A PIPETTE TIP

There is provided a pipette for aspirating and/or dispensing liquids, comprising a pipette tip and a plunger. The pipette tip has a proximal end and a distal end defining a longitudinal axis therebetween; an aperture at the distal end, and a fluid cavity extending from the aperture at least partially towards the proximal end. The plunger is positioned inside the pipette tip, and extends at least partly between the proximal and distal ends of the pipette tip into the end portion, and is movable towards and away from the aperture to aspirate or dispense fluid from the pipette tip. The pipette tip has an end portion disposed at the distal end, having an inner wall surface extending at an angle of between 2 degrees and 5 degrees relative to the longitudinal axis, for at least 5 mm.

FIELD OF THE INVENTION

The present invention relates to a pipette having a pipette tip and a plunger, the pipette tip having in particular an advantageous shape.

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 this plunger to contact the sample liquid to be aspirated. The plunger is retracted to draw in sample liquid, and is extended to dispense sample liquid. Such pipettes can be used in automated machines to improve accuracy and repeatability of pipetting actions.

The inventor has identified several problems with known pipettes, which are particularly relevant at low dispense volumes.

There is a need for an improved pipette.

SUMMARY OF THE INVENTION

A first aspect of the invention provides a pipette for aspirating and/or dispensing liquids, comprising:a pipette tip, having:a proximal end and a distal end and a longitudinal axis extending therebetween;an aperture at the distal end,a fluid cavity extending from the aperture at least partially towards the proximal end;the pipette tip comprising an end portion disposed at the distal end, having an inner wall surface extending at an angle of at most 5 degrees relative to the longitudinal axis, for at least 5 mm; anda plunger positioned inside the pipette tip, configured to extend at least partly between the proximal and distal ends of the pipette tip into the end portion, and movable towards and away from the aperture to aspirate and/or dispense fluid from the pipette tip.

The inner wall surface may extend at an angle of between 2 degrees and 5 degrees relative to the longitudinal axis, for at least 5 mm.

The pipette tip geometry specified in the first aspect of the invention, specifically the inner wall surface extending at an angle of at most 5 degrees relative to the longitudinal axis, for at least 5 mm, provides a significantly steeper angle than the wide angle pipette tip of the known pipette referred to in the background section. This narrow angle pipette tip has several significant advantages over known pipette tip geometries.

Firstly, it enables the pipette tip to be used in an adapted way compared to known pipette tips, with what will be referred to as a “post-sample airgap”. When performing non-contact dispensing, i.e. dispensing in which the sample liquid forms one or more droplets after leaving the pipette tip, before reaching a sample container or a sample in a sample container, a liquid sample must be travelling at a high enough velocity to detach from the tip. In known pipette tips, it is difficult to achieve this velocity with small volumes, because the plunger stroke is relatively short. The inventors have identified that a way to increase the plunger stroke is to introduce a small airgap (or other gas) after the liquid sample is aspirated, i.e. to continue to withdraw the plunger after the sample has been aspirated, to draw in air. The narrow angle tip of the first aspect ensures that this airgap can be introduced in a controlled manner. In known pipette tips, the inventors have identified that this mechanism is not viable in a pipette tip having a plunger. This is because the geometry of a known pipette tip, which has a much wider pipette tip angle than the pipette of the first aspect, is such that the liquid would attach to one side of the inner wall surface of the pipette tip and/or plunger due to surface tension. This would lead to poor dispense performance in a post-sample airgap method. The narrow angle of the pipette tip of the first aspect provides a more uniform liquid attachment, so mitigates this problem.

Secondly, the inventors have identified that it enables the pipette tip to be used in a further adapted way to known pipette tips, with what will be referred to as a “pre-sample airgap”. In such a mechanism, the plunger can be initially retracted to draw in a gas, such as air, and then subsequently retracted to draw in a sample liquid.

The advantage of using a pre-sample airgap mechanism is that all of the liquid that is aspirated can be dispensed, i.e. there is no dead volume within the pipette tip. The dead volume is a gap between the plunger and pipette tip resulting from manufacturing tolerances which do not permit a perfect fit. Without the pre-sample airgap, some of the liquid sample would remain in this gap between the plunger and the tip.

The narrow angle tip also ensures the liquid sample drawn in remains as a single slug that can be fully ejected on dispensing, as opposed to sticking to one side of the inner wall surface of the pipette tip. This allows very low volumes (<200 nl) to be handled.

The tip being configured for use with a pre-sample airgap has an additional advantage. Traditional positive displacement pipettes require a minimum volume of liquid to be aspirated to prime them correctly. Dispense performance can be compromised if they are not primed correctly. The pre-sample air gap described above removes the need for a priming volume, meaning low source-volumes (<500 nl) and low dispensing volumes (<200 nl) can be handled.

Thirdly, the pipette tip geometry provides a combination of good reach and capacity. The geometry of the pipette tip allows the pipette to reach the bottom of a V-shaped well, such as a well in a PCR microplate, to extract as much liquid as possible, while having a capacity large enough to minimise the number of aspirations/dispenses required to empty or fill a well. This high capacity helps to minimise the number of loads required to perform a dispense, saving time and associated cost. The capacity of the design may be as high as 100 μl.

A further advantage of the first aspect to be noted, of this non-exhaustive list—which may be deduced from the above advantages—is that the tip geometry provides a pipette having a large dynamic range: for example, from approximately 0.1 or 0.2 μl to approximately 100 μl. The pre-sample airgap and post-sample air-gap mechanisms which are made possible by the tip geometry, as well as the overall capacity made possible by the tip geometry, provide a particularly advantageous pipette tip suitable for a variety of sample and/or source volume aspirating and/or dispensing.

The pipette may be particularly suited for use in quantitative polymerase chain reaction (“qPCR”) methods. Further optional advantageous features of the invention are set out in the following passages.

The end portion may have an outer wall surface extending at an angle of at most 5 degrees relative to the longitudinal axis, for at least 5 mm. The outer wall surface may extend at an angle of at most 4 degrees relative to the longitudinal axis, preferably at most 3.5 degrees relative to the longitudinal axis, preferably at most 3.3 degrees relative to the longitudinal axis.

The aperture may have a diameter of at most 1 mm, preferably at most 0.5 mm, further preferably at most 0.4 mm, optionally at least 0.4 mm.

The end portion may have a maximum outer diameter of at most 4 mm, preferably at most 3 mm, further preferably at most 2 mm, further preferably at most 1 mm, further preferably at most 0.7 mm, further preferably at most 0.65 mm. Optionally, the end portion110may have a maximum outer diameter of at least 0.5 mm, optionally at least 0.6 mm, optionally at least 0.65 mm

The inner wall surface of the end portion of the pipette tip may define a straight-sided shape, such as a frusto-conical or cylindrical shape.

The outer wall surface of the end portion of the pipette tip may define a straight-sided shape, such as a frusto-conical or cylindrical shape.

The plunger may have an end portion outer wall surface configured for alignment with the inner wall surface of the pipette tip end portion.

The plunger may be configured to seal the aperture when in an extended position.

The plunger may have an end portion which may substantially or entirely fill the end portion of the pipette tip when in an extended position. The plunger may have a plunger end portion may not substantially or entirely fill the end portion of the pipette tip when in an extended position.

The inner wall surface may extend at an angle of at most 4 degrees relative to the longitudinal axis; preferably at most 3 degrees relative to the longitudinal axis; further preferably at most 2 degrees relative to the longitudinal axis, preferably at most 1.9 degrees relative to the longitudinal axis, preferably at most 1.87 degrees relative to the longitudinal axis.

The inner wall surface of the end portion may extend for at least 7 mm, preferably at least 10 mm, further preferably at least 12 mm.

The pipette having any of the variations noted herein may be comprised in a liquid handling system, the liquid handling system also comprising an actuator configured to move the plunger relative to the pipette tip.

There may be provided a liquid handling system comprising:a plurality of pipettes having any of the variations noted herein; andan actuator configured to move multiple pipette tips and/or plungers of the plurality of pipettes so as to aspirate and/or dispense a fluid.

The actuator may be configured to move multiple pipette tips and/or plungers of the plurality of pipettes simultaneously so as to aspirate and/or dispense a fluid.

The plurality of pipettes may be arranged in a planar, 2D arrangement relative to one another. The plurality of pipettes may be arranged in a regular, optionally symmetrical matrix, such as a grid-like shape. The plurality of pipettes may be arranged in a square or rectangular shape.

The plurality of pipettes may be at least 10, preferably at least 100, more preferably at least 200, more preferably at least 300, more preferably 384 pipette tips. The plurality of pipettes may be arranged in a regular, optionally symmetrical matrix, such as a grid-like 16×24 matrix.

According to a second aspect of the invention, there is provided a method of aspirating a liquid comprising:providing the pipette having any of the variations noted herein;retracting the plunger relative to the pipette tip so as to aspirate a gas through the aperture into the pipette tip; and subsequentlyretracting the plunger so as to aspirate a sample liquid through the aperture into the pipette tip.

The method may further comprise:extending the plunger relative to the pipette tip so as to dispense a sample liquid through the aperture from the pipette tip; and subsequentlyextending the plunger so as to dispense a gas through the aperture from the pipette tip.

The method may further comprise:providing the pipette having any of the variations noted herein;retracting the plunger so as to aspirate a liquid through the aperture into the pipette tip; and subsequentlyretracting the plunger relative to the pipette tip so as to aspirate a gas through the aperture into the pipette tip.

The method may further comprise:extending the plunger so as to dispense a gas through the aperture from the pipette tip; and subsequentlyextending the plunger relative to the pipette tip so as to dispense a sample liquid through the aperture from the pipette tip.

DETAILED DESCRIPTION OF EMBODIMENT(S)

The pipette tip100may be a receptacle for receiving and/or containing a sample fluid, or a sample liquid. The pipette tip100may be configured for insertion into a container of sample liquid, or into sample liquid.

The pipette tip100has a proximal end101and a distal end102defining a longitudinal axis1therebetween.

The pipette tip100has an aperture108at its distal end102, as indicated inFIG.2. The aperture108may be defined by an inner wall surface111of the pipette tip100at the distal end102, specifically at an outermost distal point of the pipette tip100. The aperture108may define a substantially circular shape or circle. The aperture108may have a diameter of at most 1 mm, preferably at most 0.5 mm, further preferably at most 0.4 mm. Optionally, the aperture108may have a diameter of at most 0.35 mm, 0.3 mm, 0.25 mm, 0.1 mm. Optionally, the aperture108may have a diameter of at least 0.4 mm.

The inner wall111of the pipette tip100may extend through a support portion105and/or a main body portion106of the pipette tip100. The inner wall surface111may be substantially tubular and/or have parallel sides within the support portion105and/or main body portion106. The pipette tip100has a fluid cavity109extending from the aperture108at least partially towards the proximal end101.

The fluid cavity109may be configured to receive and/or retain a fluid, such as an airgap or sample liquid. The fluid cavity109may be substantially elongate. The fluid cavity109may be defined by the inner wall surface111of the pipette tip100. The fluid cavity109may be mostly or wholly disposed within an end portion110of the pipette tip100.

The pipette tip100comprises an end portion110disposed at the distal end102, having an inner wall surface111extending at an angle α of at most 5 degrees, or π/36 radians, or approximately 0.08 to 0.09 radians, relative to the longitudinal axis1, for at least 5 mm. The inner wall surface111may extend at an angle α of at most 4 degrees relative to the longitudinal axis1; preferably at most 3 degrees relative to the longitudinal axis1; further preferably at most 2 degrees relative to the longitudinal axis1. The angle α may be seen inFIG.3. The angle α may be at least 0 degrees, i.e. parallel to the longitudinal axis1. A pipette tip end portion110extending at an angle of at least 2 degrees or at least 1 degree relative to the longitudinal axis1may be advantageous compared to an angle of 0 degrees as it may be easier, simpler and/or cheaper to manufacture. The angle α may be measured using any appropriate angle measurement technique known to the skilled person.

The longitudinal axis1may be a central axis about which the pipette tip101and/or plunger200is disposed. The longitudinal axis1may define a central axis about which the pipette tip100and/or plunger200are disposed uniformly or symmetrically. The pipette tip100and/or plunger200may be configured so that the direction of aspirating and/or dispensing is along the longitudinal axis1.

The inner wall surface111of the end portion110may extend for at least 7 mm at an angle of at most or equal to angle α, preferably at least 10 mm at an angle of at most or equal to angle α, further preferably at least 12 mm at an angle of at most or equal to angle α. The inner wall111of the end portion110of the pipette tip100may define a straight-sided shape, such as a frusto-conical or cylindrical shape.

The end portion110may have an outer wall surface112extending at an angle ß, as best seen inFIG.3, of at most 5 degrees relative to the longitudinal axis1, for at least 5 mm. The outer wall surface112of the end portion of the pipette tip may define a straight-sided shape, such as a frusto-conical or cylindrical shape. The end portion110may have a maximum outer diameter of at most 4 mm, preferably at most 3 mm, further preferably at most 2 mm, further preferably at most 1 mm, further preferably at most 0.7 mm, further preferably at most 0.65 mm. Optionally, the end portion110may have a maximum outer diameter of at least 0.5 mm, optionally at least 0.6 mm, optionally at least 0.65 mm1055, for example as shown inFIG.10. The ring1055may be configured to provide a reaction force during use. The ring1055may be configured to position or centre the pipette tip100during storage and/or use. The ring1055may be configured to at least partly facilitate ejection of the pipette tip100from a moulding tool during manufacture.

The main body portion106may be substantially cylindrical and/or elongate. The main body portion106may have a substantially uniform inner diameter and/or outer diameter. The main body portion106may extend along at least half of the length of the pipette tip100. The main body portion106may have a larger inner and/or outer diameter than any diameter of the end portion110.

The bridging portion107may be configured to bridge the main body portion106to the end portion110. The bridging portion107may define a step between the main body portion106and the end portion110. The bridging portion107may be substantially tapered, conical and/or dome-shaped.

The plunger200is positioned inside the pipette tip100. The plunger200may be configured to move relative to the pipette tip100so as to draw in a fluid into the pipette tip100, and/or to expel a fluid from the pipette tip100. Specifically, when moving from an extended position to a retracted position, the plunger200may draw fluid, such as an airgap or sample liquid, into the pipette tip100. When moving from a retracted position to an extended position, the plunger200may expel fluid, such as an airgap or sample liquid, from the pipette tip100.

The plunger200and/or pipette tip100may be configured so that in an extended position, the plunger200may be wholly contained within the pipette tip100. The plunger200is configured to extend at least partly between the proximal and distal ends101,102of the pipette tip100into the end portion110. The plunger200may be configured to extend substantially or wholly between the proximal and distal ends101,102of the pipette tip100into the end portion110. The plunger200is movable towards and away from the aperture109to aspirate or dispense fluid from the pipette tip100. The plunger200may have an end portion outer wall surface212configured for alignment with the inner wall surface111of the pipette tip end portion110. The plunger200may comprise or consist of a polymeric material. The plunger200may comprise or consist of a homogeneous material.

The plunger200may comprise a series of portions, each having a different function, distinguishing features and/or a different shape or dimensions. The plunger200may comprise one or more of: a plunger connector portion203, a centering portion204, a main body portion206, and a sealing portion207, for example as shown inFIG.1. From the proximal end201to the distal end202, each portion may be arranged in the order: plunger connector portion203, centering portion204, main body portion206, sealing portion207and end portion210.

The plunger connector portion203of the plunger200may be configured to be received in the tip connector portion103of the pipette tip100. The plunger connector portion203may be configured for connection to a liquid handling system. The plunger connector portion203may be configured as a snap-fit connection.

The centering portion204may be configured to be received in a centering portion104of the pipette tip100, so as to centre the plunger200within the pipette tip100. The centering portion204may be substantially conical or dome-shaped.

The main body portion206of the plunger200may be configured to be received in the main body portion106of the pipette tip100. The main body portion206may be substantially cylindrical and/or elongate. The main body portion206may have a substantially uniform diameter. The main body portion206may extend along at least half of the length of the plunger, optionally at least two thirds of the length of the plunger200. The main body portion206may have a larger diameter than the diameter of the end portion210.

The sealing portion207of the plunger200may be configured to be received in the bridging portion107of the pipette tip100. The sealing portion207may be configured to form a seal against an inner wall of the pipette tip100. The sealing portion207may form a fluid-tight seal within the pipette tip, such that fluid cannot pass from a proximal side of the sealing portion207to a distal side of the sealing portion207when the plunger200is installed in the pipette tip100. The sealing portion207may be at least partly flexible. The sealing portion207may be configured to bridge the main body portion206to the end portion210. The sealing portion207may define a step between the main body portion206and the end portion210. The sealing portion207may be substantially tapered, conical and/or dome-shaped.

The end portion210of the plunger200may be configured to be received in the end portion110of the pipette tip100. The end portion210may have a smaller diameter than the sealing portion207and/or the main body portion206.

The end portion210may substantially or entirely fill the end portion110of the pipette tip100. This may be such that there is no airgap within the pipette tip end portion110when the plunger end portion210is in an extended position. The end portion210may contact the inner wall surface111of the pipette tip end portion110when the plunger end portion210is in an extended position.

The end portion210may be substantially elongate and/or conical. The end portion210may have substantially straight walls. The end portion210may have an outer wall212having a shape that complements, matches and/or corresponds to a shape of the inner wall surface111of the pipette tip end portion110. The end portion210may have an outer wall212that is aligned with and/or parallel to the inner wall surface111of the pipette tip end portion110, over at least part of the length of the inner wall surface111, substantially all of, or the entire length of the inner wall surface111.

The end portion210of the plunger200may have a substantially flat face at its distal end202. The end portion210of the plunger200may seal the aperture108of the pipette tip end portion110when the plunger200is in an extended position.

Specifically, the distal end202of the plunger200may seal the aperture108of the pipette tip end portion110. The end portion210may be configured such that the plunger distal end202is disposed at the pipette tip distal end102when the plunger200is in an extended position. The plunger200may be configured such that the plunger distal end202does not extend beyond the pipette tip distal end102when in an extended position.

The pipette10having any of the variations noted herein may be comprised in a liquid handling system (not shown), the liquid handling system also comprising an actuator configured to move the plunger200relative to the pipette tip100.

The pipette tip100and/or plunger200may be detachable and/or attachable to or from a pipetting system or apparatus. The pipette tip100may be detachable and/or attachable at its proximal end101. The plunger200may be detachable and/or attachable at its proximal end201. The pipette tip100and/or plunger may comprise a connector means or portion103,203, which may be disposed at the respective proximal end101,201, to make the pipette tip100or plunger200suitable or configured for attachment or detachment from a pipetting system or apparatus. The pipette tip100and/or plunger200may be configured so that during aspiration, sample liquid does not extend past the proximal end101, so does not pass into a liquid handling system or apparatus. In this way, sample liquid may be contained within the removable pipette tip100, preventing contamination of a liquid handling system or apparatus. This in turn makes the apparatus or system suitable for use with multiple different sample fluids, through use of removable and optionally disposable pipette tips100and/or plungers200. Some advantages of the first aspect of the invention are demonstrated inFIGS.4to8.

InFIG.4, a known, wide-angle pipette tip is shown. The figure illustrates how in this type of pipette tip, in particular one having such a wide-angled end taper, when seeking to aspirate air into the tip after the sample the sample301can attach to one side on the pipette tip and detach from the other. This can result in uneven distribution of the dispensing pressure to the sample when the plunger is actuated for dispensing, resulting in degraded dispensing performance.

A pipette tip100according to the present disclosure is shown inFIG.5. As illustrated in the Figure, the narrower angle of the end portion110of the pipette tip can help to avoid the asymmetrical attachment of the sample within the pipette tip shown inFIG.4, and thus mitigates or eliminates the related negative effects. InFIG.5, the pipette tip100is shown in an aspirating step with a pre-sample air gap method. In such a method, the plunger200can be initially retracted to draw in a gas, such as air300, as shown inFIG.5(a), and then subsequently retracted to draw in a sample liquid301, as shown inFIG.5(b). The advantage of using a pre-airgap mechanism or method is that the dead volume (sample liquid left in the pipette after dispensing) is reduced. The narrow angle pipette tip100ensures the liquid sample drawn in remains as a single slug301that can be fully ejected on dispensing. This allows very low volumes (<200 nl) to be handled. Steps in the method are described in the following passages. The steps can be implemented using an actuation mechanism such as that described in relation toFIG.9.

The method of aspirating a liquid may include the following:providing the pipette10;retracting the plunger200relative to the pipette tip100so as to aspirate a gas300through the aperture108into the pipette tip100; and subsequentlyretracting the plunger200so as to aspirate a sample liquid301through the aperture108into the pipette tip100. This may be referred to as a pre-sample airgap method.

The method may further comprise:extending the plunger200relative to the pipette tip100so as to dispense a sample liquid301through the aperture108from the pipette tip100; andsubsequently extending the plunger200so as to dispense a gas300through the aperture108from the pipette tip100.

The method may further comprise:providing the pipette10;retracting the plunger200so as to aspirate a liquid301through the aperture108into the pipette tip100; and subsequentlyretracting the plunger200relative to the pipette tip100so as to aspirate a gas302through the aperture108into the pipette tip100. This may be referred to as a post-sample airgap method.

The method may further comprise:extending the plunger200so as to dispense a gas302through the aperture108from the pipette tip100; and subsequentlyextending the plunger200relative to the pipette tip100so as to dispense a sample liquid301through the aperture108from the pipette tip100.

InFIG.6, a known, wide-angle pipette tip is shown. In this pipette tip, it can be seen that when seeking to aspirate air into the pipette tip both before and after the sample, the sample301may attach to one side on the pipette tip and detach from the other. When performing non-contact dispensing, a liquid sample must be travelling at a high enough velocity to detach from the tip. In known pipette tips, it is difficult to achieve this velocity with small volumes, because the plunger stroke is relatively short. The inventors have identified that a way to increase the plunger stroke is to introduce a small airgap (or other gas) after the liquid sample is aspirated, i.e. to continue to withdraw the plunger after the sample has been aspirated, to draw in air. In known pipette tips, such as the pipette tip ofFIG.6, the inventors have identified that this mechanism is not viable in a pipette tip having a plunger. This is because the geometry of a known pipette tip, which has a much wider pipette tip angle than the pipette of the first aspect, is such that the liquid would attach to one side of the inner wall surface of the pipette tip and/or plunger due to surface tension. This would lead to poor dispense performance in a post-airgap mechanism.

A pipette tip100according to the present disclosure is shown inFIG.7. InFIG.7, the pipette tip100is shown in an aspirating step with a pre-sample air gap300, a sample301, and a post-sample air gap302. The narrow angle tip of pipette tip100ensures that this post-sample airgap302can be introduced in a controlled manner. The narrow angle of the pipette tip100demonstrated inFIG.7provides a more uniform liquid attachment.

A further advantage of the pipette tip100of the present disclosure is that it provides a combination of good reach and capacity. This is particularly advantageous in methods involving magnetic bead clean-up, for example as demonstrated inFIG.8. During magnetic bead clean-up, magnetic beads303are pulled to the side of a microplate well400by an external magnet. Liquid301is then extracted from the well400while the magnetic beads303must remain in the well400. The geometry of the narrow angle pipette tip100is particularly suitable to avoid contact with magnetic beads.

The pipette10may be provided as a part of a liquid dispensing apparatus, which may comprise a pipetting head and/or a direct drive actuator.

The pipette tip100and/or plunger200may be configured for attachment to the apparatus by a pipette tip clamping mechanism1120. There may be provided a plate on which multiple pipette tip clamping mechanisms1120are provided. The pipette tip100may be attached to the apparatus by a pipette tip clamping mechanism1120, which may involve a clamp at the pipette tip connector portion103. The plunger200may be attached to the apparatus by a plunger clamping mechanism1140, which may involve a clamp at the plunger tip connector portion203. There may be provided a plate on which multiple plunger clamping mechanisms1140are provided.

FIG.9embodiment shows an embodiment in which the pipette tip100and plunger200are attached to the apparatus via a plurality of plates1121,1122,1123,1124. The skilled person will appreciate that the apparatus and method of the present disclosure may alternatively involve other attachment components and mechanisms. The apparatus may comprise a first plate1121, a second plate1122, a third plate1123and/or a fourth plate1124. The plunger200may be attached to the first and second plates1121,1122, which may be referred to as plunger plates. The pipette tip100may be attached to the third and fourth plates1123,1124, which may be referred to as pipette plates. The pipette tip100may be attached to the apparatus, specifically to the third and fourth plates1123,1124, by a pipette tip clamping mechanism1120, which may involve a clamp at the pipette tip connector portion103. The plunger200may be attached to the apparatus, specifically to the first and second plates1121,1122by a plunger clamping mechanism1140, which may involve a clamp at the plunger tip connector portion203. One or more plates may comprise multiple clamping mechanisms1120,1140, to clamp multiple pipette tips100and plungers200.

As regards the plunger clamping mechanism1140, there may be provided an array of plunger clamping members1147each associated with one of a plurality of plunger mounts1143. The array of plunger clamping members1147may be provided in the form of a plurality of clamping rods1147which extend axially from a first plate1121and extend into the bores defined within the plunger mount sleeves1143. Each clamping rod1147may have an enlarged head1148at its lower end which extends from a narrower neck region1149A. The enlarged head1148has an outer diameter which is less than the inner diameter of the plunger mount sleeve1143. In this manner, a small clearance is provided between the outer surface of the enlarged head1148and the inner surface of the plunger mount sleeve1143when the plunger clamping mechanism is engaged. The neck1149A has an outer diameter which is less than that of the enlarged head1148. Preferably, each clamping rod1147also has a main shaft1149B with an outer diameter which is substantially the same as the inner diameter of the region of the plunger mount sleeve1143in which it is located. The main shaft1149B slides along the inner surface of the plunger mount1143as the first plate1121is moved up and down in the axial direction relative to the second plate1122. This can help to ensure correct lateral alignment between the plunger mounts1143and the plunger clamping members1147.

As regards the pipette tip clamping mechanism1120, the tip connector portion103is configured for connection to a liquid handling system, for example with a snap-fit connection. The tip connector portion103may comprise a split tubular wall which may be defined by a plurality of flexible segments. The flexible segments may be configured to resiliently deflect in a radially outward direction to increase the outer diameter of the proximal end101of the pipette tip100from 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 portion103comprises a plurality of axially extending discontinuities or slots in the tubular wall which separate a plurality of flexible segments. The plurality of slots may be 2, 3 or 4 slots, and the plurality of flexible segments may be 2, 3 or 4 segments. The tip connector portion103may comprise any suitable number of axially extending discontinuities to define any number of flexible segments. The arrangement of flexible segments and slots enables the tip connector portion to expand without requiring significant forces to be exerted on the tip connector portion. The tip connector portion103may further comprise one or more radially extending features1126on 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 portion103may 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 portion103comprises a part-annular rib1126which protrudes from the inner surface of the tip connector portion103. 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 feature1126.

The pipette tip100may be clamped between a tip mount sleeve123and a plate, such as the fourth plate1124as shown inFIG.9. The tip mount sleeve123may be provided on a plate, such as the third plate1123.

With reference toFIG.9, one or more method steps may be carried out by one or more actuators1161,1162,1163, which may be comprised in the liquid dispensing apparatus. The one or more actuators may be controlled by one or more controllers1171.

The controller1171may comprise one or more of: a processor, a memory, one or more input ports, one or more output ports, and may comprise or be connected to a user input device.

The user input device may comprise a mouse or keyboard, a hand-held device or touchscreen, which may have a graphical user interface. There may be provided a display such as a graphical user interface, which may be configured to display outputs. The display may be configured for input of information, and present an option to select a method or mode of operation, and/or an option to activate the mode. The display may display information such as what mode the apparatus is operating in, and/or any variable or variables selected. The display may be configured to present information such as which information has been inputted.

The controller1171may be configured to receive an input, specifically data, via one or more input ports. This data may be indicative of which method or mode to operate, any operational parameters such as volume of sample liquid, number of samples, location of samples, aspirating or dispensing time, aspirating or dispensing speed, pre-sample and/or post-sample airgap volume.

The controller1171, specifically the processor of the controller, may determine, based on one or more inputs, a signal or signals to send to the one or more actuators1161,1162,1163,1164. This determination may involve a set of instructions, which may be stored in memory. The controller1171may output signals to one or more actuators1161,1162,1163,1164and/or to a conversion or switching means, such as an electrical relay.

The memory may comprise a computer readable storage medium such as a hard disk drive (HDD), flash drive, solid state drive, or any other form of general-purpose data storage, upon which information and various programs are arranged. Such programs may include, for example, one or more pre-programmed modes or methods of operation of the apparatus.

The apparatus may comprise one or more communication means which may provide a communication pathway between the controller1171via one or more input or output ports, and the one or more actuators1161,1162,1163,1164. The communication means may comprise a wire or cable, which may physically connect the controller1171to one or more actuators1161,1162,1163,1164. There may be a wire or cable to each actuator from the controller1171, for example as indicated inFIG.9. Alternatively or in addition, the communication means may comprise wireless connection, such as a transmitter and receiver.

There may be provided a first actuator1161. The first actuator may be configured to move the pipette tip100relative to the plunger200. This may allow the pipette to aspirate and/or dispense fluid. The first actuator1161may be configured to move the first and/or second plates1121,1122relative to the third and/or fourth plates1123,1124. As represented inFIG.9, the first actuator1161may move the second plate1122relative to the third plate1123. The first actuator1161may be configured to receive a signal from the controller1171to cause movement of the plunger200and/or the second plate1122relative to pipette tip100and/or the third plate1123at a specific time and/or at a specific speed and/or by a specific amount and/or in a specific direction.

There may be provided a second actuator1162. The second actuator1162may be configured to move the pipette tip100and/or plunger200relative to a fixed housing1101. As represented inFIG.9, the second actuator1162may move the third plate1123relative to a housing1101. This allows the pipette tip100and/or plunger200to be moved relative to a sample receptacle. The second actuator1162may be configured to receive a signal from the controller1171to cause movement of the pipette tip100and/or plunger200and/or the third plate1123relative to a sample container, at a specific time and/or at a specific speed and/or by a specific amount and/or in a specific direction.

The apparatus may comprise a body with a receptacle receiving area, such as a microplate receiving area, or deck, and a pipetting head positioned above the microplate receiving area. The microplate receiving area may have a substantially horizontal upper surface arranged to receive a laboratory microplate. The receiving area can be located on a height-adjustable support structure which enables the height of the microplate receiving area to be varied as required. The receiving area may be configured to retain a laboratory microplate in a fixed position. For example, the upper surface of the receiving area may comprise one or more recesses arranged to receive a microplate and to prevent lateral translation of the microplate with respect to the receiving area. The pipetting head of the apparatus may be configured to hold an array of pipettes, and may be moveable in relation to a deck to bring pipettes mounted on the pipetting head into close proximity to a microplate supported on the deck to allow liquid to be aspirated from or dispensed into the wells of the microplate.

The second actuator1162may be configured to move the second and third plates1122and1123relative to the microplate receiving area. The fixed housing1101may be attached to the microplate receiving area.

There may be provided a third actuator1163. The third actuator1163may be configured to, upon receipt of a signal from the controller1171, attach and/or disconnect the plunger from the system. The third actuator may be connected to the first plate and second plate1121,1122, so as to move the first plate1121relative to the second plate1122. The third actuator1163may be a rotary actuator, which may be configured to provide linear movement of the first plate1121relative to the second plate1122.

There may be provided a fourth actuator1164. The fourth actuator1164may be configured to, upon receipt of a signal from the controller1171, attach and/or disconnect the pipette tip100from the system. The fourth actuator may be connected to the third plate and the fourth plate1123,1124. The fourth actuator1164may be a rotary actuator.

To perform an aspirating operation, the plunger200and pipette tip100, or series of plungers and pipette tips, may be moved to the desired position relative to a liquid sample receptacle. The plunger200, or plunger200of each pipette10may then be raised within its respective pipette tip100, which may be done using the first actuator1161, which may be a direct drive actuator to move plates1121and1123relative to one another in the direction of arrows1161′. This may move the entire plunger clamping mechanism1140, and the plunger plates1121,1122away from the pipette tip clamping mechanism1120and the pipette tip plates1123,1124, as shown inFIG.9, to draw fluid into the pipette tip100. The fluid can then be dispensed as desired by moving the plunger clamping mechanism1140in the opposite direction using the direct drive actuator1161.

The direct drive actuator1161may be operable to move the plunger clamping mechanism1140in an axial direction towards or away from a plate or plates of the pipette tip clamping mechanism1120to aspirate or dispense liquid during use. There may be provided a head chassis, and the direct drive actuator1161may be fixed in relation to the head chassis. The direct drive actuator1161may extend between the head chassis and the plunger clamping mechanism1140.

The direct drive actuator1161may comprise an actuator motor, which may be mounted on the top surface of a head chassis and extends between the head chassis and the plunger. The output shaft of the actuator motor1161may be fixed to a threaded rod connected to a ball screw actuator nut. The nut may be fixed to a ball screw mount which in turn is fixed to a plunger clamp motor mount plate at the upper end of the plunger clamping mechanism1140. The direct drive actuator1161thus may extend between the head chassis and the plunger clamping mechanism1140. When the actuator motor1161is operated, the entire plunger clamping mechanism1140may be moved in the axial direction either towards or away from the pipette tip clamping mechanism1120, to move the plunger in one axial direction or another relative to the pipette tip100, depending on the direction of rotation of the actuator motor1161. In this manner, the speed of relative movement between a plunger clamped by the plunger clamping mechanism1140and the pipette tip within which it extends can be varied to a much greater extent than with known devices. This allows the apparatus to be used in a non-contact dispensing mode as well as a contact dispensing mode. When performing non-contact dispensing, a liquid sample must be travelling at a high enough velocity to detach from the tip. Sufficient velocity for non-contact dispensing can be achieved with the direct drive actuator1161, which in some instances cannot be achieved with a belt drive. Specifically, direct drive via a ball screw offers higher acceleration and deceleration of heavy loads than a belt driven system. This is particularly advantageous where the distance travelled for a dispense shot is small (for example, <1 mm), therefore high acceleration and deceleration allows the system to reach target velocity. In addition, ball screws offer higher positional accuracy and repeatability, which is has a beneficial effect on dispense performance.

The apparatus may be configured such that the controller1171, specifically the memory and processor, causes the first actuator and the second actuator1161,1162to carry out aspirating/dispensing steps.

For example, the controller1171may comprise a computer readable medium which comprises instructions that, when executed by the processor, cause the processor to send a signal to cause retraction of the plunger200within the pipette tip100so as to aspirate air to form a pre-sample air gap300;output a signal to cause insertion of the pipette tip100into a sample liquid;output a signal to cause retraction of the plunger200within the pipette tip100so as to aspirate sample liquid; andoutput a signal to cause withdrawal of the pipette tip100from the sample liquid. The computer readable medium may comprise instructions that, when executed by a processor, cause the processor to carry out any of the method steps noted herein.

The signal to cause insertion of the pipette tip100into a sample liquid may be sent to the second actuator1162. The signal to cause retraction of the plunger200within the pipette tip100so as to aspirate sample liquid may be sent to the first actuator1161. The signal to cause withdrawal of the pipette tip100from the sample liquid may be sent to the second actuator1162.

The controller1171may comprise a computer readable medium, which comprises instructions that, when executed by the processor, cause the processor to send a signal to cause disconnection of the pipette tip100and/or plunger200from the apparatus. This signal may be sent to the third actuator1163and/or the fourth actuator1164.

One, more or all actuators1161,1162,1163,1164may be configured to cause movement in the same direction. When installed, one, more or all actuators1161,1162,1163,1164may be configured to cause movement of the system in an axial direction which may be a vertical direction.

For example, a plunger and pipette tip arrangement have been described and shown in which each of the plunger and pipette tip have various portions. While these have been described in combination, the skilled person will appreciate that the advantages of the present disclosure may be achieved with any suitable combination or permutation or pipette tip or plunger portions.

While the term “airgap” has been used herein, the skilled person will appreciate that there are various suitable gases that could be used in such a method, and that “airgap” should not be limited to only air. The airgap may comprise atmospheric gas, or a gas of controlled composition.

While the term “plunger” has been used herein, the skilled person will appreciate that the term “piston” may also describe the plunger.

The term “diameter” has been used as a dimensional parameter. The skilled person will appreciate that the invention may be realised without requiring a strictly cylindrical or circular shape. As such, the term diameter may be read as lateral dimension. Embodiments involving cylindrical or circular shapes (and as such components for which the term “diameter” is particularly suitable) may be advantageous.

Where the word ‘or’ appears, this may be construed to mean ‘and/or’ such that items referred to are not necessarily mutually exclusive and may be used in any appropriate combination.