Pipetting device and method

Abstract

An automated pipetting system includes a pipettor. The pipettor includes a pipetting channel, a first plunger mechanism operable to vary pressure in the pipetting channel to draw or dispense liquid, and a second plunger mechanism operable to vary pressure in the pipetting channel to draw or dispense liquid.

Description

Technical Field

[0001] The present technology relates to automated liquid handling systems, and more particularly to apparatus and methods for aspirating and / or dispensing liquids using a pipette. Background Art

[0002] Laboratory liquid handling systems are used to transport and manipulate large quantities of liquids. The liquid handling system may include one or more pipettes for aspirating portions of a liquid sample and / or dispensing the liquid sample. In some cases, the liquid sample is aspirated and dispensed robotically, and in some cases, automatically and programmatically. Summary of the invention

[0003] According to some embodiments, an automated pipetting system includes a pipette, wherein the pipette includes a pipetting channel, a first plunger mechanism operable to change pressure in the pipetting channel to aspirate or dispense liquid, and a second plunger mechanism operable to change pressure in the pipetting channel to aspirate or dispense liquid.

[0004] According to some embodiments, the first plunger mechanism and the second plunger mechanism are operable to displace a volume of air in the pipetting channel.

[0005] According to some embodiments, the first plunger mechanism and the second plunger mechanism are operable independently of each other to change the pressure in the pipetting channel.

[0006] In some embodiments, the pipetting system includes a pipetting orifice and a liquid collection volume, and the first plunger mechanism and the second plunger mechanism are operable to change the pressure in the pipetting channel to draw liquid into the liquid collection volume through the pipetting orifice or dispense liquid from the liquid collection volume through the pipetting orifice.

[0007] The automated pipetting system may include a pipette tip removably coupled to the pipette, wherein the pipette tip includes a liquid collection volume and a pipetting orifice.

[0008] In some embodiments, the pipette includes an ejection mechanism operable to force the pipette tip out of the pipette.

[0009] According to some embodiments, the first plunger mechanism includes a first chamber and a first plunger, wherein the first plunger mechanism is operable to move the first plunger through the first chamber to change the pressure in the pipetting channel, and the second plunger mechanism includes a second chamber and a second plunger, wherein the second plunger mechanism is operable to move the second plunger through the second chamber to change the pressure in the pipetting channel.

[0010] In some embodiments, the first plunger mechanism includes a first plunger actuator operable to move the first plunger through a first chamber, the second plunger mechanism includes a second plunger actuator operable to move the second plunger through a second chamber, and the automated pipetting system includes a controller configured to automatically and programmatically control the first plunger actuator and the second plunger actuator.

[0011] The first plunger actuator and the second plunger actuator may be linear actuators.

[0012] In some embodiments, the first plunger mechanism is configured to translate the first plunger along a first plunger axis, the second plunger mechanism is configured to translate the second plunger along a second plunger axis, the first plunger has a first cross-sectional area in a plane orthogonal to the first plunger axis, the second plunger has a second cross-sectional area in a plane orthogonal to the second plunger axis, and the second cross-sectional area is greater than the first cross-sectional area.

[0013] In some embodiments, the second cross-sectional area is at least three times the first cross-sectional area.

[0014] According to some embodiments, the first plunger mechanism is configured to translate the first plunger through the first chamber, the second plunger mechanism is configured to translate the second plunger through the second chamber, the first plunger transfers the air volume in the first chamber at a first air volume transfer rate per unit translation, the second plunger transfers the air volume in the second chamber at a second air volume transfer rate per unit translation, and the second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

[0015] In some embodiments, the second air volume transfer rate per unit translation is at least three times the first air volume transfer rate per unit translation.

[0016] In some embodiments, the first plunger mechanism is configured to provide a first maximum air volume transfer, the second plunger mechanism is configured to provide a second maximum air volume transfer, and the second maximum air volume transfer is greater than the first maximum air volume transfer.

[0017] In some embodiments, the second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

[0018] In some embodiments, the first chamber has a first chamber volume, and the second chamber has a second chamber volume greater than the first chamber volume.

[0019] In some embodiments, the second chamber volume is at least ten times the volume of the first chamber.

[0020] According to some embodiments, the pipette comprises a valve to selectively control fluid communication between the second chamber and the port to atmosphere.

[0021] According to some embodiments, the pipette comprises at least one valve to selectively control fluid communication between the second chamber and the pipetting channel.In some embodiments, the first plunger is located in the pipetting channel.

[0022] According to some embodiments, the first plunger is disposed in the pipetting channel.

[0023] The automated pipetting system may include a controller configured to automatically and programmatically control the first plunger mechanism and the second plunger mechanism.

[0024] The automated pipetting system may include a pressure sensor coupled to the pipetting channel, wherein the controller is configured to receive a pipetting channel pressure signal from the pressure sensor indicating a pressure in the pipetting channel.

[0025] According to some embodiments, the pipette includes a valve to selectively control fluid communication between the second plunger mechanism and the pipetting channel, and the controller is configured to automatically and programmatically control the valve.

[0026] According to some embodiments, a method for operating an automatic pipetting system includes performing the following operations through at least one control circuit: operating a first plunger mechanism of a pipette of the automatic pipetting system to change the pressure in a pipetting channel of the pipette to aspirate or dispense liquid; and operating a second plunger mechanism of the pipette to change the pressure in the pipetting channel to aspirate or dispense liquid.

[0027] According to some embodiments, the method includes operating a first plunger mechanism and a second plunger mechanism to displace an air volume in a pipetting channel.

[0028] According to some embodiments, the method includes operating the first plunger mechanism and the second plunger mechanism independently of each other to change the pressure in the pipetting channel.

[0029] According to some embodiments, the method includes operating a first plunger mechanism and a second plunger mechanism to draw liquid into a liquid collection volume through a pipetting orifice or to dispense liquid from a liquid collection volume through a pipetting orifice.

[0030] In some embodiments, the method includes removably coupling a pipette tip to a pipette, wherein the pipette tip includes a liquid collection volume and a pipetting orifice.

[0031] In some embodiments, the method includes operating an ejection mechanism to force the pipette tip out of the pipette.

[0032] According to some embodiments, the first plunger mechanism includes a first chamber and a first plunger, the second plunger mechanism includes a second chamber and a second plunger, the method includes operating the first plunger mechanism to move the first plunger through the first chamber to change the pressure in the pipetting channel, and the method includes operating the second plunger mechanism, including moving the second plunger through the second chamber to change the pressure in the pipetting channel.

[0033] In some embodiments, the first plunger mechanism includes a first plunger actuator operable to move the first plunger through a first chamber, the second plunger mechanism includes a second plunger actuator operable to move the second plunger through a second chamber, and the method includes automatically and programmatically controlling the first plunger actuator and the second plunger actuator using a controller.

[0034] The first plunger actuator and the second plunger actuator may be linear actuators.

[0035] According to some embodiments, the first plunger mechanism is configured to translate the first plunger along a first plunger axis, the second plunger mechanism is configured to translate the second plunger along a second plunger axis, the first plunger has a first cross-sectional area in a plane orthogonal to the first plunger axis, the second plunger has a second cross-sectional area in a plane orthogonal to the second plunger axis, and the second cross-sectional area is greater than the first cross-sectional area.

[0036] In some embodiments, the second cross-sectional area is at least three times the first cross-sectional area.

[0037] According to some embodiments, the first plunger mechanism is configured to translate the first plunger through the first chamber, the second plunger mechanism is configured to translate the second plunger through the second chamber, the first plunger transfers the air volume in the first chamber at a first air volume transfer rate per unit translation, the second plunger transfers the air volume in the second chamber at a second air volume transfer rate per unit translation, and the second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

[0038] In some embodiments, the second air volume transfer rate per unit translation is at least three times the first air volume transfer rate per unit translation.

[0039] According to some embodiments, the first plunger mechanism is configured to provide a first maximum air volume transfer, the second plunger mechanism is configured to provide a second maximum air volume transfer, and the second maximum air volume transfer is greater than the first maximum air volume transfer.

[0040] In some embodiments, the second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

[0041] According to some embodiments, the first chamber has a first chamber volume, and the second chamber has a second chamber volume greater than the first chamber volume.

[0042] In some embodiments, the second chamber volume is at least ten times the volume of the first chamber.

[0043] The method may include selectively controlling fluid communication between the second chamber and the pipetting channel using a valve forming part of the pipette.In some embodiments, the first plunger is disposed in the pipetting channel.

[0044] According to some embodiments, the first plunger is disposed in the pipetting channel.

[0045] The method may include automatically and programmatically controlling the first plunger mechanism and the second plunger mechanism using a controller.

[0046] According to some embodiments, the pipette includes a pressure sensor coupled to the pipetting channel, and the controller receives a pipetting channel pressure signal from the pressure sensor indicating a pressure in the pipetting channel.

[0047] In some embodiments, the pipette includes a valve to selectively control fluid communication between the second plunger mechanism and the pipetting channel, and the method includes automatically and programmatically controlling the valve using a controller.

[0048] According to some embodiments, a pipetting system includes a pipette, which includes: a barrel; a pipetting channel; a passageway defined in the barrel and in fluid communication with the pipetting channel, the passageway including a rear chamber and a front chamber between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber to translate relative to the passage through a front plunger stroke; a rear plunger mounted in the rear chamber to translate relative to the passage through a rear plunger stroke; and a front seal surrounding the front plunger. During a first portion of the front plunger stroke, the front chamber is fluidly sealed from the rear chamber by the front seal, and translation of the front plunger in the front chamber generates a pressure change in the pipetting channel to aspirate or dispense liquid. During a second portion of the front plunger stroke, the front chamber is fluidly coupled to the rear chamber, and translation of the rear plunger in the rear chamber along the rear plunger stroke generates a pressure change in the pipetting channel to aspirate or dispense liquid.

[0049] According to some embodiments, the pipette includes a plunger assembly including both a front plunger and a rear plunger, and the plunger assembly is mounted in the passageway to translate through a plunger assembly stroke including a front plunger stroke and a rear plunger stroke.

[0050] In some embodiments, translation of the front plunger in the front chamber and translation of the rear plunger in the rear chamber displaces an air cushion (sometimes also referred to as an air cushion) in the pipetting channel.

[0051] In some embodiments, during a first portion of the front plunger stroke, the connecting opening between the front chamber and the rear chamber is blocked by the front plunger, and during a second portion of the front plunger stroke, the connecting opening is not blocked by the front plunger and the front chamber is fluidly connected to the rear chamber through the connecting opening.

[0052] In some embodiments, the front seal includes an annular sealing member that slidably engages the front plunger or barrel.

[0053] According to some embodiments, the pipetting system includes a rear seal surrounding the rear plunger.

[0054] The rear seal may include an annular sealing member slidably engaging the rear plunger or barrel.

[0055] According to some embodiments, a rear chamber is defined between the front seal and the rear seal.

[0056] The pipette may include a pressure relief valve arranged and configured to release pressure in the rear chamber during a first portion of the front plunger stroke.

[0057] According to some embodiments, the pipetting system comprises a pressure sensor arranged and configured to detect pressure in a pipetting channel.

[0058] In some embodiments, the pipetting system includes an opening mechanism selectively operable to place the rear chamber in fluid communication with the front chamber when the front plunger is not in the second portion of the front plunger stroke.

[0059] In some embodiments, the opening mechanism includes a valve selectively operable to place the rear chamber in fluid communication with the front chamber when the front plunger is not in the second portion of the front plunger's stroke.

[0060] According to some embodiments, the valve is selectively operable to place the rear chamber in fluid communication with a port to atmosphere.

[0061] In some embodiments, the pipetting system is configured such that the front seal forms a seal around the front plunger in a first portion of the front plunger stroke and a second portion of the front plunger stroke.

[0062] The pipetting system may include a pipette tip removably coupled to the barrel. The pipette tip includes a liquid collection volume fluidly coupled to the pipetting channel, and a tip orifice in fluid communication with the liquid collection volume.

[0063] According to some embodiments, a pipetting system includes: at least one actuator for driving a front plunger and a rear plunger through a front plunger stroke and a rear plunger stroke; and a controller configured to automatically and programmatically operate the at least one actuator.

[0064] In some embodiments, the front plunger stroke and the rear plunger stroke extend along the plunger axis, the front plunger has a first cross-sectional area in a plane orthogonal to the plunger axis, the rear plunger has a second cross-sectional area in a plane orthogonal to the plunger axis, and the second cross-sectional area is larger than the first cross-sectional area.

[0065] In some embodiments, the second cross-sectional area is at least three times the first cross-sectional area.

[0066] According to some embodiments, the front plunger transfers the air volume in the front chamber at a first air volume transfer rate per unit translation, the rear plunger transfers the air volume in the rear chamber at a second air volume transfer rate per unit translation, and the second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

[0067] In some embodiments, the second air volume transfer rate per unit translation is at least three times the first air volume transfer rate per unit translation.

[0068] According to some embodiments, the front plunger is configured to provide a first maximum air volume transfer in the front chamber, the rear plunger is configured to provide a second maximum air volume transfer in the rear chamber, and the second maximum air volume transfer is greater than the first maximum air volume transfer.

[0069] In some embodiments, the second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

[0070] According to some embodiments, the anterior chamber has an anterior chamber volume, and the posterior chamber has a posterior chamber volume greater than the anterior chamber volume.

[0071] In some embodiments, the volume of the posterior chamber is at least ten times the volume of the anterior chamber.

[0072] According to some embodiments, a method for pipetting a liquid includes providing a pipette, comprising: a barrel; a pipetting channel; a passageway defined in the barrel and in fluid communication with the pipetting channel, the passageway comprising a rear chamber and a front chamber located between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber to travel a front plunger stroke; a rear plunger mounted in the rear chamber to travel a rear plunger stroke; and a front seal surrounding the front plunger. The method further includes translating the front plunger through the front plunger stroke and translating the rear plunger through the rear plunger stroke to aspirate or dispense liquid. During a first portion of the front plunger stroke, the front chamber is fluidly sealed from the rear chamber by the front seal, and translation of the front plunger in the front chamber generates a pressure change in the pipetting channel to aspirate or dispense liquid. During a second portion of the front plunger stroke, the front chamber is fluidly coupled to the rear chamber, and translation of the rear plunger in the rear chamber along the rear plunger stroke generates a second pressure change in the pipetting channel to aspirate or dispense liquid.

[0073] According to some embodiments, the pipette includes a plunger component, which includes a front plunger and a rear plunger, and the plunger component is installed in a passage to translate the plunger component stroke including a front plunger stroke and a rear plunger stroke, and translating the front plunger through the front plunger stroke and translating the rear plunger through the rear plunger stroke is achieved by translating the plunger component through the plunger component stroke.

[0074] In some embodiments, translation of the front plunger in the front chamber and translation of the rear plunger in the rear chamber displaces air volume in the pipetting channel.

[0075] In some embodiments, during a first portion of the front plunger stroke, the connecting opening between the front chamber and the rear chamber is blocked by the front plunger, and during a second portion of the front plunger stroke, the connecting opening is not blocked by the front plunger and the front chamber is fluidly connected to the rear chamber through the connecting opening.

[0076] According to some embodiments, the method includes: translating the front plunger in a first direction through a first portion of the front plunger stroke to aspirate liquid; and thereafter, translating the front plunger in a second direction opposite to the first direction through the first portion of the front plunger stroke to dispense the liquid. Between translating the front plunger in the first direction and translating the front plunger in the second direction, the front plunger does not translate through the second portion of the front plunger stroke.

[0077] In some embodiments, the method includes: translating the front plunger in a first direction through a first portion and a second portion of the front plunger stroke to draw in liquid using the front plunger and the rear plunger; and thereafter, translating the front plunger in a second direction opposite to the first direction through the first portion and the second portion of the plunger stroke to dispense liquid using the front plunger and the rear plunger.

[0078] According to some embodiments, the method includes: operating an opening mechanism to place the rear chamber in fluid communication with the front chamber when the front plunger is in a first portion of the front plunger stroke; and thereafter, translating the rear plunger along the rear plunger stroke to draw liquid when the rear chamber is in fluid communication with the front chamber.

[0079] In some embodiments, the front seal forms a seal around the front plunger throughout the entire front plunger stroke and the rear plunger stroke.

[0080] According to some embodiments, a pipetting system includes a pipette, which includes: a barrel; a pipetting channel; a passage defined in the barrel and in fluid communication with the pipetting channel, the passage including a rear chamber and a front chamber located between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber to translate relative to the passage along the plunger axis; and a rear plunger mounted in the rear chamber to translate relative to the passage along the plunger axis. The translation of the front plunger in the front chamber along the plunger axis generates a change in pressure in the pipetting channel to aspirate or dispense liquid. The translation of the rear plunger in the rear chamber along the plunger axis generates a change in pressure in the pipetting channel to aspirate or dispense liquid. The front plunger has a first cross-sectional area in a plane orthogonal to the plunger axis. The rear plunger has a second cross-sectional area in a plane orthogonal to the plunger axis. The second cross-sectional area is greater than the first cross-sectional area.

[0081] In some embodiments, the pipette includes a plunger assembly including both a front plunger and a rear plunger, and the plunger assembly is mounted in the passageway for translation along the plunger axis.

[0082] According to some embodiments, a pipetting system includes a pipette, an air displacement pipette tip, and a positive displacement pipette tip. The air displacement pipette tip and the positive displacement pipette tip are alternately and removably mounted on the pipette. When the air displacement pipette tip is mounted on the pipette, the pipette is operable to draw liquid into the air displacement pipette tip. When the positive displacement pipette tip is mounted on the pipette, the pipette is operable to draw liquid into the positive displacement pipette tip.

[0083] According to some embodiments, the pipette includes a tip mounting interface configured to engage and releasably secure an air-displacement pipette tip and a positive-displacement pipette tip to the pipette.

[0084] In some embodiments, the tip mounting interface is configured to form an air-tight fit with the air displacement pipette tip when the air displacement pipette tip is mounted on the pipette.

[0085] According to some embodiments, the air displacement pipette tip includes an air displacement tip orifice, and a liquid collection volume in fluid communication with the air displacement tip orifice, and the positive displacement pipette tip includes a positive displacement tip orifice, a tip passage in fluid communication with the positive displacement tip orifice, and a piston slidably mounted in the tip passage. When the piston translates away from the positive displacement tip orifice, the positive displacement pipette tip operates to generate negative pressure at the positive displacement tip orifice to aspirate liquid.

[0086] In some embodiments, the pipette is operable to displace a volume of air in an air displacement pipette tip to generate a negative pressure at the air displacement tip orifice.

[0087] In some embodiments, the pipette includes a plunger that is translatable to generate negative pressure at the air displacement tip orifice to aspirate liquid when the air displacement pipette tip is mounted on the pipette.

[0088] In some embodiments, the pipette includes a plunger configured to engage the piston and translate the piston through the tip passage when a positive-displacement pipette tip is mounted on the pipette.

[0089] According to some embodiments, the pipette includes a plunger that can be translated to generate negative pressure at the air displacement tip orifice to aspirate liquid when an air displacement pipette tip is mounted on the pipette, and the plunger is configured to engage the piston and translate the piston through the tip passage when a positive displacement pipette tip is mounted on the pipette.

[0090] In some embodiments, the pipette includes a chamber and a pipetting channel, the pipetting channel being fluidly coupled to the liquid collection volume and the plunger being mounted to translate in the chamber to generate negative pressure in the pipetting channel when an air displacement pipette tip is mounted on the pipette.

[0091] In some embodiments, the pipette is operable in each of an air displacement mode in which an air displacement pipette tip is mounted on the pipette and, alternatively, a positive displacement mode in which a positive displacement pipette tip is mounted on the pipette, and the chamber is sealed in the air displacement mode and not sealed in the positive displacement mode.

[0092] In some embodiments, the pipette includes a barrel defining a chamber, and an annular seal surrounding the plunger between the plunger and the barrel. The annular seal seals the chamber in the air displacement mode and does not seal the chamber in the positive displacement mode.

[0093] The pipette may include a pressure sensor arranged and configured to output a detection signal indicative of the pressure in the chamber.

[0094] According to some embodiments, the pipette includes at least one plunger actuator for driving the plunger, and a controller configured to automatically and programmatically operate the at least one actuator.

[0095] In some embodiments, at least one plunger actuator comprises a linear actuator.

[0096] According to some embodiments, a positive-displacement pipette tip includes a tip body defining a tip passage; and a vent port in the tip body for relieving pressure in the tip passage between a piston and a pipette.

[0097] According to some embodiments, a pipette includes an air displacement mechanism and a positive displacement mechanism. The pipette is configured to mount an air displacement pipette tip thereon, and alternatively mount a positive displacement pipette tip thereon. When the air displacement pipette tip is mounted on the pipette, the air displacement mechanism is operable to generate a negative pressure in the air displacement pipette tip to draw liquid into the air displacement pipette tip. When the positive displacement pipette tip is mounted on the pipette, the positive displacement mechanism is operable to shift a piston of the positive displacement pipette tip to draw liquid into the positive displacement pipette tip.

[0098] According to some embodiments, the pipette includes a plunger that can be translated to generate negative pressure in the air-displacement pipette tip to aspirate liquid when an air-displacement pipette tip is mounted on the pipette, and the plunger is configured to engage a piston and translate the piston through a tip passage of the positive-displacement pipette tip when a positive-displacement pipette tip is mounted on the pipette.

[0099] According to some embodiments, a method for pipetting a liquid includes: operating the pipette to draw liquid into the air-displacement pipette tip with an air-displacement pipette tip mounted on the pipette; and thereafter, operating the pipette to draw liquid into the positive-displacement pipette tip with a positive-displacement pipette tip mounted on the pipette.

[0100] According to some embodiments, the method includes performing operations including: installing an air-displacement pipette tip on the pipette; removing the air-displacement pipette tip from the pipette; installing a positive-displacement pipette tip on the pipette; and removing the positive-displacement pipette tip from the pipette by controlling at least one control circuit of at least one actuator.

[0101] According to some embodiments, a pipette tip includes a tip member including a first end and a second end opposite the first end, the first end having an opening therein for aspirating and / or dispensing a liquid, the second end being for connecting to a pipette. A conductive electrode is disposed on the tip member and is configured to output a signal in response to contact with the liquid. The first end of the tip member includes a non-conductive tip bottom adjacent to the opening.

[0102] In some embodiments, the conductive electrode is located on an outer surface of the tip member between the first end and the second end.

[0103] In some embodiments, the conductive electrode is at least partially embedded within the surface of the tip component.

[0104] In some embodiments, the bottom of the non-conductive tip is devoid of a conductive electrode.

[0105] In some embodiments, the non-conductive tip base includes a portion of a conductive electrode having a non-conductive coating thereon.

[0106] In some embodiments, a conductive element is disposed at the second end of the tip member, and a conductive connection extends along the tip member and electrically connects the conductive electrode to the conductive element.

[0107] In some embodiments, the conductive connection extends along an outer surface of the tip member.

[0108] In some embodiments, the conductive connection is at least partially embedded within the tip component.

[0109] In some embodiments, the inner surface of the tip member is free of conductive electrodes.

[0110] In some embodiments, the inner surface of the tip component is non-conductive and the conductive electrode is a single electrode.

[0111] In some embodiments, the non-conductive tip base comprises a length of about 2 millimeters (mm) or more.

[0112] In some embodiments, the shape of the conductive electrode defines a surface area that varies with distance from the opening.

[0113] In some embodiments, the conductive electrode is configured to be coupled to a controller circuit configured to dynamically detect the level of the liquid and / or predict loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal output by the conductive electrode.

[0114] According to some embodiments, an automated pipetting system includes a robotic arm assembly including an arm member adapted to hold a pipette and an actuator mechanism configured to move the arm member along at least one axis in response to a control signal; and a controller circuit coupled to the robotic arm assembly. The controller circuit is configured to perform operations including: receiving a signal from a conductive electrode on a pipette tip, wherein the conductive electrode is located between a first end of the pipette tip and a second end of the pipette tip, the first end of the pipette tip having an opening therein for aspirating and / or dispensing liquid, the second end of the pipette tip being opposite the first end and connected to the pipette; and transmitting a control signal to the actuator mechanism in response to the signal from the conductive electrode to move the arm member toward or away from a surface of the liquid along at least one axis.

[0115] In some embodiments, the operations further include dynamically detecting a level of the liquid based on a change in capacitance indicated by a signal from the conductive electrode, optionally independent of a shape or size of the liquid container.

[0116] In some embodiments, dynamically detecting the level of the liquid includes predicting a loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal from the conductive electrode, and transmitting a control signal to the actuator mechanism in response to predicting the loss of contact.

[0117] In some embodiments, the control signal varies based on the change in capacitance to move the arm member along at least one axis toward or away from the surface of the liquid while maintaining contact between the pipette tip and the liquid.

[0118] In some embodiments, the first end of the pipette tip includes a non-conductive tip bottom adjacent the opening.

[0119] In some embodiments, the conductive electrode is located on an outer surface of the pipette tip between the first end and the second end.

[0120] In some embodiments, the conductive electrode is at least partially embedded within the surface of the pipette tip.

[0121] In some embodiments, the bottom of the non-conductive tip is devoid of a conductive electrode.

[0122] In some embodiments, the non-conductive tip base includes a portion of a conductive electrode having a non-conductive coating thereon.

[0123] In some embodiments, the interior surface of the pipette tip is free of conductive electrodes.

[0124] In some embodiments, the inner surface of the tip component is non-conductive and the conductive electrode is a single electrode.

[0125] In some embodiments, the actuator mechanism includes a first operating mode and a second operating mode, in which during aspiration, the arm member is constrained to move along at least one axis toward the liquid surface and during dispensing, the arm member is constrained to move along at least one axis away from the liquid surface.

[0126] In some embodiments, the operations further include calculating an aspirated or dispensed volume of liquid based on a distance the arm member moves along the at least one axis; and controlling subsequent movement of the arm member along the at least one axis based on the calculated aspirated or dispensed volume.

[0127] According to some embodiments, a method of operating an automated pipetting system includes executing computer-readable instructions stored in a non-transitory storage medium by a controller circuit to perform operations including: receiving a signal from a conductive electrode on a pipette tip, wherein the conductive electrode is located between a first end of the pipette tip and a second end of the pipette tip, the first end of the pipette tip having an opening therein for aspirating and / or dispensing liquid, the second end of the pipette tip being opposite the first end and connected to a pipette; and in response to the signal from the conductive electrode, transmitting a control signal to an actuator mechanism of a robotic arm assembly to move an arm member adapted to hold the pipette along at least one axis toward or away from a surface of the liquid.

[0128] In some embodiments, the operations further include dynamically detecting a level of the liquid based on a change in capacitance indicated by a signal from the conductive electrode, optionally independent of a shape or size of the liquid container.

[0129] In some embodiments, dynamically detecting the level of the liquid includes predicting a loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal from the conductive electrode, and transmitting a control signal to the actuator mechanism in response to predicting the loss of contact.

[0130] In some embodiments, the control signal varies based on the change in capacitance to move the arm member along at least one axis toward or away from the surface of the liquid while maintaining contact between the pipette tip and the liquid.

[0131] In some embodiments, the first end of the pipette tip includes a non-conductive tip base that extends beyond the conductive electrode.

[0132] In some embodiments, the conductive electrode is located on an outer surface of the pipette tip between the first end and the second end.

[0133] In some embodiments, the conductive electrode is at least partially embedded within the surface of the pipette tip.

[0134] In some embodiments, the bottom of the non-conductive tip is devoid of a conductive electrode.

[0135] In some embodiments, the interior surface of the pipette tip is free of conductive electrodes.

[0136] In some embodiments, the inner surface of the tip component is non-conductive and the conductive electrode is a single electrode.

[0137] In some embodiments, operations further include constraining the arm member to move along at least one axis toward the surface of the liquid during aspiration; and constraining the arm member to move along at least one axis away from the surface of the liquid during dispensing.

[0138] In some embodiments, the operations further include calculating an aspirated or dispensed volume of liquid based on a distance of movement of the arm member along the at least one axis; and controlling subsequent movement of the arm member along the at least one axis based on the calculated aspirated or dispensed volume.

[0139] According to some embodiments, an automated pipetting system includes: a pipette including a channel therein, a pressure sensor coupled to the channel, and at least one controller circuit. The at least one controller circuit is configured to perform operations including: receiving a signal indicating a pressure in the pipette channel from the pressure sensor, and based on the pressure indicated by the signal, performing at least one of the following: detecting evaporation of liquid in the channel; or automatically performing one or more compensation operations.

[0140] In some embodiments, the pipette includes a pipette tip having an opening therein for aspirating liquid, and detecting evaporation is performed after the pipette tip is removed from the liquid.

[0141] In some embodiments, detecting evaporation further comprises calculating an evaporation rate based on a change in pressure indicated by the signal after the pipette tip is removed from the liquid.

[0142] In some embodiments, the evaporation rate is calculated independent of the surface tension or type of liquid.

[0143] In some embodiments, the evaporation rate is calculated in proportion to the change in pressure indicated by the signal over time.

[0144] In some embodiments, detecting evaporation further comprises controlling movement of a plunger in the channel after the pipette tip is removed from the liquid. In response to the movement of the plunger, the evaporation rate is calculated based on the pressure change indicated by the signal.

[0145] In some embodiments, detecting evaporation further comprises continuously controlling a position of a plunger in a channel of the pipette such that a pressure indicated by the signal remains substantially constant over time; and calculating an evaporation rate based on the displacement of the plunger over time.

[0146] In some embodiments, automatically performing one or more compensation operations includes performing one or more evaporation compensation operations in response to detecting evaporation of the liquid in the channel based on a comparison with a threshold value.

[0147] In some embodiments, performing one or more evaporation compensation operations includes performing a pre-wetting operation before aspirating the liquid; and / or adapting one or more aspiration parameters for aspirating the liquid; and / or controlling movement of a plunger in a channel.

[0148] In some embodiments, the operations further include estimating an evaporation volume based on an evaporation rate and a duration of liquid drawing, wherein the threshold is based on a volume.

[0149] In some embodiments, the vaporization volume indicates an under-absorption amount. Performing one or more vaporization compensation operations includes: based on the under-absorption amount, adapting one or more aspiration parameters to aspirate a greater amount of liquid; and aspirating a greater amount of liquid based on the adapted one or more aspiration parameters.

[0150] In some embodiments, performing one or more evaporation compensation operations includes controlling movement of a plunger to draw air after the pipette tip is removed from the liquid to reduce or prevent liquid from dripping from the pipette tip.

[0151] In some embodiments, performing one or more evaporation compensation operations includes controlling movement of a plunger to maintain a substantially constant pressure in the pipette tip after the pipette tip is removed from the liquid.

[0152] In some embodiments, the substantially constant pressure is based on the pressure indicated by the signal after the pipette tip is removed from the liquid.

[0153] In some embodiments, the substantially constant pressure is a predetermined pressure.

[0154] In some embodiments, the operations further include calculating the volume of liquid drawn based on the pressure change indicated by the signal.

[0155] In some embodiments, automatically performing one or more compensation operations includes adapting one or more aspiration parameters based on a comparison of the aspirated volume to the target volume; and aspirating the liquid based on the adapted one or more aspiration parameters.

[0156] In some embodiments, automatically performing one or more compensation operations includes adapting aspiration speed based on a pressure change indicated by the signal relative to a pressure change threshold; and / or performing a pre-wetting operation based on a temperature of the liquid relative to a temperature threshold.

[0157] According to some embodiments, a method of operating an automated pipetting system includes executing computer-readable instructions stored in a non-transitory storage medium by at least one controller circuit to perform operations including: receiving a signal from a pressure sensor indicating a pressure in a channel of a pipette, and based on the pressure indicated by the signal, performing at least one of the following: detecting evaporation of liquid in the channel; or automatically performing one or more compensation operations.

[0158] In some embodiments, the pipette includes a pipette tip having an opening therein for aspirating liquid, and detecting evaporation is performed after the pipette tip is removed from the liquid.

[0159] In some embodiments, detecting evaporation further comprises calculating an evaporation rate based on a change in gas pressure indicated by the signal after the pipette tip is removed from the liquid.

[0160] In some embodiments, the evaporation rate is calculated independent of the surface tension or type of liquid.

[0161] In some embodiments, the evaporation rate is calculated in proportion to the change in pressure indicated by the signal over time.

[0162] In some embodiments, detecting evaporation further comprises controlling movement of a plunger in the channel after the pipette tip is removed from the liquid, and calculating the evaporation rate based on a pressure change indicated by the signal in response to the movement of the plunger.

[0163] In some embodiments, detecting evaporation further comprises continuously controlling a position of a plunger in a channel of the pipette such that a pressure indicated by the signal remains substantially constant over time, and calculating an evaporation rate based on the displacement of the plunger over time.

[0164] In some embodiments, automatically performing one or more compensation operations includes performing one or more evaporation compensation operations in response to detecting evaporation of the liquid in the channel based on a comparison with a threshold value.

[0165] In some embodiments, performing one or more evaporation compensation operations includes performing a pre-wetting operation before aspirating the liquid; and / or adapting one or more aspiration parameters to aspirate the liquid; and / or controlling movement of a plunger in a channel.

[0166] In some embodiments, the operations further include estimating an evaporation volume based on an evaporation rate and a duration of liquid drawing, wherein the threshold is based on a volume.

[0167] In some embodiments, the vaporization volume indicates an under-absorption amount. Performing one or more vaporization compensation operations includes: based on the under-absorption amount, adapting one or more aspiration parameters to aspirate a greater amount of liquid, and aspirating a greater amount of liquid based on the adapted one or more aspiration parameters.

[0168] In some embodiments, performing one or more evaporation compensation operations includes controlling movement of a plunger to draw air after the pipette tip is removed from the liquid to reduce or prevent liquid from dripping from the pipette tip.

[0169] In some embodiments, performing one or more evaporation compensation operations includes controlling movement of a plunger to maintain a substantially constant pressure in the pipette tip after the pipette tip is removed from the liquid.

[0170] In some embodiments, the substantially constant pressure is based on the pressure indicated by the signal after the pipette tip is removed from the liquid.

[0171] In some embodiments, the substantially constant pressure is a predetermined pressure.

[0172] In some embodiments, the operations further include calculating the volume of liquid drawn based on the pressure change indicated by the signal.

[0173] In some embodiments, performing one or more compensation operations includes adapting one or more aspiration parameters based on a comparison of the aspirated volume to the target volume, and aspirating liquid based on the adapted one or more aspiration parameters.

[0174] In some embodiments, automatically performing one or more compensation operations includes adapting aspiration speed based on a pressure change indicated by the signal relative to a pressure change threshold; and / or performing a pre-wetting operation based on a temperature of the liquid relative to a temperature threshold.

[0175] According to some embodiments, an automated pipetting system includes: a pipette including a channel therein, a sensor coupled to the channel, and at least one controller circuit. The controller circuit is configured to perform operations including: receiving a sensor signal from the sensor indicating a pressure change in the channel; determining a transferred air volume in the channel based on the sensor signal; and transmitting at least one control signal to control the pressure in the channel based on the transferred air volume.

[0176] In some embodiments, the operations further include identifying an air flow rate in the passage based on the pressure change, and determining the transfer air volume based on the air flow rate.

[0177] In some embodiments, the at least one control signal includes a flow restriction control signal. A flow restriction mechanism is coupled to the channel and is configured to switch between respective states providing different flow rates in response to the flow restriction control signal.

[0178] In some embodiments, the sensor is a dual sensor and the sensor signal includes first pressure data and second pressure data indicative of a first flow rate and a second flow rate, respectively.

[0179] In some embodiments, the dual sensor includes a first pressure sensor and a second pressure sensor arranged in parallel, which provide first pressure data and second pressure data respectively. The measurement range of the second pressure sensor is greater than the measurement range of the first pressure sensor.

[0180] In some embodiments, a measurement range of the second pressure sensor is greater than a measurement range of the first pressure sensor by more than an order of magnitude.

[0181] In some embodiments, at least one control signal includes a plunger actuator control signal that varies based on a change in the volume of transferred air indicated by the air flow rate in the channel. The plunger actuator is configured to dynamically control the position and / or speed of movement of the plunger in the channel in response to the plunger actuator control signal.

[0182] In some embodiments, the plunger actuator control signal is generated independent of determining a previous position or movement distance of the plunger in the channel.

[0183] In some embodiments, the at least one control signal comprises a valve control signal.The air valve is operable to couple the passage to the pressure source in response to the valve control signal.

[0184] In some embodiments, the pressure source includes a negative pressure source and a positive pressure source. One of the negative pressure source or the positive pressure source is configured to be selected to control the direction of the airflow in the channel.

[0185] In some embodiments, the operations further include receiving a pressure signal from a pressure sensor in a pipette tip coupled to the pipette; and determining a volume of liquid in the pipette tip based on the pressure signal. Transmitting at least one control signal to control a position of the plunger based on the volume of liquid in the pipette tip.

[0186] In some embodiments, a microfluidic manifold comprising a plurality of passages is configured to couple the channels to a pipette tip. One or more of the passages have a diameter of about 0.2 to 0.8 mm.

[0187] According to some embodiments, a method of operating an automated pipetting system includes executing computer-readable instructions stored in a non-transitory storage medium by at least one controller circuit to perform operations including: receiving a sensor signal indicating a pressure change in the channel from a sensor connected to a channel of a pipette; determining a transferred air volume in the channel based on the sensor signal; and transmitting at least one control signal to control the pressure in the channel based on the transferred air volume.

[0188] In some embodiments, the operations further include identifying an air flow rate in the passage based on a pressure change indicated by the sensor signal, wherein the transferred air volume is determined based on the air flow rate.

[0189] In some embodiments, the at least one control signal includes a flow restriction control signal, and the operations further include switching a flow restriction mechanism coupled to the passageway between respective states providing different air flow rates in response to the flow restriction control signal.

[0190] In some embodiments, the sensor is a dual sensor and the sensor signal includes first pressure data and second pressure data indicative of a first flow rate and a second flow rate, respectively.

[0191] In some embodiments, the dual sensor includes a first pressure sensor and a second pressure sensor arranged in parallel, which provide first pressure data and second pressure data respectively. The measurement range of the second pressure sensor is greater than the measurement range of the first pressure sensor.

[0192] In some embodiments, a measurement range of the second pressure sensor is greater than a measurement range of the first pressure sensor by more than an order of magnitude.

[0193] In some embodiments, at least one control signal includes a plunger actuator control signal that varies based on a change in the volume of transferred air indicated by an air flow rate in the channel, and the operation further includes dynamically controlling the position and / or movement speed of a plunger in the channel in response to the plunger actuator control signal.

[0194] In some embodiments, the plunger actuator control signal is generated independent of determining a previous position or movement distance of the plunger in the channel.

[0195] In some embodiments, the at least one control signal includes a valve control signal, and the operations further include operating the air valve to couple the passage to the pressure source in response to the valve control signal.

[0196] In some embodiments, the pressure source includes a negative pressure source and a positive pressure source, and the operation further includes selecting one of the negative pressure source or the positive pressure source to control the direction of the airflow in the channel.

[0197] In some embodiments, the operations further include receiving a pressure signal from a pressure sensor in a pipette tip coupled to the pipette; and determining a volume of liquid in the pipette tip based on the pressure signal. Transmitting at least one control signal to control a position of the plunger based on the volume of liquid in the pipette tip.

[0198] In some embodiments, the sensor is coupled to at least one passage of the microfluidic manifold configured to couple the channel to a pipette tip. The at least one passage comprises a diameter of about 0.2 to 0.8 mm.

[0199] According to some embodiments, a positive displacement pipette tip comprises a tip orifice; a back chamber; a tip passage located between the tip orifice and the back chamber and in fluid communication with the tip orifice; and a piston slidably mounted in the tip passage. The piston translates backward away from the tip orifice in response to negative pressure in the back chamber, whereby the piston generates negative pressure at the tip orifice to draw liquid into the positive displacement pipette tip.

[0200] According to some embodiments, a positive displacement pipette tip includes a body defining a rear chamber, and a sliding seal between a piston and the body. The seal separates the rear chamber from a tip passage. The seal translates through the body with the piston.

[0201] In some embodiments, the body includes a body cavity, and the seal divides the body cavity into a rear chamber and an intermediate chamber between the rear chamber and the tip passage.

[0202] The positive-displacement pipette tip may include a pressure relief port in fluid communication with the intermediate chamber.

[0203] According to some embodiments, a positive displacement pipette tip includes a body and a calibration mechanism. The calibration mechanism includes at least one first calibration feature on the body and at least one second calibration feature on the piston. The first calibration feature and the second calibration feature cooperate to stop the displacement of the piston at a specified position.

[0204] A positive displacement pipette tip may include a seal on the piston that translates with the piston through the body.

[0205] According to some embodiments, a pipette includes a pipette and a positive displacement pipette tip mounted on the pipette. The positive displacement pipette tip includes a tip orifice; a rear chamber; a tip passage located between the tip orifice and the rear chamber and in fluid communication with the tip orifice; and a piston slidably mounted in the tip passage. The pipette is operable to generate a negative pressure in the rear chamber, which causes the piston to translate backwards away from the tip orifice, whereby the piston generates a negative pressure at the tip orifice to draw liquid into the positive displacement pipette tip.

[0206] According to some embodiments, the pipette is coupled to the piston by an air column, and when the piston translates, the air column is displaced within the pipette and / or positive displacement pipette tip.

[0207] According to some embodiments, a method for pipetting a liquid includes mounting a positive displacement pipette tip on a pipette. The positive displacement pipette tip includes a tip orifice; a back chamber; a tip passage located between the tip orifice and the back chamber and in fluid communication with the tip orifice; and a piston slidably mounted in the tip passage. The method further includes using the pipette to generate a negative pressure in the back chamber, which causes the piston to translate backwards away from the tip orifice, whereby the piston generates a negative pressure at the tip orifice to draw liquid into the positive displacement pipette tip.

[0208] According to some embodiments, a positive displacement pipette tip includes a tip orifice, a tip passage in fluid communication with the tip orifice, a piston slidably mounted in the tip passage, a body, and a calibration mechanism. The calibration mechanism includes at least one first calibration feature on the body and at least one second calibration feature on the piston. The first calibration feature and the second calibration feature cooperate to stop the displacement of the piston at a specified position.

[0209] According to some embodiments, the at least one first indexing feature comprises a series of first indexing features distributed axially along the longitudinal axis of the positive-displacement pipette tip.

[0210] According to some embodiments, a pipette includes a pipette and a positive displacement pipette tip mounted on the pipette. The positive displacement pipette tip includes a tip orifice, a tip passage in fluid communication with the tip orifice, a piston slidably mounted in the tip passage, a body, and a calibration mechanism. The calibration mechanism includes at least one first calibration feature on the body and at least one second calibration feature on the piston. The first calibration feature and the second calibration feature cooperate to stop the displacement of the piston at a specified position.

[0211] According to some embodiments, a method for pipetting a liquid includes mounting a positive displacement pipette tip on a pipette. The positive displacement pipette tip includes a tip orifice, a tip passage in fluid communication with the tip orifice, a piston slidably mounted in the tip passage, a body, and a calibration mechanism. The calibration mechanism includes at least one first calibration feature on the body, and at least one second calibration feature on the piston. The first calibration feature and the second calibration feature cooperate to stop the displacement of the piston at a specified position. The pipette translates the piston backward away from the tip orifice, whereby the piston generates a negative pressure at the tip orifice to draw the liquid into the positive displacement pipette tip.

[0212] According to some embodiments, a positive displacement pipette tip for use with a pipette includes a tip body, a piston, and an integrated piston restraint mechanism. The tip body includes a distal tip portion. The distal tip portion defines a tip passage. The piston is slidably mounted in the tip passage. The piston is displaceable to draw liquid into the positive displacement pipette tip. The integrated piston restraint mechanism is operable to limit movement between the piston and the tip body.

[0213] According to some embodiments, the piston restraint mechanism can be positioned in either a restraint structure and a release structure, in which the piston restraint mechanism prevents the piston from retracting beyond a specified position relative to the tip body, and in the release structure, the piston restraint mechanism does not prevent the piston from retracting beyond the specified position.

[0214] In some embodiments, the piston restraint mechanism does not restrict movement between the piston and the tip body when in the released configuration.

[0215] According to some embodiments, the piston restraint mechanism includes a latch that is movable between a latched position and an unlatched position, in which the latch engages the piston and in which the latch does not engage the piston.

[0216] In some embodiments, the latch comprises a displaceable sleeve or tab.

[0217] In some embodiments, the pipette tip comprises an interlocking insert mounted on the tip body, wherein the latch forms part of the interlocking insert.

[0218] In some embodiments, the piston restraint mechanism includes an integral interlocking feature on the piston, and the interlocking feature is configured to interlock with the latch when the piston restraint mechanism is in the restraining configuration to limit movement between the piston and the tip body.

[0219] According to some embodiments, the piston comprises an integral coupling feature configured to secure the piston to a driver forming part of the pipette.

[0220] According to some embodiments, the tip body includes a mounting section configured to engage a pipette to removably secure the positive-displacement pipette tip to the pipette.

[0221] According to some embodiments, a pipetting system includes a pipette and a positive displacement pipette tip mounted on the pipette. The positive displacement pipette tip includes a tip body, a piston, and an integrated piston constraint mechanism. The tip body includes a distal tip portion. The distal tip portion defines a tip passage. The piston is slidably mounted in the tip passage. The piston is displaceable to draw liquid into the positive displacement pipette tip. The integrated piston constraint mechanism is operable to limit movement between the piston and the tip body.

[0222] According to some embodiments, a method for pipetting a liquid includes mounting a positive displacement pipette tip on a pipette. The positive displacement pipette tip includes: a tip body including a distal tip portion, the distal tip portion defining a tip passage; a piston slidably mounted in the tip passage; and an integral piston restraint mechanism operable to limit movement between the piston and the tip body. The method further includes: using the pipette, translating the piston through the tip passage to draw liquid into the positive displacement pipette tip; and ejecting the positive displacement pipette tip from the pipette while the piston restraint mechanism limits movement between the piston and the tip body.

[0223] According to some embodiments, mounting the positive-displacement pipette tip on the pipette includes coupling a driver of the pipette to a piston, and translating the piston through the tip passage includes translating the piston using the driver.

[0224] In some embodiments, the piston constraint mechanism can be positioned in either a constraint configuration and a release configuration, wherein in the constraint configuration, the piston constraint mechanism prevents the piston from retracting beyond a specified position relative to the tip body, and in the release configuration, the piston constraint mechanism does not prevent the piston from retracting beyond a specified position, translating the piston through the tip passage includes translating the piston using a drive when the piston constraint mechanism is in the release configuration, and ejecting a positive-displacement pipette tip from the pipette includes relatively translating the drive and the piston when the piston constraint mechanism is in the constraint configuration.

[0225] In some embodiments, ejecting the positive-displacement pipette tip from the pipette comprises pushing the tip body away from the pipette using an ejector forming part of the pipette when the piston restraining mechanism is in the restraining configuration.

[0226] According to some embodiments, the piston restraint mechanism includes an integral interlocking feature on the piston; the piston restraint mechanism includes a latch forming a portion of the tip body; the latch is positionable in each of a latched position and an unlatched position, in which the latch is interlocked with the interlocking feature and in which the latch is not interlocked with the interlocking feature; mounting the positive-displacement pipette tip on the pipette includes inserting the shaft of the pipette into the tip body and thereby deflecting the latch to the unlatched position; and ejecting the positive-displacement pipette tip from the pipette includes pushing the tip body away from the shaft, in response to which the latch resiliently returns to the latched position. BRIEF DESCRIPTION OF THE DRAWINGS

[0227] The accompanying drawings, which constitute a part of this specification, illustrate embodiments of the present technology.

[0228] Figure 1 is a front view of an exemplary laboratory liquid handling system including a pipetting system according to an embodiment of the present technology.

[0229] Figure 2 yes Figure 1 A perspective view of the pipettes of a pipetting system.

[0230] Figure 3 is along Figure 2 The line 3-3 is intercepted Figure 2 Cross-sectional view of a pipette.

[0231] Figure 4 yes Figure 2 Cross-sectional view of a magnified fragment of a pipette.

[0232] Figure 5 yes Figure 2 Cross-sectional view of a magnified fragment of a pipette.

[0233] Figure 6 is along Figure 4 The line 6-6 is intercepted Figure 2 Cross-sectional view of a pipette.

[0234] Figure 7 is along Figure 3 The line 7-7 is intercepted Figure 2 Cross-sectional view of a pipette.

[0235] Figure 8 is with Figure 2 A cross-sectional view of a pipette tip used with a pipette.

[0236] Figure 9-13 yes Figure 2 A fragmentary cross-sectional view of a pipette, illustrating the operation of the pipette.

[0237] Fig.14 is a fragmentary cross-sectional view of a pipetting system according to other embodiments.

[0238] Fig.15 yes Fig.14 Exploded fragment cross-sectional view of a pipetting system.

[0239] Fig.16 and 17 yes Fig.14 A fragmentary cross-sectional view of a pipetting system with its plunger components in different positions.

[0240] Fig.18 is along Fig.14 The line 18-18 is intercepted Fig.14 Cross-sectional view of the pipetting system.

[0241] Fig.19 is along Fig.14 The line 19-19 is intercepted Fig.14 Cross-sectional view of the pipetting system.

[0242] Fig. 20 is a fragmentary cross-sectional view of a pipetting system according to other embodiments.

[0243] Fig.21 yes Fig. 20 A magnified fragmentary cross-sectional view of the pipetting system with its interchamber valve in the open position.

[0244] Fig. 22 yes Fig. 20 A magnified fragment of a cross-sectional view of the pipetting system with the interchamber valve in the closed position.

[0245] Fig.23 and Fig.24 yes Fig. 20 A fragmentary cross-sectional view of a pipetting system with its plunger components arranged in different positions.

[0246] Fig.25 is a fragmentary cross-sectional view of a pipetting system according to other embodiments.

[0247] Fig.26 and 27 yes Fig.25 An enlarged fragment cross-sectional view of the pipetting system illustrating the operation of the pipetting system.

[0248] Fig.28 is a cross-sectional view of a pipetting system according to other embodiments of the present technology.

[0249] Figure 29-32 yes Fig.28 A cross-sectional view of a pipette of a pipetting system, illustrating the operation of the pipetting system.

[0250] Fig.33 yes Fig.28 Exploded cross-sectional view of a pipette.

[0251] Fig.34 is used with Fig.28 Cross-sectional view of an air transfer tip used in conjunction with the pipetting system.

[0252] Fig.35 is used with Fig.28 Exploded cross-sectional view of a positive displacement tip used in conjunction with a pipetting system.

[0253] Fig.36 is a cross-sectional view of a pipetting system according to other embodiments of the present technology.

[0254] Fig.37 is a schematic perspective view illustrating another example of an automated liquid handling system according to some embodiments.

[0255] Fig.38 is an enlarged side view showing a conductive pipette tip according to some embodiments.

[0256] Fig.39A , 39B and 39C is shown Fig.38 A cross-sectional view of an embodiment of a tip component.

[0257] Fig.40A , 40B 40C are cross-sectional views showing embodiments of various "crown" shaped conductive electrodes.

[0258] Fig.41 is a graph showing capacitance as a function of vertical position of a pipette tip comprising a conductive electrode and a non-conductive tip base, according to some embodiments.

[0259] Fig.42 is a schematic diagram illustrating an automated pipetting system configured for evaporation detection and compensation, according to some embodiments.

[0260] Fig.43A is a schematic diagram illustrating evaporation detection according to some embodiments.

[0261] Fig.43B yes Fig.43A A magnified view of the orifice of a pipette tip, showing evaporation-induced liquid bead formation.

[0262] Fig.44A is a graph illustrating changes in pressure and transfer volume during operation of an evaporation detection operation according to some embodiments.

[0263] Fig.44B is a graph showing changes in pressure and transfer volume during operation of an evaporation detection operation according to other embodiments.

[0264] Fig.45 is a flow chart illustrating an evaporation detection operation in a pipette tip according to some embodiments.

[0265] Fig.46A and 46B is a flow chart illustrating an evaporation compensation operation in a pipette tip according to some embodiments.

[0266] Fig.47 is a side view showing a dual-meter pipette that can be used in an automated pipetting system according to some embodiments.

[0267] Fig.48 is an enlarged schematic diagram showing a dual-meter pipette according to some embodiments.

[0268] Fig.49 is a simplified schematic diagram showing the plunger and manifold assembly of a dual metering pipette according to some embodiments.

[0269] Fig.50 is a diagram showing some embodiments of the present invention. Fig.49 A magnified schematic of the manifold and flow sensor of the dual-meter pipette.

[0270] Fig.51 is an enlarged perspective view further illustrating a manifold assembly according to some embodiments.

[0271] Fig.52 is a schematic diagram showing the connection of a pressure sensor in a dual-meter pipette according to some embodiments.

[0272] Fig.53 is a schematic diagram illustrating the operation of a dual metering pipette according to some embodiments.

[0273] Fig.54 is a cross-sectional view of a pipetting system and a PD pipette tip according to other embodiments of the present technology, wherein the PD pipette tip is in an extended position.

[0274] Fig.55 yes Fig.54 Cross-sectional view of the pipetting system with the PD pipette tip in the retracted position.

[0275] Fig.56 yes Fig.54 Exploded cross-sectional view of a PD pipette tip.

[0276] Fig.57 yes Fig.54 An enlarged cross-sectional view of a PD pipette tip showing the calibration mechanism of the PD pipette tip.

[0277] Fig.58 is along Fig.54 A cross-sectional view of the PD pipette tip taken along line 58-58.

[0278] Fig.59 is along Fig.57 Cross-sectional view of the PD pipette tip taken along line 59-59.

[0279] Fig.60 is an exploded view of a pipetting system including a positive-displacement pipette tip according to some embodiments.

[0280] Fig.61 yes Fig.60 Exploded bottom perspective view of a positive displacement pipette tip.

[0281] Fig.62 is along Fig.60 The line 62-62 is intercepted Fig.60 A cross-sectional perspective view of a positive-displacement pipette tip.

[0282] Fig.63 is along Fig.60 The line 62-62 is intercepted to form Fig.60 Cross-sectional view of the tip body of a portion of a positive-displacement pipette tip.

[0283] Fig.64 is formed Fig.60 Side view of the piston of a portion of a positive displacement pipette tip.

[0284] Fig.65 is along Fig.60 The line 62-62 is intercepted to form Fig.60 Cross-sectional view of the interlocking insert of a portion of a positive-displacement pipette tip.

[0285] Figures 66-75 yes Fig.60 A schematic cross-sectional view of a pipetting system illustrating the operation of using the pipetting system. DETAILED DESCRIPTION

[0286] See also Figure 1-13 , shows an example pipetting system 101 according to certain embodiments of the present technology. According to the illustrated embodiment of the present technology, the pipetting system 101 forms an automated liquid handling system 10 ( Figure 1) is a part of the present invention. However, it should be understood that the disclosed methods, systems, and apparatus are not limited to the liquid handling system 10 or the use thereof, and the present disclosure may be applicable to other systems and applications where it is desired to aspirate and / or dispense liquid volumes. The pipetting system 101 aspirates and dispenses liquid volumes within the liquid handling system 10.

[0287] See also Figure 1 , the exemplary liquid handling system 10 includes a platform or table 12, a frame 14, a controller 20, an analytical instrument 16, a pipetting module 30, a pipetting module positioner 34A, and a pipetting system 101. The pipetting system 101 includes one or more pipettes 100. One or more receptacles, reservoirs, or containers 36 may be provided in the liquid handling system 10 to hold a liquid sample.

[0288] For the purpose of discussion and as Figure 1 and Figure 3 As indicated in , the liquid handling system 10 includes a workspace defining a Z-axis corresponding to a vertical direction, and orthogonal X-axis and Y-axis that together define a horizontal plane.

[0289] The pipetting module 30 may include a housing, a support or a base 32. In the illustrated embodiment, a plurality of pipettes 100 are mounted on the base 32. However, in other embodiments, the pipetting module 30 may only carry a single pipette 100. The pipette 100 may be arranged in a single row or in a specified XY array. The pipetting module positioner 34A may be operable to move the pipetting module 30 around the table 12. The pipetting module 30 may include one or more pipette actuators 34B to selectively lower and raise (extend and retract) the pipette 100 and / or raise and lower the base 32 relative to the table 12. The pipetting module positioning system 34A and one or more actuators 34B may be controlled by the controller 20.

[0290] See also Figure 3 , and as discussed in more detail herein, each pipette 100 can be understood to have a longitudinal axis AA and a distal portion 112A. Each pipette 100 includes a shaft 112 terminating at the distal portion 112A. Figure 1 When the system is used, each pipette 100 can be raised and lowered along its longitudinal axis AA by one or more pipette actuators 34B. In some embodiments, the axis AA is substantially parallel to the vertical axis ZZ.

[0291] The operations described herein may be performed by or through the controller 20. The actuators 34A, 34B, as well as the actuators 128A, 148A discussed below, and other devices of the liquid handling system 10 may be electronically controlled. According to some embodiments, the controller 20 programmatically performs some of the steps described, and in some embodiments, performs all of the steps described. According to some embodiments, the movement of the actuators 34A, 34B is fully automatically and programmatically performed by the controller 20. The controller 20 may be provided with an HMI 22 to receive user commands. The controller 20 may include one or more controllers.

[0292] The pipetting system 101 includes one or more pipettes 100 and one or more pipette tips 160. In an exemplary embodiment, each pipette tip 160 is mounted on a corresponding one of the pipettes 100 in a manner described below. In some embodiments, the pipette tip 160 is removable and replaceable on the pipette 100 and may actually be a disposable or consumable component of the pipetting system 101. However, in other embodiments, the pipette tip 160 may be omitted, and the structure and functionality of the pipette tip 160 may be provided as an integral part of the pipette 100.

[0293] The pipetting system 101 may include one or more pipettes 100 on a pipette module 30. The pipettes 100 may be constructed and operated in the same manner, and it should be appreciated that the subsequent description of a representative one of the pipettes 100 may be equally applicable to each of the pipettes 100. If multiple pipettes 100 are provided, the pipettes 100 may operate independently of one another or in series.

[0294] See also Figure 2-4 , the pipette 100 includes a frame 108, an interface 109, a pipetting channel 102, a pipette orifice 104, a pressure control system 106, an axis 112, an ejector mechanism 151, a tip mounting feature or adapter 156, and a manifold 175. The pressure control system 106 includes a first plunger mechanism 110, a second plunger mechanism 130, and an airflow control system 171. In an exemplary embodiment, the pipette tip 160 includes a pipetting orifice 162 and a liquid collection volume 165 in fluid communication with the pipetting channel 102. The axis 112 has a longitudinal axis or main axis AA. As discussed herein, the pipette 100 is operable to selectively operate the first plunger mechanism 110 or the second plunger mechanism 130, or the first plunger mechanism 110 and the second plunger mechanism 130, to change the pressure in the pipetting channel 102 to draw or dispense a liquid volume. It is understood that the first plunger mechanism 110 and the second plunger mechanism 130 can be operated independently and in parallel with each other to change the pressure in the pipetting channel 102 to aspirate or dispense a liquid volume.

[0295] The components of the pipette 100 may be mounted on a frame 108, which in turn is mounted on the pipette module base 32. The electrical interface 109 may operably cooperate with an electrical interface of the pipette module base 30 or another component of the liquid handling system 10 to provide power to the pipette 100 and provide control or data communication interconnections between the pipette 100 and other components of the liquid handling system 10 (e.g., an analytical instrument 16 and / or one or more remote controllers). The electrical interface 109 may include a printed circuit board (PCB).

[0296] As described above, the controller 20 may include one or more controllers that may be distributed within the liquid handling system 10. In some embodiments, the controller 20 includes one or more controllers that are integrally integrated with or embodied in the pipette 100 and are operable to perform some or all of the pipette control functions described herein. In some embodiments, the one or more controllers are embodied in and / or on the PCB 109.

[0297] See also Figure 2-5 The first piston mechanism 110 includes a shaft 112 , a guide sleeve 118 , a piston assembly 122 (including a first piston 120 ), a first annular seal (eg, an O-ring) 126 , a second annular seal (eg, an O-ring) 127 , and a first linear drive mechanism 128 .

[0298] The shaft 112 serves as a barrel for the first plunger 120. The shaft 112 defines a barrel opening 114 that is aligned with the axis AA and extends from a first end 114A to an opposite second end 114B ( Figure 4 A top opening or port 114D is defined at the second end 114B and is in fluid communication with the aperture 114. A pipette orifice 104 is defined at the first end 114A and is in fluid communication with the aperture 114.

[0299] Plunger assembly 122( Figure 5 ) includes an upper sleeve 124 and a first plunger 120 attached to the upper sleeve 124 at a front end of the upper sleeve 124. An opening 124A is defined in the upper sleeve 124. The first plunger 120 has a front end 120A ( Figure 4 ). The first plunger 120 is mounted in the guide sleeve 118 and the barrel opening 114 so that the first plunger 120 can slideably translate relative to the shaft 112 along the first plunger axis P1-P1 in the extension direction E1 and the opposite retraction direction E2. In some embodiments, the first plunger axis P1-P1 is substantially coincident with the shaft axis AA.

[0300] The first O-ring 126 ( Figure 4) forms an airtight seal between the outer diameter of the first plunger 120 and the manifold 175. The first plunger 120 is able to slide through the O-ring 126. The second O-ring 127 forms an airtight seal between the outer diameter of the shaft 112 and the manifold 175.

[0301] The outer diameter D1 of the first plunger 120 ( Figure 6 ) is smaller than the inner diameter D2 of the opening 114 ( Figure 6 ), so that the first plunger 120 and the opening 114A are radially spaced apart along their length. This spacing defines a tubular or annular air passage or channel 103 ( Figure 4 and 6 ). The channel 103 extends from the O-ring 126 to the pipette orifice 104.

[0302] The linear drive mechanism 128 includes an actuator 128A, a spindle 128B, a spindle nut 128C, and a first plunger position sensor 129 ( Figure 3 ). The actuator 128A may be an electric motor. The spindle 128B is coupled to the output end of the motor 128A to be rotationally driven thereby. In at least some embodiments, the spindle 128B is operably coupled to the output end of the motor 128A via a planetary gearbox (not shown). The spindle nut 128C is attached to the upper end of the upper sleeve 124.

[0303] The motor 128A is operable to drive the spindle 128B in each of a first direction (e.g., clockwise) and an opposite second direction (e.g., counterclockwise). When the motor 128A drives the spindle 128B in the first direction, the spindle nut 128C, the upper sleeve 124, and the first plunger 120 are thereby pulled in a retraction direction E2 relative to the opening 114. When the motor 128A drives the spindle 128B in the second direction, the spindle nut 128C, the upper sleeve 124, and the first plunger 120 are thereby pushed in an extension direction E1 relative to the opening 114. The spindle 128B translates in and out of the upper sleeve opening 124A as the plunger 120 travels.

[0304] The first plunger position sensor 129 is connected to the controller 20 to detect and monitor the position of the first plunger 120 in the opening 114. The first plunger position sensor 129 may be, for example, an encoder. The first plunger sensor 129 may be electrically connected to the PCB 109. The PCB 109 may include a controller (which forms one or more of the controller 20) that controls the motor 128A.

[0305] In use, the first chamber 115 ( Figure 4) is defined in the barrel opening 114, substantially between the front end 120A of the first plunger 120 and the first end 114A of the barrel opening 114. When the first plunger 120 is driven in the direction E1, the air volume is displaced from the first chamber 115, and the effective volume of the first chamber 115 is reduced. When the first plunger 120 is driven in the direction E2, the air volume in the first chamber 115 is replaced, and the effective volume of the first chamber 115 is increased.

[0306] The first plunger 120 can be formed of any suitable material. In some embodiments, the first plunger 120 is formed of stainless steel.

[0307] The shaft 112 can be formed of any suitable material. In some embodiments, the shaft 112 is formed of stainless steel.

[0308] The spindle 128B and the spindle nut 128C may be formed of any suitable material or materials. In some embodiments, the spindle 128B is formed of ceramic and the spindle nut 128C is formed of brass.

[0309] The second plunger mechanism 130 ( Figure 3 and Figure 5 ) includes a barrel 132, an end plug 136, a second plunger 140, a first annular seal (e.g., an O-ring) 146, a second annular seal (e.g., an O-ring) 147, and a second linear drive mechanism 148. In some embodiments (e.g., as shown) and as discussed in more detail below, the second plunger 140 is larger than the first plunger 120.

[0310] The barrel 132 defines a barrel opening 134. The barrel opening 134 may be laterally offset from the axis AA. The barrel opening 134 extends from a first end 134A to an opposite second end 134B. An end plug 136 is located at the first end 134A. The end plug 136 defines a fluid passage 136A therein.

[0311] The second plunger 140 has a front end 140A. An axially extending plunger opening 142 is defined in the plunger 140 and is closed at the end 140A. An O-ring 146 ( Figure 5 and 7 ) is mounted on the plunger 140 at the front end 140A. The O-ring 146 forms a sliding seal between the outer diameter of the second plunger 140 and the barrel 132 and translates with the second plunger 140.

[0312] The second plunger 140 is mounted in the barrel bore 134 so that the second plunger 140 is slidably translatable along a second plunger axis P2-P2 in an extension direction E3 and an opposite retraction direction E4 relative to the barrel bore 134. In some embodiments, the second plunger axis P2-P2 is laterally offset from the shaft axis AA.

[0313] The second linear drive mechanism 148 ( Figure 3 ) includes an actuator 148A, a spindle 148B, a spindle nut 148C and a first plunger position sensor 149. The actuator 148A can be a motor. The spindle 148B is coupled to the output end of the motor 148A to be rotationally driven by it. The spindle nut 148C is attached to the upper end of the second plunger 140.

[0314] The motor 148A is operable to drive the spindle 148B in each of a first direction (e.g., clockwise) and an opposite second direction (e.g., counterclockwise). When the motor 148A drives the spindle 148B in the first direction, the spindle nut 148C and the first plunger 140 are thereby pulled in a retracting direction E4 relative to the opening 134. When the motor 148A drives the spindle 148B in the second direction, the spindle nut 148C and the second plunger 140 are thereby pushed in an extending direction E3 relative to the opening 134. The spindle 148B translates in and out of the plunger opening 142 as the plunger 140 travels.

[0315] The second plunger position sensor 149 is connected to the controller 140 to detect and monitor the position of the first plunger 140 in the opening 134. The second plunger position sensor 149 may be, for example, an encoder. The second plunger position sensor 149 may be electrically connected to the PCB 109. The PCB 109 may include a controller (which forms one or more of the controllers 20) that controls the motor 148A.

[0316] Although the first and second linear drive mechanisms 128, 148 are shown as each comprising a rotary motor, a spindle, and a spindle nut arrangement, other types of linear drive mechanisms may be used instead in some embodiments, such as, but not limited to, direct linear motors.

[0317] In use, the second chamber 135 ( Figure 5 ) is defined in the barrel opening 134, substantially between the front end 140A of the second plunger 140 and the first end 134A of the barrel opening 134. When the first plunger 140 is driven in the direction E3, the air volume is displaced from the second chamber 135, and the effective volume of the second chamber 135 is reduced. When the second plunger 140 is driven in the direction E4, the air volume in the second chamber 135 is replaced, and the effective volume of the second chamber 135 is increased.

[0318] The second plunger 140 can be formed of any suitable material. In some embodiments, the second plunger 140 is formed of aluminum.

[0319] The barrel 132 can be formed of any suitable material. In some embodiments, the barrel 132 is formed of aluminum.

[0320] The spindle 148B and the spindle nut 148C may be formed of any suitable material or materials. In some embodiments, the spindle 148B may be formed of ceramic or stainless steel, while the spindle nut 148C may be formed of plastic or high temperature resistant thermoplastics (eg, polyetheretherketone (PEEK)).

[0321] The tip adapter 156 is configured to removably fix the pipette tip 160 (and a replacement pipette tip of appropriate configuration) to the end 112A of the shaft 112. In some embodiments, the tip adapter 156 forms an airtight pressure-resistant seal between the mounting section 166 and the shaft 112. In the illustrated embodiment, the tip adapter 156 includes an annular rib 156A, which is configured to form a firm friction fit with the mounting section 166 of the pipette tip, and to form an airtight pressure-resistant seal between the mounting section 166 and the shaft 112. However, other suitable pipette tip mounting structures may also be provided. For example, the tip adapter and the pipette tip may include interlocking features. The tip adapter 156 may be formed integrally with the shaft or may be formed as a separate component.

[0322] Ejector mechanism 151 ( Figure 5 and Fig.13 ) includes an ejector member or sleeve 150 slidably mounted on a guide rod 152. A spring 154 biases the ejector sleeve 150 toward the shaft end 112A in a downward direction E6. When the pipette tip 160 is picked up, the ejector sleeve 150 is pushed upward (direction E5). This upward movement and sleeve positioning can be used with a magnet and a Hall effect sensor on the sleeve 150 to detect the presence of the pipette tip 160. The upper end 150B of the ejector sleeve 150 is configured to engage the lower end of the upper sleeve 124. As described below, the lower end 150A of the ejector sleeve 150 is configured to engage the pipette tip 160. In use, when the plunger assembly 122 is fully driven downward (direction E1) by the first linear drive mechanism 128, it will abut against the upper end 114B and drive the ejector sleeve 150 in the ejection direction E6, thereby forcing the pipette tip 160 to disengage from the shaft 112.

[0323] Pipette tip 160 ( Figure 8 ) are examples of pipette tips that may be used with the pipette 100. However, it should be appreciated that other designs of pipette tips may be used instead.

[0324] The pipette tip 160 is a tubular body having a distal end 160A and a proximal end 160B. The pipette tip 160 defines a tip volume or passage 164 extending from a pipetting orifice 162 (at the distal end 160A) to an interface opening 163 (at the proximal end 160B). A mounting section 166 is provided at the proximal end 160B. As discussed herein, a portion (some or all) of the tip passage 164 may be used as a liquid collection volume 165 in use.

[0325] See also Figure 5 The airflow control system 171 includes a valve 178 , a first channel 172 , a second channel 174 , and a third channel 176 .

[0326] The first passage 172 fluidly connects or couples the second chamber 135 (via the passage 136A in the end plug 136 ) to a valve 178 .

[0327] The second passage 174 fluidly connects or couples the valve 178 to a port 174A that opens to the surrounding atmosphere.

[0328] See also Figure 4 , the third passage 176 fluidly connects or couples the valve 178 to the first barrel opening 114. More specifically, in the exemplary embodiment, the third passage 176 terminates at a port 176A between the O-rings 126, 127. The port 176A is in fluid communication with the barrel port 114D, which in turn is in fluid communication with the annular passage 103 between the first plunger 120 and the shaft 112. The passage 103 allows airflow through the pipetting channel 102 (i.e., through the opening 114) from the barrel port 114D to the pipette orifice 104.

[0329] Some or all of the channels 172, 174, 176 may be formed in whole or in part in the manifold 175. In some embodiments, each channel 172, 174, 176 has a diameter in the range of about 0.2 to 1 mm.

[0330] The pressure control system 106 may also include a pipetting channel pressure sensor 179 ( Figure 5 ).

[0331] The controller 20 is operable to control the valve 178 to adopt a first valve state, a second valve state, and a third valve state. In any of the three valve states, the channel 176 is not fluidly connected to the atmospheric port 174A. When the second chamber 135 is fluidly connected to the first opening 114, the second chamber 135 is fluidly connected to the pipetting channel 102 and the pipette orifice 104 via the first opening 114.

[0332] In the first valve state, valve 178 seals channel 172 from channels 174, 176. As a result, second chamber 135 is not fluidly connected to first opening 114 (and thus not fluidly connected to pipetting channel 102) or atmosphere port 174A.

[0333] In the second valve state, valve 178 seals channel 172 from channel 176 and opens channel 172 to channel 174. As a result, second chamber 135 is not fluidly connected to first opening 114 (and thus not fluidly connected to pipetting channel 102), and second chamber 135 is fluidly connected to atmosphere port 174A.

[0334] In the third valve state, valve 178 seals channel 172 from channel 174 and opens channel 172 to channel 176. As a result, second chamber 135 is fluidly connected to first opening 114 (and thus to pipetting channel 102), and second chamber 135 is not fluidly connected to atmosphere port 174A.

[0335] The liquid handling system 10 and the pipetting system 100 can be used according to some methods as follows to aspirate and / or dispense one or more liquid samples. In general, the first plunger mechanism 110 and the second plunger mechanism 130 are used to displace the air volume in their respective chambers 115, 135, and thereby correspondingly change the pressure in the pipetting channel 102 to aspirate the liquid sample from the liquid collection volume 165 or dispense the liquid sample into the liquid collection volume 165.

[0336] The pipette 100 can be operated in each of several different operating modes. An operator or controller 20 can select and implement an operating mode depending on the conditions or parameters of the aspiration or dispensing task.

[0337] Typically, the pipette 100 will initially be set (e.g., by the controller 20) in a manner such as Fig. 9 In the starting position shown in . In the starting position, the first plunger 120 is located at its lowest position. In some embodiments and as shown in the figure, in this lowermost starting position of the first plunger 120, the front end 120A of the first plunger 120 is substantially flush or axially overlapped with the pipette orifice 104. In the starting position, the second plunger 140 is located at its lowest position. In some embodiments and as shown in the figure, in this lowermost starting position of the second plunger 140, the front end 140A of the second plunger 140 is substantially flush or axially overlapped with the pipette orifice end plug 136.

[0338] like Fig. 9 As shown in , the pipette tip 160 is mounted on the tip adapter 156.

[0339] Then, the controller 20 may operate one or more actuators 34A, 34B, for example, to position the pipette tip 160 above the liquid sample LS. The sample LS may be disposed, for example, in a container 36. Then, the controller 20 may operate the actuator 34B, for example, to lower the distal end 160A and thereby the pipetting orifice 162 into the sample LS. In some embodiments, the distal end 160A and thereby the pipetting orifice 162 is immersed in the sample LS to at least a specified depth to ensure that the pipetting orifice 162 remains immersed in the sample during aspiration.

[0340] With the pipette 100 in the starting position and the pipetting orifice 162 immersed, the pipetting system 101 can be operated in a first aspiration mode to aspirate a portion of the sample LS. In the first aspiration mode, the valve 178 is set to a first valve state so that the pipetting channel 102 is fluid-tightly separated from the second chamber 135. Then, for example, Fig.10 , the first drive mechanism 128 is actuated to pull the first plunger 120 away from the pipette orifice 104 in a retraction direction E2. The retraction of the first plunger 120 expands the effective air volume of the first chamber 115, thereby generating a negative pressure at the pipette orifice 104. The negative pressure draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 165 (in the tip passage 164) of the pipette tip 160. The air volume or air column AC can be maintained in the tip passage 164 and the first chamber 115 between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120.

[0341] The pipette 100 can then be used to dispense the liquid sample volume LV in a first dispensing mode. In order to dispense the liquid sample volume LV, the valve 178 is set or maintained in a first valve state. The first drive mechanism 128 is actuated to push the first plunger 120 toward the pipette orifice 104 along the extension direction E1. The extension of the first plunger 120 transfers the air volume from the first chamber 115, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. The positive pressure discharges the liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162. The air column AC can be maintained between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0342] Alternatively, the pipetting system 101 can be operated in a second aspiration mode to aspirate a portion of the liquid sample LS. In the second aspiration mode, the valve 178 is set in a third valve state so that the second chamber 135 is fluidically connected to the pipetting channel 102 and is fluidically sealed from the atmospheric port 174A. Fig.11, with the pipette 100 in the starting position and the pipetting orifice 162 immersed, the second drive mechanism 148 is actuated to pull the second plunger 140 away from the end plug 136 in the retraction direction E4. The retraction of the second plunger 140 expands the effective air volume of the second chamber 135, thereby generating a negative pressure at the pipette orifice 104 (via the channel 172, the valve 178, the channel 176 and the opening 114). The negative pressure draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 165 of the pipette tip 160 (in the tip passage 164). The air volume or air column AC can be maintained in the tip passage 164 between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120.

[0343] Then, the liquid sample volume LV can be dispensed in a second dispensing mode using the pipette 100. In order to dispense the liquid sample volume LV, the valve 178 is set or maintained in a third valve state. The second drive mechanism 148 is actuated to push the second plunger 140 toward the end plug 136 along the extension direction E3. The extension of the second plunger 140 transfers the air volume from the second chamber 135, thereby generating a positive pressure (via the channel 172, the valve 178, the channel 176 and the opening 114) at the proximal end of the liquid sample volume LV. The positive pressure discharges the liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162. The air column AC can be maintained between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0344] Alternatively, the pipetting system 101 can be operated in a third aspiration mode to aspirate a portion of the liquid sample LS. In the third aspiration mode, the valve 178 is set in a third valve state so that the second chamber 135 is fluidically connected to the pipetting channel 102 and is fluidically sealed from the atmospheric port 174A. Then, for example, Fig.12 As shown in FIG. 1 , the first drive mechanism 128 is actuated to pull the first plunger 120 away from the pipette orifice 104 in a retraction direction E2. The retraction of the first plunger 120 expands the effective air volume of the first chamber 115, thereby generating a negative pressure at the pipette orifice 104. In addition, and simultaneously with the retraction of the first plunger 120, as shown in FIG. Fig.12 , the second drive mechanism 148 is actuated to pull the second plunger 140 away from the end plug 136 in a retraction direction E4. The retraction of the second plunger 140 expands the effective air volume of the second chamber 135, thereby also generating a negative pressure at the pipette orifice 104. As a result, the displacement of both plungers 120, 140 generates a negative pressure that draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 165 (in the tip passage 164) of the pipette tip 160. An air volume or air column AC can be maintained in the tip passage 164 between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120.

[0345] Then the pipette 100 can be used to distribute the liquid sample volume LV in the third distribution mode. In order to distribute the liquid sample volume LV, the valve 178 is set or maintained in the third valve state. The first drive mechanism 128 is actuated to push the first plunger 120 toward the pipette orifice 104 along the extension direction E1. The extension of the first plunger 120 transfers the air volume from the first chamber 115, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. In addition, and at the same time as the extension of the first plunger 120, the second drive mechanism 148 is actuated to push the second plunger 140 toward the end plug 136 along the extension direction E3, which transfers the air volume from the second chamber 135, thereby generating a positive pressure (via the channel 172, the valve 178, the channel 176 and the opening 114) at the proximal end of the liquid sample volume LV. As a result, the displacement of the two plungers 120, 140 generates a positive pressure, which discharges the liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162. The column of air AC may remain between the proximal end of the liquid sample volume LV and the front end 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0346] Alternatively, the pipetting system 101 can be operated in a fourth aspiration mode to aspirate a portion of the liquid sample LS. In the fourth aspiration mode, the valve 178 is also set in the third valve state, and the first drive mechanism 128 and the second drive mechanism 148 operate to retract the plungers 120, 140 in the manner described above for the third aspiration mode. However, in the fourth aspiration mode, the first plunger 120 and the second plunger 140 are retracted at different times (e.g., sequentially or alternately) from each other, rather than simultaneously.

[0347] Similarly, the pipetting system 101 can be operated in a fourth dispensing mode to dispense a portion of the liquid sample LS. In the fourth dispensing mode, the valve 178 is also set in the third valve state, and the first drive mechanism 128 and the second drive mechanism 148 operate to extend the plungers 120, 140 in the manner described above for the third dispensing mode. However, in the fourth dispensing mode, the first plunger 120 and the second plunger 140 are extended at different times from each other (e.g., sequentially or alternately), rather than simultaneously.

[0348] In some operations, the valve 178 is set in the second valve state to connect the second chamber 135 to the atmospheric port 174A. The second drive mechanism 148 is then operated to position the second plunger 140 in its starting position. The air displaced from the chamber 135 by the second plunger 140 is exhausted through the atmospheric port 174A, so that the air volume in the chamber 135 is not pressurized. The valve 178 can then be set in the first valve state or the second valve state to reseal the second chamber 135 with the atmospheric port 174A for aspiration or dispensing operations.

[0349] In operation according to some embodiments, the second plunger 140 and the valve 178 are cooperatively operated repetitive or circulating pumps, so as to, for example, draw and distribute a larger volume. In this case, the valve 178 switches between its second state and the third valve state between the movements of the second plunger 140. More specifically, the valve 178 and the second plunger 140 can be operated as follows. When the valve 178 is in the third valve state (the second chamber 135 is fluidically connected to the pipetting channel 102, and the second chamber 135 is separated and closed from the atmospheric port 174A), the second plunger 140 retracts (direction E4) to draw the liquid sample volume LV into the pipette tip 160. Then the valve 178 is placed in the second valve state (the second chamber 135 is fluidically connected to the atmospheric port 174A, and the second chamber 135 is separated and closed from the pipetting channel 102). With the valve 178 in the second valve state, the second plunger 140 extends (direction E3) to exhaust air from the second chamber 135 and returns the second plunger 140 to or toward its starting position. Since the valve 178 is in the second valve state, the aspirated liquid sample volume LV remains in the pipette tip 160 (i.e., not dispensed by the extension of the second plunger 140). Then, the valve 178 is placed in the third valve state again, and with the valve 178 in the third valve state, the second plunger 140 is retracted again (direction E4) to aspirate an additional liquid sample volume LV into the pipette tip 160. This sequence can be repeated multiple times to gradually aspirate the liquid sample volume LV into the pipette tip 160. For example, the sequence can be repeated five times, aspirating 1 ml each time, to aspirate a total of 5 ml into the pipette tip 160. The operation can also be reversed to dispense larger volume increments from the pipette tip 160 (eg, dispensing a series of five 1 ml liquid volumes from a pipette tip 160 containing 5 ml of liquid sample).

[0350] As described above, the pipetting system 101 draws the liquid sample by reducing the pressure in the pipetting channel, and distributes the liquid sample by increasing the pressure in the pipetting channel 102. However, the pressure in the pipetting channel 102 may fluctuate in response to other actions or conditions in the process. For example, in some embodiments for drawing, the pressure in the pipetting channel 102 increases with the retraction of the plunger 120 or 140. After the plunger 120, 140 stops, the inflow into the pipette tip 160 stops, and the pressure drop associated with the plunger movement becomes zero. However, due to the weight of the liquid sample in the pipette tip 160, the pressure in the pipetting channel 102 may remain negative. After the pipette tip 160 is removed from the liquid sample supply source, the pressure in the pipetting channel 102 may further drop slightly due to the reduction of buoyancy. Subsequently, due to the evaporation of the liquid sample in the pipette tip 160, the pressure in the pipetting channel 102 may slowly increase. Thus, it should be appreciated that pressure changes in the pipetting channel 102 may be caused or determined by phenomena in addition to and in addition to the movement of the plungers 120 , 140 .

[0351] The above-mentioned aspiration mode and dispensing mode can be implemented in different combinations as desired. For example, the third aspiration mode (simultaneous plunger retraction) can be used to aspirate a liquid sample volume, while the fourth dispensing mode (sequential plunger extension) can be used to dispense a liquid sample volume.

[0352] The pipette 100 can be repositioned between the absorption and distribution steps as needed. The absorption process can include absorbing the liquid volume from a single liquid sample source or multiple liquid sample sources. The distribution process can include distributing the liquid volume to a single position or multiple positions. For example, a certain amount of liquid sample can be absorbed from a single source, and then a smaller amount of the absorbed liquid sample can be distributed to corresponding different positions (e.g., the holes of the orifice plate). In certain embodiments, the liquid sample volume LV (or a portion thereof) is distributed in the analytical device 16 by the pipette 100.

[0353] In some embodiments, the controller 20 automatically and programmatically operates the valve 178 and the actuators 128A, 148A to set valve states and extend and retract the plungers 120 , 140 , as described herein.

[0354] In some embodiments, the controller 20 receives a pressure signal indicative of the gas pressure in the pipetting channel 102 from the pipetting channel pressure sensor 179. The controller 20 may monitor the pressure within the pipetting channel 102 continuously.

[0355] See also Fig.13, the pipetting system 101 can be operated to automatically remove the pipette tip 160 from the pipette 100 using the ejector mechanism 151. To eject the pipette tip 160, the controller 20 operates the first drive mechanism 128 to push the plunger assembly 122 along the extension direction E6. As the first drive mechanism 128 continues to drive the plunger assembly 122, the front end 124B of the plunger sleeve 122 will engage the upper end 150B of the ejector sleeve 150 and push the ejector sleeve 150 along the direction E6. The lower end 150A of the ejector sleeve 150 engages the mounting section 166 of the pipette tip 160 and pushes the pipette tip 160 away from the tip adapter 156. In some embodiments, the controller 20 automatically and programmatically operates the actuator 128A to eject the pipette tip 160.

[0356] As described herein, the first plunger mechanism 110 and the second plunger mechanism 120 can be operated independently of each other or together to aspirate and dispense liquid sample volumes. For a given aspiration or dispensing process, the selection of which plunger mechanism or mechanisms 120, 140 to operate can be based on or customized for the conditions or parameters of the aspiration or dispensing process. By using a dual plunger mechanism, the volume range of the pipette 100 can be expanded and can support processing of specific volume accuracy and precision without the need for multiple pipetting channels.

[0357] For example, when only a relatively small amount of liquid sample needs to be aspirated or dispensed, the pipette 100 can be operated in the first aspiration mode or the first dispensing mode. Using a smaller plunger 120 can provide higher resolution, and thus provide better accuracy and precision.

[0358] When needing to draw or distribute a relatively large amount of liquid sample, pipette 100 can operate in second draw mode or second distribution mode.Use bigger plunger 140 can make pipette 100 be able to draw and hold a larger amount of liquid sample at one time.Use bigger plunger 140 can make pipette 100 draw or distribute liquid sample at higher speed.

[0359] When a relatively large amount of liquid sample needs to be drawn or dispensed, the pipette 100 can also operate in a third draw mode or a third dispense mode, and in a fourth draw mode or a fourth dispense mode. The use of a smaller plunger 120 and a larger plunger 140 together enables the pipette 100 to draw and accommodate a larger amount of liquid sample at one time. Simultaneously transferring a smaller plunger 120 and a larger plunger 140 enables the pipette 100 to draw or dispense a liquid sample at an even higher rate.

[0360] For example, in the exemplary embodiment, the first plunger 120 has a stroke distance L1 ( Fig.12 ) and 2mm diameter D1( Figure 6), so that the first plunger mechanism 110 can transfer up to 55 microliters of air. In an exemplary embodiment, the second plunger 140 has a travel distance L5 (45 mm) Fig.12 ) and 6mm diameter D5( Figure 7 ), so that the second plunger mechanism 130 can transfer up to 1100 microliters of air. When operating in the first suction mode, the pipette 100 can suck up to 55 microliters of liquid sample. When operating in the second suction mode, the pipette 100 can suck up to 1100 microliters of liquid sample. When operating in the third suction mode or the fourth suction mode, the pipette 100 can suck up to 1155 microliters of liquid sample.

[0361] In some embodiments, the controller 20 automatically and programmatically performs the steps of operating the actuators 128A, 148A to extend and retract the plungers 120 , 140 and to eject the pipette tip 160 .

[0362] In some embodiments, the controller 20 automatically and programmatically performs the steps of operating the actuators 34A, 34B to position the pipette 100 .

[0363] As described above, in some embodiments, the second plunger 140 is larger than the first plunger 120. The first plunger 120 has a cross-sectional area A1 ( Figure 6 The second plunger 140 has a cross-sectional area A2 ( ) in a cross-sectional plane orthogonal to the second plunger axis P2-P2 (ie, the axis along which the second plunger translates to aspirate and dispense). Figure 7 ). In some embodiments (e.g., as shown), the cross-sectional area A2 of the second plunger 140 is greater than the cross-sectional area A1 of the first plunger 120. In some embodiments, the cross-sectional area A2 is at least three times the cross-sectional area A1.

[0364] In some embodiments, the cross-sectional area A1 is about 0.1 to 4 mm 2 The cross-sectional area A2 is about 1.25 to 50 mm 2 within the range.

[0365] The smaller first plunger 120 displaces the volume of air in the first chamber 115 at a first air volume displace rate per unit translation. The larger second plunger displaces the volume of air in the second chamber 135 at a second air volume displace rate per unit translation. Because the larger plunger 120 has a larger cross-sectional area, the second air volume displace rate per unit translation is greater than the first air volume displace rate per unit translation. In some embodiments, the second air volume displace rate per unit translation is at least three times the first air volume displace rate per unit translation.

[0366] In some embodiments, the first air volume transfer rate per unit translation is in the range of about 0.01 μL / sec to 100 μL / sec, and the second air volume transfer rate per unit translation is in the range of about 0.1 μL / sec to 2500 μL / sec.

[0367] In some embodiments, the pipette is configured such that the maximum volume of air that can be transferred by the second plunger 140 (when the second plunger 140 is translated through its entire stroke) is greater than the maximum volume of air that can be transferred by the first plunger 120 (when the first plunger 120 is translated through its entire stroke). In some embodiments, the maximum volume of air that can be transferred by the second plunger 140 is at least ten times the maximum volume of air that can be transferred by the first plunger 120.

[0368] In some embodiments, the maximum volume of air that can be displaced by the second plunger 140 is in the range of about 10 microliters to 5000 microliters, and the maximum volume of air that can be displaced by the first plunger 120 is in the range of about 1 microliter to 100 microliters.

[0369] In some embodiments, the maximum air volume of the second chamber 135 (when the second plunger 140 is in its fully retracted position) is at least ten times the maximum air volume of the first chamber 115 (when the first plunger 120 is in its fully retracted position). In some embodiments, the maximum air volume of the second chamber 135 is in the range of about 11 microliters to 5500 microliters, and the maximum air volume of the first chamber 115 is in the range of about 1.5 microliters to 110 microliters.

[0370] In some embodiments, and as Figure 2-7 In the exemplary embodiment shown in FIG. 1 , the first chamber 115 ( Figure 4 ; That is, the chamber containing the air volume transferred by the first plunger 120 when it translates) occupies a portion of the pipetting channel 102. Therefore, the first plunger 120 can be disposed in the pipetting channel 102 and travel through the pipetting channel 102. In some embodiments, when the first plunger 120 is fully extended, the distal end 120A of the first plunger 120 coincides with or extends beyond the pipetting orifice 104. Disposing the first plunger 120 in the shaft 112 and positioning the distal end 120A at the starting position can help minimize the dead volume in the pipetting channel 102 and allow the use of a more compact pipette. The arrangement of the first plunger mechanism 110, the shaft 112, and the ejection mechanism 151 also enables the use of a single drive mechanism to perform the aspiration / dispensing function and the tip ejection function.

[0371] See also Figure 14-19, shows an example pipetting system 201 according to other embodiments of the present technology. The pipetting system 201 can aspirate and dispense liquid volumes within a liquid handling system. For example, the pipetting system 201 can replace the automated liquid handling system 10 ( Figure 1 ) is used in the pipetting system 101 in ). However, it should be understood that the disclosed methods, systems and devices are not limited to the liquid handling system 10 or the use thereof, and the present disclosure can be applied to other systems and applications that require aspiration and / or dispensing of liquid volumes. The pipetting system 201 includes a pipette 200.

[0372] The pipetting system 201 includes one or more pipettes 200. One or more pipettes may be mounted on the pipette module 30. The pipettes 200 may be constructed and operated in the same manner, and it should be appreciated that the subsequent description of a representative pipette 200 in the pipettes 200 may be equally applicable to each of the pipettes 200. If a plurality of pipettes 200 are provided, the pipettes 200 may operate independently of one another or in series.

[0373] The pipetting system 201 includes one or more pipettes 200, a controller 20, and one or more pipette tips 160 (as referred to herein). Figure 8 In some embodiments, the pipette tip 160 is removable and replaceable on the pipette 200 and may be a disposable or consumable component of the pipetting system 201. However, in other embodiments, the pipette tip 160 may be omitted and the structure and functionality of the pipette tip 160 may be provided as an integral part of the pipette 200. The filter medium 169 ( Fig.15 ) may be provided in the pipette tip 160.

[0374] See also Fig.14 and Fig.15 , and as discussed in more detail herein, the pipette 200 can be understood to have a longitudinal axis AA and a distal portion 212A. The pipette 200 includes a tubular barrel 210, a pressure control system 206, a pipetting channel 202, a pipette orifice 204, and a tip adapter 214. The barrel 210 extends from a distal end 210A to a proximal end 210B. The barrel 210 includes an axis 212 that terminates at the distal end 210A. The pipette orifice 204 is located at the distal end 210A and is in fluid communication with the pipetting channel 202.

[0375] The pressure control system 206 includes a barrel opening or passage 220, a pressure relief port 228 to the atmosphere, a plunger assembly 240 (including a front plunger 242 and a rear plunger 244), a front seal 252, a rear seal 254, a plunger drive mechanism 258, a pressure relief valve 255 and a pressure sensor 256.

[0376] The passageway 220 is longitudinally aligned with the axis AA and extends from a front end 220A to an opposite rear end 220B. Fig.15 , passage 220 includes a front section 222D and a rear section 224D. The front seal 252 is axially located between the front section 222D and the rear section 224D. The rear seal 254 is axially located between the rear section 224D and the rear opening 220E at the rear end 210B. The front chamber 222 is defined by the front section 222D and the front seal 252 between the front seal 252 and the pipetting channel 202. The rear chamber 224 is defined by the rear section 224D, the front seal 252, and the rear seal 254 between the front seal 252 and the rear seal 254.

[0377] The front seal 252 and the rear seal 254 may each be an annular seal (eg, an O-ring). The front O-ring 252 (or other type of seal) defines a sealing opening 252A therein.

[0378] The plunger member 240 has a front or forward end 240A, an opposite rear end 240B, and an intermediate transition portion 246. The front plunger 242 extends from a front end 242A (at the front end 240A) to a rear end 242B (at the transition portion 246). The rear plunger 244 extends from a front end 244A (at the transition portion 246) to a rear end 244B (at the rear end 240B).

[0379] The front plunger 242 and the rear plunger 244 are joined, merged or connected at the transition portion 246. In some embodiments, the front plunger 242 and the rear plunger 244 are formed together as a single component. In some embodiments, the plungers 242, 244 form a rigid single component. In some embodiments, the front plunger 242 and the rear plunger 244 are formed together as an integral component.

[0380] The plunger member 240 is mounted in the passage 220 such that the plunger member 240 is slidably translatable relative to the barrel 210 along the plunger axis P4-P4 in an extension direction E8 and an opposite retraction direction E9. In some embodiments, the plunger axis P4-P4 is substantially coincident with the shaft axis AA.

[0381] The plunger member 240 is slidable to move between an initial or fully extended position (eg, Fig.14 ) and the fully retracted position (as shown in Fig.17220, through the plunger member stroke). In the fully extended position, the front plunger 242 is located in the front chamber 222, wherein its front end 242A is close to the pipetting channel 202, and the rear plunger 244 is located in the rear chamber 224, wherein its front end 244A is close to the front O-ring 252, and the front plunger 242 extends through the opening 252A in the front O-ring 252. The front O-ring 252 forms a static, airtight, pressure-resistant seal between the front O-ring 252 and the barrel 210, and forms an airtight, pressure-resistant seal between the outer diameter of the front plunger 242 and the inner diameter of the front O-ring 252. The front plunger 242 can slide through the front O-ring 252 while maintaining an airtight, pressure-resistant seal therebetween. The rear O-ring 254 forms an airtight, pressure-resistant seal between the outer diameter of the rear plunger 244 and the barrel 210. The rear plunger 244 is able to slide through the rear O-ring 254 while maintaining an airtight, pressure-resistant seal therewith.

[0382] In the exemplary pipette 200, the stroke of the plunger member 240 corresponds to the stroke of the front plunger 242 and the rear plunger 244. Fig.17 , the front plunger 242 can translate through the front plunger stroke SF relative to the passage 220. The rear plunger 244 can translate through the rear plunger stroke SR relative to the passage 220. During the first portion SF1 of the front plunger stroke SF, the front chamber 222 is fluidly sealed from the rear chamber 224 by the front seal 252. During the second portion SF2 of the front plunger stroke SF, the front chamber 222 is fluidly coupled or connected to the rear chamber 224 through the opening 252A of the front seal 252.

[0383] The plunger drive mechanism 258 is selectively operable to drive the plunger member 240 in each of the extension direction E8 and the retraction direction E9. The plunger drive mechanism 258 may be a linear drive mechanism. The plunger drive mechanism 258 may include an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes a motor. In some embodiments, the linear drive mechanism 258 includes a spindle and a spindle nut connecting rod mechanism driven by a motor. In some embodiments, the plunger drive mechanism 258 is manually operable and does not include a powered actuator. For example, an extension, a lever, a knob, or other manual drive features may be used to push and pull the plunger member 240.

[0384] In use, as the front plunger 242 is driven in the extension direction E8, air volume is displaced from the front chamber 222 and the effective volume of the front chamber 222 decreases. As the front plunger 242 is driven in the retraction direction E9, the air volume in the front chamber 222 is displaced and the effective volume of the front chamber 222 increases.

[0385] Similarly, in use, as the rear plunger 244 is driven in the extension direction E8, air volume is displaced from the rear chamber 224, and the effective volume of the rear chamber 224 decreases. As the rear plunger 244 is driven in the retraction direction E9, the air volume in the rear chamber 224 is displaced, and the effective volume of the rear chamber 224 increases.

[0386] The plunger component 240 can be formed from any suitable material or materials. In some embodiments, the plunger component 240 is formed from stainless steel.

[0387] The barrel 210 can be formed of any suitable material. In some embodiments, the barrel 210 is formed of aluminum.

[0388] The tip adapter 214 is configured to removably secure the pipette tip 160 (and appropriately configured replacement pipette tips) to the end 212A of the shaft 212 in the same manner as described above with respect to the tip adapter 156 .

[0389] Pipette tip 160 ( Figure 8 ) are examples of pipette tips that may be used with the pipette 100. However, it should be appreciated that other designs of pipette tips may be used instead.

[0390] The pressure sensor 256 is fluidly coupled to the pipetting channel 202. In some embodiments, the pressure sensor 256 is an in-line pressure sensor located in or along the pipetting channel 202.

[0391] The controller 20 is operable to control the pressure relief valve 255 to adopt an open valve state and a closed valve state. In the open valve state, the rear chamber 224 is fluidly connected to the surrounding atmosphere through the release port 228. In the closed valve state, the rear chamber 224 is not fluidly connected to the surrounding atmosphere through the release port 228.

[0392] The liquid handling system 10 and the pipetting system 201 can be used according to some methods as follows to aspirate and / or dispense one or more liquid samples. In general, the front plunger 242 and the rear plunger 244 are used to displace the air volume in their respective chambers 222, 224, and thereby correspondingly change the pressure in the pipetting channel 202 to aspirate the liquid sample from the liquid collection volume 165 or dispense the liquid sample into the liquid collection volume 165.

[0393] The pipette 200 can be operated in each of several different operating modes. An operator or controller 20 can select and implement an operating mode depending on the conditions or parameters of the aspiration or dispensing task.

[0394] Typically, the pipette 200 will initially be set (e.g., by the controller 20) in a first starting position. The starting position may be, for example, Fig.14In other embodiments, the starting position is Fig.14 The lowest fully extended position of the plunger 240 is slightly raised or retracted (i.e., the plunger member 240 is slightly raised or retracted relative to the Fig.14 Starting aspiration with this offset can help ensure that the pipette tip is completely emptied by a dispensing operation. For example, the offset of the plunger member distal end 242A from the distal end of the antechamber 222D can be in the range of about 10% to 20% of the pipetting volume.

[0395] like Fig.14 As shown in , the pipette tip 160 is mounted on the tip adapter 214.

[0396] Then, the controller 20 may operate one or more actuators 34A, 34B, for example, to position the pipette tip 160 above the liquid sample LS. The sample LS may be disposed in a container 36, for example. Then, the controller 20 may operate the actuator 34B, for example, to lower the distal end 160A, and thereby lower the pipetting orifice 162 into the sample LS. In some embodiments, the distal end 160A and thereby the pipetting orifice 162 is immersed in the sample LS to at least a specified depth to ensure that the pipetting orifice 162 remains immersed in the sample during aspiration.

[0397] With the pipette 200 in the first starting position and the pipetting orifice 162 immersed, the pipetting system 201 can be operated in a first aspiration mode to aspirate a portion of the sample LS. In the first aspiration mode, the pressure release valve 255 is set to an open valve state so that the rear chamber 224 is fluidically connected to the release port 228. In the first aspiration mode, the pipetting channel 202 is fluidically sealed from the rear chamber 224 by the front seal 252. More specifically, the front plunger 242 blocks (airtightly) the connection opening 252A in the front seal 252.

[0398] The drive mechanism 258 is then actuated to translate the plunger member 240 in the retraction direction E9 and thereby pull the front plunger 242 away from the pipette orifice 204. Fig.16 As shown in , the front plunger 242 thus translates through a portion of its first stroke SF1, but does not translate to the second portion SF2 of its stroke. The front chamber 222 is separated from the rear chamber 224 by the front seal 252 to maintain a seal. The retraction of the front plunger 242 expands the effective air volume of the front chamber 222, thereby generating a negative pressure at the pipette orifice 204. The negative pressure draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 165 (in the tip passage 164) of the pipette tip 160. The air volume or air column AC can be maintained in the tip passage 164 and the front chamber 222 between the proximal end of the liquid sample volume LV and the front end 220A of the front chamber 222.

[0399] The pipette 200 can then be used to dispense the liquid sample volume LV in a first dispensing mode. The front plunger 242 is in the first portion SF1 of its stroke so that the front chamber 222 is separated from the rear chamber 224 by the front seal 252 to maintain a seal. The pressure release valve 255 is set or maintained in an open valve state. Then, the drive mechanism 258 is actuated to transfer the plunger component 240 along the extension direction E8, and thereby push the front plunger 242 toward the pipette orifice 204 along the extension direction E8. The extension of the front plunger 242 transfers the air volume from the front chamber 222, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. The positive pressure discharges the liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162. The air column AC can be maintained between the proximal end of the liquid sample volume LV and the front end 242A of the front plunger 242 until the liquid sample volume LV is completely dispensed.

[0400] Alternatively, the pipetting system 101 can be operated in a second aspiration mode to aspirate a portion of the liquid sample LS. The pressure release valve 255 is initially set to an open valve state so that the rear chamber 224 is fluidly connected to the release port 228. The plunger member 240 is placed in a second starting position. In the second starting position, the distal end 242A of the plunger member 240 is located behind the front seal 252 (for example, slightly behind the front seal 252) so that the plunger member 242 and the front seal 252 do not separate the front chamber 222 from the rear chamber 224 in a sealed manner. Then, the controller 20 sets the pressure release valve 255 to a closed valve state so that the rear chamber 224 is fluidly sealed from the release port 228. With the pipette 200 in the second starting position and the pipetting orifice 162 immersed, the drive mechanism 258 is actuated to pull the plunger member 240 in the retraction direction E9. As Fig.17 , the front plunger 242 thereby translates some or all of the second portion SF2 of its stroke. The retraction of the rear plunger 244 expands the effective air volume of the rear chamber 224, thereby generating a negative pressure at the pipette orifice 204. The negative pressure draws an additional liquid sample volume LV of the liquid sample LS into the liquid collection volume 165 of the pipette tip 160. An air volume or air column AC can be maintained in the tip passage 164 between the proximal end of the liquid sample volume LV and the front end 242A of the first plunger 242.

[0401] Similarly, the pipette 200 can then be used to dispense the liquid sample volume LV in the second dispensing mode. The pressure release valve 255 is set or maintained in a closed valve state. The drive mechanism 258 is actuated to push the plunger member 240 along the extension direction E8. The extension translation of the plunger member 240 displaces the air volume from the rear chamber 224, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. The positive pressure discharges the liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162.

[0402] The plunger member 240 may extend beyond the front seal 252. In this case, once the front end 242A of the front plunger 242 reaches and closes the opening 252A of the front seal 252, the controller 20 may open the pressure relief valve 255. The drive mechanism 258 then continues to push the plunger member 240 along the extension direction E8. The continued extension of the plunger member 240 displaces the air volume from the front chamber 222, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. The positive pressure discharges the additional liquid sample volume LV from the liquid collection volume 165 through the pipetting orifice 162.

[0403] During the above operation, the valve 255 is opened at a specific time to allow air to be exhausted from the rear chamber 224 through the release port 228 so that the air volume in the chamber 224 is not over-pressurized (negatively or positively) due to the displacement of the rear plunger 244. When the pressure relief valve 255 is closed, the rear chamber 224 is sealed from the atmosphere so that the displacement of the rear plunger 244 can generate a pressure change in the rear chamber 224 for aspiration or dispensing operations.

[0404] As described above, the pipetting system 201 aspirates liquid samples by reducing the pressure in the pipetting channel, and dispenses liquid samples by increasing the pressure in the pipetting channel 202. However, the pressure in the pipetting channel 202 may fluctuate in response to other actions or conditions in the process, such as discussed above with respect to the pipetting system 101.

[0405] In some embodiments, controller 20 automatically and programmatically operates the pressure relief valve 255 and the actuator of the linear drive mechanism 258 to open and close the valve 255 and to extend and retract the plunger member 240 as described herein.

[0406] In some embodiments, the controller 20 receives a pressure signal indicative of the gas pressure in the pipetting channel 202 from the pipetting channel pressure sensor 256. The controller 20 may monitor the pressure in the pipetting channel 202 continuously.

[0407] The selection of which aspiration or dispensing mode to use for a given aspiration or dispensing process can be tailored to or based on the conditions or parameters of the aspiration or dispensing process. By using different sized tandem plungers, the volume range of the pipette 200 can be expanded and specific volume accuracy and precision can be supported without multiple pipetting channels.

[0408] For example, when only a relatively small amount of liquid sample needs to be aspirated or dispensed, the pipette 200 can be operated in the first aspiration mode or the first dispensing mode. Using a smaller front plunger 242 can provide higher resolution, and thus provide better accuracy and precision.

[0409] When a relatively large amount of liquid sample needs to be drawn or dispensed, the pipette 200 can operate in a second draw mode or a second dispense mode. Using a larger rear plunger 244 allows the pipette 200 to draw and accommodate a larger amount of liquid sample at one time. Using a larger rear plunger 244 allows the pipette 200 to draw or dispense liquid sample at a higher rate.

[0410] For example, in the exemplary embodiment, the first portion SF1 of the stroke of the front plunger 242 has a stroke distance L6 ( Fig.17 ) and the front plunger 242 has a diameter D6 of 2 mm ( Fig.18 ), so that the front plunger 242 can transfer up to 78.5 microliters of air. In the exemplary embodiment, the rear plunger 244 has a travel distance L7 (50mm) Fig.17 ) and 6mm diameter D7( Fig.19 ), so that the rear plunger 244 can transfer up to 1413 microliters of air. When operating in the first aspiration mode, the pipette 200 can aspirate up to 60 microliters of liquid sample. When operating in the second aspiration mode, the pipette 200 can aspirate up to 1300 microliters of liquid sample.

[0411] As described above, in some embodiments, the rear plunger 244 is larger than the front plunger 242. The front plunger 242 has a cross-sectional area A6 ( Fig.18 The rear plunger 244 has a cross-sectional area A7 ( Fig.19 ). In some embodiments (e.g., as shown), the cross-sectional area A7 of the rear plunger 244 is greater than the cross-sectional area A6 of the front plunger 242. In some embodiments, the cross-sectional area A7 is at least three times the cross-sectional area A6. In some embodiments, the cross-sectional area A6 is in the range of about 3 to 64 times the cross-sectional area A6.

[0412] In some embodiments, the cross-sectional area A6 is about 0.5 to 5 mm 2 The cross-sectional area A7 is about 5 to 85 mm 2 within the range.

[0413] The smaller front plunger 242 transfers the volume of air in the front chamber 222 at a first air volume transfer rate per unit translation. The larger rear plunger 244 transfers the volume of air in the rear chamber 224 at a second air volume transfer rate per unit translation. Because the rear plunger 244 has a larger cross-sectional area, the second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation. In some embodiments, the second air volume transfer rate per unit translation is at least three times the first air volume transfer rate per unit translation.

[0414] In some embodiments, the first air volume transfer rate per unit translation is in the range of about 0.1 μL / sec to 100 μL / sec, and the second air volume transfer rate per unit translation is in the range of about 1 μL / sec to 2500 μL / sec.

[0415] In some embodiments, the pipette 200 is configured such that the maximum volume of air that can be transferred by the rear plunger 244 (when the rear plunger 244 is translated through its entire stroke) is greater than the maximum volume of air that can be transferred by the front plunger 242 (when the front plunger 242 is translated through its entire stroke). In some embodiments, the maximum volume of air that can be transferred by the rear plunger 244 is at least ten times the maximum volume of air that can be transferred by the front plunger 242.

[0416] In some embodiments, the maximum volume of air that can be displaced by the rear plunger 244 is in the range of about 100 microliters to 5000 microliters, and the maximum volume of air that can be displaced by the front plunger 242 is in the range of about 10 microliters to 200 microliters.

[0417] In some embodiments, the volume of the rear chamber 224 is greater than the volume of the front chamber 222. In some embodiments, the volume of the rear chamber 224 is at least ten times the volume of the front chamber 222.

[0418] See also Figure 20-24 , which shows a pipetting system 301 according to other embodiments. Except as described below, the construction and use of the pipetting system 301 can be the same as the pipetting system 201.

[0419] The pipetting system 301 includes a pipette 300 to replace the pipette 200. The construction and use of the pipette 300 can be the same as the pipette 200 except as follows. The pipette 300 further includes an opening mechanism in the form of an interchamber valve 360. The interchamber valve 360 ​​includes a connecting passage 362 and a valve control mechanism 364. The connecting passage 362 can be formed in the barrel 310 and the rear chamber 324 is fluidically connected to the front chamber 322. The valve control mechanism 364 includes an actuator 364A (e.g., a solenoid) and a valve member 366.

[0420] Actuator 364A is selectively operable to place valve member 366 in a closed position ( Fig. 20 , 22 and 23) and the open position ( Fig.21 and 24 ). In the closed position, the valve member 366 blocks the connecting passage 362, so that the rear chamber 324 is not fluidly connected to the front chamber 322 through the connecting passage 362. In the open position, the valve member 366 does not block the connecting passage 362, so that the rear chamber 324 is fluidly connected to the front chamber 322 through the connecting passage 362.

[0421] In use, as described above with respect to the pipette 200, when aspirating or dispensing in the first aspiration mode or the first dispensing mode, the valve member 366 is closed (i.e., the front plunger 342 is used but the rear plunger 344 is not used for aspiration and dispensing; Fig.23 ). Therefore, during these processes, the connecting passage 362 is sealed by the valve member 366, and the opening of the front seal 352 is sealed by the front plunger 342, so that the front chamber 322 is fluid-tightly isolated from the rear chamber 324. As described above, the pressure relief valve 355 is opened during these processes.

[0422] The pipette 300 may also be used to aspirate or dispense in a second aspiration mode or a second dispense mode, similar to the second aspiration mode or the second dispense mode described above with respect to the pipette 200 .

[0423] When aspirating in the second aspiration mode (ie, aspirating using both the front plunger 342 and the rear plunger 344; e.g. Fig.24 ), the valve member 366 is opened and the pressure relief valve 355 is closed. In this embodiment, the plunger member 340 is positioned at the first starting position at the beginning of the suction step. That is, the plunger member 340 is positioned so that the front plunger 342 extends through the front seal 352 and occupies the front chamber 322. As discussed above for the pipette 200, in the first starting position, the distal end of the plunger member 340 may be in the lowest position or deviate from the lowest position. When the plunger member 340 is in the first starting position, the valve member 366 is opened and the pressure relief valve 355 is closed, and then the plunger member 340 is translated along the retraction direction E9 for suction. The plunger member 340 translates so that the front plunger 342 travels through the first part SF1 of its stroke and enters the second part SF2 of its stroke. In this case, the rear chamber 324 will be fluidly connected to the front chamber 322 (via the connecting passage 362 ) during both stroke portions SF1 , SF2 , and both plungers 342 , 344 will contribute to suction in parallel throughout the stroke of the plunger member 340 .

[0424] To dispense in the second dispensing mode (i.e., dispensing using both the front plunger 342 and the rear plunger 344 at the same time), the plunger member 340 is translated along the extension direction E8, wherein the valve member 366 is opened and the pressure relief valve 355 is closed. The plunger member 340 is translated so that the front plunger 342 travels through the second portion SF2 of its stroke and the first portion SF1 of its stroke. In this case, the rear chamber 324 will be fluidly connected to the front chamber 322 (via the connecting passage 362) during both stroke portions SF1, SF2, and the two plungers 342, 344 will contribute to dispensing in parallel throughout the entire stroke SF.

[0425] By fluidly connecting the front chamber 322 and the rear chamber 324 during the second aspiration and dispense mode, the pipette 300 can initiate aspiration retraction of the plunger member 340 while the front section 342 is disposed in the front chamber 322 and the front seal 252 seals around the plunger member 340. As a result, the pipette 300 is able to reduce the dead volume in the rear chamber 324.

[0426] See also Figure 25-27 , which shows a pipetting system 401 according to other embodiments. Except as described below, the construction and use of the pipetting system 401 can be the same as the pipetting system 301.

[0427] The pipetting system 401 includes a pipette 400 instead of the pipette 300. The pipette 400 may be constructed and used in the same manner as the pipette 300 except for the following.

[0428] The pipette 400 includes a connecting valve 460 to replace the inter-chamber valve 360 ​​and the pressure release valve 355. The connecting valve 460 can be selectively operated to fluidly connect the rear chamber 424 to the front chamber 422 (via channels 468A, 468B on either side of the front seal 452) and the atmosphere (via channel 468C to the release port 468D). In the first valve state, the connecting valve 460 separates and closes the rear chamber 424 from the front chamber 422 and opens the rear chamber 424 to the pressure release port 468D leading to the atmosphere. In the second valve state, the connecting valve 460 opens the rear chamber 424 to the front chamber 422 and separates and closes the rear chamber 424 from the pressure release port 468D. The connecting valve 460 can be an electrically controlled valve.

[0429] In use, as described above with respect to the pipette 200, when aspirating or dispensing in the first aspiration mode or the first dispensing mode, the connecting valve 460 is set in the first valve state, (i.e., aspirating and dispensing using the front plunger 442 but not the rear plunger 444; Fig. 27 ).

[0430] When aspirating in the second aspiration mode (i.e., aspirating using both the front plunger 442 and the rear plunger 444; e.g. Fig.26), the connecting valve 460 is set in the second valve state. With the connecting valve 460 set in the second valve state, the plunger member 440 then translates in the retraction direction E9 for suction. The plunger member 440 translates so that the front plunger 442 travels through the first part SF1 of its stroke and enters the second part SF2 of its stroke. In this case, the rear chamber 324 will be fluidly connected to the front chamber 422 (via the connecting valve 460) during the two stroke parts SF1, SF2, and the two plungers 442, 444 will contribute to suction in parallel throughout the entire stroke of the plunger member 340.

[0431] To dispense in the second dispensing mode (i.e., dispensing using both the front plunger 442 and the rear plunger 444), the plunger member 440 is translated along the extension direction E8, wherein the connecting valve 460 is set in the second valve state. The plunger member 440 is translated so that the front plunger 442 travels through the second part SF2 of its stroke and the first part SF1 of its stroke. In this case, the rear chamber 424 will be fluidly connected to the front chamber 422 (via the connecting valve 460) during both stroke parts SF1, SF2, and the two plungers 442, 444 will contribute to dispensing in parallel throughout the entire stroke SF.

[0432] The pipette 400 further includes an annular seal (e.g., an O-ring) 453 mounted on the rear plunger 444 to move through the rear chamber 424 with the rear plunger 444. The seal 453 forms a sliding airtight pressure-resistant seal between the front end of the rear plunger 444 and the volume of the rear chamber 424 behind the front end of the rear plunger 444. In this way, the seal 453 can reduce the dead volume in the rear chamber 424 around the rear plunger 444. Pipettes according to other embodiments (e.g., pipettes 200 and 300) may include a seal corresponding to the seal 453.

[0433] According to another embodiment, the pipette 400 may be configured and / or operated so that the front plunger 442 extends through the front seal 452 in both the first portion SF1 of the plunger stroke and the second portion SF2 of the plunger stroke (wherein the front seal 452 maintains a seal around the front plunger 442 throughout the entire stroke). That is, also in the second suction mode (when the connection valve 460 is set in the second valve state and the rear chamber 424 is fluidly connected to the front chamber 422), the front seal 452 remains blocked by the plunger member 440 throughout the complete suction stroke SF1, SF2. In this way, the front plunger 442 will always be engaged in the front seal 452. Any pressure jump caused by deformation of the front seal 452 is thereby avoided. The front seal will be subjected to less mechanical forces, thereby improving the stability and reliability of the seal.

[0434] In order to achieve this effect or function of not unsealing or disengaging the front plunger 442 from the front seal 452, Fig.25 Compared with that shown in , the front plunger 442 can be extended or lengthened. In some embodiments, the length of the front plunger 442 is at least as long as the second portion SF2 of the plunger stroke.

[0435] In other embodiments, a pressure sensor (e.g., pressure sensor 256) may be positioned and configured to detect air pressure in a rear chamber (e.g., rear chamber 224), and the controller 20 may use pressure detection data from the rear pressure sensor to control operation of the pipette in the same manner as described for the front pressure sensor.

[0436] See also Figure 28-35 , shows an exemplary pipetting system 601 according to other embodiments of the present technology. The pipetting system 601 can aspirate and dispense liquid volumes within a liquid handling system. For example, the pipetting system 601 can replace the automated liquid handling system 10 ( Figure 1 ) for use with the pipetting system 101 in ). However, it should be understood that the disclosed methods, systems, and apparatus are not limited to the liquid handling system 10 or use therein, and the present disclosure may be applicable to other systems and applications that require aspiration and / or dispensing of liquid volumes.

[0437] The pipetting system 601 is configured to be used in each of an air displacement (AD) mode and a select displacement (PD) mode. In the AD mode, the pipetting system 601 operates to aspirate and / or dispense liquid using an air displacement pipette tip. In the PD mode, the pipetting system 601 operates to aspirate and / or dispense liquid using a positive displacement pipette tip.

[0438] The pipetting system 601 includes one or more pipettes 600. One or more pipettes can be installed on the pipette module 30. The pipette 600 can be constructed and operated in the same manner, and it should be appreciated that the description of the representative pipette 600 in the pipette 600 can be equally applicable to each of the pipette 600. If a plurality of pipettes 600 are provided, the pipette 600 can be operated independently of each other or in series. For the purpose of discussion, only a pipette is described below.

[0439] The pipetting system 601 includes a pipette 600, a controller 20, one or more air displacement (AD) pipette tips 660 ( Fig.34 ) and one or more positive displacement (PD) pipette tips 670 ( Fig.35 ). The pipette tips 660 , 670 are removable and replaceable on the pipette 600 and can be effectively disposable or consumable components of the pipetting system 601 .

[0440] See also Fig.28 and33 , and as discussed in more detail herein, the pipette 600 can be understood to have a longitudinal axis AA and a distal end 600A. The pipette 600 includes a tubular barrel 610, a pressure control system 606, a pipetting channel 602, a pipette orifice 604, and a tip adapter 614. The barrel 610 extends from the distal end 610A to the proximal end 610B. The barrel 610 includes an axle 612 that terminates at the distal end 610A. The tip adapter 614 is installed or formed in the distal end 610A. The pipette orifice 604 is located at the distal end 600A and is in fluid communication with the pipetting channel 602.

[0441] The pressure control system 606 includes a barrel 610 , a plunger 640 , a rear seal 654 , a plunger drive mechanism 658 , and a pressure sensor 656 .

[0442] See also Fig.33 , cylinder 610 includes cylinder passage 620. Passage 620 is longitudinally aligned with axis AA and extends from front end 620A to opposite rear end 620B. Passage 620 terminates at rear opening 620E at proximal end 610B of cylinder 610 and is communicated with it. Cylinder passage 620 includes cylinder chamber 621. Rear seal 654 is axially located between cylinder chamber 621 and rear opening 620E at proximal end 610B. Cylinder chamber 621 is communicated with pressure sensor 656 fluid via sensor port 656A.

[0443] The rear seal 654 may be an annular seal (eg, an O-ring).

[0444] The plunger 640 has a front or leading end 640A and an opposing rearward end 640B, as well as a rearward plunger section 644 .

[0445] The plunger 640 further includes an integral piston engagement feature 646 on the front end 640A. Fig.33 As shown in , the piston engagement feature 646 includes a slot 646A. For example, as shown, the slot 646A can be configured as a blind hole. The piston engagement feature can have any suitable configuration and is not limited to a slot or an opening.

[0446] The plunger 640 is mounted in the passage 620 such that the plunger 640 is slidably translatable relative to the barrel 610 along a plunger axis P5-P5 in an extension direction E10 and an opposite retraction direction E11. In some embodiments, the plunger axis P5-P5 is substantially coincident with the shaft axis AA.

[0447] The plunger 640 can slide to a fully extended position (eg Fig.31 ) and the fully retracted position (as shown in Fig.30 ) between the two positions (relative to passage 620, through the plunger travel). As described below, the plunger 640 can also slide into the Fig.28 The AD mode starting position shown in , or alternatively can be slid into Fig.31 The PD mode starting position shown in .

[0448] In the fully extended position ( Fig.31 ), a portion of the front plunger portion 642 extends distally beyond the distal end 600A of the pipette 600. By retracting the first portion SF1 ( Fig.31 ; starting from the fully extended position), the rear end 640B of the plunger 640 is located in front of the rear seal 654, so that the passage 620 leads to the rear opening 620E.

[0449] By retracting the second part of the stroke SF2 ( Fig.30 ; after the first portion SF1), the rear end 640B of the plunger 640 is located behind the rear seal 654, so that the rear plunger segment 644 is disposed in the rear seal 654. In this portion of the stroke, the rear O-ring 654 forms an airtight, pressure-resistant seal between the outer diameter of the rear plunger segment 644 and the barrel 610, which seals the passage 620 from the rear opening 620E. The rear plunger segment 644 is able to slide through the rear O-ring 654 while maintaining an airtight, pressure-resistant seal therebetween.

[0450] The plunger drive mechanism 658 is selectively operable to drive the plunger 640 in each of the extension direction E10 and the retraction direction E11. The plunger drive mechanism 658 may be a linear drive mechanism. The plunger drive mechanism 658 may include an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes a motor. In some embodiments, the linear drive mechanism 658 includes a spindle and a spindle nut connecting rod mechanism driven by a motor. In some embodiments, the plunger drive mechanism 658 is manually operable and does not include an actuator. For example, an extension, a lever, a knob or other manual drive features can be used to push and pull the plunger component 640.

[0451] In use, when the driving plunger 640 is driven through the stroke portion SF2 in the extension direction E10, the air volume is transferred from the cylinder chamber 621, and the effective volume of the cylinder chamber 621 is reduced. As the plunger 240 is driven in the retraction direction E11, the air volume in the cylinder chamber 621 is replaced, and the effective volume of the cylinder chamber 621 increases.

[0452] The plunger 640 can be formed of any suitable material or materials. In some embodiments, the plunger 640 is formed of stainless steel.

[0453] The barrel 610 can be formed of any suitable material. In some embodiments, the barrel 610 is formed of aluminum.

[0454] The tip adapter 614 is configured to removably secure pipette tips 660 and 670 to the end 600A of the pipette 600 in the same manner as described above with respect to the tip adapter 156 .

[0455] AD Pipette Tip 660 ( Figure 28-30 34) are examples of pipette tips that can be used with pipette 600 for aspiration and dispensing in AD mode. However, it should be appreciated that pipette tips of other designs may be used instead. AD pipette tip 660 may be a tubular body constructed in the same manner as described for AD pipette tip 160, and includes a distal end 660A, a proximal end 660B, a tip volume or passage 664, a pipetting orifice 662, an interface opening 663, a mounting section 666, and a liquid collection volume 665 corresponding to members 160A, 160B, 164, 162, 163, 166, and 165, respectively.

[0456] PD Pipette Tip 670 ( Fig.31 , 32 and 35) include a tubular tip body 678 and a piston 680 slidably mounted in the tip body 678. The piston 680 can be in an extended or ready position ( Fig.31 ) and the retracted position (e.g. Fig.32 )

[0457] See also Fig.35 , the tip body 678 extends from the distal end 670A to the proximal end 670B. The tip body 678 includes a front section 678A and a rear section 678B, which together define a tip volume or passage 674. The front section 678A defines a front chamber 679A, and the rear section 678B defines a rear chamber 679B, each forming a portion of the passage 674. The rear section 678B includes a mounting section 676 and defines an interface opening 673. A pipetting orifice 672 is defined in the distal end 670A. The passage 674 terminates at the interface opening 673 and the pipetting orifice 672.

[0458] The piston 680 includes a shaft 682, a base 684, and a plunger engagement feature 686. In some embodiments, the shaft 682, the base 684, and the plunger engagement feature 686 form a rigid single component. In some embodiments, the shaft 682, the base 684, and the plunger engagement feature 686 form an integral component together.

[0459] The shaft 682 extends from a proximal end 682B fixed to the base 684 to an opposite distal end 682A. In some embodiments, when the piston 680 is in the ready position, the distal end 682A is positioned at or near the pipetting orifice 672. The front side of the base 684 can have a convex or other contoured shape to match the facing contour of the tip body 678.

[0460] The plunger engagement feature 686 shown includes two or more opposing legs 686A. The plunger engagement feature 686 is configured to be received in the slot 646A to releasably secure the piston engagement feature 646A to the plunger engagement feature 686. In some embodiments, the legs 686A have a relaxed width greater than the width of the slot 646A and are resiliently deflectable.

[0461] The liquid handling system 10 and the pipetting system 601 can be used according to some methods as follows to aspirate and / or dispense one or more liquid samples. As described above, the pipetting system 601 is configured to be used in each of an air displacement (AD) mode and a selected displacement (PD) mode.

[0462] In general, in the AD mode, the AD pipette tip 660 is mounted on the pipette 600. The plunger 640 is driven to displace the air volume in the passage 620, and thereby correspondingly change the pressure in the pipetting channel 602, to aspirate a liquid sample from or dispense a liquid sample into a liquid collection volume 665. In the AD mode, the displacement of the plunger 640 displaces or expands the air volume within the barrel 614, which generates a pressure change, and an air column may (and usually does) exist and remains between the liquid sample in the liquid collection volume 665 and the distal end 640A of the plunger 640.

[0463] In general, in PD mode, the PD pipette tip 660 is mounted on the pipette 600. The piston 680 is driven via the plunger 640 to displace the air volume in the antechamber 679A and thereby correspondingly change the pressure in the antechamber 679A to draw a liquid sample from the liquid collection volume 675 or dispense the liquid sample into the liquid collection volume 165. In PD mode, the displacement of the piston 680 displaces or expands the air volume in the antechamber 679A, which generates a pressure change. In some embodiments, the distal end 682A of the piston 680 contacts the liquid sample in the antechamber 679A.

[0464] The operator or controller 20 can select and implement the operating mode (AD mode or PD mode). For example, the operator can use the HMI 22 to indicate to the controller 20 whether the pipette tip installed on the pipette 600 or to be installed on the pipette 600 is an AD-type tip 660 or a PD-type tip 670. The controller 20 can then automatically and programmatically operate the pipetting system 601 in a manner corresponding to the type of pipette tip (e.g., as described below).

[0465] The operation of the pipetting system in AD mode will now be described in more detail. Fig.28, the AD pipette tip 660 is mounted on the tip adapter 614. For example, the AD pipette tip may be held in a tray, and the controller 20 may operate one or more actuators 34A, 34B, for example, to position the pipette 600 above the AD pipette tip 660, then drive the pipette 600 downward to insert the tip adapter 614, and then lift the pipette 600 to remove the AD pipette tip 660 from the tray. During this lifting operation, the plunger 640 may be in the AD mode starting position.

[0466] Then, the controller 20 may operate one or more actuators 34A, 34B, for example, to position the pipette tip 660 above the liquid sample LS. The sample LS may be disposed in a container 36, for example. Fig.28 As shown in , if the plunger 640 is not in the AD mode starting position, it is placed in the AD mode starting position. Then, the controller 20 can operate the actuator 34B, for example, to lower the distal end 660A, and thereby lower the pipetting orifice 662 into the sample LS. In some embodiments, the distal end 660A and thereby the pipetting orifice 662 are immersed in the sample LS to at least a specified depth to ensure that the pipetting orifice 662 remains immersed in the sample during aspiration.

[0467] With the plunger 640 in the AD mode starting position and the pipette orifice 662 immersed, the drive mechanism 658 operates to translate the plunger 640 in the retraction direction E11 through some or all of the stroke portion SF2 and thereby pull the plunger 640 away from the pipette orifice 604. Throughout the stroke portion SF2 of the retraction stroke, the pipette channel 602 is sealed by engagement between the rear seal 654 and the rear section 644 of the plunger 640 (except at the pipette orifice 604).

[0468] The retraction of the plunger 640 expands the effective air volume of the barrel chamber 621, thereby generating a negative pressure at the pipette orifice 604. The negative pressure draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 665 (in the tip passage 664) of the pipette tip 660. The plunger 640 may be further retracted until the desired amount of the liquid sample volume LV is drawn into the collection volume 665. An air volume or air column AC may remain in the barrel chamber 621 between the tip passage 664 and the proximal end of the liquid sample volume LV and the pipette 600.

[0469] Then the pipette 600 can be used to dispense the liquid sample volume LV from the AD pipette tip 660. The drive mechanism 658 operates to move the plunger 640 along the extension direction E10, and thereby pushes the plunger 640 toward the pipette orifice 604. Throughout the extension stroke, the pipetting channel 602 is sealed (except at the pipette orifice 604) by the engagement between the rear seal 654 and the rear section 644 of the plunger 640. The extension of the plunger 640 transfers the air volume from the barrel chamber 621, thereby generating a positive pressure at the proximal end of the liquid sample volume LV. The positive pressure discharges the liquid sample volume LV from the liquid collection volume 665 through the pipetting orifice 662. The air column AC can be maintained between the proximal end of the liquid sample volume LV and the front end 640A of the plunger 640 until the liquid sample volume LV is fully dispensed.

[0470] In the illustrated embodiment, the pipette 600 is not provided with a front seal 252 ( Fig.17 ) corresponding front seal. Thus, the front portion of the barrel chamber 621 is not sealed from the rear portion of the barrel chamber 624. In some embodiments or applications, the PD tip 670 is used for smaller volumes and the AD tip 660 is used for relatively larger volumes. However, in other embodiments, the pipette 600 can be configured to operate in the AD mode, for example, as described for the pipette 200 ( Fig.14 ) as discussed in .

[0471] In some embodiments, when performing an aspiration or dispensing operation in the AD mode, the controller 20 receives a pressure signal indicating the air pressure in the pipetting channel 602 from the pressure sensor 656. The controller 20 may monitor the pressure in the pipetting channel 602 continuously.

[0472] As described above, the pipetting system 601 aspirates liquid samples by reducing the pressure in the pipetting channel 602, and dispenses liquid samples by increasing the pressure in the pipetting channel 602. However, the pressure in the pipetting channel 602 may fluctuate in response to other actions or conditions in the process, such as discussed above with respect to the pipetting system 101.

[0473] The operation of the pipetting system in PD mode will now be described in more detail. Fig.31 , the PD pipette tip 670 is mounted on the tip adapter 614. For example, the PD pipette tip 670 may be held in a tray, and the controller 20 may operate one or more actuators 34A, 34B, for example, to position the pipette 600 above the PD pipette tip 670, then drive the pipette 600 downward to insert the tip adapter 614, and then lift the pipette 600 to remove the PD pipette tip 670 from the tray.

[0474] During this pick-up operation, the plunger 640 is set in the PD mode starting position ( Fig.31 ). The pipette 600 is configured such that when the PD pipette tip 670 is fully mounted on the tip adapter 614 and the piston 680 is in its forward-most position relative to the tip body 678, the plunger engagement feature 686 is received in the groove 646A of the plunger 640. In this way, the piston 680 is releasably captured by or attached to the distal end of the plunger 640.

[0475] Then, the controller 20 may operate one or more actuators 34A, 34B, for example, to position the PD pipette tip 670 above the liquid sample LS. The sample LS may be disposed in a container 36, for example. Then, the controller 20 may operate the actuator 34B, for example, to lower the distal end 670A, and thereby lower the pipetting orifice 672 into the sample LS. In some embodiments, the distal end 670A and thereby the pipetting orifice 672 is immersed in the sample LS to at least a specified depth to ensure that the pipetting orifice 672 remains immersed in the sample during aspiration.

[0476] When the plunger 640 is in the PD mode start position and the pipetting orifice 672 is immersed, the drive mechanism 658 operates to translate the plunger 640 in the retraction direction E11 through some or all of the stroke portion SF1 and thereby pull the plunger 640 away from the pipette orifice 604. Throughout the retraction stroke, the pipetting channel 602 is not sealed because the rear seal 654 does not seal the rear section 644 from the rear opening 620E.

[0477] For example, Fig.32 , the retraction of the plunger 640 retracts the piston 680 in the retraction direction E11. The retraction of the piston 680 expands the effective fluid volume of the front chamber 679A, thereby generating a negative pressure at the pipetting orifice 672. The negative pressure draws the liquid sample volume LV of the liquid sample LS into the liquid collection volume 675 (in the front chamber 679A) of the PD pipette tip 670. The plunger 640 can be further retracted until the desired amount of the liquid sample volume LV is drawn into the collection volume 675. In some embodiments, there is no air column or air volume between the distal end 682A of the piston 680 and the liquid sample volume LV.

[0478] The liquid sample volume LV can then be dispensed from the PD pipette tip 670 using the pipette 600. The drive mechanism 658 operates to move the plunger 640 in the extension direction E10 and thereby push the plunger 640 toward the pipette orifice 604. Throughout the extension stroke, the pipetting channel 602 is not sealed because the rear seal 654 does not seal the rear section 644 from the rear opening 620E.

[0479] The extension of the plunger 640 extends the piston 680 in the extension direction E10 . The extension of the piston 680 displaces the fluid volume from the antechamber 679A, thereby displacing the liquid sample volume LV from the liquid collection volume 675 through the pipetting orifice 672 .

[0480] The pipetting system 601 and pipette 600 may be used to selectively and interchangeably use the AD pipette tip 660 and the PD pipette tip 670 to perform aspiration and dispensing procedures as described above.

[0481] For example, an AD pipette tip 660 may be mounted on the pipette 600 and used for aspirating and dispensing in the AD mode. The AD pipette tip 660 is then removed (e.g., ejected) from the pipette 600, and then a PD pipette tip 670 is mounted on the pipette 600 and used for aspirating and dispensing in the PD mode. Similarly, a PD pipette tip 670 may be mounted on the pipette 600, used for aspirating and dispensing in the PD mode, then removed, and replaced with an AD pipette tip 660 for aspirating and dispensing in the AD mode.

[0482] Any number of each type of pipette tip may be used in a series of procedures (e.g., the pipetting system 601 may use a series of AD pipette tips 660 for aspirating and dispensing in AD mode (or alternatively, PD mode)) before switching to using one or more PD pipette tips 670 for aspirating and dispensing in PD mode (or AD mode).

[0483] The user need not use the pipetting system 601 and pipette 600 with both the AD pipette tip 660 and the PD pipette tip 670 .

[0484] The pipette tips 660, 670 may be removed from the pipette 600 using any suitable technique and hardware. In some embodiments, the pipette 600 includes an ejector ( Figure 28-33 For example, an ejector sleeve) pushes the pipette tips 660, 670 away from the tip adapter 614. The pipette 600 may include an ejector mechanism corresponding to the ejector mechanism 151 of the pipette 100, for example.

[0485] In some embodiments, the PD pipette tip 670 is removed from the pipette 600 in the following manner. The plunger 640 is retracted in direction E11 until the base 684 of the piston 680 abuts the tip adapter 614. The plunger 640 is retracted in direction E11 until the piston engagement feature 646 is separated or disengaged from the plunger engagement feature 686, thereby releasing the piston 680. The PD pipette tip 670 is then removed using any suitable technique or mechanism to remove the tip body 678 from the tip adapter 614.

[0486] It should be appreciated that the described pipetting systems and pipettes (eg, pipetting system 601 and pipette 600) support both positive displacement pipetting and air displacement pipetting in a single pipetting channel. If two types of tips need to be used on one instrument, there is no need to change tools.

[0487] See also Fig.36 , which shows a pipetting system 701' according to another embodiment. Except as described below, the pipetting system 701' corresponds to the pipetting system 601 and has the same structure and operation. The pipetting system 701' includes one or more AD pipette tips 660 ( Fig.36 ), and also a pipette 700' and one or more PD pipette tips 770', which correspond to the pipette 600 and PD pipette tips 770', and are constructed and operate in the same manner except as described below.

[0488] In pipette 600, plunger 740' is lengthened or extended (compared to plunger 640) so that the rear portion of plunger 740' maintains an airtight seal with rear seal 754' throughout operation of pipette 700' during its AD and PD aspiration and dispensing processes, even when plunger 740' is fully extended (e.g., Fig.36 ). In addition, the tip body 778' of the PD pipette tip 770' includes a vent port 779C' that fluidly connects the back chamber 779B' of the tip passage 774' to the surrounding atmosphere. The vent port 779C' serves as a pressure release port or passage from the tip passage 774' between the piston 780' and the pipette 700'. In this way, the vent port 779C' prevents the translation of the piston 780' (in the tip body 778') and the plunger 740' (in the barrel 710') from generating negative or positive pressure in the back chamber 779B' that may interfere with the control of the piston 780'.

[0489] As described above, automated liquid handling systems can be used to transfer specific amounts of liquids, such as reagents or samples, between designated containers. Such systems can use pipettes to both aspirate and dispense liquids. The advantages of automating liquid handling processes include increasing throughput and efficiency of operations and eliminating human error, but may depend on the accuracy and repeatability of the pipetting operation.

[0490] Fig.37 is a schematic perspective view showing yet another example of an automated liquid handling system 901 according to some embodiments. The system 901 includes similar elements to the above-described pipetting system 101 and automated liquid handling system 10, and descriptions of similar elements may be omitted for the sake of brevity.

[0491] See also Fig.37, the automated liquid handling system 901 includes a robotic arm assembly 914, which includes an arm member 912 adapted to hold one or more pipettes 900 (which may include one or more of the pipette 100 or any other suitable one or more pipettes), and an actuator mechanism 934 (which may include Figure 1 The actuator mechanism 934 is configured to respond to the control circuit 920 (which may include a pipetting module positioning system 34A and one or more actuators 34B). Figure 1 The arm member 912 is moved along at least one axis by a control signal from a controller 20). Fig.36 In the example of, the robotic arm 914 has a first horizontal movement axis (X direction, for example, forward and backward), a second horizontal movement axis (Y direction, for example, left and right) and a vertical movement axis (Z direction, for example, upward and downward). The controller circuit 920 may include at least one processor 925, a memory 910 and an input / output (I / O) circuit 915, which are operable to generate and transmit control signals to the actuator mechanism 934 to move the arm member 912 toward or away from the surface of the liquid sample LS along at least one axis. More generally, the memory 910 may be a non-transitory storage medium configured to store computer-readable instructions therein, and the controller circuit 920 may be configured to execute computer-readable instructions stored in the memory 910 to perform operations as described herein.

[0492] Fig.37 Each of the pipettes 900 is shown with an attached pipette tip 960. The pipette tip 960 may be similar to the pipette tip 160 described herein in some aspects. For example, the pipette tip 960 may include a pipette orifice or opening 962 that provides access to the pipette 900 through the tip 960, wherein the access may be used as a liquid sample collection volume. The pipette tip 960 may be an air displacement tip or a positive displacement tip as described herein. The pipette tip 960 may be removed from the pipette tip holder and moved vertically upwards in an automatic manner by the mechanical arm assembly 914 under the control of the controller circuit 920.

[0493] Other embodiments described herein may arise from the recognition that as liquid is drawn by the pipette 900 (in the liquid handling system 901 or in a stand-alone pipette 900), the volume of the liquid in the container decreases. If the size of the container, etc. is unknown, the placement of the pipette tip 160 may affect whether the correct amount of liquid can be effectively drawn into the pipette 900 (i.e., if the pipette tip 160 is positioned too high relative to the liquid level of the liquid, the desired amount of liquid may not be drawn). Thus, effective pipetting may require knowledge of variables such as the container from which the liquid is drawn, the type of liquid, the container into which the liquid is to be transferred, etc.

[0494] Capacitive liquid level detection (LLD) can be used to determine the difference in level between the sample liquid immersed and the sample liquid floating out. When the liquid level is not known to the instrument, liquid level detection can be used to detect the fill level at the beginning of aspiration or dispensing. The volume aspirated or dispensed can be calculated based on the liquid level difference and the cross-sectional area of ​​the vessel. However, these methods may not be accurate for small volumes and large cross-sectional areas. Parasitic capacitance may also cause inaccurate determination of the amount of sample or liquid volume processed.

[0495] Embodiments described herein provide a conductive pipette tip 960 configured to provide a control window for axial movement of one or more pipettes 100. In contrast to some prior art techniques, which may use a conductive tip that detects the surface of the liquid when in contact with the liquid, embodiments described herein allow for dynamic liquid level detection based on capacitance changes indicated by signals from a conductive electrode 1002 on the pipette tip 960, in some embodiments, independent of the shape and / or size of the liquid container.

[0496] The conductive pipette tip 960 includes an arrangement of a conductive region 1002 and a non-conductive region 1001 . Fig.38 is an enlarged side view showing a conductive pipette tip 960 according to some embodiments described herein. The pipette tip 960 includes a tip member 1000 having a distal end 960A having an opening or orifice 962 sized and configured for aspirating and / or dispensing liquid and an opposing proximal end 960B configured for connection to an end portion of a pipette 900. A conductive electrode 1002 extends along a surface of the pipette tip 960 (e.g., on an outer surface of the tip member 1000, and / or includes a portion integrally incorporated into a sidewall of the tip member 1000). The tip member 1000 includes a non-conductive or electrically isolated tip "bottom" or "pod" 1001 located at the end 960A of the pipette tip 960, between the pipetting hole or opening 962 and the conductive electrode 1002. The learning circuit may be implemented by (or may otherwise communicate with) a controller circuit 920 that controls the axial movement of the pipette 900 (e.g., along the Z-axis or depth direction of the liquid to be drawn). As described herein, the learning circuit may be configured to detect and continuously monitor the capacitance change caused by contact between the conductive electrode 1002 and the liquid. The inner surface of the tip component 1000 defines a passage through the pipette tip 960 and may be used as a liquid sample collection volume. The inner surface of the tip component 1000 may be non-conductive, and in some embodiments, the conductive electrode 1002 may be configured as a single electrode.

[0497] See also Fig.38, the isolated tip bottom 1001 protrudes from the conductive electrode 1002, or is otherwise located between the conductive or functional portion of the conductive electrode 1002 and the opening 962 at the end 960A of the pipette tip 1000. The outer surface of the isolated tip bottom 1001 may be free of the conductive material or layer forming the conductive electrode 1002. For example, in some embodiments, the lower portion of the conductive electrode 1002 adjacent the opening 962 may include a coating of non-conductive material thereon to provide the isolated tip bottom 1001. In some embodiments, the isolated tip bottom 1001 may be provided by a non-conductive portion of the tip member 1000 that extends beyond the conductive electrode 1002. The isolated tip bottom 1001 may extend a length or distance D of about 2 millimeters (mm) or more. The opposite end 960B of the tip member 1000 includes an electrical interface (shown as conductive element 1004) connected to the conductive interconnect 1003, and a mechanical interface for connecting to the pipette 900 (e.g., the end portion 112A of the pipette 100 described herein).

[0498] Conductive connection 1003 extends along tip member 1000 and electrically connects conductive electrode 1002 to conductive element 1004 for signal transmission (e.g., transmitting signals from conductive electrode 1002 to controller circuit 920). Conductive portions 1002, 1003, 1004 of tip member 1000 may be copper (Cu) or any suitable conductive material.

[0499] Fig.39A , 39B and 39C is shown Fig.38 Cross-sectional views of embodiments 1000a, 1000b, 1000c of the tip component 1000. Fig.39A As shown in the embodiment of , the conductive electrode 1002 and the conductive interconnect 1003 can extend along the outer surface of the tip component 1000a between its opposite ends 960A and 960B to define a conductive "wall" of the tip component 1000a, which in some embodiments extends on opposite side walls, or even completely around the side walls of the tip component 1000a. In some embodiments, as Fig.39B As shown in , the conductive interconnect 1003 may be injection molded or otherwise at least partially integrally bonded or embedded into one or more sidewalls of the tip component 1000b, rather than extending along the outer surface of the tip component 1000b. Fig.38 and 39CAs shown in , the conductive electrodes 1002 and / or the conductive interconnects 1003 may not extend completely around the perimeter or circumference of the tip component 1000c. More generally, the tip component 1000 includes one conductive region 1002 located at the bottom or distal end 960A, one conductive region 1004 located at the top or proximal end 960B (e.g., located inside the tip component 1000), and the conductive interconnects 1003, which may be embedded in the surface of the tip component 1000 or may be located on the exterior or outer surface of the tip component 1000.

[0500] The conductive electrode 1002 adjacent the end 960A of the tip member 1000 may be provided in a variety of different shapes. Fig.40A , 40B 40C are cross-sectional views of various "crown" shaped embodiments 1002a, 1002b, 1002c of the conductive electrode 1002. The crown shape of the conductive electrodes 1002a, 1002b, 1002c includes multiple end portions that protrude toward the non-conductive tip base 1001, so that when immersed in the liquid to be dispensed, the conductive surface area can increase with the immersion depth. More generally, the shape of the conductive electrode 1002 can define a surface area that varies with the distance from the opening 962. As further described in the examples below, this feature can support dynamic LLD ratio regulation in conductive liquids.

[0501] The controller circuit 920 may detect contact between the liquid to be drawn and the conductive electrode 1002 as capacitance based on a signal received from the conductive electrode 1002 . Fig.41 900c is a graph showing a variation in capacitance 900c with a vertical position 912z of a pipette tip 960 comprising a conductive electrode 1002 and a non-conductive tip base 1001 relative to the surface of a liquid LS, according to some embodiments.

[0502] See also Fig.41 , as the end 960A of the tip member 1000 moves toward the surface of the liquid LS (indicated by the vertical position 912z), the capacitance 900c indicated by the signal from the conductive electrode 1002 is substantially constant. When the non-conductive tip base 1001 contacts the liquid surface at time t=1 (as shown in (1)), the capacitance 900c remains substantially constant. The capacitance 900c remains substantially constant until the conductive electrode 1002 of the tip member 1000 contacts the surface of the liquid LS at time t=2 (as shown in (2)), at which time the signal from the electrode 1002 indicates a nearly instantaneous increase in capacitance 900c. Even though the immersion depth of the conductive electrode 1002 below the surface of the liquid LS increases at time t=3 (as shown in (3)), the increase in capacitance 900c remains substantially constant.

[0503] Still viewing Fig.41, when contact is lost between the conductive electrode 1002 and the surface of the liquid LS at time t=6 (e.g., when the liquid level drops below the conductive electrode 1002 due to insufficient movement of the robotic arm 912 to maintain contact between the conductive electrode 1002 and the liquid as the liquid level drops or rises due to aspiration or dispensing, as shown in (4)), the signal from the electrode 1002 indicates a nearly instantaneous decrease in capacitance 900c. That is, contact (or lack of contact) between the conductive electrode 1002 and the surface of the liquid LS may appear as a sudden change or jump in the detected capacitance. The detected capacitance may change or vary within a range of a few picofarads (pF). For example, the change or difference in capacitance detected between contact and loss of contact between the conductive electrode 1002 and the surface of the liquid LS may vary within a range of about 0.1 to 15 pF, such as about 0.5 to 10 pF or about 1 to 3 pF. In the example of FIG. 40 , the detected capacitance change is about 1.4 pF for contact and loss of contact between the conductive electrode 1002 and the liquid LS.

[0504] In some embodiments, the capacitance indicated by the signal from the electrode 1002 may not change based on the depth of immersion of the conductive electrode 1002 below the surface of the liquid LS (as shown by the substantially constant capacitance 900c between times t=3 and t=6). That is, the detected capacitance may be substantially independent of the contact area between the conductive electrode 1002 and the liquid LS, such that changes in immersion depth may not change the measured or indicated capacitance.

[0505] In other embodiments, the capacitance indicated by the signal from the conductive electrode 1002 may change or vary more gradually based on the depth to which the conductive electrode 1002 is immersed below the surface of the liquid, for example, where the surface area of ​​the conductive electrode shapes 1002a, 1002b, 1002c increases with immersion depth, such as Fig.12 A to 12C are shown in the examples.

[0506] Thus, the configuration of the conductive electrode 1002 and the non-conductive tip base 1001 in the exemplary tip assembly 1000 described herein can implement the capacitive sensor as an integrated circuit connected to the pipette tip 960. For example, the capacitive sensor can be integrated on a printed circuit board (e.g., which can also include the controller circuit 920 and associated motor drive circuits, readout circuits, etc.), and can be routed to the tip adapter of the pipette 900 to connect to the conductive contacts 1004 of the pipette tip 960 via a single conductive wire or cable. In some embodiments, the capacitive sensor can be configured to indicate capacitance at a desired data acquisition rate (e.g., about 1000 samples per second) with a resolution of up to about 1 femtofarad (fF). The amplitude and time resolution can allow for precise detection of liquid levels.

[0507] Thus, the controller circuit 920 can dynamically detect and continuously monitor changes in the level of the liquid based on changes in the detected capacitance due to contact (or loss of contact) between the conductive electrode 1002 and the liquid. The capacitance detected from the conductive electrode 1002 on the tip member 1000 can be used as a feedback signal or control loop to provide dynamic liquid level detection and liquid level tracking without losing contact between the pipetting orifice 962 of the pipette tip 960 and the liquid. In particular, based on the capacitance indicated by the signal from the conductive electrode 1002, the controller circuit 920 can be configured to generate and transmit a control signal to the actuator mechanism 934 of the mechanical arm assembly 914. The control signal can be changed based on the change in the detected capacitance indicated by the signal from the conductive electrode 1002 to move the arm member 912 holding one or more pipettes 100 toward or away from the surface of the liquid along at least one axis (e.g., the Z axis), thereby maintaining contact between the pipette tip 960 and the liquid, so that the non-conductive tip bottom 1001 of the tip member 1000 can always be immersed, regardless of how the liquid level changes.

[0508] To provide dynamic liquid level detection (LLD) and tracking, the non-conductive tip bottom 1001 of the tip assembly 1000 is sized to be larger than the desired control window, e.g., extending a length or dimension D of about 2 mm or more. Thus, the isolated tip bottom 1001 acts as a buffer between the conductive electrode 1002 and the surface of the liquid to be aspirated, and is therefore immersed before the conductive electrode 1002 contacts the liquid surface. Thus, the isolated tip bottom 1001 transfers the jump in capacitance 900c from the initial immersion of the tip bottom 1001 (as shown in (1) in FIG. 40 ) to the immersion or contact of the conductive electrode 1002 (as shown in (2) in FIG. 40 ).

[0509] The delay in the change in capacitance 900c due to the protruding distance D of the non-conductive tip bottom 1001 can be used to keep the pipette tip 960 immersed in the liquid. When the liquid level in the container decreases, before the opening 962 loses contact with the liquid surface, the loss of contact between the liquid and the conductive electrode 1002 can be identified based on the detected change in capacitance 900c. In response, the control arm assembly 912 moves one or more pipettes 100 along the Z axis so that the pipette tip 960 follows the liquid level during aspiration or dispensing while keeping the opening 962 submerged or immersed in the liquid.

[0510] Thus, the control signal provided to the actuator mechanism 934 may vary based on the change in the detected capacitance indicated by the signal from the conductive electrode 1002. In some embodiments, the movement of the arm member 912 may be gradual or continuous. For example, based on the previous movement along the Z-axis, the controller circuit 920 may control the movement along the Z-axis to be more continuous or smooth.

[0511] In some embodiments, the direction of movement of the arm member 912 along the Z-axis may depend on the mode, which may further reduce oscillations and smooth movement. For example, in the aspiration mode, the arm member 912 may be constrained so as to only allow the pipette tip 960 to move in a downward direction toward the liquid, while in the dispensing mode, the arm member 912 may be constrained so as to only allow the pipette tip 960 to move in an upward direction away from the liquid. That is, the actuator mechanism 934 may have a first operating mode in which the arm member 912 is constrained to move toward the liquid surface along at least one axis during aspiration, and a second operating mode in which the arm member 912 is constrained to move away from the liquid surface along at least one axis during dispensing.

[0512] In some embodiments, the controller circuit 920 may calculate or estimate the volume of liquid sucked or dispensed based on the distance of movement of the arm member 912 along the Z axis, and may control subsequent movement of the arm member 912 along the Z axis based on the calculated or estimated volume sucked or dispensed. That is, the controller circuit 920 may use the change in capacitance and the previous movement of the arm member 912 along the z axis to estimate the amount of liquid that has been dispensed or sucked, and may generate a control signal to the actuator mechanism 934 to predictively move the arm member 912 in response.

[0513] Thus, the controller circuit 920 uses the signal from the conductive electrode 1002 to measure or determine the capacitance, and monitors the change in capacitance to predict (e.g., based on a jump or sudden change in the detected capacitance due to a loss of contact between the conductive electrode 1002 and the liquid) that the non-conductive tip bottom 1001 of the pipette tip 960 will soon lose contact with the liquid, thereby continuously and dynamically monitoring the liquid level as the liquid level changes. In response, the controller circuit 920 transmits a control signal to the actuator mechanism 934 to move the arm member 912 holding one or more pipettes 100 along the Z axis (e.g., downward / toward the liquid in the aspiration mode, or upward / away from the liquid in the dispensing mode) to provide dynamic liquid level tracking.

[0514] The extension of the non-conductive tip base 1001 below or beyond the portion of the conductive electrode 1002 that provides the capacitive detection signal allows the controller to move the arm assembly 912 to follow the liquid level while keeping the opening 962 of the pipette tip 960 submerged or immersed in the liquid (due to the cushioning provided by the distance D between the conductive electrode 1002 and the other end of the non-conductive tip base 1001).

[0515] The dynamic level detection and tracking described herein can be used for a variety of liquid solutions, including conductive liquids and non-conductive liquids, regardless of the shape or size of the liquid container. For example, the embodiments described herein can be used (but are not limited to) with ethanol, MilliQ water, and saline buffer solutions. The control signal provided to the actuator mechanism 934 can be adjusted continuously (e.g., for non-conductive liquids), or can be adjusted in a stepwise manner (e.g., for highly conductive liquids).

[0516] Other embodiments described herein may arise from the recognition that during or after aspirating liquid in a pipetting or other liquid handling system, some liquid will evaporate in the channel, thereby increasing the volume of trapped air, which may result in less liquid being aspirated than expected. Without evaporation compensation, precision and accuracy in pipetting performance is not possible.

[0517] Therefore, the embodiments described herein provide a method for detecting whether there is evaporation (e.g., during or after the absorption of liquid) in the pipetting channel. If the pressure increase is detected in the channel, the system described herein is configured to automatically deploy countermeasures to prevent evaporation (or reduce the evaporation rate). Some conventional techniques may need to analyze and develop liquid categories, wherein for each liquid category developed, compensation parameters may need to be determined and updated in software. In contrast, some embodiments described herein do not need to distinguish between liquid categories and / or the evaporation amount expected for each liquid category in order to quantify and / or compensate for evaporation.

[0518] Fig.42 , 43A 43B schematically illustrate evaporation detection in a pipette tip of an automated pipetting system 1101 according to some embodiments described herein. The system 1101 includes similar elements to the above-described pipetting systems 101, 901 and automated liquid handling system 10, and descriptions of similar elements may be omitted for brevity.

[0519] See also Fig.42 and 43A , the system 1101 includes a pipette 1100, one or more pressure sensors 1156 coupled to a channel 1102 of the pipette 1100, and a controller or control circuit 1120. The controller circuit 1120 may include one or more controllers 20,920 and associated processors 925, memory 910, and I / O circuits 915 described herein. The one or more pressure sensors 1156 are fluidically coupled to the pipetting channel 1102. In some embodiments, the pressure sensor 1156 is located in or along the pipetting channel 1102 (similar to or including Fig.141100) or an in-line pressure sensor in a pipette tip 1160 attached to the distal end of the pipette 1100. In other embodiments, the channel 1102 is fluidly connected to the pressure sensor 1156 via a sensor port. The pipette tip 1160 may be removable or replaceable (such as the pipette tip 160, 960 described herein), or may be integrally incorporated into the pipette 1100. More generally, the pipette 1100 may be of any suitable type or design, and may include any suitable plunger configuration (which may include any pipette and plunger configuration described herein). The drive mechanism 1128 (including one or more actuators) may drive the plunger 1140 to absorb, dispense, and / or perform compensation operations as described herein in response to a control signal from the controller circuit 1120. The drive mechanism 1128 may be any drive mechanism described herein (e.g., 128, 148) and / or may operate in a manner similar to any drive mechanism described herein.

[0520] The operations described herein may be performed by or through the controller circuit 1120. The controller circuit 1120 receives a pressure signal from the pressure sensor 1156 indicating the pressure in the pipetting channel 1102. In particular, based on the pressure signal from the pressure sensor 1156, the controller circuit 1120 may determine a quantitative measurement of the pressure (or pressure differential) in the channel 1102. The pressure measurement may indicate the pressure of air or one or more other gases in the channel 1102. The controller circuit 1120 may operate the drive mechanism 1128 to control the movement of the plunger 1140 in response to a signal from the pressure sensor 1156 (e.g., via the feedback loop 1150) to perform the aspiration, dispensing, and / or compensation operations described herein.

[0521] See also Fig.43A, the controller circuit 1120 may detect evaporation of the liquid in the channel based on the pressure indicated by the signal from the pressure sensor 1156. For example, after aspirating the liquid, the liquid sample LS may occupy a volume V1 (filling level h1) in the pipette tip 1160 attached to the distal end of the pipette 1100, where the initial pressure in the channel 1102 is p1. The controller circuit 1120 removes the pipette tip 1160 from the container including the liquid volume, for example, by controlling the movement of the arm member 912 away from the container of the liquid volume via the actuator mechanism 934 described herein. If evaporation occurs, the number of gas phase molecules in the channel 1102 (and the volume between the plunger 1140 and the liquid sample LS) will increase. As a result, a portion of the liquid sample LS pushes through the opening 1162 in the pipette tip 1160 and forms a bead LB, causing the volume V2 (and the filling level h2) occupied by the liquid sample LS in the pipette tip 1160 to decrease. The surface tension at the surface of the bead LB increases the internal pressure p2 in the channel 1102.

[0522] Fig.43B An example of the formation of beads LB due to evaporation of EtOH solution LS is shown for a target volume of 1 μl and a tip volume of 10 μl. Fig.43B As shown in , the liquid sample LS is completely contained in the pipette tip 1160 after the pipette tip 1160 is removed from the liquid volume but before evaporation occurs. With the pipette tip 1160 removed from the liquid volume, the opening 1162 is sealed by the action of surface tension, so that the pressure change in the channel 1102 can be attributed to evaporation. As evaporation occurs, the pressure in the channel 1102 may increase, so that the liquid sample LS is forced to flow out of the opening 1162 in the tip 1160 to form a bead LB as long as the radius of the bead decreases. As evaporation continues, the bead reaches a hemispherical shape (represented by radius r1), at which time the bead radius begins to increase (represented by radius r2), and the pressure in the channel 1102 decreases again.

[0523] The controller circuit 1120 measures the pressure and the transferred volume within the channel using signals from the one or more pressure sensors 1156. More specifically, the signals from the one or more pressure sensors 1156 can be used to monitor the pressure change within the channel 1102 after aspiration, which is caused by the volume change caused by evaporation and bead formation (e.g., from volume V1 before evaporation to volume V2 after evaporation continues for a period of time).

[0524] See below Fig.44A and 44B The chart and Fig.45The flowchart of FIG. 11 describes operations that the controller circuit 1120 may perform to control the position and aspiration of the pipette 1100 and to detect changes in pressure in the detection channel 1102 to detect evaporation. Fig.44A and 44B In the graph of , line 4401 represents the gauge pressure (in Pascals (Pa)) determined based on the signal from one or more pressure sensors 1156, while line 4402 represents the volume transferred by the plunger 1140 (in microliters (μl)).

[0525] See also Fig.44A , 44B and Fig.45 , the pipette 1100 moves (e.g., via the arm member 912 in response to a control signal provided to the actuator 934) so ​​that the pipette tip 1160 contacts the liquid volume to be aspirated, as shown at step 1111. Capillary effects may force liquid into the pipette orifice 1162 in response to the contact (thereby increasing the pressure in the pipetting channel 1102, as shown at step 1112). As shown at step 1112a, the liquid sample LS is aspirated into the pipette 1100 by driving the plunger 1140 in response to a control signal from the controller circuit 1120. At step 1113, the aspiration is completed, and at step 1114, the pipette tip 1160 is removed from the liquid volume (e.g., via the arm member 912 and the actuator 934). When the pipette tip 1160 is in the air, the orifice 1162 may be substantially sealed by the surface tension of the liquid sample LS, so that the pressure change in the channel 1102 may be due to evaporation. As shown at step 1115, while the tip 1160 is in air or otherwise removed from the liquid volume, the pressure change dp / dt over time is monitored based on signals from one or more pressure sensors 1156. At step 1116, the plunger 1140 may also be moved (e.g., by the drive mechanism 1128 in response to a control signal from the controller 1120) in the channel 1102 by a relatively small distance or displacement ΔV. Dis , to detect the elasticity of the system (e.g., a combination of air column elasticity and surface tension). The volume change ΔV caused by the displacement of the plunger 1140 Dis May be small enough to prevent liquid bead LB from dripping from tip 1160.

[0526] If the signal from the one or more pressure sensors 1156 indicates an increase in pressure over time (e.g., between 1114 and 1116), evaporation of the liquid sample LS can be detected. At step 1115, the pressure can be monitored immediately after the tip 1160 is removed from the liquid volume (i.e., before bead formation LB) to ensure accuracy.

[0527] In addition to detecting evaporation, the evaporation rate is calculated at step 1118, and in some embodiments, the suction error caused by evaporation is also estimated. For example, the evaporation rate can be calculated based on the pressure change indicated by the pressure signal monitored at step 1115 over time (i.e., the slope of line 4401), and in some embodiments, it is also combined with the pressure change caused by the movement of the plunger 1140 measured at step 1116. The evaporation rate may be proportional to the change in pressure over time dp / dt. Fig.44A As shown in , the rate of change of pressure measurement (and therefore the evaporation rate) can be determined by a straight line fit of the pressure curve between the removal of the pipette tip 1160 from the liquid volume at step 1114 and the displacement of the piston or plunger at step 1116.

[0528] As described above, in some embodiments, the evaporation rate may be calculated using additional measurements of the pressure change caused by the movement of the plunger 1140 at step 1116. In particular, at step 1117, the volume change ΔV caused by the plunger displacement at step 1116 is measured. Dis The pressure change Δp caused Dis (indicated by the pressure signal of one or more pressure sensors 1156), and using this change Δp Dis The evaporation rate is calculated at step 1118. That is, Fig.44B As shown in FIG. 1 , a small volume change ΔV is generated in response to the movement of the plunger 1140 in the channel 1102. Dis The resulting pressure response Δp Dis The following equation can be used to calculate the evaporation rate E = dVe / dt from the pressure change rate measurement: Note that the described method does not require prior knowledge of the type of liquid being drawn to determine the evaporation rate. Dis / Δp Dis The dependence of the dpe / dt terms on surface tension cancel each other out, thus eliminating the liquid class dependence.

[0529] The evaporation rate can be determined by continuously controlling the position or displacement of the plunger 1140 in the channel 1102 based on the pressure indicated by the pressure signal, so that the pressure in the channel 1102 remains substantially constant. Under constant pressure conditions, the evaporation rate is directly given by the displacement rate of the plunger 1140, as shown in the following equation:

[0530] Thus, system 1101 can detect that vaporization has occurred based on the pressure (or pressure change) in channel 1102 or tip 1160 indicated by a signal from one or more pressure sensors 1156. Fig.44A and 44B The graph of FIG. 1 shows an example operation of experimental data using EtOH as the liquid sample LS, but it should be understood that the detected pressure change (and calculated evaporation rate) may be significantly different based on the material of the liquid sample LS. 2 O as liquid sample LS may cause response Fig.45 The pressure change and calculated evaporation rate of the operation are significantly smaller. In some embodiments, comparison of the difference in pressure change and / or evaporation rate can be used to identify the liquid sample LS in the pipette tip 1160. However, in the example operation described herein, the evaporation rate can be calculated independently of the surface tension or type of the liquid of the drawn liquid sample LS. That is, evaporation detection and evaporation rate calculation as described herein can be performed based on pressure change rate measurement without determining the surface tension of the liquid sample LS, and without having to know or identify the liquid type of the liquid sample LS in advance.

[0531] The evaporation rate E (as calculated at step 1118) and the aspiration time (i.e., the duration of the aspiration between steps 1112 and 1113) can be used to estimate the additional gas or vapor volume generated by evaporation during the aspiration, also referred to herein as the evaporation volume (Vevap). The evaporation volume Vevap may be equal to or otherwise indicate the amount of aspiration shortfall caused by evaporation. Therefore, embodiments described herein may use the estimated evaporation volume Vevap as a relevant parameter to determine whether the evaporation rate is tolerably low or whether the evaporation is greater than a predetermined threshold (TH) for reducing or compensating for evaporation. Such a determined threshold may vary depending on the desired accuracy; for example, if an accuracy of 5% is acceptable for a particular dispensing application, an evaporation volume less than 5% of the target volume may be tolerable, while an evaporation volume greater than 5% of the target volume may require compensation.

[0532] See again Fig.42 , the feedback loop 1150 can be used to automatically or programmatically perform compensation operations, such as based on calculating the evaporation rate from the pressure signal and comparing the evaporation rate to a threshold value. For example, if the evaporation rate E is higher than the threshold value TH, the controller circuit 1120 can initiate one or more countermeasures (e.g., by repeating the suction and by operating the drive mechanism 1128 to adapt the suction of the plunger 1140) to compensate for the detected evaporation.

[0533] Fig.46A and 46B 2 is a diagram showing the respective periods of absorption (e.g., during Fig.45 between frames 1112 and 1113) and after the tip is removed (e.g., Fig.45114 of the flow chart of the evaporation compensation operation. The compensation may include a plurality of operations performed by the controller circuit 1120 to compensate for evaporation based on the pressure signal from the pressure sensor 1156. For example, the evaporation compensation operation may include performing a pre-wetting operation (drawing and dispensing a certain amount of liquid before drawing the liquid for delivery), adapting one or more aspiration parameters (e.g., over-drawing a certain amount of liquid volume to compensate for under-drawing due to evaporation), and / or controlling the movement of the plunger 1140 in the pipetting channel 1102 (e.g., maintaining a defined or predetermined constant pressure in the pipetting channel 1102 and / or the pipette tip 1160 to avoid dripping).

[0534] See also Fig.46A , absorb (for example, in Fig.45 The calculation of the aspirated volume Va at step 1119a may take into account the expansion of the air column ( Fig.16 AC in the above example. For example, the change in the suction volume Va may be equal to or proportional to the change in the volume of the air column. In some embodiments, the suction volume Va may be calculated as follows: Va=(pi-pa)V 0 / pa+AΔx Where pi / pa represents the pressure inside / outside the channel, V 0 represents the initial air column volume, A is the plunger cross-sectional area, and Δx represents the distance the plunger moves.

[0535] At step 1121, the calculated suction volume Va is compared to the desired or target volume (Vtarget). In some embodiments, a control loop may be used to reduce or minimize the difference between the suction volume Va and the target volume Vtarget. For example, the controller circuit 1120 may include a proportional-integral-derivative controller (PID controller) that uses a control loop mechanism using feedback to continuously calculate an error value as the difference between the desired target volume Vtarget and the suction volume Va, and correct the plunger movement. In particular, if the comparison of the suction volume Va with the target volume Vtarget exceeds a desired error threshold (i.e., if Va-Vtarget>errorTH), a compensation operation may be performed at step 1123a. For example, one or more suction parameters may be adapted to reduce the suction error, and the suction may be changed or repeated based on the adapted parameters. A method for calculating the suction volume Va at step 1119a, comparing the suction volume Va with the target volume Vtarget at box 1121a, and using the comparison result (Va-Vtarget) as an input to the control loop to control or correct the plunger movement is provided. Fig.46AThe operation may be performed continuously during aspiration in order to reduce or minimize the difference between the calculated aspiration volume Va and the target volume Vtarget. Fig.46A The operation is performed with the tip immersed (e.g. Fig.45 The calculation at step 1119a is based on the known plunger position and the air volume expansion (or contraction) inferred from the measured gauge pressure. Fig.46A The operation can be performed independently of evaporation and can therefore be performed even if the evaporation rate has not been evaluated in a previous pipetting step.

[0536] Additionally or alternatively, Fig.46B In the example of FIG. 1 , the amount of the pipette tip 1160 may be determined based on the amount of the pipette tip 1160 removed from the liquid volume (e.g., Fig.45 The pressure change indicated by the signal from the pressure sensor 1156 at step 1114 is calculated at step 1119b to calculate the suction volume Va (or, if previously performed Fig.46A At this point, due to the effect of surface tension, the effect of unexpected liquid inflow during tip withdrawal will be reflected in the aspiration volume Va. If, at step 1121b, the (re)calculated aspiration volume Va is less than the target volume Vtarget by a sufficient margin, one or more aspiration parameters are adjusted at step 1123b and the aspiration is repeated. For example, a larger amount of liquid may be over-aspirated (based on a calculated or estimated evaporation rate) to compensate for the initial under-aspiration caused by evaporation, thereby ensuring that the desired amount of liquid is delivered. In some cases, it may be sufficient to report or record the aspiration error (Va-Vtarget).

[0537] At step 1122, the calculated evaporation rate E (or evaporation volume Vevap) is compared with a threshold value TH. For example, the threshold value TH may be based on volume so as to be compared with the calculated evaporation volume Vevap. If the evaporation volume or rate is below the threshold value TH, no action is taken. If the evaporation rate or volume exceeds the threshold value TH, one or more compensation operations are performed at step 1123b, and the aspiration volume Va is recalculated at step 1119b. Thus, the evaporation rate may be considered in the calculation of Va. Based on the aspiration volume Va recalculated at step 1119b, the system may decide and perform compensation measures at step 1123b to improve accuracy (e.g., repeating the pipetting step, pre-wetting, adjusting parameters, or simply recording or reporting deviations from the target volume Vtarget).

[0538] Fig.46A and 46B The operations shown in can be performed in combination or independently of each other. That is, Fig.46A and 46BThe operations can be performed sequentially or during the absorption Fig.46A without further execution after the tip is removed Fig.46B The operation can be performed after the tip is removed. Fig.46B Operations other than those performed during absorption Fig.46A operation.

[0539] As described above, the evaporation compensation operation at steps 1123a, 1123b may include, but is not limited to, pre-wetting, adapting one or more aspiration parameters, and / or controlling plunger movement. For example, a pre-wetting operation may be performed at steps 1123a, 1123b to reduce or prevent evaporation in the tip 1160. Pre-wetting may increase the humidity within the pipette tip 1160, thereby reducing or preventing evaporation in the tip air space and improving the accuracy of aspiration. Therefore, pre-wetting of the pipette tip may reduce or eliminate pressure changes indicated by the signal of one or more pressure sensors 1156.

[0540] Additionally or alternatively, as described above, one or more aspiration parameters may be adapted at steps 1123a, 1123b (e.g., over-aspiration to compensate for under-aspiration, or vice versa). For example, when aspirating water, the surface tension of the water may result in a measurable inflow into the tip 1160 during the withdrawal at step 1114, which may be corrected by reducing the amount of aspiration.

[0541] In addition to or as an alternative to the above, at step 1123b, the plunger 1140 in the pipetting channel 1102 may be controlled to move a distance sufficient to maintain a defined or predetermined constant pressure in the pipette tip 1160 and / or the channel 1102. For example, as described above, the position or displacement of the plunger 1140 in the channel 1102 may be continuously controlled based on the pressure indicated by the pressure signal so that the pressure in the channel 1102 and / or the tip 1160 remains substantially constant. The constant pressure may be a predetermined pressure, or may be based on the pressure in the channel measured immediately after the pipette tip is removed from the liquid volume (e.g., at step 1114). Thus, keeping the pressure constant or moving the plunger 1140 to draw a small amount of air (after drawing liquid and removing the tip 1160 from the liquid volume) may reduce or avoid dripping in the bead formation LB at the orifice 1162 of the pipette tip 1160. One or more pressure sensors 1156 may be positioned in the channel 1102 or the pipette tip 1160 to provide a pressure signal with a high level of accuracy (sufficient to offset tip bead formation LB) even in the presence of a small amount of trapped air, for example, as described herein with reference to dual-plunger pipettes (e.g., pipette 100), tandem-plunger pipettes (e.g., pipette 200), and / or dual-meter pipettes (e.g., pipette 1200) embodiments.

[0542] It should be understood that the adaptation of the pipetting parameters at steps 1123a, 1123b and / or other compensation operations are not limited to evaporation compensation. For example, as described above, adapting the aspiration based on the difference between the calculated aspiration volume Va and the target volume Vtarget can also provide hydrostatic pressure and capillary pressure compensation. The compensation operation may also include providing a viscosity-related pipetting speed (e.g., by adapting the aspiration speed relative to the target pressure change Δptarget based on the pressure change Δp indicated by the signal from the pressure sensor 1156), and / or heat transfer compensation (e.g., if the temperature of the liquid is below the minimum temperature, pre-wetting is initiated). Such operations can be used to effectively compensate for differences in liquid density, surface tension, wettability, and / or viscosity of the liquid sample LS.

[0543] Other embodiments described herein may be derived from the following understanding: in conventional pipetting or other liquid handling systems, an accurate piston or plunger control system is usually used to control the transfer of air. For example, some pipetting systems draw liquid into a disposable tip and distribute the liquid into another container, wherein there is an air column AC between the liquid sample LS and the pipetting channel, which is also referred to as an air displacement pipette or pipette tip. This can avoid cross contamination of the pipette with different liquid samples. The pipetting performance may depend mainly on the geometry (i.e., based on the moving distance or stroke of the piston or plunger in the internal volume or opening of the pipette) and the precision and / or accuracy of the plunger control motor operating the plunger, wherein the higher the positioning precision and accuracy, the better the pipetting performance (e.g., in terms of over-absorption or under-absorption). Therefore, conventional pipetting performance may be limited by the resolution of the encoder of the plunger control motor.

[0544] Embodiments described herein provide a dual metering pipetting system configured to control the plunger position based on the amount of air transferred in the pipetting channel, as determined by a sensor signal (e.g., as an output of a flow rate sensor coupled to the pipetting channel). The system may also include a negative pressure source or a positive pressure source coupled to a valve and / or a flow restriction mechanism. The time-varying air flow (flow rate) indicated by the sensor signal can be used to determine the amount of air transferred in the channel (i.e., the volume of air transferred). The flow rate sensor may have sufficient sensitivity to measure a wide range of flow rates (e.g., within an order of magnitude or greater measurement range), which may be difficult to achieve using conventional encoders and plunger control motors.

[0545] In some embodiments, the flow rate sensor may be implemented by a pressure sensor having sufficient sensitivity to provide a feedback loop for controlling the channel pressure / air transfer volume. For example, the flow rate sensor may be implemented by two pressure sensors (also referred to herein as dual metering or dual flow sensors) arranged in parallel across the flow constraint mechanism. Thus, the flow rate sensor, valve, and one or more pressure sources may provide a control loop to control the flow of liquid in the pipetting channel, wherein the online measurement is provided by the flow rate sensor, allowing precise and accurate control of the liquid flow. Since the plunger position can be determined based on the air transfer volume calculated from the flow rate or pressure change measurement, high-precision plunger movement may not be required, and therefore the accuracy requirements for the plunger control motor and / or encoder may be relaxed.

[0546] Fig.47 is a side view showing a dual-meter pipette that can be used in an automated pipetting system according to some embodiments. Fig.48 It is shown Fig.47 An enlarged schematic diagram of a dual metering pipette with the pipette tip removed. An automated pipetting system (e.g., 101, 901, 1101) may include one or more of the pipettes 1200 shown. If multiple pipettes 1200 are provided, the pipettes 1200 may be operated independently of each other or in series. For the purpose of discussion, only one pipette is described below.

[0547] See also Fig.47 and 48 , the pipette 1200 includes a mechanical interface 1207, a frame 1208, an electrical interface (shown as a printed circuit board) 1209, a pressure control system 1206, a tip mounting feature or adapter 1276, and a manifold 1275. The pressure control system 1206 includes sensors 1279A, 1279B, 1280, a plunger 1240 located in the pipetting channel 1202 and controlled by a drive mechanism 1228, and a switchable flow restriction mechanism 1277 (see FIG. 1278 and FIG. 1279 ) that is operable to couple the channel 1202 to a pressure source. Fig.53 ) of the airflow control system 1271. The pipette tip 1260 can be attached to a tip adapter 1276 and includes a pipetting orifice 1262 and a liquid collection volume LV, which are in fluid communication with the pipetting channel 1202 via a passage 1274 in a manifold 1275. As used herein, the pipetting channel 1202 may generally include communication features between the tip 1260 / adapter 1276 and a chamber or barrel in which the plunger 1240 is included.

[0548] The plunger mechanism can be operated in response to a control signal provided to the drive mechanism 1228 to translate the plunger 1240 to change the pressure in the pipetting channel 1202 to aspirate or dispense a liquid volume. The drive mechanism 1228 can be a linear drive system including a plunger actuator and an encoder. A linear sensor 1229 (e.g., with a resolution of about 1 μm) can be configured to measure the deflection caused by the tip 1260 contacting the side wall of the vessel.

[0549] The components of the pipette 1200 can be mounted on the frame 1208. The mechanical interface 1207 can couple the pipette 1200 to an automated pipetting system (e.g., 101, 1101) as described herein. For example, as described herein, the mechanical interface 1207 can provide a mechanical connection between the frame 1208 (including the components of the pipette 1200 thereon) and an arm member (e.g., 912) of a robotic arm assembly (e.g., 914) to control the movement of the pipette 1200 along one or more axes (e.g., Z axis).

[0550] The electrical interface 1209 may include one or more controller circuits 1220 (which may include any of the controller circuits 20, 920, 1120 described herein), including input / output (I / O) circuits (e.g., 915), memory (e.g., 910), a processor / microcontroller (e.g., 925), and drive circuits for the motor / drive mechanism 1228. Readout and pre-processing functions of the sensors 1279, 1280 may also be performed via the electrical interface 1209. More generally, the memory may be a non-transitory storage medium configured to store computer-readable instructions therein, and the controller circuit 1220 may be configured to execute the computer-readable instructions stored in the memory to perform operations as described herein.

[0551] Thus, the pipetting control operations described herein may be performed by or through the controller circuit 1220. The controller circuit 1220 receives sensor signals from one or more of the sensors 1279A, 1279B, 1280 coupled to the pipetting channel 1202. The sensors include pipetting channel pressure sensors 1279A, 1279B (which may include the pressure sensor 179 described herein) and a sensor 1280 configured to output a sensor signal from which air displacement in the channel 1202 may be determined, primarily described herein with reference to a flow rate sensor 1280. The pipetting channel pressure sensors 1279A, 1279B may include the pressure sensor 179 described herein. The flow rate sensor 1280 may be configured to output a sensor signal indicative of a flow rate in the channel 1202, for example, a flow rate detected or otherwise identified based on pressure change data of air (or other gas) in the channel 1202.

[0552] Based on the sensor signal from the sensor 1280, the controller circuit 1220 can determine the volume of air transferred in the channel 1202. The controller circuit 1120 can transmit one or more control signals (e.g., to a pressure source) to control the position of the plunger 1240 in the channel 1202 based on the volume of air transferred in the channel 1202 or otherwise in response to the signals from the pressure sensors 1279A, 1279B, 1280 to perform the aspiration and / or dispensing operations described herein. The control signals may include, but are not limited to, plunger actuator signals that directly operate the drive mechanism 1228 and / or associated control signals, such as operating or controlling the flow rate or flow restriction mechanism 1277 (see Fig.53 ) of the operating state, and / or a valve control signal for operating or controlling the operating state of valve 1278. Thus, the pressure source providing the pressure difference for driving the flow may be the plunger 1240 / actuator 1228, the pressure reservoir 1290 (see Fig.53 ) or other pump mechanism.

[0553] The valve 1278 is operable to couple the channel 1202 to a pipette tip 1260 mounted on a tip adapter 1276 and / or a pressure source in response to a valve control signal from the controller circuit 1220 (see Fig.53 ). As described in more detail below, the pressure source may include a negative pressure source and a positive pressure source, which can be selected (in response to the operation of valve 1278 and switchable flow restriction 1277) to control the direction of airflow in channel 1202.

[0554] Fig.49 It is shown Fig.48 A simplified schematic diagram of the plunger 1240 and manifold assembly 1275 of a dual metering pipette. Fig.50 yes Fig.49 FIG. 1 is an enlarged view of region L in FIG. 1 , showing the microfluidic manifold 1275 and flow rate sensor 1280 in more detail. Fig.49 and 50 , the manifold 1275 interconnects the pipetting channels 1202 and the plunger 1240 with the pressure sensors 1279, 1280 and the valve 1278. The manifold 1275 includes a plurality of microfluidic pathways 1274 therein, which are configured to couple the channels 1202 to the tip adapter 1276 in response to the operation of the valve 1278. A dead volume or static volume (i.e., residual volume of aspirated liquid that may be lost and wasted) may be defined within the region F, for example, due to the connections provided by the microfluidic pathways 1274 and / or the sensor volume.

[0555] Manifold 1275 compactly integrates pipette passage 1274, sensor 1279A, 1279B, 1280 and valve 1278 operably connected to plunger 1240, thereby reducing the distance of all interconnected fluid channels. In some such embodiments, manifold 1275 can be configured to reduce or minimize dead volume (e.g., provide a static volume of less than about 120 μl) based on one or more dimensions of the microfluidic passage or channel 1274 therein. For example, each passage 1274 in microfluidic manifold 1275 has a diameter range of about 0.2 mm to 0.8 mm. In the illustrated embodiment, flow rate sensor 1280 is connected to microfluidic passage 1274 to provide pressure change measurement described herein. Some embodiments described herein can provide accurate pressure change measurement, wherein the static volume is less than about 50 μl, or the volume range is about 50 μl to 100 μl.

[0556] Fig.51 1 is a perspective view of a manifold 1275 mounted on a portion of a PCB 1209 including pressure sensors 1279A, 1279B and a flow rate sensor 1280, also referred to herein as a manifold assembly. Fig.51 As shown in the manifold assembly of FIG. 1275 , in some embodiments, the manifold 1275 and sensors 1279, 1280 can be mounted on opposite sides of the PCB 1209, wherein the microfluidic passage 1274 is arranged below the PCB 1209 and / or passes through the PCB 1209 to connect to one or more sensors 1279 and / or 1280. The PCB 1209 may include metallized holes to prevent expansion when exposed to moisture. In some embodiments, the air connection and / or sensor connection provided by the microfluidic passage 1274 can provide a static volume of less than about 50 μl. The manifold 1275 can also be used in some embodiments without a flow rate sensor 1280 (for example, in Figure 2-13 In the dual plunger embodiment of the present invention, the dead volume is further reduced (e.g., less than about 20 μl). That is, it should be understood that the dual-meter pipette as described herein can be operated with either the single plunger or dual plunger embodiments because the air displacement is accurately measured based on the integral combination of two or more pressure sensors 1279A, 1279B in the manifold 1275 as described herein.

[0557] Fig.52 is a schematic circuit diagram showing the connections of the sensors 1279, 1280 in the manifold 1275. Fig.52, valve 1278 is operable to couple channel 1202 (including plunger 1240) to pipette tip 1260 mounted on tip adapter 1276. A pressure sensor 1279B configured to provide relatively high range pressure measurements (e.g., up to about 350 mbar or higher) is mounted on manifold 1275 and coupled to channel 1202 via microfluidic pathway 1274, which may define a relatively large swept volume (e.g., a plunger 1240 having a relatively large diameter (~6 mm) therein). A pressure sensor 1279A configured to provide relatively low range pressure measurements (e.g., up to about 10 mbar or higher) is mounted on manifold 1275 and coupled to pipette tip 1260 on tip adapter 1276 via microfluidic pathway 1274. In some embodiments, an additional pressure sensor 1256 (such as pressure sensors 256, 1156 described herein) may be included in or coupled to pipette tip 1260. A relatively small dead volume may be defined by the connections provided by microfluidic pathway 1274 and / or the sensor volume within region F.

[0558] The flow rate sensor 1280 is coupled to the pipetting channel 1202 (e.g., between the pipetting channel 1202 and the pipette tip 1260 or the tip adapter 1276), and is configured to output a sensor signal indicating the air flow rate in the channel 1202, for example, based on the detected pressure or pressure change data. For example, the flow rate sensor 1280 may be a dual-gauge or differential pressure sensor, which includes a first pressure sensor 1280A and a second pressure sensor 1280B coupled to the channel 1202 via a microfluidic passage 1274 arranged in parallel. The first pressure sensor 1280A and the second pressure sensor 1280B may output corresponding signals including first pressure data and second pressure data indicating a first flow rate and a second flow rate, respectively. In some embodiments, the measurement range of the second pressure sensor 1280B may be larger than the measurement range of the first pressure sensor 1280A, for example, an order of magnitude or more, which may allow flow measurement with an increased dynamic range. For example, a near-zero flow rate change may result in a very small pressure differential, which may be difficult or impossible to detect using a pressure sensor configured to detect larger pressure changes in channel 1202 .

[0559] Thus, in some embodiments, the first pressure sensor 1280A may be highly sensitive so as to detect sub-Pascal (Pa) changes at low pressures (e.g., less than about 50 Pa), while the second pressure sensor 1280B may have a wide measurement range so as to detect changes at high pressures (e.g., up to about 5000 Pa). The first pressure data and the second pressure data indicated by the respective outputs of the first pressure sensor 1280A and the second pressure sensor 1280B may be combined by the controller circuit 1220. That is, the controller circuit 1220 may include signal processing capabilities so as to stitch together the respective pressure data provided by the first pressure sensor 1280A and the second pressure sensor 1280B, thereby providing an increased dynamic flow measurement range.

[0560] See again Fig.47 and 48 , the controller circuit 1220 can be configured to determine the volume of air transferred in the channel 1202 based on the flow rate in the channel 1202 indicated by the signal output by the sensor 1280 (e.g., indicated by the pressure change), and can output a plunger actuator control signal to the drive mechanism 1228 based on the volume of air transferred, which can improve the accuracy of aspiration and / or dispensing. The plunger actuator control signal can continuously change based on the change in the volume of air transferred in the channel 1202 (as indicated by the changing output from the sensor 1280) to dynamically control the position and / or movement speed of the plunger 1240 in the channel 1202. For example, the controller circuit 1220 may implement a control loop by which (i) the controller circuit 1220 transmits a plunger actuator control signal to the drive mechanism 1228 to move the plunger 1240 in the channel 1202 to aspirate or dispense, (ii) the flow rate sensor 1280 outputs a signal indicating a pressure change in the channel 1202 (e.g., based on first pressure data and / or second pressure data indicated by sensor signals from the first pressure sensor 1280A and the second pressure sensor 1280B), the pressure change being caused by the movement of the plunger 1240, and (iii) the controller circuit 1220 determines the air displacement in the channel 1202 based on the pressure change (or the flow rate indicated thereby), and transmits another plunger actuator control signal to the drive mechanism 1228 to move the plunger 1240 based on the determined air displacement. Thus, the controller circuit 1220 can continuously monitor the pressure in the channel 1202 and generate a plunger actuator control signal based on the output of the sensor 1280 without relying on determining the previous position or movement of the plunger 1240 in the channel 1202, in contrast to some conventional motor / encoder assemblies that can determine the volume of air transferred based on tracking the distance the plunger moves in the pipetting channel.

[0561] See again Fig.52, flow restriction mechanism 1277 is coupled to channel 1202, for example, via microfluidic passage 1274 of manifold 1275. Flow restriction mechanism 1277 can be configured to switch between respective states, which can allow different flow rate ranges in response to flow restriction control signals from controller circuit 1220, for example, to increase or decrease flow rate based on the output of dual pressure sensors 1280A and 1280B. Valve 1278 is coupled to channel 1202, for example, between flow restriction mechanism 1277 and channel 1202. In some embodiments, as described with reference to Fig.53 As described in the example of , flow restriction mechanism 1277 and valve 1278 can be configured to connect channel 1202 to pressure source 1290.

[0562] Fig.53 1 is a schematic diagram illustrating the operation of various components of the dual-meter pipette 1200 in more detail according to some embodiments. Fig.53 , as mentioned above Fig.52 As discussed, the dual-meter pipette 1200 includes a flow rate sensor 1280 that is coupled to the pipetting channel 1202 and the switchable flow restriction 1277 via an in-line valve 1278. The flow rate sensor 1280 is implemented by a dual-meter sensor that includes a first pressure sensor 1280A and a second pressure sensor 1280B to measure the flow rate within the pipetting channel 1202, for example, based on a pressure difference or change across the variable flow restriction 1277. The first pressure sensor 1280A may be configured to measure a first, narrower pressure range (e.g., about 0 to 25 Pa or Δp=about 0.0036 psi) for a lower flow rate, while the second pressure sensor 1280B may be configured to measure a second, wider pressure range (e.g., about 0 to 500 Pa or Δp=about 0.0725 psi) at a higher flow rate. In some embodiments, the second, wider pressure range may be more than an order of magnitude higher than the first pressure range. Using two (narrower range and wider range) pressure sensors 1280A, 1280B in parallel on the flow restriction 1277 can provide the dual metering pipette 1200 with sufficient sensitivity to measure a wide range of flows. For example, the differential pressure sensors 1280A, 1280B can be operated to provide a flow rate measurement range from about 1 μl / s to 1000 μl / s.

[0563] The flow restriction mechanism 1277 is configured to provide a variable flow rate in the channel 1202, for example, within a corresponding range of about 1 μl / s to 1000 μl / s. Fig.53In an embodiment of the present invention, a flow restriction mechanism 1277 is coupled between the channel 1202 and the pressure source 1290. The pressure source 1290 may include a positive pressure reservoir 1290A and a negative pressure reservoir 1290B. The positive pressure reservoir 1290A may be configured to provide a fixed positive pressure, and the negative pressure reservoir 1290B may be configured to provide a fixed negative pressure. The flow restriction mechanism 1277 and / or the valve 1278 may be coupled to the positive pressure reservoir 1290A and the negative pressure reservoir 1290B and configured to switch between the positive pressure reservoir 1290A and the negative pressure reservoir 1290B to apply a positive pressure or a negative pressure (and thus control the direction of airflow) in the channel 1202, for example, during dispensing or aspiration, respectively.

[0564] For more details, refer to Fig.53 In an example, the flow restriction mechanism 1277 is configured to switch between corresponding flow restriction states that provide different flow rate ranges in response to a flow restriction control signal from the controller circuit 1220, for example, increasing or decreasing the flow rate based on the measurement range of the sensors 1280A and / or 1280B. For example, the switchable flow restriction mechanism 1277 may include three flow restriction states A, B, C, each of which provides a gradual reduction in flow restriction. That is, state B provides less flow restriction than state A, and state C provides less flow restriction than state B. However, the stepwise flow restriction mechanism is shown only by way of example, and it should be understood that the flow restriction mechanism 1277 may include fewer, more, or continuously changing (rather than stepwise) flow restriction states than those shown. Therefore, the switchable flow restriction mechanism 1277 and the valve 1278 are operable to provide (i) switchable flow rates (provided by multiple flow restriction states A, B, C) and (ii) switchable flow directions (provided by the positive pressure reservoir 1290A and the negative pressure reservoir 1290B).

[0565] In some embodiments, the control circuit 1220 can be configured to transmit a valve control signal to the valve 1278 to stop the flow if the volume of air transferred indicated by the flow rate sensor 1280 exceeds a threshold air transfer volume, effectively acting as a stop to movement of the plunger 1240 in other embodiments described herein. The threshold air transfer volume can be determined based on a target volume and can be calculated to compensate for various side effects during the pipetting operation.

[0566] The flow rate range in channel 1202 can be based on the pressure provided by pressure source 1290 and the switchable restriction of flow restriction mechanism 1277 (e.g., a lower pressure source can allow switching between flow rates in the range of about 1 μl / s to 100 μl / s, while a higher pressure source can allow switching between flow rates in the range of about 10 μl / s to 1000 μl / s), which is within the dynamic flow rate measurement range provided by dual pressure sensors 1280A and 1280B. In some embodiments, the response time of flow rate sensor 1280 can be less than about 5 ms, and in-line valve 1278 can switch between an open state and a closed state in less than about 1 ms (e.g., about 200 μs or less).

[0567] As described above, a control mechanism or loop may be implemented by the controller circuit 1220 based on pressure data from the pressure sensors 1280A, 1280B to improve the accuracy of over-absorption and / or under-absorption. The pressure data indicated by the signals from the pressure sensors 1280A, 1280B may also be used to dynamically control the speed or plunger position (i.e., the final position of the plunger 1240 in the channel 1202). Thus, the final position of the plunger 1240 may be controlled based on changes in the pressure data indicated by the sensor 1280, rather than by tracking the distance the plunger has moved. That is, the position of the plunger 1240 in the channel 1202 may be dynamically controlled based on changes in the flow rate or otherwise based on the volume of transferred air in the channel 1202 indicated by the signal from the sensor 1280, regardless of the previous position and / or distance of movement of the plunger 1240. In some embodiments, the pressure sensors 1279A, 1279B may be distributed along the channel, wherein the pressure sensor 1279A is included in or coupled to the pipette tip 1260 (e.g., in place of the pressure sensors 256, 1156 described herein), and the pressure sensor 1279B is further positioned along the channel, such as Fig.53 The tip pressure sensor 1279A may output a pressure signal that may be used by the controller circuit 1220 to determine the liquid volume LV in the pipette tip 1260 based on the pressure signal and to control the position of the plunger 1240 based on the determined liquid volume in the pipette tip 1260.

[0568] See also Figure 54-59 , shows an example positive displacement (PD) pipette tip 1360 according to other embodiments of the present technology. The PD pipette tip 1360 can be used in conjunction with a pipette to form a pipetting system. An example pipetting system 1301 according to an embodiment of the present technology is shown in Figure 54-59 , and includes a PD pipette tip 1360 and a pipette 1300 .

[0569] The pipetting system 1301 can aspirate and dispense liquid volumes within a liquid handling system. For example, the pipetting system 1301 can replace the automated liquid handling system 10 ( Figure 1 ) for use with the pipetting system 101 in ). However, it should be understood that the disclosed methods, systems, and apparatus are not limited to the liquid handling system 10 or use therein, and the present disclosure may be applicable to other systems and applications that require aspiration and / or dispensing of liquid volumes.

[0570] PD pipette tip 1360 is not limited to use with pipette 1300. PD pipette tip 1360 can be used with any suitable air displacement pipette. For example, PD pipette tip 1360 can be used in place of air displacement pipette tip 160.

[0571] The pipetting system 1301 includes one or more pipettes 1300. One or more pipettes can be mounted on the pipette module 30 ( Figure 1 ). The pipettes 1300 can be constructed and operated in the same manner, and it should be appreciated that the subsequent description of a representative pipette 1300 in the pipettes 1300 can be equally applicable to each of the pipettes 1300. If a plurality of pipettes 1300 are provided, the pipettes 1300 can be operated independently of each other or in series. For the purpose of discussion, only a single pipette is described below.

[0572] The pipetting system 1301 includes a pipette 1300, a controller 20, and one or more of the PD pipette tips 1360. The pipette tips 1360 are removable and replaceable on the pipette 1300 and may be effectively disposable or consumable components of the pipetting system 1301.

[0573] See also Fig.54 and 55 , the pipette 1300 can be understood to have a longitudinal axis AA and a distal end 1300A. The pipette 1300 includes a tubular barrel 1310, a pressure control system 1306, a pipetting channel 1302, a pipette orifice 1304 and a tip adapter 1314. The barrel 1310 includes an axis 1313 that terminates at the distal end 1300A. The tip adapter 1314 is mounted or formed on the distal end 1300A. The pipette orifice 1304 is located at the distal end 1300A and is in fluid communication with the pipetting channel 1302.

[0574] In some embodiments, the pressure control system 1306 includes a plunger mechanism (eg, as described and shown below). The pipette 1300 can be constructed and operated in the same manner as described herein for any of the pipettes 100, 200, 300, 400, 600, for example.

[0575] However, as discussed herein, the pressure control system 1306 is not limited to a plunger mechanism, and the pressure control system 1306 may include and use any suitable type of mechanism for controlling the pressure in the tip 1360. For example, other suitable types of pressure control mechanisms may include one or more pumps of other designs that are integrally incorporated into the pipette 1300 or that are remote from the pipette 1300 and fluidly connected to the pipette 1300.

[0576] The example pressure control system 1306 includes a cylinder 1310, a plunger 1340, a plunger drive mechanism 1358 (in Fig.54 and 55 ) and pressure sensor 1356 (shown schematically in Fig.54 and 55 Schematically shown in FIG.

[0577] See also Fig.55 , the barrel 1310 includes a barrel passage 1320. The passage 1320 is longitudinally aligned with the axis AA and extends rearwardly from a front end 1320A to an opposite rear end.

[0578] The plunger 1340 is mounted in the passage 1320 such that the plunger 1340 is slidably translatable relative to the barrel 1310 along the plunger axis P6 - P6 in an extension direction E12 and an opposite retraction direction E13 .

[0579] The plunger drive mechanism 1358 is selectively operable to drive the plunger 1340 in each of the extension direction E12 and the retraction direction E13. The plunger drive mechanism 1358 may be a linear drive mechanism. The plunger drive mechanism 1358 may include an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes a motor. In some embodiments, the plunger drive mechanism 1358 is manually operable and does not include an actuator. For example, an extension, a lever, a knob, or other manual drive features may be used to push and pull the plunger component 1340.

[0580] The tip adapter 1314 is configured to removably secure a pipette tip 1360 to the end 1300A of the pipette 1300 in the same manner as described above with respect to the tip adapter 156 .

[0581] See also Fig.54 and 56 , the PD pipette tip 1360 includes a tubular tip body 1362 and a piston unit 1380 slidably mounted in the tip body 1362. The piston unit 1380 can be in an extended or ready position ( Fig.54 ) and the retracted position (e.g. Fig.55 ). In some embodiments, the pipette tip 1360 further includes a calibration mechanism 1375.

[0582] See also Fig.56 , the tip body 1362 extends from a distal end 1362A to a proximal end 1362B. The tip body 1362 includes a front section 1364A and a rear section 1364B, which together define a combined volume or body passage 1370. The front section 1364A defines a front chamber or tip passage 1370A. The rear section 1364B defines a rear chamber 1370B ( Fig.54 ) and an intermediate chamber 1370C ( Fig.54 ). The tip passage 1370A and chambers 1370B, 1370C each form a portion of the passage 1370. The rear section 1364B includes a mounting section 1364D and defines an interface opening 1368. A tip or pipetting orifice 1366 is defined in the distal end 1362A. The passage 1370 terminates at the interface opening 1368 and the pipetting orifice 1366.

[0583] The pressure relief port 1372 is disposed in fluid communication with the intermediate chamber 1370C. The pressure relief port 1372 may be vented to or from the surrounding atmosphere.

[0584] The piston unit 1380 includes a piston 1382 and a sealing member 1388. The piston 1382 and the sealing member 1388 may be constructed as a single component that forms the piston unit 1380 as a single component, or the piston 1382 and the sealing member 1388 may be separate parts that are joined to form the piston unit 1380 as an assembly of parts.

[0585] The piston 1382 extends from a distal end 1382A to a proximal end 1382B. The piston 1380 includes a base 1384, a shaft 1385, and a rear extension 1386. In some embodiments, the base 1384, the shaft 1385, and the rear extension 1386 form a rigid single component. In some embodiments, the base 1384, the shaft 1385, and the rear extension 1386 form an integral component together.

[0586] The shaft 1385 extends from a proximal end 1385B fixed to the base 1384 to an opposite distal end 1385A. In some embodiments, the distal end 1385A is positioned at or near the pipetting orifice 1366 when the piston 1382 is in the ready or extended position. The front side of the base 1384 can have a convex or other contoured shape to match the facing contour of the tip body 1362. The base 1384 defines a pressure relief passage 1384A therein.

[0587] The example sealing member 1388 is a generally disc-shaped body or portion. The sealing member 1388 is fixed to (ie, attached to or integrally bonded to) the piston 1382 at the proximal end 1382B of the extension 1386. The sealing member 1388 has an annular peripheral sealing edge section 1388A.

[0588] The piston 1382 and the sealing member 1388 can be formed together (e.g., molded or co-molded), or formed separately and then attached to each other. In some embodiments, the piston 1382 and the sealing member 1388 form a single component or assembly. In some embodiments, the piston 1382 and the sealing member 1388 form an integral part together.

[0589] In some embodiments, piston 1382 and sealing member 1388 are formed of the same material. In some embodiments, piston 1382 and sealing member 1388 are formed of different materials from each other. In some embodiments, piston 1382 is formed of a harder material than the material of sealing member 1388. For example, sealing member 1388 may be formed of an elastomer or a thermoplastic elastomer, while piston 1382 is formed of a thermoplastic. Suitable materials for piston 1382 may include, but are not limited to, polyethylene (PE). Suitable materials for sealing member 1388 may include, but are not limited to, silicone. Other types of seals (e.g., O-rings) may be used to replace or supplement sealing member 1388.

[0590] See also Fig.54 and 58 , the peripheral sealing edge segment 1388A slidably engages the inner wall surface 1362D of the rear segment 1364B to form a sliding seal 1389 between the piston unit 1380 and the tip body 1362. The sliding seal 1389 is axially slidable along the axis P6-P6 relative to the tip body 1362. The sealing member 1388 and the seal 1389 separate, isolate and fluid-tighten the intermediate chamber 1370C from the rear chamber 1370B.

[0591] In use, the seal 1389 translates through the body 1362 together with the sealing member 1388 and the piston 1382. It should be appreciated that when the seal 1389 translates relative to the body 1362 along the axis P6-P6, the boundaries and volumes of the intermediate chamber 1370C and the rear chamber 1370B will change accordingly. That is, as the piston unit 1380 translates along the direction E12, the volume of the rear chamber 1370B increases, and the volume of the intermediate chamber 1370C decreases. As the piston unit 1380 translates along the direction E13, the volume of the rear chamber 1370B decreases, and the volume of the intermediate chamber 1370C increases.

[0592] See also Fig.57, the indexing mechanism 1375 includes a first indexing feature in the form of a set 1377A of recesses or annular grooves 1377 on the inner wall 1362C of the tip body 1362, and a second indexing feature in the form of a protrusion or annular rib 1387 formed on the base 1384. The grooves 1377 and ribs 1387 are relatively arranged and configured so that the rib 1387 can be located in each groove 1377 to maintain the piston 1382 in a corresponding axial position relative to the tip body 1362, but the rib 1387 can be moved away from the groove 1377 (upon application of sufficient force) to axially reposition the piston 1382 relative to the tip body 1362. For example, the tip body 1362 and / or the ribs 1387 can be formed of an elastically deformable material.

[0593] The grooves 1377 are continuously distributed along the axis P6-P6. In some embodiments, the grooves 1377 have a substantially uniform spacing W14 ( Fig.57 ). In some embodiments, the grooves 1377 have a pitch W14 in the range of 0.05 mm to 0.5 mm.

[0594] In some embodiments, the grooves of group 1377A include at least 10 grooves 1377. In some embodiments, the number of grooves 1377 in group 1377A ranges from about 10 to 400.

[0595] It should be appreciated that the first and second indexing features may take other forms. For example, an annular groove may be provided on the base 1384 in place of the rib 1387, and a series of annular ribs may be provided on the tip body 1362 that are located in the annular groove of the base 1384. The groove 1377 may be defined between upstanding annular ribs 1377B, or the groove 1377 may be flush with the inner diameter of the inner wall 1362C.

[0596] The liquid handling system 10 and the pipetting system 1301 can be used according to some methods as follows to aspirate and / or dispense one or more liquid samples.

[0597] In general, a PD pipette tip 1360 is mounted on the pipette 1300. The tip body 1362 forms an airtight pressure-resistant seal with the tip adapter 1314, making the back chamber 1370B airtight and pressure-resistant sealed.

[0598] The plunger 1340 is driven to displace the volume of air in the pipette passage 1320 and thereby correspondingly change the pressure in the pipette channel 1302 and the rear chamber 1370B (which is in fluid communication with the pipette channel 1302). The pressure change in the rear chamber 1370B pulls the piston unit 1380 in the retracting direction E13 (in response to the negative pressure change in the rear chamber 1370B) or pushes the piston unit 1380 in the extending direction E12 (in response to the positive pressure change in the rear chamber 1370B). The piston assembly 1380 is shown in FIG. Fig.54 is in its ready or fully extended position, and Fig.55 in the retracted position.

[0599] When the piston unit 1380 is pulled in the retraction direction E13, the shaft 1385 is displaced relative to the front section 1364A in the direction E13, which expands the fluid volume in the tip passage 1370A. This expansion generates a negative pressure in the tip passage 1370A, which draws the liquid volume LV of the liquid sample LS into the tip passage 1370A through the orifice 1366.

[0600] When the piston unit 1380 is pushed in the extension direction E12, the shaft 1385 is displaced relative to the front section 1364A in the direction E12, which displaces or reduces the volume of fluid in the tip passage 1370A. This reduction generates a positive pressure in the tip passage 1370A, which discharges or dispenses the liquid volume LV of the liquid sample LS from the tip passage 1370A through the orifice 1366.

[0601] Thus, the piston 1382 translates rearwardly (direction E13 ) away from the tip orifice 1366 in response to the negative pressure in the rear chamber 1370B, whereby the piston 1382 generates negative pressure at the tip orifice 1366 to draw liquid into the positive-displacement pipette tip 1360 through the tip orifice 1366 .

[0602] The piston 1382 translates forwardly (direction E12 ) toward the tip orifice 1366 in response to the positive pressure in the back chamber 1370B, whereby the piston 1382 generates a positive pressure in the tip passage 1370A to expel liquid from the positive displacement pipette tip 1360 through the tip orifice 1366 .

[0603] It should be appreciated that the piston unit 1380 is operably coupled to the drive mechanism of the pipette 1300 via the pipetting channel 1302 and the air column AC in the rear chamber 1370B, rather than by a direct mechanical engagement or linkage between the plunger and the piston 1382. The intervening air column AC exists and is maintained between the distal end 1300A of the pipette 1300 and the piston unit 1380.

[0604] As the base 1384 translates, the pressure relief passage 1384A allows air to flow out of and into the intermediate chamber 1370C in front of the base 1384. As the seal 1389 translates, the pressure relief port 1372 allows air to flow out of and into the intermediate chamber 1370C. In this way, the pressure in the intermediate chamber 1370C can be kept substantially constant (e.g., at ambient pressure) so that changes in the pressure in the intermediate chamber 1370C do not interfere with the displacement of the piston unit 1380.

[0605] During operation, the calibration system 1375 is used to stop the displacement of the piston 1380 at a specified, discrete axial position relative to the tip body 1362. That is, the calibration system 1375 moves the piston 1380 from one groove 1377 to the next groove 1377 along the axis P6-P6 in a stepwise manner. The step-by-step movement can enable or ensure that the pipette tip 1360 dispenses or draws a known, discrete volume for each step. The resolution or accuracy of the dispensed volume can be determined by the number of steps (e.g., grooves) provided. In some embodiments, the grooves 1377 are equidistantly spaced apart so that the discrete volumes for each step are substantially equal.

[0606] When the pipette tip 1360 is provided with a calibration system 1375 as disclosed herein, the pressure change provided by the pipette 1300 to displace the piston 1382 must also be sufficient to overcome the engagement or interlock between the calibration features (e.g., the rib 1387 and the groove 1377 in which the rib 1387 is located). In some embodiments, the controller 20 operates the pipette 1300 to deliver pressure pulses to the back chamber 1370B, wherein each pressure pulse is sufficient to move the piston 1382 one step.

[0607] In some embodiments, when performing an aspiration or dispensing operation, the controller 20 receives a pressure signal from the pressure sensor 1356 indicating the air pressure in the pipetting channel 1302. The controller 20 can continuously monitor the pressure in the pipetting channel 1302. In some embodiments, the controller 20 monitors the pressure in the pipetting channel 1302 using a dual metering flow sensor (e.g., dual metering flow sensor 1280) as described herein.

[0608] As described above, the pipetting system 1301 aspirates liquid samples by reducing the pressure in the pipetting channel 1302, and dispenses liquid samples by increasing the pressure in the pipetting channel 1302. However, the pressure in the pipetting channel 1302 may fluctuate in response to other actions or conditions in the process, such as discussed above with respect to the pipetting system 101.

[0609] See also Figure 60-75, shows an example positive displacement (PD) pipette tip 1440 according to other embodiments of the present technology. The PD pipette tip 1440 can be used in conjunction with a pipette to form a pipetting system. An example pipetting system 1401 according to an embodiment of the present technology is shown in Figure 60-75 , and includes a PD pipette tip 1440 and a pipette 1400 .

[0610] The pipetting system 1401 can aspirate and dispense liquid volumes within a liquid handling system. For example, the pipetting system 1401 can replace the automated liquid handling system 10 ( Figure 1 ) for use with the pipetting system 101 in ). However, it should be understood that the disclosed methods, systems, and apparatus are not limited to the liquid handling system 10 or use therein, and the present disclosure may be applicable to other systems and applications that require aspiration and / or dispensing of liquid volumes.

[0611] PD pipette tip 1440 is not limited to use with pipette 1400. PD pipette tip 1440 can be used with any suitable positive displacement pipette. For example, PD pipette tip 1440 can be used in place of air displacement pipette tip 160.

[0612] See also Fig.60 , the pipetting system 1401 includes one or more pipettes 1400. One or more pipettes can be mounted on the pipette module 30 ( Figure 1 ). The pipettes 1400 can be constructed and operated in the same manner, and it should be appreciated that the subsequent description of a representative pipette 1400 in the pipettes 1400 can be equally applicable to each of the pipettes 1400. If a plurality of pipettes 1400 are provided, the pipettes 1400 can be operated independently of each other or in series. For the purpose of discussion, only a single pipette is described below.

[0613] The pipetting system 1401 includes a pipette 1400, a controller 20, and one or more of the PD pipette tips 1440. The pipette tips 1440 are removable and replaceable on the pipette 1400 and may be effectively disposable or consumable components of the pipetting system 1401.

[0614] The pipette 1400 may be constructed and operated, for example, in the same manner as described herein with respect to the pipette 600 .

[0615] See also Fig.60 and 66, the pipette 1400 can be understood to have a longitudinal axis AA and a distal end 1400A. The pipette 1400 includes a pipette orifice 1404, a tubular barrel 1410, a tubular tip adapter 1416, a driver (in the form of a plunger) 1420, a plunger drive mechanism 1424, and an ejection system 1431. The barrel 1410 includes a pipette shaft 1414 that terminates at the distal end 1400A. The tip adapter 1416 is mounted or formed on the distal end 1400A. The pipette orifice 1404 is located at the distal end 1400A.

[0616] See also Fig.66 , the barrel 1410 includes a barrel passage 1412. The passage 1412 is longitudinally aligned with the axis AA and extends rearwardly from the distal end 1400A to an opposite rear end.

[0617] The plunger 1420 serves as a driver and is mounted in the passage 1412 so that the plunger 1420 can slidably translate relative to the barrel 1410 along the plunger axis P7-P7 in an extension direction E14 and an opposite retraction direction E16 ( Fig.66 ).

[0618] The plunger 1420 includes an integral piston engagement or coupling feature 1422 ( Fig.66 ). In some embodiments and as shown, the piston coupling feature 1422 includes a groove 1422A. For example, the piston coupling feature 1422 can be constructed and operated in the same manner as described herein for the piston coupling feature 646.

[0619] The plunger drive mechanism 1424 is selectively operable to drive the plunger 1420 to translate in each of the extension direction E14 and the retraction direction E16. The plunger drive mechanism 1424 may be a linear drive mechanism. The plunger drive mechanism 1424 may include an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes a motor. In some embodiments, the plunger drive mechanism 1424 is manually operable and does not include an actuator. For example, an extension, a lever, a knob, or other manual drive features may be used to push and pull the plunger member 1424.

[0620] The tip adapter 1416 is configured to removably secure a pipette tip 1440 to the end 1400A of the pipette 1400 in the same manner as described above with respect to the tip adapter 156 .

[0621] See also Fig.60 and 66, the ejection system 1431 includes an ejector member or sleeve 1430 and an ejector drive mechanism 1432. The ejector sleeve 1430 is mounted around the barrel 1410 so that the ejector sleeve 1430 can be slidably translated relative to the barrel 1410 along the ejector axis P8-P8 in the extension direction E18 and the opposite retraction direction E20. The ejector axis P8-P8 can be coaxial with the plunger axis P7-P7.

[0622] See also Figure 61-65 , the PD pipette tip 1440 includes a tubular tip body 1450, a piston 1460 slidably mounted in the tip body 1450, and an integrated piston constraint mechanism 1471. The piston constraint mechanism 1471 includes an interlocking insert 1470.

[0623] See also Fig.63 , the tip body 1450 extends from a distal end 1450A to a proximal end 1450B. The tip body 1450 includes a distal tip portion or front section 1452A, a middle section 1452B, and a rear section 1452C. The front section 1452A defines a front chamber or tip passage 1455A. The rear section 1452C defines a rear chamber 1455C. The middle section 1452B defines an intermediate chamber 1455B between the tip passage 1455A and the rear chamber 1455C. The tip passage 1455A and chambers 1455B, 1455C together form a combined volume or tip body passage 1455.

[0624] The rear section 1452C includes a mounting section 1455D and defines a port opening 1458. A tip or pipetting orifice 1456 is defined in the distal end 1450A. The passageway 1455 terminates at the port opening 1458 and the pipetting orifice 1456.

[0625] The tip body 1450 may be formed of any suitable material or materials. In some embodiments, the tip body 1450 is formed of a polymer. In some embodiments, the tip body 1450 is formed of a thermoplastic. Suitable materials for the tip body 1450 may include, but are not limited to, polyethylene (PE). In some embodiments, the tip body 1450 is a rigid single component. In some embodiments, the tip body 1450 is a unitary component.

[0626] The piston 1460 can be arranged relative to the tip body 1450 along the piston axis P9-P9 ( Fig.62 ) in the extended or ready position ( Fig.62 and 66 ) and the retracted position (e.g. Fig.70 )

[0627] Piston 1460( Fig.64) extends from the distal end 1460A to the proximal end 1460B. The piston 1460 includes a piston shaft 1462, a sealing feature or rib 1462A, an intermediate portion 1463, a rear extension 1464, an interlocking feature or flange 1466, and an integral plunger engagement or coupling feature 1468.

[0628] The piston shaft 1462 extends rearwardly from the distal end 1460A. An annular sealing rib 1462A is located at the distal end 1460A and forms a dynamic seal with the inner diameter of the front passage 1455A. In some embodiments, when the piston 1460 is in the ready or extended position, the distal end 1460A is positioned at or near the pipetting orifice 1456.

[0629] The middle section 1463 extends rearward from the proximal end of the piston shaft 1462. In some embodiments, the outer diameter of the middle section 1463 is greater than the outer diameter of the piston shaft 1462.

[0630] The rear extension 1464 extends rearward from the proximal end of the middle section 1463. In some embodiments, the outer diameter of the rear extension 1464 is greater than the outer diameter of the middle section 1463.

[0631] The plunger coupling feature 1468 is located or formed on the proximal end of the rear extension 1464. The plunger coupling feature 1468 is configured to be received in the groove 1422A to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468. The plunger coupling feature 1468 shown includes two or more opposed, resiliently deflectable legs 1468A that are configured to be received in the groove 1422A to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468. However, any suitable structure that enables the plunger coupling feature 1468 to be releasably coupled to the piston coupling feature 1422 may be used for the plunger coupling feature 1468.

[0632] For example, the plunger coupling feature 1468 may include two or more opposing, resiliently deflectable legs 1468A configured to be received in the slots 1422A to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468 .

[0633] Flange 1466 is annular and is axially positioned between plunger coupling feature 1468 and intermediate section 1463. Flange 1466 protrudes radially outward from rear extension 1464. In some embodiments, flange 1466 is substantially concentric with axis P9-P9. In some embodiments, flange 1466 has a width W20 ( Fig.64 ).

[0634] The piston 1460 may be formed of any suitable material or materials. In some embodiments, the piston 1460 is formed of a polymer. In some embodiments, the piston 1460 is formed of a thermoplastic. Suitable materials for the piston 1382 may include plastics, thermoplastics, or high temperature resistant thermoplastics, such as polyetheretherketone (PEEK). In some embodiments, the piston shaft 1462, the middle section 1463, the rear extension 1464, the flange 1466, and the plunger coupling feature 1468 form a rigid single component. In some embodiments, the piston shaft 1462, the middle section 1463, the rear extension 1464, the flange 1466, and the plunger coupling feature 1468 form an integral component together.

[0635] like Fig.62 As shown in FIG. 14 , the interlocking insert 1470 is located in the rear chamber 1455C. The interlocking insert 1470 is fixed in the rear chamber 1455C to prevent relative axial displacement between the interlocking insert 1470 and the tip body 1450.

[0636] Interlocking insert 1470 ( Fig.65 ) has a distal end 1470A and an opposing proximal end 1470B. The interlocking insert 1470 is tubular and includes a front section 1472A (at end 1470A) defining a front opening 1474A and a rear section 1472B (at end 1470B) defining a rear opening 1474B. A passage 1474 extends from opening 1474A to opening 1474B. A pair of opposing slots 1475 extend through the front section 1472A from the rear section 1472B toward the distal end 1470A.

[0637] The interlocking insert 1470 further includes a latch in the form of a pair of opposing latch legs 1476. Each leg 1476 has a leg axis P10-P10 and extends axially from a proximal end 1476B to a distal end 1476A. Each proximal end 1476B is connected to the rear section 1472B, and each distal end 1476A is free so that the leg 1476 cantilevers out from the rear section 1472B. The legs 1476 are circumferentially spaced from each other about the axis P9-P9 and are circumferentially aligned with the slot 1475.

[0638] The interlocking insert 1470 may be formed of any suitable material or materials. In some embodiments, the interlocking insert 1470 is formed of a polymer and / or a synthetic polymer. In some embodiments, the interlocking insert 1470 is formed of a thermoplastic. Suitable materials for the interlocking insert 1470 may include, but are not limited to, polyvinyl chloride (PVC). In some embodiments, the interlocking insert 1470 is a rigid, single component. In some embodiments, the interlocking insert 1470 is a unitary component.

[0639] The interlocking insert 1470 can be fastened or bonded (e.g., by adhesive or co-molding) to the tip body 1450. In other embodiments, the interlocking insert 1470 is integrally formed with the tip body 1450. In some embodiments, the interlocking insert 1470 and the tip body 1450 are together formed into a single or unitary component. In other embodiments, the interlocking insert 1470 is secured to the tip body 1450 by mating mechanical features on the interlocking insert 1470 and the tip body 1450.

[0640] The piston restraint mechanism 1471 is operable to selectively limit movement between the piston 1460 and the tip body 1450. The piston restraint mechanism 1471 includes a flange 1466 and a latch leg 1476 of the interlocking insert 1470. The latch leg 1476 can be positioned in a latched position (e.g., Fig.62 and 66 and unlatched positions (as shown in Fig.68 The piston restraint mechanism 1471 may be positioned in a restraint structure (such as Fig.62 and 66 ) and the release structure (as shown in Fig.68 In each of the ).

[0641] When the piston restraint mechanism 1471 is in the restraining structure, the latch leg 1476 is in the latched position and interlocks with the flange 1466 to prevent the axial displacement of the piston 1460 in the retraction direction E24 beyond a specified position relative to the tip body 1450.

[0642] When the piston restraint mechanism 1471 is in the release configuration, the latch legs 1476 do not interlock with the flanges 1466, so that they permit axial displacement of the piston 1460 in the retraction direction E24 beyond a specified position relative to the tip body 1450. In some embodiments and as shown, when in the release configuration, the piston restraint mechanism 1471 does not restrict movement between the piston 1460 and the tip body 1450.

[0643] In the latched position, the legs 1476 are inclined, tapered or angled radially inwardly such that the axis P10-P10 of each leg 1476 forms an angle AL ( Fig.65 ). In the latched position, the distal end 1470A of the leg 1476 is axially aligned with a portion of the flange 1466. In some embodiments, the angle AL is in the range of about 2 degrees to 30 degrees.

[0644] In some embodiments, the insert 1470 is configured such that in the latched position, the legs 1476 are elastically bent, folded, or deflected outwardly from their relaxed position (ie, in direction E28; Fig.65). As a result, the leg 1476 is continuously loaded against the rear section 1464 of the piston 1460 and the distal end 1470A of the leg 1476 is thereby maintained aligned with the flange 1466.

[0645] In some embodiments, the leg 1476 is resilient along its length so that the leg 1476 can be resiliently bent, folded, or deflected from a latched position to an unlatched position. In some embodiments, the proximal end 1476B is resiliently connected to the rear section 1472B so that the leg 1476 can be resiliently deflected about the connection from a locked position to an unlatched position.

[0646] The liquid handling system 10 and the pipetting system 1401 can be used according to some methods as follows to aspirate and / or dispense one or more liquid samples.

[0647] First, the PD pipette tip 1440 is placed as shown in FIG. Fig.62 and Fig.66 In the constrained configuration shown in . For example, the tip 1440 can be held in a pipette tip supply rack.

[0648] If not already retracted, the plunger 1420 is retracted (eg, Fig.66 ). Fig.66 As shown in , the pipette shaft 1414 moves along the insertion direction I to insert the pipette distal end 1400A into the mounting section 1455D. Fig.67 As shown in , the pipette shaft 1414 is further inserted into the tip body 1450 until the tip adapter 1416 engages the leg 1476. Fig.68 As shown in , the pipette shaft 1414 is further inserted in this manner until the tip adapter 1416 reaches a specified depth within the rear chamber 1455C. Fig.68 As shown in , the plunger 1420 can be retracted relative to the pipette shaft 1414 to provide clearance between the piston 1460 and the distal end of the plunger 1420. When the tip adapter 1416 is translated to a specified depth, the outer diameter of the tip adapter 1416 shifts or forces the legs 1476 to pivot, fold or deflect in the opposite radially outward direction E28 to their unlatched position. Fig.68 As shown in , tip 1440 is thereby in its released configuration.

[0649] During insertion of the pipette shaft 1414, the ejector sleeve 1430 is positioned away from the distal end 1400A or displaced relative to the barrel 1410 in the retraction direction E20 to make room for the tip body 1450. For example, when the pipette shaft 1414 is inserted, the ejector sleeve 1430 can be driven by the tip body 1450 in the retraction direction E20.

[0650] Then, if Fig.69As shown in FIG. 1 , the plunger drive mechanism 1424 drives the plunger 1420 to translate along the extension direction E14 until the piston coupling feature 1422 interlocks or couples with the plunger coupling feature 1468. The plunger 1420 is thereby mechanically coupled to the piston 1460.

[0651] With the tip 1440 in the released configuration and the plunger 1420 and piston 1460 coupled, the pipette 1400 and tip 1440 may be used in the manner described herein with respect to the pipette tip 670 ( Fig.32 ) is aspirated and dispensed in the manner described above. Plunger 1420 is driven by plunger drive mechanism 1424 in directions E14 and E16 to translate piston 1460 through tip passage 1455A while tip 1440 remains in the release configuration.

[0652] When the piston 1460 is pulled by the plunger 1420 in the retraction direction E24, the piston shaft 1462 translates relative to the front section 1452A in the direction E24 (e.g., as Fig.70 ), which expands the volume of fluid in the tip passage 1455A. This expansion generates a negative pressure in the tip passage 1455A, which draws the liquid volume LV of the liquid sample LS into the tip passage 1455A through the orifice 1456.

[0653] When the piston 1460 is pushed by the plunger 1420 along the extension direction E22, the piston shaft 1462 translates along the direction E22 relative to the front section 1452A (e.g., as Fig.71 ), which displaces or reduces the volume of fluid in the tip passage 1455A. This reduction generates a positive pressure in the tip passage 1455A, which discharges or dispenses the liquid volume LV of the liquid sample LS from the tip passage 1455A through the orifice 1456.

[0654] When it is no longer desired to use the pipette tip 1440 on the pipette 1400, the piston restraint mechanism 1471 may be used to remove the tip 1440 from the pipette 1400 as follows.

[0655] With tip 1440 in a released configuration and plunger 1420 and piston 1460 coupled (eg, Fig.71 As shown in FIG. 1 , the ejector drive mechanism 1432 translates the ejector sleeve 1430 relative to the pipette shaft 1414 in the extension direction E18, while the plunger drive mechanism 1424 drives the plunger 1420 relative to the pipette shaft 1414 in the direction E14. Fig.72 As shown in , the tip body 1450 and the piston 1460 are thereby pushed in the forward direction F relative to the pipette shaft 1414. As a result, the tip adapter 1416 slides out from between the legs 1476, which allows the legs 1476 to elastically return in the radial direction E30 (by bending, pivoting or folding, as shown in FIG. Fig.72 and 73 ).

[0656] The ejector sleeve 1430 and plunger 1420 are driven in this manner until the tip 1440 and pipette 1400 reach Fig.73 . The leg 1476 is thereby returned to its latched position and the tip 1440 adopts its restrained configuration. In some embodiments, the plunger 1420 translates along the extension direction E14 with the ejector sleeve 1430 to maintain the relative axial positioning between the flange 1466 and the distal end 1476A of the leg 1476, so that the distal end 1476A is closed around the piston 1460 behind the flange 1466.

[0657] like Fig.74 As shown in FIG. 1 , the tip 1440 is in a constrained configuration and the plunger 1420 and piston 1460 are as shown in FIG. Fig.73 In the case of the connection shown in FIG. 1 , the plunger drive mechanism 1424 drives the plunger 1420 to translate in the retraction direction E16 relative to the pipette shaft 1414 and the tip body 1450. The engagement between the leg 1476 and the flange 1466 prevents the piston 1460 from moving in the direction E24 ( Fig.70 ) translates relative to the tip body (i.e., legs 1476 hold piston 1460 in place). As a result, Fig.74 As shown in , the piston coupling feature 1422 is separated from the plunger coupling feature 1468 (ie, the plunger 1420 is disconnected from the piston 1460).

[0658] Then, if Fig.75 As shown in FIG. 1 , the ejector drive mechanism 1432 translates the ejector sleeve 1430 relative to the pipette shaft 1414 in the extension direction E18 to force the tip body 1450 (and thereby the tip 1440 ) to disengage the pipette 1400 in the forward direction F.

[0659] In other embodiments, the latch legs 1476 are integrally formed with the tip body 1450. In some embodiments, an integral latch or latching feature other than the latch legs 1476 is provided on the pipette tip to selectively restrain the piston 1460. Each latch can be configured as a tab, protrusion, or sleeve.

[0660] Piston coupling features and plunger coupling features of other designs may be used in place of piston coupling feature 1422 and plunger coupling feature 1468 to releasably couple the plunger to the piston.

[0661] In some embodiments, the interlocking features 1466, 1476 may be provided with other designs or configurations.

[0662] In some embodiments, the PD pipette tip 1440 is provided with a vent hole 1452V ( Fig.63 ) or other vent passage to prevent overpressure (positive or negative) in the rear chamber 1455C, which could interfere with the operation of the pipette or cause damage to the pipette (e.g., damage to the pressure sensor).

[0663] The present technology has been described herein with reference to the accompanying drawings, in which exemplary embodiments of the present technology are shown. In the accompanying drawings, the relative sizes of regions or features may be exaggerated for clarity. However, the present technology may 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 be thorough and complete and will fully convey the scope of the present technology to those skilled in the art.

[0664] It should be understood that although the terms first, second, etc. may be used herein to describe various elements, components, regions, layers, and / or sections, these elements, components, regions, layers, and / or sections should not be limited to these terms. These terms may only be used to distinguish one element, component, region, layer, or section from another region, layer, or section. Therefore, the first element, component, region, layer, or section discussed below may be referred to as the second element, component, region, layer, or section without departing from the teachings of the present technology.

[0665] For ease of description, spatially relative terms such as "below," "below," "lower," "above," "upper," etc. may be used herein to describe the relationship of one element or feature to another element or elements or one or more features as shown in the figures. It should be understood that in addition to the orientation depicted in the figures, spatially relative terms are intended to cover different orientations of the device in use or operation. For example, if the device in the drawings is flipped, the elements described as being "below" or "below" other elements or features would then be oriented "above" the other elements or features. Therefore, the exemplary term "below" can cover both the above and below orientations. The device can be oriented in other ways (rotated 90° or in other orientations), and the spatially relative descriptive language used herein is interpreted accordingly.

[0666] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless expressly stated otherwise. It should also be understood that the terms "comprising", "including", "comprising", and / or "comprising" when used in this specification indicate the presence of the indicated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or combinations thereof. It should be understood that when an element is referred to as being "connected" or "coupled" to another element, it may be directly connected or coupled to the other element, or there may also be intervening elements. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0667] The term "automatically" means that the operation is substantially and completely performed without human intervention or manual input and may be programmatically directed or performed.

[0668] The term "programmatically" refers to operations directed and / or performed primarily electronically by computer program modules, codes, and / or instructions.

[0669] The term "electronically" includes both wireless and wired connections between components.

[0670] Those skilled in the art may make many variations and modifications with the benefit of this disclosure without departing from the spirit and scope of the present invention. Therefore, it must be understood that the illustrated embodiments are described only for the purpose of illustration and should not be considered as limiting the present invention as defined by the appended claims. Therefore, the appended claims should be understood to include not only the combination of elements described literally, but also all equivalent elements for performing substantially the same functions in substantially the same manner to obtain substantially the same results. Therefore, the claims should be understood to include the content specifically shown and described above, the content that is conceptually equivalent, and the content that contains the basic idea of ​​the present invention.

Claims

1. An automatic liquid transfer system, comprising: A pipette comprising: Pipetting channel; a first plunger mechanism operable to vary pressure in the pipetting channel to aspirate or dispense liquid; and A second plunger mechanism is operable to vary pressure in the pipetting channel to aspirate or dispense the liquid.

2. The automatic pipetting system according to claim 1, wherein: The first plunger mechanism and the second plunger mechanism are operable to displace a volume of air in the pipetting channel.

3. The automatic pipetting system according to claim 1, wherein: The first plunger mechanism and the second plunger mechanism are operable independently of each other to change the pressure in the pipetting channel.

4. The automatic pipetting system according to claim 1, wherein: The pipetting system comprises a pipetting orifice and a liquid collection volume; and The first and second plunger mechanisms are operable to change pressure in the pipetting channel to draw the liquid into the liquid collection volume through the pipetting orifice or dispense the liquid from the liquid collection volume through the pipetting orifice.

5. The automatic pipetting system according to claim 4, wherein: The automated pipetting system includes a pipette tip removably coupled to the pipette, wherein the pipette tip includes the liquid collection volume and the pipetting orifice.

6. The automatic pipetting system according to claim 5, wherein: The pipette includes an ejection mechanism operable to force the pipette tip out of the pipette.

7. The automatic pipetting system according to claim 1, wherein: the first plunger mechanism comprising a first chamber and a first plunger, wherein the first plunger mechanism is operable to move the first plunger through the first chamber to change the pressure in the pipetting channel; and The second plunger mechanism includes a second chamber and a second plunger, wherein the second plunger mechanism is operable to move the second plunger through the second chamber to change the pressure in the pipetting channel.

8. The automatic pipetting system according to claim 7, wherein: The first plunger mechanism includes a first plunger actuator operable to move the first plunger through the first chamber; the second plunger mechanism comprises a second plunger actuator operable to move the second plunger through the second chamber; and The automated pipetting system includes a controller configured to automatically and programmatically control the first plunger actuator and the second plunger actuator.

9. The automatic pipetting system according to claim 8, wherein: The first plunger actuator and the second plunger actuator are linear actuators.

10. The automatic pipetting system according to claim 7, wherein: The first plunger mechanism is configured to translate the first plunger along a first plunger axis; the second plunger mechanism being configured to translate the second plunger along a second plunger axis; The first plunger has a first cross-sectional area in a plane orthogonal to the first plunger axis; The second plunger has a second cross-sectional area in a plane orthogonal to the second plunger axis; and The second cross-sectional area is greater than the first cross-sectional area.

11. The automatic pipetting system according to claim 10, wherein: The second cross-sectional area is at least three times the first cross-sectional area.

12. The automatic pipetting system according to claim 7, wherein: the first plunger mechanism being configured to translate the first plunger through the first chamber; the second plunger mechanism being configured to translate the second plunger through the second chamber; the first plunger displaces a volume of air in the first chamber at a first air volume displacement rate per unit translation; the second plunger displaces the volume of air in the second chamber at a second air volume displacement rate per unit translation; and The second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

13. The automatic pipetting system according to claim 12, wherein: The second air volume transfer rate per unit translation is at least three times greater than the first air volume transfer rate per unit translation.

14. The automatic pipetting system according to claim 7, wherein: the first plunger mechanism being configured to provide a first maximum air volume transfer; the second plunger mechanism being configured to provide a second maximum air volume transfer; and The second maximum air volume transfer is greater than the first maximum air volume transfer.

15. The automatic pipetting system according to claim 14, wherein: The second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

16. The automatic pipetting system according to claim 7, wherein: The first chamber has a first chamber volume; and The second chamber has a second chamber volume greater than the first chamber volume.

17. The automatic pipetting system according to claim 16, wherein: The volume of the second chamber is at least ten times the volume of the first chamber.

18. The automatic pipetting system according to claim 7, wherein: The pipette includes a valve to selectively control fluid communication between the second chamber and a port to atmosphere.

19. The automatic pipetting system according to claim 7, wherein: The pipette includes at least one valve to selectively control fluid communication between the second chamber and the pipetting channel.

20. The automatic pipetting system according to claim 19, wherein: The first plunger is disposed in the pipetting channel.

21. The automatic pipetting system according to claim 7, wherein: The first plunger is disposed in the pipetting channel.

22. The automatic pipetting system according to claim 1, wherein: The automated pipetting system includes a controller configured to automatically and programmatically control the first plunger mechanism and the second plunger mechanism.

23. The automatic pipetting system according to claim 22, wherein: The automated pipetting system includes a pressure sensor coupled to the pipetting channel, wherein the controller is configured to receive a pipetting channel pressure signal from the pressure sensor indicating a pressure in the pipetting channel.

24. The automated pipetting system of claim 22, wherein: The pipette includes a valve to selectively control fluid communication between the second plunger mechanism and the pipetting channel; and The controller is configured to automatically and programmatically control the valve.

25. A method of operating an automated pipetting system, the method comprising: The at least one control circuit performs the following operations: operating a first plunger mechanism of a pipette of the automatic pipetting system to change the pressure in a pipetting channel of the pipette to aspirate or dispense liquid; and The second plunger mechanism of the pipette is operated to change the pressure in the pipetting channel to aspirate or dispense the liquid.

26. The method according to claim 25, wherein: The method includes operating a first plunger mechanism and a second plunger mechanism to displace an air volume in the pipetting channel.

27. The method according to claim 25, wherein: The method includes operating the first plunger mechanism and the second plunger mechanism independently of each other to change the pressure in the pipetting channel.

28. The method according to claim 25, wherein: The method includes operating the first plunger mechanism and the second plunger mechanism to draw the liquid into the liquid collection volume through the pipetting orifice or dispense the liquid from the liquid collection volume through the pipetting orifice.

29. The method according to claim 28, wherein: The method includes removably coupling a pipette tip to the pipette, wherein the pipette tip includes the liquid collection volume and the pipetting orifice.

30. The method of claim 29, wherein: The method includes operating an ejection mechanism to force the pipette tip out of the pipette.

31. The method of claim 25, wherein: The first plunger mechanism includes a first chamber and a first plunger; The second plunger mechanism includes a second chamber and a second plunger; The method includes operating the first plunger mechanism to move the first plunger through the first chamber to change the pressure in the pipetting channel; and The method includes operating a second plunger mechanism, including moving the second plunger through the second chamber to change the pressure in the pipetting channel.

32. The method of claim 31, wherein: The first plunger mechanism includes a first plunger actuator operable to move the first plunger through the first chamber; the second plunger mechanism comprises a second plunger actuator operable to move the second plunger through the second chamber; and The method includes automatically and programmatically controlling the first plunger actuator and the second plunger actuator using a controller.

33. The method of claim 32, wherein: The first plunger actuator and the second plunger actuator are linear actuators.

34. The method of claim 31, wherein: The first plunger mechanism is configured to translate the first plunger along a first plunger axis; The second plunger mechanism is configured to translate the second plunger along a second plunger axis; The first plunger has a first cross-sectional area in a plane orthogonal to the first plunger axis; The second plunger has a second cross-sectional area in a plane orthogonal to the second plunger axis; and The second cross-sectional area is greater than the first cross-sectional area.

35. The method of claim 34, wherein: The second cross-sectional area is at least three times the first cross-sectional area.

36. The method of claim 31, wherein: the first plunger mechanism being configured to translate the first plunger through the first chamber; the second plunger mechanism being configured to translate the second plunger through the second chamber; the first plunger displaces a volume of air in the first chamber at a first air volume displacement rate per unit translation; the second plunger displaces the volume of air in the second chamber at a second air volume displacement rate per unit translation; and The second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

37. The method of claim 36, wherein: The second air volume transfer rate per unit translation is at least three times greater than the first air volume transfer rate per unit translation.

38. The method of claim 31, wherein: the first plunger mechanism being configured to provide a first maximum air volume transfer; the second plunger mechanism being configured to provide a second maximum air volume transfer; and The second maximum air volume transfer is greater than the first maximum air volume transfer.

39. The method of claim 38, wherein: The second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

40. The method of claim 31, wherein: The first chamber has a first chamber volume; and The second chamber has a second chamber volume greater than the first chamber volume.

41. The method of claim 40, wherein: The volume of the second chamber is at least ten times the volume of the first chamber.

42. The method of claim 31, wherein: The method includes selectively controlling fluid communication between the second chamber and the pipetting channel using a valve forming part of the pipette.

43. The method of claim 42, wherein: The first plunger is disposed in the pipetting channel.

44. The method of claim 31, wherein: The first plunger is disposed in the pipetting channel.

45. The method of claim 25, wherein: The method includes automatically and programmatically controlling the first plunger mechanism and the second plunger mechanism using a controller.

46. ​​The method of claim 45, wherein: The pipette includes a pressure sensor coupled to the pipetting channel; and The controller receives a pipetting channel pressure signal from the pressure sensor indicating a pressure in the pipetting channel.

47. The method of claim 45, wherein: The pipette includes a valve to selectively control fluid communication between the second plunger mechanism and the pipetting channel; and The method includes automatically and programmatically controlling the valve using the controller.

48. A liquid transfer system comprising: A pipette comprising: Cylinder; Pipetting channel; a passageway defined in the barrel and in fluid communication with the pipetting channel, the passageway comprising a rear chamber and a front chamber between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber for translation relative to the passage through a front plunger stroke; a rear plunger mounted in the rear chamber for translation relative to the passage through a rear plunger stroke; and a front seal surrounding the front plunger; in: During a first portion of the front plunger's stroke, the front chamber is fluidly sealed from the rear chamber by the front seal, and translation of the front plunger in the front chamber generates a pressure change in the pipetting channel to aspirate or dispense liquid; and During a second portion of the front plunger stroke, the front chamber is fluidly coupled to the rear chamber, and translation of the rear plunger in the rear chamber along the rear plunger stroke generates a pressure change in the pipetting channel to aspirate or dispense the liquid.

49. The pipetting system of claim 48, wherein: The pipette includes a plunger component, the plunger component including both a front plunger and a rear plunger; and The plunger member is mounted in the passageway to translate through a plunger member stroke including the front plunger stroke and the rear plunger stroke.

50. The pipetting system of claim 48, wherein: Translation of the front plunger in the front chamber and translation of the rear plunger in the rear chamber displaces the column of air in the pipetting channel.

51. The pipetting system of claim 48, wherein: During a first portion of the front plunger's stroke, the connecting opening between the front chamber and the rear chamber is blocked by the front plunger; and During a second portion of the front plunger's stroke, the connection opening is unobstructed by the front plunger and the front chamber is fluidly coupled to the rear chamber through the connection opening.

52. The pipetting system of claim 48, wherein: The front seal includes an annular sealing member slidably engaging the front plunger or the barrel.

53. The pipetting system of claim 48, wherein: The pipetting system includes a rear seal surrounding the rear plunger.

54. The pipetting system of claim 53, wherein: The rear seal includes an annular sealing member slidably engaging the rear plunger or the barrel.

55. The pipetting system of claim 53, wherein: The rear chamber is defined between the front seal and the rear seal.

56. The pipetting system of claim 48, wherein: The pipetting system includes a pressure relief valve arranged and configured to release pressure in the rear chamber during a first portion of the front plunger stroke.

57. The pipetting system of claim 48, wherein: The pipetting system includes a pressure sensor arranged and configured to detect pressure in the pipetting channel.

58. The pipetting system of claim 48, wherein: The pipetting system includes an opening mechanism selectively operable to place the rear chamber in fluid communication with the front chamber when the front plunger is not in the second portion of the front plunger stroke.

59. The pipetting system of claim 58, wherein: The opening mechanism includes a valve selectively operable to place the rear chamber in fluid communication with the front chamber when the front plunger is not in the second portion of the front plunger stroke.

60. The pipetting system of claim 59, wherein: The valve is selectively operable to place the rear chamber in fluid communication with a port to atmosphere.

61. The pipetting system of claim 58, wherein: The pipetting system is configured such that a front seal forms a seal around the front plunger in a first portion of the front plunger stroke and in a second portion of the front plunger stroke.

62. The pipetting system of claim 48, wherein: The pipetting system includes a pipette tip removably coupled to a barrel, wherein the pipette tip includes a liquid collection volume fluidly coupled to the pipetting channel, and a tip orifice in fluid communication with the liquid collection volume.

63. The pipetting system of claim 48, wherein: The pipetting system comprises: at least one actuator for driving the front plunger and the rear plunger through the front plunger stroke and the rear plunger stroke; and A controller is configured to automatically and programmatically operate the at least one actuator.

64. The pipetting system of claim 48, wherein: The front plunger stroke and the rear plunger stroke extend along the plunger axis; The front plunger has a first cross-sectional area in a plane orthogonal to the plunger axis; The rear plunger has a second cross-sectional area in a plane orthogonal to the plunger axis; and The second cross-sectional area is greater than the first cross-sectional area.

65. The pipetting system of claim 64, wherein: The second cross-sectional area is at least three times the first cross-sectional area.

66. The pipetting system of claim 48, wherein: the front plunger displacing a volume of air in the front chamber at a first air volume displacing rate per unit translation; The rear plunger displaces the volume of air in the rear chamber at a second air volume displacement rate per unit translation; and The second air volume transfer rate per unit translation is greater than the first air volume transfer rate per unit translation.

67. The pipetting system of claim 66, wherein: The second air volume transfer rate per unit translation is at least three times greater than the first air volume transfer rate per unit translation.

68. The pipetting system of claim 48, wherein: the front plunger being configured to provide a first maximum air volume transfer in the front chamber; The rear plunger is configured to provide a second maximum air volume transfer in the rear chamber; and The second maximum air volume transfer is greater than the first maximum air volume transfer.

69. The pipetting system of claim 68, wherein: The second maximum air volume transfer is at least ten times greater than the first maximum air volume transfer.

70. The pipetting system of claim 48, wherein: The antechamber has an antechamber volume; and The rear chamber has a rear chamber volume greater than a volume of the front chamber.

71. The pipetting system of claim 70, wherein: The volume of the rear chamber is at least ten times the volume of the front chamber.

72. A method for pipetting a liquid, the method comprising: A pipette is provided, comprising: Cylinder; Pipetting channel; a passageway defined in the barrel and in fluid communication with the pipetting channel, the passageway comprising a rear chamber and a front chamber between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber to perform a front plunger stroke; a rear plunger installed in the rear chamber to perform a rear plunger stroke; and a front seal surrounding the front plunger; The front plunger is translated through the front plunger stroke and the rear plunger is translated through the rear plunger stroke to aspirate or dispense liquid, wherein: During a first portion of the front plunger's stroke, the front chamber is fluidly sealed from the rear chamber by the front seal, and translation of the front plunger in the front chamber generates a pressure change in the pipetting channel to aspirate or dispense liquid; and During a second portion of the front plunger stroke, the front chamber is fluidly coupled to the rear chamber, and translation of the rear plunger in the rear chamber along the rear plunger stroke generates a second pressure change in the pipetting channel to aspirate or dispense the liquid.

73. The method of claim 72, wherein: The pipette includes a plunger component, the plunger component including both a front plunger and a rear plunger; The plunger member is mounted in the passageway to translate through a plunger member stroke including the front plunger stroke and the rear plunger stroke; and Translation of the front plunger through the front plunger stroke and translation of the rear plunger through the rear plunger stroke is accomplished by translating the plunger member through the plunger member stroke.

74. The method of claim 72, wherein: Translation of the front plunger in the front chamber and translation of the rear plunger in the rear chamber displaces air volume in the pipetting channel.

75. The method of claim 72, wherein: During a first portion of the front plunger's stroke, the connecting opening between the front chamber and the rear chamber is blocked by the front plunger; and During a second portion of the front plunger's stroke, the connection opening is unobstructed by the front plunger and the front chamber is fluidly coupled to the rear chamber through the connection opening.

76. The method of claim 72, wherein: The method comprises: translating the front plunger in a first direction through a first portion of the front plunger stroke to aspirate the liquid; and thereafter translating the front plunger in a second direction opposite the first direction through a first portion of the front plunger travel to dispense the liquid; Wherein between translating the front plunger in the first direction and translating the front plunger in the second direction, the front plunger does not translate through a second portion of the front plunger travel.

77. The method of claim 72, wherein: The method comprises: translating the front plunger in a first direction through a first portion and a second portion of the front plunger stroke to draw the liquid using the front plunger and the rear plunger; and thereafter The front plunger is translated in a second direction opposite the first direction through first and second portions of the plunger travel to dispense the liquid using the front plunger and the rear plunger.

78. The method of claim 72, wherein: The method comprises: With the front plunger in the first portion of the front plunger stroke, operating the opening mechanism to place the rear chamber in fluid communication with the front chamber; and thereafter With the rear chamber in fluid communication with the front chamber, the rear plunger is translated along the rear plunger stroke to aspirate the liquid.

79. The method of claim 78, wherein: The front seal forms a seal around the front plunger throughout the front plunger stroke and the rear plunger stroke.

80. A liquid transfer system comprising: A pipette comprising: Cylinder; Pipetting channel; a passageway defined in the barrel and in fluid communication with the pipetting channel, the passageway comprising a rear chamber and a front chamber between the rear chamber and the pipetting channel; a front plunger mounted in the front chamber for translation relative to the passageway along a plunger axis; and a rear plunger mounted in the rear chamber for translation relative to the passageway along a plunger axis; in: Translation of the front plunger in the front chamber along the plunger axis generates a pressure change in the pipetting channel to aspirate or dispense liquid; The translation of the rear plunger in the rear chamber along the plunger axis generates a pressure change in the pipetting channel to aspirate or dispense the liquid; The front plunger has a first cross-sectional area in a plane orthogonal to the plunger axis; The rear plunger has a second cross-sectional area in a plane orthogonal to the plunger axis; and The second cross-sectional area is greater than the first cross-sectional area.

81. The pipetting system of claim 80, wherein: The pipette includes a plunger component, the plunger component including both a front plunger and a rear plunger; and The plunger member is mounted in the passageway for translation along the plunger axis.

82. A liquid transfer system comprising: Pipettes; air displacement pipette tips; as well as positive displacement pipette tip; in: The air-displacement pipette tip and the positive-displacement pipette tip are alternately and removably mountable on the pipette; When the air displacement pipette tip is mounted on the pipette, the pipette is operable to draw liquid into the air displacement pipette tip; and When the positive-displacement pipette tip is mounted on the pipette, the pipette is operable to draw liquid into the positive-displacement pipette tip.

83. The pipetting system of claim 82, wherein: The pipette includes a tip mounting interface configured to engage and releasably secure the air-displacement pipette tip and the positive-displacement pipette tip to the pipette.

84. The pipetting system of claim 83, wherein: The tip mounting interface is configured to form an air-tight fit with the air-displacement pipette tip when the air-displacement pipette tip is mounted on the pipette.

85. The pipetting system of claim 82, wherein: The air displacement pipette tip comprises: air displacement tip orifice; and a liquid collection volume in fluid communication with the air displacement tip orifice; and the positive displacement pipette tip comprises: positive displacement tip orifice; a tip passage in fluid communication with the positive-displacement tip orifice; and a piston slidably mounted in the tip passage; Wherein when the piston translates away from the positive-displacement tip orifice, the positive-displacement pipette tip is operable to generate negative pressure at the positive-displacement tip orifice to aspirate the liquid.

86. The pipetting system of claim 85, wherein: The pipette is operable to displace a volume of air in the air displacement pipette tip to generate a negative pressure at the air displacement tip orifice.

87. The pipetting system of claim 85, wherein: The pipette includes a plunger that is translatable to generate negative pressure at the air displacement tip orifice to aspirate the liquid when the air displacement pipette tip is mounted on the pipette.

88. The pipetting system of claim 85, wherein: The pipette includes a plunger configured to engage the piston and translate the piston through the tip passage when the positive-displacement pipette tip is mounted on the pipette.

89. The pipetting system of claim 85, wherein: The pipette includes a plunger; When the air displacement pipette tip is mounted on the pipette, the plunger is translatable to generate negative pressure at the air displacement tip orifice to aspirate the liquid; and The plunger is configured to engage the piston and translate the piston through the tip passage when the positive-displacement pipette tip is mounted on the pipette.

90. The pipetting system of claim 89, wherein: The pipette includes a chamber and a pipetting channel; the pipetting channel being fluidly coupled to the liquid collection volume when the air displacement pipette tip is mounted on the pipette; and The plunger is mounted to translate in the chamber to generate negative pressure in the pipetting channel.

91. The pipetting system of claim 90, wherein: said pipette being operable in each of an air displacement mode in which said air displacement pipette tip is mounted on said pipette and, alternatively, a positive displacement mode in which said positive displacement pipette tip is mounted on said pipette; and The chamber is sealed in the air displacement mode and is not sealed in the positive displacement mode.

92. The pipetting system of claim 91, wherein: The pipette comprises: a barrel defining the chamber; and an annular seal surrounding the plunger between the plunger and the barrel; and The annular seal seals the chamber in the air displacement mode and does not seal the chamber in the positive displacement mode.

93. The pipetting system of claim 91, wherein: The pipette includes a pressure sensor arranged and configured to output a detection signal indicative of the pressure in the chamber.

94. The pipetting system of claim 89, wherein: The pipette comprises: at least one plunger actuator for driving the plunger; and A controller is configured to automatically and programmatically operate the at least one actuator.

95. The pipetting system of claim 94, wherein: The at least one plunger actuator comprises a linear actuator.

96. The pipetting system of claim 85, wherein: The positive-displacement pipette tip includes a tip body defining the tip passage; and A vent port in the tip body for relieving pressure in a tip passage between the piston and the pipette.

97. A pipette comprising: Air displacement mechanism; as well as Positive displacement mechanism; in: The pipette is configured to mount an air-displacement pipette tip thereon, and alternatively to mount a positive-displacement pipette tip thereon; When the air displacement pipette tip is mounted on the pipette, the air displacement mechanism is operable to generate negative pressure in the air displacement pipette tip to draw the liquid into the air displacement pipette tip; and When the positive-displacement pipette tip is mounted on the pipette, the positive-displacement mechanism is operable to displace a piston of the positive-displacement pipette tip to draw the liquid into the positive-displacement pipette tip.

98. The pipette of claim 97, wherein: The pipette includes a plunger; When the air displacement pipette tip is mounted on the pipette, the plunger is translatable to generate the negative pressure in the air displacement pipette tip to aspirate the liquid; and The plunger is configured to engage the piston and translate the piston through a tip passage of the positive-displacement pipette tip when the positive-displacement pipette tip is mounted on the pipette.

99. A method for pipetting a liquid, the method comprising: With the air displacement pipette tip mounted on the pipette, operating the pipette to draw liquid into the air displacement pipette tip; And thereafter With a positive-displacement pipette tip mounted on the pipette, operating the pipette draws liquid into the positive-displacement pipette tip.

100. The method of claim 99, wherein: The method includes controlling at least one control circuit of at least one actuator to perform operations including: mounting the air displacement pipette tip on the pipette; removing the air displacement pipette tip from the pipette; mounting the positive displacement pipette tip on the pipette; as well as Remove the positive displacement pipette tip from the pipette.

101. A pipette tip comprising: a tip member, the tip member comprising a first end and a second end opposite the first end, the first end having an opening for aspirating and / or dispensing liquid, the second end for connecting to a pipette; as well as a conductive electrode located on the tip member and configured to output a signal in response to contact with the liquid, The first end of the tip member includes a non-conductive tip bottom adjacent the opening.

102. The pipette tip of claim 101, wherein: The conductive electrode is located on an outer surface of the tip member between the first end and the second end.

103. The pipette tip of claim 101, wherein: The conductive electrode is at least partially embedded in a surface of the tip member.

104. The pipette tip of claim 101, wherein: The bottom of the non-conductive tip is devoid of the conductive electrode.

105. The pipette tip of claim 101, wherein: The non-conductive tip base includes a portion of the conductive electrode having a non-conductive coating thereon.

106. The pipette tip of claim 101, wherein: The pipette tip further comprises: a conductive element at the second end of the tip member; and An electrically conductive connection extends along the tip member and electrically connects the electrically conductive electrode to the electrically conductive element.

107. The pipette tip of claim 106, wherein: The electrically conductive connection extends along an outer surface of the tip member.

108. The pipette tip of claim 106, wherein: The electrically conductive connection is at least partially embedded in the tip component.

109. The pipette tip of claim 101, wherein: The inner surface of the tip member is free of the conductive electrode.

110. The pipette tip of claim 109, wherein: The inner surface of the tip member is non-conductive, and the conductive electrode is a single electrode.

111. The pipette tip of claim 101, wherein: The non-conductive tip base includes a length of about 2 millimeters (mm) or more.

112. The pipette tip of claim 101, wherein: The conductive electrode has a shape defining a surface area that varies with distance from the opening.

113. The pipette tip of claim 101, wherein: The conductive electrode is configured to be coupled to a controller circuit configured to dynamically detect the level of the liquid and / or predict a loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal output by the conductive electrode.

114. An automatic liquid transfer system, comprising: a robotic arm assembly comprising an arm member adapted to hold a pipette and an actuator mechanism configured to move the arm member along at least one axis in response to a control signal; as well as A controller circuit coupled to the robotic arm assembly and configured to perform operations including: receiving a signal from a conductive electrode on a pipette tip, wherein the conductive electrode is located between a first end of the pipette tip having an opening therein for aspirating and / or dispensing liquid and a second end of the pipette tip opposite the first end and connected to the pipette; as well as In response to the signal from the conductive electrode, the control signal is transmitted to the actuator mechanism to move the arm member along the at least one axis toward or away from the surface of the liquid.

115. The system of claim 114, wherein: The operations further include dynamically detecting a level of the liquid based on a change in capacitance indicated by a signal from the conductive electrode, optionally independent of a shape or size of the liquid container.

116. The system of claim 115, wherein: dynamically detecting the level of the liquid includes predicting a loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal from the conductive electrode, Wherein the control signal is transmitted to the actuator mechanism in response to predicting a loss of contact.

117. The system of claim 115, wherein: The control signal varies based on the change in capacitance to move the arm member along the at least one axis toward or away from the liquid surface while maintaining contact between the pipette tip and the liquid.

118. The system of claim 114, wherein: The first end of the pipette tip includes a non-conductive tip bottom adjacent the opening.

119. The system of claim 118, wherein: The conductive electrode is located on an outer surface of the pipette tip between the first end and the second end.

120. The system of claim 118, wherein: The conductive electrode is at least partially embedded in the surface of the pipette tip.

121. The system of claim 118, wherein: The non-conductive tip has no conductive electrode at the bottom.

122. The system of claim 118, wherein: The non-conductive tip base includes a portion of a conductive electrode having a non-conductive coating thereon.

123. The system of claim 118, wherein: The inner surface of the pipette tip is free of the conductive electrode.

124. The system of claim 123, wherein: The inner surface of the tip member is non-conductive, and the conductive electrode is a single electrode.

125. The system of claim 114, wherein: The actuator mechanism includes a first operating mode in which the arm member is constrained to move along the at least one axis toward the liquid surface during aspiration and a second operating mode in which the arm member is constrained to move along the at least one axis away from the liquid surface during dispensing.

126. The system of claim 114, wherein: The operations further include: calculating the volume of liquid aspirated or dispensed based on the distance the arm member moves along the at least one axis; and Subsequent movement of the arm member along the at least one axis is controlled based on the calculated aspiration or dispense volume.

127. A method of operating an automated pipetting system, the method comprising: The computer readable instructions stored in the non-transitory storage medium are executed by the controller circuit to perform operations including: receiving a signal from a conductive electrode on a pipette tip, wherein the conductive electrode is located between a first end of the pipette tip having an opening therein for aspirating and / or dispensing liquid and a second end of the pipette tip opposite the first end and connected to the pipette; as well as In response to the signal from the conductive electrode, a control signal is transmitted to an actuator mechanism of a robotic arm assembly to move an arm member adapted to hold the pipette toward or away from a surface of the liquid along at least one axis.

128. The method of claim 127, wherein: The operations further include: The level of the liquid is dynamically detected based on a change in capacitance indicated by a signal from the conductive electrode, optionally independent of a shape or size of the liquid container.

129. The method of claim 128, wherein: Dynamically detecting the liquid level of the liquid includes: predicting a loss of contact between the pipette tip and the liquid based on a change in capacitance indicated by a signal from the conductive electrode, Wherein the control signal is transmitted to the actuator mechanism in response to predicting a loss of contact.

130. The method of claim 128, wherein: The control signal varies based on the change in the capacitance to move the arm member along the at least one axis toward or away from the liquid surface while maintaining contact between the pipette tip and the liquid.

131. The method of claim 127, wherein: The first end of the pipette tip includes a non-conductive tip base extending beyond the conductive electrode.

132. The method of claim 131, wherein: The conductive electrode is located on an outer surface of the pipette tip between the first end and the second end.

133. The method of claim 131, wherein: The conductive electrode is at least partially embedded in the surface of the pipette tip.

134. The method of claim 131, wherein: The bottom of the non-conductive tip is devoid of the conductive electrode.

135. The method of claim 131, wherein: The inner surface of the pipette tip is free of the conductive electrode.

136. The method of claim 135, wherein: The inner surface of the tip member is non-conductive, and the conductive electrode is a single electrode.

137. The method of claim 127, wherein: The operations further include: constraining the arm member to move along the at least one axis toward the liquid surface during the suctioning; and The arm member is constrained to move along the at least one axis away from the liquid surface during the dispensing.

138. The method of claim 127, wherein: The operations further include: calculating the volume of liquid aspirated or dispensed based on the distance of movement of the arm member along at least one axis; and Subsequent movement of the arm member along the at least one axis is controlled based on the calculated aspiration or dispense volume.

139. An automatic liquid transfer system, comprising: These include pipettes for channels; a pressure sensor coupled to the passage; as well as At least one controller circuit configured to perform operations comprising: receiving a signal from the pressure sensor indicative of the pressure in the pipette channel; and Based on the pressure indicated by the signal, perform at least one of the following: detecting evaporation of liquid in the channel; or One or more compensation actions are automatically performed.

140. The system of claim 139, wherein: The pipette comprises a pipette tip having an opening therein for aspirating the liquid, and wherein detecting the evaporation is performed after removing the pipette tip from the liquid.

141. The system of claim 140, wherein: Detecting the evaporation further comprises: The evaporation rate is calculated based on the change in pressure indicated by the signal after the pipette tip is removed from the liquid.

142. The system of claim 141, wherein: The evaporation rate is calculated independent of the surface tension or type of the liquid.

143. The system of claim 141, wherein: The evaporation rate is calculated in proportion to the change in pressure indicated by the signal over time.

144. The system of claim 141, wherein: Detecting the evaporation further comprises: controlling movement of a plunger in the channel after removing the pipette tip from the liquid, The evaporation rate is calculated based on a pressure change indicated by the signal in response to movement of the plunger.

145. The system of claim 139, wherein: Detecting the evaporation further comprises: continuously controlling the position of a plunger in a channel of the pipette so that the pressure indicated by the signal remains substantially constant over time; and The evaporation rate was calculated based on the displacement of the plunger over time.

146. The system of claim 140, wherein: Automatically performing the one or more compensation operations includes performing one or more evaporation compensation operations in response to detecting evaporation of liquid in the channel based on a comparison with a threshold value.

147. The system of claim 146, wherein: Performing the one or more evaporation compensation operations includes: performing a pre-wetting operation before aspirating the liquid; and / or Adapting one or more aspiration parameters to aspirate the liquid; and / or Controlling the movement of the plunger in the channel.

148. The system of claim 147, wherein: The operations further include: An evaporation volume is estimated based on the evaporation rate and a duration of the liquid drawing, wherein the threshold is based on volume.

149. The system of claim 148, wherein: The vaporization volume indicates an amount of inhalation shortfall, and wherein performing the one or more vaporization compensation operations comprises: Based on the under-aspiration amount, adapting the one or more aspiration parameters to aspirate a greater amount of the liquid; and A greater amount of liquid is aspirated based on the adapted one or more aspiration parameters.

150. The system of claim 147, wherein: Performing the one or more evaporation compensation operations includes: After the pipette tip is removed from the liquid, the movement of the plunger is controlled to draw air to reduce or prevent the liquid from dripping from the pipette tip.

151. The system of claim 147, wherein: Performing the one or more evaporation compensation operations includes: After the pipette tip is removed from the liquid, movement of the plunger is controlled to maintain a substantially constant pressure in the pipette tip.

152. The system of claim 151, wherein: The substantially constant pressure is based on the pressure indicated by the signal after the pipette tip is removed from the liquid.

153. The system of claim 151, wherein: The substantially constant pressure is a predetermined pressure.

154. The system of claim 139, wherein: The operations further include: The volume of liquid sucked is calculated based on the pressure change indicated by the signal.

155. The system of claim 154, wherein: Automatically performing the one or more compensation operations includes: adapting one or more aspiration parameters based on the comparison of the aspiration volume to a target volume; and The liquid is aspirated based on the adapted one or more aspiration parameters.

156. The system of claim 139, wherein: Automatically performing the one or more compensation operations includes: adapting the suction speed based on a change in pressure indicated by the signal relative to a pressure change threshold; and / or A pre-wetting operation is performed based on the temperature of the liquid relative to a temperature threshold.

157. A method of operating an automated pipetting system, the method comprising: At least one controller circuit executes computer readable instructions stored in a non-transitory storage medium to perform operations including: receiving a signal from a pressure sensor indicative of a pressure in a channel of the pipette; and Based on the pressure indicated by the signal, perform at least one of the following: detecting evaporation of liquid in the channel; or One or more compensation actions are automatically performed.

158. The method of claim 157, wherein: The pipette comprises a pipette tip having an opening therein for aspirating the liquid, and wherein detecting the evaporation is performed after removing the pipette tip from the liquid.

159. The method of claim 158, wherein: Detecting the evaporation further comprises: The evaporation rate is calculated based on the change in gas pressure indicated by the signal after the pipette tip is removed from the liquid.

160. The method of claim 159, wherein: The evaporation rate is calculated independent of the surface tension or type of the liquid.

161. The method of claim 159, wherein: The evaporation rate is calculated in proportion to the change in pressure indicated by the signal over time.

162. The method of claim 159, wherein: Detecting the evaporation further comprises: controlling movement of a plunger in the channel after the pipette tip is removed from the liquid, The evaporation rate is calculated based on a pressure change indicated by the signal in response to movement of the plunger.

163. The method of claim 157, wherein: Detecting the evaporation further comprises: continuously controlling the position of a plunger in a channel of the pipette so that the pressure indicated by the signal remains substantially constant over time; and The evaporation rate was calculated based on the displacement of the plunger over time.

164. The method of claim 158, wherein: Automatically performing the one or more compensation operations includes performing one or more evaporation compensation operations in response to detecting evaporation of liquid in the channel based on a comparison with a threshold value.

165. The method of claim 164, wherein: Performing the one or more evaporation compensation operations includes: performing a pre-wetting operation before aspirating the liquid; and / or Adapting one or more aspiration parameters to aspirate the liquid; and / or Controlling the movement of the plunger in the channel.

166. The method of claim 165, wherein: The operations further include: An evaporation volume is estimated based on the evaporation rate and a duration of the liquid drawing, wherein the threshold is based on volume.

167. The method of claim 166, wherein: The vaporization volume indicates an amount of inhalation shortfall, and wherein performing the one or more vaporization compensation operations comprises: Based on the under-aspiration amount, adapting the one or more aspiration parameters to aspirate a greater amount of the liquid; and A greater amount of liquid is aspirated based on the adapted one or more aspiration parameters.

168. The method of claim 165, wherein: Performing the one or more evaporation compensation operations includes: After the pipette tip is removed from the liquid, the movement of the plunger is controlled to draw air to reduce or prevent the liquid from dripping from the pipette tip.

169. The method of claim 165, wherein: Performing the one or more evaporation compensation operations includes: Movement of the plunger is controlled to maintain a substantially constant pressure in the pipette tip after the pipette tip is removed from the liquid.

170. The method of claim 169, wherein: The substantially constant pressure is based on the pressure indicated by the signal after the pipette tip is removed from the liquid.

171. The method of claim 169, wherein: The substantially constant pressure is a predetermined pressure.

172. The method of claim 157, wherein: The operations further include: The volume of liquid sucked is calculated based on the pressure change indicated by the signal.

173. The method of claim 172, wherein: Performing the one or more compensation operations includes: adapting one or more aspiration parameters based on the comparison of the aspiration volume to a target volume; and The liquid is aspirated based on the adapted one or more aspiration parameters.

174. The method of claim 157, wherein: Automatically performing one or more compensation operations includes: adapting the suction speed based on a change in pressure indicated by the signal relative to a pressure change threshold; and / or A pre-wetting operation is performed based on the temperature of the liquid relative to a temperature threshold.

175. An automatic liquid transfer system, comprising: These include pipettes for channels; a sensor coupled to the channel; as well as At least one controller circuit configured to perform operations comprising: receiving a sensor signal from the sensor indicative of a change in pressure in the passage; determining a volume of displaced air in the passage based on the sensor signal; as well as At least one control signal is transmitted based on the diverted air volume to control the pressure in the passage.

176. The system of claim 175, wherein: The operations further include identifying an air flow rate in the passageway based on the pressure change, wherein the diverted air volume is determined based on the air flow rate.

177. The system of claim 176, wherein: The at least one control signal comprises a flow restriction control signal, and further comprises: A flow restriction mechanism is coupled to the passage and is configured to switch between respective states providing different flow rates in response to the flow restriction control signal.

178. The system of claim 177, wherein: The sensor comprises a dual sensor, wherein the sensor signal comprises first pressure data and second pressure data indicative of a first flow rate and a second flow rate, respectively.

179. The system of claim 178, wherein: The dual sensor includes a first pressure sensor and a second pressure sensor arranged in parallel, which respectively provide first pressure data and second pressure data, wherein a measuring range of the second pressure sensor is greater than a measuring range of the first pressure sensor.

180. The system of claim 179, wherein: A measuring range of the second pressure sensor is greater than a measuring range of the first pressure sensor by more than one order of magnitude.

181. The system of claim 176, wherein: The at least one control signal includes a plunger actuator control signal that varies based on a change in the volume of transferred air indicated by the air flow rate in the passage, and further includes: A plunger actuator is configured to dynamically control the position and / or speed of movement of a plunger in the channel in response to the plunger actuator control signal.

182. The system of claim 181, wherein: The plunger actuator control signal is generated independently of determining a previous position or movement distance of the plunger in the passage.

183. The system of claim 177, wherein: The at least one control signal comprises a valve control signal, and further comprises: An air valve is operable to couple the passage to a pressure source in response to the valve control signal.

184. The system of claim 183, wherein: The pressure source includes a negative pressure source and a positive pressure source, wherein one of the negative pressure source or the positive pressure source is configured to be selected to control the direction of airflow in the channel.

185. The system of claim 175, wherein: The operations further include: receiving a pressure signal from a pressure sensor coupled to a pipette tip of the pipette; and determining a volume of liquid in the pipette tip based on the pressure signal, The at least one control signal is transmitted to control the position of the plunger based on the volume of liquid in the pipette tip.

186. The system of claim 175, wherein: The system further comprises: A microfluidic manifold comprising a plurality of passages configured to couple the channels to a pipette tip, wherein one or more of the passages comprises a diameter of approximately 0.2 to 0.8 mm.

187. A method of operating an automated pipetting system, the method comprising: At least one controller circuit executes computer readable instructions stored in a non-transitory storage medium to perform operations including: receiving a sensor signal from a sensor coupled to a channel of the pipette indicative of a pressure change in the channel; determining a volume of displaced air in the passage based on the sensor signal; as well as At least one control signal is transmitted based on the diverted air volume to control the pressure in the passage.

188. The method of claim 187, wherein: The operations further include: identifying an air flow rate in the passage based on the pressure change indicated by the sensor signal, Wherein the transferred air volume is determined based on the air flow rate.

189. The method of claim 188, wherein: The at least one control signal further comprises a flow restriction control signal, and wherein the operations further comprise: In response to the flow restriction control signal, a flow restriction mechanism coupled to the passageway is switched between respective states providing different air flow rates.

190. The method of claim 189, wherein: The sensor comprises a dual sensor, wherein the sensor signal comprises first pressure data and second pressure data indicative of a first flow rate and a second flow rate, respectively.

191. The method of claim 190, wherein: The dual sensor includes a first pressure sensor and a second pressure sensor arranged in parallel, which respectively provide first pressure data and second pressure data, wherein a measuring range of the second pressure sensor is greater than a measuring range of the first pressure sensor.

192. The method of claim 191, wherein: A measuring range of the second pressure sensor is greater than a measuring range of the first pressure sensor by more than one order of magnitude.

193. The method according to claim 188, wherein: The at least one control signal comprises a plunger actuator control signal that varies based on a change in a volume of displaced air indicated by an air flow rate in the passage, and wherein the operations further comprise: The position and / or speed of movement of the plunger in the channel is dynamically controlled in response to the plunger actuator control signal.

194. The method of claim 193, wherein: The plunger actuator control signal is generated independently of determining a previous position or movement distance of the plunger in the passage.

195. The method of claim 189, wherein: The at least one control signal comprises a valve control signal, and wherein the operations further comprise: An air valve is operated in response to the valve control signal to couple the passage to a pressure source.

196. The method of claim 195, wherein: The pressure source includes a negative pressure source and a positive pressure source, wherein the operation further includes: One of the negative pressure source or the positive pressure source is selected to control the direction of airflow in the channel.

197. The method of claim 187, wherein: The operations further include: receiving a pressure signal from a pressure sensor coupled to a pipette tip of the pipette; and determining a volume of liquid in the pipette tip based on the pressure signal, The at least one control signal is transmitted to control the position of the plunger based on the volume of liquid in the pipette tip.

198. The method of claim 187, wherein: The sensor is coupled to at least one passage of a microfluidic manifold configured to couple the channel to a pipette tip, and wherein the at least one passage comprises a diameter of approximately 0.2 to 0.8 mm.

199. A positive displacement pipette tip comprising: Tip orifice; Back room; a tip passageway located between the tip orifice and the rear chamber and in fluid communication with the tip orifice; as well as a piston slidably mounted in the tip passage; Wherein the piston translates rearwardly away from the tip orifice in response to negative pressure in the rear chamber, whereby the piston generates negative pressure at the tip orifice to draw liquid into the positive-displacement pipette tip.

200. The positive displacement pipette tip of claim 199, wherein: The positive displacement pipette tip comprises: a body defining the rear chamber; and a sliding seal between the piston and the body; wherein the seal separates the rear chamber from the tip passage; and wherein the seal translates with the piston through the body.

201. The positive displacement pipette tip of claim 200, wherein: The body includes a body cavity; and The seal divides the body cavity into the posterior chamber and an intermediate chamber between the posterior chamber and the tip passage.

202. The positive displacement pipette tip of claim 201, wherein: The positive-displacement pipette tip includes a pressure relief port in fluid communication with the intermediate chamber.

203. The positive displacement pipette tip of claim 199, wherein: The positive displacement pipette tip comprises: The entity; and Calibration agencies, including: at least one first calibration feature on the body; and at least one second calibration feature on the piston; The first marking feature and the second marking feature cooperate to stop the displacement of the piston at a specified position.

204. The positive displacement pipette tip of claim 203, wherein: The positive-displacement pipette tip includes a seal on the piston, wherein the seal translates with the piston through the body.

205. A pipette comprising: Pipettes; as well as A positive displacement pipette tip mounted on the pipette, the positive displacement pipette tip comprising: Tip orifice; Back room; a tip passage located between the tip orifice and the rear chamber and in fluid communication with the tip orifice; and a piston slidably mounted in the tip passage; Wherein the pipette is operable to generate a negative pressure in the rear chamber, which causes the piston to translate rearwardly away from the tip orifice, whereby the piston generates a negative pressure at the tip orifice to draw the liquid into the positive-displacement pipette tip.

206. The pipette of claim 205, wherein: The pipette is coupled to the piston via an air column; and When the piston translates, the air column is displaced within the pipette and / or the positive-displacement pipette tip.

207. A method for pipetting a liquid, the method comprising: A positive displacement pipette tip is mounted on the pipette, the positive displacement pipette tip comprising: Tip orifice; Back room; a tip passage located between the tip orifice and the rear chamber and in fluid communication with the tip orifice; and a piston slidably mounted in the tip passage; and Using the pipette, negative pressure is generated in the back chamber, which translates the piston rearwardly away from the tip orifice, whereby the piston generates negative pressure at the tip orifice to draw liquid into the positive-displacement pipette tip.

208. A positive displacement pipette tip comprising: Tip orifice; a tip passage in fluid communication with the tip orifice; a piston slidably mounted in the tip passage; ontology; as well as Calibration agencies, including: at least one first calibration feature on the body; and at least one second calibration feature on the piston; The first marking feature and the second marking feature cooperate to stop the displacement of the piston at a specified position.

209. The positive displacement pipette tip of claim 208, wherein: The at least one first indexing structure comprises a series of first indexing structures distributed axially along the longitudinal axis of the positive-displacement pipette tip.

210. A pipette comprising: Pipettes; as well as A positive displacement pipette tip mounted on the pipette, the positive displacement pipette tip comprising: Tip orifice; a tip passage in fluid communication with the tip orifice; a piston slidably mounted in the tip passage; The entity; and Calibration agencies, including: at least one first calibration feature on the body; and at least one second calibration feature on the piston; The first marking feature and the second marking feature cooperate to stop the displacement of the piston at a specified position.

211. A method for pipetting a liquid, the method comprising: A positive displacement pipette tip is mounted on the pipette, the positive displacement pipette tip comprising: Tip orifice; a tip passage in fluid communication with the tip orifice; a piston slidably mounted in the tip passage; The entity; and Calibration agencies, including: at least one first calibration feature on the body; and at least one second calibration feature on the piston; wherein the first calibration feature and the second calibration feature cooperate to stop the displacement of the piston at a specified position; Using the pipette, the piston is translated backwards away from the tip orifice, whereby the piston generates negative pressure at the tip orifice to draw liquid into the positive-displacement pipette tip.

212. A positive-displacement pipette tip for use with a pipette, the positive-displacement pipette tip comprising: a tip body including a distal tip portion defining a tip passage; a piston slidably mounted in the tip passage, wherein the piston is displaceable to draw liquid into the positive displacement pipette tip; as well as An integral piston restraint mechanism operable to limit movement between the piston and the tip body.

213. The positive displacement pipette tip of claim 212, wherein: The piston restraint mechanism may be positioned in either a restraint configuration in which it prevents the piston from retracting beyond a specified position relative to the tip body, and a release configuration in which it does not prevent the piston from retracting beyond the specified position.

214. The positive displacement pipette tip of claim 213, wherein: When in the released configuration, the piston restraint mechanism does not restrict movement between the piston and the tip body.

215. The positive displacement pipette tip of claim 213, wherein: The piston restraint mechanism includes a latch movable between a latched position in which the latch engages the piston and an unlatched position in which the latch does not engage the piston.

216. The positive displacement pipette tip of claim 215, wherein: The latch includes a displaceable sleeve or tab.

217. The positive displacement pipette tip of claim 215, wherein: The positive-displacement pipette tip comprises an interlocking insert mounted on the tip body, wherein the latch forms a part of the interlocking insert.

218. The positive displacement pipette tip of claim 215, wherein: The piston restraint mechanism includes an integral interlocking feature on the piston; and The interlock feature is configured to interlock with the latch when the piston restraint mechanism is in the restraining configuration to limit movement between the piston and the tip body.

219. The positive displacement pipette tip of claim 212, wherein: The piston includes an integral coupling feature configured to secure the piston to a driver forming part of the pipette.

220. The positive displacement pipette tip of claim 212, wherein: The tip body includes a mounting section configured to engage the pipette to removably secure the positive-displacement pipette tip to the pipette.

221. A liquid transfer system comprising: Pipettes; as well as A positive displacement pipette tip mounted on the pipette, the positive displacement pipette tip comprising: a tip body including a distal tip portion defining a tip passage; a piston slidably mounted in the tip passage, wherein the piston is translatable to draw liquid into the positive displacement pipette tip; and An integral piston restraint mechanism operable to limit movement between the piston and the tip body.

222. A method for pipetting a liquid, the method comprising: A positive displacement pipette tip is mounted on the pipette, wherein the positive displacement pipette tip comprises: a tip body including a distal tip portion defining a tip passage; a piston slidably mounted in the tip passage; and an integral piston restraint mechanism operable to limit movement between the piston and the tip body; using the pipette, translating the piston through the tip passage to draw liquid into the positive displacement pipette tip; and The positive-displacement pipette tip is ejected from the pipette while the piston restraint mechanism limits movement between the piston and the tip body.

223. The method of claim 222, wherein: Mounting the positive displacement pipette tip on the pipette includes coupling a driver of the pipette to the piston; and Translating the piston through the tip passage includes translating the piston using the driver.

224. The method of claim 223, wherein: The piston restraint mechanism is positionable in any one of a restraining configuration in which the piston restraint mechanism prevents the piston from retracting beyond a specified position relative to the tip body, and a released configuration in which the piston restraint mechanism does not prevent the piston from retracting beyond the specified position; translating the piston through the tip passage includes translating the piston using the driver when the piston restraint mechanism is in the released configuration; and Ejecting the positive-displacement pipette tip from the pipette includes relatively translating the driver and the piston when the piston constraint mechanism is in the constrained configuration.

225. The method of claim 224, wherein: Ejecting the positive-displacement pipette tip from the pipette comprises pushing the tip body away from the pipette using an ejector forming part of the pipette when the piston restraining mechanism is in the restraining configuration.

226. The method of claim 224, wherein: The piston restraint mechanism includes an integral interlocking feature on the piston; The piston restraint mechanism comprises a latch forming part of the tip body; the latch being positionable in each of a latched position in which the latch is interlocked with the interlocking feature and an unlatched position in which the latch is not interlocked with the interlocking feature; Mounting the positive displacement pipette tip on the pipette includes inserting the pipette shaft into the tip body and thereby deflecting the latch to the unlatched position; and Ejecting the positive-displacement pipette tip from the pipette includes pushing the tip body away from the shaft, in response to which the latch resiliently returns to the latched position.

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