Pipette tip and method for automatically maintaining pipette tip depth in fluid

Abstract

A pipette tip and method for automatically maintaining pipette tip depth in a fluid during fluid transfer operations is disclosed. The pipette tip includes, for example, two electrodes that extend substantially the entire length of the pipette tip for measuring the electrical resistance between the two electrodes when immersed in a conductive fluid. A method is provided for automatically maintaining the depth of a pipette tip in a liquid throughout a pipetting operation, as the liquid level rises or falls in its container, without requiring any prior knowledge of the container geometry.

Description

[0001] Cross-reference to related applications

[0002] Pursuant to Section 119(e) of Chapter 35 of the United States Code, this application relates to and claims priority to U.S. Provisional Patent Application No. 62 / 611,161, filed December 28, 2017, entitled “A suction pipette tip and method for automatically maintaining the depth of the suction pipette tip in a fluid during a fluid transfer operation”, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The subject matter of this disclosure generally relates to liquid handling methods, and more specifically, to a pipette tip and method for automatically maintaining the depth of the pipette tip in a fluid during a fluid transfer operation. Background Technology

[0004] Automated liquid handling instruments include robots used to transfer specific volumes of liquid between designated containers. These instruments can be used in a variety of applications, including cell biology, genomics, forensics, and drug research. They assist in repetitive tasks involving the transfer of liquids across a wide range of volumes by increasing the speed and efficiency of operations, as well as improving the precision and accuracy of the transferred volumes.

[0005] Various laboratory glassware containers are commonly used in liquid handling applications. These include arrays of 96, 384, or 1536 sample wells. Plates are quite common. Depending on the size and number of sample wells, such plates can hold anywhere from tens of nanoliters to a few milliliters of liquid. Larger containers are also common, ranging from small vials holding one to two milliliters of liquid to large tubes holding tens of milliliters or bottles holding hundreds of milliliters. It is easy to understand that each unique laboratory glassware container will have a unique relationship between the volume of liquid in the container and the height of the liquid level in the container.

[0006] The accuracy and precision of the transfer volume can be affected by many factors. These factors can range from the properties of the liquid itself (such as its viscosity or surface tension) to the properties of system components (such as the hydrophobicity of the pipette tip), or even environmental conditions (such as ambient temperature and pressure).

[0007] In automated liquid handling, control variables of the instrument can have a significant impact on the volume aspirated. Such control variables include the speed of pump actuation, the delay between the end of pump actuation and the removal of the pipette tip from the liquid, and / or the speed of removal of the pipette tip from the liquid. One significant control variable that has a strong impact on pipetting performance is the depth of the pipette tip immersion below the liquid surface throughout the operation. If the pipette tip is too shallow in the liquid, the vacuum of the aspiration can cause a cavitation of the liquid at the opening of the pipette tip, causing air instead of liquid to be aspirated, and thus causing an error in the aspirated volume. If the pipette tip is too deep in the liquid, a larger surface area of the pipette tip is in contact with the liquid, and a larger volume of liquid can adhere to the pipette tip when it is retracted from the liquid. Additionally, a deeper immersion causes an increase in the hydrostatic pressure at the opening of the pipette tip, which can cause a variation in the resulting aspirated volume. Therefore, it is desirable to maintain the pipette tip at an optimal depth, even when the liquid surface is changing in the case of liquid aspiration from or dispensing into a container. Furthermore, it is important to ensure that the depth of the pipette tip in the liquid is consistent from one operation to the next throughout the pipetting operation.

[0008] Methods for detecting liquid level in the field of automated liquid handling are common and well-established in the art. However, none are capable of tracking the liquid level using real-time sensor feedback to maintain the depth of the pipette tip during a pipetting operation. In the prior art, liquid level tracking is achieved by predicting the expected liquid level change based on the required volume and geometry of the container. The geometry of the container refers to the cross-sectional area as it relates to the height in the container. From this information, the change in height associated with a particular volume change can be calculated. This method requires the geometry of the container to be characterized prior to the pipetting operation and programmed into the instrument protocol. This requirement can limit the types of labware that can be used with a particular instrument, and adds complexity to the process of programming the instrument for a particular pipetting operation. Furthermore, these types of calculations assume that the pipetting operation will aspirate or dispense a uniform, equal volume of liquid during each pipetting action, which can not be an accurate assumption. If the calibration is slightly off, the error can compound over the course of the pipetting operation, and the actual liquid level can correspond to a different liquid level than the expected liquid level based on the calculations. Therefore, there is a need for new methods to track the liquid level during a pipetting operation without adding complexity to the process.

[0009] One example of a traditional liquid level tracking method is in U.S. Patent 4,586,546, issued May 6, 1986, entitled “Liquid handling device and method.” The ‘546 patent describes a device and method for detecting the liquid level in a container, and predicting the height of the liquid and the desired height of the pipette tip in the container after a certain volume is added or removed.

[0010] There are several other common methods of automatically detecting the liquid level in a container. The simplest of these methods is based on pressure measurement. As the pipette tip enters the liquid surface, a change in the pressure inside the pipette tip is detected. This method does not require any special pipette tip design or features, and in most cases is only feasible when the pipette tip is empty. Pressure-based liquid level detection can be performed using any conventional pipette tip. One example of a pressure-based liquid level detection method is in U.S. Patent 4,794,085, titled "Apparatus and method for detecting liquid penetration from a container for aspirating and dispensing liquids," issued September 27, 1988. The '085 patent describes a pipetting device with a pressure sensor for measuring the pressure within the device. The pipette tip is moved downward in increments toward the liquid. At each stage, a syringe pump is actuated to create a pressure differential within the device. If the pipette tip has entered the liquid, the opening of the pipette tip will be obstructed, and the pressure sensor can detect the pressure differential. Another example is in U.S. Patent 8,287,806, titled "Pipetting apparatus with integrated liquid level and / or bubble detection," issued October 16, 2012. The '806 patent describes a device for detecting liquid level using pressure measurement. The pipetting device specifies the use of system liquid instead of air between the pump and the pipette tip.

[0011] The design and composition of the pipette tip can be improved to allow for more advanced liquid level sensing methods. This enhancement typically involves the placement of electrodes in the pipette tip, so that an electrical signal can be used to detect the liquid level. The most common improvement is to make the pipette tip out of a conductive plastic, and to measure the capacitance between the conductive pipette tip and the ground plane below the container holding the liquid or sample. One example of a capacitance-based liquid level detection is in U.S. Patent 4,736,638, titled "Liquid level sensor," issued April 12, 1988. The '638 patent describes a device for sensing the liquid level in a fluid delivery mechanism, which includes a conductive member supporting a container of sample liquid and a conductive pipette probe. The capacitance signal is measured between the probe and the supporting ground plane, and a change in capacitance is detected when the probe contacts the fluid.

[0012] Pipette tip designs can be further improved by providing multiple electrodes within the pipette tip to enable more advanced signal detection. Capacitance between one or both electrodes and the floor can be measured, capacitance between two electrodes can be measured, or electrical impedance between two electrodes can be measured. One example of electrical signal based liquid level detection for a pipette tip having more than one electrode is found in U.S. Patent 5,045,286, issued September 3, 1991, entitled "Device for Aspirating a Fixed Volume of Liquid." The '286 patent describes a pipette tip having two electrically conductive members disposed in the nozzle such that one electrode extends from the nozzle attachment to the lower end of the nozzle and the other electrode extends from the nozzle attachment to some distance or height above the lower end of the nozzle such that the distance or height corresponds to a fixed volume of liquid to be aspirated through the nozzle. The '286 patent also discloses various methods of manufacturing such a pipette tip. Another example is found in U.S. Patent 6,851,453, issued February 8, 2005, entitled "Fluid Dispensing Verification System." The '453 patent describes a probe for dispensing a fluid having two electrodes with the ends of the two electrodes spaced apart longitudinally from each other. The signal between the two electrodes is measured in order to detect a liquid and a surface for fluid delivery verification. Another example is found in U.S. Patent 5,550,059, issued August 27, 1996, entitled "Fluid Sensing Pipette." The '059 patent describes a probe for fluid dispensing having two concentrically arranged electrically conductive tubes insulated from each other. The signal between the two electrodes is measured to detect a liquid level. SUMMARY

[0013] Disclosed herein are devices, systems, and methods for pipetting applications. In one aspect, a pipetting device for automatically maintaining pipette tip depth in an electrically conductive fluid during a fluid transfer operation is described. The pipetting device includes a pipette tip having a fixed end with an opening, a fluid transfer end with an opening, an outer surface, and an inner surface, wherein the outer surface comprises an electrically insulating material; a first electrode and a second electrode on the outer surface of the pipette tip, the first electrode and the second electrode being spaced apart by the electrically insulating material; a frame supporting an actuator, the actuator being operatively connected to the pipette tip, wherein the pipette tip is oriented vertically with respect to the frame, and wherein the actuator is adapted to adjust the position of the pipette tip with respect to the frame; a controller electrically connected to the first electrode and the second electrode, wherein the first electrode and the second electrode are adapted to send a signal to the controller related to an electrically conductive fluid in contact with the outer surface of the pipette tip; and wherein the controller is adapted to command the actuator to move the position of the pipette tip in response to the signal.

[0014] In some embodiments, each of the first and second electrodes described herein extend the entire longitudinal length of the pipette tip from the fixed end to the fluid transfer end. In other embodiments, each of the first and second electrodes described herein terminate at a point proximate to the fixed end, wherein the point is where the first and second electrodes are electrically connected to the controller. In some cases, each of the first and second electrodes described herein terminate at a point proximate to the fluid transfer end, wherein the point is where the electrically conductive fluid can reach.

[0015] In some cases, the signal from the first and second electrodes described herein is a measure of the electrical resistance associated with the electrically conductive fluid. In some cases, the first and second electrodes described herein can be made of copper, or in other cases, electrically conductive polypropylene.

[0016] In some embodiments, the pipetting device further comprises a first and second electrical point and a first and second electrical wire connecting the first and second electrodes to a controller, respectively.

[0017] In another aspect, a method for automatically maintaining pipette tip depth in an electrically conductive fluid during a fluid transfer operation is described herein. An exemplary method comprises the steps of: providing a pipetting device comprising: a pipette tip having a fixed end with an opening, a fluid transfer end with an opening, an outer surface, and an inner surface, wherein the outer surface comprises an electrically insulating material; a first and second electrode on the outer surface of the pipette tip, the first and second electrode being spaced apart by the electrically insulating material; a frame supporting an actuator, the actuator being operatively connected to the pipette tip, wherein the pipette tip is oriented vertically relative to the frame, and wherein the actuator is adapted to move the height of the pipette tip relative to the frame; and a controller electrically connected to the first and second electrodes; providing a container fixed in height relative to the frame, the container holding an electrically conductive fluid having a first liquid level; positioning the pipette tip in the container such that at least a portion of the first and second electrodes are immersed in the electrically conductive fluid, wherein the positioning step forms a control loop between the first and second electrodes, the actuator, the controller, and the electrically conductive fluid; measuring a change in electrical resistance associated with the electrically conductive fluid by the first and second electrodes; sending a signal associated with the change to the controller by the first and second electrodes, wherein the controller is configured to command the actuator to move the pipette tip vertically in response to the signal.

[0018] In some cases, the methods described herein can further include the step of aspirating a volume of conductive fluid through the pipette tip, wherein, after the step of aspirating, the conductive fluid has a second level; commanding, by the controller, the actuator to move the pipette tip relative to the second level such that the first electrode and the second electrode remain immersed in the conductive fluid. In some cases, the methods described herein can further include the step of dispensing a volume of conductive fluid through the pipette tip, wherein, after the step of dispensing, the conductive fluid has a second level; commanding, by the controller, the actuator to move the pipette tip relative to the second level such that the first electrode and the second electrode remain immersed in the conductive fluid.

[0019] In some embodiments, the methods described herein can further include the step of maintaining, by a control loop, the pipette tip at a constant second level relative to a surface of the conductive fluid.

[0020] In yet another aspect, described herein is a pipette tip, the pipette tip comprising a body made of an electrically insulating material, the body comprising: an outer surface and an inner surface; a first electrode disposed on the outer surface; and a second electrode disposed on the outer surface, the second electrode being spaced apart from the first electrode by the electrically insulating material.

[0021] In some cases, the body described herein further comprises a device securing end; and a fluid transfer end positioned opposite the device securing end, the fluid transfer end comprising a fluid transfer opening.

[0022] In some embodiments, the pipette tip described herein can further comprise a third electrode and a fourth electrode, the third electrode and the fourth electrode disposed on the inner surface.

[0023] In some cases, each or all of the electrodes described herein can extend along an entire longitudinal length of the body from the fluid transfer end to the device securing end. In other cases, each or all of the electrodes extend a distance from the fluid transfer end to the device securing end that is less than an entire longitudinal length of the body.

[0024] In some cases, each of the electrodes described herein can be made of copper or conductive polypropylene.

[0025] In some embodiments, each of the electrodes described herein can comprise an electrical contact tab positioned at a device securing end of the electrode. In some cases, the electrical contact tab can extend to an end of the device securing end, or the electrical contact tab can extend beyond the device securing end of the pipette tip. BRIEF DESCRIPTION OF DRAWINGS

[0026] Having thus described the disclosed subject matter in general terms, reference will now be made to the accompanying drawings, which are not necessarily drawn to scale, and wherein:

[0027] FIG. 1 A cross-sectional side view of a liquid handling device is shown in accordance with example embodiments of the presently disclosed subject matter;

[0028] FIG. 2A , FIG. 2B and FIG. 2C side, perspective, and cross-sectional views of a pipette tip are shown in accordance with example embodiments of the presently disclosed subject matter;

[0029] FIG. 3A A cross-sectional view of a pipette tip attached to a liquid handling device is shown in accordance with example embodiments of the presently disclosed subject matter;

[0030] FIG. 3B An exploded side view of a pipette tip for attachment to a liquid handling device is shown in accordance with example embodiments of the presently disclosed subject matter;

[0031] FIG. 4A A schematic view of a liquid handling device to which a pipette tip is attached is shown in accordance with example embodiments of the presently disclosed subject matter; FIG. 1

[0032] A side view of a liquid handling device to which a pipette tip is attached is shown in accordance with example embodiments of the presently disclosed subject matter; FIG. 4B FIG. 1 A plot of signals and system responses measured during aspiration of a sample using an apparatus in accordance with example embodiments of the presently disclosed subject matter is shown;

[0033] FIG. 5A A plot of signals and system responses measured during dispensing of a sample using an apparatus in accordance with example embodiments of the presently disclosed subject matter is shown;

[0034] FIG. 5B ,

[0035] and FIG. 6A side views of example pipette tips at different levels, heights, or depths relative to a liquid level are shown; FIG. 6B FIG. 6C An example flowchart of a method of using a liquid handling device to automatically adjust a depth of a pipette tip in a liquid in response to varying probe resistance measurements is shown;

[0036] FIG. 7 FIG. 1 An example flowchart of a method of using a liquid handling device to automatically adjust a depth of a pipette tip in a liquid in response to varying probe resistance measurements is shown; ​​

[0037] FIG. 8A 、 FIG. 8B 、 FIG. 8C 、 FIG. 8D and FIG. 8E shows multiple views of a 20 μΙ_ -pipette tip according to yet another example embodiment of the presently disclosed subject matter;

[0038] FIG. 9A 、 FIG. 9B 、 FIG. 9C 、 FIG. 9D and FIG. 9E shows multiple views of a 20 μΙ_ -pipette tip according to yet another example embodiment of the presently disclosed subject matter;

[0039] FIG. 10A 、 FIG. 10B 、 FIG. 10C 、 FIG. 10D and FIG. 10E shows multiple views of a 200 μΙ_ -pipette tip according to yet another example embodiment of the presently disclosed subject matter;

[0040] FIG. 11A 、 FIG. 11B 、 FIG. 11C 、 FIG. 11D and FIG. 11E shows multiple views of a 200 μΙ_ -pipette tip according to yet another example embodiment of the presently disclosed subject matter; and

[0041] FIG. 12A 、 FIG. 12B 、 FIG. 12C 、 FIG. 12D and FIG. 12E shows multiple views of a pipette tip according to yet another example embodiment of the presently disclosed subject matter. DETAILED DESCRIPTION

[0042] The following detailed description is made with reference to the accompanying drawings, of which there are some, but not all embodiments of the disclosed subject matter are illustrated. The same numbers are used in the specification and figures to reference like components. The disclosed subject matter can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the disclosed subject matter set forth herein will come to mind to one skilled in the art to which the disclosed subject matter pertains, having the benefit of the teachings presented in the foregoing description and the associated drawings. Therefore, it is to be understood that the disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Moreover, although the foregoing description has been described in the context of particular embodiments, it should be appreciated that

[0043] In some embodiments, the presently disclosed subject matter provides a pipette tip and method for automatically maintaining a pipette tip depth in a fluid during a fluid transfer operation. The pipette tip and method described herein can provide real-time automatic tracking of a liquid level during a pipetting operation without prior knowledge of the container geometry. That is, the pipette tip and method of the present disclosure can reduce or eliminate the need for prior knowledge and characterization of a laboratory vessel container in order to predict changes in the height of the liquid level during a pipetting operation.

[0044] The present disclosure provides a method of maintaining a pipette tip depth in a liquid throughout a pipetting operation as the liquid level rises or falls in its container without any prior knowledge of the container geometry. For example, in a laboratory setting, a user who is inexperienced or does not have knowledge in programming a liquid handler for use with a particular laboratory vessel container can readily work with an automated liquid handler on which the pipette tip and method disclosed herein has been implemented. The user can benefit from improved ease of use that is accompanied by improved precision and accuracy of transferred volumes that result from consistent and reliable depth of the pipette tip throughout a series of liquid handling operations.

[0045] In some embodiments, the pipette tip and method described herein has a sensing mechanism in the pipette tip to track the liquid level relative to the pipette tip on an automated liquid handling instrument during a pipetting operation. That is, the pipette tip described herein includes a pair of electrodes positioned along the length of the pipette tip. The pair of electrodes can provide electrical feedback (e.g., a resistance measurement between the electrodes) that can be correlated to the depth of the pipette tip in an electrically conductive fluid. That is, the resistance value between the pipette tip electrodes will vary proportionally with the depth of the pipette tip in the fluid.

[0046] In some embodiments, the pipette tip and method described herein can improve the ease of use of an automated liquid handling instrument while maintaining or improving the reliability of pipetting results.

[0047] In some embodiments, the pipette tip and method described herein can improve the user experience of an automated liquid handling instrument by automating aspects of a pipetting operation that can otherwise require user manual programming of the instrument. In particular, by providing a method of automatically tracking a liquid level in real-time during a pipetting operation, the pipette tip and method can eliminate or reduce the need to define and specify the geometry of a laboratory vessel container. Further, the pipette tip and method described herein can eliminate, in many cases, the need for prior knowledge and characterization of a laboratory vessel container in order to predict changes in the height of the liquid level as liquid is added to or removed from the container.

[0048] In some embodiments, the pipette tip and method described herein provide a substantially transparent pipette tip, whereby a user can directly observe any liquid within the pipette tip during pipetting operations.

[0049] Reference is now made to FIG. 1 , FIG. 1 is a side view of an example of a liquid handling apparatus 1 for utilizing the pipette tip and method described herein. That is, the liquid handling apparatus 1 is a mechanized liquid handling device. The liquid handling apparatus 1 comprises a pump 2 in fluid communication with a nozzle 3 via an enclosed air volume 4. In some embodiments, the enclosed volume can be filled with a system fluid. The nozzle 3 has an opening 32 through which liquid is either sucked into or ejected out of the nozzle 3. Furthermore, in some embodiments, the liquid handling apparatus 1 can be fixed to a vertically oriented linear actuator 5, which can control the height of the nozzle 3 relative to a fixed frame 54 of the apparatus 1 and relative to a container 6 that is fixed in height relative to the fixed frame 54. However, in other cases, the linear actuator 5 can be fixed in other orientations, such as obliquely or diagonally to the fixed frame 54, etc. The container 6 holds an amount of liquid 61. The linear actuator 5 can be used to adjust the height of the liquid handling apparatus 1 so as to insert the nozzle 3 into the liquid 61 so that it can either suck or dispense the liquid 61.

[0050] When liquid 61 is removed from or added to the container 6 by the nozzle 3, the liquid level in the container 6, i.e. the liquid level 62, will respectively drop or rise. In order to keep the opening of the nozzle 3 immersed in the liquid 61 at a consistent depth as the liquid level changes, the height of the liquid handling apparatus 1 must be adjusted, thereby avoiding transfer volume errors caused by sucking air. Preferably, the height of the liquid handling apparatus 1 is controlled so that the opening of the nozzle 3 remains at a consistent depth below the liquid level 62 as the liquid level changes, to achieve maximum precision and accuracy of the transfer volume.

[0051] In automated pipetting applications, the nozzle 3 can be referred to as a pipette tip. Thus, the nozzle 3 is hereinafter referred to as a pipette tip 3, in one embodiment of the method of the present disclosure, electrical signal feedback from the pipette tip 3 is available for sensing the depth of the pipette tip 3 in the liquid 61. This signal feedback is available as an input to a control loop driving the vertical linear actuator 5 to maintain a constant depth of the pipette tip 3 in the liquid 61, even when the liquid level in the container 6 rises and drops.

[0052] The methods disclosed herein can utilize the resistivity of the conductor in the pipette tip 3. In one exemplary embodiment, the pipette tip 3 can include pipette tip electrodes 31a, 31b to provide this electrical input. Resistivity is an inherent material property that describes the degree to which a material resists the flow of electrical current. The total resistance of a body of material is related to its resistivity and geometry, as calculated by the following equation:

[0053]

[0054] where:

[0055] R is resistance (ohms)

[0056] p is resistivity (ohm-meters)

[0057] / is the length of the body between the points of electrical contact (meters)

[0058] A is the cross-sectional area of the body (square meters)

[0059] Thus, it can be appreciated that by changing the length of the body through which the current flows, the resistance of the body as measured will change proportionally.

[0060] FIG. 2A 、 FIG. 2B and FIG. 2CThe figures show a side view, a perspective view, and a cross-sectional view of one embodiment of a pipette tip 3 including a liquid level sensing mechanism. Conductive electrodes with measurable resistance (e.g., pipette tip electrodes 31a, 31b) may be provided in the liquid handling pipette tip 3. That is, in the disclosed method, two spaced-apart pipette tip electrodes 31a, 31b are included on the pipette tip 3 to measure resistance. In some embodiments, the two pipette tip electrodes 31a, 31b extend the entire longitudinal length of the pipette tip 3 from the fixed end 33 to the fluid transfer end 34. For orientation purposes, the fluid transfer end 34 includes an opening 32 of the pipette tip 3, where liquid is drawn into and dispensed from the pipette tip 3. The fixed end 33 is located opposite the fluid transfer end (i.e., at the distal end of the opening 32) and is the portion of the pipette tip 3 that interacts with and / or secures the pipette tip 3 to the liquid handling device 1. In some embodiments, the two pipette tip electrodes 31a, 31b do not extend the entire longitudinal length of the pipette tip 3, but may terminate below the fixed end 33 of the pipette tip 3. Therefore, in some cases, one or both of the pipette tip electrodes 31a, 31b have a length less than the entire longitudinal length of the pipette tip 3. Preferably, the two pipette tip electrodes 31a, 31b should terminate near the fixed end 33 of the pipette tip 3, which forms the electrical connection to the liquid handling apparatus 1. The design of this electrical connection can vary. In some embodiments, the two pipette tip electrodes 31a, 31b may terminate above the fluid transfer end 34 of the pipette tip 3. However, it should be understood that level tracking is not possible below the point on the pipette tip 3 to which the two pipette tip electrodes 31a, 31b extend. To conform to general practice of ensuring optimal fluid transfer results, only a very small length of the pipette tip 3 is immersed in the fluid (e.g., liquid 61). Therefore, the two pipette tip electrodes 31a, 31b preferably extend to or nearly extend to the fluid transfer end 34 of the pipette tip 3 to allow level tracking.

[0061] In some embodiments, the pipette tip electrodes 31a and 31b are completely spaced apart from each other by an electrically insulating material 37. Furthermore, both pipette tip electrodes 31a and 31b are exposed on the outer surface 36 of the pipette tip to allow sensing of the liquid level outside the pipette tip 3, and neither conductor is exposed on the inner surface 35 of the pipette tip to prevent sensing of the liquid level inside the pipette tip 3.

[0062] However, the design of pipette tip 3 is not limited to electrodes on its outer surface. Rather, electrodes can be positioned on any surface of pipette tip 3 without departing from the purpose of the present disclosure. For example, in some embodiments, pipette tip electrodes 31a, 31b can be disposed on the inner surface 35 of the pipette tip to allow for sensing the liquid level within pipette tip 3. That is, the liquid level within a calibrated pipette tip 3 is measured, and thus the volume of the calibrated conductive liquid. In other embodiments, the design of pipette tip 3 includes electrodes on both the outer and inner surfaces of the tip. Thus, such a design allows for sensing the liquid level both on the outside and inside of pipette tip 3.

[0063] In some embodiments, the pipette tip 3 described herein is disposable to avoid contamination from one process to another. In some cases, the pipette tip 3 is resistant to a wide range of chemicals. For example, in some cases, the pipette tip 3 is an injection molded product composed of polypropylene. Since polypropylene is an excellent electrical insulator, this material can also be used as a suitable insulating material to space apart the two pipette tip electrodes 31a, 31b. However, the present invention is not limited to pipette tips 3 made only of polypropylene, but any material that is not inconsistent with the purpose of the present disclosure can also be used. For example, in some embodiments, the pipette tip 3 described herein can be made of polyethylene, polybutylene, or other polyolefins. For simplicity of readability, the following methods will be described with polypropylene as the building material for pipette tip 3, but the present invention should not be construed as excluding other suitable materials.

[0064] One method of manufacturing a pipette tip with two conductive electrodes is a two-shot injection molding, including a first shot of a clear insulating polypropylene material to form the body and inner cone of pipette tip 3, and a second shot of a conductive polypropylene to form the two separate conductive pipette tip electrodes 31a, 31b. The result is a single part or unit composed of two different materials. Polypropylene is an excellent electrical insulator and thus a suitable insulating material for the first shot to form the body of pipette tip 3 and to space apart the two pipette tip electrodes 31a, 31b. Polypropylene can be made conductive by the addition of various conductive additives, such as conductive carbon black or various inorganic conductors known to those skilled in the art. Thus, polypropylene is a suitable material for the second shot to form the two separate conductive pipette tip electrodes 31a, 31b.

[0065] Another method of manufacturing a pipette tip having two conductive electrodes as described above is to selectively coat the exterior of the pipette tip with a conductive material. Among other techniques, this can involve printing a conductive ink or applying a conductive resin. In a preferred embodiment, the body of the pipette tip 3 is composed of electrically insulating polypropylene and is produced through an injection molding process. The conductive electrodes are applied to the pipette tip in a secondary process, in which conductive polypropylene is printed onto the exterior of the pipette tip to form a thin conductive strip. One advantage of this method is that the conductive strip can cover a very small area of the exterior of the pipette tip, leaving the majority of the pipette tip transparent to an observer. In some cases, transparency can be a desirable feature of the pipette tip for the user of the liquid handling device, as it allows the user to directly observe any liquid inside the pipette tip during pipetting operations. Conventional conductive pipette tips are completely opaque and the liquid inside the pipette tip cannot be observed.

[0066] Examples of materials for forming the conductive pipette tip electrodes 31a, 31b of the pipette tip 3 can include, but are not limited to, conductive polypropylene resin, conductive epoxy resin, conductive ink, copper, and the like. Furthermore, the conductive material used to form the conductive pipette tip electrodes 31a, 31b has an appropriate resistivity such that, given the length and cross-section of the electrode body, the total resistance can be measured with reasonable resolution. For example, a conductor composed of a copper wire applied to the outer surface 36 of the pipette tip can have an inconsequential resistivity to allow for a measurable change in resistance across the length of the pipette tip 3 without highly specialized equipment. A typical total resistance measurement for a pipette tip can be on the order of 50 kilo-ohms to about 200 kilo-ohms, the pipette tip can hold 200 μL of liquid and have electrodes composed of conductive polypropylene resin and the fluid transfer end 34 is immersed in tap water about 2 millimeters. The allowed range of resistance is much greater.

[0067] Reference is now made to FIG. 3A , FIG. 3A a block diagram of the pipette tip 3 described herein to an accessory of the liquid handling device 1 is shown. Additionally, FIG. 3B a side view of a specific example of the pipette tip 3 adapted to be attached to the liquid handling device 1 is shown. In FIG. 3A and 3BIn the illustrated embodiment, the pipette tip attachment point 12 of the liquid handling device 1 includes a pair of electrical contact points 11A, 11B to conduct electrical signals between a pair of pipette tip electrodes 31A, 31B on the pipette tip 3 and wires 13 leading to the electronic controller 7. During attachment of the pipette tip 3, each of the two electrical contact points 11a, 11b makes a good electrical connection with its respective pipette tip electrode 31 on the pipette tip 3, such that both pipette tip electrodes 31a, 31b on the pipette tip 3 are connected to the electronic controller 7 through the electrical contact points 11a, 11b. Specifically, the electrical contact point 11a is connected to the pipette tip electrode 31a, and the electrical contact point 11b is connected to the pipette tip electrode 31b. The electrical contact points 11a, 11b can be spring loaded to ensure that a reliable electrical connection with the pipette tip electrodes 31a, 31b is made each time the pipette tip 3 is attached to the liquid handling device 1. In some embodiments, a mechanism or method is implemented to ensure that the pipette tip 3 is reliably attached to the liquid handling device 1 in the proper orientation, such that the electrical contact points 11a, 11b are in good electrical connection with the pipette tip electrodes 31a, 31b. Additionally, the pipette tip 3 is attached to the liquid handling device 1 by a mechanism that ensures a reliable pneumatic seal to the conduit leading to the pump 2 to ensure proper pipette performance. As previously described herein, the pipette tip 3 is attached to the liquid handling device 1 at the fixed end 33. The design and orientation of such mechanisms and methods can vary, and their specific features fall outside the scope of the present disclosure.

[0068] In the absence of a pipette tip 3 attached to the liquid handling device 1, the electrical circuit between the two electrical contact points 11a, 11b on the liquid handling device 1 is open, and no current can flow. That is, the measured resistance is extremely high. In the case of a proper pipette tip 3 correctly attached to the liquid handling device 1, the electrical circuit between the two electrical contact points 11a, 11b will still be open, however, a slight change in the signal can be detected between the two conductors, and thus the presence of a correctly attached pipette tip 3 can be confirmed prior to performing a pipetting operation.

[0069] During pipetting operations, if the pipette tip 3 is submerged in the electrically conductive fluid, the pipette tip electrodes 31a, 31b provided in the pipette tip 3 will be electrically connected via the electrically conductive fluid. If this connection is made, there will be a probe-liquid closed circuit between the electronic controller 7, the electrical contact points 11a, 11b at the pipette tip attachment point 12, the pipette tip electrodes 31a, 31b and the electrically conductive fluid 61, causing a significant change in the signal measured by the electronic controller 7. If the depth of the pipette tip 3 in the liquid changes, the point along the length of the pipette tip 3 at which the electrically conductive fluid connects the two pipette tip electrodes 31a, 31b will change, and thus the effective length of the pipette tip electrodes 31a, 31b in the electrical circuit will change. The electrical resistance of the pipette tip electrodes 31a, 31b in the electrical circuit will thus change in proportion to the depth of the pipette tip 3 in the fluid (e.g. the liquid 61).

[0070] If a reference resistance value is taken at a certain depth, that certain depth can be maintained. The continuous resistance measurement can be used as an input to a control loop driving the vertical linear actuator 5, which is tuned to maintain the reference resistance value at a setpoint. If the liquid level on the pipette tip rises or falls, the resistance measurement will fall or rise, respectively, and the height of the pipette tip 3 can be adjusted to maintain this resistance value, and thus the depth of the pipette tip 3 as the liquid level changes.

[0071] As will be appreciated by those skilled in the art, the resistance measurement of the probe-liquid circuit can be performed in various ways. In some embodiments, the unknown resistance of the pipette tip circuit can be measured by a voltage divider circuit and an analog-to-digital signal processing unit with a known input voltage and a known resistance.

[0072] The input signal to be measured can be generated in the form of a direct current or an alternating current. In some embodiments, an alternating current signal is used to improve the performance of the system. In some embodiments that utilize a direct current signal, the electrical conductivity of the pipette tip electrodes 31 immersed in the electrically conductive liquid can deteriorate over a certain period of time in ionic liquids. It has been found that the use of an alternating current can prevent such contamination of the pipette tip electrodes.

[0073] In some embodiments, the alternating voltage signal can be simply interpreted as a direct voltage by taking the root mean square of the alternating voltage signal before conventional analog-to-digital signal processing. In preferred embodiments, the alternating signal is interpreted by lock-in amplification. This method is even able to extract a signal with a known reference frequency from a very noisy input. This method is effective in isolating the desired signal even in the presence of interference from adjacent devices performing similar or different functions. The resulting direct current signal can be processed by non-typical analog-to-digital conversion.

[0074] The methods described herein are compatible only with conductive liquids that allow current to flow between the pipette tip electrodes 31a, 31b. For non-conductive fluids, conventional level tracking is required, meaning the geometry of the laboratory glassware must be pre-programmed to predict level movement during pipetting operations. However, the methods described herein can be implemented as a quick and convenient way to calibrate the geometry of laboratory glassware containers to be used in pipetting operations utilizing non-conductive fluids. The calibration method will involve measuring the container geometry by level detection and tracking with conductive fluids. This calibration method will eliminate the need for cumbersome measurements to determine the container geometry. The calibrated geometry is useful for performing level tracking using non-conductive fluids and conventional pipette tips lacking the dual-electrode feature described herein.

[0075] Now refer to FIG. 4A and FIG. 4B The detailed description of the disclosed method using a pipette tip (e.g., as mentioned above) FIG. 1 to FIG. 3B An example of a method for automatically tracking the liquid level during the suction operation of the suction tube tip 3).

[0076] Now for reference FIG. 4A , FIG. 4A It shows FIG. 1 A block diagram of a liquid handling device 1 with a suction pipette tip 3 attached thereto. Additionally, FIG. 4B It shows FIG. 1 A side view of a specific example of a liquid handling device 1 having a suction pipette tip 3 attached thereto.

[0077] As shown in the figure, the liquid handling equipment 1 described herein includes, but is not limited to, a pump 2 and a suction head 3 that is airtightly connected to a conduit leading to the pump 2. FIG. 1 to FIG. 3B The device 1 includes an electronic controller 7 electrically connected to the suction tip electrodes 31a and 31B of the suction tube, and a vertical linear actuator 5 for vertically moving the device 1. The pump 2 can be any mechanism providing positive or negative pressure. In one example, the pump 2 can be a syringe pump, which may include, but is not limited to, a motor 21, a syringe 22, a linear motion guide 23, and a lead screw 24, such as... FIG. 4A and FIG. 4B As shown. The vertical linear actuator 5 may include, but is not limited to, a motor 51, a linear motion guide 52, a lead screw 53, and accessories connected to the fixed frame 54 of the device 1, such as... FIG. 4A and FIG. 4B As shown. The electronic controller 7 may be a microcontroller, which is capable, but not limited to, generating and receiving signals, processing signals, sending motion commands, and processing data in order to perform the electronic functions and other features described herein.

[0078] In some embodiments, the method described herein uses an electronic controller 7 to measure the resistance between electrical contacts 11a, 11b at the pipette tip attachment point 12 to identify whether the appropriate pipette tip 3 has been correctly connected to the system. If the appropriate pipette tip 3 has been correctly connected, the method can continue.

[0079] In some embodiments, the methods described herein lower the pipette tip 3 to the liquid level 62 using any automated method known in the art. FIG. 1 (As shown in the diagram). For example, the pipette tip 3 is lowered to the desired depth in the liquid. The desired depth is typically sufficient to ensure that air is not drawn in. For example, the tip of the pipette tip 3 may be about 1 mm to about 2 mm below the liquid surface 62. The electronic controller 7 then measures the resistance of the pipette tip 3 to determine a reference resistance value, which will be used as a setpoint in the control loop at the vertical position. If the liquid 61 is found to be non-conductive, the automatic tracking method is canceled, and the geometry of the container 6 must be programmed into the instrument to ensure correct tracking.

[0080] In some embodiments, the depth of the pipette tip 3 in the liquid 61 is maintained using a vertical position control loop with resistance measurement as input. FIG. 5A Curve 200 illustrates the typical resistance signal and associated vertical actuator response during suction. The control loop drives the vertical linear actuator 5 to maintain the reference resistance setpoint 81a of the suction tip 3 as shown in curve 200. As the liquid level in the container decreases, the liquid level in the suction tip 3 also decreases, and the resistance measurement increases. In some cases, the increase in resistance at the suction tip 3 is interpreted as a decrease in the A / D count measured by the electronic controller 7. If the resistance measurement increases beyond the threshold 82a shown in curve 200, meaning the A / D count has fallen below the threshold 82a, the electronic controller 7 will respond by commanding the vertical linear actuator 5 to drive the suction tip 3 down to the Z position at the threshold level 83a to track the liquid level and attempt to maintain the reference resistance setpoint 81a. The height of the liquid 61 in the container 6 will only change as the pump 2 draws liquid into the suction tip 3. When the suction is nearly complete, the liquid level on the suction tip 3 will stabilize and return to the set point 84 shown in curve 200, so that the suction tip is stabilized at the Z position corresponding to the new liquid level 85 shown in curve 200.

[0081] Typical resistance signal and associated vertical actuator response during distribution 5 FIG. 5BAs shown in curve 210. After the reference resistance setpoint 81b has been established, if the liquid level in the container rises, the liquid level on the pipette tip rises, and the resistance measurement decreases. The decrease in resistance causes the A / D count measured by the electronic controller 7 to increase. If the A / D signal exceeds the threshold level 82b, the electronic controller 7 responds to the command of the vertical linear actuator 5 to drive the pipette tip 3 upward to the Z position at the threshold level 83b in order to track the liquid level and attempt to maintain the reference resistance setpoint 81b.

[0082] Those skilled in the art will understand that various control loop techniques can be applied. For example, the loop can be controlled in a proportional manner, meaning that a small, slow change in the resistance signal will result in a small, gradual change at the Z position, and a large, rapid change in the resistance will result in a rapid change at the Z position.

[0083] Further regarding this example, FIG. 6A , FIG. 6B and FIG. 6C A side view is shown of examples of the suction pipette tip 3 at different levels, heights, or depths relative to the liquid level (i.e., liquid surface 62) of liquid 61. That is, FIG. 6A It shows the reference depth D R The pipette tip 3 is located at a reference depth, which is, for example, the desired depth to which the pipette tip 3 will be held during the pipetting operation. The pipette tip 3 has a probe resistance value R. P When at reference depth D R At this time, the pipette tip 3 has a specific probe resistance value R. P The probe resistance value R P The resistance value R of the reference probe can be measured and recorded. P Then, as the liquid level of liquid 61 changes and the measured probe resistance value R... P The Z position of the suction tip 3 can be adjusted upwards or downwards until the reference depth D is found. R and reference probe resistance value R P .For example, FIG. 6B This shows that at a depth less than the reference depth D R The suction tip 3 is located at a depth of [depth]. Therefore, the probe resistance value R [is...]. P Greater than the reference probe resistance value R P This prompts the electronic controller 7 to adjust the Z position of the suction nozzle 3 downwards until the reference depth D is reached. R Similarly, FIG. 6C This shows that at a depth greater than the reference depth D R The suction tip 3 is at a depth of [depth], therefore, the probe resistance value R P Less than the reference probe resistance value R PThis causes the electronic controller 7 to adjust the Z position of the pipette tip 3 upwards until the reference depth D is reached R .

[0084] FIG. 7 A flowchart showing an example of a method 300 of automatically adjusting the depth of a pipette tip in a liquid in response to changing probe resistance measurements using a liquid handling apparatus as described herein is shown. Thus, as the liquid level rises or falls in its container, and with or without any prior knowledge of the container geometry, the method 300 can be used to automatically maintain the depth of the pipette tip 3 in the liquid throughout the pipetting operation. The method 300 can include, but is not limited to, the following steps.

[0085] At step 310, a pipetting device is provided having a mechanism for sensing the level of liquid in its pipette tip. For example, the liquid handling apparatus 1 and pipette tip 3 as described herein are provided, wherein the pipette tip 3 includes two pipette tip electrodes 31a, 31b along the length of the pipette tip 3. These two pipette tip electrodes 31a, 31b provide an electrical feedback (e.g. a resistance measurement between the electrodes), such as a probe resistance value R P (see FIG. 6A , FIG. 6B , FIG. 6C ) etc., which can be related to the depth of the pipette tip in the electrically conductive fluid. That is, the resistance of the pipette tip electrodes will vary in proportion to the depth of the pipette tip in the liquid.

[0086] At step 315, a container is provided which contains an electrically conductive fluid to be handled. For example, in the liquid handling apparatus 1, the container 6 is provided to hold a quantity of liquid 61.

[0087] At step 320, the pipette tip of the pipetting device is positioned in the container such that its liquid level sensing mechanism is immersed in the electrically conductive fluid at a desired and known depth. For example, and referring now to FIG. 6A , the pipette tip 3 of the liquid handling apparatus 1 is positioned in the container 6 such that the pipette tip 3 is immersed in the electrically conductive fluid 61 at a required known depth, such as at a reference depth D R .

[0088] At step 325, a reference probe resistance measurement is captured and recorded. For example, and referring now to FIG. 6A , using the electronic controller 7, the reference probe resistance value R P .

[0089] At step 330, an aspiration operation is performed using the pipette tip having a mechanism for sensing a level of liquid in the pipette tip. For example, an aspiration operation is performed using the pipette tip 3 of the liquid handling apparatus 1. As such, the level of liquid in the container can rise or fall relative to the Z position of the pipette tip 3 in the electrically conductive fluid 61. Further, in this step, the electronic controller 7 continuously monitors the probe resistance value R P (see FIG. 6A 、 FIG. 6B 、 FIG. 6C ).

[0090] At step 335, the position of the pipette tip of the pipette device in the container is adjusted based on a comparison of the current probe resistance measurement to the reference probe resistance measurement. In one example, and now referring to FIG. 6B if the level has fallen relative to the pipette tip 3, the current probe resistance value R P increases. In response to the increasing probe resistance value R P , the electronic controller 7 adjusts the Z position of the pipette tip 3 downward until the reference probe resistance value R R is reached due to reaching the reference depth D P . In another example, and now referring to FIG. 6C if the level has risen relative to the pipette tip 3, the current probe resistance value R P decreases. In response to the decreasing probe resistance value R P , the electronic controller 7 adjusts the Z position of the pipette tip 3 upward until the reference probe resistance value R R is reached due to reaching the reference depth D P .

[0091] Further, and now referring to FIG. 1 to FIG. 7 , while it is known to have multiple electrically conductive bodies within a pipette tip and to measure the resistance between these bodies to determine some state of the nozzle relative to the liquid, the pipette tip and method described herein can provide the mechanism for measuring the resistance as an analog input to a position control loop to maintain the nozzle (i.e., the pipette tip 3) at some predetermined depth in the liquid. In contrast, the limitation of the conventional method is that any resistance measurement between the two electrically conductive bodies in the nozzle is taken as an on / off digital measurement to determine one of two states.

[0092] Further, and now referring to FIG. 1 to FIG. 7The pipette tips and methods described herein can be provided with certain advantageous features that are not present in conventional liquid handling systems. For example, certain features of the electrically conductive body can include, but are not limited to, two electrically conductive bodies on the outer surface of the pipette tip that both substantially extend the entire length of the pipette tip. That is, both electrically conductive bodies can extend from the top end (fixed end), where the tip is electrically and pneumatically connected to the equipment, to the bottom end (fluid transfer end), where the tip is immersed in a fluid. Similarly, certain features of the electrically conductive body can include, but are not limited to, two electrically conductive bodies on the inner surface of the pipette tip that both substantially extend the entire length of the pipette tip.

[0093] FIG. 8A FIG. 8B FIG. 8C FIG. 8D FIG. 8E Various views of a pipette tip 3 according to another example embodiment of the presently disclosed subject matter are shown. That is, FIG. 8A is a perspective view, FIG. 8B is a top view, FIG. 8C is a side view, FIG. 8D is an end view from the tip end, FIG. 8E is an end view from the wide end of the pipette tip 3. FIG. 8A FIG. 8B FIG. 8C FIG. 8D FIG. 8E The pipette tip 3 shown is an example of a 20 μL pipette tip. While this embodiment is in the context of a 20 μL pipette tip, this particular size is merely exemplary and other sizes consistent with the objects of the present disclosure are also contemplated.

[0094] The 20 μL pipette tip 3 includes a pair of electrically conductive electrodes (e.g., pipette tip electrodes 31a, 31b). In this embodiment, the pipette tip electrodes 31a, 31b are narrow electrodes that substantially extend along the full length of the 20 μL pipette tip 3 and are located on the outer surface of the 20 μL pipette tip 3. Further, each pipette tip electrode 31 terminates near the fixed end 33 of the 20 μL pipette tip 3 by a tab (or ear) 30. That is, pipette tip electrode 31a terminates by tab (or ear) 30a. Likewise, pipette tip electrode 31b terminates by tab (or ear) 30b. The tabs (or ears) 30a, 30b extend beyond the fixed end 33 of the 20 μL pipette tip 3. The tabs (or ears) 30a, 30b provide an electrical connection between the 20 μL pipette tip 3 and the liquid handling equipment 1. Also, the pipette tip electrodes 31a, 31b are completely spaced apart from each other by an electrically insulating material 37.

[0095] FIG. 9A ,​​​​​​​​FIG. 9B 、 FIG. 9C 、 FIG. 9D and FIG. 9E various views of a pipette tip 3 according to another example embodiment of the presently disclosed subject matter are shown. That is, FIG. 9A is a perspective view, FIG. 9B is a top view, FIG. 9C is a side view, FIG. 9D is an end view from the end of the tip, FIG. 9E is an end view from the wide end of the pipette tip 3. FIG. 9A 、 FIG. 9B 、 FIG. 9C 、 FIG. 9D and FIG. 9E the pipette tip 3 shown is another example of a 20 μL pipette tip.

[0096] FIG. 9A 、 FIG. 9B 、 FIG. 9C 、 FIG. 9D and FIG. 9E the 20 μL pipette tip 3 shown is substantially the same as the 20 μL pipette tip 3 shown in FIG. 8A 、 FIG. 8B 、 FIG. 8C 、 FIG. 8D and FIG. 8E except that the tabs (or ears) 30A, 30B do not extend beyond the fixed end 33 of the 20 μL pipette tip 3.

[0097] FIG. 10A 、 FIG. 10B 、 FIG. 10C 、 FIG. 10D and FIG. 10E various views of a pipette tip 3 according to another example embodiment of the presently disclosed subject matter are shown. That is, FIG. 10A is a perspective view, FIG. 10B is a top view, FIG. 10C is a side view, FIG. 10D is an end view from the end of the tip, FIG. 10E is an end view from the wide end of the pipette tip 3. FIG. 10A 、 FIG. 10B 、 FIG. 10C 、 FIG. 10D and FIG. 10E the pipette tip 3 shown is one example of a 200 μL pipette tip. Further, while this example is in the context of a 200 μL pipette tip, this particular size is merely exemplary and other sizes consistent with the objects of the present disclosure are also contemplated.

[0098] The 200 μL-pipette tip 3 includes a pair of electrically conductive electrodes (e.g., pipette tip electrodes 31a, 31b). In this embodiment, the pipette tip electrodes 31a, 31b are narrow electrodes that extend substantially along the full length of the 200 μL-pipette tip 3 and are located on the outer surface of the 200 μL-pipette tip 3. Further, each pipette tip electrode 31 terminates near the fixed end 33 of the 200 μL-pipette tip 3 by a tab (or ear) 30. That is, the pipette tip electrode 31a terminates by a tab (or ear) 30a. Likewise, the pipette tip electrode 31b terminates via a tab (or ear) 30b. The tabs (or ears) 30a, 30b extend beyond the fixed end 33 of the 200 μL-pipette tip 3. The tabs (or ears) 30a, 30b provide an electrical connection between the 200 μL-pipette tip 3 and the liquid handling apparatus 1. Likewise, the pipette tip electrodes 31a, 31b are completely spaced apart from each other by an electrically insulating material 37.

[0099] FIG. 11A FIG. 11B FIG. 11C FIG. 11D FIG. 11E Figures 1A-1E show various views of a pipette tip 3 according to yet another exemplary embodiment of the presently disclosed subject matter. That is, FIG. 11A is a perspective view, FIG. 11B is a top view, FIG. 11C is a side view, FIG. 11D is an end view from the tip end, FIG. 11E is an end view from the wide end of the pipette tip 3. FIG. 11A FIG. 11B FIG. 11C FIG. 11D FIG. 11E The pipette tip 3 shown in Figures 2A-2E is another example of a 200 μL pipette tip.

[0100] FIG. 11A FIG. 11B FIG. 11C FIG. 11D FIG. 11E The 200 μL-pipette tip 3 shown in Figures 3A-3E is substantially the same as the 200 μL-pipette tip 3 shown in Figures 1A-1E, except that the tabs (or ears) 30A, 30B do not extend beyond the fixed end 33 of the 200 μL-pipette tip 3. FIG. 10A FIG. 10B FIG. 10C FIG. 10D FIG. 10E

[0101] FIG. 12A FIG. 12B FIG. 12C FIG. 12D FIG. 12E ​​​​​​​​​​​​​​​​​​​​​Various views of a pipette tip 3 according to yet another example embodiment of the presently disclosed subject matter are shown. That is, FIG. 12A is a perspective view, FIG. 12B is a top view, FIG. 12C is a side view, FIG. 12D is an end view from the tip end, FIG. 12E is an end view from the wide end of the pipette tip 3. FIG. 12A FIG. 12B FIG. 12C FIG. 12D and FIG. 12E The pipette tip 3 shown in FIG. 12A to FIG. 12E is one example of a 200 μΐ^pipette tip. In which the pipette tip electrodes 31A, 31B are located on the inner surface of the 200 μΐ^pipette tip 3. In some embodiments, as shown in

[0102] Furthermore, and with reference now to FIG. 1 to FIG. 12E , there are many ways to manufacture the pipette tip 3 of the present disclosure disclosed above. In one example, the pipette tip 3 can be formed using a dual injection molding process. In another example, the pipette tip 3 can be formed using a 3D printing process to print conductive polypropylene strips onto the sides of the tip. In yet another example, the pipette tip 3 can be formed according to the method described with reference to U.S. Patent 5,045,286, titled "Device for aspirating a fixed quantity of liquid", issued September 3, 1991. In yet another example, the pipette tip 3 can be formed according to the method described with reference to U.S. Patent 9,346,045, titled "Conductive pipette tip", issued May 24, 2016.

[0103] In following long-standing patent law precedent, the terms "a" and "one" and "the" are meant to refer to "one or more" when used in this application, including the claims, unless otherwise explicitly defined or specifically stated otherwise (e.g., "the process" refers to one or more processes, etc.). Thus, for example, reference to "a subject" includes a plurality of subjects, unless the context clearly and unambiguously dictates otherwise (e.g., a plurality of subjects), etc.

[0104] ​​​Throughout the specification and claims, the terms "comprise", "comprises", and "comprising" are used in a non-exclusive sense, except where otherwise explicitly stated or indicated by context. Similarly, the term "comprise" and grammatical variants thereof is intended to be non-limiting, such that recitation of items in a list is not a disclaimer of additional claimable items that can be a part of the recited list.

[0105] For the purposes of the present specification and appended claims, unless otherwise indicated, all numbers expressing amounts, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, quantities, and other numerical values are to be understood as being modified in all instances by the term "about", even though the term "about" can not expressly appear with the value, amount or range. Accordingly, unless indicated to the contrary, numerical parameters set forth in the following specification and attached claims are approximations that can vary depending on the desired properties sought to be obtained by the present disclosure subject matter. At the very least, therefore, numerical parameters should not be treated as strict limitations - the appended claims and description of the exclusive property are intended to cover all possible values and sub-ranges of the specified ranges, unless it is clearly indicated otherwise. For example, when referring to a value, the term "about" can mean including in some embodiments variations of ±100% from the stated amount, in some embodiments ±50%, in some embodiments ±20%, in some embodiments ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±0.5%, and in some embodiments ±0.1%, as such variations are suitable to perform the disclosed methods or employ the disclosed compositions.

[0106] Further, the term "about", when used in conjunction with one or more numerical or value ranges, is understood to refer to all such numbers, including all numbers within the range, and to modify that range by extending the boundaries of the range by the given number above and below the stated numerical limits. Numerical ranges expressed by endpoints include all numbers included within that range, e.g., integers, including fractions thereof (e.g., 1 to 5 includes 1, 2, 3, 4, and 5, as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, etc.), and any range within the range.

[0107] While the foregoing subject matter has been described and illustrated by reference to particular embodiments, those skilled in the art will understand that various changes in form and detail can be made therein without departing from the scope of the appended claims.

Claims

1. A suction device for automatically maintaining the depth of a suction tip in a conductive fluid during a fluid transfer operation, comprising: A suction tube tip having a fixed end with an opening, a fluid transfer end with an opening, an outer surface, and an inner surface, wherein the outer surface comprises an electrically insulating material; A first electrode and a second electrode are located on the outer surface of the suction tube tip, and the first electrode and the second electrode are separated by the electrical insulating material. A frame supporting an actuator operably connected to the suction tube tip, wherein the suction tube tip is oriented vertically relative to the frame, and wherein the actuator is adapted to adjust the position of the suction tube tip relative to the frame. as well as A controller electrically connected to the first electrode and the second electrode, wherein the first electrode and the second electrode are adapted to send signals related to a conductive fluid to the controller, the conductive fluid being in contact with the outer surface of the suction tip; and wherein the controller is adapted to command the actuator to move the position of the suction tip in response to the signals. The signals from the first electrode and the second electrode are measurements of the resistance associated with the conductive fluid. During the fluid transfer operation, when fluid is drawn in or dispensed, the controller provides a resistance measurement input to the actuator to control the movement of the actuator based on changes in the resistance measurement input, thereby maintaining a constant depth of the suction nozzle in the fluid during the fluid transfer operation.

2. The suction device according to claim 1, wherein each of the first electrode and the second electrode extends the entire longitudinal length of the suction tube tip from the fixed end to the fluid transfer end.

3. The suction device according to claim 1, wherein each of the first electrode and the second electrode terminates at a point near the fixed end, wherein the point is the location where the first electrode and the second electrode are electrically connected to the controller.

4. The suction and transfer device according to claim 1, wherein each of the first electrode and the second electrode terminates at a point near the fluid transfer end, wherein the point is a location accessible to the conductive fluid.

5. The suction device according to claim 1, wherein the first electrode and the second electrode are made of copper.

6. The suction and transfer device according to claim 1, wherein the first electrode and the second electrode are made of conductive polypropylene.

7. The suction device according to claim 1 further includes a first electrode point and a second electrode point, as well as a first wire and a second wire, wherein the first wire and the second wire respectively connect the first electrode and the second electrode to the controller.

8. A method of using a pipette tip for automatically maintaining a constant depth in a conductive fluid during a fluid transfer operation, the pipette tip being configured to be operatively connected to an actuator, the pipette tip comprising: The main body, made of an electrically insulating material, comprises: The outer surface, configured to contact the conductive fluid; and Inner surface; A first electrode, the first electrode being disposed on the outer surface; and A second electrode is disposed on the outer surface and is spaced apart from the first electrode by the electrically insulating material. The first electrode and the second electrode are configured to be electrically connected to the controller, and the first electrode and the second electrode are adapted to send a signal related to the conductive fluid to the controller, wherein the controller is adapted to command the actuator to move the position of the suction tip in response to the signal; The signals from the first electrode and the second electrode are measurements of the resistance associated with the conductive fluid. During the fluid transfer operation, when fluid is drawn in or dispensed, the controller provides a resistance measurement input to the actuator to control the movement of the actuator based on changes in the resistance measurement input, thereby maintaining a constant depth of the suction nozzle in the fluid during the fluid transfer operation.

9. The method of use according to claim 8, wherein, The subject also includes: Equipment fixed end; and A fluid transfer end is positioned opposite the fixed end of the device, and the fluid transfer end includes a fluid transfer opening.

10. The method of use according to claim 8, wherein the suction pipette tip further includes a third electrode and a fourth electrode, the third electrode and the fourth electrode being disposed on the inner surface.

11. The method of use according to claim 9, wherein each or all electrodes extend from the fluid transfer end to the device fixing end along the entire longitudinal length of the body.

12. The method of use according to claim 9, wherein the distance by which each or all electrodes extends from the fluid transfer end to the device fixing end is less than the entire longitudinal length of the body.

13. The method of use according to claim 8 or 10, wherein each electrode is made of copper or conductive polypropylene.

14. The method of use according to claim 11, wherein each electrode includes an electrical contact tab positioned at the device fixed end of each electrode.

15. The method of use according to claim 14, wherein the electrical contact tab extends beyond the device fixed end of the suction tube tip.

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