GB2225223A - Automated washing equipment - Google Patents

Abstract

Automated washing equipment 10 for washing out microwells in a microwell plate usable in enzyme immunoassay techniques comprises plate manipulator 12, wash liquid dispenser array 14 for filling the microwells with wash liquid when the plate is placed thereunder, aspirating tube array 20 for aspirating wash liquid from the microwells, the arrangement being such that no repositioning of the plate is required between filling with wash liquid and aspiration thereof, and a programmable control system for regulating wash and aspirate cycles in a predetermined manner. Also disclosed are an automatic aspirator unit, microwell plate stacker system, and microwell plate transport magazine. <IMAGE>

Description

"Automated Laboratory g#uipment" This invention relates to automated laboratory eoJuipment, and more particularly but not exclusively to atmate laboratory equipment for handling and processing of multi well microtitration plates.

In the field of hioscience, tests such as immunoassays require to be carried out in large numbers on very small quantities of fluids. Such tests are carried ollt in miniature test tubes which are too small to be handled individually in the large numbers required.For reasons of ease of handling, and to facilitate the comparative multiple testing often carried out (such as, for example, the mixing of specimens with reagents at varying dilutions, i.e. microtitration), the miniature test tubes are integrated into unitary arrays with the overall form of a tray. The test tubes become small wells set into the upper surface of the tray, and are commonly standardised in a rectilinear array of eight rows of twelve columns with uniform centre- to-centre spacings.Such multi-well trays are often called micro-well plates, and the terminology is used interchangeably herein.

In diagnostic and epidemiological investigations it is a common practice to test a number of biochemical reactions collectively in the wells of a micro-well plate. At various stages in such tests it is necessary to wash out the microwells. For example, in enzyme immunoassay (EIA) it is necessary to wash out each micro-well between each step to remove unabsorbed or unreacted substances.

Various washers are currently available which wash the micro-wells of microtitration plates one row at a time as part of the EIA technique. The wash process is a careful rinsing of each individual micro-well of the plate by evacuating the fluid in the micro-well, refilling it with a controlled volume of rinse fluid, allowing a soak period, washing the micro-well again and repeating this process three or more times. On each occasion that the micro-well is refilled the remaining unbound contents are diluted by approximately 100:1, thus for a three wash cycle the unbound contents are diluted by l06:l. It is important that the wash is carefully controlled so that none of the attached components are stripped from the micro-well. Also it is preferable that there should be no overfilling leading to cross-contaminating overflow between micro-wells.

Washing and draining the wells individually is laborious, and an uneconomic use of trained laboratory staff. Manually operated equipment has been developed for washing and draining rows of eight or twelve wells simultaneously, but this procedure requires dexterity and is still timeconsuming. Machinery has been proposed for the automatic washing of micro-well plates, but the extent of automation is limited, diverse items of equipment are required which occupy relatively large spaces with various interconnections, and the plates have to be individually handled. Large scale testing using existing equipment therefore tends to be excessively demanding of time, laboratory space, and skilled personnel.

It is therefore an object of the invention to provide automated laboratory equipment for handling and processing relatively large numbers of micro-well plates with a minimum of human intervention. Subsidiary objects of the invention include the optional provision of automatic testing of the reliability of the equipment, forming the equipment as compact and largely self-contained modules, and enabling the modLles to perform alone or in various interactive combinations which can readily be rearranged for different purposes with flexibly selectable operating modes.

According to a first aspect of the present invention there is provided an automatic micro-well plate washer for washing and draining an array of micro-wells in a micro-well plate, said washer comprising a plate manipulator for receiving and manipulating a micro-well plate within the washer, an array of wash liquid dispensers disposed to match the array of micro-wells in a plate placed thereunder by the manipulator, a vertically displaceable array of aspirating tubes disposed to match the array of micro-wells in a plate placed thereunder by the manipulator and vertically displaceable by an aspirating array actuator between an upper position clear of the micro-well plate such that the plate can b moved horizontally under the aspirating tubes and horizontally withdrawn therefrom without colliding with the aspirating tubes, and a lower position in which the aspirating tubes depend into the micro-wells substantially to the bottoms of the micro-wells, the array of wash liquid dispensers and the array of aspirating tubes having mutually related positions that permit the micro-wells of a micro-well plate placed thereunder to be filled with wash fluid and to have the wash fluid aspirated therefrom without requiring repositioning of the plate between filling and aspirating operations, the washer further comprising a wash liquid supplier coupled to the array of wash liquid dispensers and operable to deliver a predetermined volume of wash liquid to the array of wash liquid dispensers, a fluid coupling means through which the array of aspirating tubes is collectively coupled to a suction source in use of the washer to perform an aspirating operation, and a programmable control system operatively connected to the manipulator, to the aspirating array actuator, and to the wash liquid supplier, the control system being such that in operation of the washer with a micro-well plate placed in the manipulator and with a suction source coupled through said fluid coupling means to said array of aspirating tubes, the manipulator is operated to transfer the plate horizontally to a position under the arrays of wash liquid dispensers and aspirating tubes, the wash liquid supplier is operated to dispense a predetermined volume of wash liquid through the array of wash liquid dispensers into all the wells simultaneously, the aspirating array actuator is subsequently operated to lower the array of aspirating tubes into the wells to aspirate the wash liquid from all of the wells simultaneously and then raise the array of aspirating tubes clear of the icre-well plate, this wash and aspirate cycle being repeated a predetermined number of times if the control system is so programmed, and finally the manipulator is operated again to transfer the washed micro-well plate horizontally to a position in which the plate can be removed from the washer.

The manipulator is preferably operated while the aspirating tubes are lowered into the micro-wells to cause the plate to undergo relatively small horizontal movements which sweep the aspirating tubes across the bottoms of the micro-wells to minimise or obviate wash liquid remaining unaspirated in the corners of micro-well bases.

It is important that all the micro-wells in a micro-well plate are properly washed and aspirated, particularly in view of the sensitivity of immunoassay tests. False test results can be caused if the washing procedure is inadequate, and incomplete aspiration can result in improper dilution of reagents which also produces false results.

Consequently it is desirable that the washer includes provision for automatically testing the reliability of the wash and aspiration operations.

Accordingly the washer of the first aspect of the present invention preferably includes an automatic test system comprising a test block having an array of dummy micro-wells whose internal dimensions substantially match the internal dimensions of micro-wells in the micro-well plates washed in normal operation of the washer, the dummy micro-wells forming an array matching the array of micro-wells in the micro-well plates washed in normal operation of the washer, at least the internal surfaces of the dummy micro-wells being formed of electrically insulating material, a test electrode being secured in the base of each dummy micro-well and being individually electrically connected to an electrical conductivity test circuit comprised within the washer, the array of aspirating tubes being electrically conductive (for example, by being formed of a metal such as stainless steel) and electrically connected in common to the electrical test circuit to form a common electrode of the test system, and a test block actuator operatively coupled to be controlled by the control system of the washer such that when a test is programmed to take place, the test block actuator is operated to move the test block to a test position in which the dummy micro-wells occupy positions which are substantially identical to the positions of the micro-wells of a real micro-well plate positioned to be washed, the wash liquid supplier is operated to dispense a nominally normal quantity of electrically conductive wash liquid into each dummy micro-well, the aspirating array actuator is operated to lower the array of electrically conductive aspirating tubes into the dummy micro-wells, with simultaneous temporary inhibition of aspiration, and to pause at a level where the lower ends of the aspirating tubes are immediately below the surface of the wash liquid if the micro-wells are correctly filled with wash liquid (preferably about one millimetre below normal surface level), and the electrical conductivity test circuit is operated during the pause in the lowering of the array of aspirating tubes into the dummy micro-wells to detect the occurrence (or non-occurrence) of electrical conductivity between the individual test electrodes in the base of each dummy micro-well and the common electrode formed by the array of electrically conductive aspirating tubes due to the dummy micro-wells containing (or not containing) the predetermined quantity of electrically conductive wash liquid, and following the resumption of lowering of the array of aspirating tubes after the pause, with simultaneous termination of the temporary inhibition of aspiration and resumption of aspiration, until the lower ends of the aspirating tubes are at a predetermined distance from the bottoms of the dummy micro-wells (preferably about half of a millimetre), the electrical conductivity test circuit is operated to detect the cessation (or non-cessation) of electrical conductivity between the test electrodes and the common electrode due to the dummy micro-wells being aspirated clear of wash liquid (or failure to drain the dummy micro-wells by aspiration). Thus the test system enables electrical testing of both the correct filling of the micro-wells with wash liquid, and the subsequent correct emptying of the micro-wells by aspiration.A failure of electrical conductivity to appear at the point in the lowering of the array of aspirating tubes to immediately below the nominal wash liquid surface level of a filled micro-well indicates a fault in the filling of the relevant micro-well or micro-wells. If the deficiency in filling is to be quantified, the point in the lowering operation at which conductivity appears can be monitored, but it may be sufficient simply to note that filling is less than the correct amount. Similarly, a failure to detect cessation of electrical conductivity at the conclusion of aspiration indicates a fault in aspiration of the relevant micro-well or micro-wells.If the deficiency in aspiration is to be quantified, the point in the raising of the array of aspiration tubes at which conductivity ceases can be monitored, but it may be sufficient simply to note that aspiration is incomplete and to conclude the eletrical test prior to raising the array of aspirating tubes.

Since each dummy micro-well has a respective test electrode which is individually connected to the test circuit, the position in the array of a micro-well inflicted with incomplete supply of wash liquid and/or with incomplete aspiration can readily be identified to facilitate identification and rectification of the relevant fault. It is considered that blockage of the dimensionally small tubes utilised for dispensing wash liquid and for aspirating the micro-wells is likely to be the most common type of fault, but faults may arise for other reasons, for example due to these tubes being damaged, or a fault in the wash liquid dispenser, or a fault in the suction source, or a leak or blockage in any of the fluid conduits of the washer.

Electrical conductivity is preferably tested by application of a suitable test voltage between the test electrodes and the common electrode. The test voltage is preferably an A.C. voltage to obviate or minimise electrolysis of the wash liquid and electrolytic corrosion of washer components.

As an alternative to the electrically conductive aspirating tubes being electrically connected in common to form a common electrode of the test system, the electrically conductive aspirating tubes may be mutually electrically isolated and individually connected to form individual electrodes in the test system, with the test electrodes in the base of each dummy micro-well being either individually electrically connected to the electrical conductivity test circuit, or electrically connected in common to the electrical conductivity test circuit to form a common electrode of the test system.

The test circuit may monitor all the dummy micro-wells simultaneously, but since the number of micro-wells is large (being 96 in a conventional micro-well Plate) the dummy micro-wells may be monitored cyclically by a tim-division multiplexing procedure.

The test block is preferably mounted within the washer, directly below the arrays of dispensers and aspirating tubes such that the test block can be moved by substantially purely vertical movement upwards to the test position, and can be withdrawn downwards from the test position by reversal of the substantially purely vertical movement.

The control system is preferably programmed so as automatically to operate the test block actuator at the conclusion of a test as described above to retract the test block to an inactive position which leaves the washer free to resume the washing of micro-well plates. Alternatively, resumption of normal washing operation could be controlled manually While the above described automatic test system does not perform a direct test of the washing and aspiration of a real micro-well plate and although direct testing on a real plate would be preferable (though possibly not practicable), a fault-free result of a test performed on the dummy microwell plate constituted by the test block can give reasonable confidence that the washer is performing correctly.

According to user requirements, the control system can be programmed so as automatically to perform tests with a frequency which gives rise to the necessary level of confidence. For example, the test could be carried out after the washing of every twenty, ten, or five micro-well plates, and in an extreme case, the test can be performed before or after, or both before and after, the washing of every single micro-well plate.

According to a second aspect of the present invention there is provided an automatic aspirator unit for aspirating liquids which may be contaminated with biologically hazardous materials, for dosing aspirated liquids with a sterilising agent, and for delivering sterilised aspirated liquids to a waste disposal conduit, the aspirator unit comprising a container which is vacuum-tight and fluid-tight, a vacuum source coupled to the container at a point above normal peak level of liquid in the container, an aspirate intake conduit coupled to the container, dosing means for dosing aspirated liquids in the container with a sterilising agent, a self-valving positive displacement drainage pump coupled between the base of the container and the waste disposal conduit, and a liquid sensor coupled to the container to sense the filling of the container with liquid to a predetermined normal peak level of liquid in the container, the liquid sensor being coupled to control the positive displacement drainage pump for intermittent operation upon liquid in the container rising to said normal peak level to drain liquid from the container into the waste conduit.

The self-valving positive displacement drainage pump is preferably a peristaltic pump of the type in which a plurality of rollers are driven along a resilient tube in the intended direction of liquid flow, the rollers being pressed againt the tube to collapse and block the portions of the tube under the rollers and form pockets of liquid in the uncollapsed tube between adjacent rollers, these pockets of liquid being driven along the tube by the movement of the rollers along the tube to cause positive displacement of liquid through the tube, the collapsed portions of the tube forming valves preventing reverse flow of liquid in the tube whether the rollers are moving or static.

The dosing means may comprise a further peristaltic pump for drip feeding of the sterilising agent into the container, or the dosing means may comprise a liquid flow restrictor (which is preferably a variable restrictor) to control the rate of flow of sterilising agent into the container under the influence of vacuum in the container, cr into a drain conduit leading from said container.

The aspirator unit preferably includes a hydrophobic filter coupled between the vacuum source and the container, the filter permitting the relatively free passage cf air or other gases while inhibiting or preventing the passage of liquids, solids, and aerosols whereby to obviate or mitigate fouling of the vacuum source by non-gaseous substances and the potential release of biologically hazardous materials. The hydrophobic filter may be passively or positively drained.

The container preferably has a substantial ullage or internal volume above the normal peak level of liquid whereby to act as a vacuum reservoir and facilitate temporary inflows of aspirate at volumetric rates in excess of the continuously sustainable volumetric rate of inflow of aspirate. At least the top of the container is preferably formed of a transparent material to enable visual inspection of the interior of the container and the contents thereof.

The vacuum source may comprise a vacuum pump mounted within the aspirator unit. The aspirator unit preferably comprises regulator means to regulate the level of sub-ambient pressure produced in operation of the vacuum source, and preferably also comprises a pressure indicator to give a visual indication of the level of sub-ambient pressure.

The aspirator unit preferably comprises pump control means selectively operable to cause temporary inhibition of operation of the positive displacement drainage pump during operation of the aspirator unit whereby to allow the temporary disconnection of the waste conduit without substantial spillage of liquid drained from the container.

According to a third aspect of the present invention there is provided an aspirator system comprisng an aspirator unit according to the second aspect of the invention in combination with a liquid waste collecting container coupled to the waste conduit of the aspirator unit, and a reservoir of sterilising agent coupled to the dosing means.

The pump control means is preferably operable to cause temporary inhibition of the drainage pump during disconnection of the waste conduit from a filled liquid waste collecting container and reconnection of the waste conduit to an empty liquid waste collection container.

The aspirator system is preferably associated with a multi-compartment container rack for holding a liquid waste collecting container, a reservoir of sterilising agent, a reservoir of salt-free flushing liquid, and a reservoir of saline wash liquid which will be connected in use to supply saline wash liquid to a washer according to the first aspect of the present invention when utilised in conjunction with the aspirator system according to the third aspect of the present invention. At the conclusion of use of the washer, the aspirator is operated to flush the washer with the salt-free flushing liquid (which may be substantially pure water) whereby to clear the washer of remenant salt and minimise corrosion of the washer. Such a container rack facilitates the use of these containers in a minimum of laboratory bench space, and helps to stabilise their locations.The containers are preferably rectiform to maximise the ratio of container volume to bench space occupied by the containers, in contrast to the conventional circular (cylindrical or conical) glass bottles or flasks customarily employed.

According to a fourth aspect of the present invention there is provided an automatic micro-well plate stacker for receiving micro-well plates in a first stack of plates, dispensing single plates from the bottom of the first stack to an external plate processor and receiving single plates returned from the external plate processor to form a second stack of plates, and for subsequently re-ordering plates by feeding externally processed plates directly from the bottom on the second stack back to the bottom of the first stack to rebuild the first stack in its original order, said stacker comprising a first vertical magazine for receiving microwell plates singly or in stacked batches to form the first stack, plate handling means for removing plates singly from the bottom of the first stack, for dispensing said single plates removed from the bottom of the first stack to the external plate processor, and for receiving externally processed single plates returned from the external plate processor to build a second stack of plates from the bottom upwards into a second vertical magazine, and stacker control means operable when all of the plates in the first stack have been so transferred via the external plate processor to the second stack to control the plate handling means to transfer the externally processed plates singly from the bottom of the second stack in the second magazine directly to the bottom of the first magazine to rebuild the first stack in the first magazine from the bottom upwards whereby to re-form the first stack of now externally processed plates in the order in which the first stack was originally formed.

The plate handling means preferably comprises first latch means at the base of the first magazine and second latch means at the base of the second magazine, each of said latch means being independently controllable by the stacker control means selectively either to permit or prevent a plate passing vertically through the bottom of the respective magazine, first plate lift means under the first magazine and second plate lift means under the second magazine, each of said plate lift means being independently controllable by the stacker control means to lift a plate into the respective magazine to form a plate stack therein from the bottom upwards, and a horizontal plate transporter controllable by the stacker control means to transport single plates beneath either of said magazines along a horizontal path towards the external plate processor and to return externally processed plates along said horizontal path to a position under a selected one of said magazines at which position the respective plate lift means is operable to lift the plate into the bottom of the respective magazine to be retained therein by the respective latch means.

Said horizontal plate transporter preferably comprises a rail-mounted carriage self-propelled by an on-carriage electric motor driving the carriage through a motor-driven pinion acting on a fixed rack mounted parallel with the rails, the motor being controllably powered through a flexible cable secured at one end to the carriage and at the other end to a fixed point on the plate stacker. The rack may be formed by a toothed belt secured along its length to a linear structural member of the plate stacker.

The magazines are preferably demountable from the stacker for transport of micro-well plates therein, the demountable magazines being provided with plate retention means to prevent the plates falling through the bottom of the magazine when the magazine is demounted.

The external plate processor may comprise the multi-well plate washer of the first aspect of the invention.

Alternatively, the external plate processor may comprise a plate reader which, in general terms, is a device for optically measuring the results of reactions that have occurred in micro-wells as manifested by changes in the optical properties of the contents of the micro-wells, such optical properties being, for example, light transmissivity, light absorbence, turbidity, or colour.

As a further alternative, the external plate processor may comprise a reagent dispenser operable to fill each microwell of a plate from the stacker with a liquid reagent, or to fill selected micro-wells of the plate while leaving the other micro-wells of that plate free of reagent, and to return the reagent-loaded plate to the stacker.

According to a fifth aspect of the present invention there is provided a combined micro-well plate washer and micro-well plate stacker wherein the washer is an automatic micro-well plate washer according to the first aspect of the present invention, and the stacker is an automatic micro-well plate stacker according to the fourth aspect of the present invention, the plate handling means of the stacker being operatively coupled to the plate manipulator of the washer for substantially horizontal transfer of plates therebetween whereby the first magazine of the stacker may be loaded with plates which are automatically transferred, washed, and ultimately restacked in the first magazine in their original order of stacking.

It may be arranged that either the programmable control system of the washer or the stacker control means of the stacker exercises predominant control of the combined washer and stacker, said control system and said control means being operatively interlinked to provide cooperative and non-conflicting combined operations of the stacker and the washer.

According to a sixth aspect of the present invention there is provided a combined micro-well plate washer, micro-well plate aspirator, and micro-well plate stacker, wherein the washer and the stacker are the combined washer and stacker according to the fifth aspect of the present invention, and the aspirator is an aspirator unit according to the second aspect of the present invention or an aspirator system according to the third aspect of the present invention, the aspirator being operatively connected to the washer to perform the aspirating function of the aspirating tubes thereof.

The washer is preferably also arranged to be supplied with salt-free flushing liquid (which may be substantially pure water) for post-operational flushing of the washer to free the washer of potentially corrosive salts contained in the wash liquid, and to obviate or mitigate the risk of crystallisation of salts within the washer and possible consequential blockages of liquid passages and liquid transfer mechanisms within the washer.

According to a seventh aspect of the present invention there is provided a micro-well plate transport magazine for containing a stack of micro-well plates and retaining the plates in the magazine during carriage of the loaded magazine.

The magazine preferably has a base aperture and includes one or more latch mechanisms disposed at the base of the magazine to allow an empty magazine or an incompletely filled magazine to be lowered vertically onto a stack of micro-well plates to cause the stack of plates to enter the magazine upwardly through the base aperture, the latch mechanism or mechanisms permitting upward passage of plates through the base aperture while preventing passage of the plates downwardly through the base aperture when the magazine is lifted with a plate or plates therein.

The magazine preferably incorporates one or more integral handles to facilitate manual lifting and carriage of the magazine.

The magazine is preferably dimensioned to form a replaceable magazine for the stacker according to the fourth aspect of the present invention, the latch mechanism or mechanisms being such as to interact with the stacker when the magazine is fitted on the stacker to release plates carried within the magazine for passage in either vertical direction through the base aperture under the control of the respective plate lifter of the stacker which is located under the magazine.

The micro-well plate transport magazine of the seventh aspect of the invention enables reliable and easy transport of relatively large stacks of micro-well plates between different locations in contrast to the difficulties and hazards of carriage of stacks of micro-well plates without the secure and easily manipulated containment provided by the magazine.

Embodiments of the invention will now be described by way of example with reference to the accompanying drawings wherein : - Fig. 1 is a perspective view of an automatic micro-well plate washer unit; Fig. 2 is a perspective view of the washer of Fig. 1 operatively coupled to an automatic micro-well plate stacker; Fig. 3 is a perspective view of an aspirator unit; Fig. 4 is a perspective view of a multi- container rack (holding one container) for use in conjunction with the aspirator of Fig. 3; Fig. 5 is a perspective view of one possible configuration of an operative combination of the washer of Fig. 1 with the stacker of Fig. 2, the aspirator of Fig. 3, and the container rack of Fig. 4; Fig. 6 is a perspective view of another possible configuration of an cooperative combination of the units depicted in Fig. 5;; Fig. 7 is a detailed plan view of the washer of Fig. 1 with certain parts thereof removed; Fig. B is a detailed sectional front elevation of the front portion of the washer of Fig. 1; Fig. 9 is a sectional view from the left of the washer of Fig. 1; Fig. 10 is a detailed sectional front elevation of the rear portion of the washer of Fig. 1; Fig. 11 is a rear elevation of a wash liquid dispenser which can be employed in the washer of Fig.

1; Fig. 12 is an underside view of the wash liquid dispenser of Fig. 11; Fig. 13 is a sectional side elevation of a test system employed in the washer of Fig. 1; Fig. 14 is a sectional front elevation of the test system of Fig. 13; Fig. 15 is a plan view of test electrode connections employed in the test system oi Fig. 13; Fig. 16 is a schematic circuit diagram of the test system of Fig. 13; Fig. 17 is a front elevation of the exterior of the aspirator unit of Fig. 3; Fig. 18 is a right end elevation of the exterior of the aspirator unit of Fig. 3; Fig. 19 is a plan view of the exterior of the aspirator unit of Fig. 3; Fig. 20 is a plan view of the aspirator unit of Fig. 3 with its cover removed; Fig. 21 is a front sectional elevation of the aspirator unit of Fig. 3; Fig. 22 is a left end sectional elevation of the aspirator unit of Fig. 3;; Fig. 23 is a detailed plan view of the stacker depicted in Figs. 2, 5 and 6, with its upper portion removed; Fig. 24 is a rear view of the portion of the stacker shown in Fig. 23; Fig. 25 is a sectional elevation of the portion of the stacker shown in Fig. 23 and is viewed from its right side; Fig. 26 is a transverse section of a plate transfer carriage employed with the stacker of Fig. 23:: Figs. 27-30 schematically illustrate various analytical configurations of some of the units of the invention to depict control hierarchies and operational schemes; Figs. 31 to 41 show a stacker in operative combination with a micro-well plate reader, and their operational procedures (mainly in the form of flow charts); Figs. 42 and 43 are respectively front and side elevations of a micro-well plate transport magazine; Fig. 44 depicts a latch mechanism for use in the magazine of Figs. 41 and 42; and Fig. 45, 46, and 47 are respectively plan, front elevation, and end elevation views, to an enlarged scale, of a micro-well plate misalignment sensor suitable for use in the stacker of Fig. 23.

Referring first te Fig. 1, a micro-well plate washer 10 has a plate-receiving frame 12 into which a single micro-well plate (not shown) is placed. The micro-well plate is an integrated rectilinear array of 96 micro-wells in 8 rows and 12 columns, as is well known in the art of immunoassays.

The frame 12, with the micro-well plate, is then moved horizontally to a position under an array 14 of wash liquid dispensers. The array 14 consists of twelve horizontal tubes plugged into a static wash liquid supply manifold 16, each tube having eight nozzles (not visible in Fig. 1) aligned with the micro-wells of the plate placed thereunder by the frame 12. A motor-driven syringe 18 functions as a wash liquid supplier to deliver a predetermined quantity of wash liquid to the manifold 16, and thence through the nozzles to be dispensed into the micro-wells of the plate being washed. The syringe 18 is visible through a window in the lid of the washer 10.

After the micro-wells are filled with wash liquid, an array 20 of aspirating tubes is lowered into the micro-wells. The array 20 consists of twelve horizontal tubes plugged into a vertically movable aspiration manifold 22 which is coupled to an external suction source (not shown in Fig. 1). Each of the horizontal tubes in the aspiration array 20 carries eight vertical fine-bore tubes (not visible in Fig. 1). The various tubes forming the array 20 are fabricated of electrically conductive material, preferably stainless steel. The manifold 22 is lowered until the lower ends of the vertical aspirating tubes in the array 20 are almost touching the bottoms of the micro-wells so that the suction applied via the manifold 22 aspirates the wash liquid out of the micro-wells to drain them.More thorough drainage can be achieved by reciprocating the plate in short horizontal movements to sweep the aspirating tubes across the bottoms of the micro-wells and thereby minimise or obviate wash liquid remaining unaspirated in the corners of the microwell bases. After aspiration, the aspirating array 20 is lifted until the aspirating tubes are clear of the micro-well plate. The mechanism for controllably lowering and raising the aspiration manifold 22 is not shown in Fig.

1, but is illustrated in and will be described with reference to Fig. 13.

The wash and aspirate cycle can be repeated as often as is required as determined by the washer's programmable control system 24. Finally the frame 12 is horizontally retracted to its original position where the washed plate can be removed.

Referring now to Fig. 2, this depicts the washer 10 of Fig.

1 coupled directly to a micro-well plate stacker 30. The stacker 30 has a first vertical magazine 32 and a second vertical magazine 34. Each of the magazines 32 and 34 can hold a stack of plates, such as those denoted by the reference 36. Plates can be loaded into the first magazine 32 either singly or in stacked batches. The magazine 32 is open down one side, with side flanges down each edge of the opening to prevent plates falling out of the magazine, to enable direct manual access to any plate in the magazine 32 for lifting plates out of the magazine 32. The magazine 32 may alternatively have a side-flanged opening in each of two opposite sides cf the magazine.

Beneath the magazines 32 and 34, but not visible in Fig.

is a plate transfer carriage which moves along a pair of rails 38 which run through to the far end of the associated washer 10. Mechanism (not shown in Fig. 2) control the vertical transfer of plates through base apertures in the magazines 32 and 34 for selective transfer of plates between the magazines and the plate transfer carriage under the control of the internal control system of the stacker 30 (which is linked to the control system 24 of the washer 10 to prevent conflicting operations).

In use of the Fig. 2 arrangement, the magazine 32 is loaded with a stack of unwashed micro-well plates. The plates are transferred singly from the bottom of the stack along the rails 38 into the washer 10 to be washed, returned to a position under the magazine 34, and pushed up into the magazine 34 to form a second stack of now-washed plates.

When the magazine 32 is emptied and washing is concluded, the control system of the stacker 30 operates the plate transfer mechanisms to remove washed plates singly from the bottom of the stack in the magazine 34 and push them up into the magazine 32 to re-build the original stack of plates, i.e. to re-form the stack in its original order.

Referring now to Fig. 3, this shows an aspirating unit 40 which is suitable for use as the suction source to power the aspiration operations of the washer 10 in Fig. 1. The aspirating unit 40 includes a fluid-tight container 42 closed by a transparent lid permitting the interior of the container 42 to be visually inspected. The aspirating unit 40 contains a vacuum pump (not visible in Fig. 3) connected to the container 42 to produce a sub-ambient pressure therein. Vacuum pressure is set by a control 44 and indicated by a gauge 46. A connector 48 allows the aspirating unit 40 to be connected by a flexible tube (not shown) or other suitable form of waste conduit to a washer drain outlet 71 (Fig. 7) and thence to the aspirating manifold 22 in the washer 10. The aspirating unit 40 will subsequently be described in considerably greater detail with reference to Figs. 17-22.

Fig. 4 shows a three-compartment rack 50 for holding and stabilising three containers similar to the single container 52 shown in Fig. 4. The three containers are preferably rectiform, as is the illustrated container 52, to maximise internal volume in relation to the bench space occupied by the container. This is in marked contrast to the conventional circular (cylindrical or conical) laboratory bottles and flasks which make relatively inefficient use of bench space. The rack 50 also constrains the containers it holds to stand closely together with a minimum of unproductive inter-container space, in contrast to the normally random spacing of unracked containers.

Fig. 5 shows one possible configuration of the units shown in Figs. 1-4. The interlinked combination of the washer 10 and the stacker 30 stand on a laboratory bench 55, while the aspirator unit 40 and the container rack 50 stand on a lower bench (or on the floor) beneath the washer 10 and the stacker 40. Fig. 5 clearly demonstrates the compactness and self-contained nature of the equipment, i.e. there is a general absence of loose or unsecured peripheral items, which improves safety and utilisation of bench space.

Fig. 6 shows another configuration of the units of Fig. 5, occupying a minimal width on a single-level deep laboratory bench or other support surface.

Fig. 7 is a plan view of the washer 10 of Fig. 1 with its top removed to show internal structural details. Internal conduits and electrical connections are omitted from Fig. 7 for the sake of clarity. The wash liquid supply manifold 16 is visible, as are the twelve sockets therein for holding the distribution tubes (removed for clarity). The wash liquid supply syringe 18, together with its drive motor 120, is visible in dashed outline at the back of the washer 10, associated with intake and outlet fluid couplings 70, the drain outlet 71, and respective control valves 72. Visible through the aperture 74 which is overlain by a micro-well plate during washing, is a test arrangement 76 which will be detailed subsequently. (Further details of the drive system for the syringe 18 are given below, in Figs. 11 and 12).

Fig. 8 is a front view of the front portion of the washer 10 of Fig. 1, with the front cover removed and some parts depicted in section. The wash liquid distribution array 14 and the array 20 of aspirating tubes can be seen in clear detail, as well as their positional relationship to the micro-wells of a plate 80 in position to be washed and aspirated. In Fig. 8, the array 20 of aspirating tubes and the aspirating manifold 22 are fully raised. The left side view of Fig. 9 shows further details of the arrangement of Fig. 8, together with details of the couplings 70 and the valves 72. The tubes of the arrays 14 and 20 are designed for easy removal and replacement to facilitate the cleaning of tube blockages.

Fig. 10 is a front view of the rear portion of the washer 10, i.e. the portion to the rear of the portion depicted in Fig.

8; compare Figs. 8 and 10 with Fig. 1 to see their mutual relationship. Fig. 10 particularly shows the wash liquid supply syringe 18 and parts of its drive system which are separately detailed in Figs. 11 and 12.

Referring now to Figs. 11 and 12, these show respectively a rear view and an underside view of the syringe 18 and its drive mechanism in a form differing slightly from that schematically shown in Figs. 1, 2, 5, 6, and 7. As shown in Figs. 11 and 12, the syringe 18 is a high quality glass barrel syringe with a Teflon piston whose barrel 110 is held static, and whose plunger 112 is mounted on a slidable carriage 114. A guide rod 113 supports and guides the carriage 114 through a linear ball bushing 115. A toothed belt 116 drives the carriage 114 and is driven by a toothed pinion 118 rotated by a reversible D.C. motor 120. The syringe barrel 110 discharges directly into a manifold 111 coupled through the valves 72 to the wash liquid supply manifold 16. A rotary encoder 121 driven by the toothed belt 116 signals the variable position of the syringe plunger 112 to the control system 24.In the modified arrangement of Figs. 11 and 12, the positions of the motor 120 and the encoder 121 are transposed from the arrangement shown in Fig. 7.

Referring now to Figs. 13 and 14, the test system 76 is an arrangement for automatically testing the reliability of the wash and aspiration operations of the washer 10. The test system 76 comprises a dummy micro-well plate formed of electrically insulating material with an array of dummy micro-wells 130 matching the micro-wells of a real microwell plate in terms of dimensions, numbers and positions.

At the bottom of each dummy micro-well 130 is a test electrode 132. Each of the test electrodes 132 is individually connected by an array of conductors on a printed circuit board 134 (Figs. 13, 14, 15), through 50-way ribbon cable connectors 136 (Fig. 15) and 50-way ribbon cables 138 (Fig. 16) to an electrical conductivity test circuit 150 as schematically outlined in Fig. 16.

The test system 76 is raised to the test position shown in Figs. 13 and 14 by an actuator consisting of a reversible D.C. electric motor 140 (Fig. 13), a crank 142, and a connecting rod 144. The crank 142 and the connecting rod 144 may be replaced by a cam and a cam follower (not shown), or by a rack and pinion drive system (not shown).

The electrically conductive aspirating tubes in the array 20 form a common electrode energised by an A.C. source 152 (Fig.

16) such that during a test, a conductivity testing circuit 154 performs a conductivity test in each of the dummy microwells 130 to detect correct filling with electrically conductive wash liquid, and subsequently to detect correct emptying by aspiration. Each dummy micro-well 130 is tested in turn by multiplexing operation of a time-division multiplexer 156 within the test circuit 154 and controlled by switch address signals on a signal path 158 from the control system 24. The multiplexer 156 individually and sequentially connects the test electrodes 132 through an interference-rejecting band-pass filter 160 and a rectifier 162 to a comparator 164 which makes individual measurements of the conductivity (or non-conductivity) between the common electrode (formed by the aspirating tubes in the array 20) and the test electrodes 132.Output signals from the comparator 164 are fed along a signal path 166 to the control system 24.

If the equipment user chooses to substitute distilled water for saline solution as wash liquid, electrical conductivities will vary by about five orders. Because of this potentially wide variation in electrical conductivity of the wash liquid, it is preferable to measure average conductivities over a number of filled micro-wells and then make appropriate adjustments in the amplification of the comparator 164 to accomodate such conductivity changes and so ensure that false readings are avoided. (For example, an incompletely filled micro-well may be bridged to an adjacent fully filled mirco-well by a thin remanent layer of highly conductive fluid, and hence give an apparent but spurious conductivity reading similar to that if the micro-well were currently filled with relatively low conductivity distilled water, falsely indicating that the micro-well was correctly filled).

In normal washing operation of the washer 10, lowering and raising of the aspiration manifold 22 is controlled by a mechanism comprising a manifold drive motor 170 (Fig.13) operated by the washer's programmable control system 24.

The motor 170 is linked to the manifold 22 by a rotary-tolinear motion converter comprising a motor-driven cam 172 and a cam follower 174. A connecting rod assembly 176 links the cam follower 174 to the manifold 22 which is guided for vertical movement by vertical slides (not shown) or any other suitable manifold movement guide.

During tests of the reliability of the wash and aspiration operations of the washer 10, actual micro-well plates are withdrawn from the washer 10, and the array of dummy microwells 130 is raised to the test position (shown in Fig. 13) by controlled operation of the motor 140 whose output shaft position is monitored by a position sensing disc 141 attached thereto. Initially, the aspiration manifold 22 is fully raised and the wash liquid dispensing syringe 18 is operated by controlled rotation of its drive motor 120 to dispense a nominally normal quantity of electrically conductive saline wash liquid into each dummy micro-well 130.Next, the motor 170 is controllably rotated to lower the electrically conductive aspirating array 20 into the dummy micro-wells 130, and to pause in the lowering movement at a level where the lower ends of the aspirating tubes in the array 20 are immediately below the surface of the wash liquid if the dummy micro-wells 130 are correctly filled with wash liquid. A suitable nominal level of penetration of the aspirating tubes into the wash liquid is about 1 millimetre, but any other suitable level of penetration may be adopted.

During this pause in the lowering of the aspirating array 20, and prior to aspirating operation of the aspirating array 20, (which is temporarily inhibited during this initial phase of lowering of the aspirating array 20), electrical conductivity tests are carried out by controlled operation of the conductivity test circuit 150 so as to determine whether or not each dummy micro-well 130 has been correctly filled with electrically conductive saline wash liquid, by detecting the occurrence or non-occurrence of electrical conductivity between the common electrode formed by the conductive aspirating array 20 and the individual test electrodes 132 in the base of each dummy micro-well 130.A conductivity test result indicating the occurrence of electrical conductivity in a given dummy micro-well 130 is taken as indicating correct filling of the given microwell, whereas a conductivity test result indicating the non-occurrence of electrical conductivity in a given dummy micro-well 130 is taken as indicating incorrect filling (partial or total non--filling) of the given micro-well.

Any incorrect filling is signalled to the control system 24, which is programmed to respond accordingly. Assuming that the control system 24 is programmed to continue the test sequence following the foregoing conductivity test procedure, the temporary inhibition of aspiration is terminated and aspiration is resumed, along with further lowering of the aspirating array 20 by further controlled rotation of the motor 170. Lowering of the aspirating array 20 is continued until the lower ends of the aspirating tubes are at a predetermined short distance (suitably 0.5 millimetres) above the bases of the dummy micro-wells 130 at which correctly functioning aspiration is effective to drain each dummy micro-well 130.At this point, vertical motion of the aspirating array 20 stops, and the electrical conductivity test circuit 150 is again activated to repeat the individual electrical conductivity tests on each dummy micro-well 130. A conductivity test result indicating the non-occurrence of electrical conductivity in a given microwell 130 is taken as indicating the correct aspiration and drainage of the given micro-well, whereas a conductivity test result indicating the occurrence of electrical conductivity in a given micro-well 130 is taken as indicating the partial or total failure to drain the given micro-well by aspiration.

Any incorrect aspiration is signalled to the control system 24, which is programmed to respond accordingly.

Thus the test system 76 and the associated test circuit 150 enables electrical testing, in a microprocessor-compatible manner, of both the correct filling of micro-wells with wash liquid, and the subsequent correct emptying of the microwells by aspiration. This is on the basis that a failure of electrical conductivity to appear at the point in lowering of the aspirating array 20 to immediately below the nominal wash liquid surface level of a filled micro-well indicates a fault in the filling of the relevant micro-well or micro-wells; similarly on the basis that a failure to detect cessation of electrical conductivity at the conclusion of aspiration indicates a fault in aspiration of the relevant micro-well or micro-wells.Since each dummy micro-well 130 has a respective test electrode 132 which is individually connected to the test circuit 150, the position in the array of a micro-well inflicted with incomplete of wash liquid and/or with incomplete aspiration can readily be identified to facilitate identification and rectification of the relevant fault. Blockage of the fine-bore dispensing and aspirating tubes is considered likely to be the most common type of fault, though other types of fault may occur, for example mechanical damage to the tubes, or faults in the wash liquid dispensing syringe 18 or in its drive mechanism, or faults in the aspirator suction source, or a leak or blockage in any of the various fluid conduits of the washer 10.

As an alternative to all the electrically conductive aspirating tubes in the aspirating array 20 being electrically connected in common to form a common electrode of the test system 76, the electrically conductive aspirating tubes in the array 20 may be mutually electrically isolated and individually connected to form individual electrodes in the test system, with the test electrodes 132 in the base of each dummy micro-well 130 being either individually electrically connected to the test circuit 150, or electrically connected in common to the test circuit 150 to form a common electrode of the test system 76.

Figs. 17, 18 and 19 show respectively front, right side, and plan views of the aspirator unit 40 depicted isometrically in Fig. 3.

Figs. 20, 21 and 22 show the interior of the aspirator unit 40 with, respectively, the cover removed, in vertical section viewed from the front, and in vertical section viewed from the left. Internal fluid conduits and electrical wiring have been omitted for clarity.

The fluid-tight container 42 (previously shown in Fig. 3) is mounted within the aspirator 40, and sealed by a transparent lid 202. An electric motor-driven vacuum pump 204 is coupled to evacuate the interior of the container 42.

In use, a point near the mid-height of the container 42 is connected through the drain outlet 71 to the washer aspirator manifold 22 to aspirate spent wash liquid out of the micro-wells of a plate being washed in the washer 10, and into the container 42.

A liquid sensor 205 mounted in the internal wall of the container 42 a short distance above the foot of the container 42 senses the filling of the container 42 with aspirate to a level which is predetermined as being the normal peak level of liquid in the container 42. The peak level liquid sensor 205 then actuates a peristaltic pump 206 (or other suitable pump) to drain aspirate from the container 42 through a drain hole 208 in the base of the container 42 and discharge into a waste conduit (not shown).

The waste conduit preferably discharges into a waste liquid collecting container as depicted in Figs. 4 and 6.

The aspirator 40 preferably contains a dosing unit (not shown) for dosing aspirate collected iSl the container 42 with a sterilising agent (e.g. liquid bleach) to neutralise biologically hazardous substances that may be contained in the aspirate. The dosing unit preferably feeds into the container 42 via a further peristaltic pump (not shown) which has the functional advantages of acting both as a positive displacement metering pump (for accurate control cf consumption of sterilising agent) and as a self-valving pump inhibiting vacuum-induced leakage through the pumps. (The dosing unit may alternatively feed through a solenoid valve (not shown) and a flow rate control valve (not shown) into the drain conduit (not shown) attached to the drain 208, with the solenoid valve being opened simultaneously with actuation of the drain pump 206).

Similarly, the use of the peristaltic pump 206 for draining the container 42 has the advantage of obviating separate liquid flow control valves (with advantages in capital and maintenance costs), and being relatively simple to clean internally. The coupling of the vacuum pump 204 to the container 42 is preferably through an in-line hydrophobic filter 210. The filter material and the internal construction of the filter 210 are such that air and other gases can pass relatively freely through the filter 210, whereas the hydrophobic properties of the filter 210 block the passage of liquids, solids (e.g. air-borne dust), and aerosols. Thereby the vacuum pump 204 is protected against internal fouling and corrosion, and release of biologically hazardous substances into the laboratory atmosphere is guarded against.

The hydrophobic filter 210 is mounted vertically above a small secondary waste collecting container (not shown). The flow of air and other substances exhausted from the main container 42 is taken via a tube or other fluid conduit to the secondary container such that excess fluid carried over by the air flow is allowed to settle into the secondary container and thus does not get into the hydrophobic filter 210 to cause it to block prematurely. Because the filter 210 is mounted vertically, any trapped excess fluid tends to drop out of the filter into the secondary container. The secondary container is emptied by the drainage pump 206.

The previously-described liquid sensor 205 is mounted in the container 42 relatively far below the lid 202 such that there is a substantial ullage, even when the aspirate reaches normal peak level. This ullage (liquid-free volume) acts as a vacuum reservoir to enable the aspirator 40 to cope with temporary influxes of aspirated liquids at volumetric flow rates in excess of the volumetric flows that could be continuously aspirated.

Fig. 23 is a plan view of the stacker 30 of Figs 2, 5 and 6 without its magazines 32 and 34, and with its top cover removed. Fig. 24 is a rear view of the Fig. 23 arrangement, while Fig. 25 is a vertical section from front to rear of the Fig. 23 arrangement, looking from the right side of the stacker 30 towards its left side. Referring first to Fig.

23, in both positions immediately under the magazine locations (compare with Fig. 2) are plate lift mechanisms 232 and 234 which are selectively and independently operable to lower a single micro-well plate from the respective magazine 32 or 34 onto a plate transport carriage 236 (shown displaced horizontally along the rails 38 to the extreme left in Fig. 23), or to raise a single micro-well plate from the carriage 236 into a selected magazine, the carriage 236 being directly under the respective magazine in each case.

Vertical passage of micro-well plates through the bases of the magazines 32 and 34 is selectively permitted or prevented by respective latch mechanisms 238 and 240 which are controllably activated to passage-permitting conditions by respective solenoids 242 and 244, and normally retained in passage-preventing conditions by respective return springs 246 and 248.

The carriage 236 is detailed in transverse vertical crosssection in Fig. 26. The upper plate-carrying platform is roller mounted (as illustrated, or slide mounted) on the rails 38 (differing slightly from those shown in Fig. 13), and internally mounts a reversible D.C. motor 260 for selfpropulsion of the carriage 236. The motor 260 is controllably powered through a trailing cable (not shown) which is supported in a slotted channel 262 integral with one of the rails 38.

The output pinion 264 of the motor 260 acts on a rack (not shown) formed by a toothed belt secured teeth-upward along the upper surface of the rail 38 containing the channel 262.

The rack-and-pinion traction system of the carriage 236 enable it to be precisely positioned, and to operate reliably over substantially greater lengths of track than is practicable with carriages propelled by linear actuators mounted on a static part of the system. When the stacker 30 is in operative combination with the washer 10 (as shown in Figs 2, 5, and 6), the carriage 236 replaces the functionally equivalent horizontally movable plate-receiving frame 12 (Fig. 1) as the plate holder during horizontal transport of micro-well plates.

The stacker 30 can incorporate a sophisticated programmable control system capable of overall direction (in a stand-alone mode or in a computer-controlled mode) of various units of laboratory equipment connected thereto, either singly or in variable combinations. Various such stacker-controlled configurations are schematically illustrated in Figs. 27-30 and described in detail below. (It should be noted that the unit denoted "Multiskan" is a micro-well plate reader marketed by the Applicants, and the "Multidrop" and "Autodrop" are units for loading micro-well plates with measured quantities of reagents, and also marketed by the Applicants). Operating procedures for such systems are detailed in the flow charts set out in Figs. 32 - 40.

Referring now to Figs. 27 - 30 in detail, Fig. 27 schematically illustrates the stacker 30 operating in standalone control mode to direct the functioning of a Multiskan 270. The stacker 30 and the Multiskan 270 are mechanically linked for automatic direct transfer of micro-well plates between them in either direction. In relation to the stacker 30, the Multiskan 270 functions as an external plate processor, and in operation, receives micro-well plates one at a time from the stacker 30 and optically scans each plate to detect one or more optical properties of substances in all or selected ones of the micro-wells before the plate is retrieved and re-stacked by the stacker 30.

The stacker 30 and the Multiskan 270 are also electrically linked by a multi-core control signal cable 272, and by an RS232C data link 274. (Power cables are not depicted in Figs. 27 - 30). The multi-core control signal cable 272 has four cores for stepper motor control signals, two cores for 'start' button connectors, and one core as a zero volt line. The configuration of Fig. 27 further includes a printer 276 linked to the stacker 30 by another RS232C data link 278.

In use of the Fig. 27 configuration, operation of the stacker 30 and operation of the Multiskan 270 are each programmed by the operator. Processing of micro-well plates is initiated from the stacker 30, the micro-wells of a plate being processed externally of the stacker 30 are optically scanned in the Multiskan 270, and the data from each plate is processed and sent to the stacker 30 along the data link 274. Received data in respect of a given microwell plate is transferred along the data link 278 to the printer 276 and printed out while the next micro-well plate is being processed in the Multiskan 270. All data from a stack of micro-well plates in the stacker 30 is printed-out before the next stack of plates is processed.

Fig. 28 schematically illustrates a variation of the configuration of Fig. 27, in which the stacker 30 operates in a computer-controlled mode under the control of a computer 280 linked to the stacker 30 by an RS232C data and control signal link link 282.

In one use of the Fig. 28 configuration, all commands from the computer 280 go to the stacker 30, and relevant commands are then sent from the stacker 30 on to the Multiskan 270.

Micro-well optical data from the Multiskan 270 is sent to the computer 280 via the stacker 30 and the data links 274 and 282.

In another use of the Fig. 28 configuration, the computercontrolled configuration is employed for data logging, for example under the programmed control of a Titersoft data logging software program. In this data logging mode of operation of the Fig. 28 configuration, both operation of the stacker 30 and of the Multiskan 270 are programmed by the operator, and plate processing is initiated from the stacker 30. The optically-scanned data obtained from each micro-well plate transferred by the stacker 30 to the Multiskan 270 is processed and sent to the computer 280 via the stacker 30. All the data from each micro-well plate in a stack of plates initially loaded into the stacker 30 is transmitted to the computer 280 before the next stack of plates is processed.

Fig. 29 schematically illustrates the stacker 30 operating in stand-alone control mode to direct the functioning of a Multidrop 290, or alternatively an Autodrop, for the loading of micro-well plates with measured quantities of reagents.

The stacker 30 and Multidrop or Autodrop 290 are mechanically linked for automatic direct transfer of micro-well plates between them in either direction. In relation to the stacker 30, the Multidrop or Autodrop 290 functions as an external plate processor, and in operation, receives micro-well plates one at a time from the stacker 30 and dispenses controlled quantities of one or more reagents and/or other selected substances into all or selected ones of the micro-wells before the plate is retrieved by the stacker 30.

The stacker 30 and the Multidrop or Autodrop 290 are also electrically linked by a multi-core control signal cable 292. The multi-core control signal cable 292 has four cores for stepper motor control signals, two cores for 'start' button connectors, and one core as a zero volt line.

Unlike the Fig. 27 configuration, the stacker 30 and the Multidrop or Autodrop 290 are not also coupled by a data link, because the external processing of the micro-well plates consists of reagent addition which does not per se generate significant scientific data. A reagent dispenser other than the proprietary Multidrop or Autodrop could alternatively be employed in the Fig. 29 configuration.

In use of the Fig. 29 configuration, priming of the reagent dispensing system 290 is performed prior to plate processing, and plate processing is initiated from the stacker 30.

Fig. 30 schematically illustrates an extension of the Fig.

29 configuration, in which the stacker 30 operates in a computer-controlled mode under the control of the computer 280 to direct the Multidrop 290. A close functional analogy between the Fig. 30 configuration and the Fig. 28 configuration can be seen by inspection.

In use of the Fig. 30 configuration, all functional commands from the computer 280 go to the stacker 30 along the data link 282. Relevant commands are then sent from the stacker 30 to the Multidrop 290 along the control cable 292 and/or along an RS232C data link 294 linking the stacker 30 with the Multidrop 290. Micro-well plates are individually transferred from the stacker 30 to the Multidrop reagent dispenser 290, controlled quantities of one or more reagents and/or other selected substances are dispensed into all or selected ones of the micro-wells, and reagent-dosed plates are retrieved and re-stacked by the stacker 30.

It should be noted that with regard to the stacker 30 being coupled to external plate-processing equipment, three types of such external equipment have been specifically described, in more than three configurations. These three types of external plate processing equipment are the washer 10 (Figs.

2, 5 and 6), the Multiskan micro-well plate scanner 270 (Figs. 27 and 28), and the Multidrop or Autodrop reagent dispenser 290 (Figs. 29 and 30).

Turning now to Fig. 31, this -is a schematic representation of the stacker/Multiskan combination employed in the configurations of Figs. 27 and 28, and illustrated for the purposes of defining certain plate positions within the combination, together with an indication of the locations of position sensors in the stacker 30. A given micro-well plate can dwell in or be transferred horizontally along the rails 38 between four plate positions denoted "1", "2", "3", and "4" in Fig. 31.

Plate position "1" (also called the "IN" position) is directly beneath the first stack-holding magazine 32 in the stacker 30 where an incoming stack of magazines would normally be collectively loaded into the stacker 30.

Plate position "2" (also called the "OUT" position) is directly beneath the second stack-holding magazine 34 in the stacker 30 where a stack of processed magazines would normally be formed for collective unloading from the stacker 30 (or, when formed in the magazine 34, would be transferred one-at-a-time back to the first magazine 32 without passing out of the stacker 30, so as to rebuild the original stack in the magazine 30 with the micro-well plates in their original top-to-bottom order).

Plate position "3" (also called the "REST" position) is within the Multiskan 270, at a position along the rails 38 intermediate the stacker 30 and the plate scanning location within the Multiskan 270 (see below).

Plate position "4" (also called the "PROCESS" position) is the scanning location within the Multiskan 270 at which the plates are scanned to determine optical properties of the contents of micro-wells and to produce appropriate electronic signals representing optical data related to identified micro-wells in the array on the plate.

For the purposes of subsequent description of the control procedures, the conventions of "left" and "right" will be adopted such that plate position "1" is furthest "right", progressing leftwards through plate positions "2" and "3" to plate position "4" as the furthest "left", i.e. as schematically depicted in Fig. 31. For the purposes of plate position within the stacker/processor combination, the above-described positions can more clearly be seen in Fig. 2 (wherein the fact that the plate processor is the plate washer 10, rather than an optical scanner, does not affect the validity of this reference to plate positions).

Moreover, as viewed from the front of the combination of items of equipment, Fig. 2 illustrates the consistency of the"left", "right" convention adopted.

Micro-well plates are carried horizontally along the rails 38 through the stacker 30 and the associated external plate processor (the Multiskan 270 in Fig. 31, or the washer 10 in Figs. 2, 5, and 6, or the Multidrop 290 in Figs. 29 and 30) by means of the carriage 236 (Figs. 23 and 26). Plates are carried vertically within the stacker 30 by means of the plate lift mechanisms 232 and 234 (Figs. 23 and 25). To detect the horizontal position of a micro-well plate, and also to enable the determination of the position of a platefree carriage 236, sensors are employed within the stacker 30 to sense carriage position, the presence or absence of a a plate on the carriage, and the alignment or misalignment of a plate on the carriage (the letter being described below with reference to Figs. 45-47).Sensors are also associated with the plate lift mechanisms 232 and 234 to determine their vertical positions, and hence of any micro-well plate carried by them.

In detail, and referring to Fig. 31, sensor "1" detects the presence or absence of the carriage 236 at position "1" (as defined above). Sensors "2a" and "2b" detect the vertical position ("up" or "down") of the plate lift mechanism 232.

Sensors "3a" and "3b" detect the vertical position ("up" or "down") of the plate lift mechanism 234. Sensor "4" detects misalignment of a micro-well plate while sensor "5" detects the presence or absence of a plate on the carriage 236. Sensor "6" detects the presence or absence of the carriage 236 at position "2" (as defined above).

Given the above-described facilities for position sensing and control (by a combination of sensors and remote-operated motors or other actuators), the microprocessor-based control system can be programmed to perform a wide range of operations. Examples of the flow charts of such operations are illustrated in Figs. 32 to 41.

Fig. 32 depicts the flow chart of a "reference routine" sequence of operations which initialises the positions of the various parts of the Fig. 31 configuration, and clears any remaining micro-well plate into the "output" stack 34.

Following initialisation, operation can be selected either to be manual or to be automatic (preferably arranged to be the 'default' or reversionary mode at power-up).

In manual mode, each micro-well plate is processed using the Multiskan 270, which signals its own errors. The Multiskan carriage position sensor (if fitted) will stop the carriage motor 260 when the carriage 236 is at position "3" (as defined with reference to Fig. 31). If the Multiskan 270 is not fitted with a carriage position sensor, the carriage motor 260 will be energised to drive for a specific time until the carriage 236 reaches position "3" (for which there is a high tolerance). When the carriage 236 is at position "3", the carriage can be manually loaded, unloaded, and/or reloaded with a micro-well plate. When the "manual" mode of operation is first selected, the carriage 236 will be moved to position "3" in an initialising operation.

In the automatic or "AUTO" mode (either as user-selected or as automatically selected at switch-on), the Fig. 31 configuration has three options for automatic function mode; 'computer control' as in Fig. 28, 'stand alone' as in Fig.

27, or 'step' mode in which individual steps are automatically performed but the progression from step to step is manually controlled.

In the 'computer control' mode, all available system functions are under the control of the computer 280, while variables are selected by the user. Variables may comprise entry of a figure for the total number of plates, date and time, a serial number for identification, the desired version of a programme, optional activation of a bar-code reader, and selection of various mechanical handling options (such as plate re-stacking). Indication of 'computer control' mode status need only be by illumination under computer control, of an LED (light-emitting diode) on the stacker 30.

In the 'stand alone' mode, the system may be set for individual micro-well plates to be processed once or processed twice. If set for 'once', the stacker 30 will output the plate after position "3" is reached. If set for 'twice' the stacker 30 will allow the plate to return to position "3" once and be re-processed under Multiskan control, e.g. for dual wavelength and 2 print. After the second return of the plate to position "3", the stacker 30 will output the plate. For either setting, a plate processing cycle is initiated by pressing the 'start' button on the stacker 30.

The flow chart for the sequence of operations in the 'process once' mode is depicted in Fig. 33.

The flow chart for the sequence of operations in the 'process twice' mode is depicted in Fig. 34.

When the system of Fig. 31 is operated in the 'step mode', the totality of sequential operations is divided into four blocks or subsequences, as depicted in the operational flow chart of Fig. 35. In summary, faults or maloperations cause a temporary cessation of functioning, which notifies the operator, allows corrective action to be taken where appropriate, and allows restart at the operator's discretion. If a 'pause' (cycle interrupt) is manually commanded during execution of an operation in any of the blocks shown in Fig. 35, the control system allows all the operations in that block to finish, and then suspends further functioning until the 'pause' control is manually operated for a second time, which initiates a re-start of functioning.The 'get plate' sequence of operations and the plate lift mechanism position sensor logic are detailed in Fig. 36; verification of successful pickup and alignment of a micro-well plate is carried out on the first movement of the carriage 236, i.e. upon horizontal movement of the carriage 236 past sensors '4' and '5'. The operational logic depicted in Fig. 36 is reversed in sequence for re-stacking (i.e. successive transfer of plates out of the magazine 34 and directly into the magazine 32 without leaving the stacker 30).

The optional 'rest' or pause of the carriage 236 in position "3" is ignored except in three situations, i.e. when the 'read plate twice' function is selected, or 'manual' mode is selected, or when the system is under the control of the computer 280.

The external (out-of-stacker) 'process' function varies according to the nature of the external plate processing equipment that is operationally linked to the stacker 30.

When the external plate processing equipment is the Multiskan 270 (as in Figs. 27 and .28) the 'process' function comprises blanking and reading (optical scanning) of the micro-well plate in the Multiskan 270. When the external plate processing equipment is a reagent dispenser such as the Autodrop or Multidrop 290 (as in Figs 29 and 30), the 'process' function comprises priming and dispensing of reagent or other liquid into the micro-well plate in the Autodrop or Multidrop 290. When the external plate processing equipment is the washer 10 (as in Figs. 2, 5, and 6), the 'process' function comprises positioning of the micro-well plate in the washer 10 and application of one or more fill/aspirate cycles, optionally preceded and/or succeeded by use of the fill/aspirate test system 76 and 150 (Figs. 13 - 16).

The 'output plate' sequence of operations and the plate lift mechanism position sensor logic are detailed in Fig. 37; verification of a successful 'output plate' operation is carried out on the first movement of the carriage 236, i.e.

upon horizontal movement of the carriage 236 past sensor "5". The operational logic depicted in Fig. 37 is reversed in sequence for re-stacking.

The 'empty' sequence of operations which detects and responds to the 'input' magazine 32 being empty of plates (or not empty) is depicted in the operational flow chart of Fig. 38. When the 'empty' control sequence pertains, a 'stack empty' indication will be given if no plate is seen by sensor "5" (the 'plate present' sensor which detects the presence or absence of a micro-well plate on the carriage 236).

Fig. 39 depicts the operational flow chart of the 're-stack' sequence of operations in the stacker 30, by which a stack of processed plates in the 'out' magazine 34 is transferred (without leaving the stacker 30 and without being externally processed) one at a time to the 'in' magazine 32 to re-build the original (incoming unprocessed) stack of micro-well plates within the magazine 32 in the vertical order in which they were first presented prior to being externally processed in whichever item of external equipment was concurrently linked to the stacker 30.

Ih the above-described control system, the 'stop' keyswitch is active at all times such that if pressed during any of the above-described functional cycles, the equipment will stop immediately and remain stationary until re-started by pressing the 'start' button. In order to ensure that the equipment is properly initialised and that the various movable parts are not in mutually conflicting positions at the re-commencement of operation, the equipment follows the 're-start' sequence of operations depicted in the operational flow chart of Fig. 40 upon the 'start' button being pressed.

During use of the above-described control system, an 'error' (malfunction) indication will be given if any of the sensors (Fig. 31) remain in either of their detection states (e.g.

for switch-type sensors, the switch being either open or closed) for a specified time during a given cycle or sequence of operations, or if plate misalignment is sensed at any time. The 'error' status of the control system can be cleared for resumption of normal operation by pressing the 'stop' button.

Identification of individual micro-well plates can be facilitated by marking each plate with a distinctive bar code, which may, for example, be printed on a self-adhesive label stuck on the edge of the plate in a position to be read by a suitable bar code reader incorporated in the stacker 30. As utilised in a computer-controlled configuration, such as Fig. 28 or Fig. 30, the information from the bar code reader (not shown) is passed to the computer 280 for decoding and processing. The system is preferably arranged to recognise and respond appropriately to such bar code error conditions as 'bar code not read', 'bar code read too many times', and 'bar code read in wrong sequence'.

An overall view of the various alternative operational modes described above is schematically summarised in Fig. 41.

Turning now to Figs. 42 and 43 these respectively illustrate front and side views of a vertical magazine 300 for containing and transporting stacks of micro-well plates.

The magazine 300 is rectangular in plan with internal dimensions that are a clearance fit around the plates to be held in the magazine. The front face of the magazine 300 is open down a full-height central strip such that while the edges of the front face retain the plates, the open centre permits visual inspection of the contained plates, and manual access thereto (e.g. to lift a plate out of the magazine or to controllably lower a plate into the magazine). The magazine 300 has integral handles 301 to facilitate lifting of the magazine.

The magazine 300 has a base fitting 302 which may be formed to allow the magazine 300 to be fitted into a stacker (for example, as shown in Fig. 2). In the latter case, the base fitting 302 will have a plate-sized aperture therein and may contain one or several spaced-apart latch mechanisms for automatic retention of plates (to prevent them falling through the base aperture) except when the magazine is fitted on a stacker.

An example of such a latch mechanism is shown in Fig. 44, and consists of a pawl 350 having a cranked slot 352 by which the pawl 350 is loosely suspended on a pair of pins 354 secured to the magazine base fitting 302.

The magazine 300 preferably has four such latch mechanisms, with one being mounted at each corner of the base fitting 302.

When the magazine is lifted, the pawls 350 will hang downwards such that their teeth 356 project into the base aperture to prevent any plate passing down between them.

This position is shown in dashed outline in Fig. 44.

When the magazine is lowered over a stack of micro-well plates, the pawls 350 are pushed upwards, such movement being possible because the slot 352 in each pawl 350 is longer than the spacing of the respective pair of pins 354.

However, the cranked shape of the slot 352 results in each pawl 350 tilting outwards away from the base aperture of the magazine 300 as the pawls 350 are pushed upwards, to finish in the position shown in full outline in Fig. 44. The base aperture is now free for unimpeded passage of plates therethrough.

If the magazine 300 is lowered over a stack of plates, it can pass down over the stack since the latch mechanisms are automatically released as described above. When the magazine is lifted again, the pawls 350 swing back automatically to catch the second plate from the bottom of the stack, thus lifting the stack of plates except for the lowermost plate.

The magazine 300 therefore enables easy handling of relatively large numbers of micro-well plates as a single batch.

Referring now to Figs. 45, 45, and 47, these show, to an enlarged scale, a sensor mechanism 40C suitable for use as the previously mentioned plate misalignment sensor "4" (Fig. 31). Fig. 45 is a plan view, Fig. 46 is a front elevation, and Fig. 47 is an end elevation ef tho sensor mechanism 400.

The mechanism 400 comprises a horizontal shaft 402 pivotally mounted at each end on brackets 404 and 406 for swinging movement about a horizontal axis. Although not shown in Fig. 23, the sensor mechanism 400 would ho, mounted on the stacker 30 between the plate lift mechanisms 232 and 234, with the shaft 402 horizontal and a short distance above the rails 38.

A pair of sensor pins 408 are secured to and protect radially downwards from the shaft 402. The height of the shaft 402 above the rails 38 and the downwardly projecting lengths of the pins 408 are such that the lower ends of the pins 408 just clear a correctly aligned micro-well plate carried beneath the sensor mechanism 400 on the carriage 236 (Figs. 23 and 26).

However, should a micro-well plate be misaligned on the carriage 236 such that projections or keys on the underside of the micro-well plate fail to seat correctly in corresponding holes or slots (not shown) in the upper part of the carriage 236, the misaligned plate will ride above its normal, correctly aligned and seated position on top of the carriage 236. The mis-aligned micro-well plate will therefore impinge on the sensor pins 408 and swing the shaft 402 as the carriage 236 carries the mis-aligned plate under the sensor mechanism 400.

The outboard end of the shaft 402 supported by the bracket 406 carries an arm 410 which is secured to and rctates with the shaft 402. The free end of the arm 410 cooperates with a known form of opto-sensor 412 mounted cn the bracket 406 such that the undeflected arm 410 interrupts the optical path through the opto-sensor 412 te inhibit an output signal, whereas any rotational movement cf the shaft 402 away from its natural gravity-maintained position as shown in Figs 45-47 swings the arm 410 out of the optical path through the opto-sensor 412 to activate the cptc-sensor 412 and produce an electrical output signal in known manner.

Thus a mis-aligned micro-well plate cn the carriage 236 will impinge on the sensor pins 408, rotate the shaft 402 by a small but adequate angle, pivot the arm 410 by the same angle, and activate the opto-sensor 412 to produce an electrical output signal indicative of a mis-aligned plate having been sensed.

In manual operation of the stacker 30 fitted with the abovedescribed sensor mechanism 400, an output signal from the opto-sensor 412 indicative of plate misalignment is preferably arranged to cause the carriage 236 to ha7t t position 11311 (Fig. 31) and signal a "r,isalignrcnt" error as envisaged in Figs. 32, 33, 34, 35 and 39. Miselignmcnt of the micro-W7el1 plate can be manually corrected, and plate processing manually re-started.

In automatic or computer-controlled operation of the stacker 30 fitted with the above-described sensor mechanism 400, the control system is preferably programmed such that upon an output signal from the opto-sensor 412 indicative of plate misalignment, the carriage 236 halts at position "3" (Fig.

31) and then promptly returns to position "1" under the "input" magazine stack 30 where the lift mechanism 232 is operated to return the mis-aligned micro-well plate to the bottom of the "input" stack of plates in the magazine 30.

The control system then promptly re-commences the plate retrieval and transport cycle by releasing the newly returned plate from the magazine 30, lowering the plate onto the carriage 236, and then moving the carriage 236 leftwards from position "1" towards (but not necessarily right UP to) position "4". If the micro-well plate is now correctly aligned and properly seated on the carriage 236, movement cf and operations on the plate continue normally. On the other hand, if the sensor mechanism 400 registers that the same micro-well plate is again mis-aligned for the second time in succession, it is assumed that alignment cannot be achieved and the carriage 236 is traversed directly and without the plate being externally processed to position "2" under the "output magazine 32 where the twice mis-aligned plate is ejected up into the "output stack in the magazine 32, the computer 280 or other relevant control/reccrdiny system simultaneously registering a "missed plates in the sequence of micro-well plates undergoing de-stacking, external processing, and re-stacking.

While certain modifications and variations have been described above, the invention is not restricted thereto and other modifications and variations can be adopted without departing from the scope of the invention, as defined in the appended claims.

Claims (48)

CLAIMS:

1. An automatic micro-well plate washer for washing and draining an array of micro-wells in a micro-well plate, said washer comprising a plate manipulator for receiving and manipulating a micro-well plate within the washer, an array of wash liquid dispensers disposed to match the array of micro-wells in a plate placed thereunder by the manipulator, a vertically displaceable array of aspirating tubes disposed to match the array of micro-wells in a plate placed thereunder by the manipulator and vertically displaceable by an aspirating array actuator between an upper position clear of the micro-well plate such that the plate can be moved horizontally under the aspirating tubes and horizontally withdrawn therefrom without colliding with the aspirating tubes, and a lower position in which the aspirating tubes depend into the micro-wells substantially to the bottoms of the micro-wells, the array of wash liquid dispensers and the array of aspirating tubes having mutually related positions that permit the micro-wells of a micro-well plate placed thereunder to be filled with wash fluid and to have the wash fluid aspirated therefrom without requiring repositioning of the plate between filling and aspirating operations, the washer further comprising a wash liquid supplier coupled to the array of wash liquid dispensers and operable to deliver a predetermined volume of wash liquid to the array of wash liquid dispensers, a fluid coupling means through which the array of aspirating tubes is collectively coupled to a suction source in use of the washer to perform an aspirating operation, and a programmable control system operatively connected to the manipulator, to the aspirating array actuator, and to the wash liquid supplier,

the control system being such that in operation of the washer with a micro-well plate placed in the manipulator and with a suction source coupled through said fluid coupling means to said array of aspirating tubes, the manipulator is operated to transfer the plate horizontally to a position under the arrays of wash liquid dispensers and aspirating tubes, the wash liquid supplier is operated to dispense a predetermined volume of wash liquid through the array of wash liquid dispensers into all the wells simultaneously, the aspirating array actuator is subsequently operated to lower the array of aspirating tubes into the wells to aspirate the wash liquid from all of the wells simultaneously and then raise the array of aspirating tubes clear of the micro-well plate, this wash and aspirate cycle being repeated a predetermined number of times if the control system is so programmed, and finally the manipulator is operated again to transfer the washed micro-well plate horizontally to a position in which the plate can be removed from the washer.

2. A washer as claimed in Claim 1 wherein the manipulator is operated while the aspirating tubes are lowered into the micro-wells to cause the plate to undergo relatively small horizontal movements which sweep the aspirating tubes across the bottoms of the micro-wells to minimise or obviate wash liquid remaining unaspirated in the corners of micro-well bases.

3. A washer as claimed in Claim 1 or Claim 2 wherein the washer includes an automatic test system comprising a test block having an array of dummy micro-wells whose internal dimensions substantially match the internal dimensions of micro-wells in the micro-well plates washed in normal operation of the washer, the dummy micro-wells forming an array matching the array of micro-wells in the micro-well plates washed in normal operation of the washer, at least the internal surfaces of the dummy micro-wells being formed of electrically insulating material, a test electrode being secured in the base of each dummy micro-well and being individually electrically connected to an electrical conductivity test circuit comprised within the washer, the array of aspirating tubes being electrically conductive and electrically connected in common to the electrical test circuit to form a common electrode of the test system, and a test block actuator operatively coupled to be controlled by the control system of the washer such that when a test is programmed to take place, the test block actuator is operated to move the test block to a test position in which the dummy micro-wells occupy positions which are substantially identical to the positions of the micro-wells of a real micro-well plate positioned to be washed, the wash liquid supplier is operated to dispense a nominally normal quantity of electrically conductive wash liquid into each dummy micro-well, the aspirating array actuator is operated to lower the array of electrically conductive aspirating tubes into the dummy micro-wells, with simultaneous temporary inhibition of aspiration, and to pause at a level where the lower ends of the aspirating tubes are immediately below the surface of the wash liquid if the micro-wells are correctly filled with wash liquid, and the electrical conductivity test circuit is operated during the pause in the lowering of the array of aspirating tubes into the dummy micro-wells to detect the occurrence (or non-occurrence) of electrical conductivity between the individual test electrodes in the base of each dummy micro-well and the common electrode formed by the array of electrically conductive aspirating tubes due to the dummy micro-wells containing (or not containing) the predetermined quantity of electrically conductive wash liquid, and following the resumption of lowering of the array of aspirating tubes after the pause, with simultaneous termination of the temporary inhibition of aspiration and resumption of aspiration, until the lower ends of the aspirating tubes are at a predetermined distance from the bottoms of the dummy micro-wells, the electrical conductivity test circuit is operated to detect the cessation (or non-cessation) of electrical conductivity between the test electrodes and the common electrode due to the dummy micro-wells being aspirated clear of wash liquid (or failure to drain the dummy micro-wells by aspiration).

4. A washer as claimed in Claim 3 wherein electrical conductivity is tested by application of a suitable test voltage between the test electrodes and the common electrode.

5. A washer as claimed in Claim 4 wherein the test voltage is an A.C. voltage to obviate or minimise electrolysis of the wash liquid and electrolytic corrosion of washer components.

6. A washer as claimed in Claim 3 or Claim 4 or Claim 5 modified in that the electrically conductive aspirating tubes are mutually electrically isolated and individually connected to form individual electrodes in the test system, with the test electrodes in the base of each dummy microwell being either individually electrically connected to the electrical conductivity test circuit, or electrically connected in common to the electrical conductivity test circuit to form a common electrode of the test system.

7. A washer as claimed in any of Claims 3 to 6 wherein the dummy micro-wells are monitored cyclically by a time-division multiplexing procedure.

8. A washer as claimed in any of Claims 3 to 7 wherein the test block is mounted within the washer, directly below the arrays of dispensers and aspirating tubes such that the test block can be moved by substantially purely vertical movement upwards to the test position, and can be withdrawn downwards from the test position by reversal of the substantially purely vertical movement.

9. A washer as claimed in any of Claims 3 to 8 wherein the control system is programmed so as automatically to operate the test block actuator at the conclusion of a test to retract the test block to an inactive position which leaves the washer free to resume the washing of micro-well plates.

10. An automatic aspirator unit for aspirating liquids which may be contaminated with biologically hazardous materials, for dosing aspirated liquids with a sterilising agent, and for delivering sterilised aspirated liquids to a waste disposal conduit, the aspirator unit comprising a container which is vacuum-tight and fluid-tight, a vacuum source coupled to the container at a point above normal peak level of liquid in the container, an aspirate intake conduit coupled to the container, dosing means for dosing aspirated liquids in the container with a sterilising agent, a selfvalving positive displacement drainage pump coupled between the base of the container and the waste disposal conduit, and a liquid sensor coupled to the container to sense the filling of the container with liquid to a predetermined normal peak level of liquid in the container, the liquid sensor being coupled to control the positive displacement drainage pump for intermittent operation upon liquid in the container rising to said normal peak level to drain liquid from the container into the waste conduit.

11. An aspirator unit as claimed in Claim 10 wherein the self-valving positive displacement drainage pump is a peristaltic pump of the type in which a plurality of rollers are driven along a resilient tube in the intended direction of liquid flow, the rollers being pressed against the tube to collapse and block the portions of the tube under the rollers and form pockets of liquid in the uncollapsed tube between adjacent rollers, these pockets of liquid being driven along the tube by the movement of the rollers along the tube to cause positive displacement of liquid through the tube, the collapsed portions of the tube forming valves preventing reverse flow of liquid in the tube whether the rollers are moving or static.

12. An aspirator unit as claimed in Claim 11 wherein the dosing means comprises a further peristaltic pump for drip feeding of the sterilising agent into the container.

13. An aspirator unit as claimed in Claim 10 or Claim 11 or Claim 12 wherein the aspirator unit includes a hydrophobic filter coupled between the vacuum source and the container, the filter permitting the relatively free passage of air or other gases while inhibiting or preventing the passage of liquids, solids, and aerosols whereby to obviate or mitigate fouling of the vacuum source by non-gaseous substances and the potential release of biologically hazardous materials.

14. An aspirator unit as claimed in any of Claims 10 to 13 wherein the container has a substantial ullage or internal volume above the normal peak level of liquid whereby to act as a vacuum reservoir and facilitate temporary inflows of aspirate at volumetric rates in excess of the continuously sustainable volumetric rate of inflow of aspirate.

15. An aspirator unit as claimed in any of Claims 10 to 14 wherein at least the top of the container is formed of a transparent material to enable visual inspection of the interior of the container and the contents thereof.

16. An aspirator unit as claimed in any of Claims 10 to 15 wherein the vacuum source comprises a vacuum pump mounted within the aspirator unit, and the aspirator unit comprises regulator means to regulate the level of sub-ambient pressure produced in operation of the vacuum source.

17. An aspirator unit as claimed in any of Claims 10 to 16 wherein the aspirator unit comprises pump control means selectively operable to cause temporary inhibition of operation of the positive displacement drainage pump during operation of the aspirator unit whereby to allow the temporary disconnection of the waste conduit without substantial spillage of liquid drained from the container.

18. An aspirator system comprising an aspirator unit as claimed in any of Claims 10 to 17, in combination with a liquid waste collecting container coupled to the waste conduit of the aspirator unit, and a reservoir of sterilising agent coupled to the dosing means.

19. An aspirator system as claimed in Claim 18 wherein the aspirator unit is an aspirator unit as claimed in Claim 17, and the pump control means is operable to cause temporary inhibition of the drainage pump during disconnection of the waste conduit from a filled liquid waste collecting container and reconnection of the waste conduit to an empty liquid waste collection container.

20. An aspirator system as claimed in Claim 18 or Claim 19, wherein the aspirator system is operatively associated with a multi-compartment container rack for holding a liquid waste collecting container, a reservoir of sterilising agent, a reservoir of salt-free flushing liquid, and a reservoir of saline wash liquid connected in use to supply saline wash liquid to a washer as claimed in any of Claims 1 to 9 when said washer is utilised in conjunction with said aspirator system, said aspirator system being operable at the conclusion of use of the washer to flush the washer with the salt-free flushing liquid whereby to clear the washer of remenant salt and minimise corrosion of the washer.

21. An aspirator system as claimed in Claim 20 wherein the containers are rectiform to maximise the ratio of container volume to bench space occupied by the containers.

22. An automatic micro-well plate stacker for receiving micro-well plates in a first stack of plates, dispensing single plates from the bottom of the first stack to an external plate processor and receiving single plates returned from the external plate processor to form a second stack of plates, and for subsequently re-ordering plates by feeding externally processed plates directly from the bottom of the second stack back to the bottom of the first stack to rebuild the first stack in its original order, said stacker comprising a first vertical magazine for receiving microwell plates singly or in stacked batches to form the first stack, plate handling means for removing plates singly from the bottom of the first stack, for dispensing said single plates removed from the bottom of the first stack to the external plate processor, and for receiving externally processed single plates returned from the external plate processor to build a second stack of plates from the bottom upwards into a second vertical magazine, and stacker control means operable when all of the plates in the first stack have been so transferred via the external plate processor to the second stack to control the plate handling means to transfer the externally processed plates singly from the bottom of the second stack in the second magazine directly to the bottom of the first magazine to rebuild the first stack in the first magazine from the bottom upwards whereby to re-form the first stack of now externally processed plates in the order in which the first stack was originally formed.

23. A stacker as claimed in Claim 22 wherein the plate handling means comprises first latch means at the base of the first magazine and second latch means at the base of the second magazine, each of said latch means being independently controllable by the stacker control means selectively either to permit or prevent a plate passing vertically through the bottom of the respective magazine, first plate lift means under the first magazine and second plate lift means under the second magazine, each of said plate lift means being independently controllable by the stacker control means to lift a plate into the respective magazine to form a plate stack therein from the bottom upwards, and a horizontal plate transporter controllable by the stacker control means to transport single plates beneath either of said magazines along a horizontal path towards the external plate processor and to return externally processed plates along said horizontal path to a position under a selected one of said magazines at which position the respective plate lift means is operable to lift the plate into the bottom of the respective magazine to be retained therein by the respective latch means.

24. A stacker as claimed in Claim 23 wherein said horizontal plate transporter comprises a rail-mounted carriage self-propelled by an on-carriage electric motor driving the carriage through a motor-driven pinion acting on a fixed rack mounted parallel with the rails, the motor being controllably powered through a flexible cable secured at one end to the carriage and at the other end to a fixed point on the plate stacker.

25. A stacker as claimed in Claim 24 wherein the rack is formed by a toothed belt secured along its length to a linear structural member of the plate stacker.

26. A stacker as claimed in any of Claims 22 to 25 wherein the magazines are demountable from the stacker for transport of micro-well plates therein, the demountable magazines being provided with plate retention means to prevent the plates falling through the bottom of the magazine when the magazine is demounted.

27. A stacker as claimed in any of Claims 22 to 26 wherein the external plate processor comprises a multi-well plate washer as claimed in any of Claims 1 to 9.

28. A stacker as claimed in any of Claims 22 to 26 wherein the external plate processor comprises a plate reader for optically measuring the results of reactions that have occured in micro-wells as manifested by changes in the optical properties of the contents of the micro-wells.

29. A stacker as claimed in any of Claims 22 to 26 wherein the external plate processor comprises a reagent dispenser operable to fill each micro-well of a plate from the stacker with a liquid reagent and/or with another selected substance, or to fill selected micro-wells of the plate while leaving the other micro-wells of that plate free of reagent and/or other selected substance, and to return the reagent-loaded plate to the stacker.

30. A combined micro-well plate washer and micro-well plate stacker wherein the washer is an automatic micro-well plate washer as claimed in any of Claims 1 to 9, and the stacker is an automatic micro-well plate stacker as claimed in any of Claims 22 to 26, the plate handling means of the stacker being operatively coupled to the plate manipulator of the washer for substantially horizontal transfer of plates therebetween whereby the first magazine of the stacker may be loaded with plates which are automatically transferred, washed, and ultimately restacked in the first magazine in their original order of stacking.

31. A combined washer and stacker as claimed in Claim 30 wherein either the programmable control system of the washer or the stacker control means of the stacker exercises predominant control of the combined washer and stacker, said control system and said control means being operatively interlinked to provide cooperative and non-conflicting combined operations of the stacker and the washer.

32. A combined micro-well plate washer, micro-well plate aspirator, and micro-well plate stacker, wherein the washer and the stacker are the combined washer and stacker as claimed in Claim 30 or in Claim 31, and the aspirator is an aspirator unit as claimed in any of Claims 10 to 17 or an aspirator system as claimed in any of Claims 18 to 21, the aspirator being operatively connected to the washer to perform the aspirating function of the aspirating tubes thereof.

33. A combined washer, aspirator, and stacker as claimed in Claim 32 wherein the washer is also arranged to be supplied with salt-free flushing liquid for post-operational flushing of the washer to free the washer of potentially corrosive salts contained in the wash liquid, and to obviate or mitigate the risk of crystallisation of salts within the washer and possible consequential blockages of liquid passages and liquid transfer mechanisms within the washer.

34. A micro-well plate transport magazine for containing a stack of micro-well plates and retaining the plates in the magazine during carriage of the loaded magazine.

35. A micro-well plate transport magazine as claimed in Claim 34 wherein the magazine has a base aperture and includes one or more latch mechanisms disposed at the base of the magazine to allow an empty magazine or an incompletely filled magazine to be lowered vertically onto a stack of micro-well plates to cause the stack of plates to enter the magazine upwardly through the base aperture, the latch mechanism or mechanisms permitting upward passage of plates through the base aperture while preventing passage of the plates downwardly through the base aperture when the magazine is lifted with a plate or plates therein.

36. A micro-well plate transport magazine as claimed in Claim 35 wherein the magazine is dimensioned to form a replaceable magazine for the stacker as claimed in any of Claims 22 to 29, the latch mechanism or mechanisms being such as to interact with the stacker when the magazine is fitted on to the stacker to release plates carried within the magazine for passage in either vertical direction through the base aperture under the control of the respective plate lifter of the stacker which is located under the magazine.

37. A micro-well plate transport magazine as claimed in Claim 34 or Claim 35 or Claim 36 wherein the magazine incorporates one or more integral handles to facilitate manual lifting and carriage of the magazine.

38. An automatic micro-well plate washer, substantially as hereinbefore described with reference to and as illustrated in Figs. 1,2,5,6,7,8,9,10,11, and 12 of the accompanying drawings.

39. An automatic micro-well plate washer as claimed in Claim 38, including an automatic test system and substantially as hereinbefore described with reference to and as illustrated in Figs. 7,8,9,13,14,15, and 16 of the accompanying drawings.

40. An automatic aspirator unit, substantially as hereinbefore described with reference to and as illustrated in Figs. 3,5,6,17,18,19,20,21, and 22 of the accompanying drawings.

41. An aspirator system comprising an aspirator unit as claimed in Claim 40, in operative association with a multicompartment container rack substantially as hereinbefore described with reference to and as illustrated in Figs. 4, 5, and 6 of the accompanying drawings.

42. An automatic micro-well plate stacker, substantially as hereinbefore described with reference to and as illustrated in Figs. 2,5,6,23,24,25, and 26 of the accompanying drawings.

43. A combined micro-well plate washer and micro-well plate stacker, substantially as hereinbefore described with reference to and as illustrated in Figs. 2,5, and 6 of the accompanying drawings.

44. A combined micro-well plate washer, micro-well plate aspirator, and micro-well plate stacker, substantially as hereinbefore described with reference to and as illustrated in Figs. 5 and 6 of the accompanying drawings.

45. A micro-well plate transport magazine, substantially as hereinbefore described with reference to and as illustrated in Figs. 42,43, and 44 of the accompanying drawings.

46. A stacker as claimed in Claim 42, in combination with external plate processing equipment, substantially as hereinbefore described with reference to and as illustrated in Fig. 27 or Fig. 28 or Fig. 29 or Fig. 30 of the accompanying drawings.

47. A stacker as claimed in Claim 42, in combination with external plate processing equipment substantially as hereinbefore described with reference to and as illustrated in Fig. 31 of the accompanying drawings.

48. A combined stacker and external plate processing equipment as claimed in Claim 47, when programmed to operate in accordance with any one or more of the functional routines substantially as hereinbefore described with reference to and as illustrated in Figs. 32 to 41.