WO2000033086A1

WO2000033086A1 - Workstation for microbiological tests

Info

Publication number: WO2000033086A1
Application number: PCT/EP1999/009213
Authority: WO
Inventors: Günter Neumann; Peter Adib
Original assignee: Luigs & Neumann Feinmechanik Und Elektrotechnik Gmbh
Priority date: 1998-11-27
Filing date: 1999-11-26
Publication date: 2000-06-08
Also published as: AU3035100A; DE19854919A1

Abstract

A workstation for microbiological tests contains a dispenser head for receiving and dosing small samples of liquids. Said dispenser head is mounted on a cross member and can be displaced in a vertical and horizontal direction by means of regulating motors. The cross member is connected to a base plate by mounting columns, said base plate also supporting a sample container which can be displaced crosswise in relation to the dispenser head, for supplying a sample, and an object support onto which the dosed samples are output. The samples can be collected and deposited fully automatically and with a high degree of precision. The base plate also supports additional units such as a cleaning bath for the capillaries of the dispenser head and a position calibration unit and an optical control unit for the capillaries.

Description

Work place for microbiological tests

The invention relates to a workplace for microbiological tests with the features specified in the preamble of claim 1.

For microbiological examinations, small dosed quantities of the material to be examined are often applied to a slide with the aid of a pipette or capillary, for example in order to interact with other materials or to be subjected to other treatments or examinations. Workplaces for such microbiological tests have so far been put together from case to case from individual components, the most important of which is a manipulator with which the required minimal movements can be reproducibly carried out. The remaining components were placed more or less arbitrarily in suitable places and fixed.

The invention is based on the object of creating a complete workstation for microbiological tests, in particular genetic engineering work, which already contains the facilities required for this purpose, in an operable manner and in a suitable arrangement for each other, for all relevant work, so that no time-consuming conversions between different tests or experiments required are.

This object is achieved by the features specified in claim 1. Developments of the invention are characterized in the subclaims.

The movability of the dispenser head between a sample delivery point, at which the samples to be examined are fed in a tray that can be positioned there, and one Sample delivery point, at which dosed samples are dispensed onto a slide, enables fast, targeted work, which can also be automated by appropriate control. If the samples are fed into microwave plates, which are characterized by a large number of small recesses for holding individual samples, then, for example, when using a dispenser head with a row arrangement of capillaries or pipettes, preferably piezoelectric micropipettes, a corresponding number of samples can be taken out simultaneously several wells of the microwave plate can be removed, which is possible by exact positioning of the pipettes in relation to the wells, i.e. the dispenser head relative to the plate, and these samples are transported to the slide by the dispenser head method and can be dispensed there in exact doses at precisely definable positions become.

For example, if several substances are to be brought together on the slide, this can be achieved with pinpoint accuracy, even if a plurality of samples are to be processed simultaneously on one slide. The position calibration unit arranged in the range of motion of the dispenser head permits exact adjustment of the droplets emerging from the pipettes, so that they are deposited on the specimen slide at precisely defined unloading positions. A rinsing bath also provided in the movement area of the dispenser head allows the pipettes to be cleaned between the taking of different samples, so that undesired mixing or contamination of the substances taken up and dispensed by the pipettes can be avoided.

The control of the movements of the dispenser head in the horizontal and vertical directions for sampling, sample transport and sample dispensing can be carried out very precisely with the aid of control circuits for the corresponding one-part motors, so that the desired positions can be approached reproducibly with the highest accuracy.

In the interest of rationally carrying out a large number of similar work, the work station according to the invention can have a specimen slide unit for a large number of specimen slides, for example in the form of a carousel or turntable, during whose gradual rotation different specimen slides can be brought one after the other into the dispensing area of the dispenser head. If one provides for an additional displaceability of the turntable transversely to the transport direction of the dispenser head, the number of dispensing positions of the pipette contents can be multiplied, since, for example, with a row arrangement of pipettes or capillaries, dosed samples are also dispensed in a row on the slide, and when this is done offset by a piece by the above-mentioned transverse displacement, a further row of samples can be placed next to the first one, etc., until the capacity of the object carrier is reached. Because the turntable can be replaced, work can be carried out practically continuously, since a turntable with filled slides can be removed for further treatment and replaced by a new one, whose slides can then immediately take up new samples.

It is also expedient to arrange an optical control unit in the movement area of the dispenser head to check the position of the pipette tips in order to take into account any deviations from a target position when regulating the motors and thereby to ensure that the pipettes move exactly to the desired positions. Such Kontrollemheit can zweckmaßi- gerweise also the possibility of observing from the Pi ^¬ petten exiting droplets, including photographic logging include, in order to determine in this way whether the Tropfchenabgabe goes or properly before possibly by contamination of pipettes uncontrolled conditions occurred are, which require an exact dosage compromise. The exact alignment of several pipettes can also be checked in this way.

An expedient design of the traverse for an exact guidance of the dispenser head consists in providing two parallel guide shafts for mounting the dispenser head, the dispenser head being suspended in a height-stable manner on a guide shaft and being guided on the other guide shaft in a laterally stable manner. The suspension can expediently take place via angled ball guides or rollers with which the dispenser head hangs on the upper guide shaft, for example, while two ball guides or rollers provided on both sides of the lower guide shaft prevent the dispenser head from swinging around the upper shaft. This arrangement can also be interchanged. A drive spindle can be arranged parallel to the two guide shafts, which is driven by a one-piece motor, possibly via a play-free gear, and engages play-free in an adjusting nut of the dispenser head, so that it can be delicately moved by rotating the drive spindle.

A variant of the workplace according to the invention is not to attach the crossbar to two guide columns anchored on a base plate, but to a rotatably mounted guide column which allows the crossbar to be pivoted through a horizontal angle. Here, the entire traverse can be moved in the longitudinal direction on the mounting column in order to bring the dispenser head attached at one end into the various working positions. At the other end of the traverse, for example, there is an automatically operating gripping device for sample containers if desired, for example to remove the aforementioned microwave plates from a delivery point and insert them into a carriage, which is then moved into the desired position, where the dispenser head can take the samples. For this purpose, the assembly column can pivot the crosshead into the required position so that the entire workflow can be automated even further. The invention will now be explained in more detail with reference to exemplary embodiments illustrated in the accompanying drawings. Show it:

Figure 1 is a schematic side view of an embodiment of the workplace according to the invention;

FIG. 2 shows a plan view of the work station illustrated in FIG. 1;

Figure 3 shows a modified form of the invention; and

Figures 4A and B details of the dispenser head mounting m the crossbar.

In Figure 1, a base plate 4 can be seen, which carries two assembly columns 1.3, to which in turn a cross member 1.0 is attached. A dispenser head 1.1 can be moved along the traverse in arrow A with the aid of an adjusting motor 1.5 and positioned exactly. Another one-part motor 1.4 allows a precisely controlled raising and lowering of the dispenser head 1.1 in the direction of arrow B. For this purpose, the one-part motor 1.4 rotates a square rod 1.8, which is coupled in the dispenser head to an eccentric mechanism which causes the vertical movement of the dispenser head. The longitudinal displacement of the dispenser head 1.1 takes place along two guide shafts 6.5 (see also FIG. 4) on which the dispenser head is mounted. A drive spindle 6.6, which is driven by the actuator motor 1.5, runs parallel to the guide shafts 6.5 and engages a nut which is mounted in the dispenser head 1.1 without play, so that the dispenser head can be moved along the guide shafts when the drive spindle rotates. At the bottom, several pipettes or capillaries 1.9 protrude from the dispenser head 1.1, which are connected in the dispenser head to pumps for drawing material from a sample container.

In the area of the left end position of the dispenser head there is an optical control unit 5 below the base plate, but accessible through it, with the aid of which there is an optical control unit 5 have the capillaries 1.9 observed. In the case of dispenser heads with several rows of capillaries, the alignment of the capillaries can be checked using a positioning axis 5.2 and corrected if necessary. The observation is carried out by a lens 5.1 with the aid of a deflection mirror, not shown.

As can be seen better in FIG. 2, there is a carriage 2.0 with a sample holder for feeding the samples to be examined in the movement area of the dispenser head. The sample container is expediently provided with a cooling device for the samples so that they do not evaporate during long-term tests. In the exemplary embodiment shown, a microwell bowl 2.1 is seated in the slide as a sample container, which contains a multiplicity of depressions for samples which can be sucked off by the capillaries 1.9 of the dispenser head 1.1. This sample container can be moved in the direction of the double arrow C transversely to the direction of movement of the dispenser head, so that the samples can be moved one after the other under the capillaries in order to be sucked up by them. The exact positioning of the sample container 2.1 can be controlled with the aid of a control device 2.4, which can work, for example, with a magnetic strip, which allows exact position sensing and determination. Such a measuring device is also used in the example described here for the positioning of the dispenser head 1.1, and a measuring strip (magnetic strip) 1.2 is provided in the cross member 1.0 for its longitudinal displacement.

A bath 2.2 can also be seen in FIGS. 1 and 2, in which the capillaries can be immersed for cleaning, for example by means of ultrasound. In addition, a position calibration unit 2.3 is provided, with the aid of which the capillary position can be precisely calibrated, so that any position deviations can be entered into the positioning control loop as a correction variable when working and the desired positions of the capillaries are actually approached exactly. In FIGS. 1 and 2 one can see on the right side a slide unit 3.0 in the form of a turntable 3.2, which can be exchangeable, as indicated by the arrow F pointing upwards, and which carries a star-shaped arrangement of slides 3.1, which are individually underneath the capillaries 1.9 of the dispenser head 1.1 can be moved if it is in its right position. The turntable 3.2 can be rotated in the direction of the double arrow D with the aid of a motor, which is not specifically illustrated, in order to bring the individual slides 3.1 under the dispenser head. In addition, the drive 3.3 allows a transverse displacement in the direction of the arrow E in small steps, so that a whole number of parallel sample droplets from the capillaries 1.9 can be deposited in parallel rows on a slide 3.1. In addition to the double arrows in the drawings, the directions of movement of the various parts are also indicated by an arrowhead and an arrow end as circles with a point or cross.

A modified embodiment compared to FIGS. 1 and 2 is shown in FIG. 3. The mounting column 1.3 is mounted here in a swivel bearing with rotary drive 1.7 on the base plate 4, and the crossbar 1.0 is slidably mounted with its guide shafts 6.5 in the mounting column 13, the displacement movement again with the aid of a motor-driven drive spindle 6.6, the spindle nut of which is seated in the assembly column 1.3. In this variant, the dispenser head 1.1 is arranged at one end of the traverse 1.0, while an automatic gripping device 1.6 for sample containers, for example in the form of the aforementioned microwave plates, is provided at the other end. By rotating the mounting column 1.3, the dispenser head 1.1 or the gripping device 1.6 can be brought to the desired position, depending on the requirements. The remaining parts of this embodiment correspond to the elements already explained in connection with FIGS. 1 and 2. Figure 4 shows two representations A and B the diagram of the mounting of the dispenser head 1.1 on the two guide shafts 6.5, the left figure A illustrating the bearing diagram from the side and the right figure B in section. As FIG. B shows, the dispenser head 1.1 hangs on the upper guide shaft 6.5 with roller or ball guides 6.1 arranged at an angle to one another. Another roller or ball guide 6.2 rolls on the underside of the upper guide shaft 6.5, and this three-point guide ensures the basic fixation of the dispenser head. The dispenser head is supported laterally on the lower guide shaft 6.5 with further ball or roller guides 6.3 or 6.4, so that the dispenser head cannot oscillate on the upper guide shaft. In the right figure B, the drive spindle 6.6 for the longitudinal advance of the dispenser head is also shown. This Fuhrungspπnzip can also be used in the variant according to FIG. 3, the roller or ball guides and the spindle nut then sitting in the assembly column 1.3 and the guide shafts 6.5 and the drive spindle 6.6 running through them.

Further explanations result from the following summary description of the individual assemblies:

1. The traverse

As a transfer axis, the traverse 1.0 has a stepper motor drive for positioning the dispenser head 1.1 and an eccentric drive for lowering the dispenser head e.g. for taking samples.

2. The dispenser head 1. 1

One or more piezoelectric micropipettes are received in the dispenser head and electrically contacted.

These specially drawn capillaries 1.9 with a glued-on piezo element can be controlled separately and against a stream of microdroplets. Other connections of the capillaries, not shown, are pressure connections for the holding and suction pressure and for blowing out or cleaning the capillaries.

The dispenser head 1.1 is attached to the slide of the transfer axis and can be positioned in the X direction with the help of the motor 1.5 and lowered via an eccentric drive (motor 1.4), e.g. for absorbing liquids.

3. Optical control unit 5. 0

With the optics coupled in from below via mirrors, the shape of the drops, the tear-off from the dispenser and the size of the drops, the volume of which is approx. 110 pL, can be determined with the aid of a stroboscopic light source. You also get a statement about defective or blocked dispenser units. The motor Y-axis and the beam paths coupled in via mirrors enable a control of several capillaries 1.9 arranged one behind the other.

4th Bath chamber

The bath chamber axis positions the microwave plates with the samples in the Y direction (arrow C). In the rear position (retraction position) of the bath chamber axis, the microwave plate is freely accessible for an automatic pick and place machine.

A winding and cleaning chamber (bath 2.2) is attached to the front of the bath chamber axis. In addition to the cleaning chamber, the position calibration unit 2.3 is attached for measuring the impact points of the drops. Due to the minimal misalignment of the dispensers, the location coordinates of the drops are not to be equated with the dispenser head position. It is therefore necessary to determine the relative coordinates for the exact positioning of the drops. A measuring device suitable for this consists of two thin V-shaped wires which, when the drops hit, emit a vibration pulse to an electronic Pass on the acoustic sensor (loudspeaker). This pulse is recorded electronically. The calculated difference dimensions between the dispenser head axis, reference coordinates and drop position can be included in the positioning command for applying the drops to the slide.

5. Whether ect carrier unit 3. 0

This unit can be positioned along a Y axis which, together with the X axis of the dispenser head 1.1, can apply any drop grid to a slide. The turntable 3.2 enables several slides 3.1 to be fixed using e.g. Spring force or vacuum. This ring is also removable as a whole, so that it e.g. can be completely changed for further processing.

All axes are motorized and equipped with a control loop system so that the correct positioning can be maintained and the positions can be documented.

In the variant shown in FIG. 3, the crossmember is rotatably mounted with the mounting column. The dispenser head 1.1 is located on the front of the traverse and a gripping mechanism 1.6 for the microwell plates 2.1 is located on the rear. This traverse can therefore also take on the function of a pick and place robot, which takes the plates out of a magazine, positions them on the axis of the bath chamber and can then reset the magazine.

6. Storage

Two ball guides 6.1 on each side represent a prismatic guide. The dispenser head thus lies on the upper guide shaft 6.5 due to its own weight and is secured with a ball guide 6.2 pretensioned by springs. The lower bearing unit serves as protection against rotation, in which two ball guides 6.3 serve as fixed sides and a third ball guide 6.4 switches the game off by a spring preload. The roles of the two guide shafts can also be reversed.

The compact design and the arrangement of the movable axes enable a large number of work steps to be carried out with just six motor drives, e.g.

1 - Recording from the medium

2 - Dispense from the medium

3 - coils of micropumps

4 - optical control of the function of the micropumps

5 - position calibration

6 - Release position for changing the microwave plates

7 - Positioning multiple targets (slides)

8 - Dispense with any grid dimensions on the target.

The positioning accuracy is guaranteed by a ground spindle, a play-free adjustable plastic nut and by using a control circuit.

The guide system for the exact movement of the dispenser head consists of ground and hardened precision shafts and high-precision ball guides. This construction of bearings permits a compact, precise guided bearing design with ei ^¬ nem unlimited track, similar to recirculating ball bearings, but with higher precision.

Claims

PATENT CLAIMS

1. Work station for microbiological examinations with a dispenser head that can be moved in several axes of motion for taking and dosing small liquid samples, and with a sample holder for feeding samples to be examined, and with a slide for taking dosed samples, characterized in that the one-position motors (1.4, 1.5 ) vertically and longitudinally displaceable dispenser head (1.1) is mounted on a crossmember (1.0), which in turn is supported by at least one mounting column (1.3) connected to a base plate (4.0), that within the longitudinal displacement range of the dispenser head (1.1) the sample holder (2.1 ) is arranged so as to be transversely displaceable, and that the specimen slide (3.1) is seated on such a movable support unit (3.0) that it can be positioned in the longitudinal displacement area of the dispenser head (1.1) for receiving dosed samples.

2. Work station according to claim 1, characterized in that the dispenser head (1.1) along the crossmember (1.0) is displaceable and the crossmember is carried by two mounting columns (1.3).

3. Workstation according to claim 1, characterized in that the mounting column (1.3) is rotatably mounted and the longitudinally displaceably mounted cross member (1.0) at one end the dispenser head (1.1) and at its other end a gripping device (1.6) for sample holder (2.1) carries.

4. Work station according to claim 1, 2 or 3, characterized in that the dispenser head (1.1) is equipped with a plurality of metering capillaries (1.9).

5. Work station according to one of the preceding claims, characterized in that the sample container (2.1) is formed by a shell with a large number of small recesses for receiving individual samples, which can be used in a slide (2.0) which can be displaced transversely to the dispenser head guide.

6. Work station according to one of the preceding claims, characterized in that a capillary rinsing bath (2.2) is arranged in the range of movement of the dispenser head (1.1).

7. Work station according to one of the preceding claims, characterized in that a position calibration unit (2.3) for the capillaries (1.9) is arranged in the range of movement of the dispenser head (1.1).

8. Work station according to one of the preceding claims, characterized in that the slide unit (3.0) has an optionally interchangeable turntable (3.2) with a plurality of receptacles for slides (3.1) which are individually movable in the range of movement of the dispenser head (1.1).

9. Workplace according to claim 8, characterized by a rotational movement and translational movement allowing storage for the turntable (3.2).

10. Workplace according to one of the preceding claims, characterized by a in the range of motion of the dispenser Head (1.1) arranged optical control unit (5.0), optionally with a camera connection, for observing the droplets emerging from the capillaries (1.9).

11. Workstation according to one of the preceding claims, characterized in that the crossmember (10) contains two parallel guide shafts (6.5), on one of which the dispenser head (1.1) with angularly arranged ball or roller guides (6.1,6.2) hangs and on the other of which it is guided in a pendulum-free manner by means of ball or roller guides (6.3, 6.4) arranged on both sides.

12. Workplace according to claim 11, characterized in that in the crossmember (1.0) a parallel to the guide shafts (6.5) running drive spindle (6.6) for the longitudinal adjustment of the dispenser head (1.1) is mounted and coupled to a one-piece motor (1.5).

13. Workplace according to one of the preceding claims, characterized in that the one-piece motors (1.4, 1.5) for the dispenser head position can be controlled via control loops