Spr sensor cell, spr sensor, and method for manufacturing spr sensor cell

The present invention relates to an SPR sensor cell, a method for manufacturing an SPR sensor and an SPR sensor cell, specifically, an SPR sensor cell including an optical waveguide, an SPR sensor including the SPR sensor cell, and a method for manufacturing the SPR sensor cell.

Conventionally, SPR (Surface Plasmon Resonance) sensors equipped with optical fibers have been used in fields such as chemical analysis and biochemical analysis.

In an SPR sensor including an optical fiber, a metal thin film is formed on the outer peripheral surface of the tip of the optical fiber, an analysis sample is fixed, and light is introduced into the optical fiber. Then, the light having a specific wavelength in the introduced light causes surface plasmon resonance in the metal thin film, and attenuates the light intensity.

In such an SPR sensor, the wavelength at which surface plasmon resonance is generated usually differs depending on the refractive index of the analytical sample fixed to the optical fiber and the like.

Therefore, by measuring the wavelength at which the light intensity decays after the occurrence of surface plasmon resonance, the wavelength at which the surface plasmon resonance occurs can be specified, and if it is detected that the decaying wavelength has changed, the surface plasmon resonance can be detected. Since it can be confirmed that the wavelength to be generated has changed, it is possible to confirm the change in the refractive index of the analysis sample.

As a result, such an SPR sensor can be used for various chemical and biochemical analyzes such as measurement of sample concentration and detection of immune response.

For example, when the sample is a solution, the refractive index of the sample (solution) depends on the concentration of the solution. Therefore, the concentration of the sample can be detected by measuring the refractive index of the sample (solution) with the SPR sensor in which the sample (solution) is in contact with the metal thin film, and the refractive index has changed. By confirming, it can be confirmed that the concentration of the sample (solution) has changed.

Further, in the analysis of the immune reaction, for example, the antibody is fixed on the metal thin film of the optical fiber in the SPR sensor via the dielectric film, the sample is brought into contact with the antibody, and surface plasmon resonance is generated. At this time, if the antibody and the sample undergo an immune reaction, the refractive index of the sample changes. Therefore, by confirming that the refractive index of the sample has changed before and after the contact between the antibody and the sample, the antibody and the sample can be used. Can be judged to have an immune reaction.

However, the SPR sensor provided with such an optical fiber has a problem that it is difficult to form a metal thin film and fix an analysis sample because the tip of the optical fiber has a fine cylindrical shape.

In order to solve such a problem, for example, a core through which light is transmitted and a clad covering the core are provided, and a through hole is formed at a predetermined position of the clad up to the surface of the core, and the through hole is formed. An SPR sensor cell in which a metal thin film is formed on the surface of the core at the corresponding position has been proposed (see, for example, Patent Document 1).

According to this SPR sensor cell, it is easy to form a metal thin film for generating surface plasmon resonance on the core surface and to fix the analysis sample on the surface.

<p><patcit num="1"><text>Japanese Unexamined Patent Publication No. 2000-19100</text></patcit></p>

<p> However, in recent years, further improvement of the detection accuracy of the SPR sensor cell has been required in various chemical analyzes and biochemical analyzes such as measurement of sample concentration and detection of immune reaction.</p><p> An object of the present invention is to provide a method for manufacturing an SPR sensor cell, an SPR sensor, and an SPR sensor cell having excellent detection accuracy.</p>

<p> In order to achieve the above object, the SPR sensor cell of the present invention includes a detection unit and a sample arrangement unit adjacent to the detection unit, and the detection unit includes an underclad layer made of a first resin and a second resin. A resin comprising an optical waveguide including a core layer coated on the underclad layer, and the first resin is permeated into the second resin on a surface layer of the core layer in contact with the underclad layer. It is characterized in that a mixed layer is formed.</p><p> According to such an SPR sensor cell, since a resin mixed layer made of a second resin permeated with the first resin is formed in the core layer, it is possible to accurately detect the concentration and change of the sample.</p><p> Further, the SPR sensor of the present invention is characterized by including the above-mentioned SPR sensor cell.</p><p> Since this SPR sensor uses an SPR sensor cell in which a resin mixed layer made of a second resin impregnated with the first resin is formed in the core layer, it is possible to accurately detect the concentration and change of the sample. ..</p><p> Further, the method for manufacturing the SPR sensor cell of the present invention includes a step of forming a core layer made of a second resin on a substrate in a predetermined pattern, and coating the core layer with the first resin on the substrate. At the same time, the steps of applying and heating the first resin so as to permeate the surface layer of the core layer and curing the first resin form an underclad layer made of the first resin, and the above. It is characterized by comprising a step of forming a resin mixed layer in which the first resin is permeated into the second resin on the surface layer of the core layer in contact with the underclad layer.</p><p> According to such a method for manufacturing an SPR sensor cell, a resin mixed layer made of a second resin infiltrated with the first resin can be formed in the core layer, so that the concentration and change of the sample can be detected accurately. SPR sensor cells can be manufactured.</p>

<p> According to the method for manufacturing the SPR sensor cell, the SPR sensor, and the SPR sensor cell of the present invention, the detection accuracy can be improved by a simple configuration.</p>

<figref num="1">It is a perspective view which shows one Embodiment of the SPR sensor cell of this invention.</figref><figref num="2">It is sectional drawing of the SPR sensor cell shown in FIG.</figref><figref num="3">It is a process diagram which shows the manufacturing method of the SPR sensor cell shown in FIG. 1, (a) is the process of forming the core layer made of 2nd resin on the substrate, (b) is the process | 1 The step of applying and heating the resin so as to coat the core layer and allow the first resin to permeate the surface layer of the core layer. In (c), the first resin is cured and the underclad layer made of the first resin is formed. The step of forming a resin mixed layer on the surface layer in contact with the underclad layer of the core layer, (d) is a step of peeling the substrate from the core layer and the underclad layer, and (e) is the step of peeling the substrate. A step of forming a protective layer on the surfaces of the core layer and the underclad layer exposed by the operation, (f) is a step of forming an overclad layer on the surface of the protective layer, and (g) is a step of forming an overclad layer on the surface of the protective layer. The process of forming a metal thin film on the surface of the protective layer exposed from the surface so as to cover the core layer is shown.</figref><figref num="4">It is sectional drawing which shows the other embodiment of the SPR sensor cell of this invention.</figref><figref num="5">FIG. 5 is a schematic side sectional view showing an embodiment of the SPR sensor of the present invention.</figref>

FIG. 1 is a perspective view showing an embodiment of the SPR sensor cell of the present invention. FIG. 2 is a cross-sectional view of the SPR sensor cell shown in FIG.

As shown in FIGS. 1 and 2, the SPR sensor cell 1 is formed in a bottomed frame shape having a substantially rectangular plan view, and includes a detection unit 30 and a sample arrangement unit 31 adjacent to the detection unit 30. ..

The detection unit 30 is provided to detect the state of the sample arranged in the sample arrangement unit 31 and its change, and includes an optical waveguide 2.

In the following description of the SPR sensor cell 1, when the direction is referred to, the state when the sample is placed in the SPR sensor cell 1 is used as the upper and lower reference. That is, in FIG. 1, the upper side of the paper surface is the upper side, and the lower side of the paper surface is the lower side.

In the present embodiment, the optical waveguide 2 is the SPR sensor cell 1 itself, and includes an underclad layer 3, a core layer 4, a protective layer 5, and an overclad layer 6.

The underclad layer 3 is made of a first resin (described later), and is formed in a substantially rectangular flat plate shape in a plan view having a predetermined thickness in the vertical direction.

The core layer 4 is made of a second resin (described later) different from the first resin (described later), and is in a direction orthogonal to both the width direction (direction orthogonal to the thickness direction, the same applies hereinafter) and the thickness direction of the underclad layer 3. It is formed in a substantially prismatic shape (specifically, a rectangular cross section flattening in the width direction) extending in the width direction, and is covered (embedded) in the underclad layer 3 at the upper end portion of the substantially central portion in the width direction of the underclad layer 3. In the following description of the SPR sensor cell 1, the direction in which the core layer 4 extends is defined as the propagation direction in which light propagates in the optical waveguide 2.

Further, the core layer 4 is arranged so that both sides in the propagation direction are flush with both sides in the propagation direction of the underclad layer 3 and the upper surface thereof is flush with the upper surface of the underclad layer 3. That is, the upper surface of the core layer 4 is exposed from the underclad layer 3.

If the core layer 4 is coated (embedded) in the underclad layer 3 so that its upper surface is flush with the upper surface of the underclad layer 3, the metal thin film 7 (described later) or the metal particle layer 8 (described later) When the metal material (described later) and the metal particles 10 (described later) are formed, the metal material (described later) and the metal particles 10 (described later) can be efficiently arranged only on the upper side of the core layer 4.

Further, the core layer 4 is formed of a single resin layer 22 and a resin mixed layer 23.

The single resin layer 22 is formed in a substantially prismatic shape (specifically, a rectangular cross section flattening in the width direction), and is arranged so that the upper surface thereof is flush with the upper surface of the underclad layer 3.

More specifically, the single resin layer 22 is formed in a substantially prismatic shape having a shorter thickness direction length and a shorter width direction length and the same propagation direction length with respect to the entire core layer 4. The resin mixed layer 23 is coated (embedded) at the upper end of the core layer 4 at the substantially central portion in the width direction.

The resin mixed layer 23 is formed as a surface layer in contact with the underclad layer 3 of the core layer 4, and more specifically, in the lower portion of the core layer 4 and both side portions in the width direction, a cross-sectional view that surrounds the single resin layer 22 is omitted. It is formed in a concave shape (U-shape). Further, the resin mixed layer 23 is arranged so that its upper surface is flush with the upper surfaces of the underclad layer 3 and the single resin layer 22.

That is, the upper surface of the core layer 4 is formed flush with the underclad layer 3 from the single resin layer 22 and the resin mixed layer 23, and both sides and the lower surface in the width direction are formed from the resin mixed layer 23. ing.

Further, a light source 12 (described later) and an optical measuring instrument 13 (described later) are optically connected to both ends of the core layer 4 in the propagation direction.

If necessary, the protective layer 5 is formed as a thin layer having the same shape as the underclad layer 3 in a plan view so as to cover all the upper surfaces of the underclad layer 3 and the core layer 4.

When the protective layer 5 is formed, for example, when the sample is liquid, it is possible to prevent the core layer 4 from swelling due to the sample.

The overclad layer 6 is formed on the protective layer 5 in a rectangular frame shape in a plan view so that the outer periphery thereof is substantially the same as the outer periphery of the underclad layer 3 in a plan view.

As a result, the optical waveguide 2 is formed in a bottomed frame shape with the protective layer 5 formed on the underclad layer 3 and the core layer 4 as the bottom wall and the overclad layer 6 as the side wall.

The sample arranging unit 31 is provided to accommodate the sample to be analyzed by the SPR sensor 11 (described later), and is arranged so as to be adjacent to the detection unit 30.

More specifically, the sample arranging portion 31 is partitioned above the core layer 4 as a portion surrounded by the protective layer 5 and the overclad layer 6.

Further, a metal thin film 7 is provided in such a sample arrangement portion 31.

As shown in FIG. 2, the metal thin film 7 is formed so as to uniformly cover the protective layer 5 in the sample arrangement portion 31. That is, the metal thin film 7 is formed so as to uniformly cover the upper surface of the core layer 4.

Although not described in detail, the SPR sensor cell 1 may be provided with a support member (not shown) that supports the optical waveguide 2 if necessary.

FIG. 3 is a process diagram showing a manufacturing method of the SPR sensor cell shown in FIG.

Next, a method of manufacturing the SPR sensor cell 1 will be described with reference to FIG.

In this method, first, as shown in FIG. 3A, a flat plate-shaped substrate 9 is prepared, and then the core layer 4 is formed on the substrate 9.

The substrate 9 is formed of, for example, a ceramic material such as silicon, glass, for example, a metal material such as copper, aluminum, stainless steel, ferroalloy, for example, a resin material such as polyimide, glass-epoxy, polyethylene terephthalate (PET), and the like. ing. Preferably, it is made of a ceramic material. The thickness of the substrate 9 is, for example, 10 to 5000 μm, preferably 10 to 1500 μm.

The core layer 4 is formed of a second resin, and examples of such a second resin include a polyimide resin, a polyamide resin, a silicone resin, an epoxy resin, an acrylic resin, or a fluorinated modified product thereof or heavy hydrogen. Examples thereof include a modified product and a resin material such as a modified fluorene product. These resin materials are preferably used as a photosensitive resin by blending a photosensitive agent.

To form the core layer 4, for example, the above-mentioned resin varnish (resin solution) is prepared, the varnish is applied to the surface of the substrate 9 in the above-mentioned predetermined pattern, dried, and heated if necessary. Let it cure. When a photosensitive resin is used, a varnish is applied to the entire surface of the substrate 9, dried, irradiated with ultraviolet rays through a photomask, developed into a pattern, and then heat-cured if necessary.

As the heating conditions, the heating temperature is, for example, 70 to 250 ° C, preferably 70 to 150 ° C, and the heating time is, for example, 10 seconds to 2 hours, preferably 5 minutes to 1 hour. ..

The thickness of the core layer 4 thus formed is, for example, 2 to 150 μm, and the width is, for example, 2 to 150 μm.

Next, in this method, as shown in FIG. 3 (b), the core layer 4 is coated on the substrate 9, and the first resin is infiltrated into the surface layer of the core layer 4 in contact with the first resin. , The first resin is applied and heated in the above pattern.

Examples of the first resin include resin materials similar to those described above, which are adjusted to have a lower refractive index than the single resin layer 22 of the core layer 4.

To apply the first resin onto the substrate 9, for example, a varnish (resin solution) of the above-mentioned resin is prepared, and the varnish is applied onto the substrate 9 by, for example, casting, a spin coater, or the like to form the core layer 4. After coating so as to cover the core layer 4, the first resin is heated so as to permeate the core layer 4 (second resin).

As the heating conditions, the heating temperature is, for example, 60 to 150 ° C., preferably 100 to 150, and the heating time is, for example, 1 to 30 minutes.

When a photosensitive resin is used, it is then irradiated with ultraviolet rays. At this time, if necessary, ultraviolet rays are irradiated through a photomask, and if necessary, development is performed.

Next, in this method, as shown in FIG. 3C, the first resin is cured by heating, for example, to form the underclad layer 3 made of the first resin. At this time, as the core layer 4, a resin mixed layer 23 in which the first resin is permeated into the second resin is formed on the surface layer in contact with the underclad layer 3 of the core layer 4, and is embedded in the resin mixed layer 23. The single resin layer 22 to be formed is formed.

As the heating conditions, the heating temperature is, for example, 70 to 250 ° C, preferably 70 to 150 ° C, and the heating time is, for example, 10 seconds to 2 hours, preferably 5 minutes to 1 hour. ..

The thickness of the underclad layer 3 thus formed from the surface of the core layer 4 is, for example, 2 to 500 μm.

The thickness of each side of the resin mixed layer 23 surrounding the single resin layer 22 and the thickness of the single resin layer 22 are not particularly limited, and the degree of penetration of the first resin into the second resin and the like are not particularly limited. Is determined as appropriate.

As a result, the underclad layer 3 and the core layer 4 are formed flush with each other on the lower surface in contact with the substrate 9.

The refractive index of the underclad layer 3 formed in this way is set lower than the refractive index of the single resin layer 22 of the core layer 4, and is, for example, 1.42 or more and less than 1.55.

Further, the refractive index of the single resin layer 22 of the core layer 4 is set higher than the refractive index of the underclad layer 3, for example, 1.44 or more and 1.65 or less.

Further, the refractive index of the resin mixed layer 23 usually exceeds the refractive index of the underclad layer 3 and is less than the refractive index of the single resin layer 22, and specifically, in the laminating direction thereof, the underclad layer 3 From the side toward the single resin layer 22 side, the refractive index of the underclad layer 3 is continuously changed to the refractive index of the single resin layer 22.

Next, in this method, as shown in FIG. 3D, the substrate 9 is peeled from the underclad layer 3 and the core layer 4, and the underclad layer 3 and the core layer 4 are turned upside down.

Then, the surface of the underclad layer 3 and the core layer 4 that was in contact with the substrate 9 is exposed as the upper surface.

Then, in this method, as shown in FIG. 3 (e), the protective layer 5 is formed on the underclad layer 3 and the core layer 4.

Examples of the material forming the protective layer 5 include silicon dioxide and aluminum oxide, and preferably, from these materials, a material adjusted to have a lower refractive index than that of the core layer 4 can be mentioned.

Examples of the method for forming the protective layer 5 include a sputtering method and a vapor deposition method, and a sputtering method is preferable.

The thickness of the protective layer 5 thus formed is, for example, 1 to 100 nm, preferably 5 to 20 nm. Further, the refractive index of the protective layer 5 is set lower than the refractive index of the core layer 4, for example, 1.25 or more and less than 1.55.

Then, in this method, as shown in FIG. 3 (f), the overclad layer 6 is formed on the protective layer 5 in the pattern described above.

As the material for forming the overclad layer 6, the same resin material (first resin) as the underclad layer 3 described above is used.

In order to form the overclad layer 6, for example, a sheet having a rectangular frame shape in a plan view is separately formed from the above-mentioned material, and the sheet is laminated on the protective layer 5 as the overclad layer 6.

When the overclad layer 6 is laminated on the protective layer 5, the surface of the protective layer 5 may be previously treated with a known primer such as a silane coupling agent and then laminated. If the surface of the protective layer 5 is treated with the above-mentioned primer, when the metal thin film 7 and the metal particle layer 8 (described later) are formed, the metal material (described later) and the metal particles 10 (described later) are subjected to the protective layer 5 Can be firmly fixed to.

Examples of the silane coupling agent include amino group-containing silane coupling agents such as γ-aminopropyltriethoxysilane.

When treating a silane coupling agent as a primer, for example, an alcohol solution of the silane coupling agent is applied to the protective layer 5, and then heat treatment is performed.

Further, in order to form the overclad layer 6, for example, the above-mentioned resin varnish (resin solution) is prepared, the varnish is applied to the surface of the protective layer 5 in the above-mentioned pattern, and then dried and required. It can also be cured by. When a photosensitive resin is used, a varnish is applied to the entire surface of the protective layer 5, dried, exposed through a photomask, and if necessary, heated after exposure, and then developed into a pattern. It can also be heated.

The thickness of the overclad layer 6 thus formed is, for example, 5 to 200 μm, preferably 25 to 100 μm. Further, the refractive index of the overclad layer 6 is set lower than the refractive index of the core layer 4, and is set in the same manner as, for example, the refractive index of the underclad layer 3. When the refractive index of the protective layer 5 is lower than the refractive index of the core layer 4, the refractive index of the overclad layer 6 does not necessarily have to be lower than the refractive index of the core layer 4.

Further, in such an overclad layer 6, the size and shape of the sample arranging portion 31 are not particularly limited, and are appropriately determined according to the type and application of the sample. When the SPR sensor cell 1 is to be miniaturized, the sample arrangement portion 31 is preferably formed small.

Next, in this method, as shown in FIG. 3 (g), the metal thin film 7 is formed so as to cover the core layer 4 in the sample arrangement portion 31.

Examples of the metal material forming the metal thin film 7 include gold, silver, platinum, copper, aluminum, and alloys thereof.

These metal materials can be used alone or in combination of two or more.

In order to form the metal thin film 7, for example, if necessary, first, a resist having a reverse pattern of the pattern of the metal thin film 7 is formed to mask the periphery of the portion where the metal thin film 7 is formed. Then, for example, a metal thin film 7 is formed on the upper surface of the core layer 4 (the core layer 4 exposed from the resist formed if necessary) by a vapor deposition method such as a vacuum vapor deposition method, an ion plating method, or a sputtering method. After that, if a resist is formed, the resist is removed by etching, peeling, or the like.

A plurality of metal thin films 7 can be laminated if necessary.

The thickness of the metal thin film 7 thus formed (in the case of a plurality of laminated metal thin films, the total thickness thereof) is, for example, 40 to 70 nm, preferably 50 to 60 nm.

In this way, the SPR sensor cell 1 can be manufactured.

According to such a manufacturing method of the SPR sensor cell 1, a resin mixed layer 23 made of a second resin permeated with the first resin can be formed in the core layer 4, so that the concentration and change of the sample can be accurately measured. A well-detectable SPR sensor cell 1 can be manufactured.

Then, in the SPR sensor cell 1, the metal thin film 7 and the sample are brought into contact with each other by accommodating (arranging) the sample in the sample arranging portion 31. That is, the sample is surrounded by the overclad layer 6 in the sample arrangement portion 31.

According to such an SPR sensor cell 1, it is possible to accurately detect the concentration and change of the sample.

That is, according to such an SPR sensor cell 1, since the resin mixed layer 23 made of the second resin permeated with the first resin is formed in the core layer 4, the concentration and change of the sample can be detected accurately. can do.

FIG. 4 is a cross-sectional view showing another embodiment of the SPR sensor cell of the present invention. The members corresponding to the above-mentioned members are designated by the same reference numerals in FIG. 4, and detailed description thereof will be omitted.

In the above description, the sample arranging portion 31 is provided with the metal thin film 7, but for example, the sample arranging portion 31 may be provided with the metal particle layer 8 instead of the metal thin film 7.

As shown in FIG. 4, the metal particle layer 8 is formed so as to uniformly cover the protective layer 5 in the sample arrangement portion 31. That is, the metal particle layer 8 is formed so as to uniformly cover the upper surface of the core layer 4.

The metal particles 10 forming the metal particle layer 8 include, for example, particles made of a metal such as gold, silver, copper, aluminum, chromium, and platinum, for example, the surface of inorganic particles such as silica and carbon black is made of the above-mentioned metal. Examples thereof include coated particles, for example, particles in which the surface of organic particles such as resin is coated with the above-mentioned metal. Particles made of metal are preferable, and chromium particles and gold particles are more preferable.

The average particle size of the metal particles 10 is calculated as, for example, the average value of any 100 particles observed by electron microscopy, and is, for example, 5 to 300 nm, preferably 10 to 150 nm.

To form the metal particle layer 8, although not shown in detail, for example, the above-mentioned metal particles 10 are dispersed in a known solvent to prepare a particle dispersion, and the particle dispersion is applied to the protective layer 5. ,dry.

A gold particle dispersion liquid in which gold particles are dispersed as the metal particles 10 is commercially available, and examples thereof include the EMGC series (manufactured by British BioCell International Ltd.).

In the metal particle layer 8 thus formed, the metal particles 10 are preferably formed as a single particle layer without being laminated with each other in the thickness direction. Further, the metal particles 10 are arranged independently with a slight interval so as not to come into contact with each other.

Then, in a plan view, the metal particle layer 8 is, for example, 15 to 60%, preferably 20 to 50% of the surface area of the core layer 4 exposed from the underclad layer 3, that is, the area of the sample arrangement portion 31. Covers%. When the metal particle layer 8 covers the core layer 4 exposed from the underclad layer 3 at the above ratio (coating ratio), almost all the metal particles 10 are independently arranged as a single particle layer. Since the metal particle layer 8 is formed, the concentration and change of the sample can be detected more accurately.

Then, in the SPR sensor cell 1, the metal particle layer 8 and the sample are brought into contact with each other by accommodating (arranging) the sample in the sample arranging portion 31. That is, the sample is surrounded by the overclad layer 6 in the sample arrangement portion 31.

According to such an SPR sensor cell 1, it is possible to accurately detect the concentration and change of the sample.

That is, according to such an SPR sensor cell 1, since the overclad layer 6 is formed so as to surround the sample in contact with the metal particle layer 8, the sample can be easily arranged on the surface of the metal particle layer 8. Therefore, workability can be improved.

FIG. 5 is a schematic side sectional view showing an embodiment of the SPR sensor of the present invention.

Next, the SPR sensor 11 including the SPR sensor cell 1 will be described with reference to FIG.

As shown in FIG. 5, the SPR sensor 11 includes a light source 12, an optical measuring instrument 13, and the SPR sensor cell 1 described above.

The light source 12 is a known light source such as a white light source or a monochromatic light light source, and is connected to a light source side optical fiber 15 via a light source side optical connector 14, and the light source side optical fiber 15 is a light source side optical fiber. It is connected to one end of the SPR sensor cell 1 (core layer 4) in the propagation direction via the block 16.

Further, the measuring instrument side optical fiber 18 is connected to the other end of the SPR sensor cell 1 (core layer 4) in the propagation direction via the measuring instrument side optical fiber block 17, and the measuring instrument side optical fiber 18 is connected to the measuring instrument side optical fiber 18. , It is connected to the optical measuring instrument 13 via the measuring instrument side optical connector 19.

Although not shown, the optical measuring instrument 13 is connected to a known arithmetic processing unit to enable data display, storage, and processing.

Further, in such an SPR sensor 11, the SPR sensor cell 1 is fixed by a known sensor cell fixing device (not shown). The sensor cell fixing device (not shown) is movable along a predetermined direction (for example, the width direction of the SPR sensor cell 1), whereby the SPR sensor cell 1 is arranged at an arbitrary position.

Further, the light source side optical fiber 15 is fixed to the light source side optical fiber fixing device 20, and the measuring instrument side optical fiber 18 is fixed to the measuring instrument side optical fiber fixing device 21.

The light source side optical fiber fixing device 20 and the measuring instrument side optical fiber fixing device 21 are fixed on a known 6-axis moving stage (not shown), and are fixed in the propagation direction and the width direction (propagation direction and horizontal) of the optical fiber. It is movable in the direction orthogonal to the direction (direction orthogonal to the direction) and the thickness direction (direction orthogonal to the propagation direction) and the rotation direction (three directions) about each of these directions (three directions).

According to such an SPR sensor 11, the light source 12, the light source side optical fiber 15, the SPR sensor cell 1 (core layer 4), the measuring instrument side optical fiber 18, and the optical measuring instrument 13 can be arranged on one axis. Light can be introduced from the light source 12 so as to transmit the light.

Then, in this SPR sensor 11, the above-mentioned SPR sensor cell 1, that is, the SPR sensor cell 1 in which the resin mixed layer 23 made of the second resin permeated with the first resin is formed in the core layer 4, is used. It is possible to accurately detect sample concentrations and changes.

Hereinafter, one usage mode of the SPR sensor 11 will be described.

In this embodiment, for example, first, the sample is housed (placed) in the sample placement part 31 of the SPR sensor cell 1 shown in FIG. 5, and the sample and the metal thin film 7 (or the metal particle layer 8) are brought into contact with each other. Next, a predetermined light from the light source 12 is introduced into the SPR sensor cell 1 (core layer 4) via the light source side optical fiber 15 (see the broken line arrow L1 shown in FIG. 5).

The light introduced into the SPR sensor cell 1 (core layer 4) is transmitted through the SPR sensor cell 1 (core layer 4) while repeating total reflection in the core layer 4, and some light is transmitted to the upper surface of the core layer 4. In, the metal thin film 7 (or the metal particle layer 8) is incident on the metal thin film 7 (or the metal particle layer 8) through the protective layer 5, and is attenuated by surface plasmon resonance.

After that, the light transmitted through the SPR sensor cell 1 (core layer 4) is introduced into the optical measuring instrument 13 via the measuring instrument side optical fiber 18 (see the broken line arrow L2 shown in FIG. 5).

That is, in the SPR sensor 11, the light introduced into the optical measuring instrument 13 has the light intensity of the wavelength at which the surface plasmon resonance is generated in the core layer 4 attenuated.

Since the wavelength at which surface plasmon resonance is generated depends on the refractive index of the sample accommodated (arranged) in the SPR sensor cell 1, the attenuation of the light intensity of the light introduced into the optical measuring instrument 13 is detected. Changes in the refractive index of the sample can be detected.

More specifically, for example, when a white light source is used as the light source 12, the optical measuring instrument 13 measures the wavelength at which the light intensity decays after transmission through the SPR sensor cell 1 (wavelength at which surface plasmon resonance occurs). If it is detected that the decaying wavelength has changed, the change in the refractive index of the sample can be confirmed.

Further, for example, when a monochromatic light source is used as the light source 12, the optical measuring instrument 13 measures the change in the light intensity (degree of attenuation) of the monochromatic light after transmission through the SPR sensor cell 1, and the degree of attenuation is measured. If the change is detected, it can be confirmed that the wavelength at which the surface plasmon resonance is generated has changed, and the change in the refractive index of the sample can be confirmed in the same manner as described above.

Therefore, such an SPR sensor 11 can be used for various chemical analyzes and biochemical analyzes such as measurement of sample concentration and detection of immune reaction based on the change in the refractive index of the sample.

More specifically, for example, when the sample is a solution, the refractive index of the sample (solution) depends on the concentration of the solution, so that the sample (solution) is made into a metal thin film 7 (or a metal particle layer 8). ), The concentration of the sample can be measured by detecting the refractive index of the sample (solution). Further, if it is detected that the refractive index of the sample (solution) has changed, it can be confirmed that the concentration of the sample (solution) has changed.

Further, in the detection of the immune reaction, for example, the antibody is fixed on the metal thin film 7 (or the metal particle layer 8) of the SPR sensor cell 1 via the dielectric film, and the sample is brought into contact with the antibody. At this time, if the antibody and the sample undergo an immune reaction, the refractive index of the sample changes. Therefore, by detecting that the refractive index of the sample changes before and after the contact between the antibody and the sample, the antibody and the sample are immunized. It can be judged that it has reacted.

Then, according to the manufacturing method of the SPR sensor cell 1, the SPR sensor 11, and the SPR sensor cell 1 as described above, the detection sensitivity can be improved by a simple configuration.

In the above-described embodiment, one core layer 4 is formed in the SPR sensor cell 1, but the number of core layers 4 is not particularly limited, and a plurality of core layers 4 may be formed at intervals in the width direction. it can.

When the optical waveguide 2 includes a plurality of core layers 4, the SPR sensor 11 including the SPR sensor cell 1 can analyze the sample a plurality of times at the same time, so that the analysis efficiency can be improved.

Further, in the above-described embodiment, the core layer 4 is formed in a substantially prismatic shape, but the shape of the core layer 4 is not particularly limited, and the core layer 4 is formed, for example, in a substantially semicircular shape (semi-cylinder) in cross section. It can be formed into any shape such as a shape) and a substantially convex shape (convex column shape) in cross-sectional view.

Further, in the above-described embodiment, the metal thin film 7 (or the metal particle layer 8) is formed so as to cover all the protective layer 5 in the sample arrangement portion 31, but the metal thin film 7 (or the metal particle layer 8) is formed. 8) can also be formed only on the upper side of the core layer 4 so as to cover at least the core layer 4.

Further, in the above-described embodiment, the upper end portion of the SPR sensor cell 1 is open, but the upper end portion of the SPR sensor cell 1 may be provided with a lid covering the sample arrangement portion 31. According to this, it is possible to prevent the sample from coming into contact with the outside air during the measurement.

Further, the lid covering the sample arranging portion 31 is provided with an injection port for injecting a sample (liquid) into the sample arranging portion 31 and a discharge port for discharging the sample from the sample arranging portion 31, and the sample is provided. , It is also possible to inject from the injection port, pass through the sample arrangement portion 31, and discharge from the discharge port. According to this, the physical characteristics of the sample can be continuously measured while flowing the sample in the sample arrangement unit 31.

<p> Examples and Comparative Examples will be shown below to describe the present invention in more detail, but the present invention is not limited to the Examples and Comparative Examples.</p><p> Production Example 1 (Manufacturing of first resin) Bisphenoxyethanol fluorenglycidyl ether 35 parts by mass, alicyclic epoxy resin 3', 4'-epoxycyclohexylmethyl-3,4-epoxycyclohexanecarboxylate 40 parts by mass, (3', 4'-epoxycyclohexane) methyl- 25 parts by mass of 3', 4'-epoxycyclohexylcarboxylate and 50% by mass of propion carbonate solution of 4,4'-bis [di (β-hydroxyethoxy) phenylsulfinio] phenylsulfide-bis-hexafluoroantimonate 2 A first resin (non-solvent-based photosensitive epoxy resin composition) was prepared by mixing parts by mass.</p><p> Manufacturing example 2 (Manufacturing of second resin) Bisphenoxyenoxol Fluorenglycidyl ether 70 parts by mass, 1,3,3-tris {4- [2- (3-oxecnyl)] butoxyphenyl} butane 30 parts by mass and 4,4'-bis [di (β-hydroxy) Ethoxy) Phenyl Sulfinio] A second resin (photosensitive epoxy resin composition) was prepared by dissolving 1 part by mass of a 50 mass% propion carbonate solution of phenyl sulfide-bis-hexafluoroantimonate in ethyl lactate.</p><p> Example 1 The solvent is volatilized by applying the second resin obtained in Production Example 2 on a silicon substrate (board) into a substantially prismatic shape with a thickness of 50 μm and a width of 50 μm, and then heating at 70 ° C for 10 minutes. I let you. Next, the reaction was completed by irradiating with ultraviolet rays through a photomask and further heating at 70 ° C. for 10 minutes. Next, it was developed with a developer of γ-butyrolactone to form a substantially prismatic core layer having a thickness of 50 μm and a width of 50 μm (see FIG. 3 (a)).</p><p> Next, the first resin obtained in Production Example 1 was applied onto the substrate so as to cover the core layer so that the thickness from the surface (upper surface) of the core layer was 100 μm, and 5 at 140 ° C. Heated for minutes. By this heat treatment, the first resin permeated into the second resin on the surface layer of the core layer (see Fig. 3 (b)).</p><p> The reaction was then completed by irradiation with ultraviolet light and further heating at 120 ° C. for 10 minutes. As a result, an underclad layer is formed, and a resin mixed layer in which the first resin is permeated into the second resin is formed on the surface layer in contact with the underclad layer of the core layer, and is embedded in the resin mixed layer. A single resin layer was formed (see Fig. 3 (c)).</p><p> Next, the silicon substrate was peeled off from the underclad layer and the core layer (see FIG. 3D), and the underclad layer and the core layer were turned upside down.</p><p> Next, a silicon dioxide thin film having a thickness of 10 nm was formed as a protective layer on the underclad layer and the core layer by a sputtering method (see FIG. 3 (e)).</p><p> Next, on the underclad layer and the core layer, the overclad layer was formed in a shape having an opening by using the first resin, thereby partitioning the sample arrangement portion (see FIG. 3 (f)). ..</p><p> Next, a 1 nm chromium thin film and a 50 nm gold thin film were sequentially laminated on the sample arrangement portion (opening of the overclad layer) by a sputtering method to form a metal thin film (see FIG. 3 (g)).</p><p> In this way, an SPR sensor cell was obtained. The refractive index of the underclad layer is 1.531, the refractive index of the single resin layer is 1.584, and the refractive index of the mixed resin layer is from the underclad layer side to the single resin layer side in the laminating direction. It changed continuously from 1.531 to 1.584.</p><p> Example 2 Instead of laminating the chromium thin film and the gold thin film, a gold particle dispersion (EMGC50, manufactured by British BioCell International Ltd.) is applied to the protective layer in the sample container, dried, and then the gold particles that do not adhere to the protective layer. An SPR sensor cell was obtained in the same manner as in Example 1 except that the protective layer in the sample container was washed with ethanol to form a metal particle layer on the protective layer (see FIG. 4). .. The coverage with metal particles (gold particles) was 30%.</p><p> Comparative example 1 A resin mixed layer is provided in the same manner as in Example 1 except that the step of heating at 140 ° C. for 5 minutes is omitted to prevent the first resin from penetrating into the second resin (the surface layer of the core layer). No SPR sensor cell was obtained.</p><p> Comparative example 2 A resin mixed layer is provided in the same manner as in Example 2 except that the step of heating at 140 ° C. for 5 minutes is omitted to prevent the first resin from penetrating into the second resin (the surface layer of the core layer). No SPR sensor cell was obtained.</p><p> Evaluation The SPR sensor cells obtained in each Example and each Comparative Example were fixed to an SPR sensor (see FIG. 5).</p><p> After that, 5 kinds of ethylene glycol aqueous solutions having different concentrations as samples (concentration: 1% by mass (refractive index: 1.33389), 5% by mass (refractive index: 1.33764), 10% by mass (refractive index) are placed in the sample housing of the SPR sensor cell. : 1.34245), 20% by mass (refractive index: 1.35231), 30% by mass (refractive index: 1.36249)) was charged in 50 μL, and from one end of the core layer, the wavelength was 555 nm in Example 1 and Comparative Example 1, and Example 2 and In Comparative Example 2, light having a wavelength of 633 nm was incident, and the intensity of the light emitted from the other end was measured.</p><p> Then, the transmittance (%) was determined when the light intensity was 100% in the absence of the ethylene glycol aqueous solution.</p><p> Then, with the refractive index of the ethylene glycol aqueous solution as the X-axis and the transmittance as the Y-axis, the relationship between them was plotted on the XY coordinates to create a calibration curve, and the slope thereof was obtained. The values are shown in Table 1. The larger the slope (absolute value), the higher the detection sensitivity.</p><p><tables num="1"><img file="JP2012107902A_D0001.tif" /></tables></p><p> result Each example in which the resin mixed layer was formed had a larger inclination (absolute value) than the comparative example in which the resin mixed layer was not formed.</p>

1 SPR sensor cell 2 Optical waveguide 3 Underclad layer 4 core layer 6 Overclad layer 11 SPR sensor 23 Resin mixed layer 30 Detector 31 Sample placement section