Method and device for aspirating or dispensing liquid

Abstract

A liquid handling system for dispensing liquid is provided that includes a pipette tip and a plunger. The pipette tip has a longitudinal axis extending between a proximal end and a distal end, an opening at the distal end, a fluid cavity extending from the opening at least partially to the proximal end, and an end portion disposed at the distal end. The end portion has an inner wall extending at an angle of up to 10 degrees relative to the longitudinal axis. The plunger is positioned within the pipette tip and configured to extend between the proximal and distal ends of the pipette tip and is movable into and away from the opening. The system is configured to perform at least two different methods of operation for dispensing liquid.

Description

[Technical field]

[0001] The present invention relates to a method for dispensing liquids, and in particular to a method for dispensing liquids using a pipette tip having a plunger. [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. In a typical pipette, known as a "positive displacement" pipette, this internal plunger comes into contact with the sample liquid to be aspirated. The plunger is retracted away from an orifice to draw in the sample liquid, and is moved towards the orifice to dispense the sample liquid.

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

[0005] 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; an end portion at the distal end having an inner wall extending at an angle of up to 10 degrees relative to the longitudinal axis; A pipette tip having a plunger positioned within the pipette tip and configured to extend within an end portion between the proximal and distal ends of the pipette tip, the plunger being movable into and away from the opening; a liquid treatment device for aspirating and / or dispensing a liquid, the liquid treatment device comprising: retracting the plunger within the pipette tip to aspirate air and form a pre-sample air gap; Inserting a pipette tip into a sample liquid; retracting the plunger within the pipette tip to aspirate the sample liquid; Withdrawing the pipette tip from the sample liquid; The present invention provides a method for aspirating and / or dispensing a sample liquid, comprising:

[0006] The liquid handling device may include a seal configured to form a liquid-tight seal between the plunger and the pipette tip.

[0007] The geometry of the pipette tip specified in the first aspect of the invention, in particular the inner wall extending at an angle of at most 10 degrees, preferably 5 degrees, relative to the longitudinal axis, results in a much steeper angle than the shallow pipette tips of the known pipettes mentioned in the Background section. This steep pipette tip has several important advantages over the known pipette tip geometries:

[0008] The inventors have identified that what they call a "pre-sample air gap" allows the pipette tip to be used in an improved liquid aspiration method. In such a method, the plunger is first retracted to draw in a gas such as air, and then subsequently retracted to draw in the sample liquid. The advantage of using the pre-sample air gap method is that capillary filling of the tip is avoided, reducing dead volume (sample liquid remaining in the pipette after dispensing). The high angle tip allows the aspirated liquid sample to remain in a single slug that can be released completely upon dispensing, rather than sticking to one side of the inner wall of the pipette tip. This allows for very small volumes (<200 nl) to be processed.

[0009] 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).

[0010] The method may further include retracting the plunger in the pipette tip to aspirate air and form a post-sample air gap. Specifically, this may further involve continuing to retract the plunger after the sample has been aspirated to aspirate air or another gas. This has the following advantages: 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 liquid in the sample container, the liquid sample must travel at a sufficiently fast speed to leave the pipette tip. In known pipette tips, this speed is difficult to reach with small volumes due to the relatively short plunger stroke. The post-sample air gap developed by the inventors provides a way to increase the plunger stroke by introducing a small air gap (or other gas) after the liquid sample has been aspirated, i.e. by using a post-sample air gap. The high angle tip of the first embodiment allows this air gap to be introduced in a controlled manner. The inventors have identified that in known pipette tips, this mechanism is not feasible in pipette tips with plungers. This is because known pipette tip geometries, which have a much shallower pipette tip angle than the pipette of the first embodiment, tend to cause 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 steeper angle of the pipette tip of the first embodiment mitigates this problem by providing a more uniform deposition of liquid.

[0011] The method may further include moving the plunger within the pipette tip and dispensing the aspirated sample liquid such that the sample liquid leaves the pipette tip without contacting the sample receptacle. This may involve the sample liquid separating to form one or more droplets after leaving the pipette tip and before reaching the sample container or liquid within the sample container. As noted above, this may be referred to as a "non-contact" dispensing method. This may involve further moving the plunger and expelling the pre-sample air gap.

[0012] The method may further include moving the plunger within the pipette tip and dispensing the aspirated sample liquid such that the sample liquid contacts the sample receptacle and / or liquid, such as the sample fluid, within the sample receptacle without leaving the pipette tip. This may be referred to as a contact dispensing method. This may involve further moving the plunger and expelling the pre-sample air gap.

[0013] Moving the plunger and dispensing fluid, ie, sample liquid or air gap, may involve moving the plunger in an extension direction, which may be a downward direction.

[0014] The receptacle may be a well or a series of wells, a plate such as an assay plate or microplate, a tray, a tube or a series of tubes, any suitable container, or a liquid in a sample vessel.

[0015] The method may further include, as a preliminary step, moving the pipette tip up and down, which may be performed before any other aspirating and / or dispensing or preparation steps of the method.

[0016] A second aspect of the present invention provides a computer program executable on a computer readable medium comprising instructions which, when executed by a computer processor, cause the processor to carry out the steps of: outputting a signal to retract a plunger within the pipette tip to aspirate air and form a pre-sample air gap; outputting a signal to insert the pipette tip into the sample liquid; outputting a signal to retract a plunger within the pipette tip to aspirate sample liquid; and A process of outputting a signal to withdraw the pipette tip from the sample liquid.

[0017] The computer program may include instructions that, when executed by a processor, cause the processor to output signals to perform the methods described herein, and any of the embodiments or variations thereof. The processor may be included in or operably connected to a liquid treatment system having any of the features described herein for performing the described methods.

[0018] A third 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; an end portion at the distal end having an inner wall extending at an angle of up to 10 degrees relative to the longitudinal axis; A pipette tip having a plunger positioned within the pipette tip and configured to extend between a proximal end and a distal end of the pipette tip, the plunger being movable into and away from the opening; Equipped with A liquid handling system for aspirating and / or dispensing liquid is provided that is configured to perform at least two different operating methods for aspirating or dispensing liquid.

[0019] The instructions contained in the preferably non-transitory computer readable medium may be configured to cause the system to perform at least two different methods of operation for aspirating or dispensing liquid.

[0020] Each of the methods of operation may be one of the following: A contact dispensing method that does not create a pre- or post-sample air gap; A non-contact dispensing method that does not create a pre- or post-sample air gap; A non-contact dispensing method that does not create a pre-sample air gap but does create a post-sample air gap; Contact dispensing method, creating a pre-sample air gap; A non-contact dispensing method that creates a pre-sample air gap; and A non-contact dispensing method that creates a pre-sample air gap and a post-sample air gap.

[0021] When a system is configured to perform a particular method, it may be considered to have a corresponding mode of operation. The system may therefore be configured to have: Contact dispensing mode with no pre- or post-sample air gap; Non-contact dispensing mode with no pre- or post-sample air gap; Non-contact dispensing mode, where there is no pre-sample air gap but there is a post-sample air gap; Contact dispensing mode with pre-sample air gap; Non-contact dispensing mode with pre-sample air gap Non-contact dispensing mode with pre-sample and post-sample air gaps; and Contact dispense mode with pre-sample and post-sample air gaps.

[0022] The system may be configured to operate in at least two different operational modes for aspirating or dispensing liquid.

[0023] The at least two methods or modes of operation may include at least one pre-sample air gap method or mode, and at least one method or mode without a pre-sample air gap.

[0024] The two operating methods or modes may include at least one non-contact dispensing method or mode and at least one contact dispensing method or mode.

[0025] The two operating methods or modes may include at least one post-sample air-gap method or mode, and at least one no-post-sample air-gap method or mode.

[0026] The system may include an actuator configured to move a plunger relative to the pipette tip and to implement at least two methods or modes of operation.

[0027] The system may include a computer-readable medium comprising instructions that, when executed by a processor, cause the processor to perform the following steps: outputting a signal to retract a plunger within the pipette tip to aspirate air and form a pre-sample air gap; outputting a signal to insert the pipette tip into the sample liquid; outputting a signal to retract a plunger within the pipette tip to aspirate sample liquid; Output a signal to withdraw the pipette tip from the sample liquid.

[0028] The computer readable medium may include instructions that, when executed by a processor, cause the processor to send a signal to an actuator to effect any of the aspirating and / or dispensing method steps described herein.

[0029] The inner wall of the pipette tip end, which extends at an angle of up to 10 degrees to the longitudinal axis, may itself extend at least 5 mm from the distal end.

[0030] The ends may have outer walls extending at an angle of up to 10 degrees to the longitudinal axis, preferably at least 5mm.

[0031] A fourth 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; an end portion at the distal end having an inner wall extending at an angle of up to 10 degrees relative to the longitudinal axis; A pipette tip having a plunger positioned within the pipette tip and configured to extend within an end between the proximal and distal ends of the pipette tip, the plunger being movable into and away from the opening; a seal configured to form a fluid-tight seal between the plunger and the pipette tip; Equipped with retracting the plunger within the pipette tip to aspirate air and form a pre-sample air gap; Inserting a pipette tip into a sample liquid; retracting the plunger within the pipette tip to aspirate sample liquid; withdrawing the pipette tip from the sample liquid; The present invention provides a liquid treatment device for aspirating and / or dispensing liquid, the liquid treatment device being configured to perform the steps of:

[0032] Hereinafter, an embodiment of the present invention will be described with reference to the accompanying drawings. [Brief description of the drawings]

[0033] [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](a) illustrates a non-contact dispensing method without a pre-sample air gap but with a post-sample air gap; (b) illustrates a non-contact dispensing method without a pre-sample air gap but with a post-sample air gap; (c) illustrates a non-contact dispensing method without a pre-sample air gap but with a post-sample air gap; (d) illustrates a non-contact dispensing method without a pre-sample air gap but with a post-sample air gap; (e) illustrates a non-contact dispensing method without a pre-sample air gap but with a post-sample air gap. [Diagram 5] (a) is a diagram showing a contact dispensing method for creating a pre-sample air gap; (b) is a diagram showing a contact dispensing method for creating a pre-sample air gap; (c) is a diagram showing a contact dispensing method for creating a pre-sample air gap; (d) is a diagram showing a contact dispensing method for creating a pre-sample air gap; (e) is a diagram showing a contact dispensing method for creating a pre-sample air gap. [Figure 6] (a) is a diagram showing a non-contact dispensing method for creating a pre-sample air gap; (b) is a diagram showing a non-contact dispensing method for creating a pre-sample air gap; (c) is a diagram showing a non-contact dispensing method for creating a pre-sample air gap; (d) is a diagram showing a non-contact dispensing method for creating a pre-sample air gap; (e) is a diagram showing a non-contact dispensing method for creating a pre-sample air gap. [Figure 7] (a) illustrates a non-contact dispensing method for creating pre-sample and post-sample air gaps; (b) illustrates a non-contact dispensing method for creating pre-sample and post-sample air gaps; (c) illustrates a non-contact dispensing method for creating pre-sample and post-sample air gaps; (d) illustrates a non-contact dispensing method for creating pre-sample and post-sample air gaps; (e) illustrates a non-contact dispensing method for creating pre-sample and post-sample air gaps. [Figure 8] FIG. 1 is a schematic diagram of a liquid dispensing device. [Figure 9] FIG. 2 is a diagram of a portion of a pipette tip. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] 1 shows a pipette 10 for aspirating and / or dispensing liquid. The pipette 10 comprises a pipette tip 100 and a plunger 200.

[0035] 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.

[0036] Pipette tip 100 has a proximal end 101 and a distal end 102, with proximal end 101 and distal end 102 defining a longitudinal axis 1 extending therebetween.

[0037] 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.

[0038] 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 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.

[0039] The pipette tip 100 comprises an end 110 at the distal end 102 with an inner wall surface 111 which extends at an angle α of at most 10 degrees, or π / 18 radians, or about 0.17-0.18 radians, relative to the longitudinal axis 1, optionally at least 5 mm. Preferably, the inner wall surface 111 extends 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, and at least 5 mm. 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, 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 that extends 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 because it may be easier, simpler, and / or cheaper to manufacture. The angle α may be measured using any suitable angle measurement technique known to those of skill in the art.

[0040] 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.

[0041] The inner wall surface 111 of the end 110 may extend at least 5 mm at an angle equal to the angle α, preferably at least 7 mm, preferably at least 10 mm at an angle equal to the angle α, and more preferably at least 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.

[0042] End 110 may have an outer wall surface 112 that optionally extends at least 5 mm at an angle β of at most 10 degrees, preferably at most 5 degrees, relative to longitudinal axis 1, as best seen in FIG. 3. 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. End 110 may have 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, and more preferably at most 0.65 mm. Optionally, 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.

[0043] The pipette tip 100 may be substantially elongated and extend between its proximal end 101 and distal end 102. The pipette tip 100 may be substantially or completely hollow. The pipette tip 100 may comprise or consist of a polymeric material. The pipette tip 100 may comprise or consist of a homogenous material. The pipette tip 100 may comprise or consist of a translucent or transparent material.

[0044] The pipette tip 100 may include a series of sections, each having a different function, distinguishing feature, and / or different shape or size. The pipette tip 100 may include, for example, one or more of a tip connector section 103, a center section 104, a support section 105, a body section 106, and a bridge section 107, as shown in FIG. 1. From the proximal end 101 to the distal end 102, the sections may be arranged in the following order: tip connector section 103, center section 104, support section 105, body section 106, bridge section 107, and end section 110. The fluid cavity 109 may extend through one, more, or all of the sections of the pipette tip 100. The plunger 200 may extend through one, more, or all of the sections of the pipette tip 100.

[0045] The tip connector portion 103 may be configured to couple to a liquid handling system. The tip connector portion 103 may be configured as a snap-fit ​​connection.

[0046] The core 104 may be configured to center the plunger 200 within the pipette tip 100. The core 104 may have an inner surface that defines a tapered or conical shape.

[0047] The support 105 may include one or more ribs configured to reduce flexibility and / or improve structural integrity of the pipette tip 100. The one or more ribs may extend on an exterior surface of the pipette tip between the proximal end 101 and the distal end 102, for example, as best seen in FIG. 2. Alternatively and / or in addition to the one or more ribs, the support 105 may include a ring 1055, for example, as shown in FIG. 9. The ring 1055 may be configured to provide a reaction 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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, thereby making the device or system suitable for use with multiple different sample fluids through the use of removable and optionally disposable pipette tips 100 and / or plungers 200.

[0063] The devices of Figures 1-3 may be used in the methods of aspirating and / or dispensing of Figures 4-7. As will be appreciated by those skilled in the art from the description of Figures 1-3, the devices provided are configured to aspirate and / or dispense fluids and / or hold fluids between aspirating and dispensing. The devices are provided to perform one or more steps of the methods, which may be controlled by manual operation or may be partially or fully automated. The devices provided in the methods may have one, more, or all of the features described herein. In particular, the liquid handling device may include one or more of the features previously described, for example, as described in connection with Figures 1-3.

[0064] The device comprises a pipette tip 100 having a proximal end 101 and a distal end 102 defining a longitudinal axis 11 therebetween. The pipette tip 100 also has an opening 108 at the distal end 102 and a fluid cavity 109 extending from the opening 108 at least partially to the proximal end 101. The opening 108 admits fluid to and from the pipette tip 100, and the fluid cavity 109 of the device is configured to hold a fluid (i.e., liquid or gas), such as a sample liquid, and / or an air gap.

[0065] The pipette tip 100 also has an end 110 at the distal end 102 having an inner wall 111 that extends at an angle of up to 10 degrees relative to the longitudinal axis 11. This can be particularly advantageous when used in methods involving a pre-sample or post-sample air gap.

[0066] The device may include a plunger 200 positioned within the pipette tip 100 and configured to extend within an end between the proximal end 101 and the distal end 102 of the pipette tip 100 and movable into and away from the opening 108. The plunger is configured to create a pressure change within the pipette tip 100 to draw fluid into and / or expel fluid from the fluid cavity.

[0067] The method involves retracting the plunger 200 within the pipette tip 100, aspirating air and forming a pre-sample air gap, as described above, by reducing the pressure within the pipette tip 100, allowing atmosphere or other gas to pass through the pipette tip 100 and equalize the pressure. This air or gas provided within the pipette tip, between the opening 108 and the plunger 200, is called the pre-sample air gap because it precedes the sample in the order of aspiration into the pipette tip 100.

[0068] With the pre-sample air gap 300 maintained within the pipette tip 100, the pipette tip 100 is then inserted into the sample liquid 351. In this position, the pre-sample air gap 300 may remain within the pipette tip 100 and the sample liquid 351 may remain completely outside the pipette tip. The sample liquid 351 tends to be forced around the pipette tip 100 while being prevented from entering the pipette tip 100 by the pressure within the pipette tip 100 from the pre-sample air gap 300. Inserting the pipette tip 100 into the sample liquid 351 may involve moving the pipette tip 100 downwards relative to a fixed receptacle such as a well or series of wells, a plate such as an assay plate or microplate, a tray, any suitable container, or liquid in a sample container, and / or moving the sample liquid container upwards relative to the fixed pipette tip 100, and / or moving both the sample liquid container and the pipette tip 100 towards each other.

[0069] While remaining within the sample liquid 351, the plunger 200 is retracted within the pipette tip 100 to aspirate sample liquid 301. At this time, the pipette tip 100 is at least partially filled with sample liquid 301, which is disposed and held within the pipette tip 100 below a pre-sample air gap 300. In such a configuration, disposed directly below the plunger 200 is the pre-sample air gap 300, below which the sample liquid 301 is held as a slug of liquid, disposed between the pre-sample air gap 300 and the opening 108. Retracting the plunger 200 within the pipette tip 100 to aspirate air and form the pre-sample air gap 300 may involve retracting the plunger 200 relative to the pipette tip 100 by up to 20 mm, optionally by up to 10 mm, optionally by up to 5 mm, and optionally by up to 1 mm. The pre-sample air gap 300 may have a volume of about 30 μl, optionally up to 20 μl, optionally up to 10 μl, optionally up to 5 μl, optionally up to 3 μl. Functionally speaking, the purpose of the pre-sample air gap is to create enough space so that the aspirated sample does not wick internally into the pipette tip and reach the plunger. In practice, this distance, or the amount of the pre-sample air gap, will vary depending on the fluid being aspirated. Any gap sufficient to prevent sample liquid 301 from being wicked into the plunger may be beneficial. The fluid sample 301 is preferably kept below the taper of the pipette tip to maintain its integrity during the dispensing sequence.

[0070] The pipette tip 100 is then withdrawn from the sample liquid 351 while the pre-sample air gap 300 and sample liquid 301 are retained within the pipette tip 100. This may involve moving the pipette tip 100 upward relative to the fixed receptacle, and / or moving the receptacle downward relative to the fixed pipette tip 100, and / or moving both the receptacle and pipette tip 100 away from each other.

[0071] The method may include providing a sample liquid 351, which may be provided in a receptacle, such as a well or series of wells, an assay plate, a tray, a microplate, or any suitable container, before, during, or after providing the device. The receptacle may be provided below the device or inserted into the device at a location where the pipette tip 100 or series of pipette tips may be lowered into or adjacent to the receptacle. The device may include a body having 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 place. 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 pipettes attached to the pipetting head into proximity with a microplate supported on the deck so that liquid may be aspirated from or dispensed into the wells of the microplate.

[0072] As will be appreciated by those skilled in the art, each step may be performed one after the other, or in any order listed. However, one or more steps may be performed at least partially simultaneously. For example, the step of retracting the plunger 200 in the pipette tip 100 and aspirating the sample liquid 351 may be performed simultaneously with the insertion of the pipette tip 100 into the sample liquid 351 and / or the withdrawal of the pipette tip 100 from the sample liquid 351.

[0073] 4-7 show a method for aspirating and / or dispensing a sample liquid 301. The method includes providing a liquid-handling device for aspirating and / or dispensing a liquid, the liquid-handling device comprising a pipette tip 100 and a plunger 200 positioned within the pipette tip 100.

[0074] 4-7 show particularly advantageous combinations of steps. As one of ordinary skill in the art will appreciate, these are not the only combinations available to one skilled in the art when performing methods for aspirating and / or dispensing sample liquid 351. In particular, one skilled in the art may perform one or more steps of each method with additional steps before, after, or between the various method steps.

[0075] The method of FIG. 4 includes the following steps: 4a) inserting the pipette tip 100 into the sample liquid 351; 4b) retracting the plunger 200 within the pipette tip 100 to aspirate the sample liquid 351; 4c) withdrawing the pipette tip 100 from the sample liquid; 4d) retracting the plunger 200 within the pipette tip to aspirate air and form a post-sample air gap 302; 4e) Moving the plunger 200 within the pipette tip 100 to dispense the aspirated sample liquid 301 such that the sample liquid 301 leaves the pipette tip 100 without contacting the sample receptacle or the liquid 306 held therein.

[0076] A post-sample air gap 302, such as the post-sample air gap of step 4b, is created by a pressure drop in the pipette tip 100 caused by withdrawing the plunger 200 away from the opening 108. This draws sample liquid 301 further into the pipette tip 100 and away from the opening 108, and air or other gas is drawn through the opening 108 into the pipette tip 100 to equalize the pressure. This air or gas provided in the pipette tip 100 between the opening 108 and the sample liquid 301 is referred to as a post-sample air gap 302 because it follows the sample in the order of aspiration into the pipette tip 100. The plunger may be moved prior to step 4e to dispense the post-sample air gap.

[0077] Retracting the plunger 200 within the pipette tip 100 to aspirate air and form the post-sample air gap 302 may involve retracting the plunger 200 relative to the pipette tip 100 such that the sample liquid 301 may be accelerated during dispensing such that the sample liquid 301 has enough energy to cleanly leave the pipette tip 100 upon exiting the opening 108. This may involve retracting the plunger 200 relative to the pipette tip 100 by an amount greater than zero and up to 0.5 mm, optionally up to 0.3 mm, optionally up to 0.03 mm. The post-sample air gap 302 may have a volume of up to about 1 μl, and / or at least about 0.1 μl. The post-sample air gap must be small enough that the sample liquid 301 does not move beyond the tapered end 110 of the pipette tip 100 during the aspirating and dispensing procedure, but remains at the tapered end.

[0078] As one of ordinary skill in the art would appreciate, in a non-contact dispensing step such as step 4e, when the sample liquid 301 leaves the pipette tip, a droplet may form that is not limited to a particular shape or configuration. In step 4e, the liquid sample must come to a state where it does not contact the pipette tip 100 before reaching the receptacle. This may involve the sample liquid 301 being completely surrounded by air, thus forming a surface tension minimizing shape that may be at least partially spherical.

[0079] The method of FIG. 5 includes the following steps: 5a) retracting the plunger 200 within the pipette tip 100 to aspirate air and form a pre-sample air gap 300; 5b) inserting the pipette tip 100 into the sample liquid 351; 5c) retracting the plunger 200 within the pipette tip 100 to aspirate the sample liquid 301; 5d) withdrawing the pipette tip 100 from the sample liquid 351; 5e) Moving the plunger 200 within the pipette tip 100 to dispense the aspirated sample liquid 301 so that the sample liquid 301 comes into contact with the sample receptacle 306 without leaving the pipette tip.

[0080] In contact dispensing methods such as step 5e, the liquid sample 301 contacts the pipette tip 100 and the receptacle 306 simultaneously, for example as shown in Figure 5(e). In such a situation, surface tension from the receptacle 306 may distort the shape of the sample liquid 301 before it leaves the pipette tip 100.

[0081] The method of FIG. 6 includes the following steps: 6a) retracting the plunger 200 within the pipette tip 100 to aspirate air and form a pre-sample air gap 300; 6b) inserting the pipette tip 100 into the sample liquid 351; 6c) retracting the plunger 200 within the pipette tip 100 to aspirate the sample liquid 301; 6d) withdrawing the pipette tip 100 from the sample liquid 351; 6e) moving the plunger 200 within the pipette tip 100 to dispense the aspirated sample liquid 301 such that the sample liquid 301 leaves the pipette tip 100 without contacting the sample receptacle 306. This may cause the sample liquid to form one or more droplets 305 after leaving the pipette tip and before reaching the sample container.

[0082] The method of FIG. 7 includes the following steps: 7a) retracting the plunger 200 within the pipette tip 100 to aspirate air and form a pre-sample air gap 300; 7b) inserting the pipette tip 100 into the sample liquid 351; 7c) retracting the plunger 200 within the pipette tip 100 to aspirate the sample liquid 301; 7d) withdrawing the pipette tip 100 from the sample liquid 301; 7e) retracting the plunger 200 within the pipette tip 100 to aspirate air and form a post-sample air gap 302; 7f) moving the plunger 200 within the pipette tip 100 to dispense the aspirated sample liquid 301 such that the sample liquid 301 leaves the pipette tip 100 without contacting the sample receptacle 306. Prior to step 7f, the plunger may be moved to dispense a post-sample air gap.

[0083] A method that includes retracting the plunger 200 within the pipette tip 100 to aspirate air and form a pre-sample air gap 300 may be referred to as a pre-sample air gap method or mode of operation. Figures 5, 6, and 7 illustrate this step. Methods that do not involve this step, such as the method of Figure 4, may be referred to as a no-pre-sample air gap method or mode of operation.

[0084] Methods that include retracting the plunger 200 within the pipette tip 100 to aspirate air and form a post-sample air gap 302, such as the methods of Figures 4 and 7, may be referred to as post-sample air gap methods or modes of operation. Methods that do not involve this step, such as the methods of Figures 5 and 6, may be referred to as no-post-sample air gap methods or modes of operation.

[0085] Methods such as that of FIG. 5 that involve moving the plunger 200 within the pipette tip 100 and dispensing aspirated sample liquid 301 so that the sample liquid 301 contacts the sample receptacle 306 without leaving the pipette tip 100 may be referred to as contact dispensing methods or contact operating modes.

[0086] Methods that involve moving the plunger 200 within the pipette tip 100 and dispensing aspirated sample liquid 301 such that the sample liquid 301 leaves the pipette tip 100 without contacting the sample receptacle 306, such as the methods of Figures 4, 6, and 7, may be referred to as non-contact dispensing methods or non-contact operating modes.

[0087] The embodiment of FIG. 8 illustrates a particular 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.

[0088] 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.

[0089] 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.

[0090] 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 8. The tip mount sleeve 123 may be provided on a plate, such as the third plate 1123.

[0091] 8, one or more method steps may be performed by one or more actuators 1161, 1162, 1163 that may be included in the liquid dispensing device. The one or more actuators may be controlled by one or more controllers 1171.

[0092] The controller 1171 may include one or more of a processor, a memory, one or more input ports, one or more output ports, and a user input device.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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 8. Alternatively or in addition, the communication means may comprise a wireless connection, such as a transmitter and receiver.

[0098] A first actuator 1161 may be provided. The first actuator may be configured to move the pipette tip 100 relative to the plunger 200. This allows 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. 8, 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 plates 1121, 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.

[0099] 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. 8, 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] A fourth actuator 1164 may be provided. The fourth actuator 1164 may be configured to attach and / or detach the pipette tip 100 to and 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 1163 may be a rotational actuator.

[0104] 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. 8, 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.

[0105] 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.

[0106] The direct drive actuator 1161 may extend between the head chassis and the plunger clamping mechanism 1140. The direct drive actuator 1161 may include 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 not 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.

[0107] 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.

[0108] 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 351; outputting a signal to retract the plunger 200 within the pipette tip 100 and aspirate the sample liquid 351; outputting a signal to withdraw the pipette tip 100 from the sample liquid 351; The computer readable medium may include instructions that, when executed by a processor, cause the processor to perform any of the method steps described herein.

[0109] A signal may be sent to the second actuator 1162 to insert the pipette tip 100 into the sample liquid 351. A signal may be sent to the first actuator 1161 to retract the plunger 200 in the pipette tip 100 and aspirate the sample liquid 351. A signal may be sent to the second actuator 1162 to withdraw the pipette tip 100 from the sample liquid 351.

[0110] 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.

[0111] 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.

[0112] Either or each of the aspirating and / or dispensing methods may further include moving the pipette tip 100 up and down as a preliminary step. This may be performed by the first actuator 1161.

[0113] As will be appreciated by those skilled in the art from the teachings provided herein, a liquid dispensing device may be configured to allow a user to input one or more variables and to implement one or more operational modes or methods using the same device, thereby providing a device that is versatile and particularly suited for a variety of aspirating and dispensing methods.

[0114] Those skilled in the art will appreciate that the combinations of steps described and illustrated in FIGS. 4-7 are for illustrative purposes only and are not intended to depict the only possible combinations of steps.

[0115] Any of the method steps listed herein may be performed in the order provided or in another suitable order. Any of the method steps listed for any embodiment herein may be performed and may be performed with any other suitable method steps described herein.

[0116] 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.

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 towards the proximal end; an end provided at the distal end, having an inner wall extending at an angle of at most 10 degrees with respect to the longitudinal axis; a pipette tip; a plunger positioned inside the pipette tip, configured to extend between the proximal end and the distal end of the pipette tip, and movable towards and away from the opening; and a liquid handling system for dispensing liquid, configured to perform at least two different operating methods for dispensing liquid.

2. The system according to claim 1, wherein the at least two operating methods include at least two of the following: a contact dispensing method without creating a pre-sample air gap or a post-sample air gap; a non-contact dispensing method without creating a pre-sample air gap or a post-sample air gap; a non-contact dispensing method without creating a pre-sample air gap but creating a post-sample air gap; a contact dispensing method creating a pre-sample air gap; a non-contact dispensing method creating a pre-sample air gap; a non-contact dispensing method creating a pre-sample air gap and a post-sample air gap; and a contact dispensing method creating a pre-sample air gap and a post-sample air gap.

3. The system according to claim 1, wherein the at least two operating methods include at least one pre-sample air gap method and at least one method without a pre-sample air gap.

4. The system according to claim 1, wherein the two operating methods include at least one non-contact dispensing method and at least one contact dispensing method.

5. The system according to claim 1, wherein the two operating methods include at least one post-sample air gap method and at least one method without a post-sample air gap.

6. The system according to claim 1, further comprising an actuator configured to move the plunger with respect to the pipette tip to perform the at least two operating methods.

7. The system according to claim 1, comprising a controller including a processor and a computer-readable medium that, when executed by the processor, causes the processor to send a signal to an actuator and includes instructions to perform any of the steps of the aspiration and / or dispensing method.

8. The inner wall of the end of the pipette tip that extends at an angle of up to 10 degrees with respect to the longitudinal axis itself extends at least 5 mm from the distal end and / or The system according to claim 1, wherein the end has an outer wall that extends at an angle of up to 10 degrees with respect to the longitudinal axis and preferably extends at least 5 mm.

9. A pipette tip, 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 towards the proximal end, an end provided at the distal end having an inner wall that extends at an angle of up to 10 degrees with respect to the longitudinal axis and a pipette tip having; a plunger positioned inside the pipette tip and configured to extend between the proximal end and the distal end of the pipette tip within the end and to be movable towards and away from the opening, and a sealing portion configured to form a liquid-tight seal between the plunger and the pipette tip to provide a liquid handling device for aspirating and / or dispensing a liquid, contracting the plunger within the pipette tip to aspirate air and form a pre-sample air gap, inserting the pipette tip into a sample liquid, contracting the plunger within the pipette tip to aspirate the sample liquid, and withdrawing the pipette tip from the sample liquid including a method of dispensing a sample liquid.

10. The method according to claim 9, further comprising contracting the plunger within the pipette tip to aspirate air and form a post-sample air gap.

11. The method according to claim 9, further comprising moving the plunger within the pipette tip to dispense the aspirated sample liquid such that the sample liquid leaves the pipette tip without contacting a sample receptacle.

12. The method according to claim 9, further comprising dispensing the aspirated sample liquid by moving the plunger within the pipette tip such that the sample liquid contacts a liquid such as a sample receptacle and / or a sample fluid within the sample receptacle without leaving the pipette tip.

13. The method according to claim 9, further comprising moving the pipette tip up and down as a preliminary step.

14. A pipette tip, having 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, an end provided at the distal end having an inner wall extending at an angle of at most 10 degrees with respect to the longitudinal axis, and a plunger positioned inside the pipette tip and configured to extend between the proximal end and the distal end of the pipette tip within the end and to be movable toward and away from the opening, and a sealing portion configured to form a liquid-tight seal between the plunger and the pipette tip. A liquid handling device configured to perform the steps of contracting the plunger within the pipette tip to aspirate air and form a pre-sample air gap, inserting the pipette tip into a sample liquid, contracting the plunger within the pipette tip to aspirate the sample liquid, and withdrawing the pipette tip from the sample liquid.

15. A computer program including instructions that, when executed by a computer processor, cause the processor to perform the following steps: outputting a signal to contract a plunger within a pipette tip to aspirate air and form a pre-sample air gap; outputting a signal to insert the pipette tip into a sample liquid; outputting a signal to contract the plunger within the pipette tip to aspirate the sample liquid; and outputting a signal to withdraw the pipette tip from the sample liquid.

16. A computer-readable medium according to claim 15, including instructions that, when executed by a processor, cause the processor to generate an output signal and perform the steps according to claim 9. ​ ​

Images