WO1991019199A1 - Instrument analytique automatique - Google Patents

Instrument analytique automatique Download PDF

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Publication number
WO1991019199A1
WO1991019199A1 PCT/US1991/002104 US9102104W WO9119199A1 WO 1991019199 A1 WO1991019199 A1 WO 1991019199A1 US 9102104 W US9102104 W US 9102104W WO 9119199 A1 WO9119199 A1 WO 9119199A1
Authority
WO
WIPO (PCT)
Prior art keywords
pipette
chamber
assay
carousel
fluid
Prior art date
Application number
PCT/US1991/002104
Other languages
English (en)
Inventor
Dina Frenkel
Fareed Kureshy
Ernest W. Long
Shailendra Singh
Gary L. Webber
Original Assignee
Pb Diagnostic Systems, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Pb Diagnostic Systems, Inc. filed Critical Pb Diagnostic Systems, Inc.
Publication of WO1991019199A1 publication Critical patent/WO1991019199A1/fr

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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
    • G01N2035/00099—Characterised by type of test elements
    • 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
    • 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
    • G01N2035/00455—Controlling humidity in analyser
    • 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
    • G01N35/00584—Control arrangements for automatic analysers
    • G01N35/00722—Communications; Identification
    • G01N35/00732—Identification of carriers, materials or components in automatic analysers
    • G01N2035/00742—Type of codes
    • G01N2035/00752—Type of codes bar codes

Definitions

  • This invention relates to an automated analytical instrument for conducting assays for a component of interest in a fluid sample.
  • Automated test equipment allows large numbers of test samples to be processed rapidly. Such equipment is employed in health care institutions including hospitals and laboratories. Biological fluids, such as whole blood, plasma or serum are tested to find evidence of disease, to monitor therapeutic drug levels, etc.
  • a sample of the test fluid is typically provided in a sample cup and all of the process steps including pipetting of the sample onto an assay test element, incubation and readout of the signal obtained are carried out automatically.
  • the test instrument typically includes a series of work stations each of which performs a specific step in the test procedure.
  • the assay element or cartridge is typically transported from one work station to the next by means of a conveyor such as a carousel to enable the test steps to be accomplished sequentially.
  • the conveyor usually carries a plurality of the assay cartrdiges, each secured to a specific location on the upper surface of the conveyor.
  • the assay cartridges are spaced apart from each other in berths which are located along the periphery of the conveyor to facilitate automatic insertion and extraction.
  • Various automated analytical instruments for performing such analyses have been disclosed. However, as the state of the art advances more demands are made of such instruments and those which have been previously disclosed are not completely satisfactory in providing such enhanced capabilities. For example, consider the temperature controlled chamber.
  • the cost of manufacturing the chamber can be advantageously reduced by constructing at least a part of the chamber from a moldable polymeric material. Further, it would be advantageous to be able to dispense the sample fluid to the assay modules while the latter reside in the temperature controlled chamber. However, in providing a temperature controlled chamber having such features difficulties may be encountered in maintaining the temperature within the chamber within the narrow range typically required. For example, 37° ⁇ 0.5°C.
  • the disposable tips are typically made from resilient, moldable polymeric material for each of manufacture and cost considerations, and because the tip is positioned on the stem (typically metal) of the pipette by frictional fit, there may be some variation from tip to tip as to the distance of the tip orifice from the stem of the pipette. Since, as mentioned above, it is necessary to locate the pipette tip orifice at a predetermined, precisely controlled location above the assay element during the fluid dispense step, any variation in the positioning of the disposable pipette tip on the pipette stem can result in an error in the desired positioning of the pipette tip which can lead to an error in the assay result.
  • an automated analytical instrument which includes a temperature controlled chamber, a conveyor for carrying a plurality of assay elements, at least the part of the conveyor carrying the assay elements being within the temperature controlled chamber, apparatus for loading the assay elements onto the conveyor and for removing the assay elements therefrom, a fluid dispensing system for delivering fluid to the assay elements while the assay elements reside on the conveyor within the temperature controlled chamber and optical apparatus for providing optical readout of a signal generated by an assay element, the signal being a function of the component of interest in a sample fluid applied to the element.
  • the instrument includes a microprocessor for controlling and synchronizing the process steps for the assays performed by the assay elements.
  • the fluid dispense system which includes a pipette having a stem which is adapted to be used with disposable pipette tips, is operative in conjunction with an optical pipette locator system which utilizes a sensor comprised of a light source and a light beam detector to measure the location of the pipette tip.
  • the light source is located in a plane immediately above the assay elements carried on the surface of the conveyor.
  • the pipette is initially positioned with some measure of accuracy by apparatus such as a servo mechanism or a stepper motor and then final adjustment and precise positioning in the dispense location is provided by the optical sensor in conjunction with a microprocessor as will be described in detail below herein. After the fluid is dispensed the pipette is prepared for the next dispense step by removing the disposable tip and replacing it with a new one.
  • the temperature controlled chamber may be constructed partly of polymeric material and includes two heating elements, one arranged above the conveyor and the other below the conveyor.
  • the heating elememts are energized with pulses of electrical current which are applied at a rate preferable at least double the rate at which assay elements can be loaded onto the conveyor in the temperature controlled chamber.
  • the duration of the pulses is increased or decreased by pulse-width modulation, respectively, to raise or lower the temperature in the chamber.
  • a humidity sensor is provided within the analytical instrument and in combination with the microporcessor is used to correct the assay result provided by the assay element for the relative humidity level within the isntrument.
  • Another feature of the invention resides in the use of a bar code identification label on the assay module which is read by a bar code reader to provide information to the micro-processor relating to the specific assay to be conducted with the assay module.
  • Fig. 1 is a stylized view, partially diagrammatic, of an analytical instrument employing a cicular conveyor for moving assay modules among various work stations;
  • Fig. 2 is a stylized view, partially diagrammatic, of a pipette transport for moving the pipette between a supply of disposable tips, reagent reservoirs and compartments of an assay module, the figure also showing an optical detection system for sensing the location of a pipette tip;
  • Fig. 3 is an enlarged fragmentary view of a pipette tip within a light beam of the optical detection system
  • Fig. 4 is a block diagram showing a servo control loop of the pipette transport operative with a microprocessor for positioning the pipette within the vertical direction;
  • Fig. 5 is a flow chart showing operation of the mciroprocessor
  • Fig. 6 shows details in a block of the chart of Fig. 5 relating to the computation of additional pipette travel, including a safety check to insure that a pipette is present on the pipette barrel;
  • Fig. 7 is a timing diagram showing vertical movement of the pipette
  • Fig. 8 is a view of an analytical instrument with portions thereof indicated diagrammatically, including a perspective view of a temperature controlled chamber according to the invention with portions of the chamber shown cut away to disclose interior components thereof;
  • Fig. 9 is a sectional view of the temperature controlled chamber taken along the line 3 - 3 of Fig. 8;
  • Fig. 10 is a block diagram of a heater control system for energizing top and bottom heaters of the chamber;
  • Fig. 1 1 is a graphical illustration demonstrating the variation with relative humidity in the intensity of fluorescent signals obtained as the result of the presence of an analyte of interest in sample fluids
  • Fig. 12 is a block diagram showing the interrelationships between a microprocessor and elements of the analytical instrument.
  • Fig. 13 is a flow chart showing the operation of the microprocessor in the performance of an assay. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • FIG. 1 there is shown an analytical instrument 20 which provides automatically a sequence of process steps to accomplish an assay of a test sample.
  • a plurality of modules 22 are employed within the instrument 20 to increase the throughput rate, one process step being carried out with one module concurrently with the performance of other process steps with other modules.
  • the modules 22 are illustrated with respect to a preferred embodiment thereof which includes one or more chambers in the housing. Such chambers may be configured as wells, or reservoirs, for the storage and/or mixing of fluids which are used in the assay procedure or the chambers may culminate in an opening to permit fluids to be provided to a reaction zone within the module.
  • the chambers are formed integrally within the housing of the module.
  • the analytical instrument 20 includes a conveyor, or carousel, 24, which is rotated about an axle 26 by a motor 28.
  • the motor 28 may be mechanically coupled to the carousel 24 by a gear 30 or by a belt drive (not shown).
  • the carousel 24 carries the modules 22 from one work station to another work station, two such work stations 32 and 34 being shown, by way of example, in Fig. 1.
  • the carousel 24 rotates within a temperature controlled chamber 36 having a heater 38 for maintaining a desired temperature at the various work stations so as to allow for a process step of incubation.
  • Work station 32 is a pipetting station whereat sample fluid and any other required fluid test reagent(s) are delivered to the assay modules 22.
  • the pipettes, 40 and 42 are positioned and operated by a pipette mechanism 44 mechanically connected to the pipettes 40 and 42, as indicated by dashed lines.
  • a detectable change is effected corresponding to the presence of an analyte or component of interest in the sample fluid.
  • the detectable change may be a color change which may be read spectrophotometrically such as with a densitometer or, in an assay method based on fluorescent-labeled biologically active species or one which involves the generation of a fluorescent species as a result of a reaction between test reagents, a fluorescent output signal can be generated and read spectrofluorometrically.
  • Such detectable changes may be read from above or below the assay module.
  • a fluorometer 46 for irradiating the reaction zone within the assay module and for measuring the fluorescence emitted from the fluorescent species present therein.
  • the carousel 24 may be arranged so as to accommodate varying numbers of assay modules 22.
  • Each position, or berth 54 for holding an assay module is provided in this embodiment with a small aperture 56 to allow the irradiating illumination to reach the reaction zone in the assay module and to permit the fluorescent emissions to be collected and measured.
  • the injector 58 also serves to extract a module from a berth 54 by use of the arm 60 upon completion of a test procedure.
  • Fig. 2 provides detail in the construction of the pipette mechanism 44 of Fig. 1.
  • the pipette mechanism 44 will be described hereinafter as having a pipette transport 64 operative with only one of the pipettes, namely, the pipette 40.
  • the transport 64 provides for relative movement, in two dimensions, between the pipette 40 and a set of reservoirs 66 located at a distance from the module 22, the reservoir 66 serving to store reagents useful in the assays carried out by the instrument 20.
  • the reservoirs 66 are located on a movable table 68 which also holds a set of tips 70 which are to be affixed to a stem 72 of the pipette 40.
  • the pipette 40 is translatable in the X direction along a box beam 74 of the transport 64, and the table 68 is translatable in the Y direction by riding along a rail 76 of the transport 64.
  • a vertical drive 78 is located within the beam 74 and serves to raise and to lower the pipette 40 in the Z direction.
  • a horizontal drive 80 located within the box beam 74 drives the pipette in the X direction.
  • the vertical drive 78 and the horizontal drive 80 are of conventional design, and are indicated in simplified fashion in Fig. 2.
  • the vertical drive 78 may be described as comprising a wheel 82 slidably mounted to a spline shaft 84 which, alternatively, may have a square cross section.
  • the shaft 84 is rotated by a motor 86.
  • the horizontal drive 80 includes a base 88 which slides in the X direction along the beam 74 in response to rotation of a motor 90.
  • the motor 90 drives a belt 92 through a pulley 94, the belt 92 being connected to the base 88 for translating the base 88 upon rotation of the pulley 94 by the motor 90.
  • a fixture 96 upstanding from the base 88 slides the wheel 82 along the shaft 84 upon movement of the base 88 so that the wheel 82 stays in fixed position relative to the base 88.
  • the pipette 40 passes through the base 88 so as to be translated in the X direction by the base 88.
  • the wheel 82 is mechanically connected to the pipette 40, as by gear teeth on the wheel 82, or by means of a belt drive (not shown).
  • the mechanical connection of the wheel 82 to the pipette 40 provides for a translation of the pipette 40 in the Z direction upon rotation of the wheel 82 by the motor 86.
  • the belt drive 98 may be employed, similarly, for driving the table 68 in the Y direction in response to rotation of a motor 100 affixed to the rail 76.
  • the motor 28 is under control of the computer 62.
  • the motor 100, 90, and 86 are also under control of the computer 62. Connections of the motors 28, 100, 90, and 86 are indicated in Fig. 2 by terminals A, B. C, and D, respectively. Thereby, movement of the pipette 40 can be synchronized with a positioning of the module 22 by the carousel 24 to a location directly beneath the beam 74.
  • a slot 102 is provided in a top wall 104 of the temperature controlled chamber 36.
  • the slot 102 is parallel to the beam 74.
  • the location of the slot 102 relative to the beam 74 permits the stem 72 of the pipette 40 to be lowered through the slot 102 selectively above a desired compartment of a plurality of compartments 106 of the module 22.
  • the length of the slot 102 is commensurate with the length of the module 22 to permit displacement of the stem 72 in the X direction for alignment with a selected one of the compartments 106.
  • the slot 102 is relatively narrow, and has a width large enough to clear the stem 72 and the tip 70 mounted on the distal end of the stem 72.
  • the area occupied by the slot 102 is sufficiently small to preclude any significant amount of air flow between the interior and the exterior of the chamber 36. Thereby, the slot 102 has no more than a negligible effect in the control of the chamber temperature, which temperature is controlled by the heater 38 (Fig. 1 ).
  • an optical detection system 108 is provided to signal the microprocessor 62 when the tip 70 of the pipette 40 has advanced in the downward direction to a predetermined distance from the selected compartment 106.
  • the detection system 108 comprises a source 1 10 of light which, by way of example, may be a semiconductor diode which emits infrared radiation.
  • the detection system 108 also comprises a detector 1 12, the light being indicated by a beam 1 14.
  • the detector 1 12, which may comprise a semiconductor photodiode, modulates an electric current along line 1 16 in response to light of the beam 114 incident upon the detector 1 12.
  • the detection system 108 includes electrical comparison circuitry 1 18 for measuring the magnitude of the current on line 1 16.
  • the circuitry 1 18 comprises a comparator 120 and a resistive voltage divider 124 providing a reference voltage respectively to the comparator 120.
  • the divider 124 is shown to comprise a potentiometer for allowing manual adjustment of the reference voltage for initial alignment of the detection system 108.
  • the alignment provides for selection of comparator reference voltages in accordance with the degree of optical transparency of the tip 70.
  • the full strength of the light beam 1 14 is incident upon the detector 112 in the absence of the pipette 40.
  • the pipette 40 may be at the location of one of the reservoirs 66, as indicated in phantom view of the pipette.
  • a maximum current and voltage appear on line 116.
  • the tip 70 interrupts the light beam 1 14.
  • the line 1 16 is connected to the input terminal of comparator 120 and, accordingly, both of the comparators 120 and 122 output a logic-1 signal to the microprocessor 62 under conditions of maximum illumination of the detector 112, as occurs prior to interruption of the light beam 1 14 by the pipette 40. Interruption of the light beam 114 greatly reduces the intensity of light received at the detector 112. The extent of the interruption of the light depends on the degree of the transparency of the tip 70.
  • the tip 70 is preferably fabricated of a polymeric material which is translucent so as to reduce the intensity of the light without casting a complete shadow upon the detector 1 12.
  • the voltage reference levels of the divider 124 are set such that the amount of light transmitted by a tip is sufficient to activate the comparator 120 to output a logic-1 signal indicating a low, L, level of light received at the detector 1 12.
  • the intensity of light received by the detector 1 12 is too low to activate the comparator 120 with the result that the comparator outputs logic-0.
  • the comparison circuitry 1 18 designating the status and location of the tip 70 as the tip 70 advances along a path of travel in the Z direction to a selected compartment 106 of the module 22.
  • Fluid reagent is drawn into the pipette tip 70 by vacuum and expelled from the tip 70 by pressure delivered to the pipette 40 by a suction tube 126 under control of a control unit 128.
  • the tube 126 is flexible and of sufficient length to connect the control unit 128 with the pipette 40 at all locations of the pipette 40.
  • the control unit 128 is connected to the microprocessor 62 which commands the control unit 128 to apply vacuum for inducting fluid, and for releasing vacuum and applying positive pressure, if necessary, to expel the fluid reagent. Aspiration of fluid is done from a selected one of the reservoirs 66.
  • Expelling of the fluid reagent is accomplished only when the tip 70 is in the position for dispensing the fluid to the selected one of the compartments 106 in the designated module 22. It is noted also that aspiration of fluid reagent can be accomplished at one of the compartments 106 of the module 22 to be dispensed in another of the compartments 106.
  • a reservoir for storage of fluid reagent can be located directly within the module 22 or remote from the module 22, as at the table 68. The location of the various reservoirs 66 of the table 68 are stored in a memory of the microprocessor 62.
  • the micro-processor 62 This enables the micro-processor 62 to move the table 68 to a specific address in the Y direction, and to move the pipette 40 to a specific address in the X direction, the X and the Y components of the address fully identifying the requisite one of the reservoirs 66.
  • the microprocessor 62 stores locations of the available tips 70 held by the table 68 so that successive ones of the tips 70 can be selected for affixation to the stem 72.
  • the transport 64 is operative in the process of affixing a tip 70 to the stem 72 of a pipette 40, and in the detachment of the tip 70 from the stem 72.
  • the procedure begins by a lifting of the pipette 40 so that the tip 70 clears the slot 102. "
  • the pipette 40 is then free to move along the beam 74 to an extractor 130.
  • the extractor 130 has a semicircular channel 132 cut out in the edge of a horizontal portion of the extractor 130, the channel 132 having a diameter large enough to permit clearance of the stem 72 by the channel 132 , but small enough to permit engagement of the channel 132 with the tip 70.
  • the pipette is brought towards the extractor 130 with the tip 70 being below the channel 132.
  • the stem 72 enters the channel 132 after which the pipette 40 is raised to engage the tip 70 with the extractor 130.
  • the tip 70 remains stationary as the stem 72 lifts out of the tip 70. Thereupon, the tip 70 falls into a bin 134 for collection of used tips 70. It is advisable to employ the extractor 130 at the beginning of operation of the instrument 20 to ensure that the stem 72 is free for reception of a new tip 70.
  • the pipette 40 is brought, by displacement in the X direction, to a location above the table 68, whereupon the table 68 is translated in the Y direction to bring the stem 72 above and in registration with a selected tip 70 held by the table 68.
  • the pipette 40 then advances downward to make frictional contact with the interior surface of the tip 70. Thereupon, the pipette is raised, and the tip is retained on the distal end of the stem 72 by friction forces.
  • the distal end of the stem 72 is shown making frictional contact with the surface of a channel 136 of the tip 70.
  • the channel 136 extends along a central longitudinal axis of the tip 70 from one end of the tip to the opposite end of the tip.
  • the channel 136 has a circular cross-sectional shape of varying diameter, the diameter being larger at the top end 138 than at the bottom end 140.
  • the manner of affixing the stem 72 to the tip 70 provides substantial uniformity in the locations of successive tips 70 upon the stem 72.
  • the flexibility of the polymeric material of the tip 70 brought about by contact with the relatively rigid tube of the stem 72 and in view of some variation in frictional forces among the tips 70, it has been found that there is slight variation among the locations of the orifices 140 of the tips 70 relative to the distal end of the stem 72. This variation is sufficient to serve as a source of inaccuracy to the dispensing of fluid in the compartments 106 of the module 22.
  • the invention automatically corrects for these variations in tip location by sensing the location of the orifice 140 of the tip 70 by means of the light beam 114.
  • the procedure of the invention for correcting for the variations in tip location is explained further with reference to the diagram of Fig. 4 and the flow charts of Figs. 5-6.
  • Fig. 4 shows the feedback circuit 142 for inter-connecting the microprocessor 62 with the servo motor 86 for operation of the vertical pipette drive 78 disclosed in Fig. 2.
  • the circuit 142 includes a summer 144, a digital-to-analog converter 146, a filter 148, an amplifier 150, a shaft angle encoder 152, a memory 154 of the microprocessor 62, and an entry device 156, such as a keyboard, for entering data into the memory 154.
  • the microprocessor 62 In operation, for lowering the pipette 40 towards the module 22 (Fig. 2), the microprocessor 62 successively enters new locations on the path of travel of the pipette 40 in the Z direction. Location signals of the microprocessor 62 are applied to one input terminal of the summer 144. The present location of the tip 70, as estimated by the encoder 152 is applied to a second input terminal of the summer 144 to be subtracted from the value input at the first terminal of the summer 144. It is noted that the encoder 152 provides an accurate value of the location of the pipette stem 72, but not of the tip 70, because the position of the tip 70 relative to the stem 72 varies from tip to tip because of the frictional fit explained above. Therefore, a value of shaft angle outputted by the encoder 152 can be taken only as an estimate of the true position of the tip 70.
  • the signals outputted by the encoder 152 and by the microprocossor 62 aro formnltod digitally. Tho s.immor 144 forms tho difference of these two signals and applies the difference to the converter 146 for converting the difference from a digitally formatted signal to an analog signal.
  • the analog signal outputted by the converter 146 may be regarded as the loop error signal of the feedback circuit 142.
  • the loop error signal is filtered by the filter 148 which, in accordance with the usual practice in the construction of the feedback loops, may be a low-pass filter, and may include a lead-lag filter component.
  • the filter 148 provides stability to the feedback loop.
  • An output signal of the filter 148 is amplified by the amplifier 150, and is applied to the servo motor 86.
  • the loop gain and bandwidth, as established by the amplifier 150 and the filter 148, in conjunction with the motor 86 determines the dynamic response of the loop in a manner well known in the design of servomechanisms.
  • the motor 86 rotates towards the rotational position commanded by the microprocessor 62.
  • the functions of the summer 144 and the filter 148 can be accomplished directly within the microprocessor 62 by suitable programming of the microprocessor 62. ln such a case, the computer 62 outputs the error signal via the converter 146 directly to the amplifier 150 for driving the motor 86. Also, if desired, the servo motor 86 can be replaced with a stepping motor (not shown) which operates in response to digital pulses directing incremental rotational displacement of a rotor of the motor.
  • summer 144, converter 146, filter 148, amplifier 150 and shaft angle decoder 152 would not be required, and the microprocessor 62 would be programmed to output well-known stepping-motor control pulses for driving the motor. It is to be understood that any one of these configurations of feedback loop can be employed to operate the vertical pipette drive 78, the configuration of Fig. 4 having been shown to facilitate the teaching of the practice of the invention.
  • the microprocessor 62 continues to input further values of position along the path traveled by the pipette 40 until the light-beam comparison circuit 118 signals the microprocessor 62 of a break in the light beam.
  • the location of the tip 70 is now known accurately by virtue of contact of the tip 70 with the light beam 114.
  • the pipette 40 now travels through an additional distance to bring the tip 70 into the dispensing position relative to the module 22.
  • the value of the additional distance of positional travel is based on data stored in the memory 154.
  • the microprocessor 62 reads the memory 154 to obtain the travel data.
  • a person operating the instrument 20 provides the requisite data on additional travel based on a knowledge of the configuration of the module 22, particularly the height of the module 156 relative to a top surface 158 of the carousel 24. This height data is entered via the entry device 156 in the memory 154.
  • the operation of the feedback circuit 142 may be explained further with reference to Fig. 2 and with reference to the timing diagram of Fig. 7.
  • the tip 70 Prior to the lowering of the pipette 40, the tip 70 is at a sufficiently high elevation to permit transporting the pipette 40 in the X direction between the carousel 24 and the table 68. This is referred to in Fig. 7 as the transport level.
  • the pipette 40 then undergoes its initial descent during an interval of time identified in Fig. 7.
  • the initial descent interval ends with the breaking of the light beam 1 14. Thereupon, there is the final interval of descent in which the pipette 40 descends the additional travel. This brings the pipette tip to the dispense level indicated in Fig. 7.
  • the feedback circuit 142 raises the pipette 40 back to the transport level during a retraction interval shown in Fig. 7. Also shown in Fig. 7 is a safety level which will be described with reference to the flow charts of Figs. 5-6.
  • the flow chart describes operation of the microprocessor 62 of Fig. 2 for operating the vertical pipette drive 78 (Figs. 2 and 4) for lowering the pipette 40 to dispense fluid reagent in a compartment 106 of the module 22.
  • Initiation of the pipette descent toward the module 22 occurs at block 160.
  • the determination is made as to whether the light beam 1 14 (Fig, 2) is present.
  • the microprocessor 62 determines the presence of the light beam by examination of the high and low signals outputted by the comparison circuitry 1 18.
  • the pipette 40 Since the pipette 40 is in an elevated position, there is no blockage of the light beam 1 14 and, accordingly, the light beam 114 should be present and the comparator 120 should be outputting the logic-1 signal indicating full intensity of the light beam 114. If the beam is not present, then, at block 164, a person operating the instrument 20 is signaled to correct an apparent fault in the instrument.
  • the procedure advances to block 166 wherein the microprocessor 62 directs the lowering of the pipette 40 in the manner described above with reference to Fig. 4.
  • the microprocessor 62 continually inputs new positions along the path of travel of the pipette 40 at a rate commensurate with the dynamic response of the feedback loop 142.
  • the microprocessor 62 observes output signals of the comparison circuitry 118 to determine whether there has been an interruption of the light beam 114, this determination being performed at block 168.
  • the safety level is the lowest point at which the microprocessor 62 will allow the stem 72 to drop without interruption of the beam 1 14. If the safety level is reached, then the microprocessor 62 concludes that the tip 70 is absent, and operation proceeds to block 174 wherein the microprocessor 62 orders retraction of the pipette 40 to the transport level. As noted hereinabove, at the transport level, the pipette 40 clears the top wall 104 of the temperature controlled chamber 36 so that the stem 72 is fully visible to an operator for performing remedial action. From block 174, operation proceeds to block 176 wherein the operator is signaled to take remedial action.
  • the tip 70 is present on the stem 72 and, accordingly, at block 172 the safety level would not be reached without interruption of the light beam 1 14. Accordingly, operation proceeds from block 172 along line 178 back to block 166 wherein the microprocessor 62 continues to lower the pipette at the preset rate. The operation continues in repetitive fashion through the blocks 166, 168, and 170 until interruption of the light beam 1 14 occurs at line 180. The interruption of the light beam 114 is signaled to the microprocessor 62 by a change in the output signal of the comparison circuitry 1 18 such that signal changes from logic-1 to logic-0.
  • the output signal of the comparison circuitry 118 is at logic-0 to indicate to the microprocessor 62 that the tip 70 has reached the position of the light beam 1 14 along the path of travel of the tip 70 towards the module 22. Accordingly, at block 182, the microprocessor 62 determines the position of the dispense level (Fig. 7) so as to compute the additional amount of travel required by the tip 70 to reach the dispense level. The operation within block 182 will be described in further detail with reference to Fig. 6. In Fig. 5, the operation proceeds from block 182 via line
  • Fig. 6 shows details in the procedure of block 182 (Fig. 5) for checking the filling of the pipette tip followed by the computation of the additional travel of the pipette.
  • the procedure at line 180 proceeds to block 194 to check the intensity of the light beam.
  • both the H and the L signals of the comparison circuit 118 are at logic-0, as was noted hereinabove, which allows the microprocessor 62 to determine, at block 198, that the pipette is loaded.
  • the microprocessor reads the present pipette position as outputted by the encoder 152 (Fig. 4) .
  • the module position data designates the location of a top surface of the module 22 relative to the top surface 158 of the carousel 24. Since the distance between the light beam 1 14 and the carousel surface 158 is known and fixed, the inputting of this module data is equivalent to giving the microprocessor the distance between the top surface of the module 22 and the beam 1 14. Accordingly, at block 204, the additional distance between the beam 1 14 and the module 22 is added to the vertical distance already traveled by the pipette 40, the vertical distance being provided by the encoder 152.
  • the timing diagram of Fig. 7 has already been referred to in the description of the circuitry of Fig. 4 and the procedure of Figs. 5 and 6. Briefly, the diagram of Fig. 7 shows the descent of the pipette tip 70 at a fixed rate during the initial descent interval. This is followed by a pause in which the condition of the light beam is observed, followed by the final descent in which the pipette tip 70 is brought to the dispense level. At the conclusion of the dispense interval, the tip 70 is retracted to the transport level. The safety level is disposed between the light beam level and the dispense level. " The foregoing description provides for operation of the instrument 20 in a fashion which allows the pipette to be lowered with an accuracy which is independent of the position of the pipette tip 70 on the pipette stem 72.
  • the preferred embodiment of the temperature controlled chamber 36 has a circular form, and is operative with only a single pipette, for example, the pipette 40.
  • the pipette mechanism 44 comprises a transport 64 for moving the pipette 40 in a radial direction (X) of the chamber 36 between the chamber 36 and a selectable reservoir 66 of a plurality of reservoirs 66.
  • the reservoirs 66 are carried upon a table 68 which may be translated in a direction (Y) perpendicular to the pipette movement, X, of the transport 64 so as to enable two axes (X and Y) selection of a reservoir 66 containing a desired reagent.
  • Motorized drives for the transport 64 and the table 68 are available commercially and, accordingly, need not be described in detail herein.
  • disposable pipette tips are used typically for the delivery of one fluid only and then discarded so as to avoid contamination which could lead to errors in the assay result.
  • the table 68 carries a supply of tips 70 to be inserted upon a stem 72 of the pipette 40.
  • a tip 70 is attached to the stem 72 with frictional force by pushing the stem 72 down into a tip 70 on the table 68.
  • the tip 70 is extracted from the stem 72 by the extractor 130 shown located alongside the table 68, the extractor 130 having a hooked flange 276 with the channel 132 which envelop the tip 70 to pull off the tip 70 during an upward motion of the tip 70.
  • the temperature controlled chamber 36 comprises a top wall 104 located above the carousel 24, a bottom wall which serves as a floor 280 of the temperature controlled chamber 36 and is located below the carousel 24, and two sidewalls wherein one of the sidewalls is an outer wall 282 which extends from the top wall 104 to the bottom wall 280 and the second of the sidewalls is an inner wall 284 which extends from the top wall 104 toward a central portion of the carousel 24.
  • the top wall 104 has an annular shape.
  • An upper region 286 of the chamber 36 is bounded by the top wall 1 4, the top surface 158 of the carousel 24, the outer wall 282 and the inner wall 284.
  • a slot 102 is provided in the top wall 104 of the chamber 36.
  • the slot 102 extends in a radial direction of the oven 36, parallel to the X direction.
  • the slot 102 is located relative to the transport 64 to permit the stem 72 of the pipette 40 to be lowered through the slot 102 selectively above a desired compartment of a plurality of compartments 106 of the module 22.
  • the length of the slot 102 is commensurate with the length of the module 22 to permit displacement of the stem 72 in the X direction for alignment with a selected one of the compartments 106.
  • the slot 102 is relatively narrow, and is surrounded by a grommet 294.
  • the slot 102 has a width large enough to clear the stem 72 and the tip 70 mounted on the distal end of the stem 72.
  • the area occupied by the slot 102 is sufficiently small to preclude any significant amount of air flow between the interior and the exterior of the temperature controlled chamber 36. Thereby, the slot 102 has no more than a negligible effect in the control of the chamber temperature.
  • the chamber 36 further comprises two heaters, namely, a top heater 296 supported by the top wall 104, and a bottom heater 298 supported by the bottom wall 280 for controlling the chamber temperature.
  • the bottom heater 298 is located in a lower region 300 of the chamber 36, between the carousel 24 and the floor 280.
  • An injection port 302 is provided in the outer wall 282 facing the injector 58 to provide access to the arm 60 for inserting a module 22 in a berth 54 of the carousel 24, and for extracting the module 22 from the berth 54.
  • a frame 304 is located within the upper region 286 for supporting sensors useful in the operation of the temperature control system 20, one such sensor 306 being provided for sensing the chamber temperature.
  • the frame 304 is secured by a bracket 308 to the outer wall 282.
  • the frame 304 may be constructed as a circuit board for supporting electronic circuitry (not shown in Figs. 8 and 9) such as a preamplifier for amplifying electrical signals provided by the sensor 306.
  • Electrical cables 312, 314, and 316 connect respectively with the top heater 296, the bottom heater 298, and the sensor 306 for connecting these components to circuitry outside of the temperature controlled chamber. To facilitate maintaining of a substantially constant temperature within the chamber 36, it is advisable to minimize any flow of air between the interior of the temperature controlled chamber 36 and the external environment.
  • the inner wall 284 meets the top surface 158 of the carousel 24 at an airlock 318 which provides sufficient clearance of space between the inner wall 284 and the carousel 24 to allow for relative motion between the carousel 24 and the inner wall 284, the clearance space being sufficiently narrow to inhibit flow of air between the interior of the chamber 36 and the external environment.
  • the airlock 318 comprises an inner circular rib 320 and and an outer circular rib 322 which are spaced apart radially from each other to form a channel for receiving a lip 324 of the inner wall 284.
  • the axle 26 which supports the carousel 24 passes through an aperture 326 in the bottom wall 280.
  • the aperture 326 provides a clearance space which permits rotation of the axle 26.
  • the rotation provided by the motor 28 and gear 30 (Fig.
  • a drive unit 328 connected to the axle 26.
  • the clearance space of the aperture 326 inhibits the flow of air between the interior oof the chamber 36 and the external environment.
  • the bottom wall 280, in combination with the clearance space of the aperture 326 may be regarded as an airlock 330.
  • the remaining openings in which air may be exchanged between interior and exterior of the chamber 36 are the injection port 302 and the pipette slot 102.
  • the port 302 is essentially closed off by the structure of the injector 58 except during passage of a module 22 through the port 302.
  • the slot 102 has dimensions such that no more than a negligible amount of air is interchanged between the interior of the chamber and the external environment. For example, for a carousel 24 having a diameter of about 13 inches, the slot 102 can have a width less than about one-quarter inch and a length less than about 1.3 inches.
  • the volume of the lower region 300 is sufficiently small, and a gap 332 between the carousel 24 and the outer wall 282 is sufficiently small as to minimize airflow between the upper region 286 and the lower region 300 of the chamber 36.
  • the volume of the upper region 286 is no larger than necessary to accommodate the physical sizes of the modules 22 and the sensor assembly 334 comprising the frame 304 and the sensor 306. Minimizing the interior volume of the upper region 286 increases the dynamic response of a temperature control system 336 and reduces transients in the response of the temperature control system 336 to be described below with reference to Fig. 10.
  • the toroidal shape of the upper region 286 aids in reducing the volume of the upper region 286.
  • a plurality of apertures, or vents, in the carousel 24 together with a fin to direct the air through the aperture as the carousel is rotated One such aperture 31 1 is shown with a fin 313 for purposes of illustration. In a preferred embodiment eight such apertures, each about one-half by one-quarter inch are provided in the carousel. Further, since the carousel may be rotated in either direction it is preferred to arrange half of the fins in each direction to facilitate circulation of air irrespective of the direction of rotation.
  • the temperature control system 336 comprises the temperature sensor 306 and the heaters 296 and 298 disclosed previously in Fig. 9.
  • the temperature control system 336 comprises a temperature setting potentiometer 338, a subtracter 340, a filter 342, a summer 344, a source 346 of a reference voltage, a pulse width modulator 348, a clock pulse generator 350, and a power source 352.
  • the potentiometer 338 is connected between a voltage, V, and ground to provide a manually adjustable output voltage at terminal 354 which is applied to a first terminal of the subtracter 340.
  • An output voltage of the sensor 306 is connected to a second input terminal of the subtracter 340.
  • the subtracter 340 comprises well-known circuitry, such as that of an operational amplifier (not shown), for forming the difference between the voltages of the potentiometer 338 and the sensor 306, and applies the difference to the filter 342.
  • the heaters 296 and 298 are connected serially between output terminals of the power source 352, the source 352 applying electric current to the heaters 296 and 298 for the generation of heat. The heat is indicated symbolically by waves 356 propagating from the heaters 296 and 298 toward the temperature sensor 306.
  • the power source 352 is gated on and off by pulses provided by the generator 350 via the modulator 348.
  • the voltage reference of the source 346 is applied via the summer 344 to the modulator 348 to establish a basic width to pulses outputted by the modulator 348 to the power source 352.
  • the repetition frequency of the pulses is established by the generator 350.
  • the basic pulse width in combination with the repetition frequency, establishes a duty cycle for the administration of energizing current to the heaters 296 and 298 which is approximately correct for maintaining a temperature in the desired range, e.g., 37° ⁇ 0.5°C in the vicinity of the carousel 24.
  • An output voltage of the filter 342 is applied to the summer 344 to be added algebraically with the reference voltage of the source 346 to adjust the pulse width as needed to increase or decrease the amount of heat produced by the heaters 296 and 298. For example, if the sensor 306, in response to the chamber temperature provided by the heaters 296 and 298, outputs a voltage equal to that of the potentiometer 338, then the error signal outputted by the subtracter 340 is zero, and the modulator 348 outputs pulses at the basic pulse width.
  • the circuitry of Fig. 10 may be viewed as a feedback loop in which the waves 356 of heat complete the loop by connecting the heaters 296 and 298 to the temperature sensor 306. If the sensor 306 outputs a voltage different from that of the potentiometer 338, a loop error signal outputted by the subtracter 340 has the proper sense, positive or negative, and proper amplitude to adjust the width of the pulses outputted by the modulator 348 for maintaining the desired chamber temperature. For example, if the sensed temperature is too low, the pulse width is increased, and if the sensed temperature is too high, the pulse width is decreased.
  • the filter 342 may be a low-pass filter as is customarily employed in feedback circuitry for precise control of the dynamic response of a feedback loop.
  • the system may be controlled entirely by appropriately programming the microprocessor software.
  • the subtracter 340, filter 342, source 344, pulse width modulator 348 and clock pulse generator 350 are not necessary.
  • the main source of interruption of the temperature of the chamber is the insertion of the module 22 via the port 302 since the assay modules are typically at room temperature which typically is from fifteen to twenty degrees less than that of the chamber.
  • the introduction of assay modules to the carousel within the chamber can occur at a rate of one every ten seconds, the duration of such rate being dependent of course upon the number of open berths on the carousel.
  • the module 22 may be retained within the chamber 36 for a minute or longer prior to beginning the assay procedure in order to stabilize the module temperature
  • attainment of a desired temperature of the module and of the test material and reagents contained within the module can only be accomplished adequately by maintaining the chamber temperature in the vicinity of the carousel and the modules within the desired value, e.g., 37° ⁇ 0.5°C.
  • the perturbations in temperature resulting from the frequent injection of modules and removal of modules may well result in rapid undulations of chamber temperature which can cause the temperature in the vicinity of the carousel and the assay modules to be outside the desired range.
  • the pulse repetition frequency provided by the generator 350 is at least double the rate of introduction of modules, the Nyquist criteria.
  • the current pulses provided by the power source 352 may occur at a repetition frequency of one pulse every three seconds.
  • the average duration of a pulse may be two seconds. This provides a dynamic response to the temperature control system 336 which is adequately fast to deal with the rate of module introduction.
  • the temperature sensor 306 is placed immediately above a plane containing the top surfaces of the modules 22 so as to sense the temperature accurately at the openings of the module compartments 106.
  • the volume of the upper region 286 is minimized to reduce the amount of air which must be heated, and to reduce the amount of air currents which might otherwise flow about within the chamber 36.
  • the bottom wall 280 and the carousel 24 are formed of polymeric material having a relatively low conductivity, there are no openings, such as the injection port 302, in the lower region 300 of the chamber 36 so that the temperature of the lower region can remain stable by the inclusion of the bottom heater 298 in the lower region 300. Therefore, it is possible to construct the bottom wall 280 and the outer sidewall 282 of polymeric material which facilitates and lessens the cost of manufacture, and that only the annular top wall 78 and the cylindrical inner sidewall 284 need be formed of metal.
  • any suitable polymeric material may be used for the bottom wall and the outer sidewall such as polyurethane, polycarbonate and the like.
  • Fig. 11 it is noted that one aspect of certain types of assay elements is the dependency of the test results upon the relative humidity level in the chamber 36.
  • One type of assay element which exhibits humidity-affected results is the "dry" multilayer assay element such as is described in commonly assigned, copending United States patent application Serial No. 382,552 filed July 19, I989.
  • a fluorescent labeled species is utilized in the assay method and there is provided a fluorescent readout signal which is a function of the analyte or component of interest in the fluid sample.
  • the optical readout signal is then applied to a standard curve developed with fluids having known concentrations of the analyte or component of interest to obtain the concentration of the sample fluid.
  • the signal obtained from the assay element varies with variations in the relative humidity level within the temperature controlled chamber, it is apparent that errors can be introduced in the assay result because of humidity considerations. Accordingly, it is necessary, for such assay elements, to correct the readout signal such as by the use of a humidity sensor, which can be located within the temperature controlled chamber 36 such as on frame 304 or within the instrument 20 but outside the chamber 36.
  • the humidity value provided by the humidity sensor 310 is supplied to the microporcessor 62 which is programmed to correct the output signal in the appropriate manner.
  • Fig. 12 shows interconnections of the microprocessor 62 with various apparatus and sources of data employed in the instrument 20 of Figs. 1 , 2, and 8.
  • the following connections with the microprocessor 62 are noted, namely, the temperature sensor 306 (Figs. 8 and 9), the humidity sensor 310 (Figs. 8 and 9) , the module ejector 58 (Figs. 1 and 8), the work station 34 (Fig. 1 ) providing optical readout, a bar-code reader 358 (Fig. 8), the mechanism for positioning the table 68 (Fig. 2), the carousel driver unit 328 (Fig. 9), a shaft-angle encoder 360 (Fig.
  • the microprocessor 62 is provided with a memory unit 362 showing values of the set of graphs portrayed in Fig. 1 1. By addressing the memory 362 with measured values of the optical readout signal and the humidity, the memory 362 outputs a value for the analyte or component of interest. With respect to the bar-code reader 358, it is advantageous to locate a bar code in the form of a label 364 (Fig. 8) on a side of the module 22 to identify the module.
  • the reader 358 may be positioned at the injection port 302 alongside a path of travel of the module 22 during insertion of the module 22 by the injector 58 into the chamber 36.
  • the bar-code label 62 is placed on the side of the module 22 which faces the reader 358 so that the label 362 can be read as the module 22 passes by the reader 58 during insertion of the module 22 into the chamber 36.
  • the bar code signifies to the microprocessor 62 what tests are to be made so as to avoid a source of error as might occur were it necessary for the operator to instruct the instrument.
  • Fig. 13 is a flow chart which demonstrates use of the microprocessor 62 in the performance of the assay of a fluid sample.
  • the procedure begins with injection of the module by the injector 58.
  • the bar code of the label 362 is read by the reader 358.
  • Data read by the reader 358 is inputted to the microprocessor 62.
  • the module 22 passes through the injection port 302 and sits within a berth 54. Thereupon, the module is allowed to rotate on the carousel 24 during an interval of time sufficiently long to allow the temperature of the module and its contents to rise from the ambient room temperature to the warmer temperature within the chamber 36.
  • the specific berth 54 which holds the module 22 is identified at the time of insertion of the module, the identity of the berth being provided by the carousel position as measured by the shaft-angle encoder 360 (Fig. 9).
  • the table 68 Prior to termination of the warm-up time interval, the table 68 (Fig. 2) is positioned so as to allow the pipette 40 to obtain a new tip 70, and to be filled with a fluid sample in a selected one of the reservoirs 66.
  • the pipette is loaded with the selected sample, and is then positioned above a compartment 106 of a module 22, whereupon the reagent is dispensed by the pipette 40 to the module 22.
  • Data as to the temperature and humidity of the environment within the chamber 36 is provided by the sensors 306 and 310 to the microprocessor 62.
  • the fluid sample administered by the pipette is allowed to react with the reagent in the module compartment 106 for a predetermined interval of time.
  • the microprocessor outputs a fault signal if the temperature is incorrect. Subsequently, any other necessary reagents are dispensed to the module.
  • the module 22 is positioned at the optical readout station 34 to allow the module to be irradiated with the appropriate excitation energy.
  • a reading of the emitted energy at viewing site 50 is collected and transmitted to the microprocessor where it is adjusted for the relative humidity as described above herein.
  • the assay module is removed from the chamber.

Abstract

Instrument analytique automatique permettant de titrer un constituant d'intérêt dans un échantillon de liquide. L'instrument comprend une chambre à température régulée (36) ainsi qu'un appareil distributeur de liquide (40) destiné à distribuer du liquide dans des modules de titrage (22) portés par un convoyeur (24), lesquels se trouvent à l'intérieur de la chambre à température régulée (36). L'instrument comprend un détecteur d'humidité (310) fonctionnant avec un microprocesseur (62) afin de corriger des mesures obtenues à partir des modules de titrage (22) par un appareil optique (46) afin de compenser les effets relatifs de l'humidité sur lesdites mesures. Un lecteur de code à barres (358) fonctionnant avec des étiquettes de code à barres (364) se trouvant sur les modules de titrage fournit des informations de test au microprocesseur.
PCT/US1991/002104 1990-06-01 1991-03-27 Instrument analytique automatique WO1991019199A1 (fr)

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US53231990A 1990-06-01 1990-06-01
US532,319 1990-06-01

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US6713264B2 (en) * 1996-07-19 2004-03-30 Bayer Aktiengesellschaft Process and device for the screening of molecules with regard to their individual binding behaviour towards at least one given ligand
US6824738B1 (en) * 2000-04-14 2004-11-30 Discovery Partners International, Inc. System and method for treatment of samples on solid supports
WO2012066101A1 (fr) * 2010-11-17 2012-05-24 Andreas Hettich Gmbh & Co. Kg Enceinte de conditionnement pour le stockage d'échantillons avec contrôle du temps et procédé de stockage d'échantillons avec contrôle du temps

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GB201918889D0 (en) * 2019-12-19 2020-02-05 Vidya Holdings Ltd Improvements in or relating to assay timing

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EP0171319A1 (fr) * 1984-07-12 1986-02-12 Jean-Claude Bisconte Automate pour l'analyse et le clonage de cultures cellulaires ainsi que pour l'analyse bactériologique
JPS6361956A (ja) * 1986-09-03 1988-03-18 Fuji Photo Film Co Ltd 化学分析装置
WO1988002866A1 (fr) * 1986-10-14 1988-04-21 Serono Diagnostics Partners Appareil d'analyse automatise pour mesurer des antigenes ou des anticorps dans des fluides biologiques

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US3623844A (en) * 1969-07-17 1971-11-30 American Optical Corp Incubator and process turntable for chemical analysis apparatus for micro samples
EP0171319A1 (fr) * 1984-07-12 1986-02-12 Jean-Claude Bisconte Automate pour l'analyse et le clonage de cultures cellulaires ainsi que pour l'analyse bactériologique
JPS6361956A (ja) * 1986-09-03 1988-03-18 Fuji Photo Film Co Ltd 化学分析装置
WO1988002866A1 (fr) * 1986-10-14 1988-04-21 Serono Diagnostics Partners Appareil d'analyse automatise pour mesurer des antigenes ou des anticorps dans des fluides biologiques

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6713264B2 (en) * 1996-07-19 2004-03-30 Bayer Aktiengesellschaft Process and device for the screening of molecules with regard to their individual binding behaviour towards at least one given ligand
US6824738B1 (en) * 2000-04-14 2004-11-30 Discovery Partners International, Inc. System and method for treatment of samples on solid supports
WO2012066101A1 (fr) * 2010-11-17 2012-05-24 Andreas Hettich Gmbh & Co. Kg Enceinte de conditionnement pour le stockage d'échantillons avec contrôle du temps et procédé de stockage d'échantillons avec contrôle du temps
US9562214B2 (en) 2010-11-17 2017-02-07 Andreas Hettich Gmbh & Co. Kg Conditioning chamber for storing samples in a time-controlled manner and method for storing samples in a time-controlled manner
EP2641095B1 (fr) * 2010-11-17 2018-01-10 Andreas Hettich GmbH&Co. KG Enceinte de conditionnement pour le stockage d'échantillons avec contrôle du temps et procédé de stockage d'échantillons avec contrôle du temps

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CA2039678A1 (fr) 1991-12-02
JPH05500270A (ja) 1993-01-21
EP0484481A1 (fr) 1992-05-13

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