Patent Description:
An example of a device with such a moveable plate is known from <CIT>. The device comprises a carrier having parallel attachments that extend through the moveable plate. Each attachment is adapted to fit in a pipette tip opening and has a tube with a supporting protrusion, an O-ring surrounding the tube, and a sleeve that is axially movable on the tube between a release position and a clamping position in which the sleeve compresses and expands the O-ring. The device comprises a <NUM>st displacement mechanism for displacing a push plate in axial direction, which in turn acts on the sleeve of each attachment. The moveable plate through which the attachments extend also serves as an ejector plate and is driven by a <NUM>nd displacement mechanism for moving said plate between a stop position and an ejection position. The second displacement mechanism has rocker arms pivotably mounted on the carrier, transmission shafts that are coupled to the sleeves, and ejection shafts which are securely connected to the ejector plate.

Disposable tips are picked up by thrusting the attachments into an opening in the tip, when the stop plate is in a stop position and serves as backstop. The push plate is then actuated to displace the sleeves to the clamping position, in which the O-rings are expanded in order to securely clamp the disposable tips to the attachments. A disadvantage of such a system comprising attachments with actuatable elements is that an additional actuator is required, thereby increasing the complexity of the apparatus.

A pipette tip coupler is known from <CIT>, which also makes use of an expandable O-ring. The coupler is configured for use with specialised disposable tips, which comprise an annular groove into which the O-ring is expanded. The advantage of such a combination is that the disposable tips are not only securely clamped, but are also precisely aligned in axial direction. <CIT> also discloses a prior art liquid handling apparatus comprising a multi-channel head.

It is an object of the invention to provide a liquid handling apparatus comprising a multi-channel head of straightforward construction that can reliably pick up an array of disposable tips, and is furthermore configured to ensure precise alignment of the disposable tips during use.

The present invention resides in a liquid handling apparatus according to claim <NUM>, said liquid handling apparatus comprising a multi-channel head for aspirating and dispensing a metered amount of liquid via an array of disposable tips. The head device further comprises a carrier plate on which an array of connectors are arranged for picking up the correspondingly arranged array of disposable tips. 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. The device further comprises an alignment plate having an array of openings through which the connectors extend, and a linear displacement mechanism for moving the alignment plate in a direction z, parallel to a centre axis of the disposable tips, relative to the connectors. The head device is configured for attaching the array of disposable tips in a pick-up action, in which the alignment plate is in a stop position and the disposable tips are attached to the respective connectors by inserting the connectors into an internal passageway of the disposable tips by an amount sufficient to bring an upper 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.

According to the invention, the head device is further configured such that once the pick-up action is complete, an alignment action is performed in which the linear displacement mechanism moves the alignment plate in z-direction, relative to the connectors, by a first amount which is sufficient to close any gap between the underside of the alignment plate and the upper collar of the disposable tips, which exists due to relaxation of the deformed elastomeric seals or due to small positional variations in z-direction when the disposable tips are picked up from a holder.

The alignment action is a precision movement of e.g. <NUM> - <NUM> which ensures that during use of the disposable tips, the upper collar of each tip is in contact with the underside of the alignment plate. The disposable tips are precision-manufactured such that the collar upper surface is precisely perpendicular to the centre axis, meaning that when there is contact between plate underside and the collar surface, an orifice of each tip, through which liquid is aspirated and dispensed, is in alignment with the orifices of other disposable tips not only in z-direction (vertical direction), but also in longitudinal direction x and transverse direction y.

The apparatus of the invention thus enables tip pick-up and alignment without the need for a mechanism that directly acts on the seal to compress and deform it after the connectors have been inserted into the internal passageway of the corresponding disposable tips.

In an advantageous embodiment, the alignment plate also serves as an ejection plate and the head device is further configured to execute a release action in which the disposable tips are detached by actuating the linear displacement mechanism, so as to displace the alignment plate relative to the connectors in z direction by a second amount that is sufficient to push off each disposable tip from the corresponding connector.

Prior to use, the disposable tips are typically supported on a holder such a tray having openings on which an underside of the tip collar rests. Suitably, the multi-channel head of the apparatus is moveable in x, y and z directions and, as part of the pick-up action, is moved to a position above the holder such that the array of connectors are aligned with the array of disposable tips. The dimensions and position of the disposable tips is precisely known and the apparatus is suitably configured to lower the head towards the holder, such that the connectors are inserted into the disposable tips. The head is lowered with the alignment plate in a stop position and there is no relative movement between the connectors and the alignment plate during the pick-up action. The distance by which the head is lowered is pre-programmed based on the known dimensions and position of the disposable tips, and is an amount which will, in principle, bring the underside of the alignment plate into contact with the upper surface of each disposable tip collar.

In practice, it can happen that due to the flexibility of the disposable tip holder and differences in relative stiffness between the centre of the holder and edges of the holder, not all disposable tips come into contact with the underside of the alignment plate during the pick-up action, leading to misalignment between the tips in z-direction and possibly also in x- and y-directions. Furthermore, as a result of the pick-up action in which the elastomeric seal of each connector is deformed so as to form a sealing contact with the disposable tip internal passageway, the deformed seal may subsequently relax, causing a movement of the disposable tip relative to its connector in z-direction. This further contributes to tip misalignment in z-direction and can also lead to tip misalignment in x- and y- directions when the extent of the relaxation is uneven and the upper surface of the collar is not parallel with the underside of the alignment plate.

Tip alignment in x and y direction is particularly important when the multi-channel head and attached disposable tips are configured for use with microplates having a large number of wells with a small centre-to-centre distance between adjacent wells, such as a <NUM>-well microplate. Alignment in z-direction is also advantageous, as it minimises dead volume in reagent troughs and enables precision dispensing of liquid droplets in which the orifice of each disposable tip is arranged just above the bottom of an empty well, but is not in contact therewith. The liquid is dispensed slowly forming a droplet at the orifice of the disposable tip and contacting the bottom of the well. Subsequently, the multi-channel head retracts slowly putting the droplet down to the bottom of the well. This is sometimes referred to as contact dry dispensing.

As will be understood, the multi-channel pipetting head of the invention comprises a pipetting mechanism for aspirating and dispensing liquid via the disposable tips. In some embodiments, the pipetting mechanism comprises a cylinder block and an arrangement of pistons coupled to a piston plate. Typically, the piston plate is moveable in z-direction and may be connected to a spindle nut associated with two or more spindles. An electric motor may be provided to drive at least one of the spindles via a belt and pulley system. In other examples, the piston plate may be mounted on linear guides and driven by linear actuators. It is also possible for the multi-channel head to comprise an air-based pipetting mechanism whereby pipettors are connected to a source of vacuum / pressures in order to aspirate and dispense liquid.

A separate motor and a separate displacement mechanism are provided for automated movement of the alignment plate.

The precision downward movement of the alignment plate relative to the connectors, which constitutes the alignment action, is programmed to close any gap that exists after pick-up. The programmed distance is selected based on tests conducted using the multi-channel head, with the specific type of seals that are mounted to the connectors, in combination with the disposable tips and the holder that will be used to support them. As mentioned, the amount of the movement is small. In tests conducted using a <NUM>-channel head and a tray holding <NUM> disposable tips, a suitable displacement of the alignment plate relative to the connectors for alignment purposes is approximately <NUM>. When the alignment plate is moved in the release action, a typical displacement is in the region of <NUM> - <NUM>.

The linear displacement mechanism that drives the alignment plate must therefore be capable of relatively large movements, as well as precise, small displacements. In a preferred embodiment, the alignment plate is supported relative to the carrier plate, which forms a fixed part of the multi-channel head, via an arrangement of first and second spindles or leadscrews. Each spindle is rotationally supported via first and second bearings and comprises a spindle nut which may be a ball screw, a roller screw, or plain spindle nut. The alignment plate is coupled to the spindle nut of each spindle arrangement, preferably via a number of rods that extend through the carrier plate. A peripheral end of each spindle extends beyond the carrier plate and is coupled to a pulley sheave. The second motor is mounted to a fixed part of the multi-channel head, whereby an output shaft of the second motor extends beyond the carrier plate and is likewise coupled to a pulley sheave. The pulley sheaves form part of a belt and pulley system for rotating the spindles via rotation of the driven pulley sheave. A geared arrangement is also possible. Other suitable types of linear actuator may also be used to move the alignment plate relative to the connectors.

The connectors that extend from the carrier plate have an internal channel and may be essentially cylindrical in shape or may be somewhat conical, tapering towards the peripheral end where the seat for the seal is arranged. Suitably, the seat is formed by a cylindrical portion which has a smaller diameter relative to sections of the connector at either side in z-direction, such that the seal is axially retained on the connector. In a preferred embodiment, the seal comprises a cylindrical part and a flange part, whereby the flange part deforms when a connector is pushed into a disposable tip. In other examples, the seal may be an O-ring or an X-profile ring. The seal may be made from any suitable elastomeric material, such as NBR (Nitrile Butadiene Rubber), EPDM (Ethylene Propylene Diene Monomer rubber), silicone rubber etc..

In some embodiments, the multi-channel head comprises an array of <NUM> connectors. In other embodiments, the multi-channel head comprises <NUM> connectors. In still further embodiments, the multi-channel head comprises <NUM> connectors.

A multi-channel head according to the invention enables reliable and secure pick-up and precision alignment of disposable tips in a straightforward manner, without the need for a separate mechanism that acts directly on the seal. As a result of the accurate alignment, the multi-channel head may be used for precision dispensing of small amounts of e.g. <NUM>µL. These and other aspects of the invention are apparent from and will be elucidated with reference to the embodiments described hereinafter and with reference to the accompanying drawings.

The invention is also directed to a method of picking up and aligning an array of disposable tips using a liquid handling apparatus according to claim <NUM>.

It should be noted that items which have the same reference numbers in different figures, have the same structural features and the same functions.

<FIG> show views of a multi-channel head device <NUM> 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 <NUM>, arranged at an underside of the head device. Liquid is aspirated and then dispensed with the aid of a block of cylinders <NUM>, each one equipped with a piston <NUM> that is connected to a piston plate <NUM>. 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 <NUM> (refer <FIG>). In the depicted example, the first displacement mechanism comprises an arrangement of three spindles <NUM>, which are driven in a known manner by a belt and pulley system (generally indicated with reference numeral <NUM>).

Each connector <NUM> has an internal channel <NUM> that is in fluid communication with the cylinders <NUM>. The connectors extend from a carrier plate <NUM> that is fixed to the device housing. The head device in the depicted example has a pipetting capacity of <NUM>µL for each pipetting channel.

An example of a disposable tip <NUM> is shown in <FIG>. The disposable tip has an orifice <NUM> at one end, through which liquid is aspirated and dispensed. A collar <NUM> is provided at the opposite end and the disposable tip has central passageway <NUM>. The disposable tips are precision-manufactured, typically in an injection moulding process. An upper surface of the collar <NUM> is perpendicular to a centre axis X of the disposable tip and the tip <NUM> is rotationally symmetric about this axis. Therefore, when the upper surface <NUM> 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.

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

As may be better seen in <FIG>, which shows a perspective view of the underside of the apparatus <NUM>, the connectors <NUM> extend through corresponding openings in the moveable plate <NUM>. 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 <FIG> and the moveable plate <NUM> will be referred to as an alignment plate.

<FIG> schematically shows an individual connector <NUM> being lowered (indicated by arrow <NUM>) into the internal passageway <NUM> of a disposable tip <NUM> having a collar <NUM> that is supported on an upper surface of a tray <NUM> 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 <NUM> of the disposable tip collar <NUM> into contact with an underside <NUM> of the alignment plate <NUM>. When the head device is lowered to pick up the array of disposable tips, there is no movement of the alignment plate <NUM> relative to the connectors <NUM>. The alignment plate is in a stop position, and the plate underside <NUM> is intended to serve as a backstop for each disposable tip collar <NUM>.

In the depicted example, the seal <NUM> has an upper flange <NUM> with an outside diameter that is somewhat larger than an internal diameter of the disposable tip internal passageway <NUM>. As shown in <FIG>, the flange part <NUM> of the seal deforms in the direction indicated by arrows <NUM> when the connector <NUM> is inserted into the internal passageway <NUM> 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 <NUM> and the interior surface of the internal passageway <NUM>.

It can happen that the seal <NUM> relaxes after it has been deformed as indicated by the arrows <NUM> in <FIG>. 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 <NUM> away from the plate underside <NUM> 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 <NUM> 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 <NUM> of the alignment plate does not in fact serve as a backstop for all of the disposable tips during the initial pick-up action.

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

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

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 <NUM>-well microplate, whereby adjacent wells in the microplate have a relatively small centre-to-centre distance. The head depicted in the drawings is a <NUM>-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 <NUM>-well microplate, but also in combination with a <NUM>-well microplate.

In a further embodiment, the head includes <NUM> connectors and can be used in combination with a <NUM>-well microplate and a <NUM>-well microplate.

After use of the disposable tips, they are detached from the connectors <NUM> by a second, larger downward movement of the alignment plate <NUM> relative to the connectors <NUM>, as shown in <FIG>. The plate <NUM> exerts an axial force on the upper surface <NUM> of the collar that is sufficient to overcome the frictional engagement between the seal <NUM> and the internal passageway <NUM> and the extent of the movement L in vertical direction z is sufficient to push off the disposable tip <NUM> from the connector <NUM>. In the depicted example, the alignment plate is moved approximately <NUM> in the release action.

A preferred mechanism for actuating the alignment plate <NUM> will now be described. The alignment plate is supported relative to a housing of the device <NUM> via a first and a second spindle arrangement. The first spindle 170a is shown in <FIG>; the second spindle 170b is visible in <FIG>. 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 <NUM>, <NUM>, so as to be rotational about a vertical rotation axis. This first and second bearings <NUM>, <NUM> 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 <NUM>, which may be a ball screw, a roller screw or a plain spindle nut. The alignment plate <NUM> is fixedly connected to the spindle nut <NUM>. In the depicted example, a first end of four rods 177a, 117b, 177c, 177d are connected to the alignment plate <NUM>. The rods extend through a respective opening in a further plate of the device, which is known as an isolation plate <NUM>, and a second end of the rods are fixedly attached to a collar part <NUM>, which in turn is fixedly attached to the spindle nut <NUM>. The spindle nut is unable to rotate, meaning that driven rotation of the spindle 170a causes linear translation of the spindle nut <NUM> and the attached alignment plate <NUM>.

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

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.

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

Suitably, the apparatus controller <NUM> 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 <NUM> comprising an array of connectors for receiving the disposable tips, whereby a peripheral end of each connector is provided with a seat <NUM> on which an elastomeric seal <NUM> is arranged that surrounds an outer circumference of the connector, and whereby the connectors <NUM> extend through an alignment plate <NUM> that is moveable relative to the connectors in z-direction. The method comprises steps of:.

In an embodiment, the method comprises a further step of detaching each disposable tip from the corresponding connector <NUM> by displacing the alignment plate <NUM> in z-direction relative to the connectors <NUM> by a second amount, which is sufficient to push off the disposable tips <NUM> 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.

Examples, embodiments or optional features, whether indicated as non-limiting or not, are not to be understood as limiting the invention as claimed.

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