CA2241253A1 - Automatic immunological analyzer - Google Patents
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- CA2241253A1 CA2241253A1 CA 2241253 CA2241253A CA2241253A1 CA 2241253 A1 CA2241253 A1 CA 2241253A1 CA 2241253 CA2241253 CA 2241253 CA 2241253 A CA2241253 A CA 2241253A CA 2241253 A1 CA2241253 A1 CA 2241253A1
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Abstract
An automatic immunological analyzer, wherein reaction tube arrays are set between outer and inner circumferential edges of a reaction tube turret, and magnet-mounted pivotable magnet rings are provided therebetween. The effective B/F separation and agitation of a reagent of fine magnetic particles is carried out by making the positions of the reaction tubes and magnets stagger by one pitch in every one index time, and a photometric examination is then conducted by a chemiluminescence method. Since a method using a dedicated tip is employed for the dispensation of a sample and reagent, the tip is changed each time, so that mutual contamination does not occur. Dedicated pumps and nozzles are also used for an agitated liquid and an injected liquid.
Description
~ CA 022412~3 1998-06-23 Speci~ication Automatic immunoassay device Technical ~ield Thepresentinventionrelates toanautomaticimmunoassay device that is capable o~ e~ective and automatic immunoassay to assay speci~ic substances in a specimen ~rom an antigen-antibody reaction.
Background art Substances contained in blood and the like, such as globulin, enzymes and other proteins, hormones, bacteria, and viruses, have similar molecular structures and are present in verysmallquantitiesandarethusdi~icultto~ixandquanti~y with ordinary analysis methods. Immuno-chemical analysis methods that use an antigen-antibody reaction are generally employed to analyses these substances.
Examples o~ these immuno-chemical analysis methods using labeling substances include RIA, EIA and FIA. Methods that use these labeling substances can also be separated into, ~or example, heterogeneous methods, which require so-called B/F separation, an operation to separate immune complexes (Bound), which are ~ormed by causing an antigen-antibody reactionbetweenan antibody (antigen) labeled witha labellng substance and an antigen (antibody) in a sample, ~rom residual labeled-antigen (antibody) in a ~ree state (Free) that does not contribute to the antigen-antibody reaction, and homogeneous methods that do not require this sort o~ B/F
separation.
The EIA method (enzyme-mmllnoassay method) has superior speci~icity andsensitivity, and is commonly used in the ~ield o~ clinical tests. The EIA method normally uses labeling substances by linking to antigens or antibodies and a solid phase as mentioned above, and these are ~irstly brought into CA 022412~3 1998-06-23 contactwiththesubstancetobeassayedinthespecimen. Next, by reacting an antigen or antibody, which is labeled with an enzyme that is a labeling compound and reacts in a speci~ic ~ashion with the object o~ assay, and ~ixed. Then, B/F
separation, which completely removes the unreacted enzyme-labeled antibody, is per~ormed by repeated washing.
Therea~ter, the activity o~ the enzyme o~ the labeling substance combined with the substance under test in the sample is assayed, whereby an amount o~ the substance to be assayed in the specimen is quantitatively assayed.
Accordingly, implementing EIA method has necessitated per~orming complex operations such as apportioning, dilution, agitation, B/F separation andtrans~erring to the solidphase.
Also, intheimplementationthereo~, asolidphaseisgenerally employed As the solid phase, polystyrene beads, magnetic particles, the inner wall o~ the reaction vessel, and the like are generally known. Among them, a method has been developed whereby, for per~orming the assay with high sensitivity and rapidly, the B/F separation is per~ormed with a special-purposevesselasthesolidphaseandamagnetic deviceinwhichare inserted magnets that match this vessel, and assay equipment has been developed ~or assaying large quantities o~
samples When this sort o~ technique is used to per~orm immunoassay, each o~ the individual stages such as the suction and apportioning o~ ~ixed quantities o~ sample, agitating with the reagent, B/F separation which has various reactions associated with it, and assay during washing have - in the main - hitherto been per~ormed manually, and a large amount o~
skilled labor and time have been needed ~or the assay o~ large quantities o~ sample.
The present invention aims to automate this sort o~
immunoassay and provide an automatic immunoassay device that can assay large quantities o~ samples in a short time with a relatively compact device.
- CA 022412~3 1998-06-23 Disclosure o~ the invention The automatic immunoassay device relating to the present invention comprises:
a test tube turret that rotates intermittently at a predetermined rate, and a plurality o~ test tube holders which are disposed in two rows around the inside and around the outsidein thevicinityo~theuppersur~aceo~saidtesttubes, a test tube ~eeding means which supplies a test tube to said test tube holder, a specimen apportioning means which apportions specimens into said test tubes, a rotating magnet ring wherein magnets are disposed in atleasttwoplacesbetweenthe testtubes disposedintworows, areagentapportioningmeanswhichapportionsalabeling reagent into said test tubes, a washing means that uses B/F separation, an apportioning means which apportions an assay reagent into said test tubes, a trans~erring means that extracts the test tubes containing a reaction liquid ~rom the said test tube holder and moves them to a turret ~or assaying, an assay means that assays an amount o~ a labeled substance in the reaction liquid a~ter the reaction in said test tube, and atesttube discardingmeans that discards the testtubes ~rom said turret ~or assaying the test tubes a~ter assay Brie~ explanation o~ the drawings Figure 1 is an explanatory top view o~ an automatic ;mmllnoassay device according to the present example.
Figure 2 is a piping con~iguration diagram o~ the B/F
separation unit o~ the automatic ;mmllnoassay device.
Figure 3 is an explanatory mechanical diagram o~ the B/F
separation unit o~ the automatic ;mmllnoassay device.
Figure 4 is an explanatory mechanical diagram o~ an CA 022412~3 1998-06-23 luminescent apportioning unit.
Best mode ~or practicing the invention In the present invention, the automatic immunoassay deviceincorporatesarotatingmagnetringinwhichaplurality o~ magnets are arranged in at least two places between the two rows o~ test tubes around the outside andaroundthe inside/the magnetringrotatestogetherwiththerotationo~thetesttubes, and it is made so that once per index time the positions o~
the test tubes and the magnets are shi~ted by one pitch at a time.
The rotation o~ the test tube holder is such that a~ter the sample has been apportioned during one index time, it turns by a pitch o~ M (where M is a positive integer) ~or apportion o~ a reagent, and then rotates by -(M-l) so that it advances by a single pitch on balance. A~ter B/F separation, a reagent that assays the amount o~ labeling substance is apportioned to the test tube. Then, the test tube is moved to an assay chamber, and the amount o~ labeling substance in the reaction liquid a~ter reaction is quanti~ied by, ~or example, a chemiluminescence method. A~ter the contents o~ the assayed test tube have been sucked out, the test tube is directly discarded ~rom the assay chamber. Here, the test tube holder rotates by a pitch o~ M a~ter apportioning a sample therein, then rotates by a pitch o~ -(M-l), and a magnet ring rotates a pitch o~ N and rotates a pitch o~ -N (where N is a positive integer) accompanying with this, whereby the chemilumines-cence immunoassay method is carriedout continuously a~terB/F
separation.
Bycontinuingwiththeagitationoperationalonewithout injecting a washing liquid and without removing the reaction liquid a~ter B/F separation, it is possible to repeatedly move on to the next operation without implementing B/F separation, and to accommodate reagents that require a long reaction time.
Speci~ically, by apportioning a primary reagent alone, it is -~ CA 022412~3 1998-06-23 -possible to adopt the same reaction time as when a secondary reagent is apportioned.
By using a reagent pipette tip attachment/removal mechanism, cross-contamination o~ reagents is eliminated by the same mechanismas when exclusivepipettes areused foreach reagent As disclosed in Unexamined Published Japanese Patent Application (JP-A) No H8-15266, a unit is provided ~or agitatinganddispersingthisreagent, andbe~oreapportioning the reagent, the liquid is moved and mixed by repeatedly pressurizing and depressurizing the pipe inserted into the reagent vessel using gas pressure.
As the test tubes used in the present application, ~or example, twin-type cells with a central blocking wall as disclosed inUnexaminedPublished Japanese PatentApplication (JP-A) No. H7-27695 can be used. A single angular-type transparent cell can also be used i~ necessary. Also, as disclosed in Un~m;ned Published Japanese Utility Model Application (JP-A-U) No H5-93540, a test tube cuvette that allows passage to the le~t and right in the central part o~
the longitudinal direction o~ the two walls on the le~t and right is able to mix and agitate the reaction liquid with ~luctuations in pressure di~erence by blowing in and sucking out air in the cuvette through air holes with a removable cap.
For the material o~ the cells, a light transmittance material such as hard glass, polypropylene, polystyrene, polyacrylonitrile, polymethylpentene-l, or the like is used.
With a large number o~ washing liquid pumps, a large numbero~reagentpumpsandvariouspipes andin]ectionnozzles ~or exclusiveuse, itispossible to select the optimum washing liquid and luminescent reagent ~or the items being assayedand reagents.
Example An example o~ the present invention is explained below - . CA 022412~3 1998-06-23 .
based on the accompanying drawings Figure l is a top view o~ an example o~ an automatic immunoassay device according to the present invention.
Sample rack 2, which holds a large number o~ sample tips 1 arranged over its length and breadth, is ~ed horizontally one pitch at a time by a chain conveyor and stops at a predetermined position according to the operation o~ a sample stopper gate 3 Samples 4 are installed in sample cassettes 4', which are capable o~ holding several samples each, and a ~eed mechanism drivenbyapulsemotorisused~orlongitudinal~ree-~lowfeed, a~ter which they are stopped at a predetermined sample apportioning position 5 by ~eeding them laterally one pitch at a time, a~ter which the used sample cassettes 4', that have been sucked in and apportioned is ~ed to a return zone 6.
At the same time, test tubes 7 are ~ed longitudinally by the movement o~ racks where they are retained in two rows each, a~terwhichlateral~eedisper~ormedonepitchata time, stopping at a cuvette distribution position 8.
With regard to the sample tips 1 ~or supplying samples that have stopped at a predetermined position, the drive mechanism o~ the sample apportioning means 9 o~ a three-axis (X, Y, Z) robot 3' - which comprises an arm that can move up and down, longitudinally and laterally, and a ~eed nozzle at the tip o~ the arm - is operated to pick up the sample tips 1 one at a time and move them to a predet~rm;nedposition, pick up a sample 4 carried in sample cassette 4', into tip 1, and apportion the sample 4 into test tubes 7 in test tube holders 11, which are arranged in two rows around the inside and around the outside at the top sur~ace o~ a test tube turret 10, with sample apportioning means 9. Sample tip 1 a~ter apportioning the sample is discarded.
Meanwhile, testtuberacks7lalsoaccommodatetesttubes 7 in two rows, and the test tubes 7 that have been moved to a cuvette distribution position 8 supply test tube cuvettes -- CA 022412~3 1998-06-23 -7 to predetermained test tube holders 11 around the inside and around the outside of test tube turret 10 two at a time by using a test tube supply means 12.
Test tube turret 10 is temperature controlled all the wayroundbyatemperaturecontrolleddevice (notillustrated), andiscon~iguredsoastorotateinaspeci~iedsequence Test tube turret 10 is retained on magnet rotating ring 14 wherein magnets 13 are arrangedatintermediate positions between test tubes 7. Test tube turret 10 and magnet rotating rings 14 and 14' are driven simultaneously or independently by the operation o~ a pulse motor, and are con~igured so that test tubes 7 and magnet position 13 shi~t by a pitch o~ -1 in each index time.
To shift the shi~ting o~ test tubes 7 and rotating ring row 14' by a pitch o~ 1, it is possible to implement a shi~t inpitchof-lby theoperationo~apulse motorandbyoperating an operating spring 16 installed at the bottom o~ test tube turret 10 which causes a shift o~ 1 pitch on stopper 15 and magnet ring 14.
The samples 4 carried in test tubes 7 are diluted with diluting water to predetermined concentrations by an automatic dilutionsystem (notillustrated), andagitationand mixing are implemented. With regard to the agitation o~ the diluted liquid by an agitating/mixing unit 17, as disclosed in Unexamined Published Japanese Utility Model Application (JP-A-U) No. H5-93450, ~or example, the reaction liquidinside cuvette 7 is mixed and agitated by ~luctuations in pressure di~erencebyblowinginandsuckingoutairthrougharemovable cap Reagent tray 18 has reagent vessel units 20 accommodated inside a refrigerator (not illustrated), reagent tips 19 and a reagent tip accommodating part 21, each of which can rotate independently. Reagent unit 20 holds reagent vessels 20 accommodating a first reagent and reagent vessels 20' accommodating a second reagent corresponding to the items - ~ CA 022412~3 1998-06-23 being analyzed. Moreover, at least one reagent vessel including at least one reagent may be provided. The reagent tray18 thatholdsthemismadesoastopositionreagentvessels 20' in a predetermined place at a predetermined timing. The reagent vessels are made so that the reagents can be selected by a bar-code (not illustrated), and the selection is always performed according to the analysis.
A reagent pipette 22 can be moved and conveyed along two axes (X and Y). It picks up a reagent tip 19 held in reagent tip accommodatingpart21,thenchooses apredeterminedreagent vessel 20, apportions into the diluted sample 4 in a pre-determined test tube 7 according to the items being analyzed, andaftertipl9hasbeenuseditisreturnedtoandaccommodated in its original position in the tip rack The present apportioning process involves using an exclusive-use tip for each reagent by means of the attachment/
removal mechanism of reagent pipette 22, and there is no cross-cont~m;n~tion between reagents. Washing is not performed in this reagent apportioning process.
B/F separation washing device23 comprises 4 stages, the removal of the reaction liquid and the apportioning of washing liquid are repeated3 times, and finally, after discarding the liquid, a luminescent reagent is injected. Specifically, the first-stage B/F separation washing device disposes of the antibody liquid inside test tube 7 by suction, after which washing liquid is injected and the reaction liquid is agitated with an agitating device 24. The second-stage B/F separation washing device 23 disposes of the washing liquid by sucking it into a pipette, and apportions the washing liquid again After that, it is agitated by agitating device 24.
The third-stage B/F separation washing device sucks out the washing liquid with a pipette and apportions the washing liquid. Test tube 7 is sent to an agitation position and agitated. Furthermore, in the fourth-stage B/F separation washing, after the washing liquid has been sucked in and - CA 022412~3 1998-06-23 -_ g _ expelled, the luminescent reagent is injected and agitation is per~ormed Alternatively, in the B/F separation, by just agitating without expelling the reaction liquid, and by adapting to reagents that require along reaction time, it is also possible to prolong the reaction time by apportioning only the primary reagent and not apportioning the secondary reagent As Figure 2 shows, ~or example, the ~low used in the presentB/Fseparationprocessispiped~romB/Fwashingliquid tanks 50 through branched joints, e g., six-way joints 51 through B/F washing liquid pumps 52, and to each o~ the test tubes 7 through preheaters 53. The suction/expulsion pump 54 expels the washing liquid ~rom test tubes 7.
The reaction liquid inside test tubes 7 is agitated by usinganairpump55 ~oragitation. Thepositionso~testtubes 7 in the B/F separation process are set to POSl, POS2,..., POSn in a counterclockwise direction. In the B/F separation process in the example, a small lightweight solenoid pump is used as washing liquid pump 52, and by using dedicated pipes and exclusive-use injection nozzles, it is possible to select a washing liquid that is suited to the items being assayed ~rom the three types o~ washing li~uid For example, aprocessingmethod ~or items being assayed ~or which a B/F separation process is not implemented is shown in Figure 3, whereby solenoid 56 is excited to move pin 57 out to the le~t and insert it into a hole in hanging plate 58, wherebyhangingplate58, andexpulsionnozzle59 areprevented ~rom descending. I~ solenoid 56 is not excited, with regard to expulsion nozzle 59, expulsion nozzle 59 also descends as rack 61 descends with the rotation o~ pinion 60, but nozzle 59 that is unable to descend at pin 57 does not descend and spring 62 is simply compressed. For test tubes 7 ~or which suction and expulsion are not per~ormed, the operation o~
washing liquid injection pump 52 is stopped.
Furthermore, in the luminescent reagent apportioning unit - CA 022412~3 1998-06-23 25 shown in Figure 4, the luminescent reagent is apportioned into each o~ the test tubes 7. The luminescent reagent is, ~or example, apportioned into test tubes 7 at each position according to a preheater, using a twin series o~ syringe pumps 29 and 29' ~rom two reagent vessels 28. The apportioned luminescent reagent emits, and the amount o~ labeled enzyme in the reaction vessel - i.e., the dose o~ luminescence, which depends on the amount o~ a speci~ic antigen - is assayed. The amount of luminescence is assayed by a photon counter system, and the number o~ pulses in one second is input to a control unit In this way, a~ter B/F separation, the test tubes 7 in which the luminescent reagent is apportioned are picked up by a change device26 at optical assay position A a~ter a specific time has elapsed, moved to turret ~or assay. Then, it is rotated by 90~ and subjected to photometry by a detector 27 at position B, whereby they are quanti~ied. In the next index time, they are rotated by 90~, the liquid inside is sucked out and expelled at position C. They ~urther turn by another 90~
to position D where the test tubes 7 are discarded.
Utilizability in industry In an automatic immunoassay device relating to the present invention, as the test tubes disposed around the outside and around the inside on a test tube turret per~orm intermittentreciprocatingrotation, amagnetringwhichholds magnets set between the test tubes rotates with the same pitch as the test tubes on the way out, and rotates with pitch one greater than the test tubes on the way back. Thus, B/F
separation o~ magnetic particle reagents is per~ormed, and subsequent to the B/Fseparation, photometry isper~ormedwith a chemiluminescence method, and the used test tubes are discarded. Theapportioningo~samplesandreagentsusestips, and a~ter the sample, or a ~irst reagent, a second reagent, etc. has been sucked in the chips and apportioned, the sample CA 022412~3 1998-06-23 tips are discarded, and the reagent tips are put back in an exclusive-use tip tray, there is no cross-cont~m;n~tion As described above, the device of the present invention is a device which automates the operations per~ormed manually hitherto, is made more compact, and can cope with the immuno reaction in which a reaction time is elongated. Also, in the deviceo~thepresentinvention, byarrangingamagnetrotating ring between the test tubes arranged around the inside and outsideinthedevice, itisabletoper~ormscanninginasingle index time and continuous photometry is also made possible, and thus the device is capable o~ highly e~icient processing.
There is also no cross-contamination because the samples, reagents and washing li~uid systems all use exclusive-use piping systems and a tip system is employed.
Background art Substances contained in blood and the like, such as globulin, enzymes and other proteins, hormones, bacteria, and viruses, have similar molecular structures and are present in verysmallquantitiesandarethusdi~icultto~ixandquanti~y with ordinary analysis methods. Immuno-chemical analysis methods that use an antigen-antibody reaction are generally employed to analyses these substances.
Examples o~ these immuno-chemical analysis methods using labeling substances include RIA, EIA and FIA. Methods that use these labeling substances can also be separated into, ~or example, heterogeneous methods, which require so-called B/F separation, an operation to separate immune complexes (Bound), which are ~ormed by causing an antigen-antibody reactionbetweenan antibody (antigen) labeled witha labellng substance and an antigen (antibody) in a sample, ~rom residual labeled-antigen (antibody) in a ~ree state (Free) that does not contribute to the antigen-antibody reaction, and homogeneous methods that do not require this sort o~ B/F
separation.
The EIA method (enzyme-mmllnoassay method) has superior speci~icity andsensitivity, and is commonly used in the ~ield o~ clinical tests. The EIA method normally uses labeling substances by linking to antigens or antibodies and a solid phase as mentioned above, and these are ~irstly brought into CA 022412~3 1998-06-23 contactwiththesubstancetobeassayedinthespecimen. Next, by reacting an antigen or antibody, which is labeled with an enzyme that is a labeling compound and reacts in a speci~ic ~ashion with the object o~ assay, and ~ixed. Then, B/F
separation, which completely removes the unreacted enzyme-labeled antibody, is per~ormed by repeated washing.
Therea~ter, the activity o~ the enzyme o~ the labeling substance combined with the substance under test in the sample is assayed, whereby an amount o~ the substance to be assayed in the specimen is quantitatively assayed.
Accordingly, implementing EIA method has necessitated per~orming complex operations such as apportioning, dilution, agitation, B/F separation andtrans~erring to the solidphase.
Also, intheimplementationthereo~, asolidphaseisgenerally employed As the solid phase, polystyrene beads, magnetic particles, the inner wall o~ the reaction vessel, and the like are generally known. Among them, a method has been developed whereby, for per~orming the assay with high sensitivity and rapidly, the B/F separation is per~ormed with a special-purposevesselasthesolidphaseandamagnetic deviceinwhichare inserted magnets that match this vessel, and assay equipment has been developed ~or assaying large quantities o~
samples When this sort o~ technique is used to per~orm immunoassay, each o~ the individual stages such as the suction and apportioning o~ ~ixed quantities o~ sample, agitating with the reagent, B/F separation which has various reactions associated with it, and assay during washing have - in the main - hitherto been per~ormed manually, and a large amount o~
skilled labor and time have been needed ~or the assay o~ large quantities o~ sample.
The present invention aims to automate this sort o~
immunoassay and provide an automatic immunoassay device that can assay large quantities o~ samples in a short time with a relatively compact device.
- CA 022412~3 1998-06-23 Disclosure o~ the invention The automatic immunoassay device relating to the present invention comprises:
a test tube turret that rotates intermittently at a predetermined rate, and a plurality o~ test tube holders which are disposed in two rows around the inside and around the outsidein thevicinityo~theuppersur~aceo~saidtesttubes, a test tube ~eeding means which supplies a test tube to said test tube holder, a specimen apportioning means which apportions specimens into said test tubes, a rotating magnet ring wherein magnets are disposed in atleasttwoplacesbetweenthe testtubes disposedintworows, areagentapportioningmeanswhichapportionsalabeling reagent into said test tubes, a washing means that uses B/F separation, an apportioning means which apportions an assay reagent into said test tubes, a trans~erring means that extracts the test tubes containing a reaction liquid ~rom the said test tube holder and moves them to a turret ~or assaying, an assay means that assays an amount o~ a labeled substance in the reaction liquid a~ter the reaction in said test tube, and atesttube discardingmeans that discards the testtubes ~rom said turret ~or assaying the test tubes a~ter assay Brie~ explanation o~ the drawings Figure 1 is an explanatory top view o~ an automatic ;mmllnoassay device according to the present example.
Figure 2 is a piping con~iguration diagram o~ the B/F
separation unit o~ the automatic ;mmllnoassay device.
Figure 3 is an explanatory mechanical diagram o~ the B/F
separation unit o~ the automatic ;mmllnoassay device.
Figure 4 is an explanatory mechanical diagram o~ an CA 022412~3 1998-06-23 luminescent apportioning unit.
Best mode ~or practicing the invention In the present invention, the automatic immunoassay deviceincorporatesarotatingmagnetringinwhichaplurality o~ magnets are arranged in at least two places between the two rows o~ test tubes around the outside andaroundthe inside/the magnetringrotatestogetherwiththerotationo~thetesttubes, and it is made so that once per index time the positions o~
the test tubes and the magnets are shi~ted by one pitch at a time.
The rotation o~ the test tube holder is such that a~ter the sample has been apportioned during one index time, it turns by a pitch o~ M (where M is a positive integer) ~or apportion o~ a reagent, and then rotates by -(M-l) so that it advances by a single pitch on balance. A~ter B/F separation, a reagent that assays the amount o~ labeling substance is apportioned to the test tube. Then, the test tube is moved to an assay chamber, and the amount o~ labeling substance in the reaction liquid a~ter reaction is quanti~ied by, ~or example, a chemiluminescence method. A~ter the contents o~ the assayed test tube have been sucked out, the test tube is directly discarded ~rom the assay chamber. Here, the test tube holder rotates by a pitch o~ M a~ter apportioning a sample therein, then rotates by a pitch o~ -(M-l), and a magnet ring rotates a pitch o~ N and rotates a pitch o~ -N (where N is a positive integer) accompanying with this, whereby the chemilumines-cence immunoassay method is carriedout continuously a~terB/F
separation.
Bycontinuingwiththeagitationoperationalonewithout injecting a washing liquid and without removing the reaction liquid a~ter B/F separation, it is possible to repeatedly move on to the next operation without implementing B/F separation, and to accommodate reagents that require a long reaction time.
Speci~ically, by apportioning a primary reagent alone, it is -~ CA 022412~3 1998-06-23 -possible to adopt the same reaction time as when a secondary reagent is apportioned.
By using a reagent pipette tip attachment/removal mechanism, cross-contamination o~ reagents is eliminated by the same mechanismas when exclusivepipettes areused foreach reagent As disclosed in Unexamined Published Japanese Patent Application (JP-A) No H8-15266, a unit is provided ~or agitatinganddispersingthisreagent, andbe~oreapportioning the reagent, the liquid is moved and mixed by repeatedly pressurizing and depressurizing the pipe inserted into the reagent vessel using gas pressure.
As the test tubes used in the present application, ~or example, twin-type cells with a central blocking wall as disclosed inUnexaminedPublished Japanese PatentApplication (JP-A) No. H7-27695 can be used. A single angular-type transparent cell can also be used i~ necessary. Also, as disclosed in Un~m;ned Published Japanese Utility Model Application (JP-A-U) No H5-93540, a test tube cuvette that allows passage to the le~t and right in the central part o~
the longitudinal direction o~ the two walls on the le~t and right is able to mix and agitate the reaction liquid with ~luctuations in pressure di~erence by blowing in and sucking out air in the cuvette through air holes with a removable cap.
For the material o~ the cells, a light transmittance material such as hard glass, polypropylene, polystyrene, polyacrylonitrile, polymethylpentene-l, or the like is used.
With a large number o~ washing liquid pumps, a large numbero~reagentpumpsandvariouspipes andin]ectionnozzles ~or exclusiveuse, itispossible to select the optimum washing liquid and luminescent reagent ~or the items being assayedand reagents.
Example An example o~ the present invention is explained below - . CA 022412~3 1998-06-23 .
based on the accompanying drawings Figure l is a top view o~ an example o~ an automatic immunoassay device according to the present invention.
Sample rack 2, which holds a large number o~ sample tips 1 arranged over its length and breadth, is ~ed horizontally one pitch at a time by a chain conveyor and stops at a predetermined position according to the operation o~ a sample stopper gate 3 Samples 4 are installed in sample cassettes 4', which are capable o~ holding several samples each, and a ~eed mechanism drivenbyapulsemotorisused~orlongitudinal~ree-~lowfeed, a~ter which they are stopped at a predetermined sample apportioning position 5 by ~eeding them laterally one pitch at a time, a~ter which the used sample cassettes 4', that have been sucked in and apportioned is ~ed to a return zone 6.
At the same time, test tubes 7 are ~ed longitudinally by the movement o~ racks where they are retained in two rows each, a~terwhichlateral~eedisper~ormedonepitchata time, stopping at a cuvette distribution position 8.
With regard to the sample tips 1 ~or supplying samples that have stopped at a predetermined position, the drive mechanism o~ the sample apportioning means 9 o~ a three-axis (X, Y, Z) robot 3' - which comprises an arm that can move up and down, longitudinally and laterally, and a ~eed nozzle at the tip o~ the arm - is operated to pick up the sample tips 1 one at a time and move them to a predet~rm;nedposition, pick up a sample 4 carried in sample cassette 4', into tip 1, and apportion the sample 4 into test tubes 7 in test tube holders 11, which are arranged in two rows around the inside and around the outside at the top sur~ace o~ a test tube turret 10, with sample apportioning means 9. Sample tip 1 a~ter apportioning the sample is discarded.
Meanwhile, testtuberacks7lalsoaccommodatetesttubes 7 in two rows, and the test tubes 7 that have been moved to a cuvette distribution position 8 supply test tube cuvettes -- CA 022412~3 1998-06-23 -7 to predetermained test tube holders 11 around the inside and around the outside of test tube turret 10 two at a time by using a test tube supply means 12.
Test tube turret 10 is temperature controlled all the wayroundbyatemperaturecontrolleddevice (notillustrated), andiscon~iguredsoastorotateinaspeci~iedsequence Test tube turret 10 is retained on magnet rotating ring 14 wherein magnets 13 are arrangedatintermediate positions between test tubes 7. Test tube turret 10 and magnet rotating rings 14 and 14' are driven simultaneously or independently by the operation o~ a pulse motor, and are con~igured so that test tubes 7 and magnet position 13 shi~t by a pitch o~ -1 in each index time.
To shift the shi~ting o~ test tubes 7 and rotating ring row 14' by a pitch o~ 1, it is possible to implement a shi~t inpitchof-lby theoperationo~apulse motorandbyoperating an operating spring 16 installed at the bottom o~ test tube turret 10 which causes a shift o~ 1 pitch on stopper 15 and magnet ring 14.
The samples 4 carried in test tubes 7 are diluted with diluting water to predetermined concentrations by an automatic dilutionsystem (notillustrated), andagitationand mixing are implemented. With regard to the agitation o~ the diluted liquid by an agitating/mixing unit 17, as disclosed in Unexamined Published Japanese Utility Model Application (JP-A-U) No. H5-93450, ~or example, the reaction liquidinside cuvette 7 is mixed and agitated by ~luctuations in pressure di~erencebyblowinginandsuckingoutairthrougharemovable cap Reagent tray 18 has reagent vessel units 20 accommodated inside a refrigerator (not illustrated), reagent tips 19 and a reagent tip accommodating part 21, each of which can rotate independently. Reagent unit 20 holds reagent vessels 20 accommodating a first reagent and reagent vessels 20' accommodating a second reagent corresponding to the items - ~ CA 022412~3 1998-06-23 being analyzed. Moreover, at least one reagent vessel including at least one reagent may be provided. The reagent tray18 thatholdsthemismadesoastopositionreagentvessels 20' in a predetermined place at a predetermined timing. The reagent vessels are made so that the reagents can be selected by a bar-code (not illustrated), and the selection is always performed according to the analysis.
A reagent pipette 22 can be moved and conveyed along two axes (X and Y). It picks up a reagent tip 19 held in reagent tip accommodatingpart21,thenchooses apredeterminedreagent vessel 20, apportions into the diluted sample 4 in a pre-determined test tube 7 according to the items being analyzed, andaftertipl9hasbeenuseditisreturnedtoandaccommodated in its original position in the tip rack The present apportioning process involves using an exclusive-use tip for each reagent by means of the attachment/
removal mechanism of reagent pipette 22, and there is no cross-cont~m;n~tion between reagents. Washing is not performed in this reagent apportioning process.
B/F separation washing device23 comprises 4 stages, the removal of the reaction liquid and the apportioning of washing liquid are repeated3 times, and finally, after discarding the liquid, a luminescent reagent is injected. Specifically, the first-stage B/F separation washing device disposes of the antibody liquid inside test tube 7 by suction, after which washing liquid is injected and the reaction liquid is agitated with an agitating device 24. The second-stage B/F separation washing device 23 disposes of the washing liquid by sucking it into a pipette, and apportions the washing liquid again After that, it is agitated by agitating device 24.
The third-stage B/F separation washing device sucks out the washing liquid with a pipette and apportions the washing liquid. Test tube 7 is sent to an agitation position and agitated. Furthermore, in the fourth-stage B/F separation washing, after the washing liquid has been sucked in and - CA 022412~3 1998-06-23 -_ g _ expelled, the luminescent reagent is injected and agitation is per~ormed Alternatively, in the B/F separation, by just agitating without expelling the reaction liquid, and by adapting to reagents that require along reaction time, it is also possible to prolong the reaction time by apportioning only the primary reagent and not apportioning the secondary reagent As Figure 2 shows, ~or example, the ~low used in the presentB/Fseparationprocessispiped~romB/Fwashingliquid tanks 50 through branched joints, e g., six-way joints 51 through B/F washing liquid pumps 52, and to each o~ the test tubes 7 through preheaters 53. The suction/expulsion pump 54 expels the washing liquid ~rom test tubes 7.
The reaction liquid inside test tubes 7 is agitated by usinganairpump55 ~oragitation. Thepositionso~testtubes 7 in the B/F separation process are set to POSl, POS2,..., POSn in a counterclockwise direction. In the B/F separation process in the example, a small lightweight solenoid pump is used as washing liquid pump 52, and by using dedicated pipes and exclusive-use injection nozzles, it is possible to select a washing liquid that is suited to the items being assayed ~rom the three types o~ washing li~uid For example, aprocessingmethod ~or items being assayed ~or which a B/F separation process is not implemented is shown in Figure 3, whereby solenoid 56 is excited to move pin 57 out to the le~t and insert it into a hole in hanging plate 58, wherebyhangingplate58, andexpulsionnozzle59 areprevented ~rom descending. I~ solenoid 56 is not excited, with regard to expulsion nozzle 59, expulsion nozzle 59 also descends as rack 61 descends with the rotation o~ pinion 60, but nozzle 59 that is unable to descend at pin 57 does not descend and spring 62 is simply compressed. For test tubes 7 ~or which suction and expulsion are not per~ormed, the operation o~
washing liquid injection pump 52 is stopped.
Furthermore, in the luminescent reagent apportioning unit - CA 022412~3 1998-06-23 25 shown in Figure 4, the luminescent reagent is apportioned into each o~ the test tubes 7. The luminescent reagent is, ~or example, apportioned into test tubes 7 at each position according to a preheater, using a twin series o~ syringe pumps 29 and 29' ~rom two reagent vessels 28. The apportioned luminescent reagent emits, and the amount o~ labeled enzyme in the reaction vessel - i.e., the dose o~ luminescence, which depends on the amount o~ a speci~ic antigen - is assayed. The amount of luminescence is assayed by a photon counter system, and the number o~ pulses in one second is input to a control unit In this way, a~ter B/F separation, the test tubes 7 in which the luminescent reagent is apportioned are picked up by a change device26 at optical assay position A a~ter a specific time has elapsed, moved to turret ~or assay. Then, it is rotated by 90~ and subjected to photometry by a detector 27 at position B, whereby they are quanti~ied. In the next index time, they are rotated by 90~, the liquid inside is sucked out and expelled at position C. They ~urther turn by another 90~
to position D where the test tubes 7 are discarded.
Utilizability in industry In an automatic immunoassay device relating to the present invention, as the test tubes disposed around the outside and around the inside on a test tube turret per~orm intermittentreciprocatingrotation, amagnetringwhichholds magnets set between the test tubes rotates with the same pitch as the test tubes on the way out, and rotates with pitch one greater than the test tubes on the way back. Thus, B/F
separation o~ magnetic particle reagents is per~ormed, and subsequent to the B/Fseparation, photometry isper~ormedwith a chemiluminescence method, and the used test tubes are discarded. Theapportioningo~samplesandreagentsusestips, and a~ter the sample, or a ~irst reagent, a second reagent, etc. has been sucked in the chips and apportioned, the sample CA 022412~3 1998-06-23 tips are discarded, and the reagent tips are put back in an exclusive-use tip tray, there is no cross-cont~m;n~tion As described above, the device of the present invention is a device which automates the operations per~ormed manually hitherto, is made more compact, and can cope with the immuno reaction in which a reaction time is elongated. Also, in the deviceo~thepresentinvention, byarrangingamagnetrotating ring between the test tubes arranged around the inside and outsideinthedevice, itisabletoper~ormscanninginasingle index time and continuous photometry is also made possible, and thus the device is capable o~ highly e~icient processing.
There is also no cross-contamination because the samples, reagents and washing li~uid systems all use exclusive-use piping systems and a tip system is employed.
Claims (6)
1. An automatic immunoassay device which comprises a test tube turret that rotates intermittently at a predetermined rate, and a plurality of test tube holders which are disposed in two rows around the inside and around the outside in the vicinity of the upper surface of said test tubes, a test tube feeding means which supplies a test tube to said test tube holder, a specimen apportioning means which apportions specimens into said test tubes, a rotating magnet ring wherein magnets are disposed in at least two places between the test tubes disposed in two rows, a reagent apportioning means which apportions a labeling reagent into said test tubes, a washing means that uses B/F separation, an apportioning means which apportions an assay reagent into said test tubes, a transferring means that extracts the test tubes containing a reaction liquid from the said test tube holder and moves them to a turret for assaying, an assay means that assays an amount of a labeled substance in the reaction liquid after the reaction in said test tube, and a test tube discarding means that discards the test tubes from said turret for assaying the test tubes after assay.
2. An automatic immunoassay device according to Claim 1, wherein the magnet ring rotates together with the rotation of the test tubes, and the positions of the test tubes and magnets are scanned over a single pitch once per index time.
3. An automatic immunoassay device according to Claim 1, wherein the rotation of the test tube holder is such that it turns by a pitch of M and then turns by a pitch of -(M-l) after apportion of the sample, and together with this the magnet ring turns by a pitch of N and turns by a pitch of -N, wherein M and N are positive integers, and a chemiluminescence immunoassay method is successively performed after B/F separation.
4. An automatic immunoassay device according to Claim 1, wherein the immuno reaction time is prolonged without removing the reaction liquid after B/F separation.
5. An automatic immunoassay device according to Claim 1, wherein apportioning is performed by an exclusive-use pipette tip for each reagent with the use of a reagent pipette tip attachment/removal mechanism.
6. An automatic immunoassay device according to Claim 1, wherein separate washing liquid pumps are used for each type of washing liquid and in each stage, and from individual luminescent reagent pumps to exclusive pipes and exclusive injection nozzles are used for each type of luminescent reagents.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP299240/1996 | 1996-10-24 | ||
| JP29924096A JPH10123136A (en) | 1996-10-24 | 1996-10-24 | Automatic immunoanalysis device |
| PCT/JP1997/003793 WO1998018008A1 (en) | 1996-10-24 | 1997-10-21 | Automatic immunological analyzer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2241253A1 true CA2241253A1 (en) | 1998-04-30 |
Family
ID=29404532
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2241253 Abandoned CA2241253A1 (en) | 1996-10-24 | 1997-10-21 | Automatic immunological analyzer |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2241253A1 (en) |
-
1997
- 1997-10-21 CA CA 2241253 patent/CA2241253A1/en not_active Abandoned
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