JP2002277390A - Measuring chip - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make positional precision and handlability excellent, in a measuring chip used for a measuring instrument such as a surface plasmon resonance measuring instrument using total reflectance attenuation. SOLUTION: Measuring units 10 of which each comprises a dielectric block 11 and a thin film layer 12 formed in one face of the block 11 to contact with a sample are plurally arrayed integratedly in one line to constitute a measuring unit-coupled body 8.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a measurement chip used for a surface plasmon resonance measuring device for quantitatively analyzing a substance in a sample by utilizing the generation of surface plasmon.

[0002]

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

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

A surface plasmon resonance measuring apparatus using the above-mentioned system basically includes, 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, A light source for generating a beam, and the light beam is applied to a dielectric block so that various incident angles including a surface plasmon resonance condition can be obtained under a condition of total reflection at an interface between the dielectric block and the metal film. And an optical detection means for measuring the intensity of the light beam totally reflected at the interface to detect the state of surface plasmon resonance.

In order to obtain various angles of incidence as described above, a relatively narrow light beam may be deflected and 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 made to enter the interface in a state of convergent light or divergent light. In the former case, the light beam whose reflection angle changes with the deflection of the light beam is 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 the change in the reflection angle. Can be detected. On the other hand, the latter case can be detected by an area sensor extending in a direction in which all light beams reflected at various reflection angles can be received.

[0006] In the surface plasmon resonance measurement device with the above structure, has when a light beam impinges the total reflection angle or more specific angle of incidence theta _SP the metal film, the electric field distribution in the sample in contact with the metal film An evanescent wave is generated, and surface plasmon is excited at the interface between the metal film and the sample by the evanescent wave. When the wave number 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 light is transferred to the surface plasmon. The intensity of the reflected light drops sharply. This decrease in light intensity is generally detected as a dark line by the light detection means.

[0007] The above resonance occurs only when the incident beam is p-polarized. Therefore, it is necessary to set in advance so 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 the attenuated total reflection (ATR) occurs, the dielectric constant of the sample is obtained. That is, the wave number of the surface plasmon is K
_{When SP} and the angular frequency of the surface plasmon are ω, c is the speed of light in vacuum, ε _m and ε _s are the metal and the dielectric constant of the sample, respectively, there is the following relationship.

[0009]

(Equation 1) If the dielectric constant ε _s of the sample is known, the concentration of the specific substance in the sample can be determined based on a predetermined calibration curve or the like, so that by knowing the incident angle θ _{SP at} which the reflected light intensity decreases, the A specific substance can be quantitatively analyzed.

In a conventional surface plasmon resonance measuring apparatus using the above system, it is practically necessary to change a metal film to be brought into contact with a sample every measurement. Therefore, conventionally, it has been considered that a single measurement unit is formed as a chip by fixing the metal film to a dielectric block, and this measurement unit is disposable for each sample (for example, Japanese Patent Application No. 2000-210). 016633).

Further, as a similar measuring device utilizing the attenuated total reflection (ATR), for example, "Spectroscopy", Vol. 47, No. 1 (1998), pp. 21-23 and 26-27.
A leak mode sensor described on the page is also known. This leak mode sensor is basically formed of, 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 entering the dielectric block at various angles so as to obtain a total reflection condition at an interface between the dielectric block and the cladding layer. The optical system comprises an optical system and light detecting means for measuring the intensity of the light beam totally reflected at the interface to detect the excited state of the waveguide mode, that is, the attenuated total reflection state.

In the leakage mode sensor having the above configuration,
When the light beam is incident on the cladding layer through the dielectric block at an incident angle equal to or greater than the total reflection angle, only light having a specific wave number at a specific incident angle is transmitted through the cladding layer. The light propagates 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, so that total reflection attenuation occurs in which the intensity of 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 characteristics of the sample related thereto are analyzed by knowing the specific incident angle at which the total reflection attenuation occurs. be able to.

In the case of using this leaky mode sensor, as in the case of using the above-mentioned surface plasmon resonance measuring apparatus, one measuring unit chip-fixed by fixing the cladding layer and the optical waveguide layer to the dielectric block is used. Make up,
This measurement unit can be disposable for each sample.

[0014]

However, when the conventional measuring chip as described above is used, a problem has been recognized that it is difficult to obtain positional accuracy on a measuring device such as a surface plasmon resonance measuring device. In order to achieve highly reproducible and highly accurate measurement in a measuring device using attenuated total reflection, the light beam must be converted into a dielectric block and a thin film layer (a metal film in the case of using surface plasmon resonance). , It is necessary to make the light incident on the interface with the cladding layer in a predetermined incident angle range, but it is difficult to obtain the position accuracy of the measuring chip on the measuring device. Naturally, the incident angle range varies, and measurement accuracy is impaired.

Further, when the conventional measuring chip as described above is used, there is also a problem that the handling property is poor and it is difficult to improve the efficiency of the measuring process.

The present invention has been made in view of the above circumstances, and has as its object to provide a measurement chip which can easily obtain positional accuracy on a measuring device such as a surface plasmon resonance measuring device and has excellent handling properties.

[0017]

One measuring chip 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 brought into contact with a sample, and a light beam generator. An optical system for causing the light beam to enter the dielectric block so as to be totally reflected at the interface between the dielectric block and the thin film layer, and to include various incident angle components; A light detection means for measuring the intensity of the light beam totally reflected at the interface to detect the state of attenuated total reflection, a measuring chip used in a measuring device utilizing attenuated total reflection, wherein the dielectric A plurality of measurement units each composed of a block and a thin film layer are arranged in a line and integrated.

Another measuring chip according to the present invention is designed especially for the above-mentioned surface plasmon resonance measuring apparatus, and includes a dielectric block and a sample formed on one surface of the dielectric block and brought into contact with a sample. A thin film layer made of a metal film, a light source for generating a light beam, and the light beam with respect to the dielectric block, under the condition of total reflection at an interface between the dielectric block and the metal film, and various A surface plasmon resonance device comprising: an optical system for causing incidence so as to include an incident angle component; and light detection means for measuring the intensity of a light beam totally reflected at the interface and detecting a state of attenuated total reflection by surface plasmon resonance. In a measurement chip used in a measurement device, a plurality of measurement units each including the dielectric block and the metal film are integrated in a line. It is an feature.

Still another measuring chip according to the present invention is designed especially for the above-mentioned leaky mode sensor, and includes a dielectric block, a cladding layer formed on one surface of the dielectric block, and a dielectric layer. A thin film layer formed of an optical waveguide layer formed thereon and brought into contact with a sample, a light source for generating a light beam, and applying the light beam to the dielectric block with respect to an interface between the dielectric block and the cladding layer. The total reflection condition is satisfied, and an optical system that is incident so as to include various incident angle components, and the intensity of the light beam totally reflected at the interface is measured, and the total intensity is measured by exciting the waveguide mode in the optical waveguide layer. A measuring chip used for a leaky mode sensor comprising: a light detecting means for detecting a state of reflection attenuation; wherein the dielectric block, the cladding layer, and the optical waveguide layer are provided. Ranaru measurement unit is more than 1 1
It is characterized by being integrated in a line.

In the measuring chip of the present invention having the above-described configuration, the dielectric blocks of the plurality of integrated measuring units are formed separately from each other, and these dielectric blocks are connected by a connecting member to form an integrated body. May be used. Alternatively, the dielectric blocks of the plurality of integrated measurement units may be formed from one common member.

In the measuring chip according to the present invention, it is preferable that a sample holding mechanism for holding a sample is provided on the thin film layer.

Materials suitable for forming the dielectric block include, for example, glass and transparent resin. When a transparent resin is used, it is desirable that the sample holding mechanism is also formed integrally with the dielectric block.

On the other hand, it is preferable that a sensing medium which shows a binding reaction with a specific substance in a sample is fixed on the thin film layer.

[0024]

The measuring chip according to the present invention comprises a dielectric block and a thin film layer (a metal film when using surface plasmon resonance, and a cladding layer when using waveguide mode excitation). And the optical waveguide layer) are integrated in a line in a row, so that the entire measurement unit is compared with the case where the measurement unit having such a configuration is used alone as a measurement chip. It becomes larger, whereby the positional accuracy on the measuring device is easily obtained, and the handleability is excellent.

If the position accuracy of the measuring chip on the measuring device is easily obtained, the measuring accuracy is improved, and if the measuring chip is excellent in handleability, the efficiency of the measuring operation is improved.

Further, since the measuring chip according to the present invention has a plurality of measuring units, it is possible to supply or discharge a plurality of measuring units by a single chip supplying or discharging operation to the measuring device. Become
This also contributes to the improvement of the efficiency of the measurement operation.

[0027]

Embodiments of the present invention will be described below in detail with reference to the drawings. FIG. 1 is a plan view showing the overall shape of one surface plasmon resonance measurement device using a measurement chip according to the present invention, and FIG. 2 shows a perspective view of a main part of the device. FIG. 3 shows a measurement unit connected body 8 which is a measurement chip according to the first embodiment of the present invention.
It is shown.

As shown in FIG. 3, the linked measuring unit 8 comprises eight measuring units 10 connected by a connecting member 9 as an example. The measurement unit 10 is, for example, a transparent dielectric block 11 whose outer shape is formed in a substantially rectangular parallelepiped, and, for example, gold formed on the bottom surface of a hole 11b provided in a shape dug from the upper surface of the dielectric block 11,
And a metal film 12 made of silver, copper, aluminum, or the like. A portion around the hole 11b of the dielectric block 11 forms a sample holding frame 11c that holds a 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, for example, injection molding a transparent resin or the like. In this example, the sensing substance 14 is fixed on the metal film 12, which will be described later in detail.

The surface plasmon resonance measurement apparatus shown in FIGS. 1 and 2 uses a support for supporting the measurement unit 10 as a support.
It has a slide block 2 slidably engaged with two guide rods 1, 1 arranged in parallel with each other and capable of linearly moving along the two in the direction of arrow Y in the figure. A precision screw 3 arranged in parallel with the guide rods 1, 1 is screwed into the slide block 2.
Is rotated forward and backward by a pulse motor 4 constituting a support driving means. Then, the measurement unit connected body 8 is set on the slide block 2, whereby the measurement units 10 are supported by the slide block 2 in a state where eight measurement units 10 are arranged in a line.

The driving of the pulse motor 4 is controlled by a motor controller 5. That is, an 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 is input to the motor controller 5, and the motor controller 5 Reference numeral 5 controls the driving of the pulse motor 4 based on the signal S10.

As shown in FIG. 4, for example, a plurality (12 in this example) of the linked measuring unit bodies 8 are set together on the plate 40, and transported and handled in this state. In other words, the measuring unit 10 is transported and handled in 96 units by this one plate 40.

When a plurality of measurement units 10 are collectively handled as the measurement unit connected 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 measurement unit 10. It is desirable. The dispenser 45 is connected to the measuring unit 10
The number of dispensing nozzles 46 equal to the number of
Since the liquid sample can be simultaneously dispensed to a plurality of measurement units 10 of one measurement unit connected body 8,
The efficiency of the sample supply operation can be improved.

Returning to the apparatus of FIGS. 1 and 2, a slide block 2 moving along the guide rods 1, 1 is sandwiched from above and below the guide rods 1, 1 as shown in a side view in FIG. Microlens array 6 and eight photodetectors 7a, 7b, 7c, 7d, 7e, 7f, 7g and 7
h. The microlens array 6 includes eight measurement units 10 set on the slide block 2.
Has eight convex lenses 6a to 6h, respectively. 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, respectively. Each of the photodetectors 7a to 7h
It is composed of a line sensor in which a large number of light receiving elements are arranged in one line, and the light receiving elements are arranged such that the arrangement direction of the light receiving elements is the direction of arrow X in FIG.

On the optical axis of each convex lens 6a-h of the micro lens array 6, optical fibers 34a-h are provided, respectively.
Light beams emitted from them in a divergent light state
30 enter the convex lenses 6a to 6h, respectively. FIG. 7 shows an optical system including the optical fibers 34a to 34h and a light source combined with the optical system. Hereinafter, the configuration of FIG. 7 will be described.

In this embodiment, a semiconductor laser 31 that emits a light beam (laser beam) 30 having a wavelength in the infrared region, for example, is used as a light source. A light beam 30 emitted forward (to the right in the drawing) from the semiconductor laser 31 in a divergent light state
Are collimated by a collimator lens 32, then condensed by a condenser lens 33, and made incident on an optical fiber 34m. The optical fiber 34m is connected to the optical coupler unit 35. The optical coupler unit 35
An optical coupler that splits input light into two systems at a split ratio of 50:50 is provided in three stages, whereby
The light beam 30 input to the optical fiber 34m is branched into eight systems with the same light intensity as each other, and the branched light beams 30 are respectively divided into optical fibers 34a, 34b, 34c, 34d, 34e,
It is led to 34f, 34g and 34h.

The light passing surfaces of the optical components disposed on the front side of the semiconductor laser 31, including the end faces of the optical fibers 34a to 34h and 34m, have an AR (non-reflection) with respect to the oscillation wavelength of the semiconductor laser 31. Coat is given. As a result, it is possible to prevent the light reflected by those surfaces from returning to the semiconductor laser 31 and causing a problem such as generation of noise.

The element end face of the semiconductor laser 31 is coated with an LR (low reflection) coat on both the front end face and the rear end face, so that the semiconductor laser 31 emits a light beam also to the rear side. I do. The light beam emitted in the diverging light state on the rear side, that is, the backward emitted light 30R is converted into parallel light by the collimator lens 36, and then collected by the condenser lens 37. A mirror 38 is disposed at a position where the rear emission light 30R is converged by the condenser lens 37. The rear emission light 30R is reflected by the mirror 38 and reflected by the semiconductor laser 31R.
Feedback to

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

Hereinafter, a sample analysis by the surface plasmon resonance measuring apparatus having the above configuration will be described. When performing the sample analysis, first, the slide block 2 is set to the first standby position indicated by the arrow W1 in FIG. 1, and the unit 40a of the slide block 2 is moved from the plate 40 (see FIG. 4) to the first set position.
The two measurement unit connected bodies 8 are set. Note that a liquid sample 15 (see FIG. 6) to be measured is stored in advance in the hole 10b of each measuring unit 10 of the linked measuring unit 8. The setting of the linked measuring unit assembly 8 is performed by the measuring unit supply / discharge mechanism 70.

The measuring unit supply / discharge mechanism 70 is movable, for example, in a direction perpendicular to the direction in which the guide rods 1, 1 are arranged, that is, in the direction indicated by the arrow H in FIG. 1, and in the vertical direction, that is, in a direction perpendicular to the plane of FIG. The left and right ends have suction cups for holding the left and right ends of the linked measuring unit assembly 8 by suction. This measuring unit supply / discharge mechanism 70
Moves down to a position above the measurement unit linked body 8 to be taken out on the plate 40, and then descends while holding the measurement unit linked body 8 by suction, and then moves down the slide block 2 at the first standby position. The measuring unit linked body 8 is moved to a position directly above, and then descends to incorporate the measuring unit linked body 8 into the unit setting portion 2a of the slide block 2, and then releases the suction holding and moves up to move the measuring unit linked body 8 to the slide block 2. Set to.

When the linked measuring unit assembly 8 is set as described above, the pulse motor 4 is driven under the control of the motor controller 5, and the slide block 2 is set to the measuring position indicated by the solid line in FIG. Hereinafter, the surface plasmon resonance measurement performed at this measurement position will be described with reference to FIG. Here, of the eight measuring units 10 of the linked measuring unit 8, one is set to match the optical fiber 34a and the photodetector 7a.
The description will be made by taking one measurement unit 10 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. Then, as shown in FIG. 6, the light beam 30 is emitted in the state of divergent light from the tip of the optical fiber 34a. This light beam 30 is collected by the convex lens 6a of the micro lens array 6,
The light enters the dielectric block 11 in a convergent light state, and enters the interface 11a between the dielectric block 11 and the metal film 12 while containing various incident angle components. The range of the incident angle θ is a range including an angle range in which the condition of total reflection of the light beam 30 at the interface 11a is obtained and 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 disposed in advance so that the polarization direction thereof becomes a predetermined direction, and the optical fiber 34m and the optical fibers 34a to 34h use polarization plane preserving fibers.
What is necessary is just to control the polarization direction of the light beam 30 emitted from a to 34h. Alternatively, use a wave plate or polarizing plate to
The direction of the 30 polarizations may be controlled.

The light beam 30 incident on the interface 11a is totally reflected at the interface 11a, and the light beam 30 totally reflected is
a. The light beam 30 is at the interface as described above.
Since the light beam 11a is incident on the light beam 11a with various incident angle components, the light beam 30 totally reflected includes components reflected at various reflection angles.

As described above, when the light beam 30 is totally reflected,
An evanescent wave exudes from the interface 11a to the metal film 12 side. When the light beam 30 enters 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, so that the reflected light intensity I drops sharply.
This decrease in reflected light intensity is observed as a dark line D in the totally reflected light beam 30. FIG. 8 schematically shows the relationship between the incident angle θ and the reflected light intensity I when this total reflection attenuation phenomenon occurs.

Therefore, the detected light amount of each light receiving element is checked from the light amount detection signal S output by the light detector 7a, and the incident angle (total reflection attenuation angle) θ _SP is determined based on the position of the light receiving element where the dark line is detected. The specific substance in the sample 15 can be quantitatively analyzed based on the obtained relationship curve between the reflected light intensity I and the incident angle θ 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, since the slide block 2 is formed of a frame-shaped member having an opening 2b penetrating in the left-right direction, the light beam 30 is not interrupted by the slide block 2 and the measurement unit set therein. 10 can be irradiated. 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 . In other words, in this case, the sensing substance depends on the binding state between the specific substance and the sensing substance 14.
Since the refractive index of 14 changes and the characteristic curve of FIG. 8 moves in the left-right direction, 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 samples to be analyzed.

The above measuring operation is performed for the other seven measuring units.
The same is done for 10 measurement units in parallel.
The measurement for the sample 15 stored in the
It is. Note that the light beams 30 for the eight measurement units 10 are
Irradiation and total reflection attenuation angle θ _SPDetection is strict with each other
Need not be done at the same time
They may be slightly offset from each other.

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

The signal processing section 61 has eight photodetectors 7a.
To h, or a common one for the eight photodetectors 7a to 7h.
The light amount detection signals S output from the photodetectors 7a to 7h may be sequentially processed.

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

Next, another measuring unit connected body 8 on the plate 40 is set in the unit setting section 2a of the slide block 2 by the measuring unit supply / discharge mechanism 70 in the same manner as described above. The measurement on the sample 15 stored in the individual measurement units 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 above case, and the slide block 2 is moved in the direction indicated by the arrow in FIG. The second standby position indicated by W2 is set. Then, the measuring unit connecting body 8 is detached from the slide block 2 by the measuring unit supplying / discharging mechanism 71 formed in the same manner as the above-mentioned measuring unit supplying / discharging mechanism 70, and is attached to the left and right sides of the guide rods 1, 1. It is mounted on one of the mounting tables 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 indicated by the arrow W1 in FIG. Then, another measuring unit connecting body 8 on the plate 40 is connected to the unit setting section 2 of the slide block 2 by the measuring unit supply / discharge mechanism 70 in the same manner as described above.
a, and the measurement on the sample 15 stored in the eight measurement units 10 of the measurement unit connection body 8 is
This is also performed in the same manner as described above.

When the measurement using the measuring unit 10 of the second connected measuring unit 8 is completed, the pulse motor 4
Is rotated to set the slide block 2 at the second standby position. Then, the measurement unit connecting body 8 is removed from the slide block 2 by the measurement unit supply / discharge mechanism 71, and is mounted on the vacant mounting table 42.

Next, the measuring unit connected body 8 mounted on another mounting table 42, that is, the first measuring unit connected body 8 is moved to the unit setting section 2a of the slide block 2 by the measuring unit supply / discharge mechanism 71. The measurement is performed on the samples 15 that are set and stored in the eight measurement units 10 of the connected measurement unit assembly 8 in the same manner as the previous time.
At this time, if a predetermined time has not elapsed after the first measurement using the first measurement unit connected body 8 is completed, the slide block 2 is set to a measurement position indicated by a solid line in FIG. After that, it is only necessary to wait for a while for a while and then start the measurement.

When the second measurement of the first connected measurement unit 8 is completed, the pulse motor 4 is rotated to set the slide block 2 to the second standby position. Then, the first measurement unit connected body 8 is removed from the slide block 2 by the measurement unit supply / discharge mechanism 71, and is mounted on the empty mounting table 42.

Next, the measuring unit connected body 8 mounted on another mounting table 42, that is, the second measuring unit connected body 8 is moved to the unit setting section 2a of the slide block 2 by the measuring unit supply / discharge mechanism 71. The measurement is performed on the samples 15 that are set and stored in the eight measurement units 10 of the connected measurement unit assembly 8 in the same manner as the previous time.

When the second measurement using the second connected measuring unit 8 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 connected body 8 is removed from the slide block 2 by the measurement unit supply / discharge mechanism 71, and is mounted on the vacant mounting table 42.

Thereafter, the same operation is repeated, so that the measurement by the first connected measuring unit 8 and the measurement by the second connected measuring unit 8 are alternately performed. By doing so, the measurement waiting time of one of the connected measuring units 8 can be effectively used, and the measurement by the other connected measuring unit 8 can be performed during that time, thereby improving the efficiency of the measuring operation.

When a predetermined number of measurements are completed on the sample 15 held in the measuring unit 10 of one measuring unit connected body 8, the slide block 2 on which the measuring unit connected body 8 is set is placed in the first standby state. Returned to position.
Then, the measurement unit connecting body 8 is detached from the slide block 2 by the measurement unit supply / discharge mechanism 70, and is discharged onto the discharge plate 41.

Next, another measuring unit connected body 8 on the plate 40, that is, the third measuring unit connected body 8 is set on the unit setting section 2a of the slide block 2 by the measuring unit supply / discharge mechanism 70, and the measurement is continued. Sample 15 stored in measurement unit 10 of unit connected body 8
Is measured. In the same manner, the plate 40
The connected measurement unit bodies 8 stored in the storage unit can be successively used 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 a measurement unit 10, and the measurement unit connected body 8, which is an aggregate of the measurement units 10, is used as a measurement chip for the slide block 2. Since the replacement is possible, the measurement unit connected body 8 holding the sample 15 for which measurement has been completed is removed from the slide block 2 and the new measurement unit connected body 8 is supported by the slide block 2 so that the new sample 15 is transferred. Measurement can be performed one after another, and measurement of a large number of samples 15 can be performed in a shorter time.

It is not always necessary to set the slide block 2 to the above-mentioned second standby position, and to make it possible to replace the linked measuring unit 8 set on the slide block 2 there. But if you do so,
As described above, it can be said that measurement can be performed by another measurement unit connected body 8 by effectively utilizing the waiting time of measurement by one measurement unit connected body 8, and the efficiency of the measurement operation is improved.

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 measuring unit is connected thereto. By rotating the turntable every time the body 8 is ejected, it is possible to temporarily mount a larger number of measurement unit connected bodies 8 in the middle of measurement on the turntable. Become.

Furthermore, it is not always necessary to move the linked measuring unit 8, that is, the measuring unit 10, between the standby position and the measuring position by using the slide block 2 or the like. That is, a support that supports the plurality of measurement units 10 is fixed, and if the measurement unit 10 is set on the support, there is a state where the measurement unit 10 can be irradiated with a measurement light beam as it is. You may do so. However, in such a case, since the support is inevitably provided in a state very close to the optical system and the light detecting means, the setting and removal of the measuring unit 10 with respect to the support is automatically performed. In the case of performing this by means, it is necessary to adopt an automatic means having a structure capable of reliably avoiding interference with the optical system and the light detecting means.

When the support is moved, the manner of movement is not limited to the linear movement in the above embodiment, but a turntable that rotates intermittently at a predetermined angle as the support is used. A plurality of measurement units may be supported on a circumference around the moving axis, and the measurement units may be moved along the circumference by rotating the turntable. In this case, for example, 16 measurement units are supported on a turntable, and half of the 8 measurement units are irradiated with a light beam at a time, and when the measurement for them is completed, the turntable is turned 180 °. It is possible to adopt a configuration in which the remaining eight measurement units are moved to irradiate the light beams simultaneously.

An embodiment of the measuring chip held on such a turntable will be described later in detail.

The measuring chip according to the present invention is not limited to a measuring device for simultaneously irradiating a plurality of measuring units with a light beam, but also has a support for supporting a plurality of measuring units and a single optical system for irradiating the light beam. However, the present invention is also applicable to a measuring apparatus configured to move the support when the measurement for one measuring unit is completed and set another measuring unit to a position to receive the light beam irradiation.

Next, the connected measuring unit 8 described above
A measurement chip according to another embodiment of the present invention, which can be used instead of, will be described.

FIG. 9 shows a linked measuring unit 80 as a measuring chip according to the second embodiment of the present invention. In this measurement unit connection body 80, for example, one prismatic dielectric bar 81 is formed using the same material as the dielectric block 11 shown in FIG. 3, and a plurality of bottomed holes 82 are formed here. The part of the bar 81 around it is used as a sample holding part,
The metal film 12 and the sensing substance 14 are formed on the bottom surface of the hole 82. That is, in the measurement unit coupling body 80, a measurement unit is configured for each hole 82.

The connected measuring unit 80 having the above configuration
Is easier to manufacture and reduces costs compared to a configuration in which one measuring unit 10 is formed one by one as in the case of the linked measuring unit 8 shown in FIG. it can.

FIG. 10 shows a linked measuring unit 90 as a measuring chip according to the third embodiment of the present invention. The measurement unit connector 90 has measurement units 95 fitted and fixed in a plurality of unit support holes 92 formed in a unit support plate 91, respectively. The measuring unit 95 is basically the measuring unit 10 shown in FIG.
However, it is fitted in the tapered unit support hole 92 so that it does not pass through the unit support hole 92. In addition to fitting the measurement unit 95 into the unit support hole 92, it is also necessary to adhere the measurement unit 95 to the unit support plate 91 or to ultrasonically weld them so that they are more firmly fixed. desirable.

The above-described connected measuring unit assemblies 8, 80, and 90 are formed so that a plurality of measuring units are fixed inseparably from each other and are larger than a measuring chip formed as a single measuring unit. Therefore, the position accuracy on the surface plasmon resonance measurement device can be easily obtained, and since there is no need to hold a small measurement unit, the handling efficiency is excellent and it can contribute to the improvement of the efficiency of the measurement processing. In addition, since such a measurement unit connected body 8, 80, and 90 includes one plurality of measurement units, a plurality of measurement units can be connected to the surface plasmon resonance measurement apparatus by one chip supply or discharge operation. It becomes possible to supply or discharge, and this also contributes to the improvement of the efficiency of the measurement operation.

Next, a fourth embodiment of the present invention will be described. FIG. 11 shows a side view of a linked measuring unit 8 ′ according to the fourth embodiment of the present invention and a surface plasmon resonance measuring apparatus using the same. FIG. 1
In FIG. 1, elements that are the same as the elements in FIG. 6 are given the same reference numerals, and descriptions thereof will be omitted unless otherwise necessary (the same applies hereinafter).

The linked measuring unit 8 'is different from the linked measuring unit 8 shown in FIG. 3 in the configuration of the measuring unit. That is, the measurement unit 10 ′ used here is the same as the measurement unit linked body 8.
This is a form in which the sensing substance 14 is removed from the measurement unit 10 of FIG. Otherwise, the measurement unit connected body 8
And basically the same.

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

Also in this surface plasmon resonance measuring apparatus, a linked measuring unit 8 ′ in which a plurality of measuring units 10 ′ are integrated is supported by a slide block 2, and the measuring units 10 ′ are simultaneously irradiated with a light beam 30. The surface plasmon resonance measurement apparatus is configured to perform measurement on a large number of samples 15 in a short time because the measurement is performed by the measurement units 10 ′ in parallel. Will be possible.

Next, a fifth embodiment of the present invention will be described. FIG. 12 shows a side view of a connected measuring unit 108 according to the fourth embodiment of the present invention and a measuring apparatus using the same. The measuring device using the total reflection attenuation is the leak mode sensor described above, and is configured to use the measuring unit connecting body 108 formed into a measuring chip in this example as well. As in the case of the measuring units 8 and 8 ', the linked measuring unit 108 is formed by integrating a plurality of linked measuring units 110 in a line. Dielectric block 1 that constitutes this measurement unit 110
A cladding layer 111 is formed on one surface (the bottom surface of the hole 11b), and an optical waveguide layer 112 is further formed thereon.

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

In this leaky mode sensor, when the light beam 30 in the converging light state is made to enter the cladding layer 111 through the dielectric block 11 at an incident angle equal to or larger than the total reflection angle,
Although the light beam 30 is totally reflected at the interface 11a between the dielectric block 11 and the cladding layer 111, the light of a specific wave number transmitted through the cladding layer 111 and incident on the optical waveguide layer 112 at a specific incident angle is reflected by the optical waveguide. The layer 112 propagates in a guided mode. When the waveguide mode is excited in this manner, most of the incident light is taken into the optical waveguide layer 112, and thus the total reflection attenuation occurs in which the intensity of the light totally reflected at the interface 11a sharply decreases.

Since the wave number of the 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 the total reflection attenuation 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.

In this leak mode sensor, the slide block 2 supports the measurement unit connected body 108 in which a plurality of measurement units 110 are integrated, and the measurement units
The leak mode sensor is configured to irradiate the light beam 30 simultaneously to the measurement units 110 so that the measurement by the measurement units 110 can be performed in parallel. It can be done in time.

Next, a sixth embodiment of the present invention will be described. FIG. 13 shows a side view of a linked measuring unit 108 'according to the sixth embodiment of the present invention and a measuring device using the same. This measuring device is also the leak mode sensor described above, and is configured to use the linked measuring unit 108 'formed into a measuring chip in this example as well. As in the case of the measuring units 8 and 8 ', the connecting unit for measuring unit 108' is also formed by integrating a plurality of measuring units 110 'in a line. This measuring unit 110 'is different from the measuring 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 shown in 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, for example, 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 of FIG. 8, but the refractive index of the sensing substance 14 varies depending on the bonding state between the specific substance and the sensing substance 14. Since the effective refractive index of the optical waveguide layer 112 changes, and this changes the relationship, the antigen-antibody reaction can be detected according to the attenuated total reflection angle θ _SP .

The connected measuring unit 8 ', 10 described above
8 and 108 ′ are also formed such that a plurality of measurement units are fixed so as to be inseparable from each other and are larger than a measurement chip that is a measurement chip by itself.
Position accuracy on a surface plasmon resonance measurement device or a leak mode sensor is easily obtained, and since there is no need to hold a small measurement unit, it is excellent in handling properties and can contribute to improvement in efficiency of measurement processing. In addition, such measuring unit connected bodies 8 ', 108 and 10
8 'is also equipped with a plurality of measurement units, so that it is possible to supply or discharge a plurality of measurement units by a single chip supply or discharge operation to the measurement device. It can contribute to the improvement of work efficiency.

Next, a seventh embodiment of the present invention will be described. FIG. 14 shows a planar shape of a connected measurement unit 200 that is a measurement chip according to the seventh embodiment of the present invention. As shown in FIG.
Is a unit support plate 201 formed by dividing an annular plate into three equal parts.
In addition, as an example, six measurement units 10 are fixed. These measurement units 10 are similar to the measurement unit 10 shown in FIG. 3, and are used for surface plasmon resonance measurement. These measurement units 10 are arranged along an arc centered on the center of the ring.

The measuring unit connected body 200 having such a configuration is
As described above, a turntable can be applied to a measuring device having a structure in which a plurality of measurement units are supported on a circumference around the rotation axis and the turntable is rotated by a predetermined angle. . In this case, for example, if three turntables 200 are held at equal angular intervals on the turntable, a total of 18
Can be supported.

In such a case, a plurality of measuring units 10 held on the turntable may be irradiated with a light beam at the same time, or the turntable may be intermittently rotated at the same angular interval as the mounting pitch of the measuring units 10. The light beam may be sequentially applied to each of the measurement units 10 by moving the light source.

[Brief description of the drawings]

FIG. 1 is an overall plan view showing an example of a surface plasmon resonance measurement device using a measurement chip 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. 1;

FIG. 3 is a perspective view showing a linked measuring unit according to the first embodiment of the present invention.

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

FIG. 5 is a front view showing a unit for supplying a sample to the connected measurement unit of FIG. 3;

FIG. 6 is a side view showing a main part of the surface plasmon resonance measuring apparatus of FIG. 1;

FIG. 7 is a plan view showing an optical system of the surface plasmon resonance measuring apparatus of FIG. 1;

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

FIG. 9 is a perspective view showing a connected measuring unit according to the second embodiment of the present invention.

FIG. 10 is a perspective view showing a linked measuring unit according to a third embodiment of the present invention.

FIG. 11 is a side view showing a connected measurement unit according to a fourth embodiment of the present invention and a main part of a surface plasmon resonance measurement apparatus using the same.

FIG. 12 is a side view showing a main part of a connected measuring unit according to a fifth embodiment of the present invention and a leak mode sensor using the same.

FIG. 13 is a side view showing a main part of a connected measuring unit according to a sixth embodiment of the present invention and a leak mode sensor using the same.

FIG. 14 is a plan view showing a linked measuring unit according to a seventh embodiment of the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 1 Guide rod 2 Slide block 3 Precision screw 4 Pulse motor 5 Motor controller 6 Micro lens array 7a-h Photodetector 8, 8 ', 108, 108', 200 Measurement unit connection body 9 Connection member 10, 10 'Measurement unit 11 Dielectric block 11a Interface between dielectric block and thin film layer 12 Metal film 14 Sensing substance 30 Light beam 31 Semiconductor laser 32 Collimator lens 33 Condenser lens 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 45 Dispenser 46 Dispensing nozzle 47 Support member 61 Signal processing unit 62 Display unit 70, 71 Measuring unit supply / discharge mechanism 80, 90 Measuring unit connector 81 Dielectric bar 91 Unit support plate 92 Unit support hole 95 Measuring unit 110 110 'Measuring unit 111 Cladding layer 112 Optical waveguide layer 200 unit support plate

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 2G058 AA09 CC14 CC17 CD01 CD21 CF22 ED16 GA02 2G059 AA01 BB12 CC17 DD12 DD13 EE02 FF11 GG01 GG04 HH01 JJ03 JJ11 JJ17 JJ19 JJ20 KK04 PP01

Claims (8)

[Claims] 1. A dielectric block; a thin film layer formed on one surface of the dielectric block and brought into contact with a sample; a light source for generating a light beam; An optical system that is totally reflected at the interface between the dielectric block and the thin film layer, and is incident so as to include various incident angle components, and measures the intensity of the light beam totally reflected at the interface to reduce the total reflection attenuation. A measurement chip for use in a measurement device utilizing attenuated total reflection, comprising: a light detection unit for detecting a state, wherein a plurality of measurement units each including the dielectric block and the thin film layer are arranged in a line and integrated. A measuring chip characterized by being made. 2. A dielectric block, a thin film layer formed on one surface of the dielectric block and made of a metal film which is brought into contact with a sample, a light source for generating a light beam, and the light beam is transmitted to the dielectric block. On the other hand, the total reflection condition is satisfied at the interface between the dielectric block and the metal film, and an optical system that is incident so as to include various incident angle components, and the intensity of the light beam totally reflected at the interface is measured. And a light detecting means for detecting a state of attenuated total reflection by surface plasmon resonance. A measuring chip used for a measuring device utilizing attenuated total reflection, the measuring unit comprising the dielectric block and a metal film A plurality of measuring chips are arranged and integrated in a line. 3. A thin film layer comprising a dielectric block, a cladding layer formed on one surface of the dielectric block, and an optical waveguide layer formed thereon and brought into contact with a sample, and a light source for generating a light beam An optical system that causes the light beam to enter the dielectric block at a total reflection condition at an interface between the dielectric block and the cladding layer, and to include various incident angle components; Measuring the intensity of the totally reflected light beam, and light detecting means for detecting the state of total reflection attenuation due to the excitation of the waveguide mode in the optical waveguide layer, a measuring device utilizing total reflection attenuation A measurement chip to be used, wherein a plurality of measurement units each including the dielectric block, the cladding layer, and the optical waveguide layer are arranged in a line and integrated. 4. The dielectric blocks of the plurality of integrated measurement units are formed separately from each other, and these dielectric blocks are connected and integrated by a connecting member. Item 4. The measurement chip according to any one of Items 1 to 3. 5. The measuring chip according to claim 1, wherein each dielectric block of the plurality of integrated measuring units is formed of one common member. 6. The measuring chip according to claim 1, wherein a sample holding mechanism for holding a sample is provided on the thin film layer. 7. The measuring chip according to claim 1, wherein the dielectric block is made of one of glass and transparent resin. 8. The measuring chip according to claim 1, wherein a sensing medium that shows a binding reaction with a specific substance in a sample is fixed on the thin film layer.