Eyepiece optical device, optical measurement system, and optical measurement method

Abstract

This eyepiece optical device is characterized by comprising: an eyepiece member that comes into contact with a cornea; a recess that is formed on the cornea-side surface of the eyepiece member and is recessed in a spherical shape; and a light source unit that is positioned outside of the recess and that irradiates the aqueous humor inside the cornea with light. Provided as a result is an eyepiece optical device with which it is possible to suppress variations in the amount of light emitted to the aqueous humor.

Description

Eyepiece optical device, optical measurement system, and optical measurement method

[0001] The present invention relates to an eyepiece optical device, an optical measurement system, and an optical measurement method.

[0002] A technique has been known in the past to analyze substances contained in the aqueous humor located inside the cornea of ​​a subject's eyeball and use it for diagnosis. This technique requires extracting aqueous humor from under the cornea by puncturing, which places a heavy burden on the subject.

[0003] Patent Documents 1 to 4 disclose techniques for non-invasively examining the eyeball of a subject. In these techniques, coherent light is incident laterally on the nose or ear side of the subject's eyeball, and is transmitted through the aqueous humor in a direction approximately perpendicular to the direction of the eye axis (the line connecting the apex of the cornea and the fovea centralis).

[0004] Japanese Patent Publication No. 6-503245 Japanese Patent Publication No. 2018-175760 Japanese Patent Publication No. 2018-175481 Japanese Patent Publication No. 2011-83342

[0005] The present inventors investigated the feasibility of measuring the concentrations of aqueous humor metabolites by irradiating the eye with excitation light and measuring fluorescence. When coherent light is used as the excitation light in fluorescence measurement, interference fringes corresponding to the thickness of the cornea and the length sandwiched between the boundaries of the space filled with aqueous humor appear in the fluorescence spectrum, and these interference fringes hinder concentration analysis.

[0006] Therefore, the inventors further investigated the use of incoherent light as excitation light in fluorescence measurement. Incoherent light has the problem that the amount of excitation light varies depending on the observation area due to the influence of the corneal shape as well as the fact that it diffuses from the light-emitting surface.

[0007] The present invention has been made in view of the above, and provides an eyepiece optical device, an optical measurement system, and an optical measurement method that can suppress variations in the amount of light irradiated onto aqueous humor.

[0008] In order to solve the above-mentioned problems and achieve the object, the eyepiece optical device of the present invention is characterized by comprising an eyepiece member that comes into contact with the cornea, a spherically concave recess formed on the surface of the eyepiece member facing the cornea, and a light source unit located outside the recess and irradiating light onto the aqueous humor in the cornea.

[0009] In addition, an eyepiece optical device according to one aspect of the present invention is characterized in that, in the above invention, the light source unit has a light-emitting unit that emits light and a light diffusion member that diffuses the light emitted by the light-emitting unit.

[0010] Furthermore, an eyepiece optical device according to one aspect of the present invention is characterized in that, in the above invention, the light source unit irradiates light from a position that is point-symmetric with respect to a point located on a straight line connecting the center of the spherical surface of the recess and the vertex of the recess.

[0011] In addition, in the eyepiece optical device according to one aspect of the present invention, the light source section is annular and surrounds the outer periphery of the recess.

[0012] In addition, an eyepiece optical device according to one aspect of the present invention is characterized in that, in the above invention, it is provided with a light shielding plate provided on the surface of the eyepiece member opposite the cornea, which prevents light emitted by the light source unit from entering the light receiving device directly or by reflection.

[0013] Furthermore, an eyepiece optical device according to one aspect of the present invention is characterized in that, in the above invention, the light source unit irradiates light in a direction inclined at a predetermined angle toward the cornea from a direction perpendicular to a straight line connecting the center of the spherical surface of the recess and the vertex of the recess.

[0014] In addition, an eyepiece optical device according to one aspect of the present invention is characterized in that, in the above invention, the light source unit irradiates incoherent light.

[0015] Furthermore, an optical measurement system according to one aspect of the present invention is characterized by comprising the above-described eyepiece optical device, a focusing lens that focuses light from the aqueous humor, a coupler that couples the light focused by the focusing lens to an optical fiber, and a spectroscope that performs spectroscopic measurement of the light introduced from the optical fiber.

[0016] Moreover, in the above-mentioned invention, an optical measurement system according to one aspect of the present invention further comprises a bandpass filter that transmits only light of a predetermined wavelength band from the light from the aqueous humor.

[0017] Furthermore, an optical measurement method according to one aspect of the present invention is an optical measurement method using an eyepiece optical device comprising an eyepiece member that contacts the cornea, a spherically concave recess formed on the cornea-facing surface of the eyepiece member, and a light source unit located outside the recess and that irradiates light onto the aqueous humor in the cornea, and is characterized by including an administration step of administering a fluorescent label to a subject, a contact step of bringing the eyepiece optical device into contact with the cornea of ​​the subject, a light irradiation step of irradiating light from the eyepiece optical device onto the aqueous humor of the subject, and a spectroscopic measurement step of spectroscopically measuring the fluorescence emitted by the fluorescent label in the aqueous humor.

[0018] In addition, in the optical measurement method according to one aspect of the present invention, the administration step is characterized in that the fluorescent label is administered to the subject by intraocular administration, oral administration, or intravenous administration.

[0019] In addition, in an optical measurement method according to one aspect of the present invention, the light irradiation step includes irradiating the aqueous humor of the subject with excitation light that excites the fluorescent label from the eyepiece optical device.

[0020] In addition, in the optical measurement method according to one aspect of the present invention, the fluorescent label emits fluorescence when irradiated with excitation light in a state where the fluorescent label is bound to a target molecule.

[0021] In addition, an optical measurement method according to one aspect of the present invention is characterized in that the fluorescent label emits fluorescence when irradiated with excitation light before and after binding to a target molecule.

[0022] According to the present invention, it is possible to realize an eyepiece optical device, an optical measurement system, and an optical measurement method that can suppress variations in the amount of light irradiated onto aqueous humor.

[0023] FIG. 1 is a schematic diagram of an optical measurement system according to a first embodiment of the present invention. FIG. 2 is a view taken along an arrow A of the eyepiece optical device shown in FIG. 1. FIG. 3 is an enlarged view of the light source unit. FIG. 4 is a cross-sectional view corresponding to line B-B in FIG. 3. FIG. 5 is a diagram showing the results of a simulation of the optical path of light emitted from the light-emitting unit. FIG. 6 is a diagram showing the results of a simulation of the optical path of light emitted from the light-emitting unit. FIG. 7 is a diagram showing the results of a simulation of the optical path of light emitted from the light-emitting unit. FIG. 8 is a flowchart showing the steps of an optical measurement method. FIG. 9 is a diagram showing a state before an antibody binds to a target molecule. FIG. 10 is a diagram showing a state after an antibody binds to a target molecule. FIG. 11 is a diagram showing a state before an antibody binds to a target molecule. FIG. 12 is a diagram showing a state after an antibody binds to a target molecule. FIG. 13 is an enlarged view of an eyepiece optical device according to a second embodiment of the present invention. FIG. 14 is a cross-sectional view of the eyepiece optical device shown in FIG. 13. FIG. 15 is an enlarged view of the light source unit according to a first modification. FIG. 16 is an enlarged view of the light source unit according to a second modification.

[0024] The eyepiece optical device, optical measurement system, and optical measurement method of the present invention will be described in detail below with reference to embodiments, but the present invention is not limited to these.

[0025] (Embodiment 1) [Configuration of Optical Measurement System] Fig. 1 is a schematic diagram of an optical measurement system according to embodiment 1 of the present invention. As shown in Fig. 1, the optical measurement system 100 includes an ocular optical device 1 that irradiates light toward the aqueous humor in the cornea while in contact with the cornea, and a light-receiving device 2 that performs spectroscopic measurement of light from the aqueous humor. In the present invention, "contact" refers to a state in which the ocular optical device 1 of the present invention is in contact with the cornea, and indicates a state similar to "wearing," "mounting," "attaching," "abutting," etc.

[0026] The optical measurement system 100 can be used to measure metabolites in aqueous humor, which is located inside the cornea and regulates intraocular pressure. Aqueous humor contains a variety of metabolites, and it is believed that there is a correlation between these substances and eye diseases. Therefore, there is a demand for technology to identify and measure the concentrations of metabolites in aqueous humor.

[0027] When a fluorescent label such as an antibody is administered to a subject, the antibody binds to the target molecule to be measured in the subject's aqueous humor. When excitation light is irradiated onto the subject's aqueous humor from the eyepiece optical device 1, the bound substance emits fluorescence. The concentration of the target molecule can be measured by spectroscopically measuring this fluorescence using the light-receiving device 2.

[0028] [Configuration of Eyepiece Optical Device] Fig. 2 is a view of the eyepiece optical device shown in Fig. 1 as seen from the arrow A. As shown in Fig. 2, the eyepiece optical device 1 includes an eyepiece member 11, a recess 12, a light source unit 13, and a light blocking plate 14.

[0029] The eyepiece 11 comes into contact with the cornea and is made of a material used in soft contact lenses, such as pHEMA (polyhydroxyethyl methacrylate) or SHG (silicone hydrogel), but may also be made of a material used in hard contact lenses.

[0030] The recess 12 is formed on the cornea side of the eyepiece and is spherically concave. The recess 12 has a curvature that is approximately the same as that of the cornea, and when a subject wears the eyepiece optical device 1, the recess 12 comes into contact with the cornea so as to conform to the cornea.

[0031] The light source unit 13 is located outside the recess 12 and irradiates light onto the aqueous humor in the cornea. The light source unit 13 is annular and surrounds the outer periphery of the recess 12. The light source unit 13 irradiates incoherent light.

[0032] Fig. 3 is an enlarged view of the light source unit 13. As shown in Fig. 3, the light source unit 13 includes a light-emitting unit 13a that emits light and a light diffusion member 13b that diffuses the light emitted by the light-emitting unit 13a.

[0033] The light-emitting unit 13a is, for example, a light-emitting diode. The light-emitting unit 13a irradiates, for example, excitation light that excites the antibody-target molecule complex. The light-emitting unit 13a is preferably disposed at a position symmetrical with respect to a point located on a line connecting the center of the spherical surface of the recess 12 and the vertex of the recess 12.

[0034] Fig. 4 is a cross-sectional view corresponding to line B-B in Fig. 3. As shown in Fig. 4, the light diffusing member 13b has a curved, protruding shape toward the cornea. The light diffusing member 13b is realized by forming random projections and depressions on one side of a sheet made of resin such as polycarbonate.

[0035] 1 , the light-shielding plate 14 is provided on the surface of the eyepiece 11 opposite the cornea, has light-shielding properties, and has an opening in the center. As a result, the light-shielding plate 14 prevents light (excitation light) emitted by the light source unit 13 from entering the light-receiving device 2 directly or by reflection, and selectively allows fluorescence from the aqueous humor to enter the light-receiving device 2.

[0036] [Configuration of Light-Receiving Device] As shown in FIG. 1, the light-receiving device 2 includes a condenser lens 21, a filter 22, a coupler 23, an optical fiber 24, and a spectrometer 25.

[0037] The condenser lens 21 is an objective lens that condenses light from the aqueous humor.

[0038] The filter 22 is a bandpass filter that transmits only light of a predetermined wavelength band from the aqueous humor. Specifically, the filter 22 is a bandpass filter that does not transmit the excitation light from the light emitter 13 a, but selectively transmits only the fluorescence emitted by a complex between a fluorescent label such as an antibody and a target molecule.

[0039] The coupler 23 couples the light collected by the collecting lens 21 into an optical fiber 24 .

[0040] The optical fiber 24 introduces light from the aqueous humor into the spectroscope 25 .

[0041] The spectroscope 25 performs spectroscopic measurement of the light introduced from the optical fiber 24. Note that the light condensed by the condenser lens 21 may be directly incident on the spectroscope 25. In this case, the coupler 23 and the optical fiber 24 are not necessary.

[0042] 5 to 7 are diagrams showing the results of a simulation of the optical path of light emitted from the light-emitting unit. In this simulation, the direction parallel to the equatorial plane of the eyeball is the x-axis, the direction along the ocular axis toward the vertex of the cornea is the y-axis, and the direction perpendicular to the x-axis and y-axis is the z-axis. The origin was set so that the vertex of the cornea was located at the coordinates (0, 13, 0).

[0043] The light emitting unit 13a is located at y=14, x ２ +z ２ =14 ２ , and light is emitted from (-14, 14, 0) in two-dimensional space. 5 to 7 show the optical paths of the light emitted from the light-emitting unit 13a and spreading over an 8° angle at intervals of 0.16°. The distribution of the light quantity from the light-emitting unit 13a is expressed as a Lambertian function L(θ) = L(1-cos ２ θ), there is a fluctuation of about 0.5% in the amount of light.

[0044] The light emitted from the light-emitting unit 13a is refracted at the front and back surfaces of the cornea. In the examples shown in Figures 5 to 7, which will be described below, the results of simulations performed with different corneal sizes will be explained, since the size of the cornea varies from person to person.

[0045] In the example of FIG. 5, the simulation was performed with the radius to the corneal surface set to 7.7 mm and the radius to the corneal back surface set to 6.6 mm.

[0046] In the example of FIG. 6, the simulation was performed with the radius to the corneal surface set to 8.35 mm and the radius to the corneal back surface set to 7.25 mm.

[0047] In the example of FIG. 7, the simulation was performed with the radius to the corneal surface being 9.0 mm and the radius to the corneal back surface being 7.9 mm.

[0048] The light intensity in the fluorescence light intensity observation region C is estimated from the results of FIGS. 5 to 7 . The fluorescence light intensity observation region C is a circle with a radius of 0.5 mm centered at coordinates (0, 11, 0). Based on the estimation results, a simulation is performed to minimize the variation in light intensity in the fluorescence light intensity observation region C due to individual differences in corneal size. It is therefore preferable that the light-emitting surface of the light-emitting unit 13 a be positioned at an angle of 14° from the line connecting the center of the spherical surface of the recess 12 and the apex of the recess 12. In this case, the light source unit 13 irradiates light in a direction inclined 14° toward the cornea from the direction perpendicular to the line connecting the center of the spherical surface of the recess 12 and the apex of the recess 12.

[0049] In the first embodiment, the light source unit 13 emits light in a direction tilted by 14° toward the cornea from a direction perpendicular to the line connecting the center of the spherical surface of the recess 12 and the apex of the recess 12, but this is not limiting. The light source unit 13 may emit light in a direction tilted by a predetermined angle toward the cornea from a direction perpendicular to the line connecting the center of the spherical surface of the recess 12 and the apex of the recess 12. The predetermined angle may be selected appropriately depending on, for example, the shape of the cornea of ​​the subject.

[0050] [Optical Measurement Method] Next, an optical measurement method using the optical measurement system 100 will be described. Fig. 8 is a flowchart showing the steps of the optical measurement method. As shown in Fig. 8, first, a fluorescent label such as an antibody is administered to a subject (step S1: administration step). Specifically, the antibody is administered to the subject by intraocular administration, oral administration, or intravenous administration.

[0051] 9 is a diagram showing the state before the antibody binds to the target molecule. As shown in Fig. 9, target molecules AN1 and AN2 to be measured are present in the aqueous humor. Fluorescently labeled antibodies X1 and X2 are then administered.

[0052] Next, the ocular optical device 1 is fitted to the cornea of ​​the subject (step S2: fitting step).

[0053] Then, excitation light for exciting antibodies is irradiated onto the aqueous humor of the subject from the light source unit 13 of the eyepiece optical device 1 (step S3: light irradiation step).

[0054] Fig. 10 is a diagram showing the state after antibodies bind to target molecules. As shown in Fig. 10, when antibodies X1 and X2 are administered to a subject, antibody X1 binds to target molecule AN1, and antibody X2 binds to target molecule AN2. When excitation light is irradiated from light source unit 13 in this state, antibody X1 bound to target molecule AN1 emits fluorescence F1, and antibody X2 bound to target molecule AN2 emits fluorescence F2.

[0055] Thereafter, light from the aqueous humor is introduced into the spectroscope 25 and subjected to spectroscopic measurement (step S4: spectroscopic measurement step). For example, if the fluorescent label is fluorescein, the wavelength of the excitation light is 494 nm and the peak wavelength of the fluorescence is 521 nm. Therefore, the filter 22 is a bandpass filter that does not transmit wavelengths around 494 nm and selectively transmits wavelengths around 521 nm. As a result, it is possible to measure only the fluorescence, thereby improving measurement accuracy. Furthermore, by previously obtaining the correlation between the fluorescence intensity and the concentration value of the measurement target, it is possible to calculate the concentration value of the measurement target from the fluorescence intensity.

[0056] According to the above-described first embodiment, since light is irradiated onto the aqueous humor from the light source unit 13, substances contained in the aqueous humor of the subject can be analyzed non-invasively, and variation in the amount of light irradiated onto the aqueous humor can also be suppressed.

[0057] Furthermore, according to the first embodiment, the light emitted by the light emitting portion 13a is diffused by the light diffusing member 13b, so that it is possible to suppress variations in the amount of light irradiated onto the aqueous humor.

[0058] Furthermore, according to embodiment 1, the light source unit 13 irradiates light from a position that is point-symmetric with respect to a point located on a straight line connecting the center of the spherical surface of the recess 12 and the vertex of the recess 12, thereby suppressing variation in the amount of light irradiated onto the aqueous humor.

[0059] Furthermore, according to the first embodiment, the light source unit 13 is annular and surrounds the outer periphery of the recess 12, so that variations in the amount of light irradiated onto the aqueous humor can be suppressed.

[0060] Furthermore, according to embodiment 1, since the light source unit 13 emits incoherent light, even if there are individual differences in corneal shape (corneal radius of curvature, size, palpebral fissure width, etc.), a uniform amount of excitation light can be irradiated onto the aqueous humor, thereby suppressing variations in the amount of fluorescent light due to individual differences in corneal shape.

[0061] [Specific Examples of Target Molecules] (Specific Example 1) A specific example of a target molecule is vascular endothelial growth factor (VEGF). VEGF is a glycoprotein that constitutes the VEGF family, which includes VEGFA, VEGFB, VEGFC, VEGFD, placental growth factor (PlGF), and the like.

[0062] Among them, VEGFA not only induces the proliferation and migration of vascular endothelial cells, but also promotes their permeability, thereby promoting angiogenesis. VEGFA expression is controlled by HIF1α, a hypoxia-inducible factor, and its expression is induced under hypoxic conditions. Although VEGFA is expressed under physiological conditions, it is known that the concentration of VEGF is significantly elevated compared to the steady state in diseases such as age-related macular degeneration, retinal vein occlusion, diabetic retinopathy, choroidal neovascularization in pathological myopia, retinopathy of prematurity, and neovascular glaucoma.

[0063] There are known to be three types of VEGF receptors: VEGFR1, VEGFR2, and VEGFR3. It is known that VEGFR1 and VEGFR2 are mainly expressed in the eye. VEGFR1 is mainly expressed in inflammatory cells, and VEGFR2 is expressed in vascular endothelial cells. It is known that VEGFA, VEGFB, and PlGF bind to VEGFR1 to cause inflammation, and that binding of VEGFA to VEGFR2 not only causes inflammation but also increases vascular permeability and angiogenesis.

[0064] (Specific Example 2) A specific example of a target molecule is angiopoietin (Ang). Ang includes Ang-1 and Ang-2, and it is known that when ischemia or inflammation occurs, Ang-2 increases, resulting in increased vascular permeability.

[0065] Specific Example 3 A specific example of a target molecule is galectin-1. Galectin-1 binds to VEGFR2 in retinal vascular endothelial cells in a VEGF-independent manner, promoting receptor phosphorylation and cell proliferation, thereby inducing angiogenesis.

[0066] (Specific Example 4) Other specific examples of target molecules that are known as angiogenesis-promoting factors include bFGF (basic fibroblast growth factor, FGF2), HGF (hepatocyte growth factor), EGF (epidermal growth factor), and EPO (erythropoietin).

[0067] [Observing Pharmacokinetics] When observing the behavior of a drug administered to a subject, the fluorescent label emits fluorescence when irradiated with excitation light before and after binding to the target molecule.

[0068] Fig. 11 is a diagram showing the state before the antibody binds to the target molecule. Fig. 12 is a diagram showing the state after the antibody binds to the target molecule. As shown in Figs. 11 and 12, the fluorescently labeled antibody X11 emits fluorescence F11 before and after binding to the target molecule AN11. By irradiating it with excitation light from the eyepiece optical device 1 to generate fluorescence F11, the movement of the antibody X11 in the aqueous humor can be observed.

[0069] Currently, there are several types of anti-VEGF drugs, and the drug can be selected depending on whether the cytokine is dominant, Ang-2 dominant, or other cytokines. However, in actual clinical practice, it is not realistic to invasively collect aqueous humor every time a drug is administered. If the types of target molecules, such as cytokines, present in the anterior chamber (inside the eye) are known, it will be possible to select drugs that are effective against the target cytokines.

[0070] Known inflammatory cytokines include TNFa (Tumor Necrosis Factor alpha), IL-6 (Interleukin-6), IL-8, TGFb2 (Transforming Growth Factor beta 2), SFRP1 (Secreted Frizzled-Related Protein-1), MCP-1 (Monocyte Chemotactic Protein-1), and CCL2.

[0071] More than 40 types of inflammatory cytokines are detected in cataract patients, and it has been reported that the expression levels of six cytokines, namely, IL-1ra (Interleukin-1 receptor antagonist), MCP-1, RANTES (Regulated on Activation, Normal T Expressed and Secreted), IL-6, IL-8, and PDGF-BB (Platelet-Derived Growth Factor), are significantly different between cataract patients with no high myopia and those with high myopia. It has been reported that inflammatory cytokines obtained from cataract patients with high myopia were significantly higher in MCP-1 (MCAF) and lower in IL-1ra compared to cataract patients without high myopia (Zhu X, Zhang K, He W, Yang J, Sun X, Jiang C, Dai J, Lu Y. Proinflammatory status in the aqueous humor of high myopic cataract eyes. Exp Eye Res. 2016 Jan:142:13-8.).

[0072] These reports also suggest that it is possible to monitor the pathological condition by examining all target molecules such as cytokines present in the anterior chamber (inside the eye).

[0073] It can also be useful for selecting medications for patients who are undergoing treatment, such as switching from a conventional medication to a different medication. By using the technology of the present invention, which can measure these cytokines in the anterior chamber, it is possible to understand the concentration of each cytokine and use this information to help with appropriate medication use.

[0074] There are several types of drugs for treating age-related macular degeneration, one of which is pegaptanib sodium, a molecule (a single-stranded nucleic acid anti-VEGF aptamer PEGylated with polyethylene glycol (polyethylene glycol)) that binds to the target molecule (VEGF165 protein). Ranibizumab is a Fab (fragment antigen binding) fragment of a monoclonal antibody that binds to the target molecule (VEGFA). Aflibercept is a recombinant fusion protein consisting of the extracellular domains of human VEGFR1 and VEGFR2 proteins and the Fc portion of human antibody IgG1, and binds to target molecules (VEGFA, VEGFB, PlGF). Brolucizumab is a fusion protein (single-chain variable fragment) that binds to a target molecule (VEGFA). Faricimab is the first bispecific antibody (an antibody that binds to a target molecule) in the field of ophthalmology that targets both Ang-2 and VEGFA (target molecules).

[0075] [Specific Examples of Fluorescent Labels] Specific examples of fluorescent labels used in the field of ophthalmology, which are currently covered by health insurance, include fluorescein fluorescent angiography and indocyanine green fluorescent angiography.

[0076] The molecular weight of fluorescein is 332.31 g / mol, and it is excited at wavelengths around 500 nm. The size of fluorescein is less than 3 nm. Fluorescein is usually administered intravenously in 3-5 mL of a 10% solution. After the test, the urine may darken and the skin may turn yellow, but these changes gradually disappear within about 24 hours.

[0077] Indocyanine green has a molecular weight of 774.96 g / mol and is excited by wavelengths longer than 700 nm, but unlike fluorescein, it does not discolor urine or skin. Its size is less than 6.3 nm. For adults, 25 mg of indocyanine green is dissolved in 2 mL of water for injection and typically administered via the antecubital vein.

[0078] After injection, both fluorescein and indocyanine green reach the eye via the bloodstream approximately 10-15 seconds after injection, and emit fluorescence when exposed to excitation light of the appropriate wavelength. It is known that oral fluorescein administration allows the dye to reach the eye approximately 20 minutes later. Anaphylaxis and anaphylactoid shock have been reported to occur in 0.08-1.48% of cases with fluorescein, with a reported mortality rate of 0-0.005%. Meanwhile, the incidence of serious adverse reactions with indocyanine green has been reported to be 0.0042%, with a mortality rate of 0%.

[0079] Here, the relationship between the metabolism of a molecule of interest (target molecule) in a disease and the fluorescence intensity will be described. Antibodies are useful proteins for detecting and diagnosing various molecules (antigens). In 2011, the Graduate School of Engineering at the University of Tokyo and others created a recombinant antibody fragment fluorescently labeled with a certain dye near the end of the antibody. This resulted in a phenomenon in which the fluorescence, which is quenched by amino acids in the antibody alone, is significantly increased upon binding to the antigen (Abe R, Ohashi H, Iijima I, Ihara M, Takagi H, Hohsaka T, Ueda H. "Quenchbodies": quench-based antibody probes that show antigen-dependent fluorescence. J Am Chem Soc. 2011 Nov. 2011). 2; 133(43):17386-94. They demonstrated that by utilizing the phenomenon that fluorescence quenched by amino acids in antibodies is significantly increased upon binding to an antigen, various molecules, such as low-molecular-weight compounds like morphine and heroin, or biomarker proteins, which are present in amounts of just one billionth of a gram per mL, can be easily detected by simply mixing them together and measuring their fluorescence intensity. Based on this principle, the present invention measures the concentration of cytokines (VEGF family, Ang-2, galectin-1, etc.) in the anterior chamber by administering special antibodies (recombinant antibody fragments fluorescently labeled with a certain dye near the antibody terminus).

[0080] Currently, antibodies such as ranibizumab, aflibercept, brolucizumab, and faricimab, which can be administered intravitreously, bind to various cytokines, including various VEGFs, preventing them from binding to VEGF receptors expressed on cells, thereby preventing the onset of disease. These antibodies are widely used as therapeutic agents. The concentration of cytokines in the anterior chamber is measured by administering special antibodies that emit fluorescence upon binding to various cytokines (VEGF family members, Ang-2, galectin-1, etc.) in the anterior chamber. A distinctive feature of these antibodies is that they do not emit fluorescence unless the target substance (e.g., cytokine) binds to the antibody that binds to the target substance; therefore, simply administering the antibody does not produce fluorescence. The concentration of these antibodies decreases with metabolism, but the rate of disappearance varies depending on the presence or absence of the vitreous. For example, the concentration of ranibizumab in the vitreous humor is approximately 90,000 times higher than the serum concentration, and its elimination half-life is estimated to be approximately 9 days. The elimination half-life of aflibercept in various intraocular tissues is reported to be 115 to 132 hours, and the half-life of faricimab in the aqueous humor is reported to be in the range of 6.08 to 13.4 days, and although there are individual differences, they are eliminated within half a month.

[0081] (Embodiment 2) Fig. 13 is an enlarged view of an eyepiece optical device according to embodiment 2 of the present invention. Fig. 14 is a cross-sectional view of the eyepiece optical device shown in Fig. 13. As shown in Figs. 13 and 14, the eyepiece optical device 1A comprises an eyepiece member 11, a recess 12, a light source unit 13, a light-shielding plate 14, a light-shielding film 15A, and a light-guiding material 16A.

[0082] The light-shielding film 15A is provided on the cornea-side surface of the eyepiece 11, and blocks part of the light emitted from the light source unit 13. The light-shielding film 15A is, for example, a gold-plated film.

[0083] The light-guiding material 16A guides light from the light-emitting unit 13a to the cornea. The light-guiding material 16A has a conical surface shape that extends in a direction tilted 14° from a direction perpendicular to a line connecting the center of the spherical surface of the recess 12 and the apex of the recess 12. The light-guiding material 16A preferably has a refractive index greater than that of the eyepiece 11 and is made of a material that totally reflects light at the interface with the eyepiece 11.

[0084] According to the second embodiment described above, the light-shielding film 15A prevents unnecessary light from entering the cornea, and the light-guiding material 16A guides the light from the light-emitting portion 13a to the cornea, thereby improving the measurement accuracy.

[0085] [Modifications of Light Source Unit] (Modification 1) Fig. 15 is an enlarged view of a light source unit according to Modification 1. As shown in Fig. 15, the light source unit 13B has four light-emitting units 13Ba and four light diffusion members 13Bb.

[0086] As shown in Modification 1, the light source unit does not have to be annular, but it is preferable that the light emitting units are arranged on the circumference of a circle centered at a point located on a line connecting the center of the spherical surface of the recess 12 and the vertex of the recess 12. In this case, it is preferable that the light emitting units are arranged at positions that are point symmetric with respect to the point located on the line connecting the center of the spherical surface of the recess 12 and the vertex of the recess 12, and it is preferable that two or more light emitting units are arranged point symmetrically. This makes it possible to suppress variations in the amount of light irradiated onto the aqueous humor.

[0087] (Modification 2) Fig. 16 is an enlarged view of a light source unit according to Modification 2. As shown in Fig. 16, a light source unit 13C has a light-emitting unit 13Ca.

[0088] As shown in Modification 2, the light-emitting unit may be a round light source and may not have a light-diffusing material. However, as in Modification 1, it is preferable that the light-emitting unit is arranged at a position that is point-symmetric with respect to a point located on a line connecting the center of the spherical surface of the recess 12 and the vertex of the recess 12. This makes it possible to suppress variations in the amount of light irradiated onto the aqueous humor.

[0089] REFERENCE SIGNS LIST 1, 1A Eyepiece optical device 2 Light receiving device 11 Eyepiece member 12 Recess 13, 13B, 13C Light source section 13a, 13Ba, 13Ca Light emitting section 13b, 13Bb Light diffusing member 14 Light blocking plate 15A Light blocking film 16A Light guiding material 21 Condenser lens 22 Filter 23 Coupler 24 Optical fiber 25 Spectrometer 100 Optical measurement system

Claims

1. An eyepiece optical device comprising: an eyepiece member that contacts the cornea; a spherically concave recess formed on the surface of the eyepiece member facing the cornea; and a light source unit located outside the recess and that irradiates light onto the aqueous humor in the cornea.

2. The eyepiece optical device according to claim 1, characterized in that the light source section comprises: a light-emitting section that emits light; and a light diffusion member that diffuses the light emitted by the light-emitting section.

3. The eyepiece optical device according to claim 1, wherein the light source unit emits light from a position that is point-symmetric with respect to a point located on a line connecting the center of the spherical surface of the recess and the vertex of the recess.

4. The eyepiece optical device according to claim 1, wherein the light source section is annular and surrounds the outer periphery of the recess.

5. The eyepiece optical device according to claim 1, further comprising a light shielding plate provided on the surface of the eyepiece member opposite the cornea, which prevents light emitted by the light source unit from entering the light receiving device directly or by reflection.

6. The eyepiece optical device according to claim 1, characterized in that the light source unit irradiates light in a direction inclined at a predetermined angle toward the cornea from a direction perpendicular to a line connecting the center of the spherical surface of the recess and the vertex of the recess.

7. The eyepiece optical device according to claim 1, wherein the light source unit emits incoherent light.

8. An optical measurement system comprising: the eyepiece optical device according to claim 1; a focusing lens for focusing light from the aqueous humor; a coupler for coupling the light focused by the focusing lens to an optical fiber; and a spectroscope for performing spectroscopic measurement of the light introduced from the optical fiber.

9. The optical measurement system according to claim 8, further comprising a bandpass filter that transmits only light of a predetermined wavelength band from the light from the aqueous humor.

10. An optical measurement method using an eyepiece optical device comprising: an eyepiece member that contacts the cornea; a spherically recessed recess formed on the surface of the eyepiece member facing the cornea; and a light source unit located outside the recess and irradiating light onto the aqueous humor in the cornea, the optical measurement method comprising: an administration step of administering a fluorescent label to a subject; a contact step of bringing the eyepiece optical device into contact with the cornea of ​​the subject; a light irradiation step of irradiating light from the eyepiece optical device onto the aqueous humor of the subject; and a spectroscopic measurement step of spectroscopically measuring the fluorescence emitted by the fluorescent label in the aqueous humor.

11. The optical measurement method according to claim 10, wherein the administration step administers the fluorescent label to the subject by intraocular administration, oral administration, or intravenous administration.

12. The optical measurement method according to claim 10, wherein the light irradiation step includes irradiating the aqueous humor of the subject with excitation light that excites the fluorescent label from the eyepiece optical device.

13. The optical measurement method according to claim 10, wherein the fluorescent label emits fluorescence when irradiated with excitation light while bound to the target molecule.

14. The optical measurement method according to claim 10, wherein the fluorescent label emits fluorescence when irradiated with excitation light before and after binding to the target molecule.

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