Patent Application
20230241600
The invention relates to a multi-channel head of a liquid handling apparatus for picking up array of disposable tips, dispensing a metered amount of liquid therewith and then detaching the disposable tips after use. The multi-channel head includes a movable plate through which an array of connectors extend, whereby the plate is driven by a separate actuator and is used as a backstop when picking up the disposable tips.
An example of a device with such a moveable plate is known from US 2019/0314808. 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 1st 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 2nd 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 US 10898892, 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.
It is an object of the invention to provide a multi-channel head device 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 multi-channel head device of a liquid handling apparatus 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 further equipped with a motor for driving the linear displacement mechanism and a controller, in communication with the motor, for controlling the position of the alignment plate in z-direction. The head device is configured to attach 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 controller of the multi-channel head device is programmed 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. 0.1 – 2.0 mm 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 controller of the head device is further programmed 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. The second amount of linear displacement associated with the release action is significantly greater than the first amount of linear displacement associated with the alignment action.
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 384-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 96-channel head and a tray holding 96 disposable tips, a suitable displacement of the alignment plate relative to the connectors for alignment purposes is approximately 0.6 mm. When the alignment plate is moved in the release action, a typical displacement is in the region of 10.0 – 15.0 mm.
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 96 connectors. In other embodiments, the multi-channel head comprises 384 connectors. In still further embodiments, the multi-channel head comprises 1536 connectors.
It will be appreciated by those skilled in the art that two or more of the above-mentioned embodiments, implementations, and/or aspects of the invention may be combined in any way deemed useful.
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. 0.1 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.
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.
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 µL for each pipetting channel.
An example of a disposable tip 200 is shown in
Typically, an array of disposable tips 200 are held in a suitable tray 250 arranged in a box 260, such as shown in
As may be better seen in
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
It can happen that the seal 140 relaxes after it has been deformed as indicated by the arrows 303 in
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.
As shown in
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.
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.
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
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
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.
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 100 is shown in
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:
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.
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.
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.
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.
100 multi-channel head device
102 spindles of 1st displacement mechanism
103 pulley drive of 1st displacement mechanism
105 1st 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
150
s lower surface of alignment plate
170
a, 170b 1st & 2nd spindles of 2nd displacement mechanism
171, 172 1st and 2nd bearings for rotationally supporting each spindle
175 spindle nut
176 collar part fixed to spindle nut
177
a – 177d rods connecting alignment plate to collar part
180 2nd motor for driving 2nd displacement mechanism
181 pulley sheave attached to output shaft of 2nd motor
185
a, 185b pulley sheave attached to end of 1st & 2nd spindles respectively
187 idlers
190 pulley belt
200 disposable tip
210 tip orifice
220 upper collar of disposable tip
220
s 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
| Number | Date | Country | Kind |
|---|---|---|---|
| 21217461.9 | Dec 2021 | EP | regional |
