JP2003222628A - Receptor/ligand association method and reactor used therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a receptor/ligand association reaction method for efficiently associating a receptor or a ligand to the ligand or the receptor that is immobilized to a unit for biochemical analysis, and for generating quantitatively improved data with improved reproducibility, and to provide a reactor used for the method. <P>SOLUTION: A plurality of adsorbing regions containing a receptor or a ligand retain units 1 for biochemical analysis that are formed separately into a reaction bath 7. A reaction liquid 11 containing the ligand or receptor where minute magnetic beads that are labeled by a labeled substance are combined is accommodated in the reaction bath. A magnetic field for inverting the direction across the plurality of adsorbing regions is formed. The ligand or receptor contained in the reaction solution is forcibly moved across the plurality of adsorbing regions. Then, the ligand or receptor contained in the reaction solution is selectively associated with the receptor or ligand contained in the plurality of adsorbing regions. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a receptor-ligand association reaction method and a reactor used therefor, and more specifically, to a ligand or receptor immobilized on a biochemical analysis unit, efficiently,
The present invention relates to a receptor-ligand association reaction method and a reactor used for the method, which allows a receptor or a ligand to undergo an association reaction and can generate data for biochemical analysis with excellent reproducibility and excellent quantification.

[0002]

2. Description of the Related Art When a radiation is irradiated, the energy of the radiation is absorbed, stored and recorded, and then excited by using an electromagnetic wave of a specific wavelength range. A photostimulable phosphor having the property of emitting a stimulating amount of light is used as a radiation detection material, and a substance having a radioactive label is administered to an organism, and then the organism or tissue of the organism is treated. A portion of the sample is used as a sample, and this sample is overlapped with a stimulable phosphor sheet provided with a stimulable phosphor layer for a certain period of time to store and record radiation energy in the stimulable phosphor. , Scanning the stimulable phosphor layer with electromagnetic waves to excite the stimulable phosphor and photoelectrically detecting the stimulable light emitted from the stimulable phosphor to generate a digital image signal. Image processing, CRT On a recording material such as a display unit or on the photographic film, the autoradiographic analyzing system is configured to reproduce an image has been known (for example, Kokoku 1-70884 and JP Kokoku 1-70
882, Japanese Patent Publication No. 4-3962, etc.).

An autoradiography analysis system using a stimulable phosphor sheet as a radiation detecting material not only requires a chemical treatment called a developing treatment, unlike the case where a photographic film is used, but also was obtained. By subjecting the digital data to data processing, there is an advantage that the analysis data can be reproduced or a quantitative analysis by a computer can be performed as desired.

On the other hand, there is known a fluorescence analysis system using a fluorescent substance such as a fluorescent dye as a labeling substance instead of the radioactive labeling substance in the autoradiography analysis system. According to this fluorescence analysis system, by detecting the fluorescence emitted from the fluorescent substance, the gene sequence, the expression level of the gene, the metabolism, absorption, and excretion routes of the administered substance in the experimental mouse, the state, the separation of the protein, Identification or evaluation of molecular weight and characteristics can be performed. For example, a solution containing plural kinds of protein molecules to be electrophoresed is electrophoresed on the gel support, and then the gel support is subjected to fluorescence. An image is generated by staining the electrophoresed protein by immersing it in a solution containing a dye, exciting the fluorescent dye with excitation light, and detecting the resulting fluorescence, and then producing an image on the gel support. The position and quantitative distribution of protein molecules can be detected. Alternatively, by Western blotting,
A probe and a protein molecule prepared by transferring at least a part of the electrophoresed protein molecule onto a transfer support such as nitrocellulose and labeling an antibody that specifically reacts with the target protein with a fluorescent dye are prepared. By selectively associating and selectively labeling a protein molecule that binds only to an antibody that specifically reacts,
By exciting the fluorescent dye with the excitation light and detecting the generated fluorescence, an image can be generated and the position and quantitative distribution of the protein molecule on the transfer support can be detected. In addition, after adding a fluorescent dye to a solution containing a plurality of DNA fragments to be electrophoresed, the plurality of DNA fragments are electrophoresed on a gel support, or on a gel support containing a fluorescent dye. , A plurality of DNA fragments are electrophoresed, or a plurality of DNA fragments are electrophoresed on a gel support, and then the gel support is immersed in a solution containing a fluorescent dye. DNA fragments are labeled, a fluorescent dye is excited by excitation light, and the resulting fluorescence is detected to generate an image, and the distribution of DNA on the gel support is detected, or a plurality of DNAs are detected.
The fragments are electrophoresed on a gel support, followed by DNA
Denaturation, and then by Southern blotting, at least a part of the denatured DNA fragment is transferred onto a transfer support such as nitrocellulose, and DNA or RNA complementary to the target DNA is fluorescent dye. A probe DNA or probe RN prepared by hybridizing a probe prepared by labeling with
Only the DNA fragment complementary to A is selectively labeled, the fluorescent dye is excited by the excitation light, and the resulting fluorescence is detected to generate an image, so that the DNA of interest on the transfer support is detected. The distribution can be detected. further,
DN containing a target gene labeled with a labeling substance
A DNA probe complementary to A is prepared, hybridized with the DNA on the transcription support, and the enzyme is allowed to bind to the complementary DNA labeled with a labeling substance, and then contacted with a fluorescent substrate for fluorescence. An image is generated by changing the substrate to a fluorescent substance that emits fluorescence, exciting the generated fluorescent substance with excitation light, and detecting the generated fluorescence,
It is also possible to detect the distribution of the target DNA on the transcription support. This fluorescence analysis system has an advantage that gene sequences and the like can be easily detected without using radioactive substances.

Similarly, a specific binding substance such as protein or nucleic acid is immobilized on a biochemical analysis unit such as a membrane filter and is labeled with a labeling substance which causes chemiluminescence by contacting with a chemiluminescent substrate. A substance derived from a living body is specifically bound to a specific binding substance,
Visible light generated by contact between the chemiluminescent substrate and the labeling substance by bringing the chemiluminescent substrate into contact with the binding substance of the specific binding substance selectively labeled with the labeling substance and the substance of biological origin The chemiluminescence in the wavelength range is photoelectrically detected, a digital signal is generated, image processing is performed, and C
A chemiluminescence analysis system is also known in which a chemiluminescence image is displayed on a display means such as RT or a recording material such as a photographic film to obtain information on a substance of biological origin such as gene information.

Furthermore, in recent years, cells at different positions on the surface of a carrier such as a slide glass plate or a membrane filter,
Viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNA
A specific binding substance, such as A, DNA, or RNA, which can be specifically bound to a substance of biological origin and whose base sequence, base length, composition, etc. is known, is dropped using a spotter device. , Forming a large number of independent spots, then cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, c
A substance derived from a living body, such as DNA, DNA, or mRNA, which is collected from the living body by extraction or isolation, or which is further subjected to a chemical treatment, a chemical modification, or the like, such as a fluorescent substance or a dye. A substance labeled with a labeling substance is bound to a specific binding substance by hybridization or the like, to a microarray that is specifically bound,
A microarray analysis system has been developed which irradiates excitation light and photoelectrically detects light such as fluorescence emitted from a labeling substance such as a fluorescent substance or a dye to analyze a substance derived from a living body. According to this microarray analysis system,
A large number of spots of specific binding substances are formed at high density at different positions on the surface of a carrier such as a slide glass plate or a membrane filter, and the substance of biological origin labeled with the labeling substance is hybridized, thus In time, there is an advantage that it is possible to analyze a substance of biological origin.

In addition, cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNAs, DNAs, RNAs, etc. derived from living organisms are located at different positions on the surface of a carrier such as a membrane filter. The specific binding substance that can specifically bind to the substance of which the base sequence, base length, composition, etc. are known is dropped using a spotter device to form a large number of independent spots. , Then, cells, viruses, hormones, tumor markers, enzymes, antibodies, antigens, abzymes, other proteins, nucleic acids, cDNAs, DNAs, mRNAs, etc., collected from the living body by extraction or isolation, or
Furthermore, a substance derived from a living body, which has been subjected to a chemical treatment, a chemical modification, or the like, and which is labeled with a radioactive labeling substance, is specifically bound to a specific binding substance by hybridization or the like. Macro array,
The stimulable phosphor layer containing the stimulable phosphor is brought into close contact with the stimulable phosphor sheet, and the stimulable phosphor layer is exposed.
After that, the photostimulable phosphor layer is irradiated with excitation light, the photostimulable light emitted from the photostimulable phosphor layer is photoelectrically detected, and biochemical analysis data is generated. A macroarray analysis system using a radiolabeled substance for analyzing is also developed.

[0008]

In a microarray analysis system or a macroarray analysis system, a solution containing a specific binding substance is dropped at different positions on the surface of a biochemical analysis unit such as a membrane filter, and a large number of A specific substance contained in the spot-like region is a biological substance labeled with a radioactive substance, a fluorescent substance, or a labeling substance that causes chemiluminescence when contacted with a chemiluminescent substrate. By hybridizing with the binding substance, the specific binding substance is selectively labeled, and the stimulable phosphor layer of the stimulable phosphor sheet is changed by the radioactive labeling substance selectively contained in a large number of spot-shaped regions. Exposed, the exposed photostimulable phosphor layer, scanned by excitation light, to excite the photostimulable phosphor contained in the photostimulable phosphor layer, Photostimulated photostimulable light emitted from the photostimulable phosphor is generated photoelectrically to generate data for biochemical analysis, or a large number of spot-shaped regions are scanned with excitation light to form a large number of spot-shaped regions. Exciting the fluorescent substance selectively contained, photoelectrically detecting the fluorescence emitted from the fluorescent substance, to generate biochemical analysis data, or
It is required to generate data for biochemical analysis by contacting a chemiluminescent substrate with a labeling substance selectively contained in many spot-like regions and photoelectrically detecting chemiluminescence emitted from the labeling substance. Has been done.

In the case of hybridizing a specific binding substance with a substance of biological origin, conventionally, an experimenter manually performed biochemistry such as a membrane filter in which a large number of spot-shaped regions containing the specific binding substance were formed. The analysis unit is placed in a hybridization bag, and a substance derived from a living body labeled with a labeling substance that causes chemiluminescence by contacting with a radioactive labeling substance, a fluorescent substance, or a chemiluminescent substrate is placed in the hybridization bag. Add a hybridization solution containing the product, and apply vibration to the hybridization bag to move the substance of biological origin by convection or diffusion to hybridize the specific binding substance and the substance of biological origin. Remove from hybridization bag and fill with wash solution Placed in the vessel for cleaning was generally.

However, the experimenter manually puts the unit for biochemical analysis in the hybridization bag, adds the hybridization solution, and vibrates the hybridization bag so that the specific binding substance and the biological origin can be obtained. When hybridizing the substance of
It is difficult to uniformly contact the hybridization solution with a large number of spot-shaped regions containing the specific binding substance, and therefore the specific binding substance and the substance of biological origin cannot be efficiently hybridized. There was a problem.

Further, the experimenter manually puts the unit for biochemical analysis in the hybridization bag, adds the hybridization solution, and vibrates the hybridization bag so that the specific binding substance and the biogenic substance are derived. Hybridize the substance of the above, remove the unit for biochemical analysis from the hybridization bag,
When the washing solution is placed in a container filled with a washing solution and washed, it is unavoidable that the results of hybridization vary depending on the experimenter and the reproducibility is deteriorated.
Even the same experimenter has a problem that the reproducibility may decrease.

[0012] An antigen or an antibody is fixed to a biochemical analysis unit such as a membrane filter, and a ligand and a receptor are associated with each other as in the case of binding the antibody or the antigen to the fixed antigen or the antibody by an antigen-antibody reaction. In the case of reacting, there is a similar problem. Furthermore, a target DNA fixed to a biochemical analysis unit such as a membrane filter is hybridized with a probe DNA labeled with a hapten such as digoxigenin, and further chemiluminescence Antibodies to haptens such as digoxigenin that are labeled with an enzyme that causes chemiluminescence when contacted with a substrate, and haptens such as digoxigenin that is labeled with an enzyme that has the property of producing a fluorescent substance when contacted with a fluorescent substrate. antibody , The antigen-antibody reaction, by binding to a hapten that is labeled probes DNA, even when the target DNA is labeled, there is a similar problem.

Therefore, according to the present invention, the ligand or receptor immobilized on the biochemical analysis unit can be efficiently associated with the receptor or the ligand, and the reproducibility and the quantification are excellent. Receptor that makes it possible to generate data for chemical analysis
An object of the present invention is to provide a ligand association reaction method and a reactor used therefor.

[0014]

The object of the present invention is to:
Multiple absorptive regions containing receptors or ligands
The biochemical analysis units formed apart from each other are held in a reaction tank, and a reaction solution containing a ligand or a receptor labeled with a labeling substance, to which minute magnetic beads are bound, is contained in the reaction tank. , Across the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank, to generate a magnetic field whose direction is reversed, the ligand or receptor contained in the reaction solution, Crossing over the plurality of absorptive regions of the biochemical analysis unit, forcibly moved, contained in the reaction solution in the receptor or ligand contained in the plurality of absorptive regions of the biochemical analysis unit. Receptor-ligand association reaction method characterized by selectively associating different ligands or receptors.

In the present invention, the receptor-ligand association reaction includes a hybridization reaction and an antigen-antibody reaction.

According to the present invention, magnetic fields having different directions are alternately generated across a plurality of absorptive regions formed on the substrate of the biochemical analysis unit held in the reaction tank. , The ligands or receptors contained in the reaction solution and bound to the magnetic beads are forcibly moved alternately from different directions across the absorptive region of the biochemical analysis unit held in the reaction tank. Was, therefore,
Even when the receptor or ligand is contained in the deep part of the multiple adsorptive regions of the biochemical analysis unit,
The probability that the receptors or ligands contained in the plurality of adsorptive regions of the biochemical analysis unit will associate with the ligands or receptors contained in the reaction solution can be significantly increased, and therefore, the receptor-ligand association reaction can be achieved. It is possible to greatly improve the efficiency of.

[0017] In a preferred aspect of the present invention, at least one coil is supplied with electric currents having different directions at predetermined time intervals so that the plurality of biochemical analysis units held in the reaction tank have the plurality of units. It is configured to generate a magnetic field that crosses the adsorptive region and has its orientation reversed every predetermined time.

In a preferred embodiment of the present invention, at least one coil is supplied with electric currents having different directions at predetermined time intervals so that a plurality of absorptive regions of the biochemical analysis unit held in the reaction tank are provided. Since the orientation of the magnetic beads is such that the orientation of the magnetic field is reversed every predetermined time, the ligands or receptors contained in the reaction solution and bound to the magnetic beads are alternated every predetermined time. , From different directions, across the absorptive region of the biochemical analysis unit held in the reaction vessel, and thus the receptor or ligand is transferred to the biochemical analysis unit's absorptive regions. Even if it is contained in the deep part of the biochemical analysis unit, the receptor or ligand contained in the multiple absorptive regions of the biochemical analysis unit and the ligand contained in the reaction solution Or the probability of receptor and is associated can be greatly increased, thus, the efficiency of the receptor-ligand association reaction, it is possible to greatly improve.

In the present invention, the magnetic beads are 1 nm.
The particle size is preferably from 1 to 1 μm, more preferably from 10 nm to 10 μm.

In the present invention, the material for forming the magnetic beads is not particularly limited as long as it has magnetism. For example, ferrite or the like may be used to form the magnetic beads of the present invention. it can.

In the present invention, the method for binding the magnetic beads to the ligand or the receptor is not particularly limited, and streptavidin-labeled magnetic beads (trade name: Dynanavies), biotin-labeled RNA,
The magnetic beads can be bound to the ligand or receptor by a method such as reacting with DNA or a protein (for example, an antibody or an antigen) by a covalent bond or an ionic bond.

In the present invention, the method for generating a magnetic field is
The magnetic field is not particularly limited, and a magnetic field can be generated by energizing a coil, for example.

In a preferred embodiment of the present invention, an alternating current is supplied to the coil so as to traverse a plurality of absorptive regions of the biochemical analysis unit, and the direction of the absorptive region is changed at predetermined intervals.
It is configured to generate a reversing magnetic field.

In a preferred embodiment of the present invention, a biochemical analysis unit having a plurality of absorptive regions containing a specific binding substance separated from each other is held in a reaction tank, and the biochemical analysis unit is held in the reaction tank. , A reaction solution containing a substance derived from a living body labeled with a labeling substance, to which microscopic magnetic beads are bound, and traversing the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank. , A magnetic field whose direction is reversed to generate a bio-derived substance contained in the reaction solution, across the plurality of absorptive regions of the biochemical analysis unit, and forcibly moved, The specific binding substance contained in the plurality of absorptive regions of the biochemical analysis unit is configured to selectively hybridize the substance of biological origin contained in the reaction solution.

In a preferred embodiment of the present invention, a unit for biochemical analysis in which a plurality of absorptive regions containing a specific binding substance are formed separately from each other is held in a reaction tank, and the biochemical analysis unit is held in the reaction tank. , Labeled with a hapten, containing a reaction solution containing a substance of biological origin to which microscopic magnetic beads are bound, traverses the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank, A magnetic field whose direction is reversed is generated, and the substance of biological origin contained in the reaction solution is forcedly moved across the plurality of absorptive regions of the biochemical analysis unit, and The specific binding substance contained in the plurality of adsorptive regions of the chemical analysis unit is selectively hybridized with the substance of biological origin contained in the reaction solution, and the labeled enzyme is added in the reaction tank. By Labeled, containing an antibody solution containing an antibody to the hapten to which microscopic magnetic beads are bound, traverses the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank, its direction is It is configured to generate a reversing magnetic field to cause the hapten contained in the plurality of absorptive regions of the biochemical analysis unit to react with the antibody labeled with the labeling enzyme with the antigen-antibody reaction.

In the present invention, examples of the hapten / antibody combination include digoxigenin / anti-digoxigenin antibody, theophylline / anti-theophylline antibody, fluorescein / anti-fluorescein antibody and the like.
It is also possible to use a combination of biotin / avidin, antigen / antibody, etc., instead of the hapten / antibody.

[0027] In a further preferred aspect of the present invention, a plurality of absorptive regions containing a specific binding substance are held in a reaction tank to hold a biochemical analysis unit, which is formed in the reaction tank. Labeled by the hapten,
A magnetic field in which a reaction solution containing a substance derived from a living body to which minute magnetic beads are bound is accommodated and which traverses the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank and the direction thereof is reversed. To produce a substance of biological origin contained in the reaction solution, across the plurality of absorptive regions of the biochemical analysis unit, forcibly moved, the biochemical analysis unit of the By selectively hybridizing a substance of biological origin contained in the reaction solution with a specific binding substance contained in a plurality of adsorptive regions, and bringing the substance into contact with a chemiluminescent substrate in the reaction tank. The biochemical analysis unit containing an antibody solution containing an antibody to the hapten, which is labeled with an enzyme that causes chemiluminescence, and to which microscopic magnetic beads are bound, and is held in the reaction tank. Across a number of absorptive regions, generating a magnetic field whose direction is reversed, and contacting the haptens contained in the plurality of absorptive regions of the biochemical analysis unit with a chemiluminescent substrate An antibody labeled with an enzyme that produces luminescence is configured to react with an antigen-antibody.

In another preferred embodiment of the present invention, a biochemical analysis unit having a plurality of absorptive regions containing a specific binding substance separated from each other is held in the reaction tank, Inside, labeled by the hapten,
A magnetic field in which a reaction solution containing a substance derived from a living body to which minute magnetic beads are bound is accommodated and which traverses the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank and the direction thereof is reversed. To produce a substance of biological origin contained in the reaction solution, across the plurality of absorptive regions of the biochemical analysis unit, forcibly moved, the biochemical analysis unit of the Specific binding substances contained in a plurality of absorptive regions, a substance of biological origin contained in the reaction solution is selectively hybridized, and in the reaction vessel, by contacting with a fluorescent substrate, The plurality of biochemical analysis units, which are labeled with an enzyme that produces a fluorescent substance, contain an antibody solution containing an antibody to the hapten to which microscopic magnetic beads are bound, and are held in the reaction tank. A magnetic field is generated that crosses the absorptive region and its direction is reversed, and the hapten contained in the plurality of absorptive regions of the biochemical analysis unit is brought into contact with a fluorescent substrate to generate a fluorescent substance. The antibody labeled with the enzyme that causes the antigen-antibody reaction is configured.

[0029] In a preferred aspect of the present invention, the biochemical analysis unit includes a substrate having a plurality of holes separated from each other, and the plurality of absorptive regions are formed on the substrate. The adsorptive material filled in the plurality of pores is made to contain a receptor or a ligand.

[0030] In a further preferred aspect of the present invention, the biochemical analysis unit includes a substrate having a plurality of through holes spaced apart from each other, and the plurality of absorptive regions are formed on the substrate. The receptor material or the ligand is contained in the absorptive material filled in the plurality of through-holes thus formed, and thus formed.

In a further preferred aspect of the present invention, the plurality of absorptive regions of the biochemical analysis unit have an absorptive film containing an absorptive material in a plurality of through holes formed in the substrate. Is press-fitted, and the adsorptive membrane is made to contain a receptor or a ligand.

In a further preferred aspect of the present invention, the biochemical analysis unit includes a substrate having a plurality of recesses spaced apart from each other, and the plurality of absorptive regions are formed on the substrate. Further, the adsorptive material filled in the plurality of recesses is made to contain a receptor or a ligand.

[0033] In another preferred aspect of the present invention, the biochemical analysis unit is configured such that an absorptive substrate and a plurality of through-holes are formed separately from each other, and at least one surface of the absorptive substrate is formed. A plurality of absorptive regions are formed by closely contacting the substrates, and the absorptive substrates in the plurality of through holes formed in the substrate are made to contain a receptor or a ligand.

In a preferred embodiment of the present invention, the biochemical analysis unit is formed with 10 or more absorptive regions.

[0035] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 50 or more absorptive regions.

[0036] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 100 or more absorptive regions.

In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 500 or more absorptive regions.

[0038] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 1000 or more absorptive regions.

In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 5000 or more absorptive regions.

[0040] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 10,000 or more absorptive regions.

[0041] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 50,000 or more absorptive regions.

[0042] In a further preferred aspect of the present invention, the biochemical analysis unit is formed with 100,000 or more absorptive regions.

[0043] In a preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 5 mm 2.

[0044] In a further preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 1 mm 2.

In a further preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 0.5 mm 2.

[0046] In a further preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 0.1 mm 2.

[0047] In a further preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 0.05 mm 2.

[0048] In a further preferred aspect of the present invention, each of the plurality of absorptive regions of the biochemical analysis unit has a size of less than 0.01 mm 2.

[0049] In a preferred aspect of the present invention, the plurality of absorptive regions are provided in the biochemical analysis unit.
It is formed with a density of 10 pieces / square centimeter or more.

[0050] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 50 or more per cm 2.

[0051] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 100 or more per cm 2.

[0052] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 500 or more per cm 2.

[0053] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 1,000 or more per cm 2.

[0054] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 5,000 or more per cm 2.

[0055] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 10,000 or more per cm 2.

[0056] In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 50,000 or more per cm 2.

In a further preferred aspect of the present invention, the plurality of absorptive regions are formed in the biochemical analysis unit at a density of 100,000 per square centimeter or more.

[0058] In a preferred aspect of the present invention, the plurality of absorptive regions are provided in the biochemical analysis unit.
It is formed in a regular pattern.

[0059] In a preferred aspect of the present invention, the plurality of through holes are formed in a substantially circular shape in the substrate of the biochemical analysis unit.

In the present invention, the plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive material filled in the plurality of holes formed in the substrate. Alternatively, if the plurality of absorptive regions of the biochemical analysis unit are formed by allowing the absorptive substrate in the plurality of through holes formed in the substrate to contain a receptor or a ligand, it is preferable. ,
The substrate of the biochemical analysis unit has a property of attenuating the energy of radiation.

According to a preferred embodiment of the present invention, since the substrate of the biochemical analysis unit has a property of attenuating the energy of radiation, the biochemical analysis unit has a high density of absorptive regions. A bio-derived substance labeled with a radioactive labeling substance is hybridized with a specific binding substance formed in a plurality of absorptive regions of the biochemical analysis unit to selectively label the biochemical substance. A support for the stimulable phosphor sheet is obtained by superimposing the analytical unit and the stimulable phosphor sheet on which the stimulable phosphor layer is formed, and by using a radioactive labeling substance selectively contained in a plurality of absorptive regions. When the stimulable phosphor layer formed on the substrate is exposed and the radiation data is recorded on the stimulable phosphor layer of the stimulable phosphor sheet, it is also released from the radioactive labeling substance contained in each absorptive region. Electron beam Beta rays can be effectively prevented from scattering in the substrate of the biochemical analysis unit, and therefore, the electron beams (beta rays emitted from the radiolabeled substance contained in each adsorptive region can be prevented. ) Is selectively incident on the region of the corresponding photostimulable phosphor layer to expose only the region of the corresponding photostimulable phosphor layer. By scanning multiple stimulable phosphor layers with excitation light and photoelectrically detecting the stimulable light emitted from the stimulable phosphor layers, high resolution and highly quantitative biochemical analysis It becomes possible to generate data for.

[0062] In a preferred aspect of the present invention, when the substrate of the biochemical analysis unit is exposed to radiation by a distance equal to the distance between the adjacent absorptive regions, Energy of 1/5
It has the following property of damping.

[0063] In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits radiation through the substrate by a distance equal to a distance between the adjacent absorptive regions, The energy of radiation
It has the property of being attenuated to 1/10 or less.

[0064] In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits radiation through the substrate by a distance equal to a distance between the adjacent absorptive regions, The energy of radiation
It has the property of being attenuated to 1/50 or less.

In a further preferred aspect of the present invention, when radiation is transmitted through the substrate by a distance equal to the distance between the absorptive regions of the substrate of the biochemical analysis unit, The energy of radiation
It has the property of being attenuated to 1/100 or less.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits radiation through the substrate by a distance equal to the distance between the adsorbing regions adjacent to each other, The energy of radiation
It has the property of being attenuated to 1/500 or less.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit has radiation transmitted through the substrate by a distance equal to the distance between the adjacent absorptive regions, The energy of radiation
It has the property of being attenuated to 1/1000 or less.

In the present invention, when the plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive material filled in the plurality of holes formed in the substrate Alternatively, if the plurality of absorptive regions of the biochemical analysis unit are formed by allowing the absorptive substrate in the plurality of through holes formed in the substrate to contain a receptor or a ligand, it is preferable. ,
The substrate of the biochemical analysis unit has a property of attenuating light energy.

According to a preferred embodiment of the present invention, since the substrate of the biochemical analysis unit has a property of attenuating the energy of light, the biochemical analysis unit substrate has a high absorptive region. Select a substance of biological origin that is labeled with a labeling substance that forms chemiluminescence by contacting with a fluorescent substance or a chemiluminescent substrate to the specific binding substance that is formed to a density and is contained in multiple adsorptive regions. By the way
Even when bonded, it is effective that the fluorescence and chemiluminescence emitted from a large number of adsorptive regions are scattered in the substrate and mixed with the fluorescence and chemiluminescence emitted from the adsorbing regions adjacent to each other. Therefore, it is possible to prevent fluorescence, and thus it is possible to photoelectrically detect fluorescence or chemiluminescence to generate biochemical analysis data with excellent quantitativeness.

Further, according to a preferred embodiment of the present invention, since the substrate of the biochemical analysis unit has a property of attenuating light energy, the absorptive region is formed on the substrate of the biochemical analysis unit. Are formed at a high density, and substances of biological origin labeled with fluorescent substances are selectively bound to specific binding substances contained in multiple absorptive regions and then excited to multiple absorptive regions. When light is irradiated to excite the fluorescent substance contained in the absorptive region, the excitation light incident on each absorptive region is scattered and is incident on the absorptive regions adjacent to each other, and the absorptive regions adjacent to the absorptive region are adsorbed. It is possible to effectively prevent the fluorescent substance contained in the intrinsic region from being excited.

[0071] In a preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light in the substrate by a distance equal to the distance between the adsorbing regions adjacent to each other, Has the property of attenuating the energy of 1/5 or less.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light through the substrate by a distance equal to the distance between the adjacent absorptive regions, 1/10 of the energy of light
It has the following property of damping.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light through the substrate by a distance equal to the distance between the adjacent absorptive regions, 1/50 the energy of light
It has the following property of damping.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light through the substrate by a distance equal to the distance between the adjacent absorptive regions, 1/10 of the energy of light
It has the property of being attenuated to 0 or less.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light through the substrate by a distance equal to the distance between the adjacent absorptive regions, 1/50 the energy of light
It has the property of being attenuated to 0 or less.

In a further preferred aspect of the present invention, when the substrate of the biochemical analysis unit transmits light through the substrate by a distance equal to the distance between the adjacent absorptive regions, 1/10 of the energy of light
It has the property of being attenuated to 00 or less.

In the present invention, a plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive material filled in the plurality of holes formed in the substrate. Alternatively, when the plurality of absorptive regions of the biochemical analysis unit are formed by containing the receptor or the ligand in the absorptive substrate in the plurality of through holes formed in the substrate, the biochemical analysis is performed. The material for forming the substrate of the analysis unit preferably has a property of attenuating radiation and / or light, but is not particularly limited and may be an inorganic compound material or an organic compound material. Can also be used,
Metal material, ceramic material or plastic material
Preferably used.

In the present invention, the plurality of absorptive regions of the biochemical analysis unit are formed by containing the receptor or the ligand in the absorptive material filled in the plurality of holes formed in the substrate. Alternatively, when a plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive substrate in a plurality of through holes formed in the substrate, the biochemical analysis is performed. Examples of the inorganic compound material that can be preferably used to form the substrate of the unit for use include gold, silver,
Copper, zinc, aluminum, titanium, tantalum, chrome,
Metals such as iron, nickel, cobalt, lead, tin and selenium;
Alloys such as brass, stainless steel and bronze; silicon materials such as silicon, amorphous silicon, glass, quartz, silicon carbide and silicon nitride; metal oxides such as aluminum oxide, magnesium oxide and zirconium oxide; tungsten carbide, calcium carbonate, sulfuric acid. Inorganic salts such as calcium, hydroxyapatite and gallium arsenide can be mentioned. These may have any structure in a polycrystalline sintered body such as single crystal, amorphous, or ceramic.

In the present invention, the plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive material filled in the plurality of holes formed in the substrate. Alternatively, when a plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive substrate in a plurality of through holes formed in the substrate, the biochemical analysis is performed. As the organic compound material that can be used to form the substrate of the unit for use, a polymer compound is preferably used, and a polymer compound that can be preferably used is, for example, a polyolefin such as polyethylene or polypropylene; polymethylmethacrylate. , Butyl acrylate /
Acrylic resins such as methylmethacrylate copolymers; polyacrylonitrile; polyvinyl chloride; polyvinylidene chloride; polyvinylidene fluoride; polytetrafluoroethylene; polychlorotrifluoroethylene; polycarbonate; polyesters such as polyethylene naphthalate and polyethylene terephthalate; nylon 6 Polyamide; Polysulfone; Polyphenylene sulfide; Silicon resin such as polydiphenylsiloxane; Phenolic resin such as novolac; Epoxy resin; Polyurethane; Polystyrene; Butadiene-styrene copolymer; Cellulose Polysaccharides such as cellulose acetate, nitrocellulose, starch, calcium alginate, hydroxypropylmethylcellulose; ; Chitosan; lacquer; gelatin, collagen, copolymers of polyamides and these high molecular compounds, such as keratin, and the like.
These may be a composite material, if necessary, can be filled with metal oxide particles or glass fiber,
It is also possible to blend and use an organic compound material.

Generally, the larger the specific gravity is, the higher the radiation attenuating ability is. Therefore, the plurality of absorptive regions of the biochemical analysis unit are receptive to the absorptive material filled in the plurality of holes formed in the substrate. Alternatively, when it is formed by containing a ligand, or when the plurality of absorptive regions of the biochemical analysis unit are formed by containing a receptor or a ligand in the absorptive substrate in the plurality of through holes formed in the substrate. If formed, the substrate of the biochemical analysis unit is preferably formed of a compound material or a composite material having a specific gravity of 1.0 g / cm ³ or more, and a specific gravity of 1.5 g / cm ³ or more. , 23 g / cm ³ or less of the compound material or the composite material is particularly preferable.

In general, the greater the light scattering and / or absorption, the higher the light attenuating ability. Therefore, the plurality of absorptive regions of the biochemical analysis unit are filled in the plurality of holes formed in the substrate. If the adsorbent material is formed by containing a receptor or a ligand in the adsorbed material, or if a plurality of absorptive regions of the biochemical analysis unit are formed in the plurality of through holes formed in the substrate In the case where the substrate of the biochemical analysis unit is formed by containing a receptor or a ligand, the absorbance per 1 cm of thickness is preferably 0.3 or more, and the thickness of 1 c
More preferably, the absorbance per m is 1 or more.
Here, the absorbance is calculated by calculating the A / T by placing an integrating sphere immediately after the plate having a thickness of Tcm and measuring the transmitted light amount A at the wavelength of the probe light or the emission light used for the measurement with a spectrophotometer. By being asked. In order to improve the light attenuating ability, a light scatterer or a light absorber may be contained in the substrate of the biochemical analysis unit.
Fine particles of a material different from the material forming the substrate of the biochemical analysis unit are used as the light scatterer, and pigments or dyes are used as the light absorber.

In another preferred embodiment of the present invention, the biochemical analysis unit comprises an absorptive substrate,
The plurality of absorptive regions are formed by allowing the absorptive substrate to contain a receptor or a ligand.

In the present invention, a porous material or a fibrous material is preferably used as the absorptive material for forming the absorptive region or the absorptive substrate of the biochemical analysis unit. The absorptive region or the absorptive substrate can be formed by using the porous material and the fiber material together.

In the present invention, the porous material used to form the adsorptive region of the biochemical analysis unit or the adsorptive substrate may be either an organic material or an inorganic material, or an organic / inorganic composite. .

In the present invention, the organic porous material used for forming the absorptive region or the absorptive substrate of the biochemical analysis unit is not particularly limited, but is a carbon material such as activated carbon or a membrane. A material capable of forming a filter is preferably used. Specifically, nylons such as nylon 6, nylon 6,6, nylon 4,10; nitrocellulose, cellulose acetate,
Cellulose derivatives such as cellulose acetate butyrate; collagen; alginic acid, calcium alginate, alginic acid /
Alginic acids such as polylysine polyion complex; polyolefins such as polyethylene and polypropylene; polyvinyl chloride; polyvinylidene chloride; polyfluoride such as polyvinylidene fluoride and polytetrafluoride; and copolymers or composites thereof. .

In the present invention, the inorganic porous material used to form the adsorptive region or the adsorptive substrate of the biochemical analysis unit is not particularly limited, but preferably, for example, platinum, Examples thereof include metals such as gold, iron, silver, nickel and aluminum; metal oxides such as alumina, silica, titania and zeolite; metal salts such as hydroxyapatite and calcium sulfate, and complexes thereof.

In the present invention, the fibrous material used for forming the adsorptive region or the adsorptive substrate of the biochemical analysis unit is not particularly limited, but preferably, for example, nylon 6 or nylon. Nylons such as 6,6 and nylon 4,10, nitrocellulose,
Examples thereof include cellulose derivatives such as cellulose acetate and cellulose butyrate.

In the present invention, the absorptive region of the biochemical analysis unit is subjected to electrolytic treatment, plasma treatment, oxidation treatment such as arc discharge; primer treatment using a silane coupling agent, titanium coupling agent or the like; surfactant. It can also be formed by surface treatment such as treatment.

The above object of the present invention is also provided with a biochemical analysis unit holding section capable of holding a biochemical analysis unit in which a plurality of absorptive regions containing a receptor or a ligand are formed apart from each other. A reaction tank capable of accommodating a reaction solution containing a ligand or a receptor, and a magnetic field generation for generating a magnetic field whose direction is reversed across the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank It is achieved by a reactor characterized in that it is equipped with means.

According to the present invention, the reactor is provided with the biochemical analysis unit holding portion capable of holding the biochemical analysis unit in which a plurality of absorptive regions containing the receptor or the ligand are formed apart from each other. , A reaction tank capable of accommodating a reaction solution containing a ligand or a receptor, and a magnetic field generating means for generating a magnetic field whose direction is reversed across a plurality of absorptive regions of the biochemical analysis unit held in the reaction tank. Because it has, it is labeled with a labeling substance,
A plurality of absorptive regions of the biochemical analysis unit held in the reaction tank are prepared by preparing a reaction solution containing a ligand or a receptor to which microscopic magnetic beads are bound, and storing the reaction solution in the reaction tank. Contained in the reaction solution by generating a magnetic field whose direction is reversed across
The magnetic bead-bound ligands or receptors can be forced to alternate, from different directions, across the absorptive region of the biochemical analysis unit held in the reaction vessel, thus: Even when the receptor or ligand is contained in the deep portion of the multiple adsorption regions of the biochemical analysis unit, the receptor or ligand contained in the multiple adsorption regions of the biochemical analysis unit and the reaction solution It is possible to significantly increase the probability of association with the ligand or receptor contained in the, and thus to significantly improve the efficiency of the receptor-ligand association reaction.

In a preferred embodiment of the present invention, the magnetic field generating means is composed of at least one coil and a power supply capable of supplying different currents to the at least one coil.

In a further preferred aspect of the present invention, the power source is an AC power source.

[0093]

Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.

FIG. 1 is a schematic perspective view of a biochemical analysis unit used in the receptor-ligand association reaction method according to a preferred embodiment of the present invention.

As shown in FIG. 1, the biochemical analysis unit 1 according to this embodiment comprises a substrate 2 formed of silicon nitride and having a large number of substantially circular through holes 3 formed therein at a high density. Nylon 6 is filled inside the large number of through holes 3 to form a large number of dot-shaped absorptive regions 4.

Although not shown exactly in FIG. 1, in the present embodiment, the substantially circular through holes 3 having a size of about 0.01 mm 2 are regularly arranged in a matrix of 120 columns × 160 rows. Is formed on the substrate 2,
Therefore, a total of 19200 absorptive regions 4 are formed. The absorptive region 4 is formed by filling a large number of through holes 3 with nylon 6 so that the surface thereof is located at the same height as the surface of the substrate 2.

In the biochemical analysis, in a large number of absorptive regions 4 regularly formed in the biochemical analysis unit 1, for example, as a specific binding substance, a plurality of different cDNAs whose base sequences are known are different from each other. Are dropped using a spotting device and adsorbed in the absorptive region 4.

FIG. 2 is a schematic front view of the spotting device.

As shown in FIG. 2, the spotting device is equipped with an injector 5 and a CCD camera 6 for injecting a solution of a specific binding substance toward the surface of the biochemical analysis unit 1. Injector 5
While observing the tip of the injector and the absorptive region 4 of the biochemical analysis unit 1 on which the specific binding substance should be dropped, the tip of the injector 5 and the center of the absorptive region 4 on which the specific binding substance should be dropped. When and match, from the injector 5,
It is configured such that a plurality of specific binding substances such as cDNAs having different known base sequences are dropped, and in the many dot-shaped absorptive regions 4 of the biochemical analysis unit 1,
The specific binding substance is guaranteed to be able to be dripped accurately.

[0100] Then, the specific binding substance such as cDNA adsorbed on the large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 is separated from the substance derived from the living body labeled with the labeling substance. , Selectively, hybridized.

FIG. 3 is a schematic perspective view of a reactor used in the method of receptor / ligand association reaction according to a preferred embodiment of the present invention.

As shown in FIG. 3, the reactor according to the present embodiment comprises a reaction tank 7 for containing a reaction solution, and the reaction tank 7 holds a biochemical analysis unit 1 for holding a biochemical analysis unit. A holding portion 8 is provided.

FIG. 4 is a schematic plan view of the reactor shown in FIG.

As shown in FIG. 4, the reactor according to the present embodiment has a pair of coils 9a,
9b, and the coils 9a and 9b are connected to AC power supplies 10a and 10b, respectively.

When selectively binding a specific binding substance such as cDNA with a radioactive labeling substance, a reaction solution 11 containing a substance derived from a living body which is a probe labeled with a radioactive labeling substance is prepared.

On the other hand, with a fluorescent substance such as a fluorescent dye,
In the case of selectively labeling a specific binding substance such as cDNA, a reaction solution 11 containing a substance of biological origin which is a probe labeled with a fluorescent substance such as a fluorescent dye is prepared.

[0107] The cDNA may be labeled with a labeling enzyme that produces chemiluminescence by contacting it with a chemiluminescent substrate.
In the case of selectively labeling a specific binding substance such as, a reaction solution 11 containing a substance of biological origin labeled with a hapten such as digoxigenin is prepared.

Two or more living body-derived substances among living body-derived substances labeled with radioactive labeling substances, living body-derived substances labeled with fluorescent substances such as fluorescent dyes, and living body-derived substances labeled with haptens such as digoxigenin It is also possible to prepare a reaction solution containing the substance of, and in the present embodiment, a substance of biological origin labeled with a radioactive labeling substance, a substance of biological origin labeled with a fluorescent substance, and a hapten such as digoxigenin. A reaction solution containing the substance derived from the living body is prepared.

In the present embodiment, the reaction solution 11 is prepared by previously binding minute magnetic beads to a substance of biological origin. Magnetic beads are, for example, biotin-labeled substances of biological origin,
Magnetic beads labeled with streptavidin
Can be bound by a method such as reacting

In hybridization, first, the biochemical analysis unit 1 is set by the user in the biochemical analysis unit holding portion 8 of the reaction tank 7.

Then, the reaction solution 11 is supplied into the reaction tank 7.

When the reaction tank 7 is filled with the reaction solution 11, the magnetic fields having different directions are alternately crossed across the many absorptive regions 4 of the biochemical analysis unit 1 held in the reaction tank 7. AC power source 10a,
Current is supplied from 10b to the coils 9a and 9b.

The coils 9a and 9b have, for example, 0.1
An alternating current of Hz is supplied, and the direction of the magnetic field that crosses the large number of absorptive regions 4 of the biochemical analysis unit 1 held in the reaction tank 7 is reversed every 10 seconds.

Therefore, since the magnetic beads are bound to the substance derived from the living body contained in the reaction solution 11, the substance derived from the living body is subjected to the magnetic field in which the direction is reversed at a predetermined time interval, so that the reaction tank is heated. 7 is forcibly moved, and alternately, forcibly moved from different directions across the absorptive region 4 formed on the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7. It

As a result, a specific binding substance such as cDNA contained in a large number of adsorptive regions 4 of the biochemical analysis unit 1 was labeled with a biogenic substance labeled with a radioactive labeling substance, or a fluorescent substance. The biological substance and the biological substance labeled with a hapten such as digoxigenin are selectively hybridized.

As described above, in this embodiment, the substance of biological origin contained in the reaction solution is adsorbed by the biochemical analysis unit 1 held in the biochemical analysis unit holding section 8 of the reaction tank 7. When the substance of biological origin is moved by convection or diffusion to cross the region 4 alternately in different directions and alternately, and when the specific binding substance and the substance of biological origin are hybridized, In comparison, it is possible to significantly improve the efficiency of hybridization, and a substance derived from a living body can be used as a specific binding substance contained in a deep part of a plurality of absorptive regions of the biochemical analysis unit. The probability of encountering can be greatly increased, and it becomes possible to hybridize a specific binding substance and a substance of biological origin as desired.

When a predetermined time has passed, the AC power source 10
The supply of current from the coils a and 10b to the coils 9a and 9b is stopped, and the hybridization is completed.

Next, the reaction solution 11 is discharged from the reaction tank 7, and the cleaning solution is further supplied into the reaction tank 7 to clean the many absorptive regions 4 of the biochemical analysis unit 1.

When the washing operation is completed, the washing solution is discharged from the reaction tank 7.

Thus, the radiation data of the radioactive labeling substance as the labeling substance and the fluorescence data of the fluorescent substance such as the fluorescent dye are recorded in the large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1. . The fluorescence data recorded in the absorptive region 4 of the biochemical analysis unit 1 is read by a scanner described later to generate biochemical analysis data.

On the other hand, the radiation data of the radio-labeled substance is transferred to the stimulable phosphor sheet, and the radiation data transferred to the stimulable phosphor sheet is read by a scanner described later for biochemical analysis. Data is generated.

On the other hand, in order to record chemiluminescence data in a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1, further chemiluminescence is generated by bringing the chemiluminescence substrate into contact. An antibody solution containing an antibody against a hapten such as digoxigenin labeled with the enzyme is prepared and supplied into the reaction tank 7.

Fine magnetic beads are also previously bound to the antibody contained in the antibody solution by the method described above.

When the reaction tank 7 is filled with the antibody solution, magnetic fields of different directions are formed on the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7 and the numerous absorptive regions 4 are formed. Current is supplied to the coils 9a and 9b from the AC power supplies 10a and 10b so as to be alternately generated across the coils.

As a result, it is labeled with an enzyme that produces chemiluminescence by contacting it with a chemiluminescent substrate,
The antibody to which the magnetic beads are bound is forcibly moved in the reaction tank 7 by a magnetic field whose direction is reversed every predetermined time, and is alternately held in the reaction tank 7 in different directions for biochemical analysis. It is forcibly moved across the adsorptive region 4 formed on the substrate 2 of the unit 1 for use.

Therefore, the specific binding substance contained in the large number of adsorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 is selectively labeled with the hybridized substance derived from the living body. The hapten such as digoxigenin can be efficiently bound to an antibody labeled with an enzyme that causes chemiluminescence by contacting with a chemiluminescent substrate by an antigen-antibody reaction.

When a predetermined time has passed, the AC power source 10
The supply of current from the coils a and 10b to the coils 9a and 9b is stopped, and the antigen-antibody reaction is completed.

Next, the reaction solution 11 is discharged from the reaction tank 7, and the cleaning solution is further supplied into the reaction tank 7 to clean the many absorptive regions 4 of the biochemical analysis unit 1.

When the cleaning operation is completed, the cleaning solution is discharged from the reaction tank 7.

As described above, the chemiluminescence data is recorded in the many absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1. The chemiluminescence data recorded in the absorptive region 4 of the biochemical analysis unit 1 is read by a cooling CCD camera of a data generation system described later, and biochemical analysis data is generated.

FIG. 5 is a schematic perspective view of a stimulable phosphor sheet used in the receptor-ligand association reaction method according to a preferred embodiment of the present invention.

As shown in FIG. 5, the stimulable phosphor sheet 20 according to this embodiment has a large number of substantially circular through holes 2.
2 includes a nickel-made support 21 formed regularly, and a stimulable phosphor is embedded in a large number of through holes 22 formed in the support 21 to form a large number of stimulable phosphor layers. The area 24 is formed in a dot shape.

The large number of through holes 22 are formed in the support 21 in the same pattern as the large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1, and each stimulable phosphor layer region is formed. 24 is formed to have the same size as the absorptive region 4 formed on the substrate 2 of the biochemical analysis unit 1.

Therefore, although not shown exactly in FIG. 5, the substantially circular stimulable phosphor layer region 24 of 19200 having a size of about 0.01 mm 2 is formed on the substrate of the biochemical analysis unit 1. The matrix 21 is formed in a matrix on the support 21 of the stimulable phosphor sheet 20 by the same regular pattern as the large number of the absorptive regions 4 formed in 2.

Further, in this embodiment, the support 21
The stimulable phosphor is embedded in the through hole 22 formed in the support 21 so that the surface of the stimulable phosphor layer region 24 and the surface of the stimulable phosphor layer region 24 are located at the same height. A phosphor sheet 20 is formed.

FIG. 6 shows a large number of stimulable phosphor layers formed on the stimulable phosphor sheet 20 by the radioactive labeling substance contained in the large number of absorptive regions 4 formed in the biochemical analysis unit 1. FIG. 6 is a schematic cross-sectional view showing a method of exposing a region 24.

As shown in FIG. 6, upon exposure,
The absorptive property so that the large number of absorptive regions 4 formed in the biochemical analysis unit 1 face the large number of stimulable phosphor layer regions 24 formed on the support 21 of the stimulable phosphor sheet 20. The phosphor sheet 20 and the biochemical analysis unit 1 are superposed.

In this way, each of the stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20 and the absorptive regions 4 formed on the biochemical analysis unit 1 over a predetermined period of time. By arranging them to face each other, a large number of stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20 are exposed by the radioactive labeling substance contained in the absorptive region 4.

At this time, an electron beam (β ray) is emitted from the radiolabeled substance adsorbed in the absorptive region 4, but the absorptive region 4 of the biochemical analysis unit 1 has a property of attenuating radiation energy. Since it is formed on the substrate 2 formed of the silicon nitride, which is separated from each other,
The electron beam (β-ray) emitted from each absorptive region 4 is scattered in the substrate 2 of the biochemical analysis unit 1 and mixed with the electron beam (β-ray) emitted from the adjacent absorptive region 4. It is possible to effectively prevent the light from entering the photostimulable phosphor layer region 24 facing the adsorbing regions 4 adjacent to each other.
Further, the large number of stimulable phosphor layer regions 24 of the stimulable phosphor sheet 20 are stimulated in the plurality of through holes 22 formed in the nickel support 21 having a property of attenuating the energy of radiation. Beam (β-ray) emitted from each absorptive region 4 because it is formed by embedding a fluorescent substance
It is possible to effectively prevent the light from being scattered in the support 21 of the stimulable phosphor sheet 20 and entering the stimulable phosphor layer region 24 adjacent to the opposing stimulable phosphor layer region 24. Therefore, the electron beam (β-ray) emitted from the radio-labeled substance contained in the adsorptive region 4 can be converted into
An electron beam (β-ray) emitted from the radiolabel substance contained in the absorptive region 4 can be selectively made incident on the stimulable phosphor layer region 24 facing the absorptive region 4.
Of the electron beam (β
It is possible to reliably prevent the photostimulable phosphor from being exposed by being incident on the photostimulable phosphor layer region 24 to be exposed by a line.

Thus, a large number of stimulable phosphor layer regions 24 formed on the support 21 of the stimulable phosphor sheet 20 are
Radiation data of radiolabeled substances are recorded.

FIG. 7 shows the radiation data and biochemical analysis unit 1 of the radiolabeled substance recorded in a large number of stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20.
9 is a schematic perspective view of a scanner that reads fluorescence data recorded in a large number of absorptive regions 4 and generates biochemical analysis data. FIG. 8 is a schematic perspective view showing details of a scanner near a photomultiplier. Is.

The scanner according to the present embodiment is provided with a large number of biochemical analysis units 1 and radiation data of radiolabeled substances recorded in a large number of stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20. Is configured to be able to read fluorescence data such as a fluorescent dye recorded in the absorptive region 4 of the first laser excitation light source 31 which emits a laser light 34 having a wavelength of 640 nm and a laser light 34 having a wavelength of 532 nm. Second laser excitation light source 32 for emitting light, 473n
The third laser excitation light source 33 which emits the laser light 34 having a wavelength of m is provided.

In the present embodiment, the first laser excitation light source 31 is composed of a semiconductor laser light source, and the second laser excitation light source 32 and the third laser excitation light source 33.
Is composed of a second harmonic generation element.

The laser light 34 emitted from the first laser excitation light source 31 is collimated by the collimator lens 35 and then reflected by the mirror 46. In the optical path of the laser light 34 emitted from the first laser excitation light source 31 and reflected by the mirror 46, the first dichroic mirror 37 and 532 nm that transmit the laser light 4 of 640 nm and reflect the light of wavelength 532 nm. A second dichroic mirror 48 that transmits light of the above wavelength and reflects light of the wavelength of 473 nm is provided, and the laser light 34 generated by the first laser excitation light source 31 is provided.
Passes through the first dichroic mirror 37 and the second dichroic mirror 48 and enters the mirror 39.

On the other hand, the laser light 34 emitted from the second laser excitation light source 32 is made into parallel light by the collimator lens 40 and then reflected by the first dichroic mirror 37, and its direction is 90 degrees. After being changed, the light passes through the second dichroic mirror 48 and enters the mirror 39.

The laser light 34 emitted from the third laser excitation light source 33 is made into parallel light by the collimator lens 41 and then reflected by the second dichroic mirror 48, and its direction is 90 degrees. After being changed, it is incident on the mirror 39.

The laser beam 34 incident on the mirror 39 is reflected by the mirror 39 and further incident on the mirror 42 and reflected.

Laser light 3 reflected by mirror 42
A perforated mirror 44 formed by a concave mirror having a hole 43 formed in the center is arranged in the optical path of No. 4, and the laser light 34 reflected by the mirror 42 passes through the hole 43 of the perforated mirror 44. It passes through and enters the concave mirror 48.

Laser light 34 incident on the concave mirror 48
Is reflected by the concave mirror 48, and the optical head 4
It is incident on 5.

The optical head 45 is provided with a mirror 46 and an aspherical lens 47. The laser light 34 incident on the optical head 45 is reflected by the mirror 46, and the aspherical lens 47 causes the glass plate of the stage 50 to be reflected. It is incident on the stimulable phosphor sheet 20 placed on 51 or the biochemical analysis unit 1.

A laser beam 34 is applied to the stimulable phosphor sheet 20.
Is incident, the stimulable phosphor layer region 24 formed on the support 21 of the stimulable phosphor sheet 20 is excited, stimulable light 55 is emitted, and laser light is emitted to the biochemical analysis unit 1. When 34 is incident, a fluorescent substance such as a fluorescent dye contained in the absorptive region 4 is excited and fluorescence 55 is emitted.

Photostimulated light 55 emitted from the stimulable phosphor layer region 24 of the stimulable phosphor sheet 20 or fluorescence 55 emitted from the absorptive region 4 of the biochemical analysis unit 1.
Is condensed on a mirror 46 by an aspherical lens 47 provided in the optical head 45, is reflected by the mirror 46 on the same side as the optical path of the laser light 34, becomes parallel light, and is incident on a concave mirror 48. To do.

The photostimulable light 55 or fluorescent light 55 that has entered the concave mirror 48 is reflected by the concave mirror 48,
The light enters the perforated mirror 44.

The photostimulable light 55 or the fluorescent light 55 which has entered the perforated mirror 44 is reflected downward by the perforated mirror 44 formed by a concave mirror and enters the filter unit 58, as shown in FIG. Then, the light of a predetermined wavelength is cut off, enters the photomultiplier 60, and is photoelectrically detected.

As shown in FIG. 8, the filter unit 58 includes four filter members 61a, 61b, 61c,
61d, the filter unit 58 is configured to be movable in the left-right direction in FIG. 8 by a motor (not shown).

FIG. 9 is a schematic sectional view taken along the line AA of FIG.

As shown in FIG. 9, the filter member 61
a includes a filter 62a, and the filter 62a uses the first laser excitation light source 31 to perform the biochemical analysis unit 1
Is a filter member used when exciting the fluorescent substance contained in the large number of absorptive regions 4 formed in the above to read the fluorescence 55, and cuts light having a wavelength of 640 nm,
It has a property of transmitting light having a wavelength longer than 40 nm.

FIG. 10 is a schematic sectional view taken along the line BB of FIG.

As shown in FIG. 10, the filter member 6
1b includes a filter 62b, and the filter 62b includes a second
Is a filter member used when exciting the fluorescent substance contained in a large number of absorptive regions 4 formed in the biochemical analysis unit 1 by using the laser excitation light source 32 and reading the fluorescence 55, Cuts light with a wavelength of 532 nm,
It has a property of transmitting light having a wavelength longer than 532 nm.

FIG. 11 is a schematic sectional view taken along the line CC of FIG.

As shown in FIG. 11, the filter member 6
1c includes a filter 62c, and the filter 62c includes a third filter 62c.
Is a filter member used when the fluorescent substance contained in the large number of absorptive regions 4 formed in the biochemical analysis unit 1 is excited by using the laser excitation light source 33 of FIG. , 473 nm is cut off, and light with a wavelength longer than 473 nm is transmitted.

FIG. 12 is a schematic sectional view taken along the line DD of FIG.

As shown in FIG. 12, the filter member 6
1d includes a filter 62d, and the filter 62d includes a first
Of the stimulable phosphor sheet 2 using the laser excitation light source 31 of
Photostimulation light 55 emitted from the stimulable phosphor layer region 24 by exciting a large number of stimulable phosphor layer regions 24 formed in 0.
Is a filter used when reading, and has a property of transmitting only the light in the wavelength range of the stimulable light 55 emitted from the stimulable phosphor layer region 24 and cutting the light of the wavelength of 640 nm. There is.

Therefore, the filter members 61a, 61b, 61c, 61d, depending on the laser excitation light source to be used.
Is selectively placed in front of the photomultiplier 60, the photomultiplier 60 can photoelectrically detect only the light to be detected.

The analog data photoelectrically detected by the photomultiplier 60 and generated is converted into digital data by the A / D converter 63 and sent to the data processing device 64.

Although not shown in FIG. 7, the optical head 45 is configured to be movable in the main scanning direction indicated by arrow X and the sub-scanning direction indicated by arrow Y in FIG. The entire surface of the biochemical analysis unit 1 is configured to be scanned by the laser light 34.

FIG. 13 is a schematic plan view of the scanning mechanism of the optical head.

In FIG. 13, for simplification, the optical system except the optical head 45 and the optical paths of the laser light 34 and the fluorescent light 55 or the stimulated light 55 are omitted.

As shown in FIG. 13, the optical head 45
The scanning mechanism that scans the substrate 70 includes a substrate 70, and a sub-scanning pulse motor 71 and a pair of rails 72 and 62 are provided on the substrate 70.
13 are fixed, and on the substrate 70, a substrate 7 that is movable in the sub-scanning direction indicated by an arrow Y in FIG.
3 and 3 are provided.

A threaded hole (not shown) is formed in the movable substrate 73, and a threaded rod 74 rotated by the sub-scanning pulse motor 71 is formed in this hole. Engaged.

A main scanning stepping motor 75 is provided on the movable substrate 73, and the main scanning stepping motor 75 uses the endless belt 76 for adjoining the adsorbing regions 4 formed in the biochemical analysis unit 1. That is,
The stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20 can be driven intermittently at a pitch equal to the distance between adjacent stimulable phosphor layer regions 24. The optical head 45 is fixed to the endless belt 76, and when the endless belt 76 is driven by the main scanning stepping motor 75, the optical head 45 is moved in the main scanning direction indicated by an arrow X in FIG. Has been done.

In FIG. 13, 67 is the optical head 45.
Is a linear encoder for detecting the position in the main scanning direction, and 78 is a slit of the linear encoder 77.

Therefore, the main scanning stepping motor 7
5, the endless belt 76 is intermittently driven in the main scanning direction, and when scanning of one line is completed, the substrate 73 is intermittently moved in the sub scanning direction by the sub scanning pulse motor 71. The optical head 45 is
In FIG. 13, all the stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20 by the laser light 34 are moved in the main scanning direction indicated by the arrow X and the sub-scanning direction indicated by the arrow Y. Alternatively, all the absorptive regions 4 formed in the biochemical analysis unit 1 are scanned.

FIG. 14 is a block diagram showing the control system, input system, drive system and detection system of the scanner shown in FIG.

As shown in FIG. 14, the scanner control system includes a control unit 80 for controlling the operation of the entire scanner, a data processing device 64, and a memory 55. The scanner input system includes: A keyboard 81 that is operated by the user and can input various instruction signals
Is equipped with.

As shown in FIG. 14, the scanner drive system intermittently moves the optical head 45 in the main scanning direction and the main scanning stepping motor 75, and intermittently moves the optical head 45 in the sub scanning direction. Sub-scanning pulse motor 7
1 and 4 filter members 61a, 61b, 61c, 6
A filter unit motor 82 for moving the filter unit 58 having 1d is provided.

The control unit 80 includes a first laser pumping light source 31, a second laser pumping light source 32 or a third laser pumping light source 32.
In addition to selectively outputting the drive signal to the laser excitation light source 33, the drive signal can be output to the filter unit motor 82.

Further, as shown in FIG. 14, the detection system of the scanner includes a photomultiplier 60 and a linear encoder 77 for detecting the position of the optical head 45 in the main scanning direction.

In the present embodiment, the control unit 80 uses the first laser pumping light source 31, the second laser pumping light source 32 or the third laser pumping light source 32 according to the position detection signal of the optical head 45 input from the linear encoder 77. The laser excitation light source 33 is configured to be on / off controllable.

The scanner constructed as described above uses a large number of photostimulable substances due to the radioactive labeling substance contained in the large number of absorptive regions 4 formed in the biochemical analysis unit 1 in the following manner. The phosphor layer region 24 is exposed, and the radiation data of the radiolabel substance recorded in the stimulable phosphor layer region 24 of the stimulable phosphor sheet 20 is read to generate biochemical analysis data.

First, the stimulable phosphor sheet 20 is placed on the glass plate 51 of the stage 50.

Next, the keyboard 8 is set by the user.
An instruction signal for scanning a large number of stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20 with the laser beam 34 is input to the first column.

The instruction signal input to the keyboard 81 is
Input to the control unit 80, the control unit 80 outputs a drive signal to the filter unit motor 82 in accordance with the instruction signal, and the filter unit 5
Photostimulable light 55 emitted from the stimulable phosphor by moving 8
The filter member 61d provided with the filter 62d having the property of transmitting only the light in the wavelength range of 640 nm and cutting the light of the wavelength of 640 nm is located in the optical path of the stimulated light 55.

Further, the control unit 80 outputs a drive signal to the main scanning stepping motor 75 to move the optical head 45 in the main scanning direction, and based on the position detection signal of the optical head 45 inputted from the linear encoder, The first stimulable phosphor layer region 2 among the many stimulable phosphor layer regions 24 formed on the stimulable phosphor sheet 20.
4 at a position where the laser beam 34 can be irradiated.
When it is confirmed that 5 has been reached, a stop signal is output to the main scanning stepping motor 75 and a drive signal is output to the first laser excitation light source 31 to activate the first laser excitation light source 31, Laser light 34 having a wavelength of 640 nm
To emit.

The laser light 34 emitted from the first laser excitation light source 31 is made into parallel light by the collimator lens 35, and then enters the mirror 46 and is reflected.

Laser light 3 reflected by mirror 46
The light beam 4 passes through the first dichroic mirror 37 and the second dichroic mirror 48 and enters the mirror 39.

The laser light 34 incident on the mirror 39 is reflected by the mirror 39 and further incident on the mirror 42 and reflected.

Laser light 3 reflected by mirror 42
4 passes through the hole 43 of the perforated mirror 44 and enters the concave mirror 48.

Laser light 34 incident on the concave mirror 48
Is reflected by the concave mirror 48, and the optical head 4
It is incident on 5.

Laser light 34 incident on the optical head 45
Is reflected by the mirror 46, and by the aspherical lens 47, the first stimulable phosphor layer region 24 of the stimulable phosphor sheet 20 placed on the glass plate 51 of the stage 50.
Is focused on.

In the present embodiment, the photostimulable phosphor layer regions 24 are formed by embedding the photostimulable phosphor in the through holes 22 formed in the nickel support 21. Therefore, in each stimulable phosphor layer region 24, the laser light 34 is scattered and enters into the adjacent stimulable phosphor layer regions 24, and the adjacent stimulable phosphor layer regions 24. It becomes possible to effectively prevent the stimulable phosphor contained therein from being excited.

The laser light 34 causes the stimulable phosphor sheet 20.
First stimulable phosphor layer region 2 formed on the support 21 of
When incident on 4, the stimulable phosphor contained in the first stimulable phosphor layer region 24 formed on the stimulable phosphor sheet 20 is excited by the laser light 34 to generate the first stimulable phosphor. The stimulated emission 55 is emitted from the phosphor layer region 24.

The photostimulable light 55 emitted from the first photostimulable phosphor region 15 of the stimulable phosphor sheet 20 is collected by the aspherical lens 47 provided in the optical head 45,
The light is reflected by the mirror 46 to the same side as the optical path of the laser light 34, becomes parallel light, and enters the concave mirror 48.

The photostimulable light 55 incident on the concave mirror 48 is
The perforated mirror 44 is reflected by the concave mirror 48.
Incident on.

The photostimulable light 55 incident on the perforated mirror 44.
Is reflected downward by the perforated mirror 44 formed by the concave mirror and enters the filter 62d of the filter unit 58, as shown in FIG.

The filter 62d transmits only the light in the wavelength region of the stimulable light 55 emitted from the stimulable phosphor, and emits 640n.
Since it has a property of cutting off light having a wavelength of m, light having a wavelength of 640 nm, which is excitation light, is cut, and light in the wavelength range of stimulable light 55 emitted from the stimulable phosphor layer region 24. Only the light passes through the filter 62d and is photoelectrically detected by the photomultiplier 60.

The analog signal photoelectrically detected by the photomultiplier 60 and generated is output to the A / D converter 63, converted into a digital signal, and output to the data processing device 64.

When a predetermined time, for example, several microseconds elapses after the first laser excitation light source 31 is turned on, the control unit 80 outputs a drive stop signal to the first laser excitation light source 31, The driving of the first laser excitation light source 31 is stopped, and a drive signal is output to the main scanning stepping motor 75 to cause the optical head 45 to move to the adjacent stimulable phosphors formed on the stimulable phosphor sheet 20. It is moved by a pitch equal to the distance between the layer regions 24.

On the basis of the position detection signal of the optical head 45 input from the linear encoder 77, the optical head 45
Are moved by one pitch equal to the distance between the adjacent photostimulable phosphor layer regions 24, and the first laser excitation light source 31
The stimulable phosphor sheet 2 emits the laser light 34 emitted from the
When it is confirmed that the second stimulable phosphor layer region 24 formed in 0 has been moved to a position where it can be irradiated, the control unit 80 outputs a drive signal to the first laser excitation light source 31. , Turn on the first laser excitation light source 31,
The laser beam 34 excites the stimulable phosphor contained in the second stimulable phosphor layer region 24 formed on the stimulable phosphor sheet 20.

Similarly, the laser beam 34 is irradiated on the second stimulable phosphor layer region 24 formed on the stimulable phosphor sheet 20 for a predetermined time, and the second stimulable phosphor is obtained. The stimulable phosphor contained in the layer region 24 is excited, and the stimulable light 55 emitted from the second stimulable phosphor layer region 24 is photoelectrically detected by the photomultiplier 60. Then, when the analog data is generated, the control unit 80 outputs an off signal to the first laser excitation light source 31 to turn off the first laser excitation light source 31, and also to drive the main scanning stepping motor 75. A signal is output to move the optical head 45 by one pitch equal to the distance between the adjacent photostimulable phosphor layer regions 24.

Thus, the first laser excitation light source 31 is repeatedly turned on and off in synchronization with the intermittent movement of the optical head 45, and based on the position detection signal of the optical head 45 input from the linear encoder 77, Optical head 45
However, when it is confirmed that the scanning by the laser beam 34 on the stimulable phosphor layer region 24 on the first line has been completed by moving by one line in the main scanning direction, the control unit 80 causes the main scanning A drive signal is output to the stepping motor 75 to return the optical head 45 to the original position, and a drive signal is output to the sub-scanning pulse motor 71.
The movable substrate 73 is moved by one line in the sub-scanning direction.

Based on the position detection signal of the optical head 45 input from the linear encoder 77, the optical head 45
Is returned to its original position, and the movable substrate 73 is
When it is confirmed that the line has been moved by one line in the sub-scanning direction, the control unit 80 causes the stimulable phosphor layer area 24 of the first line of the stimulable phosphor sheet 20 to be detected.
In the same manner as the irradiation of the laser light 34 emitted from the first laser excitation light source 31 sequentially, the stimulable phosphor layer region 24 of the second line is sequentially irradiated with the first laser excitation light source. The laser beam 34 emitted from 31 is irradiated to excite the stimulable phosphor contained in the stimulable phosphor layer region 24 in the second line, and emitted from the stimulable phosphor layer region 24. Photomultiplier 60 sequentially
To be detected photoelectrically.

The analog data photoelectrically detected by the photomultiplier 60 and generated are converted into digital data by the A / D converter 63 and sent to the data processing device 64.

Thus, all the stimulable phosphor layer regions 24 formed on the support 21 of the stimulable phosphor sheet 20.
Are scanned by the laser light 34 emitted from the first laser excitation light source 31, and all the stimulable phosphor layer regions 2 are scanned.
The stimulable phosphor contained in 4 is excited, and the emitted stimulable light 55 is photoelectrically detected by the photomultiplier 60, and the generated analog data is A / D.
When converted into digital data by the converter 63 and sent to the data processing device 64, a drive stop signal is sent from the control unit 80 to the first laser excitation light source 31.
And the driving of the first laser excitation light source 31 is stopped.

As described above, the stimulable phosphor sheet 2 is used.
The radiation data recorded in a large number of stimulable phosphor layer regions 24 of 0 are read to generate biochemical analysis data.

On the other hand, when the fluorescence data of the fluorescent substance recorded in the many absorptive regions 4 formed in the biochemical analysis unit 1 is read and the digital data for biochemical analysis is generated, first, by the user. The biochemical analysis unit 1 is set on the glass plate 51 of the stage 50.

[0207] Next, the keyboard 8
A fluorescent substance identification signal that identifies the type of the fluorescent substance that is the labeling substance is input to 1, and an instruction signal that the fluorescence data should be read is input.

The fluorescent substance specifying signal and the instruction signal input to the keyboard 81 are input to the control unit 80, and when the control unit 80 receives the fluorescent substance specifying signal and the instruction signal, it is stored in a memory (not shown). The laser excitation light source to be used is determined according to the table shown in FIG.
It is determined which of b and 62c is to be located in the optical path of the fluorescent light 55.

[0209] For example, Rhodamine (registered trademark) that can be most efficiently excited by a laser having a wavelength of 532 nm as a fluorescent substance for labeling a substance of biological origin
Is used and is input to the keyboard 81, the control unit 80 selects the second laser excitation light source 32, selects the filter 62b, and outputs a drive signal to the filter unit motor 82. Then, the filter unit 58 is moved to cut off the light having the wavelength of 532 nm, and the filter member 61b having the property of transmitting the light having the wavelength longer than 532 nm is released from the biochemical analysis unit 1. It is located in the optical path of the fluorescent light 55 to be formed.

Further, the control unit 80 outputs a drive signal to the main scanning stepping motor 75 to move the optical head 45 in the main scanning direction, and based on the position detection signal of the optical head 45 input from the linear encoder, When it is confirmed that the optical head 45 has reached the position where the laser beam 34 can be irradiated to the first absorptive region 4 among the many absorptive regions 4 formed in the biochemical analysis unit 1. , A stop signal is output to the main scanning stepping motor 75, and a drive signal is output to the second laser excitation light source 32 to activate the second laser excitation light source 32.
A laser beam 34 having a wavelength of 532 nm is emitted.

The laser light 34 emitted from the second laser excitation light source 32 is made into parallel light by the collimator lens 40, and then enters the first dichroic mirror 37 and is reflected.

The laser beam 34 reflected by the first dichroic mirror 37 passes through the second dichroic mirror 48 and enters the mirror 39.

The laser light 34 incident on the mirror 39 is reflected by the mirror 39 and further incident on the mirror 42 and reflected.

Laser light 3 reflected by mirror 42
4 passes through the hole 43 of the perforated mirror 44 and enters the concave mirror 48.

Laser light 34 incident on the concave mirror 48
Is reflected by the concave mirror 48, and the optical head 4
It is incident on 5.

Laser light 34 incident on the optical head 45
Is reflected by the mirror 46, and is focused by the aspherical lens 47 on the first absorptive region 4 of the biochemical analysis unit 1 placed on the glass plate 51 of the stage 50.

In this embodiment, the absorptive regions 4 of the biochemical analysis unit 1 are formed by filling nylon 6 into the through holes 3 formed in the substrate made of aluminum. Therefore, the laser light 34 incident on the first absorptive regions 4 of the biochemical analysis unit 1 is scattered and enters the adjacent absorptive regions 4 to enter the absorptive regions 4 adjacent to each other. It becomes possible to effectively prevent exciting the contained fluorescent substance.

The laser beam 34 is emitted from the biochemical analysis unit 1
When incident on the first absorptive region 4 formed on the substrate 2 of the above, the laser light 34 causes a fluorescent substance such as a fluorescent dye contained in the first absorptive region 4 of the biochemical analysis unit 1, for example, Rhodamine is excited and emits fluorescence.

The fluorescent light 55 emitted from the rhodamine is condensed by the aspherical lens 47 provided in the optical head 45, reflected by the mirror 46 to the same side as the optical path of the laser light 34, and made into parallel light. , Enters the concave mirror 48.

The fluorescent light 55 that has entered the concave mirror 48 is reflected by the concave mirror 48 and enters the perforated mirror 44.

The fluorescent light 55 entering the perforated mirror 44 is
The perforated mirror 44 formed by the concave mirror reflects the light downward as shown in FIG. 8 and makes it incident on the filter 62b of the filter unit 58.

Since the filter 62b has a property of cutting light having a wavelength of 532 nm and transmitting light having a wavelength longer than 532 nm, light having a wavelength of 532 nm, which is excitation light, is cut and emitted from rhodamine. Fluorescence 55
Only the light in the wavelength range of (4) passes through the filter 62b and is photoelectrically detected by the photomultiplier 60.

The analog signal photoelectrically detected by the photomultiplier 60 and generated is output to the A / D converter 63, converted into a digital signal, and output to the data processing device 64.

After the second laser excitation light source 32 is turned on, when a predetermined time, for example, several microseconds has elapsed, the control unit 80 outputs a drive stop signal to the second laser excitation light source 32, The drive of the second laser excitation light source 32 is stopped, and a drive signal is output to the main scanning stepping motor 75 to cause the optical head 45 to move to the adsorbing regions 4 adjacent to each other formed in the biochemical analysis unit 1.
Move by a pitch equal to the distance between.

On the basis of the position detection signal of the optical head 45 input from the linear encoder 77, the optical head 45
Is moved by one pitch equal to the distance between the adjacent absorptive regions 4 formed in the biochemical analysis unit 1,
Laser light 34 emitted from the second laser excitation light source 32
Is confirmed to have moved to a position where the second absorptive region 4 formed in the biochemical analysis unit 1 can be irradiated, the control unit 80 sends a drive signal to the second laser excitation light source 32. Output the second laser excitation light source 3
2 is turned on, and the laser beam 34 excites the fluorescent substance, for example, rhodamine, contained in the second absorptive region 4 formed in the biochemical analysis unit 1.

Similarly, the laser beam 34 is irradiated to the second absorptive region 4 formed in the biochemical analysis unit 1 for a predetermined time, and the fluorescence 55 emitted from the second absorptive region 4 is emitted. However, with Photomultiplier 60,
When photoelectrically detected and analog data is generated,
The control unit 80 uses the second laser excitation light source 3
2 to turn off the second laser excitation light source 32 and to output the main scanning stepping motor 75.
Then, a drive signal is output to move the optical head 45 by one pitch equal to the distance between the adsorbing regions 4 adjacent to each other formed in the biochemical analysis unit 1.

Thus, the first laser excitation light source 31 is repeatedly turned on and off in synchronization with the intermittent movement of the optical head 45, and based on the position detection signal of the optical head 45 inputted from the linear encoder 77, Optical head 45
Is moved by one line in the main scanning direction, and all the absorptive regions 4 of the first line of the biochemical analysis unit 1 are moved.
When it is confirmed that the laser beam 34 is scanned by the laser beam 34, the control unit 80 outputs a drive signal to the main scanning stepping motor 75 to return the optical head 45 to the original position, and at the same time, the sub scanning pulse motor. 71
A driving signal is output to the movable substrate 73 to move the movable substrate 73 by one line in the sub-scanning direction.

On the basis of the position detection signal of the optical head 45 input from the linear encoder 77, the optical head 45
Is returned to its original position, and the movable substrate 73 is
When it is confirmed that the line has been moved by one line in the sub-scanning direction, the control unit 80 causes the absorptive region 4 of the first line formed in the biochemical analysis unit 1 to be formed.
Then, in the same manner as irradiating the laser beam 34 emitted from the second laser excitation light source 32 in sequence, the absorptive region 4 of the second line formed in the biochemical analysis unit 1
Rhodamine contained in is excited and fluorescence 55 emitted from the adsorptive region 4 of the second line is sequentially detected photoelectrically by the photomultiplier 60.

The analog data photoelectrically detected by the photomultiplier 60 and generated are converted into digital data by the A / D converter 63 and sent to the data processing device 64.

In this way, all the absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 are scanned by the laser beam 34 emitted from the second laser excitation light source 32, and the biochemical analysis unit 1 is scanned. Rhodamine contained in all the absorptive regions 4 formed in A is excited, the emitted fluorescence 55 is photoelectrically detected by the photomultiplier 60, and the generated analog data is A
When converted into digital data by the / D converter 63 and sent to the data processing device 64, a drive stop signal is output from the control unit 80 to the second laser excitation light source 32, and the second laser excitation light source 32 is emitted. The driving of 32 is stopped.

As described above, the fluorescence data recorded in the many absorptive regions 4 of the biochemical analysis unit 1 is read, and the biochemical analysis data is generated.

[0232] FIG. 15 is a schematic front view of a data generation system for reading the chemiluminescence data recorded in a large number of absorptive regions 4 of the biochemical analysis unit 1 to generate biochemical analysis data.

The data generation system shown in FIG.
The chemiluminescence data recorded in the many absorptive regions 4 of the biochemical analysis unit 1 can be read to generate biochemical analysis data, and at the same time, a large number of the absorptive regions 4 of the biochemical analysis unit 1 can be generated. It is configured so that the recorded fluorescence data of a fluorescent substance such as a fluorescent dye can be read to generate biochemical analysis data.

As shown in FIG. 15, the data generation system comprises a cooled CCD camera 91, a dark box 92 and a personal computer 93. The personal computer 93 includes a CRT 94 and a keyboard 95.

FIG. 16 is a schematic vertical sectional view of the cooled CCD camera 91.

As shown in FIG. 16, the cooled CCD camera 91 is disposed in front of the CCD 96, a heat transfer plate 97 made of a metal such as aluminum, a Peltier element 98 for cooling the CCD 86, and the CCD 96. Shutter 99, and A / D converter 100 for converting analog data generated by CCD 96 into digital data,
A data buffer 101 for temporarily storing the data digitized by the A / D converter 100, and a cooling CC
And a camera control circuit 102 for controlling the operation of the D camera 91.

The opening formed between the dark box 82 and the dark box 82 is closed by a glass plate 105, and a radiation fin 106 for radiating the heat generated by the Peltier element 98 is provided around the cooling CCD camera 91. It is formed over almost the entire surface in the direction.

Inside the dark box 92 in front of the glass plate 105,
Camera lens 107 having lens focus adjustment function
Is installed.

FIG. 17 is a schematic vertical sectional view of the dark box 92.

As shown in FIG. 17, an LED light source 110 that emits excitation light is provided in the dark box 92, and the LED light source 110 is provided with a removable filter 111 and an upper surface of the filter 111. The diffusion plate 113 is provided, and the excitation light is emitted through the diffusion plate 113 toward a biochemical analysis unit (not shown) mounted thereon. The chemical analysis unit is guaranteed to be evenly illuminated.
The filter 111 has a property of cutting light harmful to the excitation of the fluorescent substance other than the wavelength near the excitation light and transmitting only the light of the wavelength near the excitation light. On the front surface of the camera lens 107, a filter 112 that cuts off light having a wavelength near the excitation light is detachably provided.

FIG. 18 is a block diagram of the periphery of the personal computer 93 which constitutes the data generating system.

As shown in FIG. 17, the personal computer 93 includes a CPU 120 for controlling the exposure of the cooled CCD camera 81, a data transfer means 121 for reading out digital data generated by the cooled CCD camera 91 from the data buffer 101, and a digital transfer means 121. Based on the data storage means 122 for storing data, the data processing means 123 for performing data processing on the digital data stored in the data storage means 122, and the digital data stored in the data storage means 122, on the screen of the CRT 84. Data display means 124 for displaying visible data is provided.

The LED light source 110 has a light source control means 125.
The light source control unit 125 is configured to receive an instruction signal from the keyboard 95 via the CPU 120. The CPU 120 is configured to be able to output various signals to the camera control circuit 102 of the cooled CCD camera 91.

The data generation system shown in FIGS. 15 to 18 is derived from a living body selectively hybridized with a specific binding substance contained in a large number of absorptive regions 4 of the biochemical analysis unit 1. The hapten, such as digoxigenin, which labels the substance of FIG. The chemiluminescence data detected by the CCD 96 of the CCD camera 91 and recorded in the numerous absorptive regions 4 of the biochemical analysis unit 1 are read to generate biochemical analysis data, and at the same time, the biochemical analysis unit 1 A large number of absorptive regions 4 formed on the substrate 2 are irradiated with excitation light from the LED light source 110, and the biochemical analysis unit 1
Of the fluorescent substance such as a fluorescent dye selectively contained in a large number of the absorptive regions 4 of the fluorescent substance, and the fluorescence emitted by the fluorescent substance is passed through the camera lens 107 to the CC of the cooling CCD camera 91.
The fluorescence data recorded in a large number of absorptive regions 4 of the biochemical analysis unit 1 detected by D96 is read, and the biochemical analysis data can be generated.

When reading the chemiluminescence data, the filter 112 is removed and the LED light source 110 is held in the off state, and a large number of absorptive regions 4 of the biochemical analysis unit 1 are selected on the diffusion plate 113. The chemiluminescent substrate is contacted with the labeling enzyme that labels the antibody contained in the
The biochemical analysis unit 1 that emits chemiluminescence is placed.

Next, the camera lens 1 is set by the user.
07, the lens focus is adjusted, and the dark box 92
Is closed.

After that, when the user inputs the exposure start signal to the keyboard 95, the exposure start signal changes to the CPU 12
0, the camera control circuit 1 of the cooled CCD camera 91
02, and the camera control circuit 102 opens the shutter 99 to start the exposure of the CCD 96.

The chemiluminescence emitted from the absorptive region 4 of the biochemical analysis unit 1 enters the photoelectric surface of the CCD 96 of the cooled CCD camera 91 through the camera lens 107 and forms an image on the photoelectric surface. . The CCD 96 thus receives the light of the image formed on the photocathode and stores it in the form of charges.

In this embodiment, since the substrate 2 of the biochemical analysis unit 1 is made of aluminum having a property of attenuating light, chemiluminescence emitted from the labeling enzyme is biochemical. It can be reliably prevented from being scattered within the substrate 2 of the analysis unit 1 and being mixed with the chemiluminescence emitted from the labeling enzyme contained in the adsorbing regions 4 adjacent to each other.

When the predetermined exposure time has elapsed, the CPU 12
0 outputs an exposure completion signal to the camera control circuit 102 of the cooled CCD camera 91.

Upon receiving the exposure completion signal from the CPU 120, the camera control circuit 102 transfers the analog data accumulated by the CCD 96 in the form of electric charge to the A / D converter 100, digitizes it, and temporarily stores it in the data buffer 101. To memorize.

At the same time when the exposure completion signal is output to the camera control circuit 102, the CPU 120 causes the data transfer means 1 to operate.
21 outputs a data transfer signal to the cooled CCD camera 9
The digital data is read from the first data buffer 101 and stored in the data storage means 122.

When a data processing signal is input to the keyboard 95 by the user, the CPU 120 causes the data processing means 123 to output the digital data stored in the data storage means 122, and the data processing means 123.
Then, according to the user's instruction, the data processing is executed and stored in the data storage means 122.

Next, when the user inputs a data display signal to the keyboard 95, the CPU 120 outputs the data display signal to the data display means 124, and the biochemical analysis based on the digital data stored in the data storage means 122. Data is displayed on the screen of the CRT 94.

In this way, the chemiluminescence data recorded in the many absorptive regions 4 of the biochemical analysis data 1 is read, and the biochemical analysis data is generated.

On the other hand, when the fluorescence data recorded in the many absorptive regions 4 of the biochemical analysis data 1 is read to generate the biochemical analysis data, first, the biochemical analysis unit 1 Are placed on the diffusion plate 103.

Next, the LED light source 11 is selected by the user.
0 is turned on, the lens focus is adjusted using the camera lens 107, and the dark box 92 is closed.

After that, when the user inputs an exposure start signal to the keyboard 95, the LED light source 110 is turned on by the light source control means 125, and excitation light is emitted toward the biochemical analysis unit 1. At the same time, the exposure start signal is sent to the cooling CCD camera 9 via the CPU 120.
1 is input to the camera control circuit 102, the camera control circuit 102 opens the shutter 99, and the exposure of the CCD 96 is started.

The excitation light emitted from the LED light source 110 is filtered by the filter 111 to eliminate wavelength components other than those in the vicinity of the wavelength of the excitation light, and is made uniform by the diffusion plate 113, whereby the biochemical analysis unit 1 Is irradiated.

As a result, the fluorescent substance selectively contained in the large number of absorptive regions 4 of the biochemical analysis unit 1 is excited by the excitation light to emit fluorescence.

The fluorescence emitted from the absorptive region 4 of the biochemical analysis unit 1 passes through the filter 112 and the camera lens 107, and the CCD 96 of the cooled CCD camera 91.
Incident on the photocathode and forms an image on the photocathode.

Since the filter 112 cuts off the light having the wavelength of the excitation light, only the fluorescence emitted from the fluorescent substance selectively contained in the many absorptive regions 4 of the biochemical analysis unit 1 is extracted. Is received by the CCD 96.

The CCD 96 receives the light of the image thus formed on the photocathode and accumulates it in the form of electric charge.

Here, in the present embodiment, the substrate 2 of the biochemical analysis unit 1 is formed of aluminum having a property of attenuating light, so that fluorescence emitted from a fluorescent substance such as a fluorescent dye is not emitted. , The adsorptive regions 4 adjacent to each other scattered in the substrate 2 of the biochemical analysis unit 1
It is possible to reliably prevent the fluorescent light emitted from the mixture from mixing.

When the predetermined exposure time elapses, the CPU 12
0 outputs an exposure completion signal to the camera control circuit 102 of the cooled CCD camera 91.

Upon receiving the exposure completion signal from the CPU 120, the camera control circuit 102 transfers the analog data accumulated by the CCD 96 in the form of electric charge to the A / D converter 100, digitizes it, and temporarily stores it in the data buffer 101. To memorize.

At the same time when the exposure completion signal is output to the camera control circuit 102, the CPU 120 controls the data transfer means 1
21 outputs a data transfer signal to the cooled CCD camera 9
The digital data is read from the first data buffer 101 and stored in the data storage means 122.

When a data processing signal is input to the keyboard 95 by the user, the CPU 120 causes the data processing means 123 to output the digital data stored in the data storage means 122, and the data processing means 123.
Then, according to the user's instruction, the data processing is executed and stored in the data storage means 122.

Next, when the user inputs a data display signal to the keyboard 95, the CPU 120 outputs the data display signal to the data display means 124, and the biochemical analysis based on the digital data stored in the data storage means 122. Data is displayed on the screen of the CRT 94.

According to this embodiment, a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7 by the coils 9a and 9b have different magnetic fields. The bio-derived substances contained in the reaction solution and bound to the magnetic beads are generated alternately by the biochemical analysis unit holding section 8 of the reaction tank 7 for biochemical analysis. Alternately forced to move across the absorptive region 4 of the unit 1 in different directions, thus moving the biogenic substance by convection or diffusion to move the specific binding substance and the biogenic substance. It is possible to significantly improve the efficiency of hybridization compared to the case of hybridizing,
A substance of biological origin can significantly increase the probability of encountering a specific binding substance contained in a deep portion of a plurality of adsorptive regions of a biochemical analysis unit, and, as desired,
It becomes possible to hybridize the specific binding substance and the substance of biological origin.

Further, according to this embodiment, the coil 9
Magnetic fields of different directions are alternately generated by a and 9b across a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7. The antibodies contained in the antibody solution and bound to the magnetic beads are alternately crossed across the absorptive region 4 of the biochemical analysis unit 1 held by the biochemical analysis unit holding section 8 of the reaction tank 7, The specific binding substances that are forcibly moved in different directions and are therefore included in the large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1,
Alternatively, the hapten such as digoxigenin labeling the hybridized substance derived from the living body is bound to the chemiluminescent substrate by the antigen-antibody reaction, and the antibody bound with the enzyme that causes the chemiluminescence is efficiently bound to the hapten. It becomes possible to combine them physically. According to the present embodiment, using the same reactor, the specific binding substance contained in the large number of adsorptive regions 4 of the biochemical analysis unit 1 is treated with a substance of biological origin labeled with a hapten such as digoxigenin. , An antibody labeled with an enzyme that selectively produces a chemiluminescence by hybridizing and then contacting with a chemiluminescence substrate, and an antigen-antibody reaction with a hapten such as digoxigenin that labels a substance of biological origin. It becomes possible to record the chemiluminescence data in the absorptive region 4 of the biochemical analysis unit 1 by binding by using the hapten such as digoxigenin which is extremely efficient and has a small molecular weight. Of the specific binding substance adsorbed in the adsorptive region 4 of the biochemical analysis unit 1, selectively Since is soybean, the specific binding substances and a substance derived from a living organism, as desired, can be hybridized,
By reading the chemiluminescence data, it becomes possible to generate data for biochemical analysis with excellent quantitativeness.

The present invention is not limited to the above embodiments, and various modifications can be made within the scope of the invention described in the claims, and these are also included in the scope of the present invention. It goes without saying that it is a thing.

For example, in the above-described embodiment, the substance derived from the living body labeled with the radioactive labeling substance and the substance derived from the living body labeled with the fluorescent substance are adsorbed on the many absorptive regions 4 of the biochemical analysis unit 1. The specific binding substance is selectively hybridized with a large number of absorptive regions 4 of the biochemical analysis unit 1.
The specific binding substance adsorbed on the enzyme is selectively hybridized with a substance of biological origin labeled with a hapten such as digoxigenin, and further labeled with an enzyme that causes chemiluminescence by contacting with a chemiluminescent substrate. Antibodies against haptens such as digoxigenin, haptens such as digoxigenin that is labeled with a substance of biological origin as an antigen, are configured to bind by an antigen-antibody reaction. The present invention can be widely applied to not only antibody reactions but also hybridization reactions and antigen-antibody reactions in general, and further to receptor-ligand association reactions in general.

[0274] In the above embodiment, the specific binding substance immobilized on the adsorptive region 4 of the biochemical analysis unit 1 is hybridized with a substance of biological origin labeled with a hapten such as digoxigenin, and , An antibody against a hapten such as digoxigenin that is labeled with an enzyme that causes chemiluminescence by contacting with a chemiluminescent substrate is bound to a hapten such as digoxigenin that labels a substance of biological origin by an antigen-antibody reaction. , Is configured to selectively record chemiluminescence data in a large number of absorptive regions 4 of the biochemical analysis unit 1, but is labeled with a labeling substance that causes chemiluminescence by contact with a chemiluminescence substrate. The bio-derived substance is adsorbed on a large number of absorptive regions 4 of the biochemical analysis unit 1. The specific binding substances are, selectively, by hybridizing, in a number of the absorptive regions 4 of the biochemical analysis unit 1, may be recorded chemiluminescence data.

[0275] Further, in the above-mentioned embodiment, a specific binding substance such as cDNA immobilized on a large number of absorptive regions 4 of the biochemical analysis unit 1 is labeled with a substance derived from a living body labeled with a fluorescent substance, Selectively, by hybridizing, a large number of absorptive regions 4 of the biochemical analysis unit 1
Although it is configured to record fluorescence data, a specific binding substance such as cDNA immobilized on a large number of adsorptive regions 4 of the biochemical analysis unit 1 was labeled with a hapten such as digoxigenin. An antibody to a hapten labeled with an enzyme that causes a fluorescent substance to be produced by selectively hybridizing a substance derived from a living body and further contacting it with a fluorescent substrate, and labeling the substance of a living body by an antigen-antibody reaction It is also possible to record fluorescence data in a large number of absorptive regions 4 of the biochemical analysis unit 1 by binding to the hapten that is present.

[0276] Furthermore, in the above-mentioned embodiment, the reaction solution contains a substance of biological origin labeled with a radioactive labeling substance and a substance of biological origin labeled with a fluorescent substance such as a fluorescent dye. , It is not always necessary to include a biologically-derived substance labeled with a radioactive labeling substance and a biologically-derived substance labeled with a fluorescent substance such as a fluorescent dye;
It suffices to include a substance derived from a living body that is labeled with at least one type of labeling substance that produces chemiluminescence when brought into contact with a fluorescent substance such as a fluorescent dye and a chemiluminescent substrate.

Further, in the above-mentioned embodiment, the substrate 2 of the biochemical analysis unit 1 in which magnetic fields of different directions are held in the reaction tank 7 by the pair of coils 9a and 9b.
, Which are alternately generated so as to traverse a large number of absorptive regions 4 formed in the above, but a pair of coils 9a and 9b are used to hold the magnetic fields in different directions in the reaction tank 7. It is not always necessary to alternately generate so as to traverse a large number of absorptive regions 4 formed on the substrate 2 of the analysis unit 1, and one coil is used to generate magnetic fields of different directions in the reaction tank 7. It is possible to alternately generate so as to traverse a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 held in the above, and by using three or more coils, magnetic fields of different directions can be obtained. However, it is also possible to alternately generate so as to traverse a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7.

Further, in the above-mentioned embodiment, alternating current is supplied to the pair of coils 9a, 9b from the alternating current power sources 10a, 10b to the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7. The magnetic field that crosses the formed a number of absorptive regions 4 is generated so that the direction thereof is reversed every predetermined time, but it is not always necessary to supply alternating current to the pair of coils 9a and 9b. However, electric currents having different directions are supplied to the pair of coils 9a and 9b, and a magnetic field whose direction is reversed at a predetermined time is held in the reaction tank 7. The substrate 2 of the biochemical analysis unit 1 It may be generated so as to traverse the large number of absorptive regions 4 formed in the above.

In the above embodiment, alternating current is supplied to the pair of coils 9a and 9b from the alternating current power supplies 10a and 10b to the substrate 2 of the biochemical analysis unit 1 held in the reaction tank 7. A magnetic field that traverses the formed large number of absorptive regions 4 is generated so that its direction is reversed every predetermined time, but it is held in the reaction tank 7 by using the coils 9a and 9b. It is not always necessary to generate a magnetic field that traverses a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 so that the direction thereof is reversed every predetermined time. The method of generating a magnetic field that crosses a large number of absorptive regions 4 formed on the substrate 2 of the biochemical analysis unit 1 held in It is not limited.

In the above embodiment, 1920
An approximately circular adsorptive region 4 having a size of about 0.01 square millimeters of 0 is formed on the biochemical analysis unit 1 in a matrix according to a regular pattern with a density of about 5000 pieces / square centimeter. However, it is not always necessary to form the absorptive region 4 in a substantially circular shape, and the absorptive region 4 can be formed in an arbitrary shape, for example, a rectangular shape.

Further, in the above embodiment, 192
The substantially circular adsorptive regions 4 having a size of about 0.01 square millimeters of 00 are formed in the biochemical analysis unit 1 in a matrix according to a regular pattern with a density of about 5000 pieces / square centimeter. However, the number and size of the absorptive regions 4 may vary depending on the purpose.
The adsorbent region 4 is arbitrarily selected and preferably has a size of 10 or more and less than 5 mm 2.
Are formed in the biochemical analysis unit 1 at a density of 10 pieces / square centimeter or more.

In the above embodiment, 1920
An approximately circular adsorptive region 4 having a size of about 0.01 square millimeters of 0 is formed on the biochemical analysis unit 1 in a matrix according to a regular pattern with a density of about 5000 pieces / square centimeter. However, it is not always necessary to form the absorptive region 4 of the biochemical analysis unit 1 in the biochemical analysis unit 1 in a regular pattern.

Further, in the above embodiment, the biochemical analysis unit 1 has nylon 6 filled inside a large number of through holes 3 formed in the substrate 2 made of silicon nitride,
Although it has a large number of absorptive regions 4 formed, it is not always necessary that the absorptive regions 4 of the biochemical analysis unit 1 are formed of nylon 6, and instead of nylon 6, activated carbon or the like is used. Porous carbon materials or nylons such as nylon 6,6, nylon 4,10; cellulose derivatives such as nitrocellulose, cellulose acetate, cellulose butyrate acetate; collagen; alginates such as alginic acid, calcium alginate, alginic acid / polylysine polyion complex Polyolefins such as polyethylene and polypropylene; Polyvinyl chloride; Polyvinylidene chloride; Polyfluoride such as polyvinylidene fluoride and polytetrafluoride; and adsorption of biochemical analysis unit 1 by a copolymer or complex thereof. Sex area 4 Can be formed, furthermore,
Metals such as platinum, gold, iron, silver, nickel and aluminum; metal oxides such as alumina, silica, titania and zeolite; metal salts such as hydroxyapatite and calcium sulfate and inorganic porous materials such as composites thereof or more The absorptive region 4 of the biochemical analysis unit 1 may be formed by the bundle of fibers.

Further, in the above-mentioned embodiment, the substrate 2 of the biochemical analysis unit 1 is formed of silicon nitride, but it is not always necessary to form the substrate 2 of silicon nitride, and silicon, amorphous silicon, Silicon materials such as glass, quartz, silicon carbide and silicon nitride; metal oxides such as aluminum oxide, magnesium oxide and zirconium oxide; tungsten carbide
Non-conductive inorganic compound materials such as inorganic salts such as calcium carbonate, calcium sulfate, hydroxyapatite, gallium arsenide, and polyolefins such as polyethylene and polypropylene; acrylic resins such as polymethylmethacrylate and butylacrylate / methylmethacrylate copolymers; Polyacrylonitrile; Polyvinyl chloride; Polyvinylidene chloride; Polyvinylidene fluoride; Polytetrafluoroethylene; Polychlorotrifluoroethylene; Polycarbonate; Polyesters such as polyethylene naphthalate and polyethylene terephthalate; Nylon 6, Nylon 6,6, Nylon 4,10 Such as nylon; polyimide; polysulfone; polyphenylene sulfide;
Silicone resins such as polydiphenylsiloxane; phenolic resins such as novolac; epoxy resins; polyurethane; polystyrene; butadiene-styrene copolymers; cellulose, cellulose acetate, nitrocellulose, starch, polysaccharides such as calcium alginate, hydroxypropylmethylcellulose; chitin. Chitosan; Urushi;
The substrate 2 of the biochemical analysis unit 1 can also be formed of a non-conductive organic compound material such as a polyamide such as gelatin, collagen, keratin, or a copolymer of these high molecular compounds. Furthermore, if the surface of the substrate 2 is covered with a non-conductive material, gold, silver, copper, zinc, aluminum, titanium, tantalum, chromium, iron, nickel,
The substrate 2 of the biochemical analysis unit 1 can also be formed from a metal material such as a metal such as cobalt, lead, tin, or selenium; an alloy such as brass, stainless steel, or bronze.

Further, in the above-mentioned embodiment, the large number of absorptive regions 4 of the biochemical analysis unit 1 are formed by filling the large number of through holes 3 formed in the substrate 2 with nylon 6. However, it is also possible to form a large number of absorptive regions 4 by press-fitting an absorptive film formed of an absorptive material such as nylon 6 into a large number of through holes formed in the substrate.

Further, in the above-mentioned embodiment, in the many absorptive regions 4 of the biochemical analysis unit 1, the many through holes 3 formed in the substrate 2 are filled with nylon 6,
Although formed, a substrate with a large number of through holes is adhered to at least one side of the absorptive substrate formed of an absorptive material such as a membrane filter, and a large number of absorptive substrates inside the through holes are used. It is also possible to form the absorptive region 4 of.

Further, in the above embodiment, the large number of absorptive regions 4 of the biochemical analysis unit 1 are formed by filling the large number of through holes 3 formed in the substrate 2 with nylon 6. However, a solution containing a specific binding substance is dropped onto an absorptive substrate formed of an absorptive material such as a membrane filter in a regular pattern to separate the absorptive regions 4 containing the specific binding substance from each other. Then, it may be formed.

[0288]

INDUSTRIAL APPLICABILITY According to the present invention, a ligand or a receptor immobilized on a biochemical analysis unit can be efficiently caused to undergo an association reaction with the receptor or the ligand, and further, the reproducibility and the quantification are excellent. It becomes possible to provide a receptor-ligand association reaction method and a reactor used for the same, which makes it possible to generate biochemical analysis data.

[Brief description of drawings]

FIG. 1 is a schematic perspective view of a biochemical analysis unit used in a receptor-ligand association reaction method according to a preferred embodiment of the present invention.

FIG. 2 is a schematic front view of a spotting device.

FIG. 3 is a schematic perspective view of a reactor used in the method of receptor / ligand association reaction according to a preferred embodiment of the present invention.

FIG. 4 is a schematic plan view of a reactor used in the method of receptor-ligand association reaction according to a preferred embodiment of the present invention.

FIG. 5 is a schematic perspective view of a stimulable phosphor sheet.

FIG. 6 is a diagram showing the radiolabeled substance contained in a large number of absorptive regions formed in the biochemical analysis unit,
It is a schematic sectional drawing which shows the method of exposing many photostimulable fluorescent substance layer areas formed in the stimulable fluorescent substance sheet.

FIG. 7 is a diagram showing radiation data of radiolabeled substances recorded in a large number of stimulable phosphor layer regions formed on a stimulable phosphor sheet and recorded in a large number of absorptive regions of a biochemical analysis unit. It is a schematic perspective view of the scanner which reads the fluorescence data and produces | generates the data for biochemical analysis.

8 is a schematic perspective view showing details near the photomultiplier of the scanner shown in FIG. 7. FIG.

9 is a schematic cross-sectional view taken along the line AA of FIG.

10 is a schematic cross-sectional view taken along the line BB of FIG.

11 is a schematic cross-sectional view taken along the line CC of FIG.

12 is a schematic cross-sectional view taken along the line DD of FIG.

FIG. 13 is a schematic plan view of a scanning mechanism of an optical head.

14 is a block diagram showing a control system, an input system, a drive system and a detection system of the scanner shown in FIG.

FIG. 15 is a schematic front view of a data generation system that reads chemiluminescence data recorded in a large number of absorptive regions 4 of the biochemical analysis unit 1 to generate biochemical analysis data.

FIG. 16 is a schematic vertical sectional view of a cooled CCD camera.

FIG. 17 is a schematic vertical sectional view of a dark box.

FIG. 18 is a block diagram of the periphery of a personal computer included in the data generation system.

[Explanation of symbols]

1 Biochemical analysis unit 2 substrates 3 through holes 4 Adsorbable area 5 injectors 6 CCD camera 7 Reaction tank 8 Biochemical analysis unit holder 9a, 9b coil 10a, 10b AC power supply 20 Storage phosphor sheet 21 Support 22 Through hole 24 Photostimulable phosphor layer area 31 First Laser Excitation Light Source 32 Second laser excitation light source 33 Third Laser Excitation Light Source 34 Laser light 35 Collimator lens 36 mirror 37 First Dichroic Mirror 38 Second dichroic mirror 39 mirror 40 collimator lens 41 Collimator lens 42 mirror 43 Holes for Mirror 44 holed mirror 45 Optical head 46 mirror 47 Aspherical lens 48 concave mirror 50 stages 51 glass plate 55 Fluorescence or stimulated emission 58 Filter unit 60 Photomultiplier 61a, 61b, 61c, 61d Filter member 62a, 62b, 62c, 62d filters 63 A / D converter 64 data processor 70 board 71 Sub-scanning pulse motor 72 a pair of rails 73 Movable board 74 rod 75 Main scanning stepping motor 76 endless belt 77 Linear encoder 78 Linear encoder slit 80 control unit 81 keyboard 82 Filter unit motor 91 Cooled CCD camera 92 Dark Box 93 personal computer 94 CRT 95 keyboard 96 CCD 97 Heat transfer plate 98 Peltier element 99 shutter 100 A / D converter 101 image data buffer 102 camera control circuit 105 glass plate 106 radiation fin 107 camera lens 110 LED light source 111 Filter 112 filters 113 Diffuser 120 CPU 121 data transfer means 122 data storage means 123 Data processing means 124 Data display means 125 light source control means

Claims (5)

[Claims] 1. A biochemical analysis unit in which a plurality of absorptive regions containing a receptor or a ligand are formed separately from each other is held in a reaction tank, and the reaction tank is labeled with a labeling substance, A reaction solution containing a ligand or a receptor to which various magnetic beads are bound is housed, and a magnetic field whose direction is reversed across the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank is generated. Then, the ligand or receptor contained in the reaction solution is forced to move across the plurality of absorptive regions of the biochemical analysis unit, and the plurality of adsorption of the biochemical analysis unit is adsorbed. Receptor characterized by selectively associating the ligand or receptor contained in the reaction solution with the receptor or ligand contained in the sex region. -Ligand association reaction method. 2. At least one coil is supplied with electric currents having different directions at predetermined time intervals so as to traverse the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank, The receptor-ligand association reaction method according to claim 1, wherein a magnetic field whose direction is reversed is generated every predetermined time. 3. The receptor-ligand association reaction method according to claim 1, wherein the minute magnetic beads are bound to a ligand or a receptor by a covalent bond or an ionic bond. 4. The biochemical analysis unit comprises a substrate having a plurality of holes formed therein, and each of the plurality of absorptive regions is filled with an absorptive material in the holes formed in the substrate. The receptor-ligand association reaction method according to claim 1, wherein the receptor-ligand association reaction method is carried out. 5. A reaction containing a ligand or a receptor, which is provided with a biochemical analysis unit holding portion capable of holding a biochemical analysis unit formed by separating a plurality of absorptive regions containing a receptor or a ligand from each other. A reaction tank capable of containing a solution, and a magnetic field generating means for generating a magnetic field whose direction is reversed across the plurality of absorptive regions of the biochemical analysis unit held in the reaction tank, Characterized reactor.