CA1095285A - Continuously reading analyzer - Google Patents
Continuously reading analyzerInfo
- Publication number
- CA1095285A CA1095285A CA288,776A CA288776A CA1095285A CA 1095285 A CA1095285 A CA 1095285A CA 288776 A CA288776 A CA 288776A CA 1095285 A CA1095285 A CA 1095285A
- Authority
- CA
- Canada
- Prior art keywords
- substrate
- analyzer
- stations
- sample
- monitoring
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
- G01N2035/00039—Transport arrangements specific to flat sample substrates, e.g. pusher blade
- G01N2035/00049—Transport arrangements specific to flat sample substrates, e.g. pusher blade for loading/unloading a carousel
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N35/00029—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides
- G01N2035/00089—Magazines
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
- G01N2035/00346—Heating or cooling arrangements
- G01N2035/00356—Holding samples at elevated temperature (incubation)
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Automatic Analysis And Handling Materials Therefor (AREA)
- Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
Abstract
Abstract of the Disclosure A multichannel analyzer is provided for potentiometric or radiometric analysis of an analyte interacting with a substrate, each channel having sensing means for substantially continuously detecting initial and subsequent responses generated when a test sample is deposited on the substrate.
Description
9s~3s BACKGROUND OF T~E INVENTION
1) Field of the Invention This lnvention relates to apparatus for detecting the level of certain analytes in biological liquids, such apparatus being commonly known as clinical analyzers.
1) Field of the Invention This lnvention relates to apparatus for detecting the level of certain analytes in biological liquids, such apparatus being commonly known as clinical analyzers.
2) State of the P_ior Art Clinical analyzers have been developed to permit analysis of biological liquids, such as blood serum, whereby physicians can ascertain, e.g., the presence of infection or disease. Such liquids, if added to appropriate reagents, which can be either in a liquid or in a dried, coated form genera-te a signal, e.g.
in the form of a color change or fluorescence. Detection of such radiation signals after a suitable incubation period is usually done in a single station as a fina] step. Generally such analysis is called radiometric detection. Alternatively, certain ionic blood components are detected potentiometrically by means of potentials generated by ion selective electrodes, hereinafter ISE's. Included in such tests are the ions Cle, Na~, K~ and the like. Whether the test is potentiometric or radio-metric, it relies upon a substrate to generate a signal of therespective kinds described, in the presence of the test com-ponent of the biological liquid.
Recent innovations have providecl ISE's in essentially planar, dried form, suitable for use in pairs in an analy~er.
Although remarkable accuracy is achievable by such devices, it has been discovered that occasionally the paired electrodes are shorted together, and therefore useless for testing for ion activity. Also, a pair of ISE's designed for testing for Cl can be assigned erroneously for tes-ting for Na~, for example.
Such defects and errors can occur even with good quality control ~2- ~
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in manufacturing. When a defective or erroneous substrate is used, the problem is detected, if at all, in the analyzers of the prior art only when the read station is reached, necessi-tating that the whole test be repeated. If the wrong type of ISE substrate has been used, it is possible that the error might not be detected at all so that a false result is reportecl.
In any event, the container from which the sample in question was drawn for analysis generally might no longer be available, in which case a new blood sample must be drawn from the patient to repeat the test with a new substrate.
Yet another problem which can exist in some solid electrodes is a differential rate of equilibrium arising out of a nonuniformity of coating thickness and chemistry. That is, with some electrodes it is not possible to predict that a steady-state equilibrium will be reached in all cases in x minutes, unless "x" is selected to be as lony as the longest possible time. An arbitrary selection of a larye value of "x"
results in wasted throuyhput time compared to wha~ would be available iE individual equilibrium times were known.
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.
Defective substrates can also occur in radio-metric analyzers~ ~hich as noted above rely upon a single photometer or colorimeter to read each substrate at the end of a test. For example, insufficient or incorrect chemicals may have been added to form -the substrate. Such a problem will be detected, if at all, only ~hen the single read station, hereinafter called "single channel~
is finally reached, necessitating the retrieval of another blood sample from the patient to repeat the test.
Single channel analyzers of the type described `
above inherently require the read statlon to be lastj because any attempt -to place the read station earlier in the sequence would cause all other test samples to be delayed for n times t minutes, where n is the number of substrates to be read and t is thç duration of the incubation period. The through-put of the machine would be greatly delayed beyond that which is economically practical O
The analyzer disclosed in United States Patent No. 3~832,135 is an example of the radiometric analyzers described above. Although there are a plurality of radiometers in that analyzer, there is only one radiometer for each test~
so that on~a test-by-test basis, it provides only a single channel read-out.
In the Centria system of Union Carbide, described in Clinical Chemistry, ~olume 21, No. 9, page 1305 (1975), through-put is increased by using three detection stations for radioactive immunoassays~ This system fails to utilize such multiple stations to provide early detection of possibly erroneous substrates5 in part because an interme1iate process . -- . , .
. . .
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step (centrifuge separation) prevents such early detection.
That is, after the sample is added to the reagent it is transferred into an intermediate incubator/separator (I/S) station, a~ter which the I/S stations are manually moved to a reader module that contains the detection stations. Furthermore, there is not even any appreciation that such early detection is desirable or could avoid errors.
Scintillation counters for the analysis of radioactive samples have been developed with multichannel 10 read-out, as shown for example in U.S. Patent No. 4,005,292 issued January 25, 1977. However, as with the Centria system~ no attempt has been made in such systems to utilize such multichannel read-outs to provide early detection of erroneous~substr tes.
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2t5 ~i SUMMARY OF l'HE INVENTION
The above-described objects are carried out by the provision of a substantiall~ con.tinuously monitoring, . multichannel clinical analyzer f`or a~alytes of sample liquids dèposited on a substrate. The problems of the prior art devices are solved by obtaining a record.of the initial and subsequent signals generated by the substrate, and this in turn is achieved by transferring the substrates directly to the read sta.tions after the sample is deposited, without passing the.substrate through intermediate, non-readlng stations as is common in prior art analyzers. The use of : ;
multichannels avoids the delay in processing that would occur in a continuously monitoring single channel analyzer.
More specifically, in accordance with one aspect o~
the invention, such an analyzer is provided comprising a plurality of stations, each of which is constructed to receive a substrate bearing a sample for analysis; individual sensing means at each of said stations for detecting initial and subsequent sample responses of a received substrate; means for.monitoring such responses at each of said stations; and multiplexing means for repeatedly switching said monitoring means to each o~ said stati.ons; whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations. The sensing means includes :
at least one of the foll.owing: means for detecting -the existence of equilibrium conditions in the substrate, defect test means for determining operabili.ty of the substrate ~or the analyte of choice, and discriminating means for discriminating between . a substrate for one ana]yte and a substrate for a different
in the form of a color change or fluorescence. Detection of such radiation signals after a suitable incubation period is usually done in a single station as a fina] step. Generally such analysis is called radiometric detection. Alternatively, certain ionic blood components are detected potentiometrically by means of potentials generated by ion selective electrodes, hereinafter ISE's. Included in such tests are the ions Cle, Na~, K~ and the like. Whether the test is potentiometric or radio-metric, it relies upon a substrate to generate a signal of therespective kinds described, in the presence of the test com-ponent of the biological liquid.
Recent innovations have providecl ISE's in essentially planar, dried form, suitable for use in pairs in an analy~er.
Although remarkable accuracy is achievable by such devices, it has been discovered that occasionally the paired electrodes are shorted together, and therefore useless for testing for ion activity. Also, a pair of ISE's designed for testing for Cl can be assigned erroneously for tes-ting for Na~, for example.
Such defects and errors can occur even with good quality control ~2- ~
.~
S2~
in manufacturing. When a defective or erroneous substrate is used, the problem is detected, if at all, in the analyzers of the prior art only when the read station is reached, necessi-tating that the whole test be repeated. If the wrong type of ISE substrate has been used, it is possible that the error might not be detected at all so that a false result is reportecl.
In any event, the container from which the sample in question was drawn for analysis generally might no longer be available, in which case a new blood sample must be drawn from the patient to repeat the test with a new substrate.
Yet another problem which can exist in some solid electrodes is a differential rate of equilibrium arising out of a nonuniformity of coating thickness and chemistry. That is, with some electrodes it is not possible to predict that a steady-state equilibrium will be reached in all cases in x minutes, unless "x" is selected to be as lony as the longest possible time. An arbitrary selection of a larye value of "x"
results in wasted throuyhput time compared to wha~ would be available iE individual equilibrium times were known.
. . ,, . ~
2~5i ..~
.
Defective substrates can also occur in radio-metric analyzers~ ~hich as noted above rely upon a single photometer or colorimeter to read each substrate at the end of a test. For example, insufficient or incorrect chemicals may have been added to form -the substrate. Such a problem will be detected, if at all, only ~hen the single read station, hereinafter called "single channel~
is finally reached, necessitating the retrieval of another blood sample from the patient to repeat the test.
Single channel analyzers of the type described `
above inherently require the read statlon to be lastj because any attempt -to place the read station earlier in the sequence would cause all other test samples to be delayed for n times t minutes, where n is the number of substrates to be read and t is thç duration of the incubation period. The through-put of the machine would be greatly delayed beyond that which is economically practical O
The analyzer disclosed in United States Patent No. 3~832,135 is an example of the radiometric analyzers described above. Although there are a plurality of radiometers in that analyzer, there is only one radiometer for each test~
so that on~a test-by-test basis, it provides only a single channel read-out.
In the Centria system of Union Carbide, described in Clinical Chemistry, ~olume 21, No. 9, page 1305 (1975), through-put is increased by using three detection stations for radioactive immunoassays~ This system fails to utilize such multiple stations to provide early detection of possibly erroneous substrates5 in part because an interme1iate process . -- . , .
. . .
$
step (centrifuge separation) prevents such early detection.
That is, after the sample is added to the reagent it is transferred into an intermediate incubator/separator (I/S) station, a~ter which the I/S stations are manually moved to a reader module that contains the detection stations. Furthermore, there is not even any appreciation that such early detection is desirable or could avoid errors.
Scintillation counters for the analysis of radioactive samples have been developed with multichannel 10 read-out, as shown for example in U.S. Patent No. 4,005,292 issued January 25, 1977. However, as with the Centria system~ no attempt has been made in such systems to utilize such multichannel read-outs to provide early detection of erroneous~substr tes.
.. ..
.:
.
;. ~ . .
.: ., , , : :
2t5 ~i SUMMARY OF l'HE INVENTION
The above-described objects are carried out by the provision of a substantiall~ con.tinuously monitoring, . multichannel clinical analyzer f`or a~alytes of sample liquids dèposited on a substrate. The problems of the prior art devices are solved by obtaining a record.of the initial and subsequent signals generated by the substrate, and this in turn is achieved by transferring the substrates directly to the read sta.tions after the sample is deposited, without passing the.substrate through intermediate, non-readlng stations as is common in prior art analyzers. The use of : ;
multichannels avoids the delay in processing that would occur in a continuously monitoring single channel analyzer.
More specifically, in accordance with one aspect o~
the invention, such an analyzer is provided comprising a plurality of stations, each of which is constructed to receive a substrate bearing a sample for analysis; individual sensing means at each of said stations for detecting initial and subsequent sample responses of a received substrate; means for.monitoring such responses at each of said stations; and multiplexing means for repeatedly switching said monitoring means to each o~ said stati.ons; whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations. The sensing means includes :
at least one of the foll.owing: means for detecting -the existence of equilibrium conditions in the substrate, defect test means for determining operabili.ty of the substrate ~or the analyte of choice, and discriminating means for discriminating between . a substrate for one ana]yte and a substrate for a different
3 analyte ~ -6-... . .. . . . ..
.... .. ........
A preferred use of the invention is the detection of ion activity, as with the use of ion-selective electrodes.
Therefore, in accordance with another aspect of the invention, there is provided a continuously moni.toring, multichannel analyzer for ion activity of sample biological liquids .
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deposited on a substrate containing a pair of ion-selective electrodes, said analyzer comprising a plurality o~ stations each o~ which is capable of receiving a substrate for analysis; individual sensing means at each of said stations for detecting initial and subsequent potentiometric signals in the substrate generated by the sample, said sensing means including an electrometer; monitoring means for monitoring said signal at each o~ said stations;
and multiplexing means for repeatedly switching said monitoring means to each of said stations; whereby sub-stantially simultaneous~ repetitive mQnitOring is obtained : of changes occurring at all of said stations.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a plan view of an analyzer constructed in accordance with the invention;
Figs. 2 and 3 are perspective views of one embodiment of an arrangement of stations o~ the analyzer, only one station being shown for clarity;
~ ig. 4 iS a perspective view o~ the interior of the station of Fig. 3~ the cover plate having been broken away;
Fig. 5 is a plan view o~ the interior of the station o~ ~ig. 4, ~ ig. 6 is an elevational view o~ the pivot menber o~ the station;
- - ` , .
`" ~0~52~35, Fig. 7 is a schematic view of a circuit useful in the station of the invention, Figs. 8a and 8b are representative plots of the electrometer output and the first derivative of that output, respectively;
Fig. 9 is a fragmentary ele-vational view, partly schematic, in section of the stations and the loading and unloading means;
Fig. 10 is a fragmentary plan view o~ the transfer means use~ul in loading the stations;
Fig~ 11 is a fragmentary elevational view in section of the means shown in Fig. 10;
Fig. 12 is a fragmentary elevational view in section of the metering station, taken generally along line XII-XII of Fig. l;
Fig. 13 is an elevational view in section o~ means for supplying the slides to the transfer means~ taken generall~
along line XIII-XIII of Fig l;
; Fig. 14 is a plan view of another embodiment of the invention; and Fig. 15 is a fragmentary elevational view in section o:~ one of the stations illustrated in Fig. 14.
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DESCRIPTION OF T~lE~ PR~FERRED~F.~B DI~ENIS
~ lthough the invention is hereinafter descrihed in connection with a multichannel, continuously monitoring potentiometric analyzer for reading ISE's~ a preferred embodiment~ it is not so limited except where stated. Thus~
the invention can also be applied to a continuously . monitoring analyzer using multiple radiometric detectors~
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preferably either photometers or fluorimeters or both, which read any suitable substrate incorporating, for example, reagents that create a dye in proportion to the analyte being measured, to provide early detection of a defective or erroneous reaction.
Such reagents can be in solwtion or in the form of a dried coating.
In the case o~ potentiometric analyzers, the substrate which makes the test possible comprises a supported pair of electrodes selective to the ion activity o~ choice; thus the name ion-selective electrodes or ISE's. Such electrodes, by the use of a salt bridge, permit the generation of an electrical signal, in the presence of the sample test liquid, that is indicative of the test ion activity and thus the concentration, in a manner well known in -the art~ As used herein, "response"
not otherwise limited includes an electrical signal derived from paired electrodes, and also includes any detectable response o~
the substrate that is indicative of the level of analyte of choice. Thus, ~Isubstrate~ and "response", except where limited, are used in their broadest sense to include liquid or dried coating test elements, and both potentiometric and radiometric detection, respectively.
Any generally planar form of the ISE's can be used, preferably in pairs to permit a reference sample to be deposited along with the test sample. One convenient form, illustrated as a slide 10, Figs. l and 10, is that disclosed in ~esearch Disclosure, Vol. 1S7, May 1977, Publication No. 15767, published by Industrial Opportunities Ltd., Homewell, Havant Hampshire P091EF United Kingdom.
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-~4~4~ Such a slide comprises, as best seen in Fig. 10, a frame 12 the bottom surface of which is supportingly attached to a pair o~ ISE's 14 and 16 having a generally planar strip form, and a bridge 18 used to promote ionic migration between the reference sarnple and the test sample deposited over the electrodes. The bridge is located in one opening 20 of the frame 12, and sil~er chloride coated surfaces of the ~SE's are exposed in two openings 22 o~ the frame, for purposes of making readings as hereinafter described.
An analyzer constructed in accordance ~ith the invehtion can be designed to receive substrates ~or reading only a~ter the test sample has contacted the substrate, or it can be designed to receive the substrates before that event~ to be read "in blank." The ~ormer situation~
shown in Figs. 1-12, preferably utilizes, in conjunction ~;
~ith an analyzer 30 on a platform 31, means 170 for trans~erring a substrate 10 contacted with a sample direc-tly to the analyzer~ without passing through intermediate stations. Such an a~rangement insures that the analyzer 30 will sense the initial signal generated by the samples when they ~irst contact the ISE~s. The liquid samples can be deposited from containers C onto the ISE substrate or slide 10 by hand or by any suitable dispenser or metering station 230, Figs. 1 and 12. The slides 10 can be loaded onto trarlsfer means 170 by hand or from a suitable supply means~280. Representative, usefu:L mechanisms for station 230 and supply means 280 are discussed hereinafter.
'~' ~ 5~
Analyr~er 30 comprises a plurality of stations each of which is provided with sensing means for sensing responses or signals from the substrates (Figs. 2-5), computer/monitoring means 166 to monitor or display the response sensed at each station ~Fig. 1), and multiplexing means 160 for repeatedly switching the monitoring means to each of the station (~ig. 1). As shown in Fig. 2, the stations can be a plurality of substantially identical, compartments removably stacked in a frame L~2, the frame being movably mounted for vertical displacement with respect to transfer means 170. A convenient mode for such displacement, Fig~ 2, cornprises mounting the frame 42 in a track or ways ~L~ mounted on a stanchion L~5 supported by a base 46. The bac~ pla-te 47 of the frame is drilled and threaded, through which is passed a rotatable lead screw 49. The screw is turned by gears 50 and 52 and a sui-table motor 53. Each of the stations or co~partments is preferably separately removably ~.ounted, to facilitate repair or replacemenk, in ~rame 42 by opposed tongues 51~
which fit into mating grooves 56 of the frame, Fig. 3. A
pair of removable~ vertically extending stop plates~ ~f which on1y the front plate 57 is shown, Figs. 3 and l~, preven-ts the stations from moving out of the grooves 56 during operation.
Preferably each station includes, for sensing initial and subsequent signals of the slide 10 contained therein, contacts or probes 60, one for each ISE, and an electrometer 120 wired -to the probes, Figs. 4 and 5. As the stations are identical, one (32) will be described.
The location of three of the others is shown in Fig. 3 by dashed arrows labeled 33-35. Station 32 comprises a ~s~
bottom wall 63, a cover plate 64 which is preferably removably mounted as by screws, front wall 65 and rear wall 66. The probes are disposed to project into a path 62 which the slide 10 follows through the compartments, defined by entrance slot 67, bottom wall 63, guide walls 68 upstanding Irom bottom wall 63, and an exit slot 69, Fig. 3. Adjacent to slot 67, wall 63 is sloped'upwardly and inwardly, Fig~ 9, for easy loading. Probes 60 are in the form of Z-shaped members with spaced teeth or serrations 70 at one end and stop flanges 71 ` 10 at the other end (Fig~ 6 ) . The Z-shaped members are held in place such as by screws 72 on a pivot mem~er 74. Member 74 in ^turn comprises a base 76 and a central, upstanding shoulder 78 perforated at ~ront portion 80 and rear portion 82. Base 76 features a pivot lug 84 journaled to guide walls 68 by a pivot pin 86, Fig. 9, at a distance sufficiently spaced above bottom wall 63 as to accommodate slide 10.
To bias pivot member 7L~ downwardly against a slide in position as shown in Fig. 9, a bias or tension spring 90 is secured at one end to front portion 80 and at its opposite end to a llnk plate 91' attached to an adjusting screw 92 mounted in front wall 94 of the compartmen-t. The spring ls selected with a spring constant sufficient to ro-tate member 7 about pivot 86 and to force teeth 70 through the nonconductive ' i~ilver chloride coating that is exposed at opening 20 of the "
' slide and into contact with the conductive silver layer below (Fig. 9). By such means, probes 60 are cons-tantly in contact with the electrodes of slide 10 to provide continuous read-out.
To raise probes 60 during loading and'unloading of the slides, a release'arm 100 is pinned at end 102 to portion 82 of the pivot member~ Figs. 5 and 90 The opposite ;~ - -12- ' , .
, ; ~
~S;2~35 end 101~ of arm 100 projects through opening 106 of rear wall 66, and terminates in handles 108. ~ solenoid 110 is disposed, Fig. 3, on arm 112 mounted on s~anchion ~5. The solenoid is provided with jaws 114 ~hich mate with handles 108 to withdraw the arm 100~ causing member 7~ to pivot away from the slide against the action of spring 900 Stop rods 116 are held in place in rear wall 66, by means such as nuts7 to stop the pivoting o~ member 74 (Fig. 9). Suitable con-ventional control means~ not shown7 are wired to the solenoid to activate it on command, and speci~ically at the time when a slide is to be moved in or out of the station.
The electrometer 120, Figs. L~ and 5, is pre~erably an FET type and can be disposed outside o~ guide walls 68 but within the compartment, The electrometer is connected via amplifier 121 a~d lines 122 to multiplexer 160, hereina~ter described. ~mpli~ier 121 can be any conventional type, such as FET (Figs. 5 and 7)0 Pre~erably, each station has its own electrometer because classic conventional multiplexers are unable ~o respond to low signal levels that are generated by the ISE's prior to the electrometer read-out. ~Iowever, a single electrometer could be incorporated in monitor/computer 166 i~ a mechanical -switching unit or some other multiplexer is incorporated to handle the signals ~rom each ~tation lacking an electrometer.
~ dditlonal circuitry for voltage and impedance test purposes hereinafter described is preferably disposed ~ithin each station 323 Fig. 7 (not shown in Figs. ~ and 5), ~or similar reasonsO That is, internal impedances o~ multiplexers make impedance and voltage comparisons impractical unless they are done prior to multiplexing. However, i~ such impedances are .. . .
S~
compensated for by computer logic, even the circuitry hereinafter detailed could be located downstream of multiplexer 160 rather than upstream.
One example of such test circuitry is a calibrating circuit 130 comprising a test voltage s1ource 132, providing a voltage ~, wlred in series with a load resistor Rl~ The calibrating circuit 130 can be closed by a double pole~
double throw switch Sl to the position B-BI, ~ig. 7. A
double pole relay 136 can be used to short out source 132 by closing switch S2 providing a zero value intercept. The electrometerls reading of a voltage nominally equal to "V"
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~ -13a-. , , ' .
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and a shorted voltage nominally equal to zero aLlow the computer, combined with monitor means 166, to calibrate itself using the eqUation Eelectrometer = kV132 ~ a~
"a" equals the zero value intercept and ~132 is the voltage of source 132.
Still further, relay 136 can be oppositely activated to close switch S3 activating a defect test circuit lL~o comprising resistors R2 and R3 and switch Sl~ in series with probes 60~ The function of this circuit is to ascertain in general the suitabili-ty and operability of the substrates selected for the test. More speciflcally, in the case of ISE's the circuît is intended to determine the internal impedance of slide 10 and thus whether the coatings of -the ISE's of slide 10 are defective or erroneous. This is done with switch Sl closed to place electrometer 120 in parallel with circuit 1~0. Switch S~ is then closed to place R2 or R3 in the circuit. R2 and R3 become voltage dividers, and ; the voltages thereacross are in part controlled by the internal impedance of the slide. By selecting the -value of R2 and R3 to gi~e a predicted ratio of electrometer readings E(open) to ER or ER within a fixed val.ue, for example between about 0.5 and 1.5, the internal impedance can be checked. Usefu:L
values for the resistors include R2, for K~ determinationg equal to above 10 M ohms, and R3, for Cl~ determination, equal to about 500 K ohmsO These values are based on the fact that typical ISE's for K~ have impedances gs between about 5 megohms and 75 megohms and for Cl~, ~s between about 50 K and 130 K ohms.
,.................................................................... ;
___ ,.. ...
Conventional compa.rator circui.t components, not shown, can be used to make the determination whether the slide is Cl~ or K~, by comparing the rati.o of Eopen and ER against a stored constant, and Eopen/ER against the . same or di~erent constant, within a suitable range such as the one noted above. Any reading outside of the set range is _ . .. _ .. ... . . . . ,, . .. .. :
~', ~ a-. ., ~ .
, 1 indicative of a defectlve coating on one or more of the electrodes, and the slide is discarded Switch S~ is of course appropria-tely selected to R2 or R3, depending on which io~ is being checked at -the time.
If, on the other hand, ER2 or ER3 is equal to zero initially~ and the first deri~ative of ER or ER is approximately equal to zero as explained below, then the paired electrodes of slide lO are shorted together as a pair and agaln the slide must be discarded.
By these means~ circuit 140 becomes a discriminator circuit which determines, for slides 10 having impedances that are operative in the firs-t place, i.e.~ not equal to zero, whether the slide is sui~able for measuring Cl~ or whether it is suitable for measuring KQ. The impedance value must be com-parable to that expected for the desired test~ or the compu~er will register a failure' and a new 31lde 10 is automatically selected for remetering from the sample container still at station 230.
To pro~ide a means of ascertaining equilibrium con-ditions in the substrate, a circuit to ascertain the rate ofchange o~ the signal is included. ~ preferred form of such a c~rcuit is a conventional differentiator circuit 1~8, comprising an amplifier 150, such as an FET type, capacitor 152, and ; resistor R5 in parallel with the amplifier 150, Fig. 7. Such a circuit preferably is located between multiplexer 160 and monitor/computer 166, as shown, or it can be included as a component of each of stations 32-39. It is useful in ascertaining ' ' ~15-. , . ~
z~ ~
an equilibration in the initial signal, prior to loss of source of sample at -the metering station as hereina~ter described. That is, since the voltage values detected by the electrometer with Sl in the left hand position, ~ig. 7 . could be caused by a shorted pair or by the condition activity unknown = aCtiVitY re~erence ~1uidg - -15a-, " ; : ~
s a derivative not equal to zero will be indicative of the latter and the slide need not be discarded. Furthermore, continuous monitoring of the first derivative allows monitor 166 to determine ~rhen equilibration is complete and équilibrium is reached, so that the final reading can be taken~ Some slide - constructs may require longer equilibration time than others, and circuit 148 insures that the time at which equilibrium conditions are reached, will be detected for each slide. Thus, each slide will be rçtained in its station or compartment only long enough to obtain a stable reading.
Alternatively, the circuit lL~8 could be located in monitor/computer 166.
The plots sho~n in Fig. 8a and 8b illustra-te the usefulness of the differentiator circuit. The electrometer reading of zero at time tl, Fig 8a, could mean a shorted pair of electrodes. However, circuit lL~8 detects that the first derivati~e at time tl is not zero, Fig. 8b, so that the short can be ruled out. Such time-varying signals, are to be expected for some initial period of time for the ISE's described.
Although the electrometer readin~ oontinues to fluc-tuate until time t3, the detection of a zero first derivative at time t3 is indicative that a stable e~uilibrium condi-tion has been reached and the final reading can be taken.
A conventional second derivative differentiator circuit, not shown~ can be added at point A, ~ig. 7, to discrim-inate a momentary d~ = ~ at time t2~ from the actual equilibriumconditions at time t3. Alternatively, computer 166 can require . , ' ~ '~
; -16-: ' ''' more than one ~irst derivative reading to be equal to zero, to distinguish from the nonequilibrium condition existing at time t2.
Compartments 33-39, not shown, are substantially . identical to that descrlbed for compartment 3~
It wiIl be readily appreciated that the compartments or stations should each provide an electrical shield. Preferabl.y this is achie~ed by constructing walls 63, 65, 66~ cover plate 64, and the exterior side walls fr^m a yrounded conductlve material, such as ccpper.
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m e rest of the compartments, such as interior walls 68, can be nonconductive materials such as plastic.
To maintain a unif'orm temperature for the compartments, ~rame 42 can be cooled by su:Ltable means, f`or example, passageways 154 which extend above (~ig. ~), below and between the compartments. These càrry a liquid for heat exchange. The liquid can be brought in via inlets 156 and removed via outlets 158 (Fig. 3).
Lines 12~ extend f'rom each station or compartment through a grommet 159 (Fig. 5) and opening on wall 66 and are connected to multiplexer 160~ Figs. 2-3, shown as being mol~ted on frame 42. Alternatively, multiplexer 160 can be fixed to an immovable support, f'or example, base 46.
A line 162 connects from outlet posts 164 of the multiplexer to computer/monitor 166 (F'ig. 1). Any conventional multiplexer can be used, such as the Datel Model MM8 Mul-tiplexer, manufactured by Datel Systems, Inc. Although multiplexing~ technically speaking, is well known to be a noncontinuous transmission of individual signals arising from the repeated switching to each of several broadcast sources, such switching occurs at such a rapid rate that, practically speaking, continuous reading o~ each station 32-39 is achieved. Thus, typical delays between each resding of s-tation 32, f`or example, are on the order of` 1 millisecond, compared to a much slower signal change rate, generated by the substrate, of about 1/6 of' a millivolt per second The millisecond dela~ is more than ample to detect such a signal change through the d;ff'erentiator circuit 148.
Computer/monitor 166 can be of' conventional construction, including on its face appropriate dials, gauges or o-ther indicators 168. A keyboard, not shown, can be added ~or ease in control. The progra~ning of ' such a cornputer can~be by means of' hardware or by an .
i2~
appropriate program, as is well known. A variet~ of micro-processors are available in the art for such proposes.
Alternatively, only a monitor 166 can be included, the control of the apparatus being provided by a general purpose computer, .not shown.
A.s shown, moni.tor/computer 166 preferably includes differentiator circuit 148, but not the electrometer or any of the test circùitry illustrated in ~ig. 7.. However, with appropriate adjustments as mentioned above, i-t is contemplated that monitor~computer 166 could include such circuitry, so _. . . , ,_ . . ... . . . . . ~
that the sensing means of each station 32-39 includas only the probes 60.
Circuitry similar to that described above can be used in stations 32-39 to detect radiometric signals, except of course without an electrome-ter 120 and its calibrator circuit 130. In such a caseg a photocell detects light reflected from or transmitted through the substrate inserted into path 62, and the differentiator circuit, if it detects a zero first derivative after a suitable initial t:Lme increment, will indicate that no reaction is occurring or is occurring at the wrong wavelength.
. Such results are indicative that the substrate is de~ective or erroneous and must be di.scarded ~ithout ~ai-ting for "completion"
of the test.
As suggested above, it is important that the initial signal generated by the sample on the substrate, whether a measure of a poten-tial or a densi.ty change, be detected : by the analyzer to determine if the substrate must be discarded and a new one usedg or if the substrate is 3p. properly functioning and can be retained. By such a procedure, .
.
8~i if a new substrate is needed, the same container C of sample can be used to deposit a fresh sample on that new substrate, since that container can be left in the metering position at station 230 (hereinafter described) for the short length of time the initial reading requires. However, to prevent undue dela~ in the presentation of a new serum sample at station 230, it is preferred that the initia1 reading be taken as soon as possible. It has been found that .a useful time limit is .~ . !
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30 seconds after the sample initially contacts the substrate.This time is su~icient for a computer decision to be made concerning the substrates3 and is not long compared to the total processing time. Thereafter, if a "go" signal is -~ generated by the test circuits, the container C from which the sample was taken can be moved out of the metering position at station 230 to a discard station, not shown. To insure that an initial reading is obtained, the substrate with the sample on it is placed within the anal~zer directly after the sample is deposited~ As used herein, "transferring directly"
means transferring without proceeding through an intermediate processing station. Preferably such direct transfer takes place within 30 seconds from the time the sample is deposited on the slide.
Such a direct loading can be done by a transfer means 170, although loading can also be done by hand.
Such a means can be constructed, Figs. 10 and llg to comprise an arm 172 mounted on a rotatable pla-tform 174 fixed to a drive shaft 176 driven by gears 178 and 180, and motor 182.
Within arm 172 is reciprocated a pusher element 184 guided between tracks or ways 186 and 188. Each track is appropria^tely recessed a-t 190 to accommodate both the pusher element 184 and a slide 10. Spr:ings 192 and l9L~ serve as a gripping means to temporarily retain -the slide in arm 172.
To reciprocate element 184 in the tracks, a two-member crank 196 is eccentrically journaled to element 184 at end 198, and a-t its opposite end 200, to a drive shaft 202 driven by motor 204.
Motor 182 is activated to rotate arm 172 into a position aligned with slot 67, Fig. 9. Then motor 204 is activated so that crank 196 causes pusher element 184 to eJect the slide 10 out of tracks 186 and 188 into slot 67 .
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Transfer means 170 also serves to provide non-sequential access of the substrates to compartments 32-39 as soon as computer,/monitor 166 identifies a compartment that can be used. That is~ slides can be removed from compartments 32-39 by means of incoming new slides pushing out the "finished"
slides through slot 69. A conveyor belt 206, shown in phantom, Fig. 9 , can be used to remove and discard such "finished" slides. Such use of transfer arm 172 and an incoming slide 10 to eject the old slides depends, as noted, 10 on a computer-generated signal that the old sli.de has reached ~;
equilibrium and that a ~inal reading has been taken. Since such conditions can vary from slide to slide, the vertical movement of frame 42 past transfer arm 172 allows nonsequential selection of the first compartment ready to be occupi.ed by a new slide.
Alternatively, a separate unloading mechanism 210 can be utilized at a level 211 which is different from the loading level of arm 172, permitting unloading to occur separately frorn loading. Such a mechanism can comprise a pusher arm 212 secured to a pin 214 having flanges 216 mounted between tracks 218, of which only one is shown, Fig. 9.
Pin 214 is jou.rnaled to a crank 220 at end 221, the crank being secured a.t its other end 222 to a pivo~ 224. Intermediate the crank ends, the crank accommodates a roller 226 in a slot 228, ; eccentrically mounted on the rotating face of motor 229.
To deposit a test sample and a reference sample on sllde 10 automatically~ a dispensing station 230 is .. .
.. . .. .... ...
preferably included. Such Q dispenser includesg Figs. 1 and 12, a turntable 232 provided around its rim with apertures 234 which accommodate containers C. Such containers con~eniently have the form of a cup, and to provide accurate dispensing of stable, pendant drops the cup preferably includes an apertured platform 240. Such an apertured platform can be constructed as described in Research Disclosure, Vol~ 133 May 19753 Publication No. 13360, published by Industrial Opportuni-ties ~td., Homewellg EIavant, Hampshire, P09 lEF, UK~
so that a fixed, predictable drop volume, such as 10 ~1, is formed when the liquid in the container is pressurized by means such as hose 2LL2~ even when the properties of the liquid vary from patient to patient. Hose 242 is located at a metering frame 244, Fig. 1, which includes a separate dispenser -tube 246-which dispenses a similarly sized drop of reference fluid ha;ving a known concentration Or the ion being analyzed. Because the reference fluid is always the same, it is not necessary tha-t tip 248 of tube 246 be constructed with the same features as pla-tform 240, although it can be. Tube 246 is suitabl~ supported a-t station 244~ such as by arm 250.
To touch off the pendant drops onto slide 10, a,rm 172 is raised an appropriate dis-tance, arrows 252~
until the slide contacts the drops, but not so far as to contact the slide to tube 246 or platform 240. A suitable mechanism to achie~e -this action comprises the mounting o~
shaft 176, ~ig. 11~ for reciprocal mo-tion in platform 31.
Preferably, a collar 254 is fixed to the shaft and an eccentric 256 is coupled to -the co]lar and activated by ~0 motor 258 to raise platform 174 and arm 172 at -the appropriate time.
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9~2~
The indexing of table 232 is achieved by a motor 260 activated by computer/monitor 1660 Preferably~ the computer 166 is programmed to delay any advance of motor 260 until the initial response is detected, i~e., the tests described above have indicated that the substrate is operative for the analyte of choice, however long such delay might take.
Alternatively, the ad~ance o~ the turntable can be delayed 30 seconds by a delay circuit~ Fig. 12, which can comprise a limit switch 262 which alerts computer 166 that dispensing has begun, and a conventional 30-second timer 264 which delays the signal from the computer to motor 260.
This permits the initial reading of the substrate as noted above~ before the sample container from which the sample ~as taken is moved away from station 230.
Blank slides 10 can be inserted into arm 172 by hand, or, preferably, by an automatic supply means 280, Fig. 130 Such a mechanism comprises a turntable 282 dri~en by a rotating shaft 28l~ gears 286 and 288, and motor 290.
The turntable carries a plurality of cartridges or containers 292 removably confined within housings 294 spaced around the circ~ference of turntable 282. Each cartrid~e contains a stack of the slides 10 appropriate to the test to be run, the slides ' .'' ' - -' ~ ' '~ ', o~
of any given cartridge all being specific for the same test.
~n e~jector 300 is mounted below turntable 282, and is contructed similarly to ejector 210. That is, a pusher arm 312 is connected -to a pin 314 which rides in a track 318 as directed by a cran~ 320 pi~oting at 324 and driven by a roller 326 and motor 329. Arm 312 slides into a slot 330 in cartridge 292 to eject a slide 10 ou-t exit slot 332 into the waiting -transfer arm 172. Arm 312 is then withdrawn, and either another slide from the same cartridge, or a slide from another cartridge~ is pushed out b~ arm 312 when transfer arm 172 returns to pick up another slide As will be apparent from the preceding, the operation of the aforedescribed apparatus is in the reverse order from that in 'which the stations were described. That is, suppl~
means or station 280 is first acti~ated to eject a ~lank slide f'rom its car-tridge 292 into transfer arm 172. Arm 172 is rotated counterc~ockwise, Fig. 1, until the blank slide is positioned under metering ~rame 244 of dispenser station 230. At the same time~ turntable 232 is rota-teduntil 20 cup or container C of choice is positioned under hose 242, and a penclant drop is formed at platform 240 and at end 248 of hose 246. Arm 172 is raised -to touch off -the drops, is lowered, and :t.S rota-ted further until aligned with slot 67 of one o~ the stations 32-39. During -the slide and sample dispensing, analyzer 30 indexes frame 42 up or down screw L~g until the appropria-te statîon is at the level of arm 172 when it arri~es with a new slide bearing deposited test and reference fluids~ ~otor 204 is activated, and pusher .. . . `
element 184 ejects the slide into the station of the analy~er, preferably within 30 seconds from the time the drops were touched off onto the slide. As the slide advances into the compartments of that station, arm 100 is pulled to raise probes 60, and released when the slide is in the position shown, Fig. 9. The defect test circuit 140 is activated, and the first derivative is considered to be certain the substrate is not defective or erroneous as to type. If the substrate must be replaced, immediately a new slide is dispensed by supply means 280, a sample drop is dispensed onto the new slide at station 230 from the same cup as before, and the old slide is discarded or replaced by the new one. If the substrate is tested to be satisfactory, turntable 23 can index to a new cup C or deposit the same sample in the same cup on a different slide, for a different ion concentration. The first derivative continues to be measured ~ntil an approprlate zero derivative value is ;
reached, at which time a final reading is taken by the electro-meter and the slide can be discarded.
Appropriate control circuitry, not shown, can be used to insure that the aforedescribed machine functions are followed in their necessary order. For exampleg conventional limit switches can be positioned to detect completion of a movemen-t which is a condition precedent. An optical detecting circult can be used, including a light source, not shown, on arm 350, Fig. 2, positioned to detect slit 67 and thereby initiate a command that designates that the indexing of frame 42 to the station 32-39 of choice is completed. -Figs. 14 and 15 illustrate an alternate embodiment wherein the substrate is read "in blank" at the several -- -' stations of the analy~er ~efore any fluid is deposited b~ the metering s-tation, as well as a~-terwards. Parts similar to those previously described bear the same reference numeral to which the dis-tinguishing suffix "a" has been applied.
As in the previous embodiment, slides lOa are dispensed by a supply mechanism 280a comprising a ~urntable 282a~ a plurality of cartridges 292a, and an ejector, not shown. Samples are metered from a metering frame 244a at dispenser station 230a, again using a turntable 232a bearing 10 . sample cups C. Unlike the previous embodiment, howe~er, sta-tions or compartments 32a~ 33a, etc-. are disposed on a turntable 400 which replaces the trans~er means 170 ~f the previous embodiment, turntable 400 being the means by which each slide, now in a reading compartment, is moved in-to position at the dispensing stations 230a. Each compartment 32a, etc.~ such as compartment 32a, Fig. 15, has all the circuitry, probes 60a and probe release arm lOOa as described before, except -that in addition an additional switch Sl', shown in phantom, Fïg. 7, is needed, along with a dispensing slot 402 formed in compartment cover plate 64a to receive the sample and reference drops. To complete the electrical isola-tion of compartment 32a, pivoting metal doors 404 mounted on spring biased rods 406 can be disposed in slot 402 to be pushed o~t of the way by dispensing tube 246a and the sample cup, not shown. Either frame 2l~4a or turntable 400 moves towards the other to cause touch-off of the drops.
Since the slides cannot pass completely through turntable 400, d:iscarding is achieved by a pusher element 410 mounted on a track 412 and activated by a crank 414 ~der the compartment, which eJects the "~inished" slide out -the entrance 0- ~ slo-t 67a through which it came.
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This arrangement permits the substrate or slide 10 to be tested with no sample present. Such tests include the "short" test obtained by reading the electrometer when Sl is in position C-C' and Sl' is closed to connect voltage source 132 to the ISE's. If the reading is not equal to the nominal zero value obtained by thereafter closing 52 to short out voltage source 132, then no short exists. If` a short does exist, the slide is immediately discarded in favor of a new one even before the compar-tment is rotated into position under metering f~rame 244a~ saving sample which is otherwise lost if a defect is discovered after sample has been metered or dispensed.
An incubator 420 can also be provided, Fig. 14, into which the compartments 32a~ etc. are rotated. rrhis construction can obviate the need f'or heating or cooling tubes in the co~partment, shown as tubes 154 in Fig. 9.
The invention has been described in detail with particular reference to pref'erred embodiments thereof', but it will be understood that variations and modifications can be effected within the spirit and scope of the inven-tion.
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A preferred use of the invention is the detection of ion activity, as with the use of ion-selective electrodes.
Therefore, in accordance with another aspect of the invention, there is provided a continuously moni.toring, multichannel analyzer for ion activity of sample biological liquids .
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deposited on a substrate containing a pair of ion-selective electrodes, said analyzer comprising a plurality o~ stations each o~ which is capable of receiving a substrate for analysis; individual sensing means at each of said stations for detecting initial and subsequent potentiometric signals in the substrate generated by the sample, said sensing means including an electrometer; monitoring means for monitoring said signal at each o~ said stations;
and multiplexing means for repeatedly switching said monitoring means to each of said stations; whereby sub-stantially simultaneous~ repetitive mQnitOring is obtained : of changes occurring at all of said stations.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a plan view of an analyzer constructed in accordance with the invention;
Figs. 2 and 3 are perspective views of one embodiment of an arrangement of stations o~ the analyzer, only one station being shown for clarity;
~ ig. 4 iS a perspective view o~ the interior of the station of Fig. 3~ the cover plate having been broken away;
Fig. 5 is a plan view o~ the interior of the station o~ ~ig. 4, ~ ig. 6 is an elevational view o~ the pivot menber o~ the station;
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`" ~0~52~35, Fig. 7 is a schematic view of a circuit useful in the station of the invention, Figs. 8a and 8b are representative plots of the electrometer output and the first derivative of that output, respectively;
Fig. 9 is a fragmentary ele-vational view, partly schematic, in section of the stations and the loading and unloading means;
Fig. 10 is a fragmentary plan view o~ the transfer means use~ul in loading the stations;
Fig~ 11 is a fragmentary elevational view in section of the means shown in Fig. 10;
Fig. 12 is a fragmentary elevational view in section of the metering station, taken generally along line XII-XII of Fig. l;
Fig. 13 is an elevational view in section o~ means for supplying the slides to the transfer means~ taken generall~
along line XIII-XIII of Fig l;
; Fig. 14 is a plan view of another embodiment of the invention; and Fig. 15 is a fragmentary elevational view in section o:~ one of the stations illustrated in Fig. 14.
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DESCRIPTION OF T~lE~ PR~FERRED~F.~B DI~ENIS
~ lthough the invention is hereinafter descrihed in connection with a multichannel, continuously monitoring potentiometric analyzer for reading ISE's~ a preferred embodiment~ it is not so limited except where stated. Thus~
the invention can also be applied to a continuously . monitoring analyzer using multiple radiometric detectors~
. ' .. :
preferably either photometers or fluorimeters or both, which read any suitable substrate incorporating, for example, reagents that create a dye in proportion to the analyte being measured, to provide early detection of a defective or erroneous reaction.
Such reagents can be in solwtion or in the form of a dried coating.
In the case o~ potentiometric analyzers, the substrate which makes the test possible comprises a supported pair of electrodes selective to the ion activity o~ choice; thus the name ion-selective electrodes or ISE's. Such electrodes, by the use of a salt bridge, permit the generation of an electrical signal, in the presence of the sample test liquid, that is indicative of the test ion activity and thus the concentration, in a manner well known in -the art~ As used herein, "response"
not otherwise limited includes an electrical signal derived from paired electrodes, and also includes any detectable response o~
the substrate that is indicative of the level of analyte of choice. Thus, ~Isubstrate~ and "response", except where limited, are used in their broadest sense to include liquid or dried coating test elements, and both potentiometric and radiometric detection, respectively.
Any generally planar form of the ISE's can be used, preferably in pairs to permit a reference sample to be deposited along with the test sample. One convenient form, illustrated as a slide 10, Figs. l and 10, is that disclosed in ~esearch Disclosure, Vol. 1S7, May 1977, Publication No. 15767, published by Industrial Opportunities Ltd., Homewell, Havant Hampshire P091EF United Kingdom.
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-~4~4~ Such a slide comprises, as best seen in Fig. 10, a frame 12 the bottom surface of which is supportingly attached to a pair o~ ISE's 14 and 16 having a generally planar strip form, and a bridge 18 used to promote ionic migration between the reference sarnple and the test sample deposited over the electrodes. The bridge is located in one opening 20 of the frame 12, and sil~er chloride coated surfaces of the ~SE's are exposed in two openings 22 o~ the frame, for purposes of making readings as hereinafter described.
An analyzer constructed in accordance ~ith the invehtion can be designed to receive substrates ~or reading only a~ter the test sample has contacted the substrate, or it can be designed to receive the substrates before that event~ to be read "in blank." The ~ormer situation~
shown in Figs. 1-12, preferably utilizes, in conjunction ~;
~ith an analyzer 30 on a platform 31, means 170 for trans~erring a substrate 10 contacted with a sample direc-tly to the analyzer~ without passing through intermediate stations. Such an a~rangement insures that the analyzer 30 will sense the initial signal generated by the samples when they ~irst contact the ISE~s. The liquid samples can be deposited from containers C onto the ISE substrate or slide 10 by hand or by any suitable dispenser or metering station 230, Figs. 1 and 12. The slides 10 can be loaded onto trarlsfer means 170 by hand or from a suitable supply means~280. Representative, usefu:L mechanisms for station 230 and supply means 280 are discussed hereinafter.
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Analyr~er 30 comprises a plurality of stations each of which is provided with sensing means for sensing responses or signals from the substrates (Figs. 2-5), computer/monitoring means 166 to monitor or display the response sensed at each station ~Fig. 1), and multiplexing means 160 for repeatedly switching the monitoring means to each of the station (~ig. 1). As shown in Fig. 2, the stations can be a plurality of substantially identical, compartments removably stacked in a frame L~2, the frame being movably mounted for vertical displacement with respect to transfer means 170. A convenient mode for such displacement, Fig~ 2, cornprises mounting the frame 42 in a track or ways ~L~ mounted on a stanchion L~5 supported by a base 46. The bac~ pla-te 47 of the frame is drilled and threaded, through which is passed a rotatable lead screw 49. The screw is turned by gears 50 and 52 and a sui-table motor 53. Each of the stations or co~partments is preferably separately removably ~.ounted, to facilitate repair or replacemenk, in ~rame 42 by opposed tongues 51~
which fit into mating grooves 56 of the frame, Fig. 3. A
pair of removable~ vertically extending stop plates~ ~f which on1y the front plate 57 is shown, Figs. 3 and l~, preven-ts the stations from moving out of the grooves 56 during operation.
Preferably each station includes, for sensing initial and subsequent signals of the slide 10 contained therein, contacts or probes 60, one for each ISE, and an electrometer 120 wired -to the probes, Figs. 4 and 5. As the stations are identical, one (32) will be described.
The location of three of the others is shown in Fig. 3 by dashed arrows labeled 33-35. Station 32 comprises a ~s~
bottom wall 63, a cover plate 64 which is preferably removably mounted as by screws, front wall 65 and rear wall 66. The probes are disposed to project into a path 62 which the slide 10 follows through the compartments, defined by entrance slot 67, bottom wall 63, guide walls 68 upstanding Irom bottom wall 63, and an exit slot 69, Fig. 3. Adjacent to slot 67, wall 63 is sloped'upwardly and inwardly, Fig~ 9, for easy loading. Probes 60 are in the form of Z-shaped members with spaced teeth or serrations 70 at one end and stop flanges 71 ` 10 at the other end (Fig~ 6 ) . The Z-shaped members are held in place such as by screws 72 on a pivot mem~er 74. Member 74 in ^turn comprises a base 76 and a central, upstanding shoulder 78 perforated at ~ront portion 80 and rear portion 82. Base 76 features a pivot lug 84 journaled to guide walls 68 by a pivot pin 86, Fig. 9, at a distance sufficiently spaced above bottom wall 63 as to accommodate slide 10.
To bias pivot member 7L~ downwardly against a slide in position as shown in Fig. 9, a bias or tension spring 90 is secured at one end to front portion 80 and at its opposite end to a llnk plate 91' attached to an adjusting screw 92 mounted in front wall 94 of the compartmen-t. The spring ls selected with a spring constant sufficient to ro-tate member 7 about pivot 86 and to force teeth 70 through the nonconductive ' i~ilver chloride coating that is exposed at opening 20 of the "
' slide and into contact with the conductive silver layer below (Fig. 9). By such means, probes 60 are cons-tantly in contact with the electrodes of slide 10 to provide continuous read-out.
To raise probes 60 during loading and'unloading of the slides, a release'arm 100 is pinned at end 102 to portion 82 of the pivot member~ Figs. 5 and 90 The opposite ;~ - -12- ' , .
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~S;2~35 end 101~ of arm 100 projects through opening 106 of rear wall 66, and terminates in handles 108. ~ solenoid 110 is disposed, Fig. 3, on arm 112 mounted on s~anchion ~5. The solenoid is provided with jaws 114 ~hich mate with handles 108 to withdraw the arm 100~ causing member 7~ to pivot away from the slide against the action of spring 900 Stop rods 116 are held in place in rear wall 66, by means such as nuts7 to stop the pivoting o~ member 74 (Fig. 9). Suitable con-ventional control means~ not shown7 are wired to the solenoid to activate it on command, and speci~ically at the time when a slide is to be moved in or out of the station.
The electrometer 120, Figs. L~ and 5, is pre~erably an FET type and can be disposed outside o~ guide walls 68 but within the compartment, The electrometer is connected via amplifier 121 a~d lines 122 to multiplexer 160, hereina~ter described. ~mpli~ier 121 can be any conventional type, such as FET (Figs. 5 and 7)0 Pre~erably, each station has its own electrometer because classic conventional multiplexers are unable ~o respond to low signal levels that are generated by the ISE's prior to the electrometer read-out. ~Iowever, a single electrometer could be incorporated in monitor/computer 166 i~ a mechanical -switching unit or some other multiplexer is incorporated to handle the signals ~rom each ~tation lacking an electrometer.
~ dditlonal circuitry for voltage and impedance test purposes hereinafter described is preferably disposed ~ithin each station 323 Fig. 7 (not shown in Figs. ~ and 5), ~or similar reasonsO That is, internal impedances o~ multiplexers make impedance and voltage comparisons impractical unless they are done prior to multiplexing. However, i~ such impedances are .. . .
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compensated for by computer logic, even the circuitry hereinafter detailed could be located downstream of multiplexer 160 rather than upstream.
One example of such test circuitry is a calibrating circuit 130 comprising a test voltage s1ource 132, providing a voltage ~, wlred in series with a load resistor Rl~ The calibrating circuit 130 can be closed by a double pole~
double throw switch Sl to the position B-BI, ~ig. 7. A
double pole relay 136 can be used to short out source 132 by closing switch S2 providing a zero value intercept. The electrometerls reading of a voltage nominally equal to "V"
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and a shorted voltage nominally equal to zero aLlow the computer, combined with monitor means 166, to calibrate itself using the eqUation Eelectrometer = kV132 ~ a~
"a" equals the zero value intercept and ~132 is the voltage of source 132.
Still further, relay 136 can be oppositely activated to close switch S3 activating a defect test circuit lL~o comprising resistors R2 and R3 and switch Sl~ in series with probes 60~ The function of this circuit is to ascertain in general the suitabili-ty and operability of the substrates selected for the test. More speciflcally, in the case of ISE's the circuît is intended to determine the internal impedance of slide 10 and thus whether the coatings of -the ISE's of slide 10 are defective or erroneous. This is done with switch Sl closed to place electrometer 120 in parallel with circuit 1~0. Switch S~ is then closed to place R2 or R3 in the circuit. R2 and R3 become voltage dividers, and ; the voltages thereacross are in part controlled by the internal impedance of the slide. By selecting the -value of R2 and R3 to gi~e a predicted ratio of electrometer readings E(open) to ER or ER within a fixed val.ue, for example between about 0.5 and 1.5, the internal impedance can be checked. Usefu:L
values for the resistors include R2, for K~ determinationg equal to above 10 M ohms, and R3, for Cl~ determination, equal to about 500 K ohmsO These values are based on the fact that typical ISE's for K~ have impedances gs between about 5 megohms and 75 megohms and for Cl~, ~s between about 50 K and 130 K ohms.
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Conventional compa.rator circui.t components, not shown, can be used to make the determination whether the slide is Cl~ or K~, by comparing the rati.o of Eopen and ER against a stored constant, and Eopen/ER against the . same or di~erent constant, within a suitable range such as the one noted above. Any reading outside of the set range is _ . .. _ .. ... . . . . ,, . .. .. :
~', ~ a-. ., ~ .
, 1 indicative of a defectlve coating on one or more of the electrodes, and the slide is discarded Switch S~ is of course appropria-tely selected to R2 or R3, depending on which io~ is being checked at -the time.
If, on the other hand, ER2 or ER3 is equal to zero initially~ and the first deri~ative of ER or ER is approximately equal to zero as explained below, then the paired electrodes of slide lO are shorted together as a pair and agaln the slide must be discarded.
By these means~ circuit 140 becomes a discriminator circuit which determines, for slides 10 having impedances that are operative in the firs-t place, i.e.~ not equal to zero, whether the slide is sui~able for measuring Cl~ or whether it is suitable for measuring KQ. The impedance value must be com-parable to that expected for the desired test~ or the compu~er will register a failure' and a new 31lde 10 is automatically selected for remetering from the sample container still at station 230.
To pro~ide a means of ascertaining equilibrium con-ditions in the substrate, a circuit to ascertain the rate ofchange o~ the signal is included. ~ preferred form of such a c~rcuit is a conventional differentiator circuit 1~8, comprising an amplifier 150, such as an FET type, capacitor 152, and ; resistor R5 in parallel with the amplifier 150, Fig. 7. Such a circuit preferably is located between multiplexer 160 and monitor/computer 166, as shown, or it can be included as a component of each of stations 32-39. It is useful in ascertaining ' ' ~15-. , . ~
z~ ~
an equilibration in the initial signal, prior to loss of source of sample at -the metering station as hereina~ter described. That is, since the voltage values detected by the electrometer with Sl in the left hand position, ~ig. 7 . could be caused by a shorted pair or by the condition activity unknown = aCtiVitY re~erence ~1uidg - -15a-, " ; : ~
s a derivative not equal to zero will be indicative of the latter and the slide need not be discarded. Furthermore, continuous monitoring of the first derivative allows monitor 166 to determine ~rhen equilibration is complete and équilibrium is reached, so that the final reading can be taken~ Some slide - constructs may require longer equilibration time than others, and circuit 148 insures that the time at which equilibrium conditions are reached, will be detected for each slide. Thus, each slide will be rçtained in its station or compartment only long enough to obtain a stable reading.
Alternatively, the circuit lL~8 could be located in monitor/computer 166.
The plots sho~n in Fig. 8a and 8b illustra-te the usefulness of the differentiator circuit. The electrometer reading of zero at time tl, Fig 8a, could mean a shorted pair of electrodes. However, circuit lL~8 detects that the first derivati~e at time tl is not zero, Fig. 8b, so that the short can be ruled out. Such time-varying signals, are to be expected for some initial period of time for the ISE's described.
Although the electrometer readin~ oontinues to fluc-tuate until time t3, the detection of a zero first derivative at time t3 is indicative that a stable e~uilibrium condi-tion has been reached and the final reading can be taken.
A conventional second derivative differentiator circuit, not shown~ can be added at point A, ~ig. 7, to discrim-inate a momentary d~ = ~ at time t2~ from the actual equilibriumconditions at time t3. Alternatively, computer 166 can require . , ' ~ '~
; -16-: ' ''' more than one ~irst derivative reading to be equal to zero, to distinguish from the nonequilibrium condition existing at time t2.
Compartments 33-39, not shown, are substantially . identical to that descrlbed for compartment 3~
It wiIl be readily appreciated that the compartments or stations should each provide an electrical shield. Preferabl.y this is achie~ed by constructing walls 63, 65, 66~ cover plate 64, and the exterior side walls fr^m a yrounded conductlve material, such as ccpper.
~' :
~ :
' ' ' , ~ 16a- l.
~ - !
- ' ,.
-- _ . . . .
~0~ $
m e rest of the compartments, such as interior walls 68, can be nonconductive materials such as plastic.
To maintain a unif'orm temperature for the compartments, ~rame 42 can be cooled by su:Ltable means, f`or example, passageways 154 which extend above (~ig. ~), below and between the compartments. These càrry a liquid for heat exchange. The liquid can be brought in via inlets 156 and removed via outlets 158 (Fig. 3).
Lines 12~ extend f'rom each station or compartment through a grommet 159 (Fig. 5) and opening on wall 66 and are connected to multiplexer 160~ Figs. 2-3, shown as being mol~ted on frame 42. Alternatively, multiplexer 160 can be fixed to an immovable support, f'or example, base 46.
A line 162 connects from outlet posts 164 of the multiplexer to computer/monitor 166 (F'ig. 1). Any conventional multiplexer can be used, such as the Datel Model MM8 Mul-tiplexer, manufactured by Datel Systems, Inc. Although multiplexing~ technically speaking, is well known to be a noncontinuous transmission of individual signals arising from the repeated switching to each of several broadcast sources, such switching occurs at such a rapid rate that, practically speaking, continuous reading o~ each station 32-39 is achieved. Thus, typical delays between each resding of s-tation 32, f`or example, are on the order of` 1 millisecond, compared to a much slower signal change rate, generated by the substrate, of about 1/6 of' a millivolt per second The millisecond dela~ is more than ample to detect such a signal change through the d;ff'erentiator circuit 148.
Computer/monitor 166 can be of' conventional construction, including on its face appropriate dials, gauges or o-ther indicators 168. A keyboard, not shown, can be added ~or ease in control. The progra~ning of ' such a cornputer can~be by means of' hardware or by an .
i2~
appropriate program, as is well known. A variet~ of micro-processors are available in the art for such proposes.
Alternatively, only a monitor 166 can be included, the control of the apparatus being provided by a general purpose computer, .not shown.
A.s shown, moni.tor/computer 166 preferably includes differentiator circuit 148, but not the electrometer or any of the test circùitry illustrated in ~ig. 7.. However, with appropriate adjustments as mentioned above, i-t is contemplated that monitor~computer 166 could include such circuitry, so _. . . , ,_ . . ... . . . . . ~
that the sensing means of each station 32-39 includas only the probes 60.
Circuitry similar to that described above can be used in stations 32-39 to detect radiometric signals, except of course without an electrome-ter 120 and its calibrator circuit 130. In such a caseg a photocell detects light reflected from or transmitted through the substrate inserted into path 62, and the differentiator circuit, if it detects a zero first derivative after a suitable initial t:Lme increment, will indicate that no reaction is occurring or is occurring at the wrong wavelength.
. Such results are indicative that the substrate is de~ective or erroneous and must be di.scarded ~ithout ~ai-ting for "completion"
of the test.
As suggested above, it is important that the initial signal generated by the sample on the substrate, whether a measure of a poten-tial or a densi.ty change, be detected : by the analyzer to determine if the substrate must be discarded and a new one usedg or if the substrate is 3p. properly functioning and can be retained. By such a procedure, .
.
8~i if a new substrate is needed, the same container C of sample can be used to deposit a fresh sample on that new substrate, since that container can be left in the metering position at station 230 (hereinafter described) for the short length of time the initial reading requires. However, to prevent undue dela~ in the presentation of a new serum sample at station 230, it is preferred that the initia1 reading be taken as soon as possible. It has been found that .a useful time limit is .~ . !
-18a-,:
~s~
30 seconds after the sample initially contacts the substrate.This time is su~icient for a computer decision to be made concerning the substrates3 and is not long compared to the total processing time. Thereafter, if a "go" signal is -~ generated by the test circuits, the container C from which the sample was taken can be moved out of the metering position at station 230 to a discard station, not shown. To insure that an initial reading is obtained, the substrate with the sample on it is placed within the anal~zer directly after the sample is deposited~ As used herein, "transferring directly"
means transferring without proceeding through an intermediate processing station. Preferably such direct transfer takes place within 30 seconds from the time the sample is deposited on the slide.
Such a direct loading can be done by a transfer means 170, although loading can also be done by hand.
Such a means can be constructed, Figs. 10 and llg to comprise an arm 172 mounted on a rotatable pla-tform 174 fixed to a drive shaft 176 driven by gears 178 and 180, and motor 182.
Within arm 172 is reciprocated a pusher element 184 guided between tracks or ways 186 and 188. Each track is appropria^tely recessed a-t 190 to accommodate both the pusher element 184 and a slide 10. Spr:ings 192 and l9L~ serve as a gripping means to temporarily retain -the slide in arm 172.
To reciprocate element 184 in the tracks, a two-member crank 196 is eccentrically journaled to element 184 at end 198, and a-t its opposite end 200, to a drive shaft 202 driven by motor 204.
Motor 182 is activated to rotate arm 172 into a position aligned with slot 67, Fig. 9. Then motor 204 is activated so that crank 196 causes pusher element 184 to eJect the slide 10 out of tracks 186 and 188 into slot 67 .
.
2~
Transfer means 170 also serves to provide non-sequential access of the substrates to compartments 32-39 as soon as computer,/monitor 166 identifies a compartment that can be used. That is~ slides can be removed from compartments 32-39 by means of incoming new slides pushing out the "finished"
slides through slot 69. A conveyor belt 206, shown in phantom, Fig. 9 , can be used to remove and discard such "finished" slides. Such use of transfer arm 172 and an incoming slide 10 to eject the old slides depends, as noted, 10 on a computer-generated signal that the old sli.de has reached ~;
equilibrium and that a ~inal reading has been taken. Since such conditions can vary from slide to slide, the vertical movement of frame 42 past transfer arm 172 allows nonsequential selection of the first compartment ready to be occupi.ed by a new slide.
Alternatively, a separate unloading mechanism 210 can be utilized at a level 211 which is different from the loading level of arm 172, permitting unloading to occur separately frorn loading. Such a mechanism can comprise a pusher arm 212 secured to a pin 214 having flanges 216 mounted between tracks 218, of which only one is shown, Fig. 9.
Pin 214 is jou.rnaled to a crank 220 at end 221, the crank being secured a.t its other end 222 to a pivo~ 224. Intermediate the crank ends, the crank accommodates a roller 226 in a slot 228, ; eccentrically mounted on the rotating face of motor 229.
To deposit a test sample and a reference sample on sllde 10 automatically~ a dispensing station 230 is .. .
.. . .. .... ...
preferably included. Such Q dispenser includesg Figs. 1 and 12, a turntable 232 provided around its rim with apertures 234 which accommodate containers C. Such containers con~eniently have the form of a cup, and to provide accurate dispensing of stable, pendant drops the cup preferably includes an apertured platform 240. Such an apertured platform can be constructed as described in Research Disclosure, Vol~ 133 May 19753 Publication No. 13360, published by Industrial Opportuni-ties ~td., Homewellg EIavant, Hampshire, P09 lEF, UK~
so that a fixed, predictable drop volume, such as 10 ~1, is formed when the liquid in the container is pressurized by means such as hose 2LL2~ even when the properties of the liquid vary from patient to patient. Hose 242 is located at a metering frame 244, Fig. 1, which includes a separate dispenser -tube 246-which dispenses a similarly sized drop of reference fluid ha;ving a known concentration Or the ion being analyzed. Because the reference fluid is always the same, it is not necessary tha-t tip 248 of tube 246 be constructed with the same features as pla-tform 240, although it can be. Tube 246 is suitabl~ supported a-t station 244~ such as by arm 250.
To touch off the pendant drops onto slide 10, a,rm 172 is raised an appropriate dis-tance, arrows 252~
until the slide contacts the drops, but not so far as to contact the slide to tube 246 or platform 240. A suitable mechanism to achie~e -this action comprises the mounting o~
shaft 176, ~ig. 11~ for reciprocal mo-tion in platform 31.
Preferably, a collar 254 is fixed to the shaft and an eccentric 256 is coupled to -the co]lar and activated by ~0 motor 258 to raise platform 174 and arm 172 at -the appropriate time.
.
9~2~
The indexing of table 232 is achieved by a motor 260 activated by computer/monitor 1660 Preferably~ the computer 166 is programmed to delay any advance of motor 260 until the initial response is detected, i~e., the tests described above have indicated that the substrate is operative for the analyte of choice, however long such delay might take.
Alternatively, the ad~ance o~ the turntable can be delayed 30 seconds by a delay circuit~ Fig. 12, which can comprise a limit switch 262 which alerts computer 166 that dispensing has begun, and a conventional 30-second timer 264 which delays the signal from the computer to motor 260.
This permits the initial reading of the substrate as noted above~ before the sample container from which the sample ~as taken is moved away from station 230.
Blank slides 10 can be inserted into arm 172 by hand, or, preferably, by an automatic supply means 280, Fig. 130 Such a mechanism comprises a turntable 282 dri~en by a rotating shaft 28l~ gears 286 and 288, and motor 290.
The turntable carries a plurality of cartridges or containers 292 removably confined within housings 294 spaced around the circ~ference of turntable 282. Each cartrid~e contains a stack of the slides 10 appropriate to the test to be run, the slides ' .'' ' - -' ~ ' '~ ', o~
of any given cartridge all being specific for the same test.
~n e~jector 300 is mounted below turntable 282, and is contructed similarly to ejector 210. That is, a pusher arm 312 is connected -to a pin 314 which rides in a track 318 as directed by a cran~ 320 pi~oting at 324 and driven by a roller 326 and motor 329. Arm 312 slides into a slot 330 in cartridge 292 to eject a slide 10 ou-t exit slot 332 into the waiting -transfer arm 172. Arm 312 is then withdrawn, and either another slide from the same cartridge, or a slide from another cartridge~ is pushed out b~ arm 312 when transfer arm 172 returns to pick up another slide As will be apparent from the preceding, the operation of the aforedescribed apparatus is in the reverse order from that in 'which the stations were described. That is, suppl~
means or station 280 is first acti~ated to eject a ~lank slide f'rom its car-tridge 292 into transfer arm 172. Arm 172 is rotated counterc~ockwise, Fig. 1, until the blank slide is positioned under metering ~rame 244 of dispenser station 230. At the same time~ turntable 232 is rota-teduntil 20 cup or container C of choice is positioned under hose 242, and a penclant drop is formed at platform 240 and at end 248 of hose 246. Arm 172 is raised -to touch off -the drops, is lowered, and :t.S rota-ted further until aligned with slot 67 of one o~ the stations 32-39. During -the slide and sample dispensing, analyzer 30 indexes frame 42 up or down screw L~g until the appropria-te statîon is at the level of arm 172 when it arri~es with a new slide bearing deposited test and reference fluids~ ~otor 204 is activated, and pusher .. . . `
element 184 ejects the slide into the station of the analy~er, preferably within 30 seconds from the time the drops were touched off onto the slide. As the slide advances into the compartments of that station, arm 100 is pulled to raise probes 60, and released when the slide is in the position shown, Fig. 9. The defect test circuit 140 is activated, and the first derivative is considered to be certain the substrate is not defective or erroneous as to type. If the substrate must be replaced, immediately a new slide is dispensed by supply means 280, a sample drop is dispensed onto the new slide at station 230 from the same cup as before, and the old slide is discarded or replaced by the new one. If the substrate is tested to be satisfactory, turntable 23 can index to a new cup C or deposit the same sample in the same cup on a different slide, for a different ion concentration. The first derivative continues to be measured ~ntil an approprlate zero derivative value is ;
reached, at which time a final reading is taken by the electro-meter and the slide can be discarded.
Appropriate control circuitry, not shown, can be used to insure that the aforedescribed machine functions are followed in their necessary order. For exampleg conventional limit switches can be positioned to detect completion of a movemen-t which is a condition precedent. An optical detecting circult can be used, including a light source, not shown, on arm 350, Fig. 2, positioned to detect slit 67 and thereby initiate a command that designates that the indexing of frame 42 to the station 32-39 of choice is completed. -Figs. 14 and 15 illustrate an alternate embodiment wherein the substrate is read "in blank" at the several -- -' stations of the analy~er ~efore any fluid is deposited b~ the metering s-tation, as well as a~-terwards. Parts similar to those previously described bear the same reference numeral to which the dis-tinguishing suffix "a" has been applied.
As in the previous embodiment, slides lOa are dispensed by a supply mechanism 280a comprising a ~urntable 282a~ a plurality of cartridges 292a, and an ejector, not shown. Samples are metered from a metering frame 244a at dispenser station 230a, again using a turntable 232a bearing 10 . sample cups C. Unlike the previous embodiment, howe~er, sta-tions or compartments 32a~ 33a, etc-. are disposed on a turntable 400 which replaces the trans~er means 170 ~f the previous embodiment, turntable 400 being the means by which each slide, now in a reading compartment, is moved in-to position at the dispensing stations 230a. Each compartment 32a, etc.~ such as compartment 32a, Fig. 15, has all the circuitry, probes 60a and probe release arm lOOa as described before, except -that in addition an additional switch Sl', shown in phantom, Fïg. 7, is needed, along with a dispensing slot 402 formed in compartment cover plate 64a to receive the sample and reference drops. To complete the electrical isola-tion of compartment 32a, pivoting metal doors 404 mounted on spring biased rods 406 can be disposed in slot 402 to be pushed o~t of the way by dispensing tube 246a and the sample cup, not shown. Either frame 2l~4a or turntable 400 moves towards the other to cause touch-off of the drops.
Since the slides cannot pass completely through turntable 400, d:iscarding is achieved by a pusher element 410 mounted on a track 412 and activated by a crank 414 ~der the compartment, which eJects the "~inished" slide out -the entrance 0- ~ slo-t 67a through which it came.
. .
-2~1~
This arrangement permits the substrate or slide 10 to be tested with no sample present. Such tests include the "short" test obtained by reading the electrometer when Sl is in position C-C' and Sl' is closed to connect voltage source 132 to the ISE's. If the reading is not equal to the nominal zero value obtained by thereafter closing 52 to short out voltage source 132, then no short exists. If` a short does exist, the slide is immediately discarded in favor of a new one even before the compar-tment is rotated into position under metering f~rame 244a~ saving sample which is otherwise lost if a defect is discovered after sample has been metered or dispensed.
An incubator 420 can also be provided, Fig. 14, into which the compartments 32a~ etc. are rotated. rrhis construction can obviate the need f'or heating or cooling tubes in the co~partment, shown as tubes 154 in Fig. 9.
The invention has been described in detail with particular reference to pref'erred embodiments thereof', but it will be understood that variations and modifications can be effected within the spirit and scope of the inven-tion.
, ~
~,, ... .
Claims (23)
.
1. A multichannel analyzer for analytes of sample biological liquids in contact with a substrate, said analyzer comprising a plurality of stations, each of which is constructed to receive a substrate bearing a sample for analysis;
individual sensing means at each of said stations for sensing initial and subsequent sample responses of a received substrate;
means for monitoring such responses;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous repetitive monitoring is obtained of changes occurring at all of said stations.
individual sensing means at each of said stations for sensing initial and subsequent sample responses of a received substrate;
means for monitoring such responses;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous repetitive monitoring is obtained of changes occurring at all of said stations.
2. An analyzer as defined in claim 1, and further including dispensing means for receiving a plurality of sample containers and for metering a sample from each received container respectively onto one of such substrates, and control means for detaining an individual container at said dispensing means at least until said initial response is sensed, whereby a second sample can be taken from said individual container if said initial response indicates an inoperative substrate.
3. An analyzer as defined in claim 2, and further including transfer means for transferring directly to one of said stations, a substrate contacted with a sample, while said control means detains said individual container at said metering means.
4. An analyzer as defined in claim 1, and further including means for detecting the existence of an equilibrium condition in a received substrate.
5. An analyzer as defined in claim 4, and further including transfer means for inserting and removing said substrates into and from any one of said stations in response to detection of equilibrium conditions by said detecting means.
6. An analyzer as defined in claim 5, wherein said stations are mounted one above another in a stack, and further including means for moving said stack vertically with respect to said transfer means.
7. An analyzer as defined in claim 4, wherein said detecting means include a differentiator circuit for ascertaining the rate of change of response of a received substrate.
8. An analyzer as defined in claim 1, and further including defect test means for determining operability of the substrate for a predetermined analyte type.
9. An analyzer as defined in claim 8, wherein said sensing means include an electrometer and said defect test means include means for determining the internal impedance of said substrate.
l0. An analyzer as defined in claim 9, wherein said determining means include an external resistor in parallel with said substrate and said electrometer.
ll. An analyzer as defined in claim 10, wherein said resistor has a resistance less than the minimum impedance of said substrates.
12. An analyzer as defined in claim l, wherein said sensing means include discriminating means for discriminating between at least first and second different types of substrates.
13. An analyzer as defined in claim 12, wherein said sensing means further include an electrometer and wherein said discriminating means include a resistor having a resistance between the internal impedance of said first and second substrate types.
14. A continuously monitoring, multichannel analyzer for ionic activity of sample biological liquids deposited on a substrate containing a pair of ion-selective electrodes said analyzer comprising a plurality of stations, each of which is constructed to receive an ISE substrate for analysis;
individual sensing means at each of said stations for sensing initial and subsequent potentiometric signals of a received substrate, said sensing means including an electrometer;
means for monitoring such signals;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
individual sensing means at each of said stations for sensing initial and subsequent potentiometric signals of a received substrate, said sensing means including an electrometer;
means for monitoring such signals;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
15. An analyzer as defined in claim 14, and further including defect test means for determining operability of`
the substrate for the analyte of choice.
the substrate for the analyte of choice.
16. An analyzer as defined in claim 15, wherein said defect test means further include means for determining the internal impedance of a received substrate.
17. analyzer as defined in claim 14, and further including means for detecting the existence of equilibrium conditions in a received substrate.
18. An analyzer as defined in claim 17, wherein said detecting means include a differentiator circuit for ascertaining the rate of change of signal of a received substrate.
19, An analyzer as defined in claim 14, and further including discriminating means for discriminating between at least first and second different types of received substrates.
20. An analyzer as defined in claim 19, wherein said discriminating means include a resistor having a resistance between the internal impedance of said first and second substrate types.
21. A multichannel analyzer for analytes of sample biological liquids in contact with a substrate, said analyzer comprising a plurality of stations, each of which is constructed to receive a substrate bearing a sample for analysis;
individual sensing means at each of said stations for sensing initial and subsequent sample responses of a received substrate;
means for detecting the existence of an equilibrium condition in a received substrate;
defect test means for determining operability of a received substrate for a predetermined analyte type, means for monitoring such response;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually, whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
individual sensing means at each of said stations for sensing initial and subsequent sample responses of a received substrate;
means for detecting the existence of an equilibrium condition in a received substrate;
defect test means for determining operability of a received substrate for a predetermined analyte type, means for monitoring such response;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually, whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
22. An analyzer as defined in claim 21, wherein each of said stat-ions includes said detecting means and sand defect test means.
23. A multiplexing analyzer for analytes of sample biological liquids in contact with a substrate said analyzer comprising a plurality of stations, each of which is constructed to receive a substrate bearing a sample for analysis;
individual sensing means at each of said stations for sensing initial and subsequent sample responses in a received substrate;
dispensing means for receiving a plurality of sample containers and for metering a sample from each received container, respectively, onto one of such substrates, transfer means for transferring a substrate contacted with a sample to one of said stations, means for monitoring said responses;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
individual sensing means at each of said stations for sensing initial and subsequent sample responses in a received substrate;
dispensing means for receiving a plurality of sample containers and for metering a sample from each received container, respectively, onto one of such substrates, transfer means for transferring a substrate contacted with a sample to one of said stations, means for monitoring said responses;
and multiplexing means for repeatedly switching said monitoring means to each of said stations individually;
whereby substantially simultaneous, repetitive monitoring is obtained of changes occurring at all of said stations.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81825577A | 1977-07-22 | 1977-07-22 | |
| US818,255 | 1977-07-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095285A true CA1095285A (en) | 1981-02-10 |
Family
ID=25225070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA288,776A Expired CA1095285A (en) | 1977-07-22 | 1977-10-14 | Continuously reading analyzer |
Country Status (3)
| Country | Link |
|---|---|
| CA (1) | CA1095285A (en) |
| FR (1) | FR2398306A1 (en) |
| GB (1) | GB2001443B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0154147B1 (en) * | 1984-01-25 | 1989-04-05 | Fuji Photo Film Co., Ltd. | Apparatus for measuring ionic activity |
| AU2508292A (en) * | 1991-08-27 | 1993-03-16 | Porton Diagnostics, Inc. | Analyzer circuitry for analyzing samples on ion sensitive electrodes |
| GB9223016D0 (en) * | 1992-11-03 | 1992-12-16 | Environmental And Medical Prod | Electrochemical sensor |
| GB0127322D0 (en) * | 2001-11-14 | 2002-01-02 | Hypoguard Ltd | Test device |
| CN101303346B (en) * | 2002-02-28 | 2012-10-03 | 爱科来株式会社 | Measuring apparatus and action mechanism |
| CN114923974B (en) * | 2022-07-14 | 2022-10-04 | 深圳中食匠心食品有限公司 | Portable bread heavy metal detection device and detection method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4027979A (en) * | 1973-04-27 | 1977-06-07 | John Victor Komarniski | Multiple chemistry analyzer |
| US3902052A (en) * | 1973-06-11 | 1975-08-26 | Technicon Instr | Method and apparatus for the peak monitoring the results of analysis apparatus |
| US3918910A (en) * | 1973-07-31 | 1975-11-11 | Olympus Optical Co | System for detecting the particular chemical constituent of a fluid |
-
1977
- 1977-10-14 CA CA288,776A patent/CA1095285A/en not_active Expired
-
1978
- 1978-07-21 FR FR7821661A patent/FR2398306A1/en active Granted
- 1978-07-24 GB GB7830909A patent/GB2001443B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2398306B1 (en) | 1983-11-18 |
| FR2398306A1 (en) | 1979-02-16 |
| GB2001443B (en) | 1982-02-10 |
| GB2001443A (en) | 1979-01-31 |
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