JP2007033342A - Analysis device and analyzer - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an analyzing device and an analyzing apparatus capable of performing evaluation and tests of mixture or reaction of substances by a new method, specifically capable of real-time measuring and observing not only before and after the mixture or reaction and tests of the substances but also on their progresses. <P>SOLUTION: The analyzing device 1 comprises both a filter 2 which is provided with a plurality of pores and in which the mixture or reaction of substances occur in its vicinity or inside and an optical waveguide 3 provided for the inside or the vicinity of the filter 2. The analyzing apparatus comprises: the analyzing device 1; a light source 12 for emitting light waves to pass through the optical waveguide 3; and a detector 13 for detecting light waves which has passed through and come out of the optical waveguide 3. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an analysis device and an analysis apparatus, and more particularly, to an analysis device and an analysis apparatus capable of mixing substances or evaluating and examining reactions in a new manner.

Conventionally, analyzers using filters have been known. For example, in Patent Document 1, an electroshrinkable film-like polymer gel is provided in a hole formed in a substrate with its periphery fixed, and a DC voltage is continuously changed on the polymer gel. An ion or molecular filter characterized by forming an arbitrary micropore through which a minute amount of fluid passes through the polymer gel by applying and contracting the polymer gel, and an analyzer using the filter are disclosed. ing.
However, the filter described in Patent Document 1 can pass ions and molecules according to the pore size of the micropores, and sifts ions and molecules in the sample liquid easily and in a shorter time than before. However, only a very small amount of fluid can be delivered.

Also, in recent years, with the aim of speeding up various research and development, labor saving, resource saving, energy saving, space saving, experiment waste liquid, waste reduction, rationalization of repeated experiments, etc. An integrated chemical laboratory capable of performing chemical experiments, reactions, detection and analysis in a space, what is called a microchip, a micro TAS, or the like is disclosed.
For example, Patent Document 2 discloses a planar microchip channel for controlling a liquid-liquid interface reaction.
In Patent Document 3, a microchip that achieves a single function is configured, a plurality of chips having different single functions are taken out from the configured chips, and the target tertiary is obtained by combining these chips. A biochemical IC characterized by constituting the original chemical reaction pathway is disclosed.

However, the microchip described in Patent Document 2 requires a planar flow path for each unit operation step of reaction / detection, and it is difficult to achieve higher integration than a certain level in an analyzer using this microchip. Furthermore, since the microchip has flow paths arranged on a plane, it is difficult to make the microchip more than a certain point in terms of improvement in detection sensitivity and speed.
In addition, the biochemical IC described in Patent Document 3 has a large reaction system with a height of 6 mm or more and a width of about 5 mm, and this size is not compatible with environmental analysis that requires microliter-level microanalysis capabilities. Have difficulty.

  In addition, the microchips described in Patent Documents 2 and 3 above use a micrometer-sized flow path for mixing and reacting liquid samples and reagents. For example, the length of the flow path is extremely long with respect to the diameter. Further, in order to secure such a long flow path, even if the flow path is bypassed, the entire chip has a size of centimeter, and further miniaturization has been desired. In addition, in order to allow a liquid to flow through a channel having a very long channel length with respect to a minute diameter of a micrometer unit, it is necessary to apply a very large pressure difference such as 100 atm. Met.

  In response to the technical problems described in Patent Documents 1 to 3, the present inventors have a filter having a plurality of pores of a specific size and capable of molecular sieving and separation in a liquid, and the filter has a cylindrical shape. A microreactor was invented in which a plurality of reaction layers were formed by partitioning the inside of the tank in the radial direction. This filter can improve the collision frequency of molecules due to molecular diffusion when the liquid passes through the pores, and there are many such pores. As a result, compared to conventional microreactors, the sample / reagent mixing / reaction time can be greatly reduced, the flow path can be shortened, and the size can be further reduced. Since the amount of the sample / reagent for the reaction is small, the cost can be reduced. Furthermore, since there are a large number of the pores, the pressure loss can be made smaller than that of a conventional flat channel microchip or the like.

JP 2000-180313 A JP 2002-326963 A JP 2001-158000 A

Then, the present invention has aimed to create and establish a new form in the field of substance mixing or reaction evaluation / inspection using the above filter or microreactor.
That is, the present invention provides, for example, an analysis device and an analysis apparatus that can perform substance mixing or reaction evaluation / inspection by a new method using the above-described filter or microreactor. It is an object of the present invention to provide an analysis device and an analysis apparatus that can observe and measure not only before and after, but also the progress in real time.

As a result of intensive studies, the present inventors have found the following technical configuration and completed the present invention.
That is, the present invention is as follows.

(1) An analysis device having a plurality of pores and having a filter in which a substance is mixed or reacted in or near and an optical waveguide provided in or near the filter.
(2) The analytical device according to (1), wherein the optical waveguide has a core exposed.
(3) The analysis device according to (1) or (2), wherein the optical waveguide is an optical fiber.
(4) The analytical device according to (3), wherein the optical waveguide has a tapered outer diameter.
(5) The analytical device according to (1), wherein the optical waveguide is provided inside the filter so as to cross the pore.
(6) The analytical device according to (1), wherein the optical waveguide is provided in the filter adjacent to the pore.
(7) The analytical device according to (1), wherein the optical waveguide is provided in close contact with the surface of the filter.
(8) The analytical device according to (1), wherein the filter is made of a material having a refractive index lower than that of the material constituting the optical waveguide.
(9) An analysis apparatus including the analysis device according to any one of (1) to (8), a light source that emits a light wave that passes through the optical waveguide, and a detector that detects the light wave emitted through the optical waveguide.

In general, a light wave travels while being reflected in an optical waveguide such as an optical fiber at the interface with the outside. Actually, the light wave propagates through the optical waveguide in a state where so-called evanescent light is generated, in which the light wave is slightly dyed to the outside. At this time, if a substance that absorbs the light or a substance having a refractive index higher than that of the optical waveguide exists at a position where the evanescent light is generated, the evanescent light is absorbed or transmitted by the substance, and the light wave transmitted through the optical waveguide is The energy gradually decays.
The present invention uses the principle that the evanescent light is absorbed and transmitted in the outside of the optical waveguide and the energy of the light wave transmitted through the optical waveguide is attenuated.

  For example, when a plurality of kinds of substances are passed through a filter having a plurality of pores, the substances are mixed or reacted in the vicinity of or inside the filter (particularly the pores). Then, in the mixing or reaction region of the substance, a change in optical characteristics such as light refractive index, transmittance, and absorptivity may occur. When an optical waveguide is provided in a region where the mixing or reaction of the substance occurs and light waves are conducted through the optical waveguide, the evanescent light generated outside the optical waveguide is affected by the change in optical characteristics caused by the mixing or reaction of the substance. For example, the evanescent light is transmitted or absorbed, and the light wave transmitted through the optical waveguide is gradually attenuated. That is, the light amount (energy) on the exit side is smaller than that on the entrance side of the optical waveguide. By observing this difference in light quantity, it is possible to evaluate the mixing or reaction state of substances passing through the filter.

  The analysis device of the present invention includes a filter having a plurality of pores and in which a substance is mixed or reacted in the vicinity or inside, and an optical waveguide provided in or near the filter. Mixing or reaction evaluation / inspection can be performed. For example, not only before and after mixing or reaction / inspection of substances, but also the progress thereof can be observed and measured in real time.

The analysis device of the present invention includes a filter having a plurality of pores, in which a substance is mixed or reacted in the vicinity or inside, and an optical waveguide provided in or near the filter.
A specific example of the analysis device of the present invention, an analysis principle using the analysis device, an analysis form, and the like will be described with reference to FIG.

FIG. 1A shows an analysis device according to the present invention, which has a filter 2 having a plurality of pores and in which a substance is mixed or reacted in or near, and an optical waveguide 3 provided in or near the filter 2. 1 shows a basic configuration.
FIG. 1B shows an outline of the analysis principle using the analysis device 1 of the present invention. The evanescent light 5 oozing out to the outside of the optical waveguide 3 is partially absorbed and attenuated in the optical property changing region 6 due to mixing or reaction of substances generated in the vicinity or inside of the filter 2.

FIG.1 (c) shows the outline of the example of an analysis form using the analysis device 1 of this invention. The analysis device 1 of the present invention can be applied to the vertical microreactor 11. At that time, a light source 12 that emits a light wave that passes through the optical waveguide 3 and a detector 13 that detects the light wave emitted through the optical waveguide 3 are also provided.
Although it does not specifically limit as a light source used in the analyzer of this invention, A semiconductor laser, a light emitting diode, etc. are mentioned.

Examples of the optical waveguide used in the analysis device of the present invention include uncovered optical fibers and exposed cores such as thin glass wires.
Further, FIG. 2 shows a light having a tapered outer diameter in which only a portion located near or inside the filter 2 as the optical waveguide 3 is subjected to liquid phase etching using an aqueous hydrogen fluoride solution to make it thinner than the other portions. An example using a fiber is shown. In addition to this, the method of making the outer diameter of the optical fiber tapered may be a known method such as reducing the diameter by heating and drawing, or fusing a previously reduced optical fiber. It is.
FIG. 3 shows an example in which a so-called core-exposed optical fiber is used in which the coating material is removed only in the vicinity of or inside the filter 2 as the optical waveguide 3.

4 to 6 show the positional relationship between the filter 2 and the optical waveguide 3 in the analysis device of the present invention. 4 to 6, (a) is a view of the analytical device of the present invention as viewed from above, and (b) is a cross-sectional view of the analytical device of the present invention.
FIG. 4 shows a configuration in which the optical waveguide 3 is provided inside the filter 2 through the pores 4. Thereby, the mixing or reaction of substances occurring inside the filter 2 can be evaluated.
FIG. 5 shows a configuration in which the optical waveguide 3 is provided inside the filter 2 so as to be adjacent to the pore 4. Thereby, the mixing or reaction of substances occurring in the vicinity of or inside the filter 2 can be evaluated.
FIG. 6 shows a form in which the optical waveguide 3 is provided in close contact with the surface of the filter 2. As a result, the mixing or reaction of substances occurring in the vicinity of the filter 2 can be evaluated.

  In the above description, the embodiment in which the linear optical waveguide 3 is provided in the diametrical direction of the filter 2 as the analysis device of the present invention has been described. However, as shown in FIG. The total length of the optical waveguide can be increased by providing it in a spiral shape, or by branching and integrating a plurality of optical waveguides as shown in FIG. Further, by increasing the total length of the optical waveguide, higher detection sensitivity and a wider detection area can be obtained. 7 and 8, (a) is a view of the analytical device of the present invention as viewed from above, and (b) is a cross-sectional view of the analytical device of the present invention.

In the analysis device of the present invention, the material constituting the optical waveguide preferably has a higher refractive index relationship between the material constituting the filter and the material constituting the optical waveguide. If the refractive index of the material composing the optical waveguide is higher than the refractive index of the material composing the filter, the amount of evanescent light absorbed and transmitted by the filter is very small and more sensitive to changes in the state near the optical waveguide. Therefore, accurate analysis becomes easy.
Specifically, the refractive index of the material constituting the filter is preferably 1.44 or less, and the refractive index of the material constituting the optical waveguide is preferably 1.45 or more. For example, in the case of an optical fiber with a reduced diameter, if the difference in refractive index is sufficiently higher than the surrounding refractive index to be 0.05 or more, a very strong waveguide structure can be obtained, and the minute size as shown in FIG. Even when bending is caused, the wave can be guided with a very small loss due to bending. Therefore, even if the blocking portion is long, the loss is very small, and it is possible to detect only the absorption of evanescent light. In addition, when the surrounding refractive index is changed in the increasing direction, a loss due to bending occurs, and it can be sensitively sensitive to changes in the refractive index. As a filter material, an organic material having a refractive index near 1.40 such as polydimethylsiloxane (PDMS) can be used. Since this material can sufficiently transmit even light having a wavelength of 200 nm, it is advantageous for spectroscopic analysis using ultraviolet rays. The optical waveguide is preferably made of silica glass. In this case, the refractive index is 1.4586, and light with a wavelength of 250 to 400 nm can be sufficiently transmitted.

The analysis device and the analysis apparatus of the present invention can detect the mixing or reaction of substances occurring in the vicinity of or inside the filter by various detection methods and forms. For example, a method / form for detecting a phenomenon in which the optical refractive index, light transmittance, and light absorption rate change before and after mixing or reaction of a substance, a method / form for detecting a phenomenon in which fluorescence or other light emission occurs, Examples include methods and forms for detecting the amount of change in other luminescent labels.
As methods and forms for detecting luminescence other than fluorescence, simultaneous analysis of two or more items at once, that is, emission spectroscopy (infrared, visible, ultraviolet, X-ray, etc.), Raman spectroscopy, circular dichroism, optical rotation dispersion , Photoacoustic spectroscopy, magnetic resonance, near-field spectroscopy, nonlinear laser spectroscopy, X-ray spectroscopy, photoelectron spectroscopy, photoionization spectroscopy, mass spectrometry, surface plasmon resonance, etc.

  When the optical refractive index around the optical waveguide changes, the transmission structure of the light propagating in the optical waveguide changes due to the change in the waveguide structure near the optical waveguide. It can be detected. When the optical absorptance around the optical waveguide changes, the optical absorptance of the evanescent light changes, and the transmittance of the light propagating through the optical waveguide changes, so that a state change in the vicinity of the optical waveguide can be detected. In these measurements, a light source capable of generating light having a wavelength corresponding to the wavelength at which the light absorption change occurs, such as a laser or a light emitting diode, may be used to measure changes in light of a specific wavelength. You may measure the change of the wavelength dependence of the light transmittance using a white light source. Measuring the change in the wavelength dependence of the light transmittance has a larger amount of information to be obtained and can measure a plurality of characteristics. When measuring fluorescence or Raman light, the optical waveguide also has a function of taking light emitted in the vicinity of the optical waveguide and guiding it to the photodetector. At this time, the generated light emission component such as fluorescence enters from the side surface of the optical waveguide, and a part thereof is taken into the optical waveguide and propagates. In the method and form for detecting a phenomenon in which optical characteristics such as light refractive index, light transmittance, and light absorption rate change, the amount of light transmitted through the optical waveguide is attenuated by absorption and transmission of evanescent light. In the method and form for detecting fluorescence and other light emission, the amount of light transmitted through the optical waveguide is increased.

  In addition, the analysis device and the analysis apparatus of the present invention can perform analysis using the principle of immunoassay using an immune reaction. Among them, a general enzyme immunoassay (ELISA) method (both sandwich method and competitive method) can be used as it is. However, since the optical properties such as light refractive index, light transmittance, and light absorption change before and after the binding between the antibody and the substance to be measured, the enzyme or the enzyme or radioimmunoassay (RIA) method is used. It is not necessary to add a radiolabel or a luminescent substrate. In particular, in the ultraviolet light region with a wavelength of 250 to 400 nm, the change in light transmittance due to the binding of the enzyme is large, and the utility value is great because it can be detected without labeling. In this case, if the light transmission characteristics in the ultraviolet region of both the optical waveguide and the filter are good, the light loss in the optical waveguide and in the filter is reduced, so that the detection sensitivity is improved.

Next, a filter used in the analysis device and analysis apparatus of the present invention (hereinafter also simply referred to as the filter of the present invention) will be described in detail.
The filter of the present invention has a plurality of pores, forms a plurality of compartments of the microreactor, and when the microreactor is used vertically, even if liquid is present on the surface of the filter, a constant force (pressure etc.) ), It is possible to prevent the passage of pores due to the surface tension of the liquid by selecting the size of the pores relative to the surface tension of the liquid. Or used for separation. Further, by adding the function of holding the liquid, even in the case of chemical reaction rate limiting, the reaction can proceed without causing pressure loss by holding the mixed substance in that region. Of course, it can be used not only as a filter for a vertical microreactor as described above but also as a filter for a horizontal microreactor.

Such a filter preferably satisfies the relationship of 0.001 μm ≦ D _a μm ≦ 100 μm, where D _a μm is the diameter of the pores. The diameter D _a of the pores is preferably smaller than the length of the pore.
Satisfying the relationship of D _a ≦ T _f · V _m where V _m μm / sec is the diffusion rate of molecules in the liquid to be sieved or separated and T _f sec is the filter passage time. Is preferred.
With the above-described configuration, the collision frequency between molecules due to molecular diffusion can be improved. As a result, for example, when a liquid reagent is used, the reaction time of the reagent can be significantly shortened compared to the others.

Further, in the filter of the present invention, the plurality of pores may be in a form formed in parallel in a honeycomb shape. In this case, when one side of the pore is D _b μm, it is preferable that the relationship of 0.0005 μm ≦ D _b μm ≦ 50 μm is satisfied. Moreover, it is preferable that one side _Db of a pore is smaller than the length of a pore.
Further, in this case, when the diffusion rate of molecules in the liquid to be screened or separated is V _m μm / sec and the filter passage time of the liquid is T _f sec, the relationship of 2D _b ≦ T _f · V _m is satisfied. Is preferred.
With the above configuration, the collision frequency between molecules by molecular diffusion can be improved. As a result, for example, when a liquid reagent is used, the reaction time of the reagent can be greatly shortened compared to other reagents.

The filter of the present invention is made of an insulating material, a metal processed by a LIGA (Lithography Galvanforung and Abforming) process using an X-ray lithography method, an insulating material, an insulating material, a heater wire, an insulating material, an insulating material, an X-ray. Metal processed by lithography method, insulating material, metal processed by X-ray lithography method, insulating material in order, insulating material, metal processed by X-ray lithography method, heater with heater wire sandwiched between insulators It is preferable to consist of a laminated body in which a layer, a metal processed by an X-ray lithography method, and an insulating material are laminated in this order.
By using a laminate of an insulating material, a metal, and an insulating material, voltage can be applied only to an intermediate metal material, and an electrode function can be added to the metal material. In addition, when an electrolyte fluid exists in the upper part of a filter having two metal layers, if a voltage is applied between the metal layers, only specific ions in the fluid are transferred to the lower part of the filter by electrophoresis or electroosmotic flow. Can be sent out. Furthermore, if the filter has a heater function, the fluid flowing inside the filter can be heated to induce a chemical reaction that occurs at room temperature or higher.

Examples of the metal used here include copper, aluminum, platinum, and gold. Examples of the insulating material include glass that insulates electricity and heat, polydimethylsiloxane, acrylic resin, and the like. Examples of the heater wire include titanium, gold, platinum, tungsten, and molybdenum.
The heater may be wired so as not to overlap with the hole, and a heater wire led from an external power source may be sandwiched between insulators. Further, by using a hollow pipe instead of the heater wire and flowing a heat medium therein, heating and cooling can be performed.

  Moreover, you may use mesoporous bodies, such as a porous silica body, as a filter of this invention. Also in this mesoporous body, a heater for heating the mesoporous body can be provided. For example, the heater is adjusted to a predetermined temperature by attaching a high-resistance heating element thin film such as tungsten on the upper surface of the mesoporous filter by plating, CVD, or the like, and controlling the current to be applied. In addition, it is good also as patterning a thick vapor deposition thin film of gold | metal | money, platinum, and titanium as a heater pattern using a UV photo process.

Furthermore, a microreactor (hereinafter also simply referred to as a microreactor) that can be applied to the analysis device and the analysis apparatus of the present invention will be described.
As shown in FIG. 1 (c), the microreactor of the present invention is formed by partitioning the inside of a cylindrical tank in a radial direction with a filter to form a compartment (reaction tank). In particular, the microreactor 11 shown in FIG. 1C is formed by dividing the inside of the tank by only one filter 2 to form two compartments. However, three compartments (two or more filters 2 are used). (Reaction tank) may be formed.

  In this case, the middle compartment (second reaction tank) sandwiched between the two filters may contain a large number of fine particles having a predetermined antibody or enzyme immobilized on the surface thereof. The efficiency and selectivity of the biochemical reaction can be improved by the fine particles having a predetermined antibody or enzyme immobilized on the surface.

  Next, the manufacturing method of the main body (tank and filter) of the microreactor of the present invention will be described. The main body of the microreactor is manufactured separately from the tank portion and the filter. Further, the cylindrical tank is further divided into cylindrical portions of each compartment (reaction tank). In that case, each compartment (reaction vessel) and the filter are produced by precision machining, electromagnetic wave processing using X-rays, ultraviolet rays or electron beams, or molding. By using these prepared ones, bonding with a thermosetting resin or a photo-curing resin or activating the metal surface so that the filter is sandwiched between the compartments (reaction tanks). Since the dangling bonds of the atoms on the metal surface are exposed on the surface, surface activated bonding is performed in which atoms constituting each tank to be bonded to the dangling bonds are bonded, and the microreactor 1 is formed. Examples of the thermosetting resin include a phenol resin, an acrylic resin, an epoxy resin, a melamine resin, a silicon resin, and an acrylic modified silicon resin. Examples of the ultraviolet curable resin include epoxy acrylate resins, polyester acrylate resins, and methacrylate-modified products thereof. The curing form may be any of thermosetting, ultraviolet curing, electron beam curing, etc., as long as it can be cured.

  The present invention can perform mixing or reaction evaluation / inspection of various substances, production of useful substances such as amino acids and antibodies, food industry, pharmaceuticals, medical products, analysis, separation / purification, environmental conservation, energy generation, etc. It can be expected to be used in other fields.

It is a figure which shows the specific examples, such as an analysis device of this invention, an analysis principle using the same, and an analysis form. In the analysis device of this invention, it is a figure which shows the example which used the optical fiber whose outer diameter is a taper type as an optical waveguide. In the analysis device of this invention, it is a figure which shows the example using the optical fiber which exposed the core as an optical waveguide. In the analysis device of this invention, it is a figure which shows the form which provided the optical waveguide inside the filter so that a pore might be crossed. In the analysis device of this invention, it is a figure which shows the form which provided the optical waveguide adjacent to the pore inside the filter. It is a figure which shows the form which provided the optical waveguide closely_contact | adhered to the surface of the filter in the analysis device of this invention. In the analysis device of this invention, it is a figure which shows the form which provided the optical waveguide in the spiral inside or near the filter. It is a figure which shows the form which branched and integrated the optical waveguide in multiple in the analytical device of this invention.

Explanation of symbols

DESCRIPTION OF SYMBOLS 1 Analysis device 2 Filter 3 Optical waveguide 4 Pore 5 Evanescent light 6 Optical characteristic change area | region 11 Microreactor 12 Light source 13 Detector

Claims (9)

  An analysis device comprising a plurality of pores and a filter in which a substance is mixed or reacted in or near the inside, and an optical waveguide provided in or near the filter.   The analysis device according to claim 1, wherein the optical waveguide has a core exposed.   The analysis device according to claim 1, wherein the optical waveguide is an optical fiber.   The analysis device according to claim 3, wherein the optical waveguide has a tapered outer diameter.   The analysis device according to claim 1, wherein the optical waveguide is provided inside the filter so as to cross the pore.   The analysis device according to claim 1, wherein the optical waveguide is provided inside the filter and adjacent to the pore.   The analysis device according to claim 1, wherein the optical waveguide is provided in close contact with a surface of the filter.   The analysis device according to claim 1, wherein the filter is made of a material having a lower refractive index than a material constituting the optical waveguide.   9. An analysis apparatus comprising: the analysis device according to claim 1; a light source that emits a light wave that passes through the optical waveguide; and a detector that detects the light wave emitted through the optical waveguide.

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