, a Fabry-Perot Etalon or the like.

In the eyeball analyzer of FIG. 4, the lens 41 may be, for example, a collimator lens.

The image pickup means 20B may include, for example, an image pickup element in which light displays an image, and an image may be formed on the front surface of the image pickup element. Similar to the image pickup means 42 of the first embodiment (FIGS. 1 to 3), the image pickup means 20B may be, for example, a camera, or an image may be formed on the image pickup surface thereof. In FIG. 4, the image forming surface of the imaging means 20B is, for example, a camera lens or an infrared camera (for example, a black silicon element when the wavelength is 1.2 μm or less, an InGaAs element or HgCdTe element when the wavelength is 0.7 to 1.8 μm, and a wavelength. In the case of 1 to 5 μm, it may be an imaging surface of an InSb element or HgCdTe).

The eyeball analyzer of FIG. 4 can be used, for example, as follows. First, broadband light is emitted from the light source 10A. As in the first embodiment, the broadband light may be, for example, white light or super-continue (SC) light. The broadband light emitted from the light source 10A is converged by the lens 11, then reflected by the beam splitter 12, further converged by the lens 13, and then irradiated to the eyeball 1.

Next, the emitted light transmitted through the beam splitter 12 forms an image of at least a part of the eyeball 1 (for example, a fundus image) on the image plane 24 on the light incident side of the lens 25. Further, the emitted light is incident on the lens 25 from the image plane 24, collimated by the lens 25, and then separated by the wavelength tunable filter 32 to extract monochromatic light having a specific wavelength. The extracted monochromatic light is converged by the lens 41 and irradiated to the imaging means 20B. Then, the spectroscopic emitted light is imaged by the imaging means 20B, and the spectroscopic emitted light is two-dimensionally separated by the pixels on the image obtained by imaging. In this way, the light separating means 20 can two-dimensionally separate the emitted light emitted from the eyeball 1 according to the position of the space of the eyeball 1. The image is subjected to, for example, a spectrum analysis means (not shown) to analyze the spectral spectrum of each field of view. Thereby, even a minute change in the state of the eyeball 1 can be detected. Further, by changing the wavelength of the monochromatic light extracted by the wavelength tunable filter 32, it is possible to analyze with light having a different wavelength.

According to the eyeball analyzer including the B unit as shown in FIG. 4, for example, it has an advantage of high spatial resolution. Therefore, an eyeball analyzer including the B unit is useful for analysis using, for example, infrared light. However, the application of the eyeball analyzer including the B unit is not limited to this, and can be used, for example, for analysis using visible light. Further, for example, as in the apparatus of the first to third embodiments (1 to 3), the field of view of analysis may be expanded by scanning using a scanning mechanism (not shown) as needed.

[Fifth Embodiment]
FIG. 5 shows still another example of the configuration of the eyeball analyzer of the present invention. In the apparatus of FIG. 4, the spectroscopic means was composed only of the wavelength tunable filter 32, but as shown in the figure, the apparatus of FIG. 5 further includes a narrow band filter 33, and the spectroscopic means is separated by the wavelength tunable filter 32 and the narrow band filter 33. Means 30 are configured. The narrow band filter 33 may be any other filter instead of the narrow band filter, for example, a wide band filter or an order cut filter. Further, the narrow band filter 33 is arranged between the wavelength tunable filter 32 and the lens 41 in FIG. As for the emitted light transmitted through the wavelength variable filter 32, only the light in the required wavelength band selectively passes through the narrow band filter 33 and is irradiated to the lens 41. Other than these, the eyeball analyzer of FIG. 5 is the same as the eyeball analyzer of FIG. Further, the arrangement position of the narrow band filter 33 is not limited to the position shown in FIG. 5, and for example, it is sufficient that the emitted light transmitted through the wavelength tunable filter 23 can be incident on the narrow band filter 33. It may be between the lens 41 and the imaging means 20B or the like. The narrow band filter 33 blocks (cuts) light in an unnecessary wavelength band (light having a wavelength different from the wavelength to be detected, or light of another order) included in the emitted light transmitted through the wavelength variable filter 23. As described above, only light in the required wavelength band can be selectively transmitted.

[Sixth Embodiment]
FIG. 6 shows still another example of the configuration of the eyeball analyzer of the present invention. As shown in the figure, in this eyeball analyzer, a polarizing plate 61 is arranged between the lens 11 and the beam splitter 12 in the light irradiation means 10. Further, in the B unit 100B, the 1/2 wavelength plate 26 and the polarizing plate 27 are arranged between the lens 25 and the tunable filter 32 in the above order from the light emitting side. As in FIG. 3, the polarizing plate 27 may be a polarizing beam splitter instead of the polarizing plate, for example. Other than these, the eyeball analyzer of FIG. 6 is the same as the eyeball analyzer of FIG. The eyeball analyzer of FIG. 6 is the same as the eyeball analyzer of FIG. 3 except that it has a B unit 100B instead of the A unit 100A.

The eyeball analyzer of FIG. 6 can be used, for example, as follows. First, the same is as in FIG. 3 until the broadband light emitted from the light source 10A is applied to the eyeball 1 and further becomes the light emitted from the eyeball 1 and passes through the beam splitter 12. The emitted light transmitted through the beam splitter 12 is processed by the B unit 100B as follows. That is, first, the emitted light is processed by the image plane 24 of the light separating means 20 and the lens 25 in the same manner as in FIG. 4, and is separated according to the position of the space of the eyeball 1. Next, the emitted light transmitted through the lens 25 is incident on the 1/2 wavelength plate 26. The 1/2 wave plate 26 can be rotated, whereby the direction of linearly polarized light of the emitted light can be changed. The emitted light transmitted through the 1/2 wave plate 26 is selectively emitted with linearly polarized light in one direction by the polarizing plate 27, and then separated for each wavelength by the wavelength variable filter 32, and is monochromatic light having a specific wavelength. Is taken out. The extracted monochromatic light is processed in the same manner as in FIG. 4 by the lens 41, the imaging means 20B, and optionally the spectrum analysis means (not shown).

The eyeball analyzer of FIG. 6 can be used for Raman spectroscopy or the like by using a filter that passes only linearly polarized light, as in FIG. 3, or a circular polarizing plate is used instead of the linearly polarized light, and the eyeball 1 It may be used for detection of optical isomers inside.

[Embodiment 7]
FIG. 7 shows an example of still another configuration of the eyeball analyzer of the present invention. As shown in the figure, in this eyeball analyzer, the light irradiation means 10 replaces the lens 11 with a lens 11a, a wavelength variable filter 14, a wavelength selection filter 15, a lens 11b, and an interference system (area 19 in which the interference system is arranged). It is the same as the eyeball analyzer of FIG. 4 (Embodiment 4) except that it has. The lens 11a, the wavelength variable filter 14, the wavelength selection filter 15, and the lens 11b are arranged in the optical path of the broadband light emitted from the light source 10A in the order from the irradiation side of the broadband light. A confocal optical system may be arranged instead of the interference system. That is, the configuration of the light irradiation means 10 in the eyeball analyzer of FIG. 7 is the same as that of the light irradiation means 1 in the eyeball analyzer of FIG. 1 (Embodiment 1).

The eyeball analyzer of FIG. 7 can be used, for example, as follows. First, the light irradiation means 10 irradiates the eyeball 1 with light. Next, at least a part of the broadband light irradiated to the eyeball 1 is emitted from the eyeball 1 by reflection, fluorescence, scattering, or the like by the eyeball 1. The emitted light emitted from the eyeball 1 is converged by the lens 13 and passes through the beam splitter 12. Up to this point, it is the same as the eyeball analyzer of FIG. 1 (Embodiment 1). Further, the emitted light transmitted through the beam splitter 12 can be processed by the B unit 100B in the same manner as the eyeball analyzer of FIG. 4 (Embodiment 4).

Further, as a modification of the eyeball analyzer of FIG. 7, the eyeball analyzers of FIGS. 8 and 9 are shown. The eyeball analyzer of FIG. 8 has the eyeball of FIG. 5 (Embodiment 5) except that the light irradiation means 10 has a lens 11a, a wavelength variable filter 14, a wavelength selection filter 15 and a lens 11b instead of the lens 11. It is the same as the analyzer. The lens 11a, the wavelength variable filter 14, the wavelength selection filter 15, and the lens 11b are arranged in the optical path of the broadband light emitted from the light source 10A in the order from the irradiation side of the broadband light. The eyeball analyzer of FIG. 9 shows the eyeball of FIG. 6 (Embodiment 6) except that the light irradiation means 10 has a lens 11a, a wavelength variable filter 14, a wavelength selection filter 15 and a lens 11b instead of the lens 11. It is the same as the analyzer. The lens 11a, the wavelength variable filter 14, the wavelength selection filter 15, and the lens 11b are arranged in the optical path of the broadband light emitted from the light source 10A in the order from the irradiation side of the broadband light.

The eyeball analyzers of FIGS. 7 to 9 are examples including the B unit, as in FIGS. 4 to 6 (embodiments 4 to 6). The inclusion of the B unit has the advantage of, for example, high spatial resolution, as described above. In FIGS. 7 to 9, the wavelength tunable filter 14 and the wavelength selection filter 15 may be the same as the wavelength tunable filter 14 and the wavelength selection filter 15 of FIG. 1 (Embodiment 1), for example.

[Embodiment 8]
FIG. 10 shows an example of still another configuration of the eyeball analyzer of the present invention. As shown in the figure, this device is composed of a light irradiation means 10, A unit 200A and B unit 200B. The light irradiation means 10 includes two light sources. Further, the A unit and the B unit include an optical separation means and a spectroscopic means as in the first to seventh embodiments (FIGS. 1 to 9).

The light irradiation means 10 is composed of two light sources 10A and 10B, a reflector 71 and a lens 72, beam splitters 73, 74 and 75, a tunable filter 14, and a filter 15. The light sources 10A and 10B are not particularly limited, but may be the same as the light sources 10A of the first to sixth embodiments (FIGS. 1 to 6), for example. The reflector 71 may be, for example, a galvano mirror. The reflecting mirror 71 can change the direction of light reflection by rotation. Further, the wavelength tunable filter 14 and the wavelength selection filter 15 may be the same as the wavelength tunable filter 14 and the wavelength selection filter 15 of FIG. 1 (Embodiment 1), for example.

A lens 72 and a beam splitter 73 are arranged in this order in the optical path of the broadband light emitted from the light source 10A from the irradiation side of the broadband light, and the irradiation unit 300A is arranged by the light source 10A, the lens 72, and the beam splitter 73. Is configured. In FIG. 10, the irradiation direction of the broadband light transmitted through the irradiation unit 300A is perpendicular to the transmission direction of the light transmitted through the A unit 200A and the B unit 200B, respectively, but the angle is not particularly limited and is vertical. It does not have to be. The beam splitter 73 is arranged on the light incident side of the lens 77 in the A unit 200A. Further, a beam splitter 75 is arranged on the light emitting side of the irradiation unit 300A. The beam splitter 75 is arranged on the light incident side of the lens 76 in the B unit 200B.

A reflecting mirror 71 is arranged on the light emitting side of the light source 10B. The light from the light source 10B is reflected by the reflecting mirror 71 as described later. A wavelength tunable filter 14 and a wavelength selection filter 15 are arranged in the optical path of the reflected light in the above order. Further, in the optical path of the emitted light emitted from the eyeball 1, a beam splitter 74, a beam splitter 75, and an A unit 200A are arranged in this order from the emitting side of the emitted light.

The A unit 200A is the same as the A unit 100A of the apparatus of FIG. 2 except that the lens 76 is arranged on the light incident side of the microlens array 21. The B unit 200B is the same as the B unit 100B in FIG. 5, except that the lens 77 is arranged on the light incident side of the image plane 24. The transmission directions of the light transmitted through the A unit 200A and the B unit 200B are parallel to each other in FIG. 10, but the angle is not particularly limited to parallel and is arbitrary.

The eyeball analyzer of FIG. 10 can be used, for example, as follows. First, a wide band light is irradiated from the light source 10A. The broadband light emitted from the light source 10A passes through the lens 72 and the beam splitter 73 in this order, is reflected by the beam splitter 75, passes through the beam splitter 74, and is applied to the eyeball 1. At least a part of the broadband light irradiated to the eyeball 1 is emitted from the eyeball 1 by reflection, fluorescence, scattering, or the like by the eyeball 1. The emitted light emitted from the eyeball 1 passes through the beam splitter 74. A part of the emitted light transmitted through the beam splitter 74 passes through the beam splitter 75 and is converged by the lens 76 of the A unit 200A. The light transmitted through the lens 76 is processed by the A unit 200A in the same manner as the A unit 100A of FIG. The image formed on the image pickup means 42 of the A unit 200A is provided to, for example, a spectrum analysis means (not shown), and the spectral spectrum of each field of view is analyzed.

Further, a part of the emitted light transmitted through the beam splitter 74 is reflected by the beam splitter 75, further reflected by the beam splitter 73, and converged by the lens 77 of the B unit 200B. The light transmitted through the lens 77 is processed by the B unit 200B in the same manner as the B unit 100B of FIG. The image formed on the image pickup means 20B of the B unit 200B is provided to, for example, a spectrum analysis means (not shown), and the spectral spectrum of each field of view is analyzed.

Further, the eyeball analyzer of FIG. 10 can also be used, for example, as follows. First, the light source 10B irradiates the broadband light. The broadband light emitted from the light source 10B is reflected by the reflecting mirror 71, split by the wavelength variable filter 14, and the light of a specific wavelength is selectively transmitted by the wavelength selection filter 15, and the light is selectively transmitted. The light is reflected by the beam splitter 74 and irradiates the eyeball 1. As described above, the reflecting mirror 71 can change the direction of light reflection by rotation, whereby the inside of the eyeball 1 can be scanned to expand the analysis field of view. At least a part of the broadband light irradiated to the eyeball 1 is emitted from the eyeball 1 by reflection or the like by the eyeball 1. The emitted light emitted from the eyeball 1 is transmitted through the beam splitter 74, then transmitted or reflected through the beam splitter 75, and is processed by the A unit 200A and the B unit 100B in the same manner as the light from the light source 10A. ..

According to the apparatus of FIG. 10, for example, the two light sources (light irradiation means) 10A and 10B can be appropriately switched according to the purpose, or the two can be used at the same time. For example, one of the two light sources may be a light source that irradiates visible light, and the other may be a light source that irradiates infrared light. Further, for example, the A unit 200A and the B unit 200B can be appropriately switched according to the purpose, or the two can be used at the same time.

In addition, the configuration of the device of FIG. 10 can be changed as appropriate. For example, a polarizing plate may be used as in the apparatus of FIG. 3 or 6.

[Embodiment 9]
FIG. 11 shows an example of still another configuration of the eyeball analyzer of the present invention. This device is the same as FIG. 10 except that it has an irradiation unit (laser unit) 300B instead of the light source 10B of FIG. The laser unit 300B is a light irradiation means for coherent anti-Stoke Raman spectroscopy (CARS). The laser unit 300B includes light irradiation means (light sources) 10C and 10D, an optical path length adjusting unit 101, and a relay lens 102. The optical path length adjusting unit 101 is composed of, for example, a mirror capable of reflecting light, and reflects wideband light (Stokes light) emitted from the light source 10D. Then, as shown by the arrow in the figure, the optical path length adjusting unit 101 can adjust the optical path length of the broadband light by moving back and forth along the irradiation direction of the broadband light from the light source 10D. As a result, the optical path length adjusting unit 101 plays a role of matching the timing of incident of the broadband light and the ultrashort pulse laser (pump light and probe light) on the eyeball, which will be described later.

The light source 10D is, for example, a light source that emits super-continue light (SC). The light source 10C irradiates a laser beam (monochromatic pulsed light). The laser light uses, for example, a femtosecond or picosecond laser as a seed light, and serves as an excitation light of supercontinue light emitted from the light source 10D. The laser beam is, for example, a visible light or an infrared ultrashort pulse laser.

Further, in the apparatus of FIG. 11, the light source 10A may be a white light source, and the irradiation unit 300A may be a white light source unit including the white light source. The light source 10A may be, for example, a halogen light source or a blackbody (depending on the wavelength range). The lens 72 may be, for example, a diffuser plate, a condenser lens, a collimator lens, or the like.

The eyeball analyzer of FIG. 11 can be used, for example, as follows. First, light is emitted from the light sources 10C and 10D. The optical path length of the super-continue light emitted from the light source 10D is adjusted by the optical path length adjusting unit 101. The laser light emitted from the light source 10C is reflected by the relay lens 102. As a result, the optical paths of the super-continue light (broadband light) and the laser light overlap to form mixed light. The mixed light is reflected by the reflecting mirror 71, irradiated to the eyeball 1 by the same path as the device of FIG. 10, and the anti-Stoke Raman scattered light emitted from the eyeball 1 is further incident on the A unit 200A and the B unit 200B. To do. In the B unit 200B, the light emitted from the eyeball 1 is separated by the diffraction grating 32. Other than these, the eyeball analyzer of FIG. 11 can be used in the same manner as the apparatus of FIG. For example, in addition to or in place of the light sources 10C and 10D, the light source 10A can be irradiated with broadband light and used in the same manner as the apparatus of FIG.

According to the apparatus of FIG. 11, as described above, the eyeball 1 was irradiated with the mixed light of the super continuation light (SC) by the light source 10D and the laser light (monochromatic pulsed light) by the light source 10C, and was generated in the eyeball. The anti-Stokes laser scattered light is separated by the diffraction grating 32. In general, anti-Stoke Raman light has a much higher intensity than ordinary Raman scattered light and is not affected by luminescence light generated by pump light, so that more sensitive analysis can be performed.

According to the apparatus of FIG. 11, for example, by performing CARS using the laser unit 300B and the B unit 200B, it is possible to acquire the spatial distribution information of cataract in the eye and perform cataract mapping. Thereby, for example, cataract can be detected even in a state where the progress is not progressing. Further, by performing the CARS, for example, three-dimensional mapping of the fundus tomography (fundus photograph + depth) can be performed. For this purpose, it is preferable that the Raman scattered light has a high resolution. Further, it is preferable to use near-infrared light (wavelength 1000 to 1550 nm) having high penetrating power. However, these uses are examples, and the uses of the device of FIG. 11 are not limited to these. Further, the configuration of this device is not particularly limited. For example, a device in which the light source 10 of the device of FIG. 5 (including the B unit and not including the A unit) is changed to the laser unit 300B can be used for the same purpose as the device of FIG. In the present invention, the “fundus fault” includes a fault in the space between the fundus and the layer below the fundus.

In the apparatus of FIG. 11, the wavelength of Stokes light (light related to the excitation of molecules in the eyeball serving as a probe among the broadband light irradiated to the eyeball 1) is not particularly limited, but is, for example, 1000 to 1550 nm. is there. When analyzing the retina, fundus, etc., it is preferable that the wavelength does not exceed 1400 nm from the viewpoint of making it easier for light to reach the analysis target site in consideration of the absorption band of water in the eyeball. The wavelength of the pump light (laser light emitted from the light source 10C) is also not particularly limited, but is, for example, 700 nm or more. The output of the light source 10C is also not particularly limited, but for example, when the emission duration of the light from the light source 10C is 10 seconds, it is 15.6 mW or less.

Not limited to the device of FIG. 11, in the eyeball analyzer of the present invention, it is preferable that the wavelength, output, etc. of the light applied to the eyeball are appropriately selected in consideration of safety. In addition, the output of the light source should not exceed the maximum permissible exposure (MPE) specified in, for example, standardization of laser safety (JISC6802) and protection from optical hazards in ocular optical equipment (JIST15004-2). Is preferable. When there are multiple light sources and the maximum allowable exposure at the wavelength of each emitted light is the same (same regulated wavelength band), the sum of the outputs of all the light sources should not exceed the maximum allowable exposure. Is preferable. When there are two light sources and the maximum permissible exposure amount at each wavelength of the emitted light is different (different regulated wavelength bands), the exposure amount of the first light source and the exposure amount of the second light source However, it is preferable to satisfy the relationship of the following mathematical formula (1). The same applies when there are three or more light sources. Further, for example, as shown in FIG. 12 described later, when the mixed light is separated by the wavelength selection filter and only the light having the required wavelength is selectively irradiated to the eyeball, the eyeball is replaced with the light emitted from the light source. The exposure amount of the light applied to the light may not exceed the maximum allowable exposure amount.

(E1 / E1 _max ) + (E2 / E2 _max ) ≦ 1 (1)

E1: Exposure of the emitted light of the first light source E1 _max : Maximum allowable exposure at the wavelength of the emitted light of the first light source E2: Exposure of the emitted light of the second light source E2 _max : Output of the second light source Maximum permissible exposure at the wavelength of light emission

The mixed light reflected by the reflecting mirror 71 is separated by the wavelength selection filter 15, and only the light having a required wavelength is selectively irradiated to the eyeball 1. Specifically, for example, among the light contained in the mixed light, Stokes light (light related to excitation of molecules in the eyeball serving as a probe among the broadband light irradiated to the eyeball 1) and pump light (light source 10C). Only the laser light emitted from the eyeball 1 passes through (transmits) the wavelength selection filter 15 and is selectively irradiated to the eyeball 1.

The graph of FIG. 12 schematically shows the function of the wavelength selection filter 15. In the figure, the horizontal axis is the wavelength and the vertical axis is the transmittance. As shown in the figure, only the light having the wavelength λ _{p of the} pump light and the light having the wavelength band λ _s of the Stokes light passes through the wavelength selection filter 15, and the light having other wavelengths is cut. However, FIG. 12 is an example and does not limit the present invention in any way. For example, the wavelength λ _p of the pump light and the wavelength band λ _s of the Stokes light in FIG. 12 are examples, and the present invention is not limited thereto. Further, for example, in FIG. 12, the Stokes light has one wavelength band, but when the Stokes light has a plurality of wavelength bands, all the Stokes lights in the plurality of wavelength bands may pass through the wavelength selection filter 15. .. When there are a plurality of wavelength bands of Stokes light, for example, analysis corresponding to a plurality of diseases (for example, cataract and Alzheimer's disease) can be performed, and early diagnosis of these diseases can be supported.

By blocking (cutting) light other than the required wavelength with the wavelength selection filter 15 so that it does not enter the eyeball 1, for example, the amount of light energy incident on the eyeball 1 can be suppressed and the safety of eyeball analysis can be improved. Can be done. In addition, for example, when light other than the required wavelength disappears, scattered light and luminescence light generated in the eye are reduced, so that background light is reduced, Raman light is easily detected, and the wavelength of Raman light is changed. The accuracy of the corresponding analysis (eg, analysis of a molecule such as a specific protein) is improved.

Further, for example, as the light source 10D, a monochromatic laser light source that emits only Stokes light instead of broadband light is used, and the same effect as that of using the wavelength selection filter 15 can be obtained without using the wavelength selection filter 15. .. However, it is preferable to use wideband light because it becomes more resistant to instability (robustness) such as temperature drift of the laser output wavelength due to temperature changes.

When there are a plurality of wavelength bands of Stokes light, for example, a plurality of wavelength selection filters 15 may be used and each of them may be switched so that the wavelength band of Stokes light corresponding to each wavelength selection filter is passed. Further, for example, in addition to or instead of using a plurality of wavelength selection filters 15, the wavelength selection filter 15 may be a wavelength tunable filter.

Further, for example, the wavelength selection filter 15 may include a diffraction grating and a wavelength selection mask in order to pass Stokes light of a plurality of wavelength bands. FIG. 13 shows an example of a wavelength selection filter 15 including a diffraction grating and a wavelength selection mask. As shown in the figure, in the wavelength variable filter 15, the diffraction grating 15a, the lens 15b, the wavelength selection mask 15c, the lens 15d, and the diffraction grating 15e are arranged in the above order from the light incident side (lower side of the figure). As shown in the figure, first, the mixed light is separated by the diffraction grating 15a. The dispersed mixed light passes through the lens 15b, and only one or more (two in the figure) wavelength band light is selectively passed by the wavelength selection mask 15c. The light that has passed through the wavelength selection mask 15c is applied to the eyeball 1 after passing through the lens 15d and the diffraction grating 15e. The wavelength selection mask 15c may be, for example, a wavelength selection filter or a tunable wavelength filter. Further, in the wavelength selection filter 15 of FIG. 13, the light incident side and the light emitting side can be reversed.

[Embodiment 10]
FIG. 15 shows still another example of the eyeball analyzer of the present invention. This eyeball analyzer can analyze the eyeball 1 in the same manner as the eyeball analyzers of FIGS. 1 to 11. Further, according to the eyeball analyzer of FIG. 15, as will be described later, measurement by coherent anti-Stoke Raman spectroscopy (CARS) and optical coherence tomography (OCT) is possible, and measurement by SS-OCT as a kind of OCT is possible. Is also possible. Further, the eyeball analyzer of FIG. 15 has both an A unit and a B unit, as will be described later. The devices of FIGS. 10 and 11 also have both A and B units, as described above. Therefore, the eye analyzer of FIG. 15 can be used, for example, in the same manner as the apparatus of FIG. 10 or 11. In addition, in FIG. 15, the same member as the apparatus of FIG. 10 or 11 is indicated by the same reference numeral.

As shown in FIG. 15, this eyeball analyzer includes A unit 2000A and B unit 2000B. The A unit 2000A includes a light irradiating means 3000B, a light separating means 20 that separates emitted light (emission light) emitted (emitted) from the eyeball 1 irradiated with broadband light according to the position of the space of the eyeball 1. It includes a spectroscopic means (diffraction grating) 31 that disperses the emitted light for each wavelength. Further, the A unit 2000A further includes a lens 41 and an imaging means 42. The light separation means 20 is composed of a microlens array 21, a mask (field mask) 22, and a lens 23. The arrangement and function of the microlens array 21, the mask (field mask) 22, the lens 23, the spectroscopic means 31, the lens 41, and the imaging means 42 are the same as those of the A unit 100A in the eyeball analyzer of FIG. The light irradiation means 3000B includes a light source 10E, mirrors 601 and 602, an optical fiber 401f, lenses 701, 702 and 711, and a beam splitter 121. The light source 10E is not particularly limited. The light source 10E may be a light source that irradiates broadband light, a light source that irradiates visible light, or a light source that irradiates infrared light, as in the case of the light source 10B of FIG. Further, the light source 10E includes, for example, a light source 10C that irradiates a laser beam (monochromatic pulsed light) and a light source 10D that emits a broadband light (for example, super-continue light (SC)), as in FIG. May be good. The light irradiation means 3000B is incorporated as a part of the A unit in FIG. 15, but is not limited to this. For example, the light irradiation means 3000B may be configured as a member separate from the A unit and may be used as a light source for the A unit. Further, for example, the light irradiation means 3000B is not limited to the light source for the A unit, and may be used as the light source for the B unit as described later.

The A unit 2000A further includes mirrors 603, 604 and 605, dichroic mirrors 501 and 502, a tunable filter 14 and a wavelength selection filter 15. The wavelength tunable filter 14 and the wavelength selection filter 15 are arranged adjacent to the light incident side of the microlens array 21 in the order of the wavelength tunable filter 14 and the wavelength selection filter 15 from the light incident side. The wavelength variable filter 14 and the wavelength selection filter 15 correspond to spectroscopic means for dispersing light from a light source, similarly to the wavelength variable filter 14 and the wavelength selection filter 15 of FIG.

The B unit 2000B includes a spectrometer 1000, input ports 801 and 901, output ports 802 and 902, sample arm SA, reference arm RA, lens 704, 706 and 707, optical power meter 707p, fiber. It includes a coupler 401c and a scanning mirror (mirror) 610s.

The lenses 704 and 706 and the scanning mirror 610s allow the light to be measured (for example, the emitted light emitted from the illuminated eyeball 1) to be transmitted or reflected and introduced into the input port 901. By changing (scanning) the angle of the scanning mirror 610s, the path of the light to be measured can be adjusted and introduced into the input port 901.

Input ports 801 and 901 and output ports 802 and 902 are connected to optical fibers, respectively. These optical fibers include a sample arm SA and a reference arm RA, and are bundled by a fiber coupler 401c. The input port 801 can introduce the irradiation light from the light irradiation means 3000B into the B unit 2000B via the optical fiber. The input port 901 can introduce the light to be measured into the sample arm (optical fiber) SA. The output port 802 can introduce the light to be measured into the spectrometer 1000 via the sample arm SA and the optical fiber. Further, the output port 902 can receive the light from the light source as it is without irradiating the eyeball 1 via the reference arm (optical fiber) RA. This received light can be used as a reference light (reference). The reference light received at the output port 902 can be measured by the optical power meter 707p through the lens 707.

The spectrometer 1000 includes a lens 25, a variable wavelength filter (spectral means) 32, a lens 41 and a line camera (imaging means) 20B, and these members are in the same order as the eyeball analyzer of FIG. 4 from the light incident side. The same functions as the lens 25, the wavelength variable filter (spectral means) 32, the lens 41, and the imaging means 20B in FIG. 4 are also arranged. The line camera 20B forms an image of at least a part of the eyeball 1 on the image plane (not shown in FIG. 15).

In addition, the eyeball analyzer of FIG. 15 further includes a light irradiation means 3000A. The light irradiation means 3000A includes a light source 10A, a mirror 606, a dichroic mirror 503, a lens 705, a beam splitter 12, an optical power meter 10Ap, an objective lens 13, and an objective lens switcher 13s. The light source 10A is not particularly limited, and may be the same as the light source 10A of FIGS. 1 to 11, for example. The mirror 606, the dichroic mirror 503, the lens 705, and the beam splitter 12 can reflect, transmit, or refract the light from the light source 10A. The intensity of light from the light source 10A can be measured by the optical power meter 10Ap. Further, the objective lens 13 can be moved by the objective lens switcher 13s. For example, as will be described later, the objective lens 13 may be used for CARS measurement, and the objective lens 13 may not be used for OCT measurement.

The eyeball analysis method using the eyeball analyzer of FIG. 15 is not particularly limited, but can be performed as shown in FIGS. 16, 17, 18 or 19, for example.

16 and 17 are diagrams showing an example of an eyeball analysis method by CARS measurement using the eyeball analyzer of FIG. FIG. 16 shows the path of the incident light emitted (incident) to the eyeball 1 by the light source 10E. FIG. 17 shows the path of the emitted light emitted from the eyeball 1 irradiated with the light.

Specifically, the CARS measurement of FIGS. 16 and 17 can be performed as follows. First, as shown in FIG. 16, the supercontinue light SC1 and the pump light (excitation light) P1 are irradiated from the light source 10E. The wavelength of the super-continue light SC1 is not particularly limited, but may be, for example, a wavelength of 1100 nm to 1600 nm. The center wavelength of SC1 is not particularly limited, but may be, for example, a center wavelength of 1040 nm. The irradiation interval of SC1 is not particularly limited, but may be, for example, several tens of ps. Further, the pump light P1 is, for example, a monochromatic laser light, and may be, for example, a pulse laser. The wavelength of P1 is not particularly limited, but may be, for example, 1064 nm. The irradiation interval of P1 is also not particularly limited, but may be, for example, several ps or the like. As shown, the SC1 is reflected by the mirrors 601 and 602 in the above order, passes through the lens 711, the optical fiber 401f, the lens 701 and the beam splitter 121 in the above order, and further passes through the dichroic mirror 501. On the other hand, P1 is reflected by the mirror 603, then reflected by the dichroic mirror 501, and is combined with SC1 to become synthetic light. In this way, SC1 is excited by P1. As shown in the figure, the combined light of SC1 and P1 is transmitted through the dichroic mirror 502, reflected by the mirror 605, the mirror 606 and the dichroic mirror 503 in the above order, and then reflected by the beam splitter 12 and further the objective lens 13. It penetrates and irradiates the eyeball 1.

Next, as shown in FIG. 17, CARS light (signal light) S1 is irradiated from the eye light 1 irradiated with the combined light of SC1 and P1. The wavelength of the CARS light (signal light) S1 is not particularly limited, but may be, for example, 700 nm to 980 nm. S1 transmits through the objective lens 13 and transmits or is reflected through the beam splitter 12, the dichroic mirror 503, the mirror 606, the mirror 605, the dichroic mirror 502, the lens 703, and the mirror 604 in the above order. Then, S1 further transmits the wavelength variable filter 14, the wavelength selection filter 15, the microlens array 21, the mask (field mask) 22, the lens 23, the spectroscopic means 31, and the lens 41 in the above order, and refracts while transmitting. , Spectroscopy, etc. are performed. The S1 transmitted through the lens 41 is further irradiated with the imaging means 42 to be imaged, and the spectroscopic emitted light S1 is two-dimensionally separated by the pixels on the image obtained by the imaging. The imaging means 42 may be a two-dimensional imaging system in which S1 is two-dimensionally separated in this way. However, the present invention is not limited to this, and a three-dimensional imaging system in which S1 is three-dimensionally separated may be used.

Next, FIGS. 18 and 19 are diagrams showing an example of an eyeball analysis method by OCT measurement using the eyeball analyzer of FIG. FIG. 18 shows the path of the incident light emitted (incident) to the eyeball 1 by the light source 10E. FIG. 19 shows the path of the emitted light emitted from the eyeball 1 irradiated with the light.

Specifically, the OCT measurement of FIGS. 18 and 19 can be performed as follows. First, as shown in FIG. 18, the super-continue light SC2 is irradiated from the light source 10E. The wavelength of SC2 is not particularly limited, but for example, the center wavelength may be variable. The wavelength band of SC2 is also not particularly limited, but may be, for example, 20 nm to several hundred nm. As shown, the SC2 is reflected by the mirrors 601 and 602 in the above order, transmitted through the lens 711, the optical fiber 401f and the lens 701 in the above order, reflected by the beam splitter 121, and transmitted through the lens 702 to the input port 801. be introduced. The SC2 introduced into the input port 801 is further divided into two by the sample arm SA and the reference arm RA. The SC2 introduced into the sample arm SA transmits the input port 901 and the lens 706 in the above order, is reflected by the scanning mirror 610s, and further transmits the lens 704, the lens 705, and the beam splitter 12 in the above order, and the eyeball. Is irradiated to 1. Note that the objective lens 13 is not used in FIGS. 18 and 19. Further, the SC2 introduced into the reference arm RA passes through the lens 707, its intensity is measured by the optical power meter 707p, and is used as the reference light (reference).

Next, as shown in FIG. 19, OCT light (signal light) S2 is irradiated from the eyeball 1 irradiated with SC2. The wavelength of S2 is not particularly limited, but may be the same as the light SC2 incident on the eyeball 1, for example. S2 passes through the beam splitter 12, the lens 704, and the lens 705 in the above order, is reflected by the scanning mirror 610s, passes through the lens 706 and the input port 901, and is introduced into the spectrometer 1000 via the output port 802. .. The SC2 introduced into the spectrometer 1000 passes through the lens 25, the wavelength variable filter (spectral means) 32 and the lens 41 in the above order, is imaged by the line camera (imaging means) 20B, and is captured on the image obtained. The dispersed emitted light is two-dimensionally separated by the pixels of the above. An image of at least a part of the eyeball 1 is imaged on the image plane (not shown) by the line camera 20B, and is analyzed using the reference light (reference) introduced into the reference arm RA. The line camera (imaging means) 20B may be a two-dimensional imaging system in which S2 is two-dimensionally separated in this way. However, the present invention is not limited to this, and a three-dimensional imaging system in which S2 is three-dimensionally separated may be used.

[Embodiment 11]
FIG. 20 shows still another example of the biological tissue analyzer of the present invention. Although the examples of the eyeball analyzers have been described in the first to tenth embodiments, FIG. 20 is a biological tissue analyzer capable of analyzing biological tissues other than the eyeballs. In the apparatus of FIG. 20, the A unit replaces the microlens array 21, the mask (field mask) 22, the lens 23, the spectroscopic means (diffraction grating) 31, the lens 41, and the imaging means 42 with a lens 710 and a spectrometer 1001. Including. The spectrometer 1001 includes an optical separation means and a spectroscopic means, the spectroscopic means includes a diffraction grating, the emitted light is two-dimensionally or three-dimensionally separated by the optical separation means, and the diffraction grating The emitted light separated two-dimensionally or three-dimensionally is separated. The optical separation means and the spectroscopic means (diffraction grating) included in the spectrometer 1001 are not particularly limited, but for example, as in FIG. 15, the microlens array 21, the mask (field mask) 22, the lens 23, and the spectroscopy The means (diffraction grating) 31, the lens 41, the imaging means 42, and the like may be used. Further, in this biological tissue analyzer, a dichroic mirror 507 is arranged between the mirror 604 and the wavelength tunable filter 14. Further, in this biological tissue analyzer, a mirror 607 and a scanning mirror 611s are arranged between the dichroic mirror 502 and the mirror 605. The optical path of the reflected light of the scanning mirror 611s can be changed by changing the angle thereof. Further, this biological tissue analyzer has objective lenses 1101 and 1102 and lens switchers 1101s and 1102s instead of the objective lens 13 and the lens switcher 13s. The objective lenses 1101 and 1102 face each other, and a biological tissue (not shown) to be analyzed can be arranged between the objective lenses 1101 and 1102 for analysis. The biological tissue to be analyzed is not particularly limited and is arbitrary, and examples thereof include the above-mentioned biological tissues, and may be, for example, the skin or the wall of the digestive tract (for example, the esophagus, the stomach wall, etc.) or the circulation. It may be the tissue of the organ related to. Examples of the organs related to circulation include lungs, heart, blood vessels and the like. The tissue of the blood vessel may be, for example, a blood vessel wall, blood, or the like. With the lens switchers 1101s and 1102s, for example, as will be described later, the objective lenses 1101 and 1102 can be used for CARS measurement, and the objective lenses 1101 and 1102 can be not used for OCT measurement. In addition, this biological tissue analyzer does not have a lens 703. Other than these, the configuration of the bioanalyzer in FIG. 20 is the same as that in the eye analyzer in FIG. Further, in the biological analyzer of FIG. 20 and the biological tissue analysis method using the same, the biological tissue may be analyzed as it is without being taken out from the living body, or the living tissue may be taken out from the living body and analyzed. Good.

The biological tissue analysis method using the biological tissue analyzer of FIG. 20 is not particularly limited, but can be performed as shown in FIGS. 21, 22, 23, 24 or 25, for example.

21, 22 and 23 are diagrams showing an example of an eyeball analysis method by CARS measurement using the biological tissue analyzer of FIG. 20. FIG. 21 shows a path of incident light irradiated (incident) to a biological tissue (not shown) by the light source 10E. 22 and 23 show the path of the emitted light emitted from the living tissue irradiated with the light.

Specifically, the CARS measurement of FIGS. 21, 22 and 23 can be performed as follows. First, as shown in FIG. 21, the supercontinue light SC3 and the pump light (excitation light) P3 are irradiated from the light source 10E. Various characteristics such as the wavelength, center wavelength, and irradiation interval of the super-continue light SC3 and the pump light (excitation light) P3 are not particularly limited. For example, the super-continue light SC1 and the pump light (excitation light) P1 in FIG. It may be the same as. As shown, the SC3 is reflected by the mirrors 601 and 602 in the above order, passes through the lens 711, the optical fiber 401f, the lens 701 and the beam splitter 121 in the above order, and further passes through the dichroic mirror 501. On the other hand, P3 is reflected by the mirror 603, then reflected by the dichroic mirror 501, and is combined with SC3 to become synthetic light. In this way, SC3 is excited by P3. As shown in the figure, the combined light of SC3 and P3 is transmitted through the dichroic mirror 502, reflected by the mirror 607, the scanning mirror 611s, the mirror 605, the mirror 606 and the dichroic mirror 503 in the above order, and then reflected by the beam splitter 12. Alternatively, the light is transmitted, the intensity is measured by the optical power meter 10Ap, and the living tissue (not shown) to be analyzed is irradiated through the objective lens 1102.

Next, as shown in FIG. 22, the backscattered light S3 of CARS light (signal light) is irradiated from the living tissue irradiated with the synthetic light of SC3 and P3. The wavelength of the backscattered light S3 of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. S3 transmits through the objective lens 1102 and transmits or is reflected through the beam splitter 12, the dichroic mirror 503, the mirror 606, the mirror 605, the scanning mirror 611s, the mirror 607, the dichroic mirror 502 and the mirror 604 in the above order. Then, S3 further passes through the wavelength tunable filter 14 and the wavelength selection filter 15 in the above order, passes through the lens 710, and enters the spectrometer 1001. As described above, the spectrometer 1001 includes an optical separation means and a spectroscopic means, the spectroscopic means includes a diffraction grating, and the light separation means separates the emitted light two-dimensionally or three-dimensionally. The diffraction grating disperses the emitted light separated in two or three dimensions. The spectrometer 1001 may be a two-dimensional imaging system in which S3 is two-dimensionally separated in this way. However, the present invention is not limited to this, and a three-dimensional imaging system in which S3 is three-dimensionally separated may be used.

On the other hand, as shown in FIG. 23, the forward scattered light S3A of CARS light (signal light) is irradiated from the living tissue irradiated with the synthetic light of SC3 and P3. The wavelength of the forward scattered light S3A of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. The S3A passes through the objective lens 1101, is reflected by the dichroic mirror 507, passes through the wavelength variable filter 14 and the wavelength selection filter 15 in the above order, passes through the lens 710, and is incident on the spectrometer 1001. As described above, the spectrometer 1001 includes an optical separation means and a spectroscopic means, the spectroscopic means includes a diffraction grating, and the light separation means separates the emitted light two-dimensionally or three-dimensionally. The diffraction grating disperses the emitted light separated in two or three dimensions. The spectrometer 1001 may be a two-dimensional imaging system in which S3 is two-dimensionally separated in this way. However, the present invention is not limited to this, and a three-dimensional imaging system in which S3 is three-dimensionally separated may be used.

Next, FIGS. 24 and 25 are diagrams showing an example of an eyeball analysis method by OCT measurement using the biological tissue analyzer of FIG. 20. FIG. 24 shows the path of the incident light that is irradiated (incident) to the living tissue by the light source 10E. FIG. 25 shows the path of the emitted light emitted from the living tissue irradiated with the light.

Specifically, the OCT measurement of FIGS. 24 and 25 can be performed as follows. First, as shown in FIG. 24, the super-continue light SC4 is irradiated from the light source 10E. The characteristics of the SC4 such as the wavelength, the center wavelength, and the wavelength band are not particularly limited, but may be the same as those of the super continuation optical SC2 of FIG. 18, for example. As shown, SC4 is irradiated to the biological tissue (not shown) to be measured in FIG. 24 instead of the eyeball 1 by the same route as the super continuation light SC2 in FIG. At this time, as shown in the figure, the SC4 does not transmit the objective lenses 1101 and 1102.

Next, as shown in FIG. 25, the signal light S4 of OCT light (signal light) is irradiated from the living tissue irradiated with SC4. The wavelength of S4 is not particularly limited, but may be the same as that of light SC4 incident on a living tissue, for example. As shown, S4 is introduced into the spectrometer 1000 by the same path as the OCT light (signal light) S2 of FIG. Then, S4 is analyzed by the same method as the OCT light (signal light) S2 of FIG.

According to the bioanalyzer and bioanalysis method of the present embodiment (FIGS. 20 to 25), for example, OCT can be used to acquire three-dimensional spatial shape information of biological tissue. In addition, for example, by using CARS to acquire spectral information of a specific region based on the three-dimensional spatial shape evaluation of living tissue and evaluating the property change from the molecular information, the mechanism of the disease can be examined at an early stage. Can be done. However, the bioanalyzer and the bioanalysis method of the present embodiment are not limited to this, and for example, as described above, they can be used as a two-dimensional imaging system in which the light emitted from the biological tissue is two-dimensionally separated.

[Embodiment 12]
FIG. 26 shows still another example of the biological tissue analyzer of the present invention. As shown in the figure, in this bioanalyzer, a polarizing plate 131 and a beam splitter 122p are arranged between the light source 10A and the dichroic mirror 503. Further, this biological tissue analyzer includes a beam splitter 123p, lenses 708 and 709, and image sensors (imaging means) 708B and 709B. Other than these, the configuration of the bioanalyzer in FIG. 25 is the same as that in the bioanalyzer in FIG.

The biological tissue analysis method using the biological tissue analyzer of FIG. 26 is not particularly limited, but can be performed as shown in FIGS. 27 and 28, for example.

As shown in FIG. 27, the white light W5 is irradiated from the light source 10A. The white light W5 passes through the polarizing plate 131, the beam splitter 122p, the dichroic mirror 503 and the beam splitter 12 in the above order, and is polarized and separated when passing through the polarizing plate 131. Then, the W5 is irradiated to the biological tissue to be measured via the objective lens 1102.

Further, as shown in FIG. 28, the signal light S5 is emitted from the living tissue irradiated with the white light W5. The signal light S5 passes through the dichroic mirror 503, is reflected by the beam splitter 122p, is split into S-polarized light and P-polarized light by the beam splitter 123p, and transmits the lenses 708 and 709, respectively. The S5 transmitted through the lenses 708 and 709 is imaged and analyzed by the image sensors (imaging means) 708B and 709B. In this way, polarized light can be detected and analyzed.

According to the biological tissue analyzer and the biological tissue analysis method of the present embodiment (FIGS. 26 to 28), for example, the surface optical characteristics (polarization information) of the biological tissue to be measured are evaluated, and whether the surface state of the target is uniform. By acquiring information such as non-uniformity, more multifaceted diagnosis becomes possible. Further, the biological tissue analysis method using the biological tissue analyzer of the present embodiment is not particularly limited, and for example, the same biological tissue analysis method as in FIGS. 21 to 25 can be performed.

[Embodiment 13]
FIG. 29 shows still another example of the biological tissue analyzer of the present invention. As shown, in this bioanalyzer, the B unit has two spectrometers. That is, in this bioanalyzer, the B unit has a spectrometer 1000B in addition to the spectrometer 1000. The configuration of the spectrometer 1000B is the same as that of the spectrometer 1000. That is, the spectrometer 1000B includes a lens 25, a wavelength variable filter (spectral means) 32, a lens 41 and a lens 25b similar to the line camera (imaging means) 20B, a wavelength variable filter (spectral means) 32b, a lens 41b and a line camera ( Imaging means) 20Bb is included. These members are arranged in the same order as the biological tissue analyzer of FIG. 20 from the light incident side. In addition to the optical fiber 401f, this bioanalyzer also has another optical fiber 401fb. Further, in this biological tissue analyzer, the mirror 602 is a dichroic mirror, and further, the mirror 602b is provided. In addition, this biological tissue analyzer further includes lenses 711b, 701b and 712, dichroic mirrors 504 and 511, and an optical filter 712f. The dichroic mirrors 504, 511 and 602 are movable. Thereby, it is possible to switch the light incident on the optical fiber 401f or the optical fiber 401fb, and further, it is possible to switch the light incident on the spectrometer 1000 or the spectrometer 1000B. Therefore, according to the biological tissue analyzer of FIG. 29, it is possible to perform a method of analyzing biological tissue by wavelength sweep type optical coherence tomography (SS-OCT). Other than that, the biological tissue analyzer of FIG. 29 is the same as the biological tissue analyzer of FIG. 20.

The eyeball analysis method using the biological tissue analyzer of FIG. 29 is not particularly limited, but can be performed as shown in FIGS. 30, 31, 32 or 33, for example.

30 and 31 are examples of measurements using the optical fiber 401f and the spectrometer 1000. First, as shown in FIG. 30, the super-continue light SC6 is irradiated from the light source 10E. The characteristics of the SC6 such as the wavelength, the center wavelength, and the wavelength band are not particularly limited, but may be the same as those of the super continuation optical SC2 of FIG. 18, for example. As shown, SC4 irradiates the biological tissue (not shown) to be measured in FIG. 30 by the same route as the super continuation light SC2 in FIG. However, in FIG. 30, the sample arm SA has a lens 702, an optical filter 712f and a mirror 612, and the SC6 transmits the lens 702, the optical filter 712f and the mirror 612 in the above order and then transmits the lens 706. At this time, as shown in the figure, the SC4 does not transmit the objective lenses 1101 and 1102.

Next, as shown in FIG. 31, the backscattered light S6 of OCT light (signal light) is irradiated from the living tissue irradiated with SC6. The wavelength of S6 is not particularly limited, but may be the same as that of light SC6 incident on a living tissue, for example. As shown, S6 is introduced into the spectrometer 1000 by the same path as the OCT light (signal light) S2 of FIG. However, in FIG. 31, S6 transmitted through the lens 6 passes through the mirror 612 of the sample arm SA, the optical filter 712f and the lens 702 in the above order, then passes through the beam splitter 122, and is further reflected by the dichroic mirror 504 to spectro Introduced to the meter 1000. Then, S6 is analyzed by the same method as the OCT light (signal light) S2 of FIG.

32 and 33 are examples of measurements using the optical fiber 401fb and the spectrometer 1000B. First, as shown in FIG. 32, the super continuation light SC7 is irradiated from the light source 10E. The characteristics of the SC7 such as the wavelength, the center wavelength, and the wavelength band are not particularly limited, but may be the same as those of the super continuation optical SC2 of FIG. 18, for example. At this time, as shown in the figure, the dichroic mirrors 602 and 504 are moved out of the light path, and the dichroic mirror 511 is moved in the light path. As a result, as shown in the figure, the SC7 is not reflected by the dichroic mirror 602 and is reflected by the mirror 602b, so that it does not pass through the optical fiber 401f and passes through the lens 711b, the optical fiber 401fb and the lens 702b in the above order, and the dichroic mirror. It is reflected by 511 and incident on the beam splitter 122. After that, SC7 is irradiated to the biological tissue (not shown) to be measured in FIG. 32 by the same route as the super continuation light SC6 in FIG.

Next, as shown in FIG. 33, the backscattered light S7 of OCT light (signal light) is irradiated from the living tissue irradiated with SC7. The wavelength of S7 is not particularly limited, but may be the same as that of light SC7 incident on a living tissue, for example. As shown, S7 is not introduced into the spectrometer 1000, but is introduced into the spectrometer 1000B by a different route than in FIG. Then, S7 is analyzed by the same method as the OCT light (signal light) S2 of FIG.

According to the biological tissue analyzer and the biological tissue analysis method of the present embodiment (FIGS. 29 to 33), for example, by making the wavelength of the OCT variable (two wavelengths in the configuration of FIGS. 29 to 33), it is a measurement target. Images can be compared between the differences in the linear optical characteristics (absorption / scattering) of living tissues with respect to wavelength. Thereby, the state change of the living tissue (bleeding (wavelength-dependent absorption), canceration) can be image-evaluated and applied to diagnosis. However, this embodiment is not limited to FIGS. 29 to 33, and any modification is possible. For example, three or more spectrometers may be used, and the wavelength of OCT may be variable at three or more wavelengths.

[Embodiment 14]
FIG. 34 shows still another example of the biological tissue analyzer of the present invention. As shown in the figure, this bioanalyzer has a light source 10R for spontaneous Raman scattering measurement and a dichroic mirror 511. Further, instead of the wavelength tunable filter 14 and the wavelength selection filter 15, the wavelength tunable filter 14b and the wavelength selection filter 15b having different wavelength tunable ranges and selection ranges are provided. Other than this, the biological tissue analyzer of FIG. 34 is the same as the biological tissue analyzer of FIG. 20.

The eyeball analysis method using the biological tissue analyzer of FIG. 34 is not particularly limited, but can be performed as shown in FIGS. 35 to 37, for example.

First, as shown in FIG. 35, the super continuation light SC8 is irradiated from the light source 10R. The characteristics of the SC8 such as the wavelength, the center wavelength, and the wavelength band are not particularly limited, but may be the same as those of the super continuation optical SC2 of FIG. 18, for example. The SC8 is reflected by the dichroic mirror 511 and further reflected by the scanning mirror 611s. After that, the SC8 passes through the objective lens 1102 and irradiates the biological tissue (not shown) to be measured in FIG. 35 by the same route as the super continuation light SC3 in FIG.

Next, as shown in FIG. 36, the backscattered light S8 of the OCT light (signal light) is irradiated from the living tissue irradiated with SC8. The wavelength of S8 is not particularly limited, but may be, for example, 700 nm to 980 nm. As shown, S8 is introduced into the spectrometer 1001 by the same path as the signal light (backscattered light) S3 of FIG.

On the other hand, as shown in FIG. 37, the forward scattered light S8A of CARS light (signal light) is irradiated from the living tissue irradiated with SC8. The wavelength of the forward scattered light S8A of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. As shown in the figure, S8A is introduced into the spectrum meter 1001 by the same path as the forward scattered light S3A in FIG. 23.

Further, the biological tissue analyzer of the present embodiment can perform the biological tissue analysis method in the same manner as the biological tissue analyzer of FIG. 20 by exchanging the wavelength tunable filter 14b and the wavelength selection filter 15b, for example. Is.

According to the biological tissue analyzer and the biological tissue analysis method of the present embodiment (FIGS. 35 to 37), for example, it is possible to introduce an optical system of spontaneous Raman scattering, compare and examine it with the evaluation of the CARS optical system, and apply it for diagnosis. it can. Thereby, for example, by comparing the result for the diagnostic application of Raman scattering with the evaluation result of the CARS signal from the inside of the body several hundred μm from the surface, a multifaceted diagnosis becomes possible.

[Embodiment 15]
FIG. 38 shows still another example of the biological tissue analyzer of the present invention. As shown in the figure, this bioanalyzer is the same as the bioanalyzer of FIG. 20 except that a spatial optical modulator (SLM) 1201 is arranged between the light source 10E and the mirror 603. The spatial optical modulator 1201 corresponds to a spatial control mechanism capable of controlling at least one of the intensity and the polarization state of the light emitted from the light irradiation means (light source). As a result, it is possible to irradiate the biological tissue to be measured with light in which at least one of the light intensity and the polarized state is controlled.

The eyeball analysis method using the biological tissue analyzer of FIG. 38 is not particularly limited, but can be performed as shown in FIGS. 39, 40 or 41, for example. Note that FIGS. 39, 40 and 41 are examples of CARS measurement.

Specifically, the CARS measurement of FIGS. 39, 40 and 41 can be performed as follows. First, as shown in FIG. 39, the supercontinue light SC9 and the pump light (excitation light) P9 are irradiated from the light source 10E. Various characteristics such as the wavelength, center wavelength, and irradiation interval of the super-continue light SC9 and the pump light (excitation light) P9 are not particularly limited, but for example, the super-continue light SC1 and the pump light (excitation light) P1 in FIG. It may be the same as. After that, the pump light P9 passes through the spatial optical modulator 1201 and then is reflected by the mirror 603. Iga analyzes that SC9 and P9 pass through the objective lens 1102 in the same path as SC3 and P3 in FIG. The target biological tissue (not shown) is irradiated.

Next, as shown in FIG. 40, the backscattered light S9 of CARS light (signal light) is irradiated from the biological tissue irradiated with the synthetic light of SC9 and P9. The wavelength of the backscattered light S9 of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. As shown, S9 is introduced into the spectrometer 1001 in the same path as the backscattered light S3 in FIG.

On the other hand, as shown in FIG. 41, the forward scattered light S9A of CARS light (signal light) is irradiated from the living tissue irradiated with the synthetic light of SC9 and P9. The wavelength of the forward scattered light S9A of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. As shown, S9A is introduced into the spectrometer 1001 in the same path as the forward scattered light S3A of FIG.

According to the biological tissue analyzer and the biological tissue analysis method of the present embodiment (FIGS. 39 to 41), for example, a spatial control mechanism (SLM or the like) is introduced to control the polarization and intensity to expose the measurement target. Conditions (intensity / phase matching conditions) can be controlled. This makes it possible to take out the signal more efficiently. However, the method of using the biological tissue analyzer of the present embodiment is not limited to this, and for example, it can be used in the same manner as the biological analyzer of FIG. 20.

[Embodiment 16]
FIG. 42 shows still another example of the biological tissue analyzer of the present invention. As shown in the figure, this bioanalyzer has a wavelength tunable filter 14c and a wavelength selection filter 15c having different wavelength tunable and selection regions instead of the tunable filter 14 and the wavelength selection filter 15. Other than this, the biological tissue analyzer of FIG. 42 is the same as the biological tissue analyzer of FIG. 20. The tunable filter 14c and the wavelength selection filter 15c correspond to an "optical filter" that fixes the dispersed emitted light to a selected wavelength. This makes it possible to measure the nonlinear optical effect corresponding to the fixed wavelength. The nonlinear optical effect is, for example, at least one selected from the group consisting of second harmonic generation (SHG), third harmonic generation (THG), and two-photon absorption fluorescence (TPF), as described above. You may.

The biological tissue analysis method using the biological tissue analyzer of FIG. 42 is not particularly limited, but can be performed in the same manner as the biological analysis of FIG. 20, for example. For example, CARS measurement may be performed as shown in FIGS. 43 to 45. That is, first, as shown in FIG. 43, the supercontinue light SC10 and the pump light (excitation light) P10 are irradiated from the light source 10E. Various characteristics such as the wavelength, center wavelength, and irradiation interval of the super-continue light SC10 and the pump light (excitation light) P10 are not particularly limited. For example, the super-continue light SC1 and the pump light (excitation light) P1 in FIG. It may be the same as. As shown in the figure, SC10 and P10 proceed in the same manner as SC3 and P3 in FIG. 21, the intensity is measured by the optical power meter 10Ap, and the biological tissue to be analyzed (shown) is transmitted through the objective lens 1102. Is irradiated.

Next, as shown in FIG. 44, the backscattered light S10 of CARS light (signal light) is irradiated from the living tissue irradiated with the synthetic light of SC10 and P10. The wavelength of the backscattered light S10 of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. S10 is incident on the spectrometer 1001 by the same path as the backscattered light S3 in FIG. 22, and is analyzed in the same manner.

On the other hand, as shown in FIG. 45, the forward scattered light S10A of CARS light (signal light) is irradiated from the living tissue irradiated with the synthetic light of SC10 and P10. The wavelength of the forward scattered light S10A of the CARS light (signal light) is not particularly limited, but may be, for example, 700 nm to 980 nm. S10A is incident on the spectrometer 1001 by the same path as the forward scattered light S3A of FIG. 22, and is analyzed in the same manner.

According to the biological tissue analyzer and the biological tissue analysis method of the present embodiment (FIGS. 42 to 45), for example, as shown in the figure, nonlinear optics for detecting the wavelength of the optical filter immediately before the detector (spectrometer 1001 in the figure). It can be changed according to the effect (second harmonic generation (SHG), third harmonic generation (THG), and two-photon absorption fluorescence (TPF)). As a result, by additionally evaluating the nonlinear optical effect, for example, it is possible to evaluate the distribution of collagen (second harmonic generation) and the introduction / metabolism of a drug, and it is possible to apply it to diagnosis.

[Use of the present invention]
The eyeball analyzer and eyeball analysis method of the present invention can be used, for example, for the following purposes. However, these are examples and do not limit the present invention in any way.

In clinical practice of ophthalmology, there is a great need to analyze the retina in detail. In the conventional medical field, OCT (optical coherence tomography) analysis has been used for the analysis of the retina. However, it was impossible to analyze the molecular structure by this analysis method. On the other hand, analysis methods using Raman scattering and CARS (milliwatt level light output) have also been used. Although the molecular structure of these analysis methods can be analyzed, it is difficult to analyze the depth of the eye tissue due to the weak light output. However, if the light output is too high, it may cause damage to the eyeball. For this reason, in clinical practice, wavelength sweeping optical coherence tomography (SS-OCT), which can analyze the entire surface to the depths of a tissue even if the light output is low, has been required. According to the present invention, as described above, since it is possible to easily analyze the depth of the living tissue with a device having a simple configuration, such needs can be satisfied. For example, according to the present invention, SS-OCT can be performed with one device without using a plurality of devices, for example, as shown in Examples 1 to 10 (FIGS. 1 to 12). Specifically, according to the present invention, for example, mixed light of light having a plurality of wavelengths (for example, wideband light such as white light, white laser light, SC light, or mixed light of a plurality of monochromatic lights) is used. It is possible to measure with variable wavelength using a plurality of filters. Then, for example, as described above, the intensity of the light irradiating the living tissue can be increased by using a short wavelength when analyzing the surface of the living tissue and a long wavelength when analyzing the inner part (inside) of the living tissue. Even if it is weak, it is possible to analyze deep inside the tissue of living tissue. As an example of selectively extracting monochromatic light from the mixed light using a filter, for example, in order to extract 300 microWatt laser light from 300 mWatt white laser light, only 1/1000 laser light can be extracted by the filter. It's easy.

In the wavelength sweep type optical coherence tomography (SS-OCT), which has been widely used in the past, it is not possible to change the wavelength with one device (equipment). For this reason, since light of a plurality of wavelengths is incident at different times by using a plurality of devices (equipment), the measurement (analysis) time becomes long and the burden on the patient is heavy. On the other hand, in the present invention, for example, wavelength sweep type optical coherence tomography (SS-OCT) with variable wavelength is possible using only one device (equipment). Specifically, for example, the surface of the retina can be analyzed with one device (device) for the premacular membrane, macular hole, etc., which are diseases of the retina, and the inner part of the retina for macular degeneration. .. According to this, the analysis time can be significantly shortened as compared with the conventional SS-OCT, and the burden on the patient can be reduced.

According to the present invention, for example, in the eyeball, a plane perpendicular to the direction of light incident on the eyeball can be analyzed according to the position of the space of the eyeball. The surface to be analyzed is not particularly limited, but may be, for example, the fundus of the eye, or at least a part of the retina, cornea, or crystalline lens as described above.

Further, according to the present invention, by dispersing the light emitted from the eyeball for each wavelength, for example, in the analysis in the plane direction, it is possible to perform an analysis in which the wavelength is further changed (three-dimensional spectroscopic analysis). .. FIG. 14 schematically shows the concept of three-dimensional spectroscopic analysis in the present invention. FIG. 14 shows that in addition to the plane direction (X direction and Y direction), analysis is performed according to a change in wavelength (Z direction). By performing three-dimensional spectroscopic analysis in different wavelength bands, for example, by imaging a fundus tomographic photograph, it is possible to analyze the difference in depth due to the difference in infrared wavelength. In addition, for example, it can be used for cataract examination by utilizing absorption of a specific wavelength of visible light or infrared light. In addition, for example, spectroscopic analysis of visible light at a specific wavelength can be performed by imaging an intraocular blood vessel, an optic nerve, or the like.

Further, according to the present invention, for example, in addition to the plane direction perpendicular to the incident direction of light on the eyeball, the direction parallel to the incident direction of the light (depth direction of the eyeball) is also included in three dimensions. It is also possible to analyze. In addition to this, analysis (four-dimensional spectroscopic analysis) in which the wavelength is further changed can be performed. Further, for example, in addition to the four-dimensional spectroscopic analysis in which the wavelength is changed, a five-dimensional spectroscopic analysis in which the measurement time is changed (time is added in the measurement direction) is also possible.

Further, according to the present invention, for example, at a specific position in the space in the eyeball, the relationship between the wavelength of the emitted light from the specific position and the polarization azimuth (Δθ) of the emitted light is plotted two-dimensionally. By doing so, the state of the eyeball at the specific position can be analyzed. Examples of the state of the eyeball include the degree of disease progression and the like. More specifically, for example, from said relationship between the wavelength and the polarization azimuth angle at a particular position ([Delta] [theta]), to calculate the ratio of the L- A Supara Gin acid and D- A Supara Gin acid in the specific position, which Therefore, the degree of progression of cataract at the specific position can be determined. Further, in the same manner, by plotting the relationship between the wavelengths at various positions in the eyeball and the polarization azimuth (Δθ), the degree of progression of the disease at the various positions can be determined.

Moreover, the use of the present invention is not limited to the above description, and can be widely used for any use in eyeball analysis. For example, the present invention can be used for denaturation of proteins (crystallin and the like), analysis of substances secreted into the eyeball, and the like. Specifically, for example, it can be used for early detection of Alzheimer's disease by analysis of amyloid protein in the eyeball. In addition, for example, tryptophan in the crystalline lens constituent protein (crystallin) is formed by analyzing oxidized kynurenine or 3-hydroxykynurenine, or AGE (AGE) formed by binding a lysine residue in the protein and a sugar in the body. By analyzing advanced glycated end products), the above-mentioned early detection of cataract is also possible. Further, for example, the present invention can analyze the deep part of the fundus or the space between the fundus and the layer below the fundus by using long-wavelength light having high penetrating power, whereby the state of the optic nerve, It is possible to analyze the condition of capillaries, the condition of the retina, and the like. Further, according to the present invention, for example, the eyeball can be analyzed non-invasively and easily.

According to the present invention, for example, minute changes in the state of the eyeball can be detected, and early detection of a disease can be performed. More specifically, for example, early detection of a disease can be realized by detecting degeneration of crystallin protein in the eyeball, trace substances in the eyeball, minute changes in the retina, and the like.

Furthermore, the present invention is not limited to the eyeball, and can be used for analysis of any other biological tissue. Specifically, for example, the present invention can be applied to OCT intravascular imaging to analyze the state of the blood vessel surface. Further, for example, the present invention can be used for skin analysis to analyze the localized state of a tumor or the like (for example, how deep the tumor is from the skin surface, etc.).

In the above, examples of the eyeball analyzer and the eyeball analysis method of the present invention have been described with reference to the first to 16th embodiments, and further, examples of applications of the present invention have been described. However, the present invention is not limited to these, and any modification is possible. For example, the present invention is not limited to eye devices that include one or both of A and B units. Further, for example, as the spectroscopic method, Raman spectroscopy such as CARS has been mainly described, but the spectroscopic method that can be used in the present invention is not limited to this, and for example, general spectroscopy such as Fourier spectroscopy and time region spectroscopy. Any spectroscopic method used in the above can be used.

As described above, according to the present invention, it is possible to provide a biological tissue analysis device and a biological tissue analysis method capable of easily analyzing the depth of a biological tissue with a device having a simple configuration. As a result, the present invention can make a great contribution to early detection of various diseases related to the state of living tissues such as the eyeball.

10 Light irradiation means 10A, 10B, 10C, 10D Light source 11, 11a, 11b, 13, 23, 25, 41, 72, 76, 77 Lens 12, 73, 74, 75 Beam splitter 14 Tunable filter (spectroscopic means)
15 Wavelength selection filter (spectroscopic means)
15a, 15e Diffraction grating 15b, 15d Lens 15c Wavelength selection mask 19 Area where interference system is arranged 20 Optical separation means 20B Imaging means (optical separation means)
21 Microlens Array 22 Mask (Field of View Mask)
24 Image plane 26 1/2 wave plate 27 Polarizing plate 61 Polarizing plate or circular polarizing plate (circularly polarized light means)
42 Imaging means 30 Spectroscopic means 31 Diffraction grating (spectral means)
32 Tunable filter (spectroscopic means)
33 Narrow band filter 71 Reflector 100A, 200A A unit 100B, 200B B unit 300A Irradiation unit (white light source unit)
300B irradiation unit (laser unit)

Claims (20)

Includes light irradiation means, A unit below and B unit below,
The light irradiation means is a light irradiation means for coherent anti-Stoke Raman spectroscopy (CARS).
The A unit and the B unit share the light irradiation means, and the light irradiation means is shared.
By the light irradiation means, a mixed light of broadband light and laser light is irradiated to the living tissue, and the living tissue is irradiated.
The following A unit is a measurement unit for coherent anti-Stoke Raman spectroscopy (CARS).
The following B unit is a wavelength sweep type optical coherence tomography ( SS- OCT) unit.
Coherent anti-Stoke Raman spectroscopy (CARS) and wavelength-swept optical coherence tomography ( SS- OCT) have been used to analyze the tissue internal structure of the living tissue .
In addition, it includes an optical filter
The spectroscopic emitted light is fixed to a selected wavelength by the optical filter, and the nonlinear optical effect corresponding to the fixed wavelength is measured.
The nonlinear optical effect is at least one selected from the group consisting of Raman scattering, second harmonic generation (SHG), third harmonic generation (THG), and two-photon absorption fluorescence (TPF).
Biological tissue analyzer.

(A unit)
Including optical separation means and spectroscopic means
The spectroscopic means includes a diffraction grating.
By the light separation means, the emitted light emitted from the living tissue irradiated with the mixed light is two-dimensionally separated according to the position of the space of the living tissue.
The diffraction grating disperses the Raman scattered light contained in the two-dimensionally separated emitted light.
unit.
(B unit)
Including optical separation means and spectroscopic means
The optical separation means includes an imaging means.
The spectroscopic emitted light is imaged by the imaging means, and the dispersed emitted light is two-dimensionally separated according to the position of the space of the living tissue by the pixels on the image obtained by imaging. It is,
Further, a wavelength tunable filter is included, and the mixed light emitted from the light irradiating means is fixed to a selected wavelength by the tunable filter, or the emitted light is separated by the tunable filter. Ru is,
unit. In the B unit
The living body according to claim 1, wherein the spectroscopic emitted light is imaged by the imaging means, and the spectroscopic emitted light is two-dimensionally or three-dimensionally separated by pixels on the image obtained by imaging. Tissue analyzer. In addition, it includes an optical filter
The optical filter disperses the mixed light and selectively irradiates the living tissue with only light having a required wavelength, or disperses the emitted light emitted from the living tissue irradiated with the mixed light. The biological tissue analyzer according to claim 1 or 2 . The biological tissue analyzer according to claim 3 , wherein the optical filter is at least one of a tunable filter and a wavelength selection filter. In the B unit
The spectroscopic means includes a tunable filter.
The biological tissue analyzer according to any one of claims 1 to 4 , wherein the emitted light emitted from the biological tissue irradiated with the mixed light is separated by the wavelength tunable filter. In addition, it includes interfering or confocal optics,
The living body according to any one of claims 1 to 5 , wherein the position of the interference system or the cofocal optical system is adjusted according to a selected wavelength of the mixed light emitted from the light irradiation means. Tissue analyzer. The biological tissue analyzer according to any one of claims 1 to 6 , wherein in the A unit, the optical separation means includes a microlens array or a dichroic mirror. The CARS light irradiation means includes a wavelength selection filter.
The biological tissue analyzer according to any one of claims 1 to 7 , wherein the mixed light is separated by the wavelength selection filter and only light having a required wavelength is selectively irradiated to the biological tissue. The wavelength selection filter includes a diffraction grating and a wavelength selection mask.
The biological tissue analyzer according to claim 8 , wherein the mixed light is separated by the diffraction grating, and only light having a required wavelength passes through the wavelength selection mask and irradiates the biological tissue. In the A unit and the B unit, the spectroscopic means further includes a narrow band filter.
The spectroscopic emitted light passes through the narrow band filter.
The biological tissue analyzer according to any one of claims 1 to 9 . In the A unit
The emitted light is three-dimensionally separated by the light separating means.
The three-dimensionally separated emitted light is separated by the diffraction grating.
The biological tissue analyzer according to any one of claims 1 to 10 . In the B unit
The spectroscopic emitted light is imaged by the imaging means, and the spectroscopic emitted light is three-dimensionally separated by the pixels on the image obtained by imaging.
The biological tissue analyzer according to any one of claims 1 to 11 . In addition, including circularly polarized means,
Light incident on the living tissue is circularly polarized by the circularly polarized means.
The biological tissue analyzer according to any one of claims 1 to 12 . In addition, it includes circularly polarized light analysis means.
The biological tissue analyzer according to claim 13 , wherein the circularly polarized light analyzing means detects a difference in absorbance with respect to left and right circularly polarized light in at least a part of the biological tissue. In addition, it includes linearly polarized means
By the linearly polarized light means, the emitted light emitted from the living tissue irradiated with the light is linearly polarized.
The biological tissue analyzer according to any one of claims 1 to 14 . In addition, it includes linearly polarized light analysis means.
By analyzing the linearly polarized light by the linearly polarized light analyzing means, the difference in the refractive index with respect to the left and right circularly polarized light in at least a part of the living tissue is detected.
The biological tissue analyzer according to claim 15 . Further, the present invention includes a spatial control mechanism capable of spatially controlling at least one of the intensity and the polarization state of the light emitted from the light irradiation means.
The biological tissue analysis according to any one of claims 1 to 16 , wherein at least one of the intensity and the polarized state of the light emitted from the light irradiation means is controlled by the spatial control mechanism, and the biological tissue is irradiated. apparatus. The biological tissue analyzer according to any one of claims 1 to 17 , wherein the biological tissue is an eyeball. Using the biological tissue analyzer according to any one of claims 1 to 18 ,
The irradiation step of irradiating the living tissue with the mixed light and
A light separation step of separating the emitted light emitted from the irradiated living tissue according to the position of the space of the living tissue, and
A spectroscopic step of dispersing the mixed light irradiating the living tissue or dispersing the emitted light emitted from the irradiated living tissue is included.
Coherent anti-Stoke Raman spectroscopy (CARS) and wavelength sweeping optical coherence tomography ( SS- OCT) are used to analyze the internal structure of the living tissue.
Biological tissue analysis method. The method for analyzing biological tissue according to claim 19 , wherein the biological tissue is an eyeball.