Pipette Tips

Abstract

A pipette for aspirating and / or dispensing liquid is provided, the pipette tip having a proximal end and a distal end defining a longitudinal axis therebetween, an opening at the distal end, and a fluid cavity extending from the opening at least partially to the proximal end. The plunger is positioned within the pipette tip and extends at least partially between the proximal and distal ends of the pipette tip to an end, and is movable to and from the opening to aspirate fluid or dispense fluid from the pipette tip. The pipette tip has an end provided at the distal end having an inner wall surface extending at least 5 mm at an angle of 2 degrees to 5 degrees relative to the longitudinal axis.

Description

[Technical field]

[0001] The present invention relates to a pipette having a pipette tip and a plunger, the pipette tip having a particularly advantageous shape. [Background technology]

[0002] It is known to use pipettes to aspirate or dispense liquid samples.

[0003] It is also known to use pipettes that have a plunger located within the 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 contracted to draw in the sample liquid and expanded to dispense the sample liquid. Such pipettes can be used in automated machines to improve the accuracy and repeatability of pipetting movements.

[0004] The present inventors have identified several problems with known pipettes, particularly with regard to dispensing small volumes.

[0005] There is a need for improved pipettes. Summary of the Invention

[0006] The first aspect of the present invention is A pipette tip comprising: a proximal end, a distal end and a longitudinal axis extending therebetween; an opening at a distal end; a fluid cavity extending from the opening at least partially to the proximal end; having a pipette tip having an end at a distal end, the end having an inner wall surface extending at least 5 mm at an angle of up to 5 degrees relative to a longitudinal axis; a plunger positioned within the pipette tip, the plunger extending at least partially between the proximal and distal ends of the pipette tip and movable into and away from the opening and configured to aspirate fluid and / or dispense fluid from the pipette tip; A pipette for aspirating and / or dispensing liquid is provided, comprising:

[0007] The inner wall surface may extend at an angle of between 2 degrees and 5 degrees relative to the longitudinal axis and for at least 5 mm.

[0008] The geometry of the pipette tip specified in the first aspect of the invention, specifically the inner wall surface extending at least 5 mm at an angle of up to 5 degrees to the longitudinal axis, provides a much steeper angle than the wide-angle pipette tips of the known pipettes mentioned in the Background section. This narrow-angle pipette tip has several important advantages over the geometry of the known pipette tips.

[0009] Firstly, what is called a "post-sample air gap" allows the pipette tip to be used in an adapted manner compared to known pipette tips. When performing non-contact dispensing, i.e. dispensing in which the sample liquid forms one or more droplets after leaving the pipette tip and before reaching the sample container or the sample in the sample container, the liquid sample must travel at a sufficiently fast speed and leave the tip. In known pipette tips, this speed is difficult to reach with small volumes due to the relatively short plunger stroke. The inventors have determined that a way to increase the plunger stroke is to introduce a small air gap (or other gas) after the liquid sample has been aspirated, i.e. continue to pull the plunger after the sample has been aspirated, sucking in air. The narrow-angle tip of the first embodiment allows this air gap to be introduced in a controlled manner. The inventors have determined that in known pipette tips, this mechanism cannot be performed with pipette tips with plungers. This is because the geometry of known pipette tips, which have a much wider pipette tip angle than the pipette of the first embodiment, causes liquid to adhere to one side of the inner wall of the pipette tip and / or plunger due to surface tension. This leads to poor dispensing performance in the post-sample air gap method. The narrow angle of the pipette tip of the first embodiment alleviates this problem by providing a more uniform deposition of liquid.

[0010] Secondly, the inventors have identified that a pipette tip can be used in a more adaptive manner than known pipette tips, by what they call a "pre-sample air gap". In such a mechanism, the plunger can be first retracted to draw in a gas, such as air, and subsequently retracted to draw in sample liquid. The advantage of using a pre-sample air gap mechanism is that all of the liquid aspirated can be dispensed, i.e. there is no dead volume in the pipette tip. Dead volume is the gap between the plunger and the pipette tip that is caused by manufacturing tolerances that do not allow for a perfect fit. Without the pre-sample air gap, some liquid sample would remain in this gap between the plunger and the tip.

[0011] Narrow-angle tips also allow the aspirated liquid sample to remain as a single slug that can be released in its entirety upon dispensing, rather than being stuck to the inside wall of the pipette tip, making it possible to process very small volumes (<200 nl).

[0012] Tips configured for use with a pre-sample air gap have an additional advantage. Traditional positive displacement pipettes require a minimum amount of liquid to be aspirated in order to prime them accurately. If not primed accurately, dispensing performance can be compromised. The pre-sample air gap described above eliminates the need for a priming volume and can handle low source volumes (<500 nl) and low dispense volumes (<200 nl).

[0013] Third, the geometry of the pipette tip 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, and extract as much liquid as possible, while having a large enough volume to minimize the number of aspirates / dispenses required to empty or fill the well. This high volume helps minimize the number of fills required to perform a dispense, saving time and associated costs. The volume of the design can reach 100 μl.

[0014] Of this non-exhaustive list of advantages, a further advantage of the first described embodiment that can be deduced from the advantages above is that the tip geometry results in a pipette with a large dynamic range, e.g., from about 0.1 or 0.2 μl to about 100 μl. The pre-sample and post-sample air gap mechanisms enabled by the tip geometry, and the overall volume enabled by the tip geometry, result in a particularly advantageous pipette tip suitable for aspirating and / or dispensing a variety of sample and / or source volumes.

[0015] The pipette may be particularly suitable for use in quantitative polymerase chain reaction ("qPCR") techniques. Further optional advantageous features of the present invention are set out in the following paragraphs.

[0016] The end portion may have an outer wall surface extending at an angle of at most 5 degrees to the longitudinal axis and at least 5 mm. The outer wall surface may extend at an angle of at most 4 degrees to the longitudinal axis, preferably at most 3.5 degrees to the longitudinal axis, preferably at most 3.3 degrees to the longitudinal axis.

[0017] The opening may have a diameter of at most 1 mm, preferably at most 0.5 mm, more preferably at most 0.4 mm, optionally at least 0.4 mm.

[0018] The end may have a maximum outer diameter of at most 4mm, preferably at most 3mm, more preferably at most 2mm, more preferably at most 1mm, more preferably at most 0.7mm, more preferably at most 0.65mm. Optionally, the end 110 may have a maximum outer diameter of at least 0.5mm, optionally at least 0.6mm, optionally at least 0.65mm.

[0019] The inner wall surface at the end of the pipette tip may define a straight sided shape, such as a frusto-conical or cylindrical shape.

[0020] The outer wall surface of the end of the pipette tip may define a straight sided shape, such as a frusto-conical or cylindrical shape.

[0021] The plunger may have an outer end wall surface configured to align with an inner wall surface of the end of the pipette tip.

[0022] The plunger may be configured to seal the opening when in the extended position.

[0023] The plunger may have an end that substantially or completely occupies the end of the pipette tip when in the extended position.The plunger may have a plunger end that substantially or completely does not occupy the end of the pipette tip when in the extended position.

[0024] 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, more 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.

[0025] The inner wall surface of the end portion may extend at least 7mm, preferably at least 10mm, more preferably at least 12mm.

[0026] A pipette having any of the variations described herein may be included in a liquid handling system, which also includes an actuator configured to move the plunger relative to the pipette tip.

[0027] A plurality of pipettes having any of the variations described herein; an actuator configured to move a plurality of pipette tips and / or plungers of a plurality of pipettes to aspirate and / or dispense fluid; There may be provided a liquid treatment system comprising:

[0028] The actuator may be configured to simultaneously move multiple pipette tips and / or plungers of multiple pipettes to aspirate and / or dispense fluid.

[0029] The multiple pipettes may be arranged in a planar, 2D arrangement relative to each other. The multiple pipettes may be arranged in a regular matrix, such as a lattice, optionally a symmetric matrix. The multiple pipettes may be arranged in a square or rectangular shape.

[0030] 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 matrix, such as a 16×24 matrix in a grid, optionally in a symmetric matrix.

[0031] According to a second aspect of the present invention, Providing a pipette having any of the variations described herein; retracting the plunger against the pipette tip to draw gas through the opening into the pipette tip; and Retracting the plunger and aspirating the sample liquid through the opening into the pipette tip. A method for aspirating a liquid is provided, comprising:

[0032] The method comprises: extending the plunger against the pipette tip to dispense the sample liquid from the pipette tip through the opening; and Extending the plunger to dispense gas from the pipette tip through the opening; It may further include.

[0033] The method comprises: Providing a pipette having any of the variations described herein; Retracting the plunger to aspirate liquid through the opening into the pipette tip; and Retracting the plunger against the pipette tip to draw gas into the pipette tip through the opening; It may further include.

[0034] The method comprises: extending the plunger to dispense gas from the pipette tip through the opening; and extending the plunger against the pipette tip to dispense the sample liquid from the pipette tip through the opening; It may further include.

[0035] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings. [Brief description of the drawings]

[0036] [Figure 1] FIG. 2 is a cross-section of a pipette tip and a side view of a plunger. [Diagram 2] FIG. 2 is a perspective view of a pipette tip and plunger in an exploded state. [Diagram 3] FIG. 2 is a close-up view of the end of the pipette tip and the end of the plunger in an assembled state. [Figure 4] FIG. 1 is a schematic diagram of aspirating liquid into a wide-angle pipette tip. [Diagram 5] 1A and 1B are schematic diagrams showing how a narrow-angle pipette tip aspirates liquid; [Figure 6] FIG. 1 is a schematic diagram of aspirating liquid into a wide-angle pipette tip. [Figure 7] 1A and 1B are schematic diagrams showing how a narrow-angle pipette tip aspirates liquid; [Figure 8] FIG. 1 is a schematic diagram of the magnetic bead cleanup process with narrow angle pipette tips. [Figure 9] FIG. 1 is a schematic diagram of a liquid dispensing device. [Figure 10] FIG. 2 is a diagram of a portion of a pipette tip. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] 1 shows a pipette 10 for aspirating and / or dispensing liquid. The pipette 10 comprises a pipette tip 100 and a plunger 200.

[0038] The pipette tip 100 may be a receptacle that receives and / or contains a sample fluid or sample liquid. The pipette tip 100 may be configured to be inserted into a container of sample liquid or into the sample liquid.

[0039] The pipette tip 100 has a proximal end 101 and a distal end 102, the proximal end 101 and the distal end 102 defining a longitudinal axis 1 therebetween.

[0040] The pipette tip 100 has an opening 108 at its distal end 102, as shown in FIG. 2. The opening 108 may be defined by an inner wall surface 111 of the pipette tip 100 at the distal end 102, specifically at the outermost distal point of the pipette tip 100. The opening 108 may define a substantially circular or circular shape. The opening 108 may have a diameter of at most 1 mm, preferably at most 0.5 mm, and more preferably at most 0.4 mm. Optionally, the opening 108 may have a diameter of at most 0.35 mm, 0.3 mm, 0.25 mm, 0.1 mm. Optionally, the opening 108 may have a diameter of at least 0.4 mm.

[0041] An inner wall 111 of the pipette tip 100 may extend through the support portion 105 and / or the body portion 106 of the pipette tip 100. The inner wall surface 111 may be substantially tubular and / or parallel sided within the support portion 105 and / or the body portion 106. The pipette tip 100 has a fluid cavity 109 extending from the opening 108 at least partially to the proximal end 101. The fluid cavity 109 may be configured to receive and / or hold a fluid, such as an air gap or a sample liquid. The fluid cavity 109 may be substantially elongated. The fluid cavity 109 may be defined by the inner wall surface 111 of the pipette tip 100. The fluid cavity 109 may be located mostly or completely within the end 110 of the pipette tip 100.

[0042] The pipette tip 100 comprises an end 110 at the distal end 102 having an inner wall surface 111 extending at least 5 mm at an angle α of at most 5 degrees, or π / 36 radians, or about 0.08-0.09 radians, relative to the longitudinal axis 1. The inner wall surface 111 may extend at an angle α of at most 4 degrees relative to the longitudinal axis 1, preferably at most 3 degrees relative to the longitudinal axis 1, and more preferably at most 2 degrees relative to the longitudinal axis 1. For the angle α, see FIG. 3. The angle α may be at least 0 degrees, i.e. parallel to the longitudinal axis 1. A pipette tip end 110 extending at an angle of at least 2 degrees or at least 1 degree relative to the longitudinal axis 1 may be advantageous compared to an angle of 0 degrees, since it is easier, simpler and / or cheaper to manufacture. The angle α may be measured using any suitable angle measurement technique known to those skilled in the art.

[0043] The longitudinal axis 1 may be a central axis around which the pipette tip 101 and / or plunger 200 are disposed. The longitudinal axis 1 may define a central axis around which the pipette tip 100 and / or plunger 200 are disposed evenly or symmetrically. The pipette tip 100 and / or plunger 200 may be configured such that the direction of aspiration and / or dispensing is along the longitudinal axis 1.

[0044] The inner wall surface 111 of the end 110 may extend at most 7 mm at an angle equal to the angle α, preferably at most 10 mm at an angle equal to the angle α, and more preferably at most 12 mm at an angle equal to the angle α. The inner wall 111 of the end 110 of the pipette tip 100 may define a straight sided shape, such as a frusto-conical or cylindrical shape.

[0045] The end 110 may have an outer wall surface 112 that extends at least 5 mm at an angle β of up to 5 degrees relative to the longitudinal axis 1, as best seen in FIG. 3. The outer wall surface 112 of the end of the pipette tip may define a straight sided shape, such as a frusto-conical or cylindrical shape. The end 110 may have a maximum outer diameter of up to 4 mm, preferably up to 3 mm, more preferably up to 2 mm, more preferably up to 1 mm, more preferably up to 0.7 mm, and more preferably up to 0.65 mm. Optionally, the end 110 may have a maximum outer diameter of at least 0.5 mm, optionally at least 0.6 mm, and optionally at least 0.65 mm (1055), for example, as shown in FIG. 10. The ring 1055 may be configured to provide a counter force during use. The ring 1055 may be configured to position or center the pipette tip 100 during storage and / or use. The ring 1055 may be configured to at least partially facilitate extraction of the pipette tip 100 from a mold during manufacturing.

[0046] The body portion 106 may be substantially cylindrical and / or elongated. The body portion 106 may have a substantially uniform inner and / or outer diameter. The body portion 106 may extend along at least half of the length of the pipette tip 100. The body portion 106 may have an inner and / or outer diameter that is larger than any diameter of the end portion 110.

[0047] The bridge 107 may be configured to bridge the body portion 106 to the end portion 110. The bridge 107 may define a step between the body portion 106 and the end portion 110. The bridge 107 may be substantially tapered, conical, and / or dome-shaped.

[0048] The plunger 200 is positioned within the pipette tip 100. The plunger 200 may be configured to move relative to the pipette tip 100 to draw fluid into and / or expel fluid from the pipette tip 100. Specifically, when moving from an extended position to a retracted position, the plunger 200 may draw fluid, such as an air gap or sample liquid, into the pipette tip 100. When moving from a retracted position to an extended position, the plunger 200 may expel fluid, such as an air gap or sample liquid, from the pipette tip 100.

[0049] The plunger 200 and / or the pipette tip 100 may be configured such that in the extended position, the plunger 200 is completely contained within the pipette tip 100. The plunger 200 is configured to extend at least partially into the end 110 between the proximal end 101 and the distal end 102 of the pipette tip 100. The plunger 200 may be configured to extend substantially or completely into the end 110 between the proximal end 101 and the distal end 102 of the pipette tip 100. The plunger 200 is movable into and away from the opening 109 to aspirate or dispense fluid from the pipette tip 100. The plunger 200 may have an outer end wall surface 212 configured to align with the inner wall surface 111 of the pipette tip end 110. The plunger 200 may include or consist of a polymeric material. The plunger 200 may include or be made of a homogenous material.

[0050] The plunger 200 may include a series of portions, each having a different function, distinguishing feature, and / or different shape or size. The plunger 200 may include, for example, one or more of a plunger connector portion 203, a center portion 204, a body portion 206, and a sealing portion 207, as shown in FIG. 1. From the proximal end 201 to the distal end 202, the portions may be arranged in the following order: plunger connector portion 203, center portion 204, body portion 206, sealing portion 207, and end portion 210.

[0051] The plunger connector portion 203 of the plunger 200 may be configured to be received into the tip connector portion 103 of the pipette tip 100. The plunger connector portion 203 may be configured to be coupled to a liquid handling system. The plunger connector portion 203 may be configured as a snap-fit ​​connection.

[0052] The core 204 may be configured to be received in the center 104 of the pipette tip 100 and to center the plunger 200 within the pipette tip 100. The core 204 may be substantially conical or dome-shaped.

[0053] The body portion 206 of the plunger 200 may be configured to be received in the body portion 106 of the pipette tip 100. The body portion 206 may be substantially cylindrical and / or elongated. The body portion 206 may have a substantially uniform diameter. The body portion 206 may extend along at least half the length of the plunger, optionally at least two-thirds the length of the plunger 200. The body portion 206 may have a diameter larger than the diameter of the end portion 210.

[0054] The sealing portion 207 of the plunger 200 may be configured to be received in the bridge portion 107 of the pipette tip 100. The sealing portion 207 may be configured to form a seal against an inner wall of the pipette tip 100. The sealing portion 207 may form a fluid-tight seal within the pipette tip such that when the plunger 200 is placed within the pipette tip 100, fluid does not flow from a proximal side of the sealing portion 207 to a distal side of the sealing portion 207. The sealing portion 207 may be at least partially flexible. The sealing portion 207 may be configured to bridge the body portion 206 to the end portion 210. The sealing portion 207 may define a step between the body portion 206 and the end portion 210. The sealing portion 207 may be substantially tapered, conical, and / or domed.

[0055] The end 210 of the plunger 200 may be configured to be received in the end 110 of the pipette tip 100. The end 210 may have a smaller diameter than the sealing portion 207 and / or the body portion 206.

[0056] The end 210 may substantially or completely occupy the end 110 of the pipette tip 100. This prevents an air gap from forming within the pipette tip end 110 when the plunger end 210 is in the extended position. The end 210 may contact the inner wall surface 111 of the pipette tip end 110 when the plunger end 210 is in the extended position.

[0057] The end 210 may be substantially elongated and / or conical. The end 210 may have a substantially straight wall. The end 210 may have an outer wall 212 having a shape that complements, matches, and / or corresponds to the shape of the inner wall surface 111 of the pipette tip end 110. The end 210 may have an outer wall 212 that is aligned with and / or parallel to the inner wall surface 111 of the pipette tip end 110 along at least a portion of the length of the inner wall surface 111, substantially all of the inner wall surface 111, or the entire length of the inner wall surface 111.

[0058] The end 210 of the plunger 200 may have a substantially flat surface at its distal end 202. The end 210 of the plunger 200 may seal the opening 108 of the pipette tip end 110 when the plunger 200 is in the extended position. Specifically, the distal end 202 of the plunger 200 may seal the opening 108 of the pipette tip end 110. The end 210 may be configured such that the plunger distal end 202 is disposed at the pipette tip distal end 102 when the plunger 200 is in the extended position. The plunger 200 may be configured such that the plunger distal end 202 does not extend beyond the pipette tip distal end 102 when the plunger 200 is in the extended position.

[0059] A pipette 10 having any of the variations described herein may be included in a liquid handling system (not shown), which also includes an actuator configured to move the plunger 200 relative to the pipette tip 100.

[0060] The pipette tip 100 and / or the plunger 200 may be removable from and / or attachable to a pipetting system or device. The pipette tip 100 may be removable and / or attachable at its proximal end 101. The plunger 200 may be removable and / or attachable at its proximal end 201. The pipette tip 100 and / or the plunger may comprise a connector means or connector portion 103, 203 provided at the respective proximal end 101, 201 such that the pipette tip 100 or the plunger 200 is suitable or configured for attachment or removal to or from a pipetting system or device. The pipette tip 100 and / or the plunger 200 may be configured such that during aspiration, the sample liquid does not extend beyond the proximal end 101 and enter a liquid handling system or device. In this manner, the sample liquid may be contained within the removable pipette tip 100, preventing contamination of the liquid handling system or device. This allows the device or system to be suitable for use with a number of different sample fluids through the use of a removable and optionally disposable pipette tip 100 and / or plunger 200. Some advantages of the first aspect of the present invention are illustrated in Figures 4-8.

[0061] A known wide angle pipette tip is shown in Figure 4. The figure illustrates how in this type of pipette tip, particularly a pipette tip with such a wide angle end taper, sample 301 can adhere to one side of the pipette tip and detach from the other side when attempting to aspirate air into the tip after the sample. This can lead to uneven distribution of dispensing pressure on the sample when the plunger is actuated to dispense, resulting in poor dispensing performance.

[0062] A pipette tip 100 according to the present disclosure is shown in FIG. 5. As shown, the narrow angle of the end 110 of the pipette tip helps to avoid asymmetric deposition of the sample in the pipette tip shown in FIG. 4, thereby reducing or eliminating the associated adverse effects. FIG. 5 shows the pipette tip 100 in an aspiration step with a pre-sample air gap method. In such a method, the plunger 200 may first be contracted to draw in a gas such as air 300, as shown in FIG. 5(a), and subsequently contracted to draw in sample liquid 301, as shown in FIG. 5(b). The advantage of using a pre-air gap mechanism or method is that dead volume (sample liquid remaining in the pipette after dispensing) is reduced. The narrow angle pipette tip 100 allows the aspirated liquid sample to remain in a single slug 301 that can be completely expelled upon dispensing. This allows for very small volumes (<200 nl) to be processed. The steps in the method are described in the following sections. This step may be carried out using an actuation mechanism such as that described in connection with FIG.

[0063] The methods for aspirating liquid are as follows: Providing a pipette 10; Retracting the plunger 200 relative to the pipette tip 100 to draw gas 300 into the pipette tip 100 through the opening 108; and Retracting the plunger 200 and aspirating the sample liquid 301 through the opening 108 into the pipette tip 100; This may be referred to as the pre-sample air gap method.

[0064] The method comprises: extending the plunger 200 against the pipette tip 100 to dispense the sample liquid 301 from the pipette tip 100 through the opening 108; and Extending the plunger 200 to dispense gas 300 from the pipette tip 100 through the opening 108; It may further include.

[0065] The method comprises: Providing a pipette 10; Retracting the plunger 200 to aspirate the liquid 301 through the opening 108 into the pipette tip 100; and Retracting the plunger 200 relative to the pipette tip 100 and drawing gas 302 into the pipette tip 100 through the opening 108; This may be referred to as a post-sample air-gap method.

[0066] The method comprises: extending the plunger 200 to dispense gas 302 from the pipette tip 100 through the opening 108; and Extending the plunger 200 relative to the pipette tip 100 to dispense the sample liquid 301 from the pipette tip 100 through the opening 108; It may further include.

[0067] FIG. 6 shows a known wide-angle pipette tip. It can be seen that in this pipette tip, when trying to aspirate air into the pipette tip both before and after the sample, the sample 301 can stick to one side of the pipette tip and leave the other side. When performing non-contact dispensing, the liquid sample must move at a sufficiently fast speed to leave the tip. In the known pipette tip, this speed is difficult to reach with small amounts because the plunger stroke is relatively short. The inventors have determined that a way to increase the plunger stroke is to introduce a small air gap (or other gas) after the liquid sample is aspirated, i.e., continue to pull the plunger after the sample is aspirated, sucking in air. The inventors have determined that in known pipette tips, such as the pipette tip of FIG. 6, this mechanism cannot be performed in pipette tips with plungers. This is because the geometry of known pipette tips, which have a much wider pipette tip angle than the pipette of the first embodiment, causes the liquid to stick to one side of the pipette tip and / or plunger inner wall surface due to surface tension. This leads to poor dispensing performance in the post air gap mechanism.

[0068] A pipette tip 100 according to the present disclosure is shown in Figure 7. In Figure 7, the pipette tip 100 is shown during an aspiration step with a pre-sample air gap 300, a sample 301, and a post-sample air gap 302. The narrow tip angle of the pipette tip 100 allows for this post-sample air gap 302 to be introduced in a controlled manner. The narrow angle of the pipette tip 100 shown in Figure 7 results in a more uniform deposition of liquid.

[0069] A further advantage of the pipette tip 100 of the present disclosure is that it provides a combination of good reach and capacity. This is particularly advantageous in methods involving magnetic bead cleanup, for example as shown in FIG. 8. During magnetic bead cleanup, magnetic beads 303 are attracted to the side of a microplate well 400 by an external magnet. Liquid 301 is then extracted from the well 400, while the magnetic beads 303 must remain within the well 400. The geometry of the narrow angle pipette tip 100 is particularly suited to avoid contact with the magnetic beads.

[0070] The pipette 10 may be provided as part of a liquid dispensing device, which may include a pipetting head and / or a direct drive actuator.

[0071] The pipette tip 100 and / or plunger 200 may be configured to be attached to the device by a pipette tip clamping mechanism 1120. A plate may be provided on which a plurality of pipette tip clamping mechanisms 1120 are provided. The pipette tip 100 may be attached to the device by a pipette tip clamping mechanism 1120, which may involve a clamp at the pipette tip connector portion 103. The plunger 200 may be attached to the device by a plunger clamping mechanism 1140, which may involve a clamp at the plunger tip connector portion 203. A plate may be provided on which a plurality of plunger clamping mechanisms 1140 are provided.

[0072] The embodiment of FIG. 9 illustrates an embodiment in which the pipette tip 100 and plunger 200 are attached to the device via multiple plates 1121, 1122, 1123, 1124. One skilled in the art will appreciate that the devices and methods of the present disclosure may alternatively involve other attachment components and mechanisms. The device may include a first plate 1121, a second plate 1122, a third plate 1123, and / or a fourth plate 1124. The plunger 200 may be attached to the first and second plates 1121, 1122, which may be referred to as plunger plates. The pipette tip 100 may be attached to the third and fourth plates 1123, 1124, which may be referred to as pipette plates. The pipette tip 100 may be attached to the device, specifically the third and fourth plates 1123, 1124, by a pipette tip clamping mechanism 1120, which may involve a clamp at the pipette tip connector portion 103. The plunger 200 may be attached to the device, specifically the first and second plates 1121, 1122, by a plunger clamping mechanism 1140, which may involve a clamp at the plunger tip connector portion 203. One or more plates may include multiple clamping mechanisms 1120, 1140 to clamp multiple pipette tips 100 and plungers 200.

[0073] With regard to the plunger clamping mechanism 1140, multiple plunger clamping members 1147 may be provided, each associated with one of the multiple plunger mounts 1143. The multiple plunger clamping members 1147 may be provided in the form of multiple clamping rods 1147 extending axially from the first plate 1121 and into holes defined in the plunger mount sleeve 1143. Each clamping rod 1147 may have an enlarged head 1148 at its lower end extending from a narrower neck region 1149A. The enlarged head 1148 has an outer diameter less than the inner diameter of the plunger mount sleeve 1143. In this way, a small clearance is provided between the outer surface of the enlarged head 1148 and the inner surface of the plunger mount sleeve 1143 when the plunger clamping mechanism is engaged. The neck 1149A has an outer diameter less than the outer diameter of the enlarged head 1148. Preferably, each clamping rod 1147 also has a shaft 1149B whose outer diameter is substantially the same as the inner diameter of the region of the plunger mount sleeve 1143 in which it sits. As the first plate 1121 moves axially up and down relative to the second plate 1122, the shaft 1149B slides along the inner surface of the plunger mount 1143. This can help allow for accurate lateral alignment between the plunger mount 1143 and the plunger clamping member 1147.

[0074] With respect to the pipette tip clamping mechanism 1120, the tip connector portion 103 is configured to be coupled to a liquid handling system, for example, with a snap-fit ​​connection. The tip connector portion 103 may comprise a divided tubular wall that may be defined by a plurality of flexible segments. The flexible segments may be configured to elastically deflect in a radially outward direction to increase an outer diameter of the proximal end 101 of the pipette tip 100 from a first outer diameter where the flexible segments are not deflected and the tip connector portion is in a resting state to a second outer diameter where the flexible segments are deflected radially outward and the tip connector portion is in an expanded state. In the depicted embodiment, the tip connector portion 103 comprises a plurality of axially extending breaks or slots in the tubular wall that separate the plurality of flexible segments. The plurality of slots may be two, three, or four slots, and the plurality of flexible segments may be two, three, or four segments. The tip connector portion 103 may include any suitable number of axially extending breaks to define any number of flexible segments. The configuration of flexible segments and slots allows the tip connector portion to expand without the need to exert significant force on the tip connector portion. The tip connector portion 103 may further include one or more radially extending features 1126 on its inner surface by which a pipette tip may be coupled to a pipetting head. The radially extending features on the inner surface of the tip connector portion 103 may include radially inwardly extending projections and / or radially outwardly extending recesses or grooves. The radially extending features may extend in a circumferential direction. In the depicted embodiment, the radially extending features on the inner surface of the tip connector portion 103 include a partially annular rib 1126 that protrudes from the inner surface of the tip connector portion 103. Preferably, the second outer diameter to which the tip connector portion expands is greater than the first outer diameter by at least the radial extent of the radially extending features 1126.

[0075] The pipette tip 100 may be clamped between the tip mount sleeve 123 and a plate, such as the fourth plate 1124 as shown in Figure 9. The tip mount sleeve 123 may be provided on a plate, such as the third plate 1123.

[0076] 9, one or more method steps may be performed by one or more actuators 1161, 1162, 1163 that may be included in the liquid dispensing apparatus. The one or more actuators may be controlled by one or more controllers 1171.

[0077] The controller 1171 may 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.

[0078] The user input device may comprise a mouse or keyboard, a handheld device, or a touch screen and may have a graphical user interface. A display may be provided, such as a graphical user interface, which may be configured to display output. The display may be configured to input information and may present options to select a method or mode of operation and / or options to activate a mode. The display may display information such as in which mode the device operates and / or any variable or variables that are selected. The display may be configured to present information such as what information has been input.

[0079] The controller 1171 may be configured to receive input, specifically data, via one or more input ports, which may indicate any operational parameters such as which method or mode to operate, amount of sample liquid, number of samples, location of samples, aspirate or dispense time, aspirate or dispense rate, pre-sample and / or post-sample air gap volume, etc.

[0080] The controller 1171, and more particularly the processor of the controller, may determine, based on one or more inputs, a signal or signals to send to one or more actuators 1161, 1162, 1163, 1164. This determination may involve a set of instructions that may be stored in a memory. The controller 1171 may output a signal to one or more actuators 1161, 1162, 1163, 1164 and / or to a conversion or switching means, such as a relay.

[0081] 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, on which information and various programs are prepared. Such programs may include, for example, one or more preprogrammed modes or methods of operation of the device.

[0082] The device may comprise one or more communication means that may provide a communication path between the controller 1171 via one or more input or output ports and one or more actuators 1161, 1162, 1163, 1164. The communication means may comprise wires or cables that may physically connect the controller 1171 to one or more actuators 1161, 1162, 1163, 1164. For example, there may be wires or cables from the controller 1171 to each actuator, as shown in Figure 9. Alternatively or in addition, the communication means may comprise a wireless connection, such as a transmitter and receiver.

[0083] A first actuator 1161 may be provided. The first actuator may be configured to move the pipette tip 100 relative to the plunger 200, thereby allowing the pipette to aspirate and / or dispense fluid. The first actuator 1161 may be configured to move the first and / or second plates 1121, 1122 relative to the third and / or fourth plates 1123, 1124. As shown in FIG. 9, the first actuator 1161 may move the second plate 1122 relative to the third plate 1123. The first actuator 1161 may be configured to receive a signal from the controller 1171 and move the plunger 200 and / or the second plate 1122 relative to the pipette tip 100 and / or the third plate 1123 at a particular time and / or at a particular speed and / or by a particular amount and / or in a particular direction.

[0084] A second actuator 1162 may be provided. The second actuator 1162 may be configured to move the pipette tip 100 and / or the plunger 200 relative to the fixed housing 1101. As shown in FIG. 9, the second actuator 1162 may move the third plate 1123 relative to the housing 1101, thereby moving the pipette tip 100 and / or the plunger 200 relative to the sample receptacle. The second actuator 1162 may be configured to receive a signal from the controller 1171 and move the pipette tip 100 and / or the plunger 200 and / or the third plate 1123 relative to the sample receptacle at a specific time and / or at a specific speed and / or by a specific amount and / or in a specific direction.

[0085] The device may include a body having 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 may be located on a height-adjustable support structure that allows the height of the microplate receiving area to be changed as required. The receiving area may be configured to hold the laboratory microplate in a fixed position. For example, the upper surface of the receiving area may include one or more recesses arranged to receive the microplate and prevent lateral movement of the microplate relative to the receiving area. The pipetting head of the device may be configured to hold multiple pipettes and may be movable relative to the deck to bring the pipettes attached to the pipetting head into proximity with a microplate supported on the deck so that liquids are aspirated from or dispensed into wells of the microplate.

[0086] The second actuator 1162 may be configured to move the second and third plates 1122 and 1123 relative to the microplate receiving area. The fixed housing 1101 may be attached to the microplate receiving area.

[0087] A third actuator 1163 may be provided. The third actuator 1163 may be configured to attach and / or detach the plunger from the system upon receiving a signal from the controller 1171. The third actuator may be coupled to the first plate 1121 and the second plate 1122 and move the first plate 1121 relative to the second plate 1122. The third actuator 1163 may be a rotary actuator that may be configured to effect linear movement of the first plate 1121 relative to the second plate 1122.

[0088] A fourth actuator 1164 may be provided. The fourth actuator 1164 may be configured to attach and / or detach the pipette tip 100 from the system upon receiving a signal from the controller 1171. The fourth actuator may be coupled to the third plate 1123 and the fourth plate 1124. The fourth actuator 1164 may be a rotational actuator.

[0089] To perform an aspiration operation, the plunger 200 and pipette tip 100, or a series of plungers and pipette tips, may be moved to a desired position relative to the liquid sample receptacle. The plunger 200, or the plunger 200 of each pipette 10, may then be raised within its respective pipette tip 100, which may be done using a first actuator 1161. The first actuator 1161 may be a direct drive actuator and may move the plates 1121 and 1123 relative to each other in the direction of arrow 1161'. This may move the entire plunger clamping mechanism 1140 and the plunger plates 1121, 1122 away from the pipette tip clamping mechanism 1120 and the pipette tip plates 1123, 1124, as shown in FIG. 9, and fluid may be aspirated into the pipette tip 100. The direct drive actuator 1161 may then be used to move the plunger clamping mechanism 1140 in the opposite direction, allowing fluid to be dispensed as desired.

[0090] The direct drive actuator 1161 may be operable to move the plunger clamping mechanism 1140 axially towards or away from the plate or plates of the pipette tip clamping mechanism 1120 to aspirate or dispense liquid during use. A head chassis may be provided and the direct drive actuator 1161 may be fixed in association with the head chassis. The direct drive actuator 1161 may extend between the head chassis and the plunger clamping mechanism 1140.

[0091] The direct drive actuator 1161 may comprise an actuator motor mounted on the top surface of the head chassis and extending between the head chassis and the plunger. The output shaft of the actuator motor 1161 may be fixed to a threaded rod coupled to a ball screw actuator nut. The nut may be fixed to a ball screw mount, which may in turn be fixed to a plunger clamp motor mount plate at the top end of the plunger clamping mechanism 1140. The direct drive actuator 1161 may thus extend between the head chassis and the plunger clamping mechanism 1140. When the actuator motor 1161 is operated, the entire plunger clamping mechanism 1140 may move axially either towards or away from the pipette tip clamping mechanism 1120, moving the plunger in one axial direction or the other relative to the pipette tip 100 depending on the direction of rotation of the actuator motor 1161. In this way, the speed of relative movement between the plunger clamped by the plunger clamping mechanism 1140 and the pipette tip into which the plunger extends can be varied to a much greater extent than known devices. This allows the apparatus to be used in contact as well as non-contact dispensing modes. When performing non-contact dispensing, the liquid sample must travel at a sufficiently high speed to leave the tip. A speed sufficient for non-contact dispensing can be achieved by a direct drive actuator 1161, but in some cases cannot be achieved by a belt drive. In particular, a direct drive via a ball screw has higher acceleration and deceleration rates for heavy loads than a belt drive system. This is particularly advantageous when the distance traveled for a dispensing shot is short (e.g., <1 mm), and therefore high acceleration and deceleration rates allow the system to reach the target speed. In addition, the ball screw provides higher positional accuracy and repeatability, which has a beneficial effect on dispensing performance.

[0092] The apparatus may be configured such that the controller 1171, specifically the memory and processor, causes the first actuator 1161 and the second actuator 1162 to perform the aspirating / dispensing steps.

[0093] For example, the controller 1171 sending a signal to retract the plunger 200 within the pipette tip 100 to aspirate air and form a pre-sample air gap 300; outputting a signal to insert the pipette tip 100 into the sample liquid; outputting a signal to retract the plunger 200 within the pipette tip 100 and aspirate the sample liquid; outputting a signal to withdraw the pipette tip 100 from the sample liquid; may comprise a computer readable medium containing instructions that, when executed by a processor, cause the processor to perform any of the method steps described herein. The computer readable medium may contain instructions that, when executed by a processor, cause the processor to perform any of the method steps described herein.

[0094] A signal to insert the pipette tip 100 into the sample liquid may be sent to the second actuator 1162. A signal to retract the plunger 200 in the pipette tip 100 and aspirate the sample liquid may be sent to the first actuator 1161. A signal to withdraw the pipette tip 100 from the sample liquid may be sent to the second actuator 1162.

[0095] The controller 1171 may comprise a computer readable medium including instructions that, when executed by a processor, cause the processor to send a signal to disconnect the pipette tip 100 and / or the plunger 200 from the device. This signal may be sent to the third actuator 1163 and / or the fourth actuator 1164.

[0096] One, more, or all of the actuators 1161, 1162, 1163, 1164 may be configured to cause movement in the same direction. When installed, one, more, or all of the actuators 1161, 1162, 1163, 1164 may be configured to move the system in an axial direction, which may be a vertical direction.

[0097] Although the invention has been described above with reference to one or more preferred embodiments, it will be appreciated that various changes or modifications can be made without departing from the scope of the invention as defined in the appended claims.

[0098] For example, plunger and pipette tip configurations have been described and shown, each of the plungers and pipette tips having various parts, and although they have been described in combination, one of ordinary skill in the art will appreciate that the benefits of the present disclosure may be achieved with any suitable combination or permutation or parts of the pipette tips or plungers.

[0099] Although the term "air gap" is used herein, one of ordinary skill in the art will appreciate that there are a variety of suitable gases that may be used in such methods, and that the "air gap" should not be limited to only air. The air gap may include atmospheric gas, or a gas of controlled composition.

[0100] Although the term "plunger" has been used herein, those skilled in the art will appreciate that the term "piston" can also refer to a plunger.

[0101] The term "diameter" is used as a dimensional parameter. Those skilled in the art will appreciate that the present invention may be realized without requiring a strictly cylindrical or circular shape. As such, the term diameter may be interpreted as a transverse dimension. Embodiments with cylindrical or circular shapes (and parts for which the term "diameter" is particularly appropriate) may be advantageous.

[0102] Where the word "or" appears, it is to be construed to mean "and / or" and the referenced items are not necessarily mutually exclusive and may be used in any suitable combination.

Claims

1. A pipette tip, comprising: a proximal end, a distal end, and a longitudinal axis extending therebetween; an opening at the distal end; a fluid cavity extending at least partially from the opening toward the proximal end; and an end provided at the distal end, the end having an inner wall surface extending at least 5 mm at an angle of 2 to 5 degrees with respect to the longitudinal axis, the pipette tip; a plunger positioned inside the pipette tip, the plunger extending at least partially from the proximal end to the distal end of the pipette tip toward the end, being movable toward and away from the opening, and configured to aspirate fluid or dispense fluid from the pipette tip; A pipette for aspirating and / or dispensing a liquid, comprising the above.

2. The pipette according to claim 1, wherein the end has an outer wall surface extending at least 5 mm at an angle of at most 5 degrees with respect to the longitudinal axis.

3. The pipette according to claim 1, wherein the opening has a diameter of at most 1 mm, preferably at most 0.5 mm, more preferably at most 0.4 mm, and optionally at least 0.4 mm.

4. The pipette according to claim 1, wherein the end has a maximum outer diameter of at most 4 mm, preferably at most 3 mm, more preferably at most 2 mm, more preferably at most 1 mm, more preferably at most 0.7 mm, more preferably at most 0.65 mm, and optionally at least 0.5 mm, optionally at least 0.6 mm, optionally at least 0.65 mm.

5. The pipette according to claim 1, wherein the inner wall surface of the end of the pipette tip defines a straight side surface shape such as a frustum of a cone or a cylinder.

6. The pipette according to claim 1, wherein the outer wall surface of the end of the pipette tip defines a straight side surface shape such as a frustum of a cone or a cylinder.

7. The pipette according to claim 1, wherein the plunger has an end outer wall surface configured to be aligned with the inner wall surface of the end of the pipette tip.

8. The pipette according to claim 1, wherein the plunger is configured to seal the opening when in the extended position.

9. The pipette according to claim 1, wherein the plunger has a plunger end that substantially or completely occupies the end of the pipette tip when in the extended position.

10. The pipette according to claim 1, wherein the plunger has a plunger end that does not substantially or completely occupy the end of the pipette tip when in the extended position.

11. The pipette according to claim 1, wherein the inner wall surface extends at an angle of at most 4 degrees, preferably at most 3 degrees, more preferably 2 degrees with respect to the longitudinal axis.

12. The pipette according to claim 1, wherein the inner wall surface of the end extends at least 7 mm, preferably at least 8 mm, preferably at least 10 mm, more preferably at least 12 mm.

13. A pipette according to any one of claims 1 to 12, and an actuator configured to move the plunger with respect to the pipette tip A liquid handling system comprising.

14. A plurality of pipettes according to any one of claims 1 to 12, and an actuator configured to move a plurality of pipette tips and / or plungers of the plurality of pipettes to aspirate and / or dispense fluid A liquid handling system comprising.

15. The liquid handling system according to claim 14, wherein the actuator is configured to simultaneously move a plurality of pipette tips and / or plungers of the plurality of pipettes to aspirate and / or dispense fluid.

16. The liquid handling system according to claim 14, wherein the plurality of pipette tips are at least 10, preferably at least 100, more preferably at least 200, more preferably at least 300, more preferably 384 pipette tips.

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