PIPETTING HEAD FOR A LIQUID DISPENSING APPARATUS

A pipetting head for a liquid dispensing apparatus is provided. The pipetting head has a pipette tip clamping mechanism and a plunger clamping mechanism. The pipette tip clamping mechanism and the plunger clamping mechanism each include a mounting plate having a plurality of mounts, a clamping plate having a plurality of clamping members each associated with one of the mounts, and a drive mechanism comprising an actuator operable to drive relative movement between the clamping plate and the mounting plate in an axial direction to selectively engage the clamping mechanism. The pipetting head further includes a drive actuator operable to move the plunger clamping mechanism in the axial direction towards or away from the plates of the pipette tip clamping mechanism to aspirate or dispense liquid during use. The drive actuator is configured to operate independently of the pipette tip clamping drive mechanism and the plunger clamping drive mechanism.

FIELD OF THE INVENTION

The present invention relates to a pipetting head for a liquid dispensing apparatus, in particular to a pipetting head having a pipette tip clamping mechanism and a plunger clamping mechanism by which a pipette with a pipette tip and a plunger can be securely mounted to the pipetting head.

BACKGROUND OF THE INVENTION

It is known to use a pipette to aspirate or dispense a liquid sample.

It is also known to use a pipette having a plunger disposed in a pipette tip. A typical pipette, known as a “positive displacement” pipette, uses a plunger or piston to aspirate or dispense liquid either through direct contact with the sample liquid or via a small air gap. During use, the pipette tip and plunger are mounted on a pipetting head of a liquid dispensing apparatus, which drives the plunger relative to the tip to aspirate or dispense liquid from an aperture at the distal end of the pipette tip. Such pipettes can be used in automated machines to improve accuracy and repeatability of pipetting actions

The inventors have identified several problems with the manner in which pipettes are connected with known pipetting heads for liquid dispensing apparatuses.

There is a need for an improved pipetting head.

SUMMARY OF THE INVENTION

A first aspect of the invention provides a pipetting head for a liquid dispensing apparatus for use with an array of pipettes each having a pipette tip and a plunger disposed within the pipette tip, the pipetting head comprising: a pipette tip clamping mechanism for connecting to and clamping the pipette tips of the array of pipette during use; and a plunger clamping mechanism for connecting to and clamping the plungers of the array of pipettes during use, wherein the pipette tip clamping mechanism comprises: a pipette tip mounting plate having a plurality of pipette tip mounts each configured to couple with one of the pipette tips during use; a pipette tip clamping plate having a plurality of pipette tip clamping members each associated with one of the plurality of pipette tip mounts; a pipette tip clamping drive mechanism comprising an actuator operable to drive relative movement between the pipette tip clamping plate and the pipette tip mounting plate in an axial direction to selectively engage the pipette tip clamping mechanism by moving it between a clamp position and a release position, wherein the plunger clamping mechanism comprises: a plunger mounting plate having a plurality of plunger mounts each configured to couple with one of the plungers during use; a plunger clamping plate having a plurality of plunger clamping members each associated with one of the plurality of plunger mounts; a plunger clamping drive mechanism comprising an actuator operable to drive relative movement between the plunger clamping plate and the plunger mounting plate in the axial direction to selectively engage the plunger clamping mechanism by moving it between a clamp position and a release position, wherein the pipetting head further comprises a drive actuator operable to move the plunger clamping mechanism in the axial direction towards or away from the plates of the pipette tip clamping mechanism to aspirate or dispense liquid during use, the drive actuator being configured to operate independently of the pipette tip clamping drive mechanism and the plunger clamping drive mechanism.

This provides an extremely compact arrangement with which a large number of pipettes can be accurately and securely mounted to the pipetting head. This is of particular benefit in liquid dispensing apparatuses intended for use with standard 384 well plates, since the compact arrangement can allow 384 mounting collars and locking members to be provided to hold 384 pipettes in a 16×24 matrix. This enables liquid to be aspirated from or dispensed into a conventional 384 well plate in a single action. As used herein, the terms “clamping” and “clamp” refers to arrangements by which the pipette tip or plunger or both are both mounted and locked in place to prevent inadvertent removal. This is in contrast to arrangements in which the pipette tip or plunger are mounted without locking, for example using an interference fit or a snap-fit connection in which the pipette tip or plunger can be removed simply by pulling in an axial direction. The clamping arrangements can also improve the accuracy of aspirating and dispensing operations by preventing small relative movements that might otherwise occur between the pipetting head and the plunger or the pipette tip.

Furthermore, by providing an independently operated drive actuator for dispensing or aspirating operations, a greater variety of plunger speeds can be achieved, enabling the pipetting head to be operated precisely in both a contact dispensing mode and in a non-contact dispensing mode. This is in contrast with some known liquid handling devices in which the pipette tips and plungers are coupled to plates which are positioned along a common set of threaded rods and may only be moved relatively slowly relative to each other along the common rods.

With an independently operated drive actuator, the plunger clamping mechanism—and thus any plunger mounted thereon—can be moved relative to the pipette tip clamping mechanism to perform aspiration and dispense operations independently of the mechanisms by which the pipette tip clamps and plunger clamps are operated. The distance travelled by the plunger for a dispense shot can be small, for example in the range of 1 mm or less. Consequently, high levels of acceleration/deceleration are needed in order to reach the target velocity for non-contact dispensing. The independently operated drive actuator can be configured to accelerate and decelerate the plunger clamping mechanism at sufficiently high rates for both non-contact dispensing and contact dispensing to be possible using the same mechanism.

The term “operate independently” refers to arrangements in which the drive actuator comprises a drive mechanism separate to those of the pipette tip clamping drive mechanism and the plunger clamping drive mechanism. This allows that drive mechanism to be set according to the desired acceleration and deceleration characteristics for dispensing and aspirating operations, rather than according to the desired clamping characteristics, or forming some compromise between those characteristics. This is in direct contrast to arrangements in which the pipette tips and plungers are mounted to plates arranged along common threaded rods. In those arrangements, all of the drive mechanisms, including those of the actuator by which dispensing operations are controlled, must operate on the same thread pitch. Those arrangements may also require that the movement of the plates is synchronised in order to perform a dispensing operation. This can necessitate more complex control to ensure accurate dispensing and to prevent jamming.

The drive actuator may be an indirect drive actuator, for example comprising a motor driven belt or chain by which the plunger clamping mechanism is moved relative to the pipette tip clamping mechanism. Preferably, the drive actuator is a direct drive actuator. As used herein, the term “direct drive actuator” refers to a drive mechanism comprising a motor which is either coupled directly to the plunger clamping mechanism, or coupled to the plunger clamping mechanism via a rotationally rigid coupling. Throughout the description, the term “direct drive actuator” is used to refer to both a directly coupled arrangement and an arrangement in which the motor is coupled to the plunger clamping mechanism via a rotationally rigid coupling. The use of a direct drive actuator minimises the rotational play between the plunger clamping mechanism and the motor. This enables movement of the plunger clamping mechanism to be started and stop quickly and accurately. This is in contrast to indirect drive mechanisms in which the motor is coupled to the plunger via one or more belts or chains.

The drive actuator may be a ball screw actuator comprising a motor which is fixed in relation to a chassis of the pipetting head and a ball screw by which the motor is coupled to the plunger clamping mechanism to drive movement of the plunger clamping mechanism in the axial direction relative to both the chassis and the pipette tip clamping mechanism.

The direct drive arrangement, for example via a ball screw, has been found to offer higher levels of acceleration/deceleration of heavy loads than a belt driven system, thus enabling non-contact dispensing of low volume liquid samples. Furthermore, a direct drive arrangement offers higher positional accuracy and repeatability than an equivalent belt drive mechanism. This can have a significant impact on dispense performance.

The plunger clamping drive mechanism preferably comprises a plurality of guide rods by which the plunger clamping plate is connected to the plunger mounting plate and along which the plunger clamping plate and the plunger mounting plate are moveable in the axial direction relative to each other by the actuator of the plunger clamping mechanism. The plurality of guide rods are preferably moveable together with the plunger clamping plate and the plunger mounting plate in the axial direction by the drive actuator towards and away from the plates of the pipette tip clamping mechanism. This can help to keep the plates parallel. For example, the plurality of guide rods may comprise a four guide rods positioned in the four corners of the plunger clamping and plunger mounting plates. In other embodiments, the plunger clamping drive mechanism may comprise a plurality of actuators located at different positions around the periphery of the plunger clamping mechanism and which are configured to operate together.

The plunger clamping drive mechanism may comprise any suitable mechanism for driving relative movement in the axial direction between the plunger clamping plate and the plunger mounting plate when the actuator of the plunger clamping drive mechanism is operated. For example, the plunger clamping drive mechanism may comprise a threaded shaft connected to the actuator of the plunger clamping drive mechanism which extends through a threaded aperture which is fixed in relation to one of the plunger mounting plate and the plunger clamping plate such that the threaded shaft drives relative movement between the plunger clamping plate and the plunger mounting plate in the axial direction when rotated by the actuator. The threaded output shaft of the plunger clamping drive mechanism may be moveable in the axial direction independently of the pipette tip clamping mechanism

The entire plunger clamping drive mechanism may be moveable together with the plunger clamping plate and the plunger mounting plate in the axial direction by the drive actuator towards and away from the plates of the pipette tip clamping mechanism.

The pipette tip clamping drive mechanism may comprise a threaded shaft connected to the actuator of the pipette tip clamping drive mechanism which extends through a threaded aperture which is fixed in relation to one of the pipette tip mounting plate and the pipette tip clamping plate such that the threaded output shaft drives relative movement between the pipette tip clamping plate and the pipette tip mounting plate in the axial direction when rotated by the actuator. The threaded output shaft of the pipette tip clamping drive mechanism may be moveable in the axial direction independently of the plunger clamping mechanism.

The pipette tip clamping plate is preferably positioned below the pipette tip mounting plate. The pipette tip clamping plate may be the lowest plate in the pipetting head. As used herein, the terms “low”, “below”, and “lowest” refer to the normal orientation of the pipetting head during use.

The plurality of pipette tip clamping members may comprise a plurality of sleeves which define a clamping region. The plurality of pipette tip clamping members may be co-axial with the plurality of pipette tip mounts. The plurality of pipette tip clamping members may circumscribe the plurality of pipette tip mounts when the pipette tip clamping mechanism is engaged.

The plurality of sleeves may be defined by one or more discrete components secured to the pipette tip clamping plate. In certain preferred embodiments, the plurality of sleeves are defined by apertures in the pipette tip clamping plate itself.

Each of the plurality of pipette tip mounts may comprise a radially extending feature on its outer surface which is configured to form one half of a snap-fit connection. The clamping region of each of the plurality of sleeves may be axially adjacent to the radially extending feature on the outer surface of its associated pipette tip mount when the pipette tip clamping mechanism is in the clamp position. The clamping region of each of the plurality of sleeves may be axially offset from the radially extending feature on the outer surface of its associated pipette tip mount when the pipette tip clamping mechanism is in the release position.

The plurality of plunger mounts may comprise a plurality of axially extending sleeves. The plurality of plunger clamping members may comprise a plurality of axially extending clamping rods which extend inside the plurality of axially extending sleeves when the plunger clamping mechanism is in the clamp position.

Each of the plurality of axially extending sleeves may comprise a radially extending feature on its inner surface which is configured to form one half of a snap-fit connection. The clamping region of each of the plurality of clamping rods may be axially adjacent to the radially extending feature on the inner surface of its associated plunger mount when the plunger clamping mechanism is in the clamp position, and may be axially offset from the radially extending feature on the inner surface of its associated plunger mount when the plunger clamping mechanism is in the release position.

The pipetting head may further include at least one pipette comprising: a pipette tip having a distal end with a dispensing aperture and a proximal end with a tip connector portion for connecting the pipette tip to the pipette tip connection mechanism of the pipetting head during use; and a plunger having a distal end positioned inside the pipette tip and a proximal end with a hollow plunger connector portion for connecting the plunger to the plunger connection mechanism of the pipetting head during use, wherein the tip connector portion has a radially extending feature on its inner surface configured to form a snap-fit connection with the radially extending feature on the outer surface of one of the plurality of pipette tip mounts and is configured to resiliently deflect in a radially outward direction from a rest position, in which the tip connector portion has a first outer diameter, to an expanded position, in which the tip connector portion has a second outer diameter which is larger than the first outer diameter by at least the radial extent of the radially extending feature of the tip connector portion, and wherein the clamping region of each of the plurality of sleeves of the tip clamping mechanism has an inner diameter which is greater than or equal to the first outer diameter of the tip connector portion and is less than the second outer diameter of the tip connector portion such that the clamping region prevents the tip connector portion from deflecting to the expanded position and thereby releasing the snap-fit connection when the tip clamping mechanism is in the clamp position.

The pipetting head may further including at least one pipette comprising: a pipette tip having a distal end with a dispensing aperture and a proximal end with a tip connector portion for connecting the pipette tip to the pipette tip connection mechanism of the pipetting head during use; and a plunger having a distal end positioned inside the pipette tip and a proximal end with a hollow plunger connector portion for connecting the plunger to the plunger connection mechanism of the pipetting head during use, wherein the plunger connector portion has a radially extending feature on its outer surface configured to form a snap-fit connection with the radially extending feature on the inner surface of one of the plurality of plunger mounts and is configured to resiliently deflect in a radially inward direction from a rest position, in which the plunger connector portion has a first inner diameter, to a compressed position, in which the plunger connector portion has a second inner diameter which is smaller than the first inner diameter by at least the radial extent of the radially extending feature of the plunger connector portion, and wherein the clamping region of each of the plurality of axially extending clamping rods has an outer diameter which is less than or equal to the first inner diameter of the plunger connector portion and is greater than the second inner diameter of the plunger connector portion such that the clamping region prevents the plunger connector portion from deflecting to the compressed position and thereby releasing the snap-fit connection when the plunger clamping mechanism is in the clamp position.

According to a second aspect of the present invention, there is provided a liquid dispensing apparatus comprising: a body with a microplate receiving area; and a pipetting head according to the first aspect, the pipetting head being positioned above the microplate receiving area.

DETAILED DESCRIPTION

FIG.1shows a liquid dispensing apparatus10for use with an array of positive displacement pipettes1010. The apparatus10comprises a body12with a microplate receiving area, or deck,14and a pipetting head100positioned above the microplate receiving area14. The microplate receiving area14is has a substantially horizontal upper surface16arranged to receive a laboratory microplate. The receiving area14can be located on a height-adjustable support structure18which enables the height of the microplate receiving area14to be varied as required. The receiving area14may be configured to retain a laboratory microplate is a fixed position. For example, the upper surface16of the receiving area14may comprise one or more recesses (not shown) arranged to receive a microplate and to prevent lateral translation of the microplate with respect to the receiving area14. The apparatus10will generally be used in the orientation shown inFIG.1to retain products in wells of the microplate by gravity. The axis marked Z inFIG.1therefore represents an upward direction, with gravity acting in the opposite direction to retain the products in the wells of the microplate. References to upward and downward directions or to an axial direction therefore refer to movement along the axis marked Z inFIG.1, while references to lateral or transverse directions refer to movement in the directions marked X and Y in FIG.1. References to vertical direction or height also therefore refer to dimensions or movement along the axis marked Z inFIG.1. The pipetting head100is configured to hold an array of pipettes, as discussed below in relation toFIGS.2to9, and may be moveable in relation to the deck14to bring pipettes mounted on the pipetting head100into close proximity to a microplate supported on the deck14to allow liquid to be aspirated from or dispensed into the wells of the microplate.

FIGS.2to4show the pipetting head100in more detail. The pipetting head comprises a head chassis101having an upper head chassis part102and a lower head chassis part103which are bolted together to form the main body of the pipetting head100. The upper and lower head chassis parts are connected to the body of the apparatus by chassis support plates104. The chassis support plates104preferably enable the entire pipetting head100to be moved in the X, Y and Z directions relative to the receiving area of the apparatus in a conventional manner using one or more head actuators (not shown). The pipetting head100further comprises a pipette tip clamping mechanism120for connecting or coupling to and clamping the pipette tips of an array of positive displacement pipette tips during use, and a plunger clamping mechanism140for connecting or coupling to and clamping the plungers of the array of positive displacement pipettes during use. Mounted on the upper head chassis part102is a direct drive actuator160operable to move the plunger clamping mechanism140in the axial direction towards or away from the plates of the pipette tip clamping mechanism to aspirate or dispense liquid during use. The direct drive actuator160is fixed in relation to the head chassis101and extends between the head chassis101and the plunger clamping mechanism140.

The pipette tip clamping mechanism120comprises a pipette tip mounting plate121, a pipette tip clamping plate125positioned below the pipette tip mounting plate121and a pipette tip clamping drive mechanism130operable to drive relative movement between the pipette tip mounting plate121and the pipette tip clamping plate125. In this example, the pipette tip mounting plate121is provided as part of the lower head chassis part and the pipette tip clamping drive mechanism130is configured to move the pipette tip clamping plate125towards and away from the fixed pipette tip mounting plate121to selectively engage the pipette tip clamping mechanism120.

As best seen inFIGS.5to7, the pipette tip mounting plate121has an array of apertures122extending in the axial direction through the thickness of the pipette tip mounting plate121. Secured within each aperture122is a pipette tip mount123extending in a downward axial direction from the plate121and configured to couple with one of the pipette tips during use. Each pipette tip mount123is in the form of a tubular tip mount sleeve retained in one of the array of apertures122. In this example, the apertures122each have a restriction with a diameter which is less than the outer diameter of the tip mount sleeves123. The restrictions prevent the tip mount sleeves123from being forced through the tip mounting plate in an upward direction when the tip mount sleeves are initially inserted in the pipette tips. The upper end of the tip mount sleeve123preferably comprises an inwardly tapered end surface to assist with the insertion of components of the plunger clamping mechanism through the bore of the tip mount sleeve123. The lower end of the tip mount sleeve123preferably has an outwardly tapered end surface to assist with the insertion of the lower end of the tip mount sleeve into a pipette tip. The outer surface of each tip mount sleeve123comprises a radially extending feature on its outer surface which is configured to form one half of a snap-fit connection with a correspondingly shaped feature on the inner surface of a pipette tip. In this example, the radially extending is in the form of an annular groove124which circumscribes the tip mount sleeve123.

The pipette tip clamping plate125has an array of apertures126extending in the axial direction through the thickness of the pipette tip clamping plate125. The array of apertures126correspond in number and position to the array of apertures122of the pipette tip mounting plate121. The pipette tip clamping plate125further comprises an array of pipette tip clamping members127each associated with one of the plurality of pipette tip mounts123. In this example, the array of pipette tip clamping members127are provided in the form of a plurality of clamp sleeves127defined by the regions of the pipette tip clamping plate125which immediately surround the apertures126defined in the pipette tip clamping plate125. Each clamp sleeve127has a clamping region128with an inner diameter which is greater than the outer diameter of its respective tip mount sleeve. In this manner, a small clearance is provided between the outer surface of the tip mount sleeve123and the inner surface of the clamping region128when the pipette tip clamping mechanism is engaged, as shown inFIG.7.

Each clamp sleeve may have a substantially constant inner diameter. Alternatively, each clamp sleeve may have regions in which the inner diameter is different, as shown inFIG.7. In the illustrated example, each clamp sleeve127has a narrow region129A towards its upper end, and a tapered region129B at its bottom end. The inner diameter of the clamp sleeve127decreases in the tapered region129B from the lowermost tip to the clamping region128. With this arrangement, one or more pipette tips can be semi-secured by positioning in the pipette tip clamping plate125in an intermediate, ‘pre-lock’, position in which the tapered region129B of the clamp sleeve127is adjacent to the recess124on the outer surface of the tip mount sleeve123. This can facilitate the picking of part arrays of tips from a tip box. The picked tips can then be clamped in place by moving the pipette tip clamping plate125to the clamping position, once the picked tips have been raised above the unpicked array. A small clearance may be provided between the narrow region129A of the clamp sleeve127and the outer surface of the tip mount123. This can help to minimise the forces required to move the tip clamping plate125in the axial direction and facilitate smooth operation of the pipette tip clamping mechanism.

As best seen inFIGS.2to4, the pipette tip clamping drive mechanism130comprises a rotary actuator131and a threaded shaft132operatively connected to an output shaft of the rotary actuator131. The rotary actuator131is mounted on a tip motor support plate135which is fixed in relation to the pipette tip mounting plate121. In this example, the tip motor support plate135is mounted on the outer surface of the lower head chassis part103. The tip motor support plate135is positioned above an extension tab133which is fixed in relation to the pipette tip clamping plate. The extension tab133includes a threaded aperture133A through which the threaded shaft132extends. The pipette tip clamping mechanism130further includes a plurality of guide rods134by which the pipette tip mounting plate121and the pipette tip clamping plate125are connected. In the illustrated embodiment, the guide rods134are fixed in relation to the pipette tip mounting plate121and each extend axially through a corresponding aperture137in the pipette tip clamping plate125. Of course, it will be appreciated that the guide rods could equally be fixed in relation to the pipette tip clamping plate and extend through apertures in the pipette tip mounting plate or any other component of the pipetting head which is fixed in relation to the pipette tip mounting plate.

When the rotary actuator131is operated, the threaded shaft132rotates within the threaded aperture133A to drive the extension tab133towards or away from the tip motor support plate135, thereby causing the pipette tip clamping plate125in the axial direction towards or away from the pipette tip mounting plate121. The direction of movement is dictated by the direction of rotation of the actuator131. The guide rods134help to maintain a parallel relationship between the pipette tip mounting plate121and the pipette tip clamping plate125as the pipette tip clamping plate125moves in the axial direction towards or away from the pipette tip mounting plate121.

As best seen inFIGS.5and8to11, the plunger clamping mechanism140comprises a plunger mounting plate141, a plunger clamping plate145positioned above the plunger mounting plate141, and a plunger clamping drive mechanism150operable to drive relative movement between the plunger mounting plate141and the plunger clamping plate145. The plunger clamping mechanism140further includes a plunger clamp motor mount155positioned above both the plunger mounting plate141and the plunger clamping plate145, on which the actuator motor of the plunger clamping drive mechanism150is supported. The plunger mounting plate141and the plunger clamp motor mount155are fixed in relation to each other. In this example, the plunger mounting plate141and the plunger clamp motor mount155are provided as discrete components which are joined together for ease of manufacture and assembly. In other examples, the plunger mounting plate141and the plunger clamp motor mount155could be provided as a single component. The plunger clamping drive mechanism150is configured to move the plunger clamping plate145towards and away from the plunger mounting plate141to selectively engage the plunger clamping mechanism140.

As best seen inFIGS.8and9, the plunger mounting plate141has an array of apertures142extending in the axial direction through the thickness of the plunger mounting plate141. Secured within each aperture142is a plunger mount143extending in a downward axial direction from the plate141and configured to couple with one of the plungers during use. Each plunger mount143is in the form of a tubular plunger mount sleeve retained in one of the array of apertures142. In this example, the plunger mounts143each have a shoulder having an outer diameter which is greater than the diameter of the apertures142and which abuts against the underside of the plunger mount plate141. The shoulder helps to set the height of the plunger mount sleeve143when initially inserted into an aperture142in the plunger mount plate141. The lower end of the tip mount sleeve143preferably has an inwardly tapered end surface to assist with the insertion of a plunger into the bore of the plunger mount sleeve143. Each plunger mount sleeve143comprises a radially extending feature on its inner surface which is configured to form one half of a snap-fit connection with a correspondingly shaped feature on the outer surface of a plunger. In this example, the radially extending feature is in the form of an annular groove144in the inner surface of the plunger mount sleeve143towards its lower end.

The plunger clamping plate145has an array of recesses or apertures146extending in the axial direction. The array of apertures146of the plunger clamping plate145correspond in number and position to the array of apertures142of the plunger mounting plate141. The array of apertures146of the plunger clamping plate145may also correspond in number to the arrays of apertures122and126of the pipette tip clamping mechanism. The plunger clamping plate145further comprises an array of plunger clamping members147each associated with one of the plurality of plunger mounts143. The array of plunger clamping members is provided in the form of a plurality of clamping rods147which extend axially from the plunger clamping plate145and extend into the bores defined within the plunger mount sleeves143. Each clamping rod147has an enlarged head148at its lower end which extends from a narrower neck region149A. The enlarged head148has an outer diameter which is less than the inner diameter of the plunger mount sleeve143. In this manner, a small clearance is provided between the outer surface of the enlarged head148and the inner surface of the plunger mount sleeve143when the plunger clamping mechanism is engaged. The neck149A has an outer diameter which is less than that of the enlarged head148. Preferably, each clamping rod147also has a main shaft149B with an outer diameter which is substantially the same as the inner diameter of the region of the plunger mount sleeve143in which it is located. The main shaft149B moves axially along the bore of the plunger mount143as the plunger clamping plate145is moved up and down in the axial direction relative to the plunger mount plate141.

As best seen inFIG.13, the plunger clamping drive mechanism150comprises a rotary actuator151and a threaded shaft152operatively connected to an output shaft of the rotary actuator151. The rotary actuator151is mounted on the plunger clamp motor mount155and is thus fixed in relation to the plunger mounting plate141. The rotary actuator151is positioned above an aperture portion153of the plunger clamping plate145having a threaded aperture153A through which the threaded shaft152extends. The plunger clamping mechanism150further includes a plurality of guide rods154by which the plunger mounting plate141and the plunger clamping plate145are operatively connected. In the illustrated embodiment, the guide rods154are fixed in relation to the plunger clamping plate145and each extend axially into the bore of a corresponding cylindrical housing157extending from the underside of the plunger clamp motor mount155. Of course, it will be appreciated that the guide rods could equally be fixed in relation to the plunger mounting plate141and extend through apertures in the plunger clamping plate145or any other component of the pipetting head which is fixed in relation to the plunger clamping plate145.

When the rotary actuator151is operated, the threaded shaft152rotates within the threaded aperture153A to drive the plunger clamping plate145towards or away from the plunger mounting plate141in the axial direction. The guide rods154help to maintain a parallel relationship between the plunger mounting plate141and the plunger clamping plate145as the plunger clamping plate145moves in the axial direction towards or away from the plunger mounting plate141. The direction of movement is dictated by the direction of rotation of the actuator151. This can be seen inFIGS.10and11, in which the plunger mounting plate141is omitted for clarity. InFIG.10, the guide rods154can be seen to be extended from the cylindrical housings157, such that the plunger clamping plate145and its support plate156are in a low position away from the underside of the plunger clamp motor mount155and closer to the upper surface of the plunger mounting plate (not shown inFIGS.10and11). This is the clamping position. InFIG.11, the guide rods154are retracted into the cylindrical housings157, so that the plunger clamping plate145and its support plate156are moved axially away from the plunger mounting plate141and towards the plunger clamp motor mount plate155. This is the release position. The relative movement between the plunger clamping plate145and the plunger mounting plate141allows the plunger clamping mechanism140to be moved into any position between an engaged state, in which a plunger is clamped in position, and a disengaged, or “released” position or state, in which a plunger may be mated with or removed from the plunger mounts in an axial direction. The plunger clamping mechanism140may be configured to move to an ejection state, in which the plunger clamping plate145is moved towards the plunger mounting plate141beyond the clamping position. In this position, the enlarged heads148of the clamping rods147are axially below the radially extending features on the inner surfaces of the plunger mount sleeves143, which are instead in alignment with the narrower neck portions149A of the clamping rods. This allows the top of the plunger, i.e. the plunger connector portion, to flex inwards. Further downward movement of the clamping plate145and clamping rods147pushes the plunger downwards to release it from the snap-fit connection with the plunger mounting sleeves. When the pipette tip clamping plate125is also in a released position, further downward movement of the clamping rod using the plunger clamping drive mechanism pushes the plunger against one or more inside surfaces of the pipette tip, for example the region around the aperture at the distal end of the pipette tip, to push the pipette tip from the tip clamping mechanism. This ejects the entire pipette assembly from the pipetting head. Alternatively, the clamping rod and the plunger may be moved down together using the direct drive actuator160to push against the pipette and thereby eject the pipette tip from the apparatus. In this ejection mode, the plunger may remain on the apparatus even after the pipette tip has been ejected.

FIGS.12and13show the direct drive actuator160in more detail. The direct drive actuator160comprises an actuator motor161mounted on the top surface of the upper head chassis102. The output shaft of the actuator motor161is coupled to a threaded rod162connected to a ball screw actuator nut163. The output shaft of the actuator161may be integral with or fixed to the threaded rod162. In the illustrated embodiment, the output shaft is coupled to the threaded rod by a rotationally rigid coupling in the form of bellows coupling161A. The bellows coupling161A permits relative axial movement between the output shaft and the threaded shaft162but prevents or substantially prevents relative rotation between those two components. The nut163is fixed to a ball screw mount164so that the two move simultaneously. In the illustrated embodiment, the ball screw mount164is fixed to the plunger clamp motor mount155at the upper end of the plunger clamping mechanism140. In other embodiments, the ball screw mount164may be integrated with the plunger clamp motor mount155. The direct drive actuator160thus extends between the head chassis101and the plunger clamping mechanism140.

When the actuator motor161is operated, the entire plunger clamping mechanism140is moved in the axial direction along guide rods165either towards or away from the pipette tip clamping mechanism120, depending on the direction of rotation of the actuator motor161. The guide rods165are unthreaded. The plunger mounting plate141includes a plurality of guide sleeves166(seeFIG.8) through which the guide rods165extend. The guide sleeves166slide along the outer surface of the guide rods when the actuator motor161is operated. In this manner, a plunger clamped by the plunger clamping mechanism140can be accelerated rapidly relative to the pipette tip within which it extends independently of any restriction imposed by the speed of operation of the clamping mechanism. This allows the apparatus to be used in a non-contact dispensing mode (also known as jetting—in which liquid is dispensed from the pipette at a distance from the target so that the drop separates from the tip before it contacts the target) as well as a contact dispensing mode (in which the liquid drop forms at the pipette tip and is deposited by contact with the target). When performing non-contact dispensing, a liquid sample must be travelling at a high enough velocity to detach from the tip. The distance travelled by the plunger for a dispense shot can be small, for example in the range of 1 mm or less. Consequently, high levels of acceleration/deceleration are needed in order to reach the target velocity for non-contact dispensing. The direct drive arrangement, for example via a ball screw, can offer higher levels of acceleration/deceleration of heavy loads than a belt driven system, thus enabling non-contact dispensing of low volume liquid samples. Furthermore, a direct drive arrangement can offer higher positional accuracy and repeatability than an equivalent belt drive mechanism. This can have a significant impact on dispense performance.

FIGS.14to17show a pipette1010for use with the pipetting head ofFIGS.2to13. The pipette1010comprises a pipette tip1100and a plunger1200.

The pipette tip1100may be a receptacle for receiving and/or containing a sample fluid, or a sample liquid. The pipette tip1100may be configured for insertion into a container of sample liquid, or into sample liquid. The pipette tip1100has a proximal end1101and a distal end1102defining a longitudinal axis1001therebetween. The pipette tip1100has an aperture1108at its distal end1102, as indicated inFIG.15. The aperture1108may be defined by an inner wall surface1111of the pipette tip1100at the distal end1102, specifically at an outermost distal point of the pipette tip1100. The aperture1108may be any suitable shape, e.g. elliptical, oval, or circular. The pipette tip1100has a fluid cavity1109extending from the aperture1108at least partially towards the proximal end1101. The fluid cavity may be configured to receive and/or retain a fluid, such as an airgap or sample liquid. The fluid cavity1109may be substantially elongate. The fluid cavity may be defined by the inner wall surface of the pipette tip1100. The longitudinal axis1001may be a central axis about which the pipette tip1100and/or plunger1200is disposed. The longitudinal axis1001may define a central axis about which the pipette tip1100and/or plunger1200are disposed uniformly or symmetrically. The pipette tip1100and/or plunger1200may be configured so that the direction of aspirating and/or dispensing is along the longitudinal axis1001. The pipette tip1100may be substantially elongate, extending between its proximal and distal ends,1101,1102. The pipette tip1100may be substantially or entirely hollow. The pipette tip1100may comprise or consist of a polymeric material. The pipette tip100may comprise or consist of a homogeneous material. The pipette tip100may comprise or consist of a translucent or transparent material.

The pipette tip1100may comprise a series of portions, each having a different function, distinguishing features and/or a different shape or dimension. The pipette tip1100may comprise one or more of: a tip connector portion1103, a centering portion1104, a support portion1105, a main body portion1106, and a bridging portion1107, for example as shown inFIG.15. From the proximal end1101to the distal end1102, each portion may be arranged in the order: tip connector portion1103, centering portion1104, support portion1105, main body portion1106, bridging portion1107, and end portion1110. The fluid cavity1109may extend through one, more or all of the portions of the pipette tip1100. The plunger1200may extend through one, more or all of the portions of the pipette tip1100.

The tip connector portion1103is configured for connection to a liquid handling system, for example with a snap-fit connection. The tip connector portion1103may comprise a split tubular wall1120which may be defined by a plurality of flexible segments1121. The flexible segments1121may be configured to resiliently deflect in a radially outward direction to increase the outer diameter of the proximal end1101of the pipette tip1100from a first outer diameter, in which the flexible segments are undeflected and the tip connector portion is in a rest state, to a second outer diameter, in which the flexible segments are deflected radially outwardly and the tip connector portion is in an expanded state. In the embodiment depicted, the tip connector portion1103comprises four axially extending discontinuities or slots1122in the tubular wall1120which separate four flexible segments1121. The tip connector portion1103may comprise any suitable number of axially extending discontinuities1122to define any number of flexible segments1121, such as two, three, four, five, or six. The arrangement of flexible segments1121and slots1122enables the tip connector portion to expand without requiring significant forces to be exerted on the tip connector portion. This can reduce the insertion force required to engage the tip connector portion1103with the pipetting head.

The tip connector portion1103may further comprise one or more radially extending features1123on its inner surface by which the pipette tip may be coupled to the pipetting head. The radially extending feature on the inner surface of the tip connector portion1103may comprise a protrusion, which extends radially inward, and/or a recess or groove, which extends radially outward. The radially extending feature may extend in a circumferential direction. In the depicted embodiment, the radially extending feature on the inner surface of the tip connector portion1103comprises a part-annular rib1123which protrudes from the inner surface of the tip connector portion1103. Preferably, the second outer diameter to which the tip connector portion is increased is larger than the first outer diameter by at least the radial extent of the radially extending feature1123. The rib1123preferably comprises angled upper and lower surfaces along which the inner diameter of tip connector portion gradually increases from the rib1123to the regions of the tip connector portion above and below the rib1123. The angle of the upper surface can be selected according to the desired insertion force. The angle of the lower surface can be selected according to the desired ejection force. The upper or lower surfaces may each have an angle of from 10 to 80 degrees from the axial direction of the pipette tip, for example from 20 to 70 degrees from the axial direction of the pipette tip, 30 to 60 degrees from the axial direction of the pipette tip, or 40 to 50 degrees from the axial direction of the pipette tip.

The centering portion1104may be configured to centre the plunger1200within the pipette tip1100. The centering portion1104may have an inner surface which may have a tapered or conical shape. The support portion1105may comprise one or more structural ribs or rings, configured to reduce flexibility and/or improve structural integrity of the pipette tip1100. The one or more ribs may extend on an outer surface of the pipette tip, along at least part of the length between the proximal end1101and distal end1102, for example axially, as best seen inFIG.16. The main body portion1106may be substantially cylindrical and/or elongate. The main body portion1106may have a substantially uniform inner diameter and/or outer diameter. The main body portion1106may extend along at least half of the length of the pipette tip1100. The main body portion1106may have a larger inner and/or outer diameter than any diameter of the end portion1110. The bridging portion1107may be configured to bridge the main body portion1106to the end portion1110. The bridging portion1107may define a gradual transition or a step between the main body portion1106and the end portion1110. The bridging portion1107may be substantially tapered, conical and/or dome-shaped.

The plunger1200has a proximal end1201and a distal end1202extending along the longitudinal axis1101. The plunger1200is configured to extend at least partly between the proximal and distal ends1101,1102of the pipette tip1100into the end portion1110. The plunger1200may be configured to extend substantially or wholly between the proximal and distal ends1101,1102of the pipette tip1100into the end portion1110. The plunger1200is movable towards and away from the aperture1108to aspirate or dispense fluid from the pipette tip1100. The plunger1200may have an end portion outer wall surface1212configured for alignment with the inner wall surface1111of the pipette tip end portion1110. The plunger1200may comprise or consist of a polymeric material. The plunger1200may comprise or consist of a homogeneous material.

The plunger1200may comprise a series of portions, each having a different function, distinguishing features and/or a different shape or dimensions. The plunger1200may comprise one or more of: a plunger connector portion1203, a centering portion1204, a main body portion1206, and a sealing portion1207. From the proximal end1201to the distal end1202, each portion may be arranged in the following order: connector portion1203, centering portion1204, main body portion1206, sealing portion1207and end portion1210.

The plunger connector portion1203is configured for connection to a liquid handling system, for example with a snap-fit connection. The plunger connector portion1203may be configured to be received entirely within the tip connector portion1103of the pipette tip100. The plunger connector portion1203may comprise a split tubular wall1220which may be defined by a plurality of flexible segments1221. The flexible segments1221may be configured to resiliently deflect in a radially inward direction to decrease the inner diameter of the proximal end1201of the plunger1200from a first inner diameter, in which the flexible segments are un-deflected and the plunger connector portion is in a rest state, to a second inner diameter, in which the flexible segments are deflected radially inwardly and the plunger connector portion is in a compressed state. In the embodiment depicted, the plunger connector portion1203comprises three axially extending discontinuities or slots1222in the tubular wall1220which separate three flexible segments1221. The plunger connector portion1203may comprise any suitable number of axially extending discontinuities1222to define any number of flexible segments1221. The arrangement of flexible segments1221and slots1222enables the plunger connector portion to be compressed without significant compressive stresses. The plunger connector portion1203may further comprise one or more radially extending features1223on its outer surface by which the plunger may be coupled to the pipetting head. The radially extending feature on the outer surface of the plunger connector portion1203may comprise a protrusion, which extends radially outward, and/or a recess or groove, which extends radially inward. The radially extending feature may extend in a circumferential direction. In the depicted embodiment, the radially extending feature on the outer surface of the plunger connector portion1203comprises a bulbous head1223at the upper end of the plunger which is defined above an annular groove in the outer surface of the plunger connector portion1203. Preferably, the second inner diameter to which the plunger connector portion is decreased is smaller than the first inner diameter by at least the radial extent of the radially extending feature1223, i.e. by at least half the difference between the outer diameter of the bulbous head1223and the outer diameter at the narrowest part of the annular groove.

The plunger connector portion1203may further comprise an internal wall1224extending transversely from the inner surface of the plunger connector portion1203. The internal wall1224may be positioned distally of the flexible segments1221. The internal wall1224may be positioned proximally of the main body portion1206. The internal wall1224forms a restriction across the bore of the plunger connector portion. This provides a surface against which the head of the clamping rods can abut to eject the pipettes. The internal wall1224may extend across the full width of the interior bore of the plunger1200, as illustrated inFIG.17. However, this is not necessarily the case. The inner wall1224need only restrict the size of the bore to less than the outer diameter of the head of the clamping rod.

The centering portion1204may comprise an annular shoulder. The centering portion1204may be substantially conical or dome-shaped. In the depicted embodiment, the centering portion1204is a radially extending frustoconical shoulder. The centering portion1104of the pipette tip1100is preferably configured to receive and engage with the centering portion1204of the plunger1200to centre the alignment of the plunger. In the embodiment depicted inFIG.14, the two centering portions have corresponding geometries. The main body portion1206of the plunger1200may be configured to be received in the main body portion1106of the pipette tip1100. The main body portion1206may be substantially cylindrical and/or elongate. The main body portion1206may have a substantially uniform diameter. The main body portion1206may extend along at least half of the length of the plunger, optionally at least two thirds of the length of the plunger1200. The main body portion1206may have a larger diameter than the diameter of the end portion1210. The sealing portion1207of the plunger1200may be configured to be received in the bridging portion1107of the pipette tip1100. The sealing portion1207may be configured to form a seal against an inner wall of the pipette tip1100. The sealing portion1207may form a fluid-tight seal within the pipette tip, such that fluid cannot pass from a proximal side of the sealing portion1207to a distal side of the sealing portion1207when the plunger1200is installed in the pipette tip1100. The sealing portion1207may be at least partly flexible. The sealing portion1207may be configured to bridge the main body portion1206to the end portion1210. The sealing portion1207may define a step between the main body portion1207and the end portion1210. The sealing portion1207may be substantially tapered, conical and/or dome-shaped. The end portion1210of the plunger1200may be configured to be received in the end portion1110of the pipette tip1100. The end portion1210may have a smaller diameter than the sealing portion1207and/or the main body portion1206.

With reference toFIGS.18to22, a method of connecting a pipette1010to the pipetting head100of the present invention will now be described. Although the Figures to which the below discussion relates show only a single pipette, it will be understood that one or more of the connecting, aspirating, dispensing and ejecting operations discussed may be applicable to multiple pipettes simultaneously. For example, where the pipetting head comprises 384 mounts, the below discussion may apply to the simultaneous connection of 384 pipettes, or any subset thereof.

InFIG.18, the pipette tip clamping mechanism120and the plunger clamping mechanism140are both in their released states. When the pipette tip clamping mechanism120is in the released state, the pipette tip clamping plate125is in its uppermost position against the underside of the pipette tip mounting plate121. Crucially, in this position, the clamping regions of the tip clamp sleeves are axially offset from the annular grooves around the outer surfaces of the tip mount sleeves. When the plunger clamping mechanism140is in its released state, the plunger clamping plate145is in its uppermost position and the enlarged heads148of the plunger clamping rods147are axially offset from the annular groove on the inner surface of each of the plunger mount sleeves, as shown. The entire pipetting head100is then moved using the pipette head Z motor (not shown) axially towards an array of pipettes1010such that the tip mount sleeves are received within the tip connector portions of the pipette tips1100. During insertion of the tip mount sleeves123into the proximal ends of the pipette tips1100, the annular ribs1123on each pipette tip1100ride over the outer surface of the tip mount sleeve123, causing the tip connector portion of each tip to be outwardly deflected to the expanded position. Once the annular rib1123is received in the annular groove124, as shown inFIG.18, the flexible segments return to an un-deflected, or only partially deflected state. In this position, the tip connector portion is in a rest state and each pipette tip1100is coupled to its respective pipette tip mount sleeve123in a snap fit connection. This is step 1.

Step 2 is discussed with reference toFIG.19. In step 2, the pipette tip clamping mechanism120is engaged by lowering the pipette tip clamping plate125and moving it away from the pipette tip mounting plate, as shown inFIG.19. This causes the tip clamping sleeves127to extend around the tip connector portion1103of each pipette tip1100such that the clamping region of each tip clamping sleeve is adjacent to the snap fit connection between each pipette tip1100and its respective tip mount sleeve123. The inner diameter of the clamping region128is less than the expanded diameter of the tip connector portion1103, for example it may be substantially the same as the unexpanded, or “first”, outer diameter of the tip connector portion. With this arrangement, the tip connector portion1103is prevented from expanding fully, thus preventing the radially extending feature1123on the inner surface of the pipette tip1100from being released from the groove124on the outer surface of the tip mount sleeve123. In this manner, the pipette tip1100is “locked” or “clamped” in position without the need to exert any significant forces on the tip connector portion of the pipette tip1100. This can reduce the force required to engage the pipette tip clamping mechanism.

Between steps 1 and 2, the pipette tip clamping mechanism may optionally be moved to a partially engaged, ‘pre-lock’, position between the released and engaged states, in which the tapered region129B of each clamp sleeve127is adjacent to the recess124on the outer surface of its respective tip mount sleeve123. This can facilitate the picking of part arrays of tips from a tip box by allowing picked tips to be secured against the tip mounts without interference between the pipette tip clamping plate and the unpicked array of tips. Once the picked tips have been raised above the unpicked array by the pipetting head, the picked tips can then be fully clamped in place by moving the pipette tip clamping plate125to the clamping position.

Step 3 is discussed with reference toFIG.20. In step 3, the entire plunger clamping mechanism140is lowered using the direct drive actuator. This brings the plunger mount sleeves143into contact with the plunger connector portion1203at the upper, or proximal, ends of the plunger1200. Further downward movement of the plunger clamping mechanism140causes the inner surface of the plunger mount sleeve143to ride over the outer surface of the plunger connector portion, inwardly deflecting the plunger connector portion to the contracted or compressed position and allowing the bulbous head1223at the top of the plunger1200to be received in the groove144on the inside surface of the plunger mount sleeve143. Once the bulbous head1223is received in the groove144on the inside surface of the plunger mount sleeve143, as shown inFIG.20, the flexible segments1221of the plunger connector portion1203return to an undeflected, or partially deflected state. In this position, the plunger connector portion is in a rest state and each plunger1200is coupled to its respective plunger mount sleeve143in a snap fit connection.

Step 4 is discussed with reference toFIG.21. In step 4, the plunger clamping plate145is moved in the axial direction towards the plunger mounting plate141by the plunger clamp drive mechanism until the heads148of the plunger clamp rods are adjacent to the snap fit connection between the plunger and the plunger mount sleeve. The outer diameter of the head148of each clamping rod is greater than the inner diameter of the plunger when in the contracted state, or “second inner diameter”. For example it may be substantially the same as the inner diameter of the un-deflected plunger, or “first” inner diameter. With this arrangement, the plunger connector portion is prevented from contracting fully to the contracted position, thus preventing the bulbous head1223of the plunger1200from being released from the groove144on the inner surface of the plunger mount sleeve143. In this manner, the plunger1200is “locked” or “clamped” in position without the need to exert any significant compressive forces on the plunger connector portion. This can reduce the force required to engage the plunger clamping mechanism.

To perform an aspirating operation, the pipetting head100is moved to the desired position relative to a set of liquid samples using the pipetting head Z motor. The plunger of each pipette is then raised within its respective pipette tip using the direct drive actuator to move the entire plunger clamping mechanism away from the pipette tip clamping mechanism, as shown inFIG.22, to draw fluid into the pipette tip. The fluid can then be dispensed as desired by moving the plunger clamping mechanism in the opposite direction using the direct drive actuator.

Once the aspirating and dispensing operations are complete, the pipette or pipettes can be ejected as follows. Firstly, the plungers are each moved to the bottom of their travel inside their respective pipette tip and the tip clamping mechanism120is disengaged by moving the tip clamping plate125towards the tip mounting plate121to bring the clamp sleeves127out of alignment with the snap-fit connection between each pipette tip and its respective tip mount123, and away from the outer surfaces of the pipette tips. Next the plunger clamping plate145is moved towards the plunger mounting plate141, beyond the engaged position, such that the head148of each clamping rod147is moved out of alignment with the snap-fit connection between each plunger1200and its respective plunger mount143and instead bringing the neck portion149A of each clamping rod147into alignment with the snap-fit connection and causing the distal end surface of the head of the clamping rod to abut against the internal wall1224of the plunger connector portion1203. Since the neck portions149A of the clamping rods147have an outer diameter which is less than the second, compressed, inner diameter of the plunger connector portions1203, when the clamping rods are in this position, the plunger connector portions are not restricted from deflecting inwardly to the compressed state. Thus, continued downward movement of the plunger clamping plate145releases the bulbous heads1223of the plunger connector portions1203from the corresponding radially extending features144of the plunger mounts143to remove the plungers1200from the pipetting head. Further downward movement of the plunger clamping plate, and therefore of the clamping rods and the plungers themselves, pushes the distal end portions of the plungers against the respective portions of the pipette tips within which they are located. In this manner, the plungers and the plunger clamping mechanism can be used to release the pipette tips1100from the pipette tip mounts123, thereby ejecting the pipettes1010from the pipetting head.