MULTI-CHANNEL PIPETTING HEAD

Abstract

The invention relates to a multi-channel head (100) of a liquid handling apparatus for aspirating and dispensing a metered amount of liquid, comprising: an array of connectors (130) for picking up an array of disposable tips, whereby a peripheral end of each connector is provided with an elastomeric seal (140); an alignment plate (150) that is moveable in a z-direction and has a plurality of openings through which the connectors (130) extend, a linear displacement mechanism (170b, 175), driven by a motor (180), for moving the alignment plate (150) in z-direction relative to the connectors, and a controller for controlling the motor. The multi-channel head is configured to attach the array of disposable tips in a pick-up action, in which the multi-channel head (100) is lowered relative to the disposable tips so as to insert each connector into an internal passageway of a corresponding disposable tip by an amount sufficient to bring an upper collar of the disposable tips into contact with an underside (150s) of the alignment plate. This insertion deforms the elastomeric seal against the tip internal passageway so as to form a sealing contact therewith. The controller of the multi-channel head (100) is programmed such that once the pick-up action is complete, an alignment action is performed in which the alignment plate (150) is moved relative to connectors (130) by an amount sufficient to close any gap between the underside (150s) of the alignment plate and the upper surface of the tip collars that arises due to e.g. relaxation of the deformed seals (140).

Claims

1. A multi-channel head of a liquid handling apparatus for aspirating and dispensing a metered amount of liquid via an array of disposable tips, the multi-channel head comprising: an array of connectors for picking up the array of disposable tips, whereby a peripheral end of each connector is provided with a seat on which an elastomeric seal is arranged that surrounds an outer circumference of the connector; an alignment plate that is moveable in a z-direction, parallel to a centre axis of the disposable tips, which plate has a plurality of openings through which the connectors extend, a motor and a linear displacement mechanism, driven by the motor, for moving the alignment plate in z-direction relative to the connectors, and a controller for controlling the motor; wherein: the multi-channel head is configured to attach the array of disposable tips to the array of connectors in a pick-up action, when the alignment plate is in a stop position, in which the multi-channel head is lowered relative to the disposable tips so as to insert each connector into an internal passageway of a corresponding disposable tip by an amount sufficient to bring an upper surface of a collar of the disposable tips into contact with an underside of the alignment plate, whereby said insertion deforms the elastomeric seal against the disposable tip internal passageway so as to form a sealing contact therewith that provides the sole attachment force between each disposable tip and the respective connector; wherein, the controller is programmed to cause an alignment action to be performed, once the pick-up action is complete, in which the linear displacement mechanism moves the alignment plate from the stop position by a first amount, which is sufficient to close any gap between the underside of the alignment plate and the upper surface of the tip collars, which exists due to relaxation of the deformed elastomeric seals and/or due to small positional variations in z-direction when the disposable tips are picked up from a holder.

2. The multi-channel head of claim 1, wherein the controller is further programmed to execute a release action in which the linear displacement mechanism is actuated, so as to displace the alignment plate relative to the connectors by a second amount, greater than the first amount of linear displacement associated with the alignment action, that is sufficient to push off each disposable tip from the corresponding connector.

3. The multi-channel head of claim 1, wherein each seal comprises a flange part having a larger diameter than a cylindrical part of the seal that surrounds the outer circumference of the corresponding connector.

4. The multi-channel head of claim 1, wherein the linear displacement mechanism comprises first and second spindle arrangements, wherein the alignment plate is is coupled to a spindle nut associated with each spindle arrangement.

5. The multi-channel head of claim 3, wherein the linear displacement mechanism further comprises a belt and pulley system in which: an output shaft of the motor is coupled to a driven pulley sheave; a peripheral end of each spindle is coupled to a corresponding pulley sheave and a pulley belt connects said pulley sheaves such that the first and second spindles are rotated via the driven pulley sheave.

6. The multi-channel head of claim 1 comprising an array of 96 connectors.

7. The multi-channel head of claim 1, comprising an array of 384 connectors.

8. The multi-channel head of claim 1, comprising an array of 1536 connectors.

9. The multi-channel head of claim 1, further configured such that when the alignment action is executed, the alignment plate is displaced relative to the connectors by a first amount which lies between 0.1 and 2.0 mm.

10. Liquid handling apparatus comprising the multi-channel head of claim 1.

11. A method of picking up and aligning an array of disposable tips using a multi-channel head device comprising an array of connectors for receiving the disposable tips, whereby a peripheral end of each connector is provided with a seat on which an elastomeric seal is arranged that surrounds an outer circumference of the connector, and whereby the connectors extend through an alignment plate that is moveable relative to the connectors in a z-direction, parallel to a centre axis of the disposable tips, the method comprising steps of: lowering the multi-channel head in z-direction, with the alignment plate in a stop position, so as to insert the connectors into an internal passageway of the corresponding disposable tip, by an amount sufficient to bring an upper surface of a collar of the disposable tips into contact with an underside of the alignment plate, whereby said insertion deforms the elastomeric seal against the disposable tip internal passageway so as to form a sealing contact therewith that provides the sole attachment force between each disposable tip and the respective connector; raising the multi-channel head so as to pick up the array of disposable tips and remove them from a holder on which they are supported; and aligning the disposable tips by displacing the alignment plate in z-direction, relative to the connectors, from the stop position by a first amount which is sufficient to close any gap between the underside of the alignment plate and the upper surface of the tip collars, which exists due to relaxation of the deformed elastomeric seals and/or due to small positional variations in z-direction when the disposable tips are picked up from the holder.

12. Method of claim 11 comprising a further step of detaching each disposable tip from the corresponding connector by displacing the alignment plate in z-direction relative to the connectors by a second amount, greater than the first amount associated with the alignment action, which is sufficient to push off the disposable tips from the corresponding connectors.

13. Method of claim 11, wherein the first amount of displacement in z-direction, applied in the step of aligning, is calculated based on tests conducted using the multi-channel head, the array of disposable tips and associated holder.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIGS. 1a & 1b respectively show a front cross-sectional view and s side cross-sectional view of an embodiment of a multi-channel head according to the invention, for use in a liquid handling apparatus;

[0023] FIG. 1c is a perspective view of an underside of the multi-channel head shown in FIGS. 1a & 1b;

[0024] FIG. 2a is a perspective view of an example of a disposable tip for attachment to a connector of the multi-channel head;

[0025] FIG. 2b is a perspective view of a holder for an array of disposable tips;

[0026] FIGS. 3a-3c schematically show a disposable tip being attached to a connector, which forms part of the multi-channel head, in stages of a pick-up action

[0027] FIG. 3d schematically shows the disposable tip being aligned in an alignment action, after pick-up

[0028] FIG. 3e schematically shows a disposable tip being detached from the connector, after use, in a release action.

[0029] FIG. 4 is a perspective view of a liquid handling apparatus comprising an example of a multi-channel head device.

[0030] It should be noted that items which have the same reference numbers in different figures, have the same structural features and the same functions. Where the function and/or structure of such an item has been explained, there is no necessity for repeated explanation thereof in the detailed description.

DETAILED DESCRIPTION OF EMBODIMENTS

[0031] FIGS. 1a – 1c show views of a multi-channel head device 100 according to an embodiment of the invention, which forms part of a liquid handling apparatus that may be used in a laboratory environment to dispense a metered amount of liquid via an array of disposable tips that are attached to individual connectors 130, arranged at an underside of the head device. Liquid is aspirated and then dispensed with the aid of a block of cylinders 110, each one equipped with a piston 115 that is connected to a piston plate 120. The piston plate is moveably coupled to a fixed part of the multi-channel head device via a first displacement mechanism, driven by a first motor 105 (refer FIG. 1b). In the depicted example, the first displacement mechanism comprises an arrangement of three spindles 102, which are driven in a known manner by a belt and pulley system (generally indicated with reference numeral 103).

[0032] Each connector 130 has an internal channel 131 that is in fluid communication with the cylinders 110. The connectors extend from a carrier plate 125 that is fixed to the device housing. The head device in the depicted example has a pipetting capacity of 1000 .Math.L for each pipetting channel.

[0033] An example of a disposable tip 200 is shown in FIG. 2a. The disposable tip has an orifice 210 at one end, through which liquid is aspirated and dispensed. A collar 220 is provided at the opposite end and the disposable tip has central passageway 230. The disposable tips are precision-manufactured, typically in an injection moulding process. An upper surface of the collar 220s is perpendicular to a centre axis X of the disposable tip and the tip 200 is rotationally symmetric about this axis. Therefore, when the upper surface 220s of the collar is in contact with a planar surface, the centre axis X of each disposable tip will be perpendicular to the planar surface.

[0034] Typically, an array of disposable tips 200 are held in a suitable tray 250 arranged in a box 260, such as shown in FIG. 2b. A top surface of the tray 250 has an array of openings, whereby an underside of the collar of each disposable tip 200 is supported on the tray top surface. The connectors 130 are arranged in a corresponding array and the disposable tips are attached by lowering the head device 100, such that each connector extends into the central passageway 230 of each disposable tip 200 and establishes a sealing connection therewith. Accordingly, a peripheral end of each connector has a seat that supports a radial seal 140 made of an elastomeric material such as NBR or other suitable elastomer. Suitably, the seat 135 (refer FIG. 3a) is formed by a cylindrical portion of the connector 130, which has a relatively smaller outer diameter than adjacent portions in the z-direction, such that the seal 140 is axially retained on the connector. After the array of disposable tips has been used, they are detached from their respective connectors 130 by a moveable plate 150 of the device 100 that is displaceable relative to the connectors 130 in vertical direction z.

[0035] As may be better seen in FIG. 1c, which shows a perspective view of the underside of the apparatus 100, the connectors 130 extend through corresponding openings in the moveable plate 150. In accordance with an embodiment of the invention, the moveable plate is not only used to detach the disposable tips from the connectors, but is additionally used for alignment of the tips after attachment. This will be explained in more detail with reference to FIGS. 3a – 3e and the moveable plate 150 will be referred to as an alignment plate.

[0036] FIG. 3a schematically shows an individual connector 130 being lowered (indicated by arrow 301) into the internal passageway 230 of a disposable tip 200 having a collar 220 that is supported on an upper surface of a tray 250 that surrounds an opening in the tray. The dimensions and location of each disposable tip are precisely known and the connectors are lowered by an amount that should bring an upper surface 220s of the disposable tip collar 220 into contact with an underside 150s of the alignment plate 150. When the head device is lowered to pick up the array of disposable tips, there is no movement of the alignment plate 150 relative to the connectors 130. The alignment plate is in a stop position, and the plate underside 150s is intended to serve as a backstop for each disposable tip collar 220.

[0037] In the depicted example, the seal 140 has an upper flange 145 with an outside diameter that is somewhat larger than an internal diameter of the disposable tip internal passageway 230. As shown in FIG. 3b, the flange part 145 of the seal deforms in the direction indicated by arrows 302 when the connector 130 is inserted into the internal passageway 230 and establishes a sealed connection. The attachment between each connector and the corresponding disposable tip is established purely by the frictional engagement between the seal flange 145 and the interior surface of the internal passageway 230.

[0038] It can happen that the seal 140 relaxes after it has been deformed as indicated by the arrows 303 in FIG. 3c. Due to the frictional engagement between the seal and the interior of the internal passageway, this causes a displacement of the disposable tip and disposable tip collar 220 away from the plate underside 150s in vertical direction z, such that a gap G is created. It is possible for the created gap G to be different between different disposable tip collars, such that the orifices of the disposable tips are not in alignment in z-direction. Variations in the gap G in z-direction can also be attributable to the variable stiffness of the tray 250 that holds the disposable tips. When the connectors are inserted, it is possible for this to cause greater deformation in a central region of the tray that at the tray sides, such that the underside 150s of the alignment plate does not in fact serve as a backstop for all of the disposable tips during the initial pick-up action.

[0039] It is also possible for the created gap G to be uneven such that the upper surface 220s of a tip collar is not parallel to the plate underside 150s. This can lead to misalignment of the tip orifice in x- and/or y-direction relative to the centre axis X.

[0040] As shown in FIG. 3d, the apparatus of the invention is configured to close any created gap by moving the alignment plate 150 downward relative to the connectors 130 (as indicated by arrow 304), The amount of this first movement in vertical direction z is small, e.g. 0.1 mm to 2.0 mm, and is suitably calibrated based on tests performed with the multi-channel head and the tip support tray being used. In the depicted example, the amount of movement in the alignment action is approximately 0.6 mm. The downward movement brings the underside of the plate 150s into contact with the disposable tip collar 220, such that the orifice 210 of all attached disposable tips are in alignment with each other and are in alignment relative to the centre axis X.

[0041] As explained earlier, alignment in z-direction is advantageous for reducing dead volume, when aspirating liquid, and for contact dry dispensing of droplets. Alignment in x- and y-directions is important when the orifices of the disposable tips are inserted into a microplate, such as a 384-well microplate, whereby adjacent wells in the microplate have a relatively small centre-to-centre distance. The head depicted in the drawings is a 96-channel head. As a result of the alignment action, such a multi-channel head may be used with accuracy and reliability not only in combination with a 96-well microplate, but also in combination with a 384-well microplate.

[0042] In a further embodiment, the head includes 384 connectors and can be used in combination with a 384-well microplate and a 1156-well microplate.

[0043] After use of the disposable tips, they are detached from the connectors 130 by a second, larger downward movement of the alignment plate 150 relative to the connectors 130, as shown in FIG. 3e. The plate 150 exerts an axial force on the upper surface 220s of the collar that is sufficient to overcome the frictional engagement between the seal 140 and the internal passageway 230 and the extent of the movement L in vertical direction z is sufficient to push off the disposable tip 200 from the connector 130. In the depicted example, the alignment plate is moved approximately 12 mm in the release action.

[0044] A preferred mechanism for actuating the alignment plate 150 will now be described. The alignment plate is supported relative to a housing of the device 100 via a first and a second spindle arrangement. The first spindle 170a is shown in FIG. 1b; the second spindle 170b is visible in FIG. 1a. Each arrangement is identical and will be described in detail with reference to the first arrangement. The first spindle 170a is rotationally supported by first and second bearings 171, 172, so as to be rotational about a vertical rotation axis. This first and second bearings 171, 172 may be e.g. a ball bearing whereby an outer ring of each bearing is mounted to a fixed part of the device and the inner ring is connected to the spindle 170a. The arrangement further comprises a spindle nut 175, which may be a ball screw, a roller screw or a plain spindle nut. The alignment plate 150 is fixedly connected to the spindle nut 175. In the depicted example, a first end of four rods 177a, 117b, 177c, 177d are connected to the alignment plate 150. The rods extend through a respective opening in a further plate of the device, which is known as an isolation plate 128, and a second end of the rods are fixedly attached to a collar part 176, which in turn is fixedly attached to the spindle nut 175. The spindle nut is unable to rotate, meaning that driven rotation of the spindle 170a causes linear translation of the spindle nut 175 and the attached alignment plate 150.

[0045] The rotational drive is provided by a second motor 180, together with a second belt and pulley system. The second motor 180 may be a DC motor or a stepper motor and is mounted on the isolation plate 128, whereby an output shaft of the motor extends through an underside thereof and is coupled to a first pulley sheave 181. The first and second spindles 170a, 170b extend through the isolation plate 128 and are likewise coupled to their own respective pulley sheave 185a, 185b which are rotated by a belt 190 of the pulley system. As will be understood, the pulley system comprises a number of suitably arranged idlers 187 mounted to the underside of the insolation plate 128 which interconnect the belt in a circuit that enables the spindle pulley sheaves 185a and 185b to be rotated by the driven pulley sheave 181.

[0046] An advantage of driving the spindles via a pulley and belt system is that the second displacement mechanism exhibits minimal backlash and is thus suitable for performing the precision alignment movement of the alignment plate.

[0047] An example of a liquid handling apparatus comprising an inventive multi-channel head device 100 is shown in FIG. 4. The apparatus 400 has a robotic arm 420 which is movable in x-direction relative to a frame 410 of the apparatus. The multi-channel head device 100 is mounted to the robotic arm via a system of actuators that enable the multi-channel head to be moved relative to the arm 420 in x- and z-directions. The apparatus 400 further comprises a controller 450, which may be external or integrated in the apparatus and is suitably programmed to control the position of the head device 100 such that an array of attached disposable tips 200 can be inserted into the wells of a multi-well microplate 430. The controller may also be configured to control the pipetting mechanism of the multi-channel head and to control the second motor 180 that drives the spindles 170a, 170b for displacing the alignment plate 150 of the device 100.

[0048] Suitably, the apparatus controller 450 is configured to execute steps of an inventive method of picking up and aligning an array of disposable tips using a multi-channel head device 100 comprising an array of connectors for receiving the disposable tips, whereby a peripheral end of each connector is provided with a seat 135 on which an elastomeric seal 140 is arranged that surrounds an outer circumference of the connector, and whereby the connectors 130 extend through an alignment plate 150 that is moveable relative to the connectors in z-direction. The method comprises steps of: [0049] lowering the multi-channel head 100 in z-direction, with the alignment plate 150 in a stop position, so as to insert the connectors into an internal passageway 230 of the corresponding disposable tip 200, by an amount sufficient to bring the upper surface 220s of the tip collar 220 into contact with the underside 150s of the alignment plate, whereby said insertion deforms the elastomeric seal against the disposable tip internal passageway 230 so as to form a sealing contact therewith that provides the sole attachment force between each disposable tip and the respective connector; [0050] raising the multi-channel head so as to pick up the array of disposable tips 200 and remove them from a holder 250 on which they are supported; and [0051] aligning the disposable tips by displacing the alignment plate 150 in z-direction, relative to the connectors 130, from the stop position by a first amount which is sufficient to close any gap G between the underside 150s of the alignment plate and the upper surface 220s of the tip collars, which exists due to relaxation of the deformed elastomeric seals 140 and/or due to small positional variations in z-direction when the disposable tips are picked up from the holder.

[0052] In an embodiment, the method comprises a further step of detaching each disposable tip from the corresponding connector 130 by displacing the alignment plate 150 in z-direction relative to the connectors 130 by a second amount, which is sufficient to push off the disposable tips 200 from the corresponding connectors. The first amount of displacement in the alignment action is significantly smaller than the second amount of displacement in the release action.

[0053] Examples, embodiments or optional features, whether indicated as non-limiting or not, are not to be understood as limiting the invention as claimed. It should be noted that the above-mentioned embodiments illustrate rather than limit the invention, and that those skilled in the art will be able to design many alternative embodiments without departing from the scope of the appended claims.

[0054] In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. Use of the verb “comprise” and its conjugations does not exclude the presence of elements or steps other than those stated in a claim. The article “a” or “an” preceding an element does not exclude the presence of a plurality of such elements. The invention may be implemented by means of hardware comprising several distinct elements, and by means of a suitably programmed computer. In the device claim enumerating several means, several of these means may be embodied by one and the same item of hardware. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

LIST OF REFERENCES AND ABBREVIATIONS

[0055] The following list of references and abbreviations is provided for facilitating the interpretation of the drawings and shall not be construed as limiting the claims.

TABLE-US-00001 100 multi-channel head device 102 spindles of 1.sup.st displacement mechanism 103 pulley drive of 1.sup.st displacement mechanism 105 1.sup.st motor 110 cylinder block 115 pistons 120 piston plate 125 carrier plate for connectors 128 isolation plate 130 connectors 131 internal channel through each connector 135 seat on connector for radial seal 140 radial seal 145 flange part of radial seal 150 alignment plate 150s lower surface of alignment plate 170a, 170b 1.sup.st & 2.sup.nd spindles of 2.sup.nd displacement mechanism 171, 172 1.sup.st and 2.sup.nd bearings for rotationally supporting each spindle 175 spindle nut 176 collar part fixed to spindle nut 177a – 177d rods connecting alignment plate to collar part 180 2.sup.nd motor for driving 2.sup.nd displacement mechanism 181 pulley sheave attached to output shaft of 2.sup.nd motor 185a, 185b pulley sheave attached to end of 1.sup.st & 2nd spindles respectively 187 idlers 190 pulley belt 200 disposable tip 210 tip orifice 220 upper collar of disposable tip 220s upper surface of tip collar 230 internal passageway through disposable tip 250 tray for holding an array of disposable tips 260 box for supporting disposable tip tray 400 liquid handling apparatus 410 Frame part of apparatus 420 robotic arm 430 multi-well microplate G gap between underside of alignment plate in stop position and upper surface of tip collar, after execution of the pick-up action L displacement in z-direction of alignment plate from aligned position to a release position in which a disposable tip is pushed off a connector z vertical direction y transverse direction x longitudinal direction (perpendicular to z and y) X centre axis of a disposable tip