JP2003254905A - Measuring instrument - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To measure a large number of samples in a short time, in a measuring device such as a surface plasmon resonance measuring device. <P>SOLUTION: A plurality of measuring units 10 each of which is provided with a dielectric block, a thin film layer formed on this dielectric block, and a sample holding mechanism are supported by a supporting body 2. An individual or common light beam 30 is forced to enter parallel to each dielectric block of at least two measuring units 10 supported by the supporting body 2 from an optical system comprising optical fibers 34a-34h and the like, and a plurality of light detecting means to measure intensity of the light beam 30 totally reflected by the boundary face of the dielectric block and the thin film layer are provided, with each means made to correspond to the light beam 30. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a measuring device such as a surface plasmon resonance measuring device for analyzing a substance in a sample by utilizing the generation of surface plasmon, and more particularly to a thin film layer in contact with the sample, a metal. An evanescent wave is used to analyze a sample by measuring the change in the intensity of the totally reflected light beam by totally reflecting the light beam at the interface between the film or cladding layer and the dielectric block to generate an evanescent wave. The present invention relates to the measuring device.

[0002]

2. Description of the Related Art In a metal, free electrons oscillate collectively to generate compression waves called plasma waves. And, the quantized compression wave generated on the metal surface is
It is called surface plasmon.

Conventionally, various surface plasmon resonance measuring devices have been proposed for quantitatively analyzing a substance in a sample by utilizing the phenomenon that the surface plasmon is excited by a light wave. Among them, one that is particularly well known is one that uses a system called Kretschmann arrangement (see, for example, JP-A-6-167443).

A surface plasmon resonance measuring apparatus using the above system basically comprises, for example, a dielectric block formed in a prism shape, a metal film formed on one surface of the dielectric block and brought into contact with a sample, and a light beam. A light source for generating a beam and a dielectric block that directs the light beam to the dielectric block at the interface between the dielectric block and the metal film so that various incident angles including the surface plasmon resonance condition can be obtained. And an optical system for measuring the intensity of the light beam totally reflected at the interface to detect the state of surface plasmon resonance.

As described above, in order to obtain various incident angles, a relatively thin light beam may be deflected to be incident on the interface, or a component which is incident on the light beam at various angles may be included. As described above, a relatively thick light beam may be incident so as to be focused at the interface. In the former case, a light beam whose reflection angle changes with the deflection of the light beam can be detected by a small photodetector that moves synchronously with the deflection of the light beam, or by an area sensor extending along the direction of change of the reflection angle. Can be detected. On the other hand, in the latter case, each light beam reflected at various reflection angles can be detected by an area sensor extending in a direction in which all the light beams can be received.

In the surface plasmon resonance measuring apparatus having the above structure, when a light beam is incident on the metal film at a specific incident angle θ _SP which is equal to or greater than the total reflection angle, an electric field distribution is generated in the sample in contact with the metal film. An evanescent wave is generated, and the surface plasmon is excited at the interface between the metal film and the sample by the evanescent wave. When the wave vector of the evanescent light is equal to the wave number of the surface plasmon and the wave number matching is established, both are in a resonance state and the energy of the light is transferred to the surface plasmon, so that at the interface between the dielectric block and the metal film. The intensity of the reflected light sharply decreases. This decrease in light intensity is generally detected as a dark line by the light detecting means.

The above resonance occurs only when the incident beam is p-polarized. Therefore, it is necessary to set in advance that the light beam is incident as p-polarized light.

When the wave number of the surface plasmon is known from the incident angle θ _{SP at} which this attenuated total reflection (ATR) occurs, the dielectric constant of the sample can be obtained. That is, the wave number of the surface plasmon is K
_{Let SP be} the angular frequency of the surface plasmons be ω, c be the speed of light in a vacuum, ε _m and ε _s be the metal, and the permittivity of the sample respectively, and the following relationships are established.

[0009]

[Equation 1] If the permittivity ε _s of the sample is known, the concentration of the specific substance in the sample can be known based on a predetermined calibration curve or the like, so that the incident angle (total reflection attenuation angle) θ _{SP at which the} reflected light intensity eventually decreases.
By knowing, the specific substance in the sample can be quantitatively analyzed.

As a similar sensor utilizing the attenuated total reflection (ATR), for example, "Spectroscopic Research" Vol. 47, No. 1 (1998), pages 21 to 23 and 26 to 27.
Leakage mode sensors described on the page are also known. This leaky mode sensor is basically formed by, for example, a dielectric block formed in a prism shape, a clad layer formed on one surface of the dielectric block, and formed on the clad layer and brought into contact with a sample. An optical waveguide layer, a light source for generating a light beam, and the light beam with respect to the dielectric block, a total reflection condition is obtained at the interface between the dielectric block and the cladding layer, and the light guide layer is used. The optical system that is incident at various angles so that the attenuation of the total reflection due to the excitation of the wave mode may occur, and the intensity of the light beam totally reflected at the interface is measured to determine the excited state of the guided mode, that is, the attenuated total reflection state. And a light detecting means for detecting.

In the leak mode sensor having the above structure,
When a light beam is incident on the cladding layer through the dielectric block at an angle of incidence equal to or more than the total reflection angle, only light with a specific incident angle having a specific wave number is transmitted in the optical waveguide layer after passing through the cladding layer. It propagates in the guided mode. When the guided mode is excited in this manner, most of the incident light is taken into the optical waveguide layer, so that the total reflection attenuation occurs in which the intensity of the light totally reflected at the interface sharply decreases.
Since the wave number of the guided light depends on the refractive index of the sample on the optical waveguide layer, the refractive index of the sample and the related characteristics of the sample are analyzed by knowing the above-mentioned specific incident angle at which attenuation of total reflection occurs. be able to.

The surface plasmon resonance measuring device and the leaky mode sensor described above are used in the field of drug discovery research, etc.
It may be used for random screening to find a specific substance that binds to a given sensing substance. In this case, a sensing substance is fixed as a substance to be measured on the thin film layer (a metal film in the case of a surface plasmon resonance measuring device, a clad layer and an optical waveguide layer in the case of a leaky mode measuring device), and the sensing substance is fixed. The sample solution containing the test substance is dropped on the sample, and the above-described attenuated total reflection angle θ _SP is measured every time a predetermined time elapses.

If the analyte in the sample liquid binds to the sensing substance, this binding causes the refractive index of the sensing substance to change over time. Therefore, the attenuated total reflection angle θ _SP is measured every time a predetermined time elapses, the binding state between the analyte and the sensing substance is measured based on the value, and the specific substance that the analyte binds to the sensing substance based on the result is measured. It can be determined whether or not there is. Examples of such a combination of the specific substance and the sensing substance include, for example, an antigen and an antibody. As a specific measurement relating to such a substance, for example, a rabbit anti-human IgG antibody is used as the sensing substance, There is a measurement for detecting the presence / absence of binding to the human IgG antibody and quantifying it.

It should be noted that the angle itself of the attenuated total reflection angle θ _SP does not necessarily have to be detected in order to measure the binding state between the analyte and the sensing substance. For example, it is also possible to add a sample solution to the sensing substance, measure the angle change amount of the total reflection attenuation angle θ _SP after that, and measure the binding state based on the magnitude of the angle change amount.

[0015]

By the way, in the conventional measuring apparatus such as the surface plasmon resonance measuring apparatus and the leak mode sensor, there is a problem that it takes a long time to measure a large number of samples. Is recognized. In particular, in the case of performing several measurements at a time interval for one sample in order to detect changes in sample properties associated with, for example, an antigen-antibody reaction or a chemical reaction,
If the measurement of one sample is not completed, the measurement of a new sample cannot be started, and it takes a very long time to measure the entire sample.

In view of the above circumstances, it is an object of the present invention to provide a measuring device capable of measuring a large number of samples in a short time.

[0017]

One measuring device according to the present invention comprises a dielectric block as described above, a thin film layer formed on one surface of the dielectric block, and a sample on the surface of the thin film layer. A plurality of measurement units having a sample holding mechanism for holding the support, a support supporting the plurality of measurement units, a light source for generating a light beam, and a dielectric block for the light beam to the dielectric block. In a measuring device comprising an incident optical system that makes an incident angle at which the total reflection condition is obtained at the interface between the block and the thin film layer, and a light detection unit that measures the intensity of the light beam totally reflected at the interface, The optical system is configured to make the light beam incident in parallel on each of the dielectric blocks of at least two measurement units supported by the support, and the photodetection means, Serial and is characterized in that at least two are provided in total in correspondence to each one in the light beam incident on the dielectric block.

Another measuring device according to the present invention is a dielectric block, a thin film layer formed on one surface of the dielectric block, and a thin film layer disposed on the surface of the thin film layer to interact with a specific component in a sample. A sensing substance generated, and a plurality of measurement units provided with a sample holding mechanism for holding a sample on the surface of the sensing substance, a support supporting the plurality of measurement units, a light source for generating a light beam,
An incident optical system that causes the light beam to enter the dielectric block at an angle of incidence at which the total reflection condition is obtained at the interface between the dielectric block and the thin film layer, and the intensity of the light beam totally reflected at the interface. In the measuring device, the optical system is configured to make the light beam incident on the dielectric blocks of the at least two measuring units supported by the support body in parallel. It is characterized in that at least two photodetecting means are provided in total, one for each light beam incident on the dielectric block.

As the above-mentioned measuring device, the above-mentioned surface plasmon measuring device using a metal film as the above-mentioned thin film layer, a clad layer formed on one surface of the dielectric block,
There is the above-mentioned leaky mode measuring device which uses a layer composed of an optical waveguide layer formed on the clad layer as the thin film layer.

In the measuring device according to the present invention, there are various methods for measuring the intensity of the light beam totally reflected at the interface by the light detecting means to analyze the sample. For example, the light beam is totally reflected at the interface. The intensity of the light beam totally reflected by the interface is measured at each position corresponding to each incident angle, and the position (angle) of the dark line generated by the attenuated total reflection is measured. Sample analysis may be carried out by detecting, DVNoort, K.johansen, C.-F.Ma.
ndenius, Porous Gold in Surface Plasmon Resonance
As described in Measurement, EUROSENSORS XIII, 1999, pp.585-588, light beams with a plurality of wavelengths are made incident at an incident angle at which total reflection conditions are obtained at the interface, and total wavelength is obtained at the interface for each wavelength. The sample analysis may be performed by measuring the intensity of the reflected light beam and detecting the degree of attenuation of total reflection for each wavelength.

Also, PINikitin, ANGrigorenko, AAB
eloglazov, MVValeiko, AISavchuk, OASavchuk, Sur
face Plasmon Resonance Interferometry for Micro-Ar
rayBiosensing, EUROSENSORS XIII, 1999, pp.235-238
The light beam is incident at an angle of incidence such that total internal reflection conditions are obtained at the interface, and a portion of the light beam is split before the light beam enters the interface; The sample analysis may be performed by causing the divided light beam to interfere with the light beam totally reflected at the interface and measuring the intensity of the light beam after the interference.

Further, it is preferable that the above optical system is constructed so that the light beams are incident in parallel on the dielectric blocks of all the measurement units supported by the support.

Further, this optical system splits a single light beam emitted from each of the one or a plurality of the light sources provided, and makes the split light beams respectively enter the dielectric block. It is desirable to be configured as follows. For example, when the number of measurement units that make light beams incident in parallel is eight, one light beam emitted from one light source is branched into eight, or one light beam emitted from each of two light sources is divided into eight. Divide the light beam into 4 and total 8
It is possible to obtain a light beam of a book.

Further, the optical system is configured to flatten the light beams emitted from each of the one or more light sources provided and make the flattened light beams incident on the plurality of dielectric blocks. Good. For example, when the number of measurement units for making light beams incident in parallel is eight, one light beam emitted from one light source is flattened so as to be made incident on eight measurement units at the same time, or from two light sources. A configuration such as flattening so that one light beam emitted from each of them can be simultaneously incident on four measurement units can be adopted.

Alternatively, as described above, the light beams are not branched or flattened, and the same number of the light sources as the plurality of measurement units that make the light beams incident are provided, and the optical system is provided with these light sources. A light beam emitted from each of the light sources may be configured to be incident on each of the dielectric blocks.

In the measuring device according to the present invention,
By moving the support, the optical system, and the light detection means relatively, each measurement unit is selectively arranged at either a measurement position where the light beam is incident on the dielectric block or a standby position where the light beam is not incident. It is desirable to have a driving means to operate. It should be noted that only one standby position may be set, or a plurality of standby positions may be set.

When such a driving means is provided, as the supporting body, one that supports a plurality of measurement units linearly arranged in a line is used, while as the driving means, this supporting body and the optical system are used. It is desirable to use one that moves the light detection means and the light detection means linearly relative to each other in the arrangement direction of the plurality of measurement units.

Alternatively, in the case where the driving means as described above is provided, a supporting body that supports a plurality of measurement units arranged side by side on the circumference is used, while the supporting means and the optical system and It is also possible to use one that relatively moves the light detection means along the circumference in the direction in which the plurality of measurement units are arranged.

When the driving means as described above is provided, for example, the optical system and the light detecting means are kept stationary, and the driving means is configured to move the support. It Alternatively, conversely, the support may be kept stationary and the drive means may be arranged to move the optical system and the light detection means.

When the above driving means is provided, the number of measurement units supported by the support and the number of light beams emitted from the optical system do not necessarily match. For example, when the number of measurement units supported by the support is eight, four light beams are emitted from the optical system, and the four measurement units are first irradiated with the light beams to perform the measurement. After that, the driving means is driven to set the remaining four measuring units to the measurement positions where the light beams are irradiated, and in that state, the four measuring units are irradiated with the light beams to perform the measurement. May be.

In the measuring device according to the present invention,
It is desirable to provide a measuring unit feeding / discharging means for removing the measuring unit set to the standby position from the support and supporting the removed measuring unit again on the support.

In the measuring device according to the present invention,
The support supports a plurality of measurement units arranged side by side in one direction so that the light beams are incident in parallel to each other, and also supports a plurality of measurement units side by side in another direction intersecting with the one direction. After being configured, the support, the optical system, and the light detection means are relatively moved in the other direction, and the plurality of measurement units arranged in the other direction are sequentially incident to the light beam. It is desirable to provide a measuring unit feeding means arranged in the.

In the measuring device according to the present invention,
The dielectric block and the support may be integrally formed.

In the measuring device according to the present invention,
It is desirable that a storage means for storing the measurement unit under temperature control is provided at the standby position.

In the measuring device according to the present invention,
It is desirable that the standby position is provided with a state detecting means for detecting the state of the measuring unit.

For a while after the sample is dispensed to the measuring unit, the signal detected by the measuring device drifts.
The main cause of the drift of the detection signal is that it takes time for the dispensed sample to adapt to the measurement unit, and during that time, temperature fluctuations or the like occur in the measurement unit. The state detection means is for detecting the transient response state as described above. For example, the temperature of the measurement unit (sample) may be detected by a temperature sensor, or a sensor using an evanescent wave may be used. A change in the refractive index of the sample may be detected.

In the measuring device according to the present invention,
A timing instruction means for instructing the timing of the detection operation of the light detection means may be provided.

Further, in the measuring device according to the present invention, a plurality of optical systems are provided and a plurality of photodetection means are provided corresponding to the plurality of optical systems, that is, the measurement can be performed simultaneously by the plurality of systems. It is desirable that it is configured as follows.

[0039]

As described above, the measuring device of the present invention is a dielectric block, a thin film layer (a metal film in the case of utilizing surface plasmon resonance, and a metal film in the case of utilizing excitation of a guided mode). Are the cladding layer and the optical waveguide layer)
And, after supporting a plurality of measurement units provided with a sample holding mechanism on a support, and making a light beam enter in parallel from at least two dielectric blocks of these measurement units from an optical system, Since the light detection means is provided in correspondence with each of the light beams incident on these dielectric blocks, the measurement by the at least two measurement units can be performed in parallel.
As a result, according to the measuring apparatus of the present invention, it is possible to measure a large number of samples in a short time.

In particular, the above optical system splits or flattens one light beam emitted from the light source into a plurality of beams or flattens the light beams, so that the dielectric blocks of all the measurement units supported by the support are supported. In the case where the light beams are incident in parallel with each other, it is possible to carry out all the measurements by a plurality of measurement units supported by the support in parallel, and to measure a large number of samples in a shorter time. Can be done in.

In the measuring apparatus of the present invention, a sensing substance which interacts with a specific component in the sample is arranged on the surface of the thin film layer, and the sample is held on the surface of the sensing substance. In the above, since the state of surface plasmon resonance or the excited state of the guided mode, that is, the state of attenuated total reflection changes due to the above interaction, by capturing this change, the specific reaction between the specific component in the sample and the sensing substance. Can be detected.

Further, the support, the optical system and the light detecting means are moved relative to each other, and each measuring unit is placed at either a measurement position where the light beam is incident on the dielectric block or a standby position where the light beam is not incident. If a drive means for selectively arranging the measurement unit is provided, it becomes possible to attach and detach the measurement unit to and from the support at the standby position, and to spot the sample, thereby improving the efficiency of the measurement work. it can.

Further, in the measuring apparatus according to the present invention, a measuring unit feeding / discharging means for removing the measuring unit set at the standby position from the support and supporting the removed measuring unit again on the support is provided. If so, like the random screening described above,
It is possible to improve the efficiency of the measurement work when the measurement is performed a plurality of times for one sample. That is, in that case, once the measurement is performed on the sample of the measurement unit supported by the support, the measurement units are set to the standby position and removed from the support, and another plurality of measurement units are attached to the support. To perform measurement on the samples of those measurement units, then set the other measurement units to the standby position and remove them from the support, and then re-support the measurement unit that has already measured once. The next measurement is performed on the samples of those measurement units.
The time between a plurality of measurements for one sample can be effectively used to perform the measurement for another sample, and more samples can be measured in a shorter time.

Further, in the measuring apparatus according to the present invention, the support supports a plurality of measuring units arranged in one direction so that the light beams are incident in parallel to each other, and also in the other direction intersecting with the one direction. A plurality of measurement units are arranged so as to support a plurality of measurement units side by side, and the support, the optical system, and the light detection means are relatively moved in the other direction, and a plurality of measurements arranged in the other direction. When the measuring unit feeding means for arranging the units at the positions where the light beams are sequentially incident is provided, the work efficiency of the measurement can be further improved. That is, when such a configuration is adopted, after the light beam is incident in parallel to the plurality of measurement units arranged in the one direction to perform measurement, the support, the optical system, and the light detection unit are By relatively moving in the other direction, it is possible to immediately perform the measurement using a plurality of other measuring units arranged in the one direction, so that the measurement by a large number of measuring units can be performed within an extremely short time. It is possible to complete.

Further, in the measuring apparatus according to the present invention, when the dielectric block and the support are integrally formed, the work of supporting each dielectric block on the support becomes unnecessary. The measurement work efficiency can be further improved.

[0046]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, embodiments of the present invention will be described in detail with reference to the drawings. FIG. 1 is a plan view showing an overall shape of a surface plasmon resonance measuring apparatus according to a first embodiment of the present invention, and FIG. 2 shows a perspective shape of a main part of this apparatus.

As shown in FIGS. 1 and 2, this surface plasmon resonance measuring device is slidable on two guide rods 1, 1 arranged in parallel with each other, as a support for supporting a measuring unit 10 described later. The slide block 2 is engaged with the slide block 2 and is linearly movable along the arrow Y direction (longitudinal direction of the measuring unit connecting body 8 to be described later) in the drawing. A precision screw 3 arranged in parallel with the guide rods 1, 1 is screwed into the slide block 2, and the precision screw 3 is rotated in the forward and reverse directions by a pulse motor 4 which constitutes a support driving means. It has become so.

The drive of the pulse motor 4 is controlled by the motor controller 5. That is, the motor controller 5 receives the output signal S10 of a linear encoder (not shown) which is incorporated in the slide block 2 and detects the position of the slide block 2 in the longitudinal direction of the guide rods 1, 1 to input the motor controller 5 to the motor controller 5. Reference numeral 5 controls the drive of the pulse motor 4 based on this signal S10.

In this embodiment, as an example, a stick-shaped measuring unit connecting body 8 formed by connecting and fixing eight measuring units 10 is used.
Are arranged on the slide block 2 in a state where they are arranged in a line. FIG. 3 shows in detail the structure of the measuring unit linked body 8. As shown here, the measurement unit connected body 8 includes eight measurement units 10,
It is connected by a connecting member 9.

As shown in FIG. 3, the measuring unit 10 includes, for example, a transparent dielectric block 11 whose outer shape is formed in a substantially rectangular parallelepiped shape, and a bottom surface of a hole 11b which is formed by digging down from the upper surface of the dielectric block 11. Gold, for example, formed on
It has a metal film 12 made of silver, copper, aluminum or the like. A portion of the dielectric block 11 around the hole 11b constitutes a sample holding frame 11c for holding the sample on the metal film 12, that is, in the hole 11b. A liquid sample, for example, is stored in the hole 11b as described later.

The dielectric block 11 is formed by injection molding a transparent resin, for example, and the slide block 2
A measuring chip that can be exchanged with respect to is configured. In this example, the sensing substance 14 is fixed on the metal film 12, which will be described later in detail.

Further, as shown in FIG. 4, for example, a plurality (12 in this example) of the measuring unit linked bodies 8 are collectively set on the plate 40, and transported and handled in this state. In other words, with this single plate 40, the measuring units 10 are transported and handled in units of 96 units.

When a plurality of measuring units 10 are collectively treated as the measuring unit connecting body 8 as described above, a dispenser 45 as shown in FIG. 5 is used as a means for supplying a liquid sample to the measuring unit 10. Is desirable. This dispenser 45 is provided with the measuring unit 10 in the measuring unit connecting body 8.
As many dispensing nozzles 46 as these measuring units 10
Since it is supported by the support member 47 at the same pitch as the arrangement pitch of, the liquid sample can be simultaneously dispensed to the plurality of measurement units 10 of one measurement unit connected body 8.
The efficiency of sample supply work can be improved.

Returning to the apparatus of FIGS. 1 and 2, as shown in the side view of FIG. 6, above the guide rods 1 and 1, slide blocks 2 which move along the guide rods 1 are sandwiched from the left and right sides, respectively. Microlens array 6 and eight photodetectors 7a, 7b, 7c, 7d, 7e, 7f, 7g and 7
and h are provided. The microlens array 6 comprises eight measuring units 10 set on the slide block 2.
And eight convex lenses 6a to 6h, which are respectively matched with. On the other hand, the eight photodetectors 7a to 7h are also arranged so as to be aligned with the eight measurement units 10 set on the slide block 2. Each of the photodetectors 7a-h
It is composed of a line sensor in which a large number of light receiving elements are arranged in one row, and the light receiving elements are arranged so that they are arranged in the direction of arrow X in FIG.

Optical fibers 34a-h are respectively provided on the optical axes of the convex lenses 6a-6h of the microlens array 6.
The light beams emitted from them in a divergent light state
30 is incident on each of the convex lenses 6a to 6h. FIG. 7 shows an optical system including the optical fibers 34a to 34h and a light source combined with the optical system. The configuration of FIG. 7 will be described below.

In this example, a semiconductor laser 31 that emits a light beam (laser beam) 30 having a wavelength in the infrared region is used as the light source. A light beam 30 emitted from the semiconductor laser 31 in a divergent state to the front side (right side in the figure)
Is collimated by the collimator lens 32, then condensed by the condenser lens 33 and made incident on the optical fiber 34m. The optical fiber 34m is connected to the optical coupler unit 35. The optical coupler unit 35 is
An optical coupler that splits the input light into two systems with a splitting ratio of 50:50 is provided in three stages.
The light beams 30 input to the optical fiber 34m are divided into eight systems with equal light amounts, and the branched light beams 30 are respectively divided into optical fibers 34a, 34b, 34c, 34d, 34e,
Guided to 34f, 34g and 34h.

The optical passage surface of the optical component arranged on the front side of the semiconductor laser 31 including the end faces of the optical fibers 34a to 34h and 34m is AR (non-reflective) with respect to the oscillation wavelength of the semiconductor laser 31. It has a coat. As a result, it is possible to prevent the problem that the light reflected on those surfaces becomes the return light and is incident on the semiconductor laser 31 to generate noise, or the like.

Further, the element end face of the semiconductor laser 31 is such that both the front end face and the rear end face are LR (low reflection) coated, so that a light beam is emitted from the semiconductor laser 31 to the rear side. To do. The light beam emitted to the rear side in a divergent state, so-called rear emission light 30R is collimated by the collimator lens 36 and then condensed by the condenser lens 37. A mirror 38 is arranged at a position where the backward emitted light 30R is converged by the condenser lens 37, and the backward emitted light 30R is reflected by the mirror 38 and is reflected by the semiconductor laser 31.
Give feedback to.

At this time, the wavelength of the light passing therethrough is selected by the narrow-band bandpass filter 39 inserted between the collimator lens 36 and the condenser lens 37. The backward emission light 30R whose wavelength is selected is fed back. Therefore, the oscillation wavelength of the semiconductor laser 31 is locked to this selected wavelength, and the oscillation wavelength is stabilized.

The sample analysis by the surface plasmon resonance measuring apparatus having the above-mentioned structure will be described below. When analyzing a sample, first, the slide block 2 is set to the first standby position shown by the arrow W1 in FIG. 1, and the unit set portion 2a of this slide block 2 is placed on the plate 40 (see FIG. 4) to
One measuring unit connection 8 is set. The liquid sample 15 (see FIG. 6) to be measured is previously stored in the hole 10b of each measuring unit 10 of the measuring unit linked body 8. The set of the measurement unit connected body 8 is made by the measurement unit feeding / discharging mechanism 70.

The measuring unit feeding / discharging mechanism 70 is movable, for example, in the direction perpendicular to the direction in which the guide rods 1, 1 are arranged, that is, in the direction of arrow H in FIG. 1, and in the vertical direction, that is, in the direction perpendicular to the plane of FIG. In addition, suction cups for sucking and holding the left and right end portions of the measurement unit connecting body 8 are respectively provided at the left and right end portions. This measuring unit 70
Moves to a position above the measuring unit connecting body 8 to be taken out on the plate 40, and then descends, whereupon the measuring unit connecting body 8 is suction-held and rises, and then the slide block 2 in the first standby position is moved. The measuring unit connecting body 8 is moved to a position right above and descends there, and the measuring unit connecting body 8 is incorporated in the unit setting portion 2a of the slide block 2, and then the suction holding is released and the measuring unit connecting body 8 is raised to move the measuring unit connected body 8 to the slide block Set to.

When the measuring unit connecting body 8 is set as described above, the pulse motor 4 is driven by the motor controller 5 and the slide block 2 is set to the measuring position shown by the solid line in FIG. At this time, since the slide block 2 is moved in the longitudinal direction of the measuring unit connecting body 8 to be set at the measurement position, the inclination of the measuring unit connecting body 8 that occurs during the movement can be reduced, which may affect the measurement accuracy. Can be made smaller.

The surface plasmon resonance measurement performed at this measurement position will be described below with reference to FIG. Here, of the eight measurement units 10 of the measurement unit connection body 8, the optical fiber 34a and the photodetector 7 are included.
The description will be given taking one measurement unit 10 in a state of being matched with a as an example, but the measurement is similarly performed in the other measurement units 10.

When performing surface plasmon resonance measurement,
The semiconductor laser 31 shown in FIG. 7 is driven. Therefore, as shown in FIG. 6, the light beam 30 is emitted in a divergent state from the tip of the optical fiber 34a. This light beam 30 is condensed by the convex lens 6a of the microlens array 6,
The light enters the dielectric block 11 in the converged light state and enters the interface 11a between the dielectric block 11 and the metal film 12 in a state including various incident angle components. The range of the incident angle θ is a range including the angle range where the total reflection condition of the light beam 30 is obtained at the interface 11a and the surface plasmon resonance can occur.

The light beam 30 is incident on the interface 11a as p-polarized light. In order to do so, the semiconductor laser 31 is arranged in advance such that its polarization direction is a predetermined direction, and polarization maintaining fibers are used as the optical fibers 34m and 34a to 34h.
The polarization direction of the light beam 30 emitted from a to 34h may be controlled. Alternatively, the light beam may be converted by a wave plate or polarizing plate.
The orientation of the 30 polarizations may be controlled.

The light beam 30 incident on the interface 11a is totally reflected by the interface 11a, and the totally reflected light beam 30 is detected by the photodetector 7.
detected by a. The light beam 30 is at the interface as described above.
Since the light beam is incident on 11a in a state including various incident angle components, the totally reflected light beam 30 also includes components reflected at various reflection angles.

When the light beam 30 is totally reflected in this way,
An evanescent wave seeps out from the interface 11a toward the metal film 12 side. When the light beam 30 is incident on the interface 11a at a specific incident angle θ _SP , the evanescent wave resonates with the surface plasmon excited on the surface of the metal film 12, and therefore the reflected light intensity of this light is increased. I sharply decreases.
This decrease in the reflected light intensity is observed as a dark line D in the totally reflected light beam 30. Note that FIG. 8 schematically shows the relationship between the incident angle θ and the reflected light intensity I when the attenuation phenomenon of total reflection occurs.

Therefore, the amount of light detected for each light receiving element is checked from the light amount detection signal S output from the photodetector 7a, and the above incident angle (total reflection attenuation angle) θ _SP is determined based on the position of the light receiving element that detected the dark line. The specific substance in the sample 15 can be quantitatively analyzed based on the relationship curve of the reflected light intensity I and the incident angle θ that has been obtained and obtained in advance. The signal processing unit 61 quantitatively analyzes the specific substance in the sample 15 based on the above principle, and the analysis result is displayed on the display unit 62.

As shown in FIG. 2, the slide block 2 is composed of a frame-shaped member having an opening 2b penetrating in the left-right direction. Therefore, the light beam 30 is not blocked by the slide block 2 and the measuring unit is set. 10 can be illuminated. Further, the light beam 30 totally reflected at the interface between the dielectric block 11 and the metal film 12 of the measurement unit 10 can be detected by the photodetectors 7a to 7h without being blocked by the slide block 2.

The sensing substance 14 fixed on the surface of the metal film 12 binds to a specific substance in the sample 15. Examples of such a combination of the specific substance and the sensing substance 14 include an antigen and an antibody. In that case, the antigen-antibody reaction can be detected based on the total reflection attenuation angle θ _SP . That is, in this case, depending on the binding state between the specific substance and the sensing substance 14, the sensing substance
Since the refractive index of 14 changes and the characteristic curve of FIG. 8 changes to move to the left and right, the antigen-antibody reaction can be detected according to the attenuated total reflection angle θ _SP . In this case, both the sample 15 and the sensing substance 14 are the samples to be analyzed.

The above measurement operation is performed using the other seven measurement units.
The same is done for 10 in parallel, and 8 measurement units are used.
The measurement of the sample 15 stored in the
Be done. In addition, the light beam 30 for the eight measurement units 10
Irradiation and total reflection attenuation angle θ _SPDetection of each other is strict
Need not be done at the same time, the start or end time
It may be offset from each other.

As described above, according to the present apparatus, the measurement of each sample 15 of the eight measurement units 10 can be performed in parallel with each other, simultaneously or in a state close thereto, so that the measurement of a large number of samples can be performed in a short time. It becomes possible to do.

The signal processing section 61 includes eight photodetectors 7a.
~ H may be provided with a dedicated one, or one shared with eight photodetectors 7a ~ h
It is also possible to provide only a single number and sequentially process the light amount detection signals S output by the photodetectors 7a to 7h.

When the measurement is performed only once for one sample 15, the measurement is completed by the above operation, so the pulse motor 4 is rotated in the opposite direction to the above-mentioned case and the slide block 2 (that is, Is the measuring unit 10) The arrow W in FIG.
It is returned to the first standby position indicated by 1. Then, the measuring unit feeding / discharging mechanism 70 removes the measuring unit connecting body 8 from the slide block 2, which is, for example, a discharging plate.
Discharged over 41.

Next, another measuring unit connecting body 8 on the plate 40 is set on the unit setting portion 2a of the slide block 2 by the measuring unit supplying / discharging mechanism 70 in the same manner as described above, and the measuring unit connecting body 8 of the measuring unit connecting body 8 is moved. The measurement for the sample 15 stored in each measuring unit 10 is also performed in the same manner as described above.

On the other hand, when the measurement is performed a plurality of times on one sample 15, when the above operation is completed, the pulse motor 4 is rotated in the opposite direction to the case described above, and the slide block 2 is moved to the arrow in FIG. It is set to the second standby position indicated by W2. Then, the measuring-unit connecting / disconnecting mechanism 71 formed similarly to the above-described measuring-unit supplying / discharging mechanism 70 removes the measuring-unit connecting body 8 from the slide block 2, and the measuring-unit connecting body 8 is attached to both left and right sides of the guide rods 1, 1. They are placed on either of the placing tables 42, 42 arranged one by one.

Next, the pulse motor 4 is rotated again, and the slide block 2 is returned to the first standby position shown by the arrow W1 in FIG. Then, by the measuring unit feeding / discharging mechanism 70, another measuring unit connecting body 8 on the plate 40 is moved to the unit setting portion 2 of the slide block 2 in the same manner as described above.
The measurement for the sample 15 set in a and stored in the eight measurement units 10 of the measurement unit connection body 8 is
This is also done in the same manner as described above.

When the measurement using the measuring unit 10 of the second measuring unit connected body 8 is completed, the pulse motor 4
Is rotated and the slide block 2 is set to the second standby position. Then, the measuring-unit feeding / discharging mechanism 71 removes the measuring-unit connecting body 8 from the slide block 2, and the measuring-unit connecting body 8 is placed on the vacant table 42.

Next, the measuring unit connecting body 8 placed on another mounting table 42, that is, the first measuring unit connecting body 8 is attached to the unit setting portion 2a of the slide block 2 by the measuring unit feeding / discharging mechanism 71. The measurement of the sample 15 set and stored in the eight measurement units 10 of the measurement unit connection body 8 is performed in the same manner as the previous time.
At this time, if the predetermined time has not elapsed since the first measurement using the first measurement unit connected body 8 is completed, the slide block 2 is set to the measurement position shown by the solid line in FIG. After that, wait for a while for a while, and then start the measurement.

When the second measurement of the first measuring unit assembly 8 is completed, the pulse motor 4 is rotated and the slide block 2 is set to the second standby position. Then, the measurement unit feeding / discharging mechanism 71 removes the first measurement unit connected body 8 from the slide block 2 and mounts it on the empty mounting table 42.

Next, the measuring unit connecting body 8 placed on another mounting table 42, that is, the second measuring unit connecting body 8 is attached to the unit setting portion 2a of the slide block 2 by the measuring unit feeding / discharging mechanism 71. The measurement of the sample 15 set and stored in the eight measurement units 10 of the measurement unit connection body 8 is performed in the same manner as the previous time.

When the second measurement using the second coupling unit 8 of measurement units is completed, the pulse motor 4 is rotated and the slide block 2 is set to the second standby position. Then, the second measurement unit connection body 8 is removed from the slide block 2 by the measurement unit feeding / discharging mechanism 71, and the second measurement unit connection body 8 is placed on the empty mounting table 42.

By repeating the same operation thereafter, the measurement by the first measurement unit connection body 8 and the measurement by the second measurement unit connection body 8 are alternately performed. In this way, the waiting time for the measurement by the one measurement unit connection body 8 can be effectively used, and the measurement by the other measurement unit connection body 8 can be performed during that time, and the efficiency of the measurement work is improved.

When the measurement of the sample 15 held in the measuring unit 10 of one measuring unit connecting body 8 is completed a predetermined number of times, the slide block 2 on which the measuring unit connecting body 8 is set is placed in the first waiting state. Returned to position.
Then, the measuring unit connecting / discharging mechanism 70 removes the measuring unit connecting body 8 from the slide block 2 and discharges it onto the discharging plate 41.

Then, another measuring unit connecting body 8 on the plate 40, that is, the third measuring unit connecting body 8 is set on the unit setting portion 2a of the slide block 2 by the measuring unit feeding / discharging mechanism 70, and the measurement is continued. Sample 15 stored in the measurement unit 10 of the unit connection body 8
Is measured. Repeat for plate 40
It is possible to successively provide the measurement unit connected body 8 housed in 1) for measurement.

As described above, in the present embodiment, the sample holding frame
The dielectric block 11 having 11c, the metal film 12 and the sensing substance 14 are integrated to form the measuring unit 10, and the measuring unit connecting body 8 which is an assembly of the measuring units 10 is used as the measuring chip for the slide block 2. Since it is exchangeable, the measurement unit connected body 8 holding the sample 15 for which the measurement has been completed is removed from the slide block 2 and a new measurement unit connected body 8 is supported on the slide block 2, whereby the new sample 15 is It is possible to perform the measurements one after another, and it becomes possible to perform measurements on a large number of samples 15 in a shorter time.

It is not always necessary to set the slide block 2 to the above-mentioned second standby position so that the measuring unit connecting body 8 set on the slide block 2 can be replaced. But if you do that,
As described above, it can be said that it is particularly preferable because the waiting time for measurement by one measurement unit connection body 8 can be effectively used to perform the measurement by another measurement unit connection body 8 and the efficiency of the measurement work is improved.

In addition, when setting the second standby position as described above, instead of providing the fixed mounting table 42 described above, a turntable that intermittently rotates by a predetermined angle is provided, and the measurement unit is connected thereto. If the turntable is rotated each time the body 8 is discharged, it is possible to temporarily mount a larger number of measurement unit connected bodies 8 during measurement on the turntable. Become.

Further, it is not always necessary to use the slide block 2 or the like to move the measuring-unit connected body 8, that is, the measuring unit 10, between the standby position and the measuring position. That is, if a support that supports a plurality of measurement units 10 is fixed and the measurement unit 10 is set on the support, the measurement unit 10 is ready to be irradiated with a measurement light beam. You may do it. However, in such a case, the support is inevitably arranged in a state of being considerably close to the optical system and the light detection means, so that the setting and removal of the measurement unit 10 with respect to the support are automatically performed. When it is carried out by means, it is necessary to adopt, as the automatic means, one having a structure capable of surely avoiding interference with the optical system and the light detecting means.

Also when moving the support, the way of moving is not limited to the linear movement in the above-described embodiment, and a turntable that intermittently rotates by a predetermined angle is used as the support, and the rotation is performed. A plurality of measuring units may be supported on the circumference around the moving shaft, and the turntable may be rotated to move the measuring units along the circumference. When doing so, for example, 16 measurement units are supported on the turntable, and half of them, 8 measurement units are simultaneously irradiated with a light beam, and when the measurement for them is completed, the turntable is rotated 180 °. It is possible to employ a configuration in which the remaining eight measurement units are moved and the light beams are simultaneously emitted.

Further, the measuring unit connecting body 8 described above is used.
Instead of, it is also possible to use a connecting unit of measuring units as shown in FIG. 9 or 10. The measurement unit connection body 80 shown in FIG. 9 is made of, for example, the same material as the dielectric block 11 shown in FIG.
Is formed, a plurality of bottomed holes 82 are formed therein, the portion of the bar 81 around the bottomed holes 82 is used as a sample holding portion, and the holes are formed.
The metal film 12 and the sensing substance 14 are formed on the bottom surface of 82. That is, this measuring unit connection body 80
In, a measurement unit is configured for each hole 82.

Measuring unit connection body 80 having the above-mentioned configuration
Is easier to manufacture and realizes cost reduction compared to a structure in which one measurement unit 10 is formed one by one like the measurement unit connection body 8 shown in FIG. it can.

On the other hand, the measuring unit connecting body 90 shown in FIG.
The measurement unit 95 is fitted and supported in a plurality of unit support holes 92 formed in the unit support plate 91. The measuring unit 95 is basically the same as the measuring unit 10 shown in FIG. 3, but has an outer shape in which a part of a quadrangular pyramid is cut out and is fitted into the tapered unit supporting hole 92. It does not pass through the unit support hole 92.

In the case of applying such a measuring unit linked body 90, a plurality of measuring units 95 are respectively supported by one unit supporting plate 91 in advance, and a plurality of such unit supporting plates 91, for example, FIG. The plate 40 may be set and handled. Alternatively, one unit support plate 91 is fixed to, for example, the slide block 2 of the apparatus shown in FIG. 2, and a plurality of measurement units are attached to the unit support plate 91.
Alternatively, the measuring units 95 may be supplied one by one, and when the measurement is completed, the measuring units 95 may be removed from the unit supporting plate 91 and a plurality of new measuring units 95 may be supplied to the unit supporting plate 91.

Compared to the above-mentioned measuring unit connecting body 90, in the measuring unit connecting body 8 of FIG. 3 and the measuring unit connected body 80 of FIG. 9, a plurality of measuring units are fixed inseparably from each other. Positional accuracy on the surface plasmon resonance measuring device is easy to obtain, and since it is not necessary to hold a small measuring unit, the handling property is excellent, and the efficiency of the measurement process can be improved.

Next, a second embodiment of the present invention will be described with reference to FIG. FIG. 11 shows a side surface shape of an essential part of the surface plasmon resonance measuring apparatus according to the second embodiment. In FIG. 11, elements that are the same as the elements in FIG. 6 are given the same numbers, and descriptions thereof will be omitted unless otherwise necessary (the same applies below).

This surface plasmon resonance measuring apparatus is shown in FIG.
The configuration of the measurement unit is different from that shown in FIG. That is, the measuring unit 10 'used here is in a form in which the sensing substance 14 is removed from the measuring unit 10 shown in FIG. The other configuration is basically the same as that of the surface plasmon resonance measuring apparatus shown in FIG.

Even when the above-described measuring unit 10 'is used, the above-mentioned total reflection attenuation angle θ _SP changes according to the dielectric constant of the sample 15 in contact with the metal film 12, that is, the refractive index, so that the detected total reflection is detected. The specific substance in the sample 15 can be quantitatively analyzed based on the attenuation angle θ _SP .

Also in the surface plasmon resonance measuring apparatus according to the present embodiment, a plurality of measuring units 10 'are supported on the slide block 2 and the measuring units 10' are irradiated with the light beam 30 all at once, and the measuring units 10 'are measured. Since the measurement is performed in parallel with each other, the surface plasmon resonance measuring apparatus can measure a large number of samples 15 in a short time.

Next, a third embodiment of the present invention will be described. FIG. 12 shows a side surface shape of a main part of the measuring device according to the third embodiment of the present invention. The measuring device of the present embodiment is the leak mode sensor described above, and the measuring unit 11 is also a measurement chip in this example.
It is configured to use 0. This measuring unit 110
The cladding layer 111 is formed on one surface (bottom surface of the hole 11b) of the dielectric block 11 constituting the above, and the optical waveguide layer 112 is further formed thereon.

The dielectric block 11 is made of synthetic resin or B, for example.
It is formed using an optical glass such as K7. On the other hand, the clad layer 111 is formed into a thin film using a dielectric material having a lower refractive index than the dielectric block 11 or a metal such as gold. The optical waveguide layer 112 is also formed in a thin film shape by using a dielectric material having a higher refractive index than the cladding layer 111, for example, PMMA. The thickness of the clad layer 111 is 36.5 nm when formed from a gold thin film, and the thickness of the optical waveguide layer 112 is PM, for example.
When formed from MA, it is about 700 nm.

In the leaky mode sensor having the above structure,
When the light beam 30 in the convergent light state is made incident on the cladding layer 111 through the dielectric block 11 at an incident angle of not less than the total reflection angle, the light beam 30 is made into the dielectric block 11 and the cladding layer 11.
Light having a specific wave number, which is totally reflected at the interface 11a with 1 but is transmitted through the cladding layer 111 and is incident on the optical waveguide layer 112 at a specific incident angle, propagates through the optical waveguide layer 112 in a guided mode. . When the waveguide mode is excited in this way, most of the incident light is taken into the optical waveguide layer 112, so that the interface 11a
At this point, the total reflection attenuation occurs in which the intensity of the totally reflected light sharply decreases.

Since the wave number of guided light in the optical waveguide layer 112 depends on the refractive index of the sample 15 on the optical waveguide layer 112, by knowing the specific incident angle at which attenuation of total reflection occurs,
The refractive index of the sample 15 and the characteristics of the sample 15 related thereto can be analyzed. The signal processing unit 61 quantitatively analyzes the specific substance in the sample 15 based on the above principle, and the analysis result is displayed on the display unit 62.

Also in the leak mode sensor of this embodiment, a plurality of measuring units 110 are supported on the slide block 2, the measuring unit 110 is irradiated with the light beam 30 all at once, and the measuring units 110 perform measurement. Since the leak mode sensors are configured so that they can be performed in parallel, it is possible to measure a large number of samples 15 in a short time.

Next, a fourth embodiment of the present invention will be described. FIG. 13 shows a fourth embodiment of the present invention.
It is a side view of the main part of the measuring device. The measuring device according to the present embodiment is also a leaky mode sensor, and is configured to use a measuring unit 110 ′ that is a measurement chip. The measurement unit 110 ′ is different from the measurement unit 110 shown in FIG. 12 only in that the sensing substance 14 is fixed on the optical waveguide layer 112.

The sensing substance 14 is the measuring unit of FIG.
Like the sensing substance 14 in 10, it binds to a specific substance in the sample 15. Examples of such a combination of the specific substance and the sensing substance 14 also include an antigen and an antibody in this example. In that case, the antigen-antibody reaction can be detected based on the total reflection attenuation angle θ _SP .

That is, also in this case, the interface 11a of the light beam 30
The relationship between the incident angle θ and the reflected light intensity I is basically the same as that in FIG. 8, but the refractive index of the sensing substance 14 changes depending on the binding state between the specific substance and the sensing substance 14. Since the effective refractive index of the optical waveguide layer 112 changes and this relationship changes accordingly, the antigen-antibody reaction can be detected according to the attenuated total reflection angle θ _SP .

Next explained is the fifth embodiment of the invention. 14 and 15 show a plane shape and a side surface shape of the surface plasmon resonance measuring apparatus according to the fifth embodiment of the present invention, respectively. In the present embodiment, a pallet 200 having a plurality of wells (reservoir) 201 holding the sample 15 is used. This pallet 200 constitutes a dielectric block and a sample holding mechanism of the measurement unit, and also serves as a support for supporting the measurement unit.

That is, as shown in the enlarged view of FIG. 16, this pallet 200 is formed of the same material as the transparent dielectric block 11 of FIG. 6, and is on the bottom surface of the well 201 formed by cutting out a part of the cone. In addition, the same metal film 12 and sensing substance 14 as those shown in FIG. 6 are also fixed in this order. In addition, a dielectric block portion 202 protruding downward from each of the wells 201 is formed.
The measurement light beam 30 is made incident on the interface between 02 and the metal film 12. The well 201 is shown in FIG.
As shown in FIG. 4, a plurality of them are formed side by side in the horizontal direction (arrow P direction) and in the vertical direction (arrow Q direction).

The pallet 200 is the measuring unit feed table 2
Set in place above 10. The measuring unit feed base 210 is placed on a pair of rails 211, 211 arranged in a state of extending in the direction of the arrow P, and the driving means installed therein.
It is possible to move along these rails 211 and 211 by 212. In the present embodiment, the measurement unit feed base 210, the rail 211, and the driving means 212 constitute the measurement unit feed means.

The light beams 30 are incident in parallel on the bottom surfaces of a plurality (five in this example) of wells 201 arranged in the direction of arrow P in the pallet 200. That is, the light beam 30 emitted from one laser light source 220 in a divergent light state is collimated by the collimator lens 221, and then converted into a parallel light beam by the half mirrors 222, 223, 224 and 225 and the mirror 226.
The five branched light beams 30 are incident on the bottom surface of the well 201, that is, the interface between the dielectric block portion 202 and the metal film 12.

At this time, the branched light beams 30 are respectively separated by the cylindrical beam expanders 231, 232, 23.
The diameter is enlarged only in the plane shown in FIG. 15 by 3, 234 and 235, and mirrors 241, 242, 243, 244 and
After being reflected by 245 to change the traveling direction, the cylindrical lenses 251, 252, 253, 254, and 255 are used to change the traveling direction, respectively, as shown in FIG.
The light is collected only in the plane indicated by 5. As a result, each light beam 30 enters the interface between the dielectric block portion 202 and the metal film 12 with various incident angle components. The laser light source 220 uses a linearly polarized light beam 3
It is arranged in such a direction that 0 enters the interface in the p-polarized state.

Each of the light beams 30 totally reflected at the interface is detected by five photodetectors 7a to 7e similar to the photodetectors 7a to 7h in the first embodiment shown in FIG. . The outputs of the photodetectors 7a to 7e are processed in the same manner as in the first embodiment, and the specific substance in the sample 15 is quantitatively analyzed.

In the present embodiment, as described above, the measurement of the sample 15 stored in the five wells 201 can be performed in parallel. Then, when these measurements are completed, the driving of the laser light source 220 is once stopped, and then the driving means 212 is actuated so that the measuring unit feed base 210 (that is, the pallet 200) is indicated by an arrow in FIGS. It is sent by the arrangement pitch of the wells 201 in the Q direction. In that state, the laser light source 220 is driven again,
As a result, measurement is performed on five new samples 15. As described above, in the present embodiment, it is possible to perform measurement on a large number of samples with extremely high efficiency within a short time.

Although only one laser light source 220 is used as a light source in this embodiment, for example, two light sources are provided, and a light beam from one light source is branched into two light beams from another light source. The light beam may be branched into three to obtain a total of five light beams.

Next, a sixth embodiment of the present invention will be described. 17 and 18 show a plane shape and a side surface shape of a surface plasmon resonance measuring apparatus according to a sixth embodiment of the present invention, respectively. In the present embodiment, the same pallet 200 as that used in the fifth embodiment is used. Then, the measuring unit feed table 2 for feeding the pallet 200 by the arrangement pitch of the wells 201
The point that the 10, rails 211 and drive means 212 are provided is also the same as in the fifth embodiment.

In the pallet 200, one flattened light beam 30F is simultaneously incident on the bottom surfaces of a plurality (five in this example) of wells 201 arranged in the direction of arrow P. That is, the diameter of the light beam 30 emitted from one laser light source 220 in a divergent state is expanded only by the cylindrical beam expander 300 within the plane shown in FIG.
It is flattened to a size such that it can be simultaneously incident on the bottom surface of each well 201.

Then, the flattened light beam 30F is
Then, using the cylindrical beam expander 301,
The diameter is enlarged only in the plane shown in 8, and the large mirror 30
After being reflected by 2 and changing the traveling direction, it is condensed by the cylindrical lens 303 only within the plane shown in FIG.
Accordingly, the light beam 30F is incident on the interface between the metal film 12 in the five wells 201 and the dielectric block portion 202 with various incident angle components. Laser light source
220 is arranged so that the linearly polarized light beam 30F enters the interface in the p-polarized state.

The light beam 30F totally reflected at the interface is 2
It is detected by a photodetector 305 having, for example, a CCD element having a dimensional photodetection surface. On the front side of this photodetector 305, as shown in the front view of FIG.
Mask 3 with 0a, 310b, 310c, 310d and 310e
04 is installed. Therefore, the totally reflected light beam 30F
Of the five wells 201, the components reflected at the interfaces are different from the light passing openings 310a, 310b, 310c, 3 which are different from each other.
After passing through 10d and 310e, it is detected in five different unique regions of the photodetection surface of the photodetector 305.
The outputs of these five unique regions are independently processed in the same manner as in the first embodiment shown in FIG. 6, and the specific substance in the sample 15 is quantitatively analyzed.

Also in the present embodiment, as described above, the measurement of the sample 15 stored in the five wells 201 can be performed in parallel. When the measurement is completed, the pallet 20 is used as in the fifth embodiment.
0 is sent by the arrangement pitch of the wells 201, and measurement is performed on five new samples 15. As described above, also in the present embodiment, it is possible to perform measurement on a large number of samples with extremely high efficiency in a short time.

Although only one laser light source 220 is used as a light source in this embodiment, for example, two light sources are provided, and the width of a light beam from one light source can be incident on the bottom surfaces of the two wells 201. Alternatively, the light beams from the other light sources may be flattened to such a width that they can be incident on the bottom surfaces of the three wells 201.

Next, a seventh embodiment of the present invention will be described. FIG. 20 is a plan view showing the overall shape of the surface plasmon resonance measuring apparatus according to this embodiment. The surface plasmon resonance measuring apparatus according to the present embodiment is different from the surface plasmon resonance measuring apparatus according to the first embodiment described above in that a storage means is provided at a second standby position.

For a while after the sample 15 is dispensed to the measurement unit 10, a drift occurs in the signal detected by the measurement device.
The main cause of this detection signal drift is the dispensed sample 15
This is because it takes time for the measurement unit 10 to adapt to the measurement unit 10, and during that time, temperature fluctuations or the like occur in the measurement unit 10. In the present embodiment, after dispensing the sample 15 into the measurement unit 10, the sample 15 is stored under predetermined temperature control until the transient response time elapses,
The measurement unit connecting body 8 including the measurement unit 10 during the transient response time is prevented from occupying the measurement position.

A temperature-adjustable incubator 44 (storage means) is provided at the second standby position.
A mounting table 43 is provided inside.

Further, in order to detect whether the measurement unit 10 stored in the incubator 44 is in a transient response state, the surface plasmon resonance measuring section 55 (state detection) is provided in the incubator 44 as shown in FIG. Means) is provided.

This surface plasmon resonance measuring section 55 is composed of a semiconductor laser 56, a microlens 57 and a photodetector 58, and like the measuring section of the surface plasmon resonance measuring apparatus as described in the first embodiment, The physical properties of the sample 15 are analyzed by using surface plasmon resonance. In addition, normally, eight measurement units of the measurement unit connection body 8
Since the sample 15 is simultaneously dispensed to 10, the surface plasmon resonance measurement unit 55 is required to measure at least one measurement unit 10 for each measurement unit connected body 8 mounted on the mounting table 43. Of course, in order to do so, the surface plasmon resonance measuring section 55 may be provided by the number of the measurement unit connected bodies 8 mounted on the mounting table 43, or the surface plasmon resonance measuring section 55 can be moved to perform each measurement. The measurement may be performed for each unit connection body 8.

Further, a lid 16 may be provided on the upper surface of the measuring unit 10 in order to prevent the sample 15 from evaporating during storage.

In this embodiment, the measuring unit 10
The sample 15 is stored in the incubator 44 from the time it is dispensed until the transient response time elapses, and after the surface plasmon resonance measurement unit 55 confirms that the transient response time of the sample 15 has elapsed, it moves to the measurement position. Therefore, it is not necessary to wait the transient response time of the sample 15 at the measurement unit connected body 8 at the measurement position, so that it is possible to perform measurement on a large number of samples extremely efficiently and accurately.

In the present embodiment, the state detecting means for detecting the transient response state of the sample 15 is not limited to the above, and for example, a temperature sensor may be used to detect the temperature fluctuation of the sample 15. You may

Next, an eighth embodiment of the present invention will be described. FIG. 22 is a plan view showing the overall shape of the surface plasmon resonance measuring apparatus according to this embodiment. The surface plasmon resonance measuring apparatus according to the present embodiment is different from the surface plasmon resonance measuring apparatus according to the first embodiment described above in that a timing indicating means is provided in the photodetector.

The photodetectors 51a, 51b, 51 of the present embodiment.
c, 51d, 51e, 51f, 51g and 51h are connected to the timing instructing means 50.
The detection operation is performed in synchronization with the timing instruction signal output from 50.

The timing instruction signal may be a clock signal or a pulse signal output only during the detecting operation.

With such a structure, it is possible to simultaneously perform the measurement for the sample 15 stored in the eight measurement units 10 of the measurement unit connected body 8.
Data with high temporal correlation can be obtained among the measurement units 10. Therefore, the accuracy can be increased when comparing or correcting the data between the measurement units 10 of the measurement unit connected body 8.

Next, a ninth embodiment of the present invention will be described. FIG. 23 is a plan view showing the overall shape of the surface plasmon resonance measuring apparatus according to this embodiment. The surface plasmon resonance measuring apparatus according to the present embodiment is different from the surface plasmon resonance measuring apparatus according to the first embodiment described above in that two measuring systems are provided.

The surface plasmon resonance measuring apparatus according to the present embodiment includes guide rods 1, 1, a slide block 2, a precision screw 3, a pulse motor 4, and a photodetector 7 (7a to 7 in FIG. 1).
h), an optical fiber 34 (34a to 34h in FIG. 1), an optical coupler unit 35, a semiconductor laser 31 (not shown), and an optical system for making a light beam emitted from the semiconductor laser 31 incident on the optical coupler unit 35 (the second set is a component. "´" in the number
2), and two sets of measurement systems a and b are configured. In addition, the measuring unit feeding / discharging mechanisms 72 and 73 are the slide blocks 2 and 2
Both are accessible.

In the surface plasmon resonance measuring apparatus according to this embodiment, the same measurement may be performed by two measurement systems, or different measurement may be performed by two measurement systems as described below. Good.

When different measurement is performed by the two measurement systems a and b, for example, the measurement unit 10 is used in the measurement system a.
The measurement unit 10 in which the amount of the sensing substance 14 fixed on the metal film 12 is measured without dispensing the sample 15 to the sample 15 and the fixed amount of the sensing substance 14 is previously measured by the measuring system b in the measuring system b.
The sample 15 is dispensed into the container, the reaction between the sensing substance 14 and the sample 15 is measured, and the result obtained by the measuring system b is corrected by the result obtained by the measuring system a, thereby It becomes possible to measure the sample reaction amount of.

When performing such a measurement, first, the measurement system a measures the first measurement unit connection body 8 and then the measurement system a measures the second measurement unit connection body 8. At the same time, in the measurement system b, the measurement of the first measurement unit linked body 8 is performed, whereby the measurement can be performed efficiently.

Also in this embodiment, as described above,
Since the measurement can be performed simultaneously by the system measurement systems a and b, it is possible to perform measurement on a large number of samples in an extremely efficient manner within a short time.

Next explained is the tenth embodiment of the invention. The overall shape of the surface plasmon resonance measuring apparatus according to the present embodiment is the same as that of the surface plasmon resonance measuring apparatus shown in the first embodiment shown in FIG. The surface plasmon resonance measuring apparatus according to the present embodiment is different from the surface plasmon resonance measuring apparatus according to the first embodiment in that the method of sample analysis is changed.

As shown in the side view of FIG. 24, at the measurement position of the surface plasmon resonance measuring apparatus of the present embodiment, the optical fibers 34a-h and the CCDs 360a-h are sandwiched between the optical fibers 34a-h and the CCDs 360a-h. The collimator lenses 350a to 350h, the interference optical system, and the optical fibers 34a to h and the CCDs 360a to h are provided.
Condensing lenses 355a-h and apertures 356a-h are provided.

The interference optical system includes the polarization filters 351a to 351a.
h, half mirrors 352a-h, half mirrors 353a-h, and mirrors 354a-h.

Further, the CCDs 360a-h are the signal processing units 361.
The signal processing unit 361 is connected to the display unit 62.

The measurement of the sample by the surface plasmon resonance measuring apparatus of this embodiment will be described below. In this case, the optical fiber 34a and the CCD 360 among the eight measuring units 10 of the measuring unit connecting body 8 shown in FIG.
The description will be given taking one measurement unit 10 in a state of being matched with a as an example, but the measurement is similarly performed in the other measurement units 10.

As described in the first embodiment, the semiconductor laser 31 is driven to drive the optical beam from the tip of the optical fiber 34a.
330 is emitted in the state of divergent light. The light beam 330 is collimated by the collimator lens 350a and enters the polarization filter 351a. Interface through the polarizing filter 351a
Light beam 33 adapted to be incident as p-polarized light on 11a 33
In the case of 0, a part is split as a reference light beam 330R by the half mirror 352a, and the remaining light beam 330S transmitted through the half mirror 352a enters the interface 11a. Interface 11
The light beam 330S totally reflected by a and the reference light beam 330R reflected by the mirror 354a enter the half mirror 353a and are combined. The combined light beam 330 'is condensed by the condenser lens 355a, passes through the aperture 356a, and is detected by the CCD 360a. At this time, CC
The light beam 330 'detected by D360a is the light beam 330S.
Interference fringes are generated according to the state of interference between the reference light beam 330R and the reference light beam 330R.

Here, the sensing substance 14 fixed to the surface of the metal film 12 binds to a specific substance in the sample 15. Examples of such a combination of the specific substance and the sensing substance 14 include an antigen and an antibody. In that case, measure continuously after dispensing 15 samples and use CCD36
The presence or absence of an antigen-antibody reaction can be detected by detecting the change in the interference fringes detected by 0a. That is, in this case, when the refractive index of the sensing substance 14 changes according to the binding state between the specific substance and the sensing substance 14, the light beam 330S and the reference light beam 330R totally reflected at the interface 11a are combined by the half mirror 353a. When the interference occurs, the state of interference changes, so that the antigen-antibody reaction can be detected according to the change in the interference fringe. In this case, both the sample 15 and the sensing substance 14
It becomes the sample to be analyzed.

The signal processing section 361 detects the presence or absence of the above reaction based on the above principle, and the result is displayed on the display section 62.

The above measurement operation is performed using seven other measurement units.
The same is done for 10 in parallel, and the measurements for the samples 15 stored in the eight measurement units 10 are performed at the same time. In addition, the light beam 33 for the eight measurement units 10
The irradiation of 0 and the detection of the presence or absence of the reaction do not have to be performed at exactly the same time, and the start or end times may be slightly different from each other.

As described above, according to the present apparatus, the measurement of each sample 15 of the eight measurement units 10 can be performed in parallel with each other, simultaneously or in a state close thereto, so that the measurement of a large number of samples can be performed in a short time. It becomes possible to do.

The signal processing unit 361 includes eight CCDs 360a.
~ H may be provided with a dedicated one, or one shared with eight CCDs 360a ~ h
It is also possible to provide only one and sequentially process the light amount detection signals S output from the CCDs 360a to h.

[Brief description of drawings]

FIG. 1 is an overall plan view of a surface plasmon resonance measuring apparatus according to a first embodiment of the present invention.

FIG. 2 is a partially cutaway perspective view showing a main part of the surface plasmon resonance measuring apparatus of FIG.

FIG. 3 is a perspective view showing a measuring unit connected body used in the surface plasmon resonance measuring apparatus of FIG. 1.

4 is a plan view showing a means for accommodating the measuring unit assembly of FIG. 3; FIG.

FIG. 5 is a front view showing a means for supplying a sample to the connected measuring unit in FIG.

6 is a side view showing a main part of the surface plasmon resonance measuring apparatus of FIG.

7 is a plan view showing an optical system of the surface plasmon resonance measuring apparatus of FIG.

FIG. 8 is a graph showing a schematic relationship between a light beam incident angle and a light intensity detected by a photodetector in the surface plasmon resonance measuring apparatus.

FIG. 9 is a perspective view showing another example of the connected measuring unit used in the measuring apparatus of the present invention.

FIG. 10 is a perspective view showing still another example of the connected measuring unit used in the measuring apparatus of the present invention.

FIG. 11 is a side view showing a main part of a surface plasmon resonance measuring apparatus according to a second embodiment of the present invention.

FIG. 12 is a side view showing a main part of a leaky mode sensor according to a third embodiment of the present invention.

FIG. 13 is a side view showing a main part of a leaky mode sensor according to a fourth embodiment of the present invention.

FIG. 14 is a plan view of a surface plasmon resonance measuring apparatus according to a fifth embodiment of the present invention.

15 is a partially cutaway side view of the surface plasmon resonance measuring apparatus of FIG.

16 is an enlarged side sectional view showing a part of the surface plasmon resonance measuring apparatus of FIG.

FIG. 17 is a plan view of a surface plasmon resonance measuring apparatus according to a sixth embodiment of the present invention.

18 is a partially cutaway side view of the surface plasmon resonance measuring apparatus of FIG.

19 is an enlarged plan view showing a part of the surface plasmon resonance measuring apparatus of FIG.

FIG. 20 is an overall plan view of a surface plasmon resonance measuring apparatus according to a seventh embodiment of the present invention.

21 is a configuration diagram of storage means of the surface plasmon resonance measurement apparatus of FIG.

FIG. 22 is an overall plan view of a surface plasmon resonance measuring apparatus according to an eighth embodiment of the present invention.

FIG. 23 is an overall plan view of a surface plasmon resonance measuring apparatus according to a ninth embodiment of the present invention.

FIG. 24 is a side view showing essential parts of a surface plasmon resonance measuring apparatus according to a tenth embodiment of the present invention.

[Explanation of symbols]

1 guide rod 2 slide block 3 precision screw 4 pulse motor 5 motor controller 6 microlens array 7a to h photodetector 8 measuring unit connecting body 9 connecting member 10, 10 'measuring unit 11 dielectric block 11a dielectric block and thin film layer Interface 12 Metal film 14 Sensing substance 30 Light beam 30F Flattened light beam 31 Semiconductor laser 32 Collimator lens 33 Condenser lenses 34a-h, 34m Optical fiber 35 Optical coupler unit 36 Collimator lens 37 Condenser lens 38 Mirror 40 plate 41 discharge plate 42 mounting table 43 mounting table 44 incubator 45 dispenser 46 dispensing nozzle 47 support member 50 timing indicating means 51a to h photodetector 55 surface plasmon resonance measuring section 61 signal processing section 62 display section 70, 71, 72, 73 Measuring unit feeding / discharging mechanism 80, 90 Measuring unit connecting body 81 Dielectric bar 91 Unit supporting plate 92 Unit Knit support hole 95 Measuring unit 110 110 'Measuring unit 111 Clad layer 112 Optical waveguide layer 200 Pallet 201 Well 202 Pallet dielectric block 210 Measuring unit Sending base 211 Rail 212 Driving means 220 Laser light source 221 Collimator lens 222, 223, 224, 225 Half mirror 226 Mirror 231, 232, 233, 234, 235 Cylindrical beam expander 241, 242, 243, 244, 245 Mirror 251, 252, 253, 254, 255 Cylindrical lens 300, 301 Cylindrical beam expander 302 Mirror 303 Cylindrical lens 304 Mask 305 Photodetector 330 Light beam 350a-h Collimator lens 351a-h Polarizing filter 352a-h Half mirror 353a-h Half mirror 354a-h Mirror 355a-h Condenser lens 356a-h Aperture 361 Signal processing unit

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Hitoshi Shimizu             798 Miyadai, Kaisei-cho, Ashigarakami-gun, Kanagawa Prefecture             Shishi Film Co., Ltd. (72) Inventor Norifumi Mori             798 Miyadai, Kaisei-cho, Ashigarakami-gun, Kanagawa Prefecture             Shishi Film Co., Ltd. F-term (reference) 2G057 AA02 AB04 AB07 AC01 BA01                       BB06 HA02 HA04                 2G058 AA08 CC01 CC14 CD11 ED18                       GA01                 2G059 AA01 BB04 BB12 CC16 DD12                       DD13 DD16 EE02 EE05 EE09                       FF08 FF09 FF11 GG01 GG04                       HH01 JJ02 JJ11 JJ13 JJ17                       JJ19 JJ22 KK01 KK03 KK04                       LL04 PP04

Claims (13)

[Claims] 1. A plurality of measuring units each comprising a dielectric block, a thin film layer formed on one surface of the dielectric block, and a sample holding mechanism for holding a sample on the surface of the thin film layer, and a plurality of these measuring units. A support that supports the measurement unit, a light source that generates a light beam, and the light beam with respect to the dielectric block at an angle of incidence at which total reflection conditions are obtained at the interface between the dielectric block and the thin film layer. A measuring apparatus comprising: an incident optical system for making incident light; and a light detecting means for measuring the intensity of a light beam totally reflected at the interface, wherein the optical system comprises at least two measuring units supported by the support. The light beams are configured to be incident on the dielectric blocks in parallel, and the photodetector means corresponds to each of the light beams incident on the dielectric block. Let me give you a total of at least 2
Measuring device characterized by being provided. 2. A dielectric block, a thin film layer formed on one surface of the dielectric block, a sensing substance disposed on the surface of the thin film layer to interact with a specific component in a sample, and a sensing substance of the sensing substance. A plurality of measurement units provided with a sample holding mechanism for holding a sample on the surface, a support that supports the plurality of measurement units, a light source that generates a light beam, and the light beam to the dielectric block. And an incident optical system that makes an incident angle at which the total reflection condition is obtained at the interface between the dielectric block and the thin film layer, and a light detection unit that measures the intensity of the light beam totally reflected at the interface. In the measuring apparatus, the optical system may cause the optical beam to enter the dielectric blocks of the at least two measuring units supported by the support body in parallel. Made, said light detecting means, said dielectric least 2 in total to correspond one by one each of the light beams incident on the block
Measuring device characterized by being provided. 3. The optical system is configured to make the light beam incident on the dielectric blocks of all the measurement units supported by the support body in parallel. 1. The measuring device according to 1 or 2. 4. The optical system splits a single light beam emitted from each of the one or a plurality of light sources provided therein into a plurality of beams, and the branched light beams are respectively incident on the dielectric block. The measuring device according to any one of claims 1 to 3, wherein the measuring device is configured to operate. 5. The optical system flattens the light beams emitted from each of the one or more light sources, and makes the flattened light beams incident on a plurality of the dielectric blocks. The measuring device according to claim 1, wherein the measuring device is configured. 6. The relative position of the support, the optical system, and the light detection means is moved so that each of the measurement units has either a measurement position at which the light beam is incident on its dielectric block or a standby position at which the light beam is not incident. 6. A driving means selectively arranged on the display device according to any one of claims 1 to 5,
The measuring device according to the item. 7. The support body linearly arranges the plurality of measurement units in a line and supports the plurality of measurement units, and the driving unit includes the support body, the optical system, and the light detection unit. The measuring apparatus according to claim 6, wherein the measuring unit is linearly moved relative to the arrangement direction of the measuring units. 8. The support body supports the plurality of measurement units arranged side by side on a circumference, and the driving unit includes the support body, the optical system, and the light detection unit. 7. The measuring device according to claim 6, wherein the measuring device is relatively moved along the circumference in the arranging direction. 9. The measuring unit feeding / discharging means for removing the measuring unit set to the standby position from the supporting body and supporting the detached measuring unit again on the supporting body. Item 9. A measuring device according to any one of items 6 to 8. 10. The support supports a plurality of measurement units arranged side by side in one direction so that the light beams are incident in parallel to each other, and also supports a plurality of measurement units in another direction intersecting with the one direction. After being configured to support side by side, the support, the optical system, and the light detection means are relatively moved in the other direction, and a plurality of measurement units arranged in the other direction are sequentially moved to the light. 10. The measuring device according to claim 1, further comprising a measuring unit feeding means arranged at a position where the beam is incident. 11. The measuring device according to claim 1, wherein the dielectric block and the support are integrally formed. 12. The measuring device according to claim 6, further comprising storage means for storing the measurement unit under temperature control at the standby position. 13. The measuring apparatus according to claim 6, further comprising a state detecting unit that detects a state of the measuring unit at the standby position.