Dispensing device and method

Abstract

The automated dispensing system includes a dispenser including a dispensing channel, a first plunger mechanism operable to vary pressure in the dispensing channel to aspirate or dispense liquid, and a second plunger mechanism operable to vary pressure in the dispensing channel to aspirate 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 dispenser. [Background technology]

[0002] Laboratory liquid handling systems are used to transport and manipulate large volumes of liquid. Liquid handling systems may include one or more dispensers used to aspirate portions of a liquid sample and / or dispense a liquid sample. The aspirating and dispensing of liquid samples may be performed robotically or automatically by program. Summary of the Invention

[0003] According to some embodiments, an automated dispensing system includes a dispenser including a dispensing channel, a first plunger mechanism operable to vary pressure in the dispensing channel to aspirate or dispense liquid, and a second plunger mechanism operable to vary pressure in the dispensing 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 dispensing channel.

[0005] According to some embodiments, the first plunger mechanism and the second plunger mechanism are operable independently of one another to vary the pressure in the dispensing channel.

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

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

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

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

[0010] In some embodiments, the first plunger mechanism includes a first plunger actuator operable to move the first plunger through the first chamber, the second plunger mechanism includes a second plunger actuator operable to move the second plunger through the second chamber, and the automated dispensing system includes a controller configured to automatically 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 perpendicular to the first plunger axis, and the second plunger has a second cross-sectional area in a plane perpendicular to the second plunger axis, the second cross-sectional area being larger 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, a first plunger mechanism is configured to translate a first plunger in the first chamber and a second plunger mechanism is configured to translate a second plunger in the second chamber, the first plunger displaces an air volume in the first chamber at a first air volume displacement rate per unit translation and the second plunger displaces an air volume in the second chamber at a second air volume displacement rate per unit translation, the second air volume displacement rate per unit translation being greater than the first air volume displacement rate per unit translation.

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

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

[0017] In some embodiments, the second maximum air volume displacement is at least 10 times the first maximum air volume displacement.

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

[0019] In some embodiments, the second chamber volume is at least 10 times the volume of the first chamber.

[0020] According to some embodiments, the dispenser includes a valve that selectively controls fluid communication between the second chamber and the port to atmosphere.

[0021] According to some embodiments, the dispenser includes at least one valve that selectively controls fluid communication between the second chamber and the dispense channel. In some embodiments, the first plunger is disposed in the dispense channel.

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

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

[0024] The automated dispensing system may include a pressure sensor coupled to the dispensing channel, and the controller is configured to receive a dispensing channel pressure signal from the pressure sensor indicative of the pressure in the dispensing channel.

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

[0026] According to some embodiments, a method for operating an automated dispensing system includes performing, by at least one control circuit, operations including operating a first plunger mechanism of a dispenser of the automated dispensing system to change pressure in a dispensing channel of the dispenser to aspirate or dispense liquid, and operating a second plunger mechanism of the dispenser to change pressure in the dispensing 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 the dispensing channel.

[0028] According to some embodiments, the method includes operating a first plunger mechanism and a second plunger mechanism independently of one another to vary the pressure in the dispensing channel.

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

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

[0031] In some embodiments, the method includes operating an ejection mechanism to eject a pipette tip from the pipette.

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

[0033] In some embodiments, the first plunger mechanism includes a first plunger actuator operable to move the first plunger through the first chamber and the second plunger mechanism includes a second plunger actuator operable to move the second plunger through the second chamber, and the method includes automatically 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 perpendicular to the first plunger axis, and the second plunger has a second cross-sectional area in a plane perpendicular to the second plunger axis, the second cross-sectional area being larger 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] In some embodiments, the first plunger mechanism is configured to translate a first plunger in the first chamber and the second plunger mechanism is configured to translate a second plunger in the second chamber, the first plunger displaces an air volume in the first chamber at a first air volume displacement rate per unit translation and the second plunger displaces an air volume in the second chamber at a second air volume displacement rate per unit translation, the second air volume displacement rate per unit translation being greater than the first air volume displacement rate per unit translation.

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

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

[0040] In some embodiments, the second maximum air volume displacement is at least 10 times the first maximum air volume displacement.

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

[0042] In some embodiments, the second chamber volume is at least 10 times the volume of the first chamber.

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

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

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

[0046] According to some embodiments, the dispenser includes a pressure sensor coupled to the dispense channel, and the controller receives a dispense channel pressure signal from the pressure sensor indicative of the pressure in the dispense channel.

[0047] In some embodiments, the dispenser includes a valve that selectively controls fluid communication between the second plunger mechanism and the dispensing channel, and the method includes automatically programmatically controlling the valve using the controller.

[0048] According to some embodiments, a dispensing system includes a dispenser including a barrel, a dispensing channel, a passage defined in the barrel and in fluid communication with the dispensing channel, the passage including a rear chamber and a front chamber between the rear chamber and the dispensing channel, a front plunger mounted in the front chamber for translational movement relative to the passage on a front plunger stroke, a rear plunger mounted in the rear chamber for translational movement relative to the passage on a rear plunger stroke, and a front seal around 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 creates a change in pressure in the dispensing 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 creates a change in pressure in the dispensing channel to aspirate or dispense liquid.

[0049] According to some embodiments, the dispenser includes a plunger member including both a front plunger and a rear plunger, the plunger member mounted in the passageway for translation with a plunger member 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 in the dispensing channel.

[0051] In some embodiments, during a first portion of the front plunger stroke, a 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 coupled 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 dispensing system includes a rear seal about the rear plunger.

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

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

[0056] The dispensing system may include a pressure relief valve positioned and configured to relieve pressure in the rear chamber during a first portion of the front plunger stroke.

[0057] According to some embodiments, the dispensing system includes a pressure sensor positioned and configured to detect pressure in the dispensing channel.

[0058] In some embodiments, the dispensing 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 stroke.

[0060] According to some embodiments, the valve is selectively operable to fluidly connect the rear chamber to the port to atmosphere.

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

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

[0063] According to some embodiments, the dispensing system includes at least one actuator that drives the front and rear plungers with front and rear plunger strokes, 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 displaces the air volume in the front chamber at an air volume displacement rate per first unit translation, the rear plunger displaces the air volume in the rear chamber at an air volume displacement rate per second unit translation, and the air volume displacement rate per second unit translation is larger than the air volume displacement rate per first unit translation.

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

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

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

[0070] According to some embodiments, the front chamber has a front chamber volume, and the rear chamber has a rear chamber volume that is larger than the front chamber volume.

[0071] In some embodiments, the rear chamber volume is at least 10 times the front chamber volume.

[0072] According to some embodiments, a method for dispensing liquid includes providing a dispenser including a barrel, a dispensing channel, a passage defined in the barrel and in fluid communication with the dispensing channel, the passage including a rear chamber and a front chamber between the rear chamber and the dispensing channel, a front plunger mounted in the front chamber to move through a front plunger stroke, a rear plunger mounted in the rear chamber to move through the rear plunger stroke, and a front seal about the front plunger. The method further includes aspirating or dispensing liquid by translating the front plunger through the front plunger stroke and translating the rear plunger through the rear plunger stroke. 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 creates a change in pressure in the dispensing 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 creates a second change in pressure in the dispensing channel to aspirate or dispense liquid.

[0073] According to some embodiments, the dispenser includes a plunger member including both a front plunger and a rear plunger, the plunger member mounted in the passageway to translate a plunger member 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 are performed by translating the plunger member through the plunger member stroke.

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

[0075] In some embodiments, during a first portion of the front plunger stroke, a 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 coupled to the rear chamber through the connecting opening.

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

[0077] In some embodiments, the method includes translating the front plunger in a first direction over a first portion and a second portion of the front plunger stroke and aspirating liquid using the front and rear plungers, and then translating the front plunger in a second direction opposite the first direction over the first and second portions of the front plunger stroke and dispensing liquid using the front and rear plungers.

[0078] According to some embodiments, the method includes operating an opening mechanism to fluidly couple a rear chamber with a front chamber while a front plunger is in a first portion prior to a front plunger stroke, and then translating a rear plunger along a rear plunger stroke to suck a liquid while the rear chamber is in fluid communication with the front chamber.

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

[0080] According to some embodiments, a dispensing system includes a barrel, a dispensing channel, a passage defined in the barrel and in fluid communication with the dispensing channel, the passage including a rear chamber and a front chamber between the rear chamber and the dispensing channel, a front plunger mounted in the front chamber to translate parallel to the passage along a plunger axis, and a rear plunger mounted in the rear chamber to translate parallel to the passage along the plunger axis. Translation of the front plunger in the front chamber along the plunger axis causes a change in pressure in the dispensing channel to suck or dispense a liquid. Translation of the rear plunger in the rear chamber along the plunger axis causes a change in pressure in the dispensing channel to suck or dispense a 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 larger than the first cross-sectional area.

[0081] In some embodiments, the dispenser includes a plunger member including both the front plunger and the rear plunger, the plunger member being mounted in the passage to translate parallel to the plunger axis.

[0082] According to some embodiments, the dispensing system includes a dispenser, an air displacement pipette tip, and a positive displacement pipette tip. The air displacement pipette tip and the positive displacement pipette tip can be selectively and removably mounted on the dispenser. The dispenser is operable to aspirate a liquid into the air displacement pipette tip when the air displacement pipette tip is mounted on the dispenser. The dispenser is operable to aspirate a liquid into the positive displacement pipette tip when the positive displacement pipette tip is mounted on the dispenser.

[0083] According to some embodiments, the dispenser includes a tip attachment interface configured to engage with the air displacement pipette tip and the positive displacement pipette tip and releasably fix them to the dispenser.

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

[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. The positive displacement pipette tip operates to generate a negative pressure at the positive displacement tip orifice and aspirate a liquid when the piston translates parallel to move away from the positive displacement tip orifice.

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

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

[0088] In some embodiments, the dispenser includes a plunger configured to engage a piston and translate in a tip passageway when a positive displacement pipette tip is mounted to the dispenser.

[0089] According to some embodiments, the dispenser includes a plunger that is translatable to generate a negative pressure at an air displacement tip orifice to aspirate liquid when an air displacement pipette tip is mounted to the dispenser, and the plunger is configured to engage a piston and translate in a tip passageway when a positive displacement pipette tip is mounted to the dispenser.

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

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

[0092] In some embodiments, the dispenser includes a barrel that defines the chamber and an annular seal around 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 dispenser may include a pressure sensor arranged and configured to output a detection signal indicating the pressure in the chamber.

[0094] According to some embodiments, the dispenser includes at least one plunger actuator for driving a plunger and a controller configured to automatically program the operation of the at least one actuator.

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

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

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

[0098] According to some embodiments, the dispenser includes a plunger that is translatable to generate a negative pressure in the air displacement pipette tip to aspirate a liquid when the air displacement pipette tip is mounted on the dispenser, and the plunger is configured to engage the piston to effect translation in the tip passage of the positive displacement pipette tip when the positive displacement pipette tip is mounted on the dispenser.

[0099] According to some embodiments, a method for dispensing a liquid includes operating a dispenser to aspirate the liquid into an air displacement pipette tip while the air displacement pipette tip is mounted on the dispenser, and then operating the dispenser to aspirate the liquid into a positive displacement pipette tip while the positive displacement pipette tip is mounted on the dispenser.

[0100] According to some embodiments, the method includes performing operations including attaching an air displacement pipette tip mounted on the dispenser by at least one control circuit that controls at least one actuator, removing the air displacement pipette tip from the dispenser, attaching a positive displacement pipette tip mounted on the dispenser, and removing the positive displacement pipette tip from the dispenser.

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

[0102] In some embodiments, the conductive electrode is on the outer surface of the chip 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 chip member.

[0104] In some embodiments, the conductive electrode is not present on the non-conductive chip bottom.

[0105] In some embodiments, the non-conductive chip bottom includes a portion of the conductive electrode having a non-conductive coating.

[0106] In some embodiments, a conductive element is provided at a second end of the chip member, and a conductive connection portion extends along the chip member to electrically connect the conductive electrode to the conductive element.

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

[0108] In some embodiments, the conductive element is at least partially embedded within the chip member.

[0109] In some embodiments, the conductive electrode is not present on an inner surface of the chip member.

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

[0111] In some embodiments, the non-conductive chip bottom has 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 the 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 a 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 from the conductive electrode.

[0114] According to some embodiments, an automatic dispensing system includes a robotic arm assembly comprising an arm member configured 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 receive a signal from a conductive electrode on a pipette tip, the conductive electrode being between a first end of the pipette tip having an opening for aspirating and / or dispensing a liquid and a second end of the pipette tip opposite the first end and connected to the pipette, and to transmit a control signal to the actuator mechanism to control the arm member to approach or separate from the liquid surface along at least one axis in response to the signal from the conductive electrode.

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

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

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

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

[0119] In some embodiments, the conductive electrode is on the 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 conductive electrode is not present at the bottom of the non - conductive tip.

[0122] In some embodiments, the bottom of the non - conductive tip comprises a portion of the conductive electrode having a non - conductive coating.

[0123] In some embodiments, the conductive electrode is not present on the inner surface of the pipette tip.

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

[0125] In some embodiments, the actuator mechanism includes a first mode of operation in which the arm member is restricted in movement towards the surface of the liquid along at least one axis during aspiration, and a second mode of operation in which the arm member is restricted in movement away from the surface of the liquid along at least one axis during dispensing.

[0126] In some embodiments, the operation further includes calculating the aspiration or dispensing volume of the liquid based on the movement distance of the arm member along at least one axis, and controlling subsequent movement of the arm member along at least one axis based on the calculated aspiration or dispensing volume.

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

[0128] In some embodiments, the operation further includes dynamically detecting the level of the liquid based on a change in capacitance indicated by the signal from the conductive electrode, optionally independent of the 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 the signal from the conductive electrode, and transmitting the control signal to the actuator mechanism is in response to the prediction of the loss of contact.

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

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

[0132] In some embodiments, the conductive electrode is 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 conductive electrode is not present at the bottom of the non - conductive tip.

[0135] In some embodiments, the conductive electrode is not present on the inner surface of the pipette tip.

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

[0137] In some embodiments, the operation further includes restricting the arm member to move towards the surface of the liquid along at least one axis during aspiration and restricting the arm member to move away from the surface of the liquid along at least one axis during dispensing.

[0138] In some embodiments, the operation further includes calculating the aspiration or dispensing volume of the liquid based on the movement distance of the arm member along at least one axis and controlling the subsequent movement of the arm member along at least one axis based on the calculated aspiration or dispensing volume.

[0139] According to some embodiments, the automatic pipetting system includes a pipettor having a channel, 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, from the pressure sensor, a signal indicating the pressure in the channel of the pipettor and detecting evaporation of the liquid in the channel or automatically performing at least one of one or more compensation operations based on the pressure indicated by the signal.

[0140] In some embodiments, the dispenser comprises a pipette tip having an opening for aspirating a liquid, and detecting evaporation is performed after removal of the pipette tip from the liquid.

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

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

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

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

[0145] In some embodiments, detecting evaporation further includes continuously controlling the position of a plunger in a channel of the dispenser such that the 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 detection of evaporation of a liquid in a channel based on a comparison to a threshold.

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

[0148] In some embodiments, the operation further includes estimating an evaporation volume based on an evaporation rate and a duration of liquid suction, wherein the threshold is volume-based.

[0149] In some embodiments, the evaporation volume indicates an under-suction amount. Performing one or more evaporation compensation operations includes adapting one or more suction parameters to suck another amount of liquid based on the under-suction amount, and sucking another amount of liquid based on the adapted one or more suction parameters.

[0150] In some embodiments, performing one or more evaporation compensation operations includes controlling the movement of the plunger to suck air after removing the pipette tip from the liquid so as to suppress or avoid dripping of the liquid from the pipette tip.

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

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

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

[0154] In some embodiments, the operation further includes calculating a liquid suction volume based on a change in the pressure indicated by a signal.

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

[0156] In some embodiments, automatically performing one or more compensation operations includes adapting an aspiration rate based on a change in pressure indicated by a 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 dispensing system includes, by at least one controller circuit, executing computer-readable instructions stored on a non-transitory storage medium to receive, from a pressure sensor, a signal indicative of a pressure in a channel of a dispenser, and based on the pressure indicated by the signal, performing at least one of detecting evaporation of a liquid in the channel or automatically performing one or more compensation operations.

[0158] In some embodiments, the dispenser comprises a pipette tip having an opening for aspirating a liquid, and detecting evaporation is performed after removal of the pipette tip from the liquid.

[0159] In some embodiments, detecting evaporation further includes calculating an evaporation rate based on a change in air pressure indicated by a signal after removal of the pipette tip from the liquid.

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

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

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

[0163] In some embodiments, detecting evaporation further includes continuously controlling the position of a plunger in a dispensing channel such that the 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 detection of evaporation of a liquid in a channel based on a comparison to a threshold.

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

[0166] In some embodiments, the operation is estimating an evaporation volume based on an evaporation rate and a duration of aspiration of the liquid, and further including that the threshold is volume-based.

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

[0168] In some embodiments, performing one or more evaporation compensation operations includes controlling the movement of the plunger to draw air after removing the pipette tip from the liquid so as to suppress or avoid dripping of the liquid from the pipette tip.

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

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

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

[0172] In some embodiments, the operation further includes calculating the aspiration volume of the liquid based on a change in the pressure indicated by a signal.

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

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

[0175] According to some embodiments, an automatic dispensing system includes a dispenser having channels, a sensor coupled to the channels, and at least one controller circuit. The controller circuit is configured to perform operations including receiving from the sensor a sensor signal indicating a pressure change in the channels, determining a displaced air volume in the channels based on the sensor signal, and transmitting at least one control signal for controlling the pressure in the channels based on the displaced air volume.

[0176] In some embodiments, the operations further include specifying an air flow rate in the channels based on the pressure change, and determining the displaced air volume is based on the air flow rate.

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

[0178] In some embodiments, the sensor is a dual sensor, and the sensor signal includes first pressure data and second pressure data indicating 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 in a parallel arrangement that provide the first pressure data and the second pressure data respectively. The measurement range of the second pressure sensor is larger than the measurement range of the first pressure sensor.

[0180] In some embodiments, the measurement range of the second pressure sensor is at least two orders of magnitude larger than the measurement range of the first pressure sensor.

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

[0183] In some embodiments, at least one control signal includes a valve control signal. The air valve is operable to couple the channel to a 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. It is configured to control the direction of the air flow in the channel by selecting one of the negative pressure source or the positive pressure source.

[0185] In some embodiments, the operation further includes receiving a pressure signal from a pressure sensor in a pipette tip coupled to a dispenser and determining the volume of liquid in the pipette tip based on the pressure signal. At least one control signal is transmitted to control the position of the plunger based on the volume of liquid in the pipette tip.

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

[0187] According to some embodiments, a method of operating an automatic dispensing system includes executing, by at least one controller circuit, computer-readable instructions stored in a non-transitory memory medium to receive, from a sensor coupled to a channel of a dispenser, a sensor signal indicative of a pressure change in the channel, determine, based on the sensor signal, a displaced air volume in the channel, and transmit at least one control signal for controlling the pressure in the channel based on the displaced air volume.

[0188] In some embodiments, the operation further includes specifying an air flow rate in the channel based on the pressure change indicated by the sensor signal, and determining the displaced air volume is based on the air flow rate.

[0189] In some embodiments, the at least one control signal includes a flow rate limiting control signal. The operation further includes switching a flow rate limiting mechanism coupled to the channel between respective states that provide different air flow rates in response to the flow rate limiting 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 in a parallel arrangement that provide the first pressure data and the second pressure data, respectively. The measurement range of the second pressure sensor is larger than the measurement range of the first pressure sensor.

[0192] In some embodiments, the measurement range of the second pressure sensor is at least two orders of magnitude larger than the measurement range of the first pressure sensor.

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

[0194] In some embodiments, the plunger actuator control signal is generated independently of the determination of the past position or the movement distance of the plunger in the channel.

[0195] In some embodiments, at least one control signal includes a valve control signal, and the operation further includes operating an air valve to couple the channel to a 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 controlling the direction of the air flow in the channel by selecting one of the negative pressure source or the positive pressure source.

[0197] In some embodiments, the operation further includes receiving a pressure signal from a pressure sensor in a pipette tip coupled to a dispenser and determining the volume of the liquid in the pipette tip based on the pressure signal. At least one control signal is transmitted to control the position of the plunger based on the volume of the liquid in the pipette tip.

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

[0199] According to some embodiments, the positive displacement pipette tip includes a tip orifice, a rear chamber, a tip passage that is in fluid communication with the tip orifice between the tip orifice and the rear chamber, and a piston slidably mounted in the tip passage. The piston moves in parallel away from the tip orifice rearward in response to a negative pressure in the rear chamber, thereby generating a negative pressure at the tip orifice to suck liquid into the positive displacement pipette tip.

[0200] According to some embodiments, this positive displacement pipette tip includes a body that defines the rear chamber and a sliding seal between the piston and the body. The seal separates the rear chamber from the tip passage. The seal moves in parallel with the body along 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] This positive displacement pipette tip may include a pressure relief port in fluid communication with the intermediate chamber.

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

[0204] This positive displacement pipette tip may include a seal on the piston that moves in parallel with the body along with the piston.

[0205] According to some embodiments, the pipette comprises a dispenser and a positive displacement pipette tip mounted on the dispenser. The positive displacement pipette tip comprises a tip orifice, a rear chamber, a tip passage that is in fluid communication with the tip orifice between the tip orifice and the rear chamber, and a piston slidably mounted in the tip passage. The dispenser is operable in the rear chamber to generate a negative pressure such that the piston generates a negative pressure at the tip orifice to aspirate a liquid into the positive displacement pipette tip by translating the piston rearward away from the tip orifice.

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

[0207] According to some embodiments, a method for dispensing a liquid comprises mounting a positive displacement pipette tip on a dispenser. The positive displacement pipette tip comprises a tip orifice, a rear chamber, a tip passage that is in fluid communication with the tip orifice between the tip orifice and the rear chamber, and a piston slidably mounted in the tip passage. The method further comprises using the dispenser to generate a negative pressure in the rear chamber by translating the piston rearward away from the tip orifice such that the piston generates a negative pressure at the tip orifice to aspirate a liquid into the positive displacement pipette tip.

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

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

[0210] According to some embodiments, the pipette includes a dispenser and a positive displacement pipette tip mounted on the dispenser. 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 an indexing mechanism. The indexing mechanism includes at least one first index feature on the body and at least one second index feature on the piston. The first index feature and the second index feature cooperate to stop the displacement of the piston at a defined position.

[0211] According to some embodiments, a method for dispensing a liquid includes mounting a positive displacement pipette tip on a dispenser. 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 an indexing mechanism. The indexing mechanism includes at least one first index feature on the body and at least one second index feature on the piston. The first index feature and the second index feature cooperate to stop the displacement of the piston at a defined position. The dispenser translates the piston rearward away from the tip orifice, thereby causing the piston to generate a negative pressure at the tip orifice to aspirate the liquid into the positive displacement pipette tip.

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

[0213] According to some embodiments, the piston restraint mechanism is configurable in a restraint configuration that prevents retraction of the piston beyond a defined position relative to the tip body and a release configuration that does not prevent retraction of the piston beyond the defined position.

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

[0215] According to some embodiments, the piston restraint mechanism includes a latch movable between a latched position engaging the piston and an unlatched position not engaging the piston.

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

[0217] In some embodiments, the pipette tip includes an interlock insert mounted to the tip body, and the latch forms part of the interlock insert.

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

[0219] According to some embodiments, the piston includes an integral coupling feature configured to secure the piston to a driver that forms part of a dispenser.

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

[0221] According to some embodiments, a dispensing system includes a dispenser and a positive displacement pipette tip mounted on the dispenser. The positive displacement pipette tip includes a chip body, a piston, and an integral piston restraint mechanism. The chip body includes a distal chip portion that defines a chip passageway. The piston is slidably mounted within the chip passageway. The piston is displaceable to aspirate liquid into the positive displacement pipette tip. The integral piston restraint mechanism is operable to limit movement between the piston and the chip body.

[0222] According to some embodiments, a method for dispensing liquid includes mounting a positive displacement pipette tip on a dispenser. The positive displacement pipette tip includes a chip body that includes a distal chip portion that defines a chip passageway, a piston slidably mounted within the chip passageway, and an integral piston restraint mechanism operable to limit movement between the piston and the chip body. The method includes using the dispenser to translate the piston in the chip passageway to aspirate liquid into the positive displacement pipette tip and ejecting the positive displacement pipette tip from the dispenser while the piston restraint mechanism limits movement between the piston and the chip body.

[0223] According to some embodiments, mounting the positive displacement pipette tip on the dispenser includes coupling a driver of the dispenser to the piston, and translating the piston in the chip passageway includes translating the piston using the driver.

[0224] In some embodiments, the piston restraint mechanism can be arranged in a restraint configuration that prevents the piston from retreating beyond a specified position relative to the chip body and a release configuration that does not prevent the piston from retreating beyond the specified position. Translating the piston in the chip passage includes translating the piston using a driver while the piston restraint mechanism is in the release configuration. Ejecting a positive displacement pipette tip from the dispenser includes relatively displacing the driver and the piston while the piston restraint mechanism is in the restraint configuration.

[0225] In some embodiments, ejecting a positive displacement pipette tip from the dispenser includes pushing the chip body out of the dispenser using an ejector that forms part of the dispenser while the piston restraint mechanism is in the restraint configuration.

[0226] According to some embodiments, the piston restraint mechanism includes an integral interlock feature on the piston, and the piston restraint mechanism includes a latch that forms part of the chip body. The latch can be arranged in a latch position that interlocks with the interlock feature and a non-latch position that does not interlock with the interlock feature. Mounting the positive displacement pipette tip on the dispenser includes deflecting the latch to the non-latch position by inserting the shaft of the dispenser into the chip body. Ejecting the positive displacement pipette tip from the dispenser includes pushing the chip body out of the shaft, whereupon the latch elastically returns to the latch position.

[0227] Embodiments of the present technology are illustrated by the accompanying drawings that form a part of this specification.

Brief Description of the Drawings

[0228] [Figure 1] FIG. 1 is a front view of an exemplary laboratory liquid handling system comprising a dispensing system according to an embodiment of the present technology. [Diagram 2] FIG. 2 is a perspective view of the dispenser of the dispensing system of FIG. 1. [Diagram 3]Cross-sectional view of the dispenser of FIG. 2 along line 3-3 of FIG. 2. [Figure 4] Partial enlarged cross-sectional view of the dispenser of FIG. 2. [Diagram 5] Partial enlarged cross-sectional view of the dispenser of FIG. 2. [Figure 6] Cross-sectional view of the dispenser of FIG. 2 along line 6-6 of FIG. 4. [Figure 7] Cross-sectional view of the dispenser of FIG. 2 along line 7-7 of FIG. 3. [Figure 8] Cross-sectional view of the pipette tip used with the dispenser of FIG. 2. [Figure 9] Partial cross-sectional view of the dispenser of FIG. 2 showing the operation of the dispenser. [Figure 10] Partial cross-sectional view of the dispenser of FIG. 2 showing the operation of the dispenser. [Figure 11] Partial cross-sectional view of the dispenser of FIG. 2 showing the operation of the dispenser. [Figure 12] Partial cross-sectional view of the dispenser of FIG. 2 showing the operation of the dispenser. [Figure 13] Partial cross-sectional view of the dispenser of FIG. 2 showing the operation of the dispenser. [Figure 14] Partial cross-sectional view of a dispensing system according to another embodiment. [Figure 15] Exploded partial cross-sectional view of the dispensing system of FIG. 14. [Figure 16] Partial cross-sectional view of the dispensing system of FIG. 14 in which the plunger member is disposed at a certain position. [Figure 17] Partial cross-sectional view of the dispensing system of FIG. 14 in which the plunger member is disposed at another position. [Figure 18] Cross-sectional view of the dispensing system of FIG. 14 along line 18-18 of FIG. 14. [Figure 19] Cross-sectional view of the dispensing system of FIG. 14 along line 19-19 of FIG. 14. [Figure 20] Partial cross-sectional view of a dispensing system according to another embodiment. [Figure 21] Partial enlarged cross-sectional view of the dispensing system of FIG. 20 in which the inter-chamber valve is in the open position. [Figure 22] An enlarged partial cross-sectional view of the dispensing system of FIG. 20 with the inter-chamber valve in the closed position. [Figure 23] A partial cross-sectional view of the dispensing system of FIG. 20 with the plunger member disposed at a certain position. [Figure 24] A partial cross-sectional view of the dispensing system of FIG. 20 with the plunger member disposed at another position. [Diagram 25] A partial cross-sectional view of a dispensing system according to another embodiment. [Figure 26] An enlarged partial cross-sectional view of the dispensing system of FIG. 25 showing the operation of the dispensing system. [Figure 27] An enlarged partial cross-sectional view of the dispensing system of FIG. 25 showing the operation of the dispensing system. [Figure 28] A cross-sectional view of a dispensing system according to another embodiment of the present technology. [Figure 29] A cross-sectional view of the dispenser of the dispensing system of FIG. 28 showing the operation of the dispensing system. [Diagram 30] A cross-sectional view of the dispenser of the dispensing system of FIG. 28 showing the operation of the dispensing system. [Diagram 31] A cross-sectional view of the dispenser of the dispensing system of FIG. 28 showing the operation of the dispensing system. [Diagram 32] A cross-sectional view of the dispenser of the dispensing system of FIG. 28 showing the operation of the dispensing system. [Diagram 33] An exploded cross-sectional view of the dispenser of FIG. 28. [Diagram 34] A cross-sectional view of the air displacement tip used with the dispensing system of FIG. 28. [Diagram 35] An exploded cross-sectional view of the positive displacement tip used with the dispensing system of FIG. 28. [Diagram 36] A cross-sectional view of a dispensing system according to another embodiment of the present technology. [Figure 37] A schematic perspective view showing another example of an automatic liquid processing system according to some embodiments. [Figure 38] An enlarged side view showing a conductive pipette tip according to some embodiments. [Figure 39A] It is a cross-sectional view showing an embodiment of the chip member of FIG. 38. [Figure 39B] It is a cross-sectional view showing an embodiment of the chip member of FIG. 38. [Figure 39C] It is a cross-sectional view showing an embodiment of the chip member of FIG. 38. [Figure 40A] It is a cross-sectional view showing an embodiment of a certain "crown"-shaped conductive electrode. [Figure 40B] It is a cross-sectional view showing an embodiment of another "crown"-shaped conductive electrode. [Figure 40C] It is a cross-sectional view showing an embodiment of yet another "crown"-shaped conductive electrode. [Diagram 41] It is a diagram showing the change in capacitance associated with the vertical position of a pipette tip including a conductive electrode and a non-conductive chip bottom according to some embodiments. [Diagram 42] It is a schematic diagram showing an automatic pipetting system configured for evaporation detection and compensation according to some embodiments. [Figure 43A] It is a schematic diagram showing evaporation detection according to some embodiments. [Figure 43B] It is an enlarged view of the orifice of the pipette tip of FIG. 43A showing the formation of liquid beads due to evaporation. [Figure 44A] It is a graph showing the changes in pressure and displacement volume in an evaporation detection operation according to some embodiments. [Figure 44B] It is a graph showing the changes in pressure and displacement volume in an evaporation detection operation according to other embodiments. [Diagram 45] It is a flowchart diagram showing the operation of evaporation detection in a pipette tip according to some embodiments. [Figure 46A] It is a flowchart diagram showing the operation of evaporation compensation in a pipette tip according to some embodiments. [Figure 46B] It is a flowchart diagram showing the operation of evaporation compensation in a pipette tip according to some embodiments. [Figure 47]A side view showing a dual metering dispenser that can be used in an automatic dispensing system according to some embodiments. [Figure 48] An enlarged schematic view showing a dual metering dispenser according to some embodiments. [Figure 49] A simplified schematic view showing a plunger and a manifold assembly of a dual metering dispenser according to some embodiments. [Figure 50] An enlarged schematic view showing a manifold and a flow sensor of the dual metering dispenser of FIG. 49 according to some embodiments. [Figure 51] An enlarged perspective view further showing a manifold assembly according to some embodiments. [Figure 52] A schematic view showing the connection of a pressure sensor in a dual metering dispenser according to some embodiments. [Figure 53] A schematic view showing the operation of a dual metering dispenser according to some embodiments. [Figure 54] A cross-sectional view of a dispensing system and a PD pipette tip in an extended position according to other embodiments of the present technology. [Figure 55] A cross-sectional view of the dispensing system of FIG. 54 with the PD pipette tip in a retracted position. [Figure 56] An exploded cross-sectional view of the PD pipette tip of FIG. 54. [Figure 57] An enlarged cross-sectional view of the PD pipette tip of FIG. 54 showing an indexing mechanism of the PD pipette tip. [Figure 58] A cross-sectional view of the PD pipette tip along line 58-58 of FIG. 54. [Figure 59] A cross-sectional view of the PD pipette tip along line 59-59 of FIG. 57. [Figure 60] An exploded view of a dispensing system including a positive displacement pipette tip according to some embodiments. [Figure 61] An exploded bottom perspective view of the positive displacement pipette tip of FIG. 60. [Figure 62]A cross-sectional perspective view of a positive displacement pipette tip of FIG. 60 along line 62-62 of FIG. 60. [Figure 63] A cross-sectional view of a chip body forming a part of the positive displacement pipette tip of FIG. 60 along line 62-62 of FIG. 60. [Figure 64] A side view of a piston forming a part of the positive displacement pipette tip of FIG. 60. [Figure 65] A cross-sectional view of an interlock insert forming a part of the positive displacement pipette tip of FIG. 60 along line 62-62 of FIG. 60. [Figure 66] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 67] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 68] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 69] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 70] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 71] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 72] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 73] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 74] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60. [Figure 75] A schematic cross-sectional view of a dispensing system showing the operation of using the dispensing system of FIG. 60.

DETAILED DESCRIPTION OF THE INVENTION

[0229] Referring to FIGS. 1 - 13, these illustrate an exemplary dispensing system 101 according to a particular embodiment of the present technology. The dispensing system 101 forms part of an automated liquid handling system 10 (FIG. 1) according to the illustrated embodiment of the present technology. However, the disclosed methods, systems, and apparatuses are not limited to the liquid handling system 10 or its use therein, and it is understood that the present disclosure is applicable to other systems and applications where aspiration and / or dispensing of liquid volumes is desired. The dispensing system 101 aspirates and dispenses liquid volumes within the liquid handling system 10.

[0230] Referring to FIG. 1, an exemplary liquid handling system 10 includes a platform or deck 12, a frame 14, a controller 20, an analyzer 16, a dispensing module 30, a dispensing module positioner 34A, and a dispensing system 101. The dispensing system 101 includes one or more dispensers 100. The liquid handling system 10 may be provided with one or more receptacles, reservoirs, or containers 36 for holding liquid samples.

[0231] For purposes of detailed explanation, as shown in FIGS. 1 and 3, the liquid handling system 10 includes a workspace that defines a vertically corresponding Z - axis and orthogonal X - Y axes that integrally define a horizontal plane.

[0232] The dispensing module 30 may include a housing, a support portion, or a base 32. In the illustrated embodiment, a plurality of dispensers 100 are mounted on the base 32. However, in other embodiments, the dispensing module 30 may mount only a single dispenser 100. The dispensers 100 may be arranged, for example, in a single row or in a defined X-Y array. The dispensing module positioner 34A is operable to move the dispensing module 30 with respect to the deck 12. The dispensing module 30 may include one or more dispenser actuators 34B for selectively raising and lowering (extending and retracting) the dispenser 100 with respect to the base 32 and / or raising and lowering the base 32 with respect to the deck 12. The dispensing module positioning system 34A and the actuator 34B may be adapted to be controlled by the controller 20.

[0233] Referring to FIG. 3, as will be discussed in more detail herein, it can be appreciated that each dispenser 100 has a longitudinal axis A-A and a distal end 112A. Each dispenser 100 includes a shaft 112 that terminates at the distal end 112A. In use, according to the system of FIG. 1, each dispenser 100 is movable up and down along the longitudinal axis A-A by a dispenser actuator 34B. In some embodiments, the axis A-A is substantially parallel to the vertical axis Z-Z.

[0234] The operations described herein can be performed by or through the controller 20. The actuators 34A, 34B and the actuators 128A, 148A described below, as well as other devices of the liquid handling system 10, are electronically controllable. According to some embodiments, the controller 20 programs some and in some embodiments all of the described steps. According to some embodiments, the movement of the actuators 34A, 34B is performed by a fully automated program by the controller 20. The controller 20 may be provided with an HMI 22 for receiving user commands. The controller 20 may include one or more controllers.

[0235] The dispensing system 101 includes a dispenser 100 and one or more pipette tips 160. In an exemplary embodiment, each pipette tip 160 is mounted on one of each of the dispensers 100 as discussed below. In some embodiments, the pipette tip 160 is removable and replaceable with respect to the dispenser 100 and may be a de facto disposable or consumable part of the dispensing system 101. However, in other embodiments, the pipette tip 160 may be omitted, and the structure and function of the pipette tip 160 may be provided as an integral part of the dispenser 100.

[0236] The dispensing system 101 may include one or more dispensers 100 on the dispensing module 30. Each dispenser 100 may be configured and operate in the same manner. Naturally, the following description regarding a representative one of the dispensers 100 may equally apply to each of the dispensers 100. When a plurality of dispensers 100 are provided, these dispensers 100 may be configured to operate independently of each other or may be configured to operate in cooperation.

[0237] Referring to FIGS. 2-4, the dispenser 100 includes a frame 108, an interface 109, a dispensing channel 102, a dispenser orifice 104, a pressure control system 106, a shaft 112, a discharge mechanism 151, a chip attachment 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 air flow control system 171. In an exemplary embodiment, the pipette tip 160 includes a dispensing orifice 162 and a liquid collection volume 165 that are in fluid communication with the dispensing channel 102. The shaft 112 has a longitudinal axis or main axis A-A. As discussed herein, the dispenser 100 operates to selectively operate the first plunger mechanism 110 or the second plunger mechanism 130, or both the first plunger mechanism 110 and the second plunger mechanism 130, to vary the pressure in the dispensing channel 102 to aspirate or dispense a liquid volume. It can be appreciated that the first plunger mechanism 110 and the second plunger mechanism 130 are operable independently and in parallel to vary the pressure in the dispensing channel 102 to aspirate or dispense a liquid volume.

[0238] The components of the dispenser 100 may be mounted on the frame 108, which is in turn mounted on the dispenser module base 32. The electrical interface 109 is operably connected to the electrical interface of the dispenser module base 30 or another component of the liquid processing system 10 to supply power to the dispenser 100 and provide a control or data communication interconnect between the dispenser 100 and other components of the liquid processing system 10 (e.g., the analyzer 16 and / or the remote controller). The electrical interface 109 may include a printed wiring board (PCB).

[0239] As described above, the controller 20 may include one or more controllers, which may be distributed within the liquid processing system 10. In some embodiments, the controller 20 includes one or more controllers that are integrated with or embodied in the dispenser 100 and operate to perform some or all of the dispenser control functions described herein. In some embodiments, these one or more controllers are embodied in and / or on the PCB 109.

[0240] Referring to FIGS. 2-5, the first plunger mechanism 110 includes a shaft 112, a guide sleeve 118, a plunger assembly 122 (including the first plunger), a first annular seal (e.g., an O-ring) 126, a second annular seal (e.g., an O-ring) 127, and a first linear drive mechanism 128.

[0241] The shaft 112 functions as a barrel of the first plunger 120. The shaft 112 defines a barrel bore 114 that coincides with axis A-A and extends from a first end 114A to an opposite second end 114B (FIG. 4). A top opening or port 114D is defined at the second end 114B and is in fluid communication with the bore 114. The dispenser orifice 104 is defined at the first end 114A and is in fluid communication with the bore 114.

[0242] The plunger assembly 122 (FIG. 5) includes an upper sleeve 124 and a first plunger 120 fixed to the upper sleeve 124 at the tip of the upper sleeve 124. A bore 124A is defined in the upper sleeve 124. The first plunger 120 has a tip 120A (FIG. 4). The first plunger 120 is mounted in the guide sleeve 118 and the barrel bore 114 so as to be slidably translatable with respect to the shaft 112 along the first plunger axis P1-P1 in an extending direction E1 and an opposite retracting direction E2. In some embodiments, the first plunger axis P1-P1 substantially coincides with the shaft axis A-A.

[0243] The first O-ring 126 (FIG. 4) forms an airtight seal between the outer diameter of the first plunger 120 and the manifold 175. The first plunger 120 is slidable 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.

[0244] The outer diameter D1 (FIG. 6) of the first plunger 120 is smaller than the inner diameter D2 (FIG. 6) of the bore 114 so that the first plunger 120 and the bore 114A are radially spaced along their respective lengths. This spacing defines a tubular or annular air passage or channel 103 (FIGS. 4 and 6) between the outer diameter of the first plunger 120 and the inner diameter of the bore 114. The channel 103 extends from the O-ring 126 to the dispenser orifice 104.

[0245] The linear drive mechanism 128 includes an actuator 128A, a spindle 128B, a spindle nut 128C, and a first plunger position sensor 129 (FIG. 3). The actuator 128A may be an electric motor. The spindle 128B is coupled to the output of the motor 128A and is thereby rotationally driven. In at least some embodiments, the spindle 128B is operatively coupled to the output of the motor 128A via a planetary gearbox (not shown). The spindle nut 128C is fixed to the upper end of the upper sleeve 124.

[0246] 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 with respect to the bore 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 with respect to the bore 114. The spindle 128B translates in parallel with the movement of the plunger 120 and enters and exits the upper sleeve bore 124A.

[0247] The first plunger position sensor 129 is connected to the controller 20 and detects and monitors the position of the first plunger 120 in the bore 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 (forming one or more of the controllers 20) that induces the motor 128A.

[0248] In use, in the barrel bore 114, a first chamber 115 (FIG. 4) is defined substantially between the tip 120A of the first plunger 120 and the first end 114A of the barrel bore 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 decreases. When the first plunger 120 is driven in the direction E2, the air volume is reset to the first chamber 115 and the effective volume of the first chamber 115 increases.

[0249] The first plunger 120 may be formed of any suitable material. In some embodiments, the first plunger 120 is formed of stainless steel.

[0250] The shaft 112 may be formed of any suitable material. In some embodiments, the shaft 112 is formed of stainless steel.

[0251] The spindle 128B and the spindle nut 128C may be formed of any suitable material. In some embodiments, the spindle 128B is formed of ceramic and the spindle nut 128C is formed of brass.

[0252] The second plunger mechanism 130 (Figs. 3 and 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 (as shown, for example), the second plunger 140 is larger than the first plunger 120, as discussed in more detail below.

[0253] The barrel 132 defines a barrel bore 134. The barrel bore 134 may be laterally offset from the axis A-A. The barrel bore 134 extends from a first end 134A to an opposite second end 134B. The end plug 136 is disposed at the first end 134A. A fluid channel 136A is defined in the end plug 136.

[0254] The second plunger 140 has a tip 140A. An axially extending plunger bore 142 is defined in the plunger 140 and is closed at the end 140A. The O-ring 146 (Figs. 5 and 7) is mounted on the tip 140A of the plunger 140. 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.

[0255] The second plunger 140 is mounted in the barrel bore 134 so as to be slidably translatable with respect to the barrel bore 134 along the extending direction E3 and the opposite retracting direction E4 along the second plunger axis P2 - P2. In some embodiments, the second plunger axis P2 - P2 is laterally offset from the shaft axis A - A.

[0256] The second linear drive mechanism 148 (FIG. 3) includes an actuator 148A, a spindle 148B, a spindle nut 148C, and a first plunger position sensor 149. The actuator 148A may be an electric motor. The spindle 148B is coupled to the output of the motor 148A and is thereby rotationally driven. The spindle nut 148C is fixed to the upper end of the second plunger 140.

[0257] The motor 148A is operable to drive the spindle 148B in 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 second plunger 140 are thereby pulled in the retracting direction E4 with respect to the bore 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 the extending direction E3 with respect to the bore 134. The spindle 148B translates in parallel with the movement of the plunger 140 and enters and exits the plunger bore 142.

[0258] The second plunger position sensor 149 is connected to the controller 140 and detects and monitors the position of the first plunger 140 in the bore 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 (forming one or more of the controllers 20) that drives the motor 148A.

[0259] The illustrated first and second linear drive mechanisms 128, 148 each include a rotary motor, a spindle, and a spindle nut. However, in some embodiments, other types of linear drive mechanisms may be used as an alternative. For example, a DC linear motor may be mentioned, but it is not limited thereto.

[0260] In use, in the barrel bore 134, a second chamber 135 (FIG. 5) is substantially defined between the tip 140A of the second plunger 140 and the first end 134A of the barrel bore 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 decreases. When the second plunger 140 is driven in the direction E4, the air volume is restored to the second chamber 135, and the effective volume of the second chamber 135 increases.

[0261] The second plunger 140 may be formed of any suitable material. In some embodiments, the second plunger 140 is formed of aluminum.

[0262] The barrel 132 may be formed of any suitable material. In some embodiments, the barrel 132 is formed of aluminum.

[0263] The spindle 148B and the spindle nut 148C may be formed of any suitable material. In some embodiments, the spindle 148B may be formed of ceramic or stainless steel, and the spindle nut 148C may be formed of plastic or a heat-resistant thermoplastic resin (e.g., polyetheretherketone (PEEK)).

[0264] The tip adapter 156 is configured to removably secure a pipette tip 160 (and, preferably configured replacement pipette tips) to the end 112A of the shaft 112. In some embodiments, the tip adapter 156 forms an airtight and pressure-tight seal between the attachment portion 166 and the shaft 112. In the illustrated embodiment, the tip adapter 156 includes an annular rib 156A configured to form a secure friction fit with the attachment portion 166 of the pipette tip, as well as an airtight and pressure-tight seal between the attachment portion 166 and the shaft 112. However, other suitable pipette tip attachment structures may be provided. For example, the tip adapter and the pipette tip may include interlock features. The tip adapter 156 may be integrally formed with the shaft or formed as a separate component.

[0265] The ejection mechanism 151 (Figs. 5 and 13) comprises an ejection member or sleeve 150 slidably mounted on a guide rod 152. A spring 154 biases the ejection sleeve 150 downwardly E6 towards the end 112A of the shaft. When the pipette tip 160 is attached, the ejection sleeve 150 is pushed upward (direction E5). For this upward movement and the positioning of the sleeve, magnets and Hall effect sensors on the sleeve 150 may be used to detect the presence of the pipette tip 160. The upper end 150B of the ejection sleeve 150 is configured to engage the lower end of the upper sleeve 124. The lower end 150A of the ejection sleeve 150 is configured to engage the pipette tip 160 as discussed below. In use, when the plunger assembly 122 is fully driven downward (direction E1) by the first linear drive mechanism 128, it abuts against the upper end 114B and drives the ejection sleeve 150 in the ejection direction E6, thereby pushing the pipette tip 160 out of the shaft 112.

[0266] The pipette tip 160 (FIG. 8) is an example of a pipette tip that can be used with the dispenser 100. However, of course, pipette tips of other designs may be used as alternatives.

[0267] 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 that extends from the dispensing orifice 162 (at the distal end 160A) to the interface opening 163 (at the proximal end 160B). The attachment portion 166 is provided at the proximal end 160B. As discussed herein, part (some or all) of the chip passage 164 may be configured to function as a liquid collection volume 165 during use.

[0268] Referring to FIG. 5, the air flow control system 171 includes a valve 178, a first channel 172, a second channel 174, and a third channel 176.

[0269] The first channel 172 fluidly connects or couples the second chamber 135 (via the channel 136A in the end plug 136) to the valve 178.

[0270] The second channel 174 fluidly connects or couples the valve 178 to the port 174A to the ambient atmosphere.

[0271] Referring to FIG. 4, the third channel 176 fluidly connects or couples the valve 178 to the first barrel bore 114. More specifically, in an exemplary embodiment, the third channel 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 is also in fluid communication with the annular channel 103 between the first plunger 120 and the shaft 112. The channel 103 can pass the air flow from the barrel port 114D to the dispensing orifice 104 through the dispensing channel 102 (i.e., the bore 114).

[0272] Some or all of channels 172, 174, and 176 may be formed in the whole or part of manifold 175. In some embodiments, each of channels 172, 174, and 176 has a diameter in the range of about 0.2 to 1 mm.

[0273] Further, the pressure control system 106 may include a dispensing channel pressure sensor 179 (FIG. 5) fluidly coupled to the dispensing channel 102 via channel 176.

[0274] The controller 20 operates to control the valve 178 to the first, second, and third valve states. Channel 176 is not fluidly connected to the atmosphere port 174A in any of the three valve states. When the second chamber 135 is fluidly connected to the first bore 114, it is fluidly connected to the dispensing channel 102 and the dispenser orifice 104 via the first bore 114.

[0275] In the first valve state, the valve 178 closes channel 172 from channels 174 and 176. As a result, the second chamber 135 is not fluidly connected to the first bore 114 (and thus the dispensing channel 102) nor to the atmosphere port 174A.

[0276] In the second valve state, the valve 178 closes channel 172 from channel 176 and opens channel 172 to channel 174. As a result, the second chamber 135 is not fluidly connected to the first bore 114 (and thus the dispensing channel 102), but is fluidly connected to the atmosphere port 174A.

[0277] In the third valve state, the valve 178 closes channel 172 from channel 174 and opens channel 172 to channel 176. As a result, the second chamber 135 is fluidly connected to the first bore 114 (and thus the dispensing channel 102) and is not fluidly connected to the atmosphere port 174A.

[0278] Liquid processing system 10 and dispensing system 101 may be used as follows according to several methods to aspirate and / or dispense one or more liquid samples. Generally, by using the first and second plunger mechanisms 110, 130, the air volume in the respective chambers 115, 135 is displaced, and correspondingly, the pressure in the dispensing channel 102 is changed to aspirate the liquid sample into the liquid collection volume 165 or dispense it from the liquid collection volume 165.

[0279] The dispenser 100 is operable in each of several different operating modes. The operator or controller 20 may select and execute the operating mode according to the conditions or parameters of the aspiration or dispensing task.

[0280] Normally, the dispenser 100 will initially be set to the starting position as shown in FIG. 9 (e.g., by the controller 20). In the starting position, the first plunger 120 is disposed at its lowermost position. In some embodiments, as shown, at the lowermost starting position of the first plunger 120, the tip 120A of the first plunger 120 is substantially in the same plane as or axially aligned with the dispenser orifice 104. In the starting position, the second plunger 140 is disposed at its lowermost position. In some embodiments, as shown, at the lowermost starting position of the second plunger 140, the tip 140A of the second plunger 140 is substantially in the same plane as or axially aligned with the end plug 136.

[0281] As shown in FIG. 9, the pipette tip 160 is mounted on the tip adapter 156.

[0282] Thereafter, the controller 20 may operate the actuators 34A and 34B to place, for example, the pipette tip 160 above the liquid sample LS. The sample LS may be disposed, for example, in the container 36. Thereafter, the controller 20 may operate the actuator 34B to lower, for example, the distal end 160A and thus the dispensing orifice 162 into the sample LS. In some embodiments, the distal end 160A and thus the dispensing orifice 162 are submerged in the sample to at least a defined depth so that the dispensing orifice 162 remains submerged in the sample LS during aspiration.

[0283] With the dispenser 100 in the starting position and the dispensing orifice 162 submerged, the dispensing system 101 may operate 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 such that the dispensing channel 102 is fluid-sealed from the second chamber 135. Thereafter, the first drive mechanism 128 is actuated to pull the first plunger 120 away from the dispenser orifice 104 in the rearward direction E2, for example as shown in FIG. 10. Due to the rearward movement of the first plunger 120, the effective air volume of the first chamber 115 expands, creating a negative pressure at the dispenser orifice 104. This 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. An air volume or air cushion AC may remain in the tip passage 164 and the first chamber 115 between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120.

[0284] Thereafter, by using the dispenser 100, the liquid sample volume LV may be dispensed in the first dispensing mode. To dispense the liquid sample volume LV, the valve 178 is set or held in the first valve state. The first drive mechanism 128 operates to push the first plunger 120 in the extending direction E1 toward the dispenser orifice 104. Due to the extension of the first plunger 120, an air volume is displaced from the first chamber 115, so that a positive pressure is generated at the proximal end of the liquid sample volume LV. Due to this positive pressure, the liquid sample volume LV is expelled from the liquid collection volume 165 through the dispensing orifice 162. An air cushion AC may remain between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0285] Alternatively, the dispensing system 101 may operate in a second suction mode to suction a part of the liquid sample LS. In the second suction mode, the valve 178 is set in the third valve state such that the second chamber 135 is fluidly connected to the dispensing channel 102 and fluidly sealed from the atmosphere port 174A. With the dispenser 100 in the starting position and the dispensing orifice 162 submerged, the second drive mechanism 148 operates to pull the second plunger 140 away from the end plug 136 in the retracting direction E4, for example as shown in FIG. 11. Due to the retraction of the second plunger 140, the effective air volume of the second chamber 135 expands, so that a negative pressure is generated at the dispenser orifice 104 (via the channel 172, the valve 178, the channel 176, and the bore 114). Due to this negative pressure, the liquid sample volume LV of the liquid sample LS is drawn into the liquid collection volume 165 (in the tip passage 164) of the pipette tip 160. An air volume or an air cushion AC may remain in the tip passage 164 between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120.

[0286] Thereafter, the liquid sample volume LV may be dispensed in the second dispensing mode by using the dispenser 100. To dispense the liquid sample volume LV, the valve 178 is set or held in the third valve state. The second drive mechanism 148 is actuated to push the second plunger 140 in the extending direction E3 toward the end plug 136. Due to the extension of the second plunger 140, an air volume is displaced from the second chamber 135, so that a positive pressure is generated at the proximal end of the liquid sample volume LV (through the channel 172, the valve 178, the channel 176, and the bore 114). This positive pressure expels the liquid sample volume LV from the liquid collection volume 165 through the dispensing orifice 162. An air cushion AC may remain between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0287] Alternatively, the dispensing system 101 may operate in a third suction mode to suction a part of the liquid sample LS. In the third suction mode, the valve 178 is set to a third valve state such that the second chamber 135 is fluidly connected to the dispensing channel 102 and is fluidly sealed from the atmosphere port 174A. Thereafter, the first drive mechanism 128 is actuated to pull the first plunger 120 away from the dispensing orifice 104 in the retreat direction E2, for example as shown in FIG. 12. Due to the retreat of the first plunger 120, the effective air volume of the first chamber 115 expands, so that a negative pressure is generated at the dispensing orifice 104. At the same time as the retreat of the first plunger 120, the second drive mechanism 148 is actuated to pull the second plunger 140 away from the end plug 136 in the retreat direction E4, also as shown in FIG. 12. Due to the retreat of the second plunger 140, the effective air volume of the second chamber 135 expands, so that a negative pressure is also generated at the dispensing orifice 104. As a result, a negative pressure is generated by the displacement of either of the two plungers 120, 140, whereby the liquid sample volume LV of the liquid sample LS is drawn into the liquid collection volume 165 (in the tip passage 164) of the pipette tip 160. An air volume or air cushion AC may remain in the tip passage 164 between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120.

[0288] Thereafter, by using the dispenser 100, the liquid sample volume LV may be dispensed in the third dispensing mode. To dispense the liquid sample volume LV, the valve 178 is set or held in the third valve state. The first drive mechanism 128 operates to push the first plunger 120 in the extending direction E1 toward the dispenser orifice 104. Due to the extension of the first plunger 120, an air volume is displaced from the first chamber 115, so that a positive pressure is generated at the proximal end of the liquid sample volume LV. Also, simultaneously with the extension of the first plunger 120, the second drive mechanism 148 operates to push the second plunger 140 in the extending direction E3 toward the end plug 136, so that an air volume is displaced from the second chamber 135, and thus a positive pressure is generated at the proximal end of the liquid sample volume LV (via the channel 172, the valve 178, the channel 176, and the bore 114). As a result, a positive pressure is generated by the displacement of either of the two plungers 120, 140, whereby the liquid sample volume LV is expelled from the liquid collection volume 165 through the dispensing orifice 162. An air cushion AC may remain between the proximal end of the liquid sample volume LV and the tip 120A of the first plunger 120 until the liquid sample volume LV is completely dispensed.

[0289] Alternatively, the dispensing system 101 may operate in a fourth suction mode to suction a part of the liquid sample LS. Also in the fourth suction mode, the valve 178 is set in the third valve state, and by operating the first and second drive mechanisms 128, 148, the plungers 120, 140 are retracted as described above for the third suction mode. However, in the fourth suction mode, the first plunger 120 and the second plunger 140 are retracted at different times (e.g., sequentially or alternately) rather than simultaneously with each other.

[0290] Similarly, the dispensing system 101 may operate in a fourth dispensing mode to dispense a portion of the liquid sample LS. Also in the fourth dispensing mode, the valve 178 is set to the third valve state, and the first and second drive mechanisms 128, 148 operate to extend the plungers 120, 140 as described above for the third dispensing mode. However, in the fourth dispensing mode, the first plunger 120 and the second plunger 140 extend at different times (e.g., sequentially or alternately) rather than simultaneously with each other.

[0291] In some operations, the valve 178 is set to the second valve state to connect the second chamber 135 to the atmosphere port 174A. Thereafter, the second drive mechanism 148 operates to position the second plunger 140 at its starting position. Since the air displaced from the chamber 135 by the second plunger 140 is expelled through the atmosphere port 174A, the air volume in the chamber 135 is not pressurized. Thereafter, for the suction or dispensing operation, the valve 178 may be set to the first valve state or the second valve state to reseal the second chamber 135 with respect to the atmosphere port 174A.

[0292] In the operation according to some embodiments, in the second plunger 140 and the valve 178, for example, a reciprocating or circulating pump cooperates to suck and dispense a larger volume. In this case, the valve 178 is switched between its second and third valve states during the movement of the second plunger 140. More specifically, the valve 178 and the second plunger 140 may operate as follows. When the valve 178 is in the third valve state (fluidly connecting the second chamber 135 to the dispensing channel 102 and closing the second chamber 135 from the atmosphere port 174A), the second plunger 140 retracts (direction E4) to draw the liquid sample volume LV into the pipette tip 160. Thereafter, the valve 178 is placed in the second valve state (fluidly connecting the second chamber 135 to the atmosphere port 174A and closing the second chamber 135 from the dispensing channel 102). When the valve 178 is in the second state, the second plunger 140 extends (direction E3) to expel air from the second chamber 135 and the second plunger 140 returns to or towards 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., is not dispensed by the extension of the second plunger 140). Thereafter, the valve 178 is placed in the third valve state again, but when the valve 178 is in this third valve state, the second plunger 140 retracts again (direction E4) to draw an additional liquid sample volume LV into the pipette tip 160. By repeating this sequence a plurality of times, the liquid sample volume LV may be incrementally aspirated into the pipette tip 160. For example, by repeating this sequence 5 times, 1 ml each time for each aspiration, a total of 5 ml may be aspirated into the pipette tip 160. Also, by reversing this operation, a larger volume increment may be dispensed from the pipette tip 160 (for example, a series of five 1 ml liquid volumes may be dispensed from the pipette tip 160 containing a 5 ml liquid sample).

[0293] As described above, the dispensing system 101 sucks the liquid sample by reducing the pressure in the dispensing channel 102 and dispenses the liquid sample by increasing the pressure in the dispensing channel. However, the pressure in the dispensing channel 102 may vary according to other operations or states in this procedure. For example, in some embodiments for suction, the pressure in the dispensing channel 102 increases as the plungers 120 or 140 retract. After the plungers 120, 140 stop, the inflow into the pipette tip 160 also stops, and the pressure drop associated with the movement of the plungers becomes zero. However, the pressure in the dispensing channel 102 can maintain a negative pressure due to the weight of the liquid sample in the pipette tip 160. After the pipette tip 160 is removed from the supply of the liquid sample, the pressure in the dispensing channel 102 may drop slightly further due to the decrease in buoyancy. Thereafter, the pressure in the dispensing channel 102 may slowly increase due to the evaporation of the liquid sample in the pipette tip 160. Therefore, naturally, the pressure change in the dispensing channel 102 can be caused or contributed to by additional phenomena other than the movement of the plungers 120, 140.

[0294] The above-described suction mode and dispensing mode can be executed in different combinations as required. For example, a third suction mode (simultaneous retraction of the plungers) may be used for sucking the liquid sample volume, and a fourth dispensing mode (sequential extension of the plungers) may be used for dispensing the liquid sample volume.

[0295] The dispenser 100 may be arranged to be repositioned between the steps of aspiration and dispensing as required. The aspiration procedure may include aspirating a liquid volume from a single liquid sample source or multiple liquid sample sources. The dispensing procedure may include dispensing the liquid volume to a single location or multiple locations. For example, after an amount of liquid sample has been aspirated from a single source, a smaller amount of the aspirated liquid sample may be dispensed to different locations (e.g., wells of a well plate). In some embodiments, the liquid sample volume LV (or a portion thereof) is dispensed by the dispenser 100 to the analyzer 16.

[0296] In some embodiments, the controller 20 automatically programs the valve 178 and the actuators 128A, 148A to set the valve state and extend and retract the plungers 120, 140 as described herein.

[0297] In some embodiments, the controller 20 receives a pressure signal from the dispensing channel pressure sensor 179 indicating the air pressure in the dispensing channel 102. The controller 20 may continuously monitor the pressure in the dispensing channel 102.

[0298] Referring to FIG. 13, the dispensing system 101 can operate to automatically remove the pipette tip 160 from the dispenser 100 using the ejection mechanism 151. To eject the pipette tip 160, the controller 20 operates the first drive mechanism 128 to push the plunger assembly 122 in the extension direction E6. When the first drive mechanism 128 continues to drive the plunger assembly 122, the tip 124B of the plunger sleeve 122 engages with the upper end 150B of the ejection sleeve 150, pushing the ejection sleeve 150 in the direction E6. The lower end 150A of the ejection sleeve 150 engages with the attachment portion 166 of the pipette tip 160, pushing the pipette tip 160 out of the tip adapter 156. In some embodiments, the controller 20 automatically programs the actuator 128A to operate to eject the pipette tip 160.

[0299] As described herein, the first and second plunger mechanisms 110, 130 can operate either independently of each other or integrally to aspirate and dispense a liquid sample volume. The selection of the plunger mechanisms 110, 130 to operate for a given aspiration or dispensing procedure can be a function of the conditions or parameters of the aspiration or dispensing procedure or can be adapted to the conditions or parameters. By employing a dual plunger mechanism, the volume range of the dispenser 100 can be expanded and the process-specific volume accuracy and precision can be accommodated without the need for multiple dispensing channels.

[0300] For example, if only a relatively small volume of liquid sample is aspirated or dispensed, the dispenser 100 may be adapted to operate in a first aspiration mode or a first dispensing mode. Using a smaller plunger 120 can provide higher resolution, enabling improved accuracy and precision.

[0301] When a relatively large amount of liquid sample is aspirated or dispensed, the dispenser 100 may be configured to operate in a second aspiration mode or a second dispensing mode. Using a larger plunger 140 may enable the dispenser 100 to draw in and hold a greater amount of liquid sample at one time. Using a larger plunger 140 may enable the dispenser 100 to aspirate or dispense the liquid sample at a higher speed.

[0302] Also, when a relatively large amount of liquid sample is aspirated or dispensed, in addition to the third aspiration mode or the third dispensing mode, the dispenser 100 may be configured to operate in a fourth aspiration mode or a fourth dispensing mode. Using a combination of a smaller plunger 120 and a larger plunger 140 may enable the dispenser 100 to draw in and hold an even greater amount of liquid sample at one time. Displacing the smaller plunger 120 and the larger plunger 140 simultaneously may enable the dispenser 100 to aspirate or dispense the liquid sample at an even higher speed.

[0303] For example, in an exemplary embodiment, since the first plunger 120 has a stroke distance L1 (FIG. 12) of 25 mm and a diameter D1 (FIG. 6) of 2 mm, the first plunger mechanism 110 can displace a maximum of 55 microliters of air. In an exemplary embodiment, since the second plunger 140 has a stroke distance L5 (FIG. 12) of 45 mm and a diameter D5 (FIG. 7) of 6 mm, the second plunger mechanism 130 can displace a maximum of 1100 microliters of air. In the case of operation in the first aspiration mode, the dispenser 100 can aspirate a maximum of 55 microliters of liquid sample. In the case of operation in the second aspiration mode, the dispenser 100 can aspirate a maximum of 1100 microliters of liquid sample. In the case of operation in the third or fourth aspiration mode, the dispenser 100 can aspirate a maximum of 1155 microliters of liquid sample.

[0304] In some embodiments, the controller 20 automatically executes, in a program, steps of extending and retracting the plungers 120 and 140 and operating the actuators 128A and 148A to eject the pipette tip 160.

[0305] In some embodiments, the controller 20 automatically executes, in a program, steps of operating the actuators 34A and 34B to position the dispenser 100.

[0306] 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 (FIG. 6) in a cross-sectional plane orthogonal to the first plunger axis P1-P1 (i.e., the axis along which the first plunger translates to perform suction and dispensing). The second plunger 140 has a cross-sectional area A2 (FIG. 7) in a cross-sectional plane orthogonal to the second plunger axis P2-P2 (i.e., the axis along which the second plunger translates to perform suction and dispensing). In some embodiments, such as (as shown in the figure), the cross-sectional area A2 of the second plunger 140 is larger 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.

[0307] In some embodiments, the cross-sectional area A1 ranges from about 0.1 to 4 mm 2 and the cross-sectional area A2 ranges from about 1.25 to 50 mm 2

[0308] ​The smaller first plunger 120 displaces the air volume in the first chamber 115 at an air volume displacement rate per first unit translation. The larger second plunger displaces the air volume in the second chamber 135 at an air volume displacement rate per second unit translation. Since the larger plunger 120 also has a larger cross-sectional area, the air volume displacement rate per second unit translation is larger than the air volume displacement rate per first unit translation. In some embodiments, the air volume displacement rate per second unit translation is at least three times the air volume displacement rate per first unit translation.

[0309] In some embodiments, the air volume displacement rate per first unit translation ranges from about 0.01 microliters / s to 100 microliters / s, and the air volume displacement rate per second unit translation ranges from about 0.1 microliters / s to 2500 microliters / s.

[0310] In some embodiments, the dispenser is configured such that the maximum air volume displaceable by the second plunger 140 (when the second plunger 140 translates over its full stroke) is greater than the maximum air volume displaceable by the first plunger 120 (when the first plunger 120 translates over its full stroke). In some embodiments, the maximum air volume displaceable by the second plunger 140 is at least ten times the maximum air volume displaceable by the first plunger 120.

[0311] In some embodiments, the maximum air volume displaceable by the second plunger 140 ranges from about 10 microliters to 5000 microliters, and the maximum air volume displaceable by the first plunger 120 ranges from about 1 microliter to 100 microliters.

[0312] 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 10 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 ranges from about 11 microliters to 5500 microliters, and the maximum air volume of the first chamber 115 ranges from about 1.5 microliters to 110 microliters.

[0313] In some embodiments, as shown in the exemplary embodiments of FIGS. 2-7, the first chamber 115 (the chamber including the air volume displaced by the first plunger 120 during translation), occupies a portion of the dispensing channel 102. Accordingly, the first plunger 120 is disposed in the dispensing channel 102 and can move through the dispensing channel 102. In some embodiments, the distal end 120A of the first plunger 120 coincides with or extends beyond the dispenser orifice 104 when the first plunger 120 is fully extended. Providing the first plunger 120 in the shaft 112 and disposing the distal end 120A at the starting position helps to minimize the dead volume in the dispensing channel 102 and may enable a more compact dispenser. Also, arranging the first plunger mechanism 110, the shaft 112, and the ejection mechanism 151 enables the suction / distribution function and the chip ejection function to be performed by the use of a single drive mechanism.

[0314] Referring to FIGS. 14 to 19, these illustrate an exemplary dispensing system 201 according to another embodiment of the present technology. The dispensing system 201 is capable of aspirating and dispensing a liquid volume within a liquid processing system. The dispensing system 201 may be configured to be used in place of the dispensing system 101, for example, in the automated liquid processing system 10 (FIG. 1). However, the disclosed methods, systems, and devices are not limited to the liquid processing system 10 or its use therein, and it is understood that the present disclosure is applicable to other systems and applications where aspiration and / or dispensing of a liquid volume is desired. The dispensing system 201 includes a dispenser 200.

[0315] The dispensing system 201 includes one or more dispensers 200. The dispenser may be mounted on the dispensing module 30. Each dispenser 200 may be configured and operate in the same manner. Naturally, the following description regarding a representative one of the dispensers 200 may equally apply to each of the dispensers 200. When a plurality of dispensers 200 are provided, these dispensers 200 may operate independently of each other or may operate in cooperation.

[0316] The dispensing system 201 includes a dispenser 200, a controller 20, and one or more pipette tips 160 (as described herein with reference to FIG. 8). In some embodiments, the pipette tip 160 is removable and replaceable with respect to the dispenser 200 and may be a de facto disposable or consumable part of the dispensing system 201. However, in other embodiments, the pipette tip 160 may be omitted and the structure and function of the pipette tip 160 may be provided as an integral part of the dispenser 200. The pipette tip 160 may be provided with a filter medium 169 (FIG. 15).

[0317] Referring to FIGS. 14 and 15, as will be discussed in more detail herein, it can be appreciated that the dispenser 200 has a longitudinal axis A-A and a distal end 212A. The dispenser 200 includes a tubular barrel 210, a pressure control system 206, a dispensing channel 202, a dispenser 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 a shaft 212 that terminates at the distal end 210A. The dispenser orifice 204 is disposed at the distal end 210A and is in fluid communication with the dispensing channel 202.

[0318] The pressure control system 206 includes a barrel bore or passage 220, a pressure relief port 228 to the atmosphere, a plunger member 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.

[0319] The passage 220 is longitudinally aligned with the axis A-A and extends from a front end 220A to an opposite rear end 220B. Referring to FIG. 15, the passage 220 includes a front portion 222D and a rear portion 224D. The front seal 252 is axially disposed between the front portion 222D and the rear portion 224D. The rear seal 254 is axially disposed between the rear portion 224D and a rear opening 220E of the rear end 210B. A front chamber 222 is defined by the front portion 222D and the front seal 252 between the front seal 252 and the dispensing channel 202. A rear chamber 224 is defined by the rear portion 224D, the front seal 252, and the rear seal 254 between the front seal 252 and the rear seal 254.

[0320] The front and rear seals 252, 254 may each be an annular seal (e.g., an O-ring). The front O-ring 252 (or other type of seal) defines a seal opening 252A therein.

[0321] The plunger member 240 has a front end or tip 240A, an opposite rear end 240B, and an intermediate transition portion 246. The front plunger 242 extends from a tip 242A (at the front end 240A) to a rear end 242B (at the transition portion 246). The rear plunger 244 extends from a tip 244A (at the transition portion 246) to a rear end 244B (at the rear end 246).

[0322] The front plunger 242 and the rear plunger 244 are joined, integrated, or connected at the transition portion 246. In some embodiments, the front plunger 242 and the rear plunger 244 form an integral single member. In some embodiments, the plungers 242, 244 form a rigid single member. In some embodiments, the front plunger 242 and the rear plunger 244 form members integral with each other.

[0323] The plunger member 240 is mounted in the passage 220 so as to be slidably translatable with respect to the barrel 210 along the extension direction E8 and the opposite retraction direction E9 along the plunger axis P4 - P4. In some embodiments, the plunger axis P4 - P4 substantially coincides with the shaft axis A - A.

[0324] The plunger member 240 is slidable to translate (with a plunger member stroke relative to the passage 220) between a starting or fully extended position as shown in FIG. 14 and a fully retracted position as shown in FIG. 17. In the fully extended position, the front plunger 242 is present in the front chamber 222 with its tip 242A proximate to the dispensing channel 202, the rear plunger 244 is present in the rear chamber 224 with its tip 244A proximate 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 and pressure-tight seal between the front O-ring 252 and the barrel 210, and forms an airtight and pressure-tight seal between the outer diameter of the front plunger 242 and the inner diameter of the front O-ring 252. The front plunger 242 is slidable through the front O-ring 252 while maintaining the airtight and pressure-tight seal. The rear O-ring 254 forms an airtight and pressure-tight seal between the outer diameter of the rear plunger 244 and the barrel 210. The rear plunger 244 is slidable through the rear O-ring 254 while maintaining the airtight and pressure-tight seal.

[0325] In the exemplary dispenser 200, the stroke of the plunger member 240 corresponds to the strokes of the front plunger 242 and the rear plunger 244. Referring to FIG. 17, the front plunger 242 is translatable relative to the passage 220 with a front plunger stroke SF. The rear plunger 244 is translatable relative to the passage 220 with a rear plunger stroke SR. In a first portion SF1 of the front plunger stroke SF, the front chamber 222 is fluid-sealed from the rear chamber 224 by the front seal 252. In a second portion SF2 of the front plunger stroke SF, the front chamber 222 is fluid-coupled or connected to the rear plunger 244 through the opening 252A of the front seal 252.

[0326] The plunger drive mechanism 258 is selectively operable to drive the plunger member 240 in each of the extending direction E8 and the retracting direction E9. The plunger drive mechanism 258 may be a linear drive mechanism. The plunger drive mechanism 258 may comprise an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes an electric motor. In some embodiments, the linear drive mechanism 258 includes a spindle and a spindle nut link mechanism driven by an electric motor. In some embodiments, the plunger drive mechanism 258 is manually operable and does not include a power-driven actuator. For example, the plunger member 240 may be configured to be pushed and pulled using a manual extension portion, lever, knob, or other feature.

[0327] In use, when the front plunger 242 is driven in the extending direction E8, an air volume is displaced from the front chamber 222, reducing the effective volume of the front chamber 222. When the front plunger 242 is driven in the retracting direction E9, the air volume is reset to the front chamber 222, increasing the effective volume of the front chamber 222.

[0328] Similarly, in use, when the rear plunger 244 is driven in the extending direction E8, an air volume is displaced from the rear chamber 224, reducing the effective volume of the rear chamber 224. When the rear plunger 244 is driven in the retracting direction E9, the air volume is reset to the rear chamber 224, increasing the effective volume of the rear chamber 224.

[0329] The plunger member 240 may be formed of any suitable material. In some embodiments, the plunger member 240 is formed of stainless steel.

[0330] The barrel 210 may be formed of any suitable material. In some embodiments, the barrel 210 is formed of aluminum.

[0331] The tip adapter 214 is configured to removably secure a pipette tip 160 (and, preferably configured replacement pipette tips) to the end 212A of the shaft 212, similar to that described above with respect to the tip adapter 156.

[0332] The pipette tip 160 (FIG. 8) is an example of a pipette tip that can be used with the dispenser 100. However, of course, pipette tips of other designs may be used as an alternative.

[0333] The pressure sensor 256 is fluidly coupled to the dispensing channel 202. In some embodiments, the pressure sensor 256 is an in-line pressure sensor disposed in or along the dispensing channel 202.

[0334] The controller 20 operates to control the pressure relief valve 255 to a valve open state and a valve closed state. In the valve open state, the rear chamber 224 is fluidly connected to the ambient atmosphere through the relief port 228. In the valve closed state, the rear chamber 224 is not fluidly connected to the ambient atmosphere through the relief port 228.

[0335] The liquid processing system 10 and the dispensing system 201 may be used to aspirate and / or dispense one or more liquid samples in the following manner according to several methods. Generally, by using the front and rear plungers 242, 244, the air volume in the respective chambers 222, 224 is displaced, and correspondingly, the pressure in the dispensing channel 202 is changed to aspirate the liquid sample into the liquid collection volume 165 or dispense it from the liquid collection volume 165.

[0336] The dispenser 200 is operable in several different operating modes. The operator or the controller 20 may select and execute the operating mode according to the conditions or parameters of the aspiration or dispensing task.

[0337] Typically, the dispenser 200 will initially be set to a first starting position (e.g., by the controller 20). The starting position may be, for example, the lowest position as shown in FIG. 14. In other embodiments, the starting position is raised or retracted somewhat from the lowest fully extended position of FIG. 14 (i.e., the plunger member 240 is retracted in part relative to the position shown in FIG. 14). Initiating suction with this offset can help to completely empty the pipette tip by the dispensing operation. For example, the offset of the distal end 242A of the plunger member from the distal end 222D of the front chamber may be in the range of about 10-20% of the dispensing volume.

[0338] As shown in FIG. 14, the pipette tip 160 is mounted on the tip adapter 214.

[0339] Thereafter, the controller 20 may operate the actuators 34A, 34B to position, for example, the pipette tip 160 above the liquid sample LS. The sample LS may be disposed, for example, in the container 36. Thereafter, the controller 20 may operate the actuator 34B to lower, for example, the distal end 160A and thus the dispensing orifice 162 into the sample LS. In some embodiments, the distal end 160A and thus the dispensing orifice 162 are submerged into the sample to at least a defined depth such that the dispensing orifice 162 remains submerged in the sample LS during suction.

[0340] With the dispenser 200 in the first starting position and the dispensing orifice 162 submerged, the dispensing system 201 may operate in a first suction mode to suction a portion of the sample LS. In the first suction mode, the pressure relief valve 255 is set to the valve open state such that the rear chamber 224 is in fluid connection with the relief port 228. In the first suction mode, the dispensing channel 202 is fluid-sealed from the rear chamber 224 by the front seal 252. More specifically, the front plunger 242 closes (airtightly) the connection opening 252A in the front seal 252.

[0341] Thereafter, the drive mechanism 258 is actuated to displace the plunger member 240 in the rearward direction E9, thereby separating the front plunger 242 from the dispenser orifice 204. As a result, the front plunger 242 translates in part of its first stroke SF1 as shown in FIG. 16, but does not enter the second part SF2 of the stroke. The front chamber 222 maintains a sealed state from the rear chamber 224 by the front seal 252. As the front plunger 242 retracts, the effective air volume of the front chamber 222 expands, creating a negative pressure at the dispenser orifice 204. This 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. An air volume or air cushion AC may remain in the tip passage 164 and the front chamber 222 between the proximal end of the liquid sample volume LV and the tip 220A of the front chamber 222.

[0342] Thereafter, by using the dispenser 200, the liquid sample volume LV may be dispensed in the first dispensing mode. Since the front plunger 242 is in the first part SF1 of its stroke, the front chamber 222 is maintained in a sealed state from the rear chamber 224 by the front seal 252. The pressure relief valve 255 is set or held in the valve open state. Thereafter, the drive mechanism 258 operates to displace the plunger member 240 in the extending direction E8, thereby pushing the front plunger 242 in the extending direction E8 toward the dispenser orifice 204. As the front plunger 242 extends, an air volume is displaced from the front chamber 222, so that a positive pressure is generated at the proximal end of the liquid sample volume LV. Due to this positive pressure, the liquid sample volume LV is expelled from the liquid collection volume 165 through the dispensing orifice 162. An air cushion AC may remain between the proximal end of the liquid sample volume LV and the tip 242A of the front plunger 242 until the liquid sample volume LV is completely dispensed.

[0343] Alternatively, the dispensing system 101 may operate in a second suction mode to suction a portion of the liquid sample LS. The pressure relief valve 255 is initially set to the valve open state such that the rear chamber 224 is in fluid communication with the relief port 228. The plunger member 240 is placed in the second starting position. At the second starting position, the distal end 242A of the plunger member 240 is disposed behind (e.g., slightly behind) the front seal 252 such that the plunger member 242 and the front seal 252 do not seal the front chamber 222 from the rear chamber 224. Thereafter, the controller 20 sets the pressure relief valve 255 to the valve closed state such that the rear chamber 224 is fluid-sealed from the relief port 228. With the dispenser 200 in the second starting position and the dispensing orifice 162 submerged, the drive mechanism 258 is actuated to draw the plunger member 240 in the retraction direction E9. Thereby, the front plunger 242 translates in part or in whole of the second part SF2 of its stroke as shown in FIG. 17. Due to the retraction of the rear plunger 244, the effective air volume of the rear chamber 224 expands, generating a negative pressure at the dispenser orifice 204. This 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 cushion AC may remain in the tip passage 164 between the proximal end of the liquid sample volume LV and the tip 242A of the first plunger 242.

[0344] Similarly, thereafter, the liquid sample volume LV may be dispensed in the second dispensing mode by using the dispenser 200. The pressure relief valve 255 is set or held in the valve closed state. The drive mechanism 258 is actuated to push the plunger member 240 in the extension direction E8. Due to the translational movement of the plunger member 240 in extension, an air volume is displaced from the rear chamber 224, generating a positive pressure at the proximal end of the liquid sample volume LV. This positive pressure expels the liquid sample volume LV from the liquid collection volume 165 through the dispensing orifice 162.

[0345] The plunger member 240 is extendable beyond the front seal 252. In this case, when the tip 242A of the front plunger 242 reaches the opening 252A of the front seal 252 and closes it, the controller 20 may open the pressure relief valve 255. Thereafter, the drive mechanism 258 continues to push the plunger member 240 in the extending direction E8. Due to the continuous extension of the plunger member 240, the air volume is displaced from the front chamber 222, so a positive pressure is generated at the proximal end of the liquid sample volume LV. This positive pressure expels an additional liquid sample volume LV from the liquid collection volume 165 through the dispensing orifice 162.

[0346] In the above operation, the valve 255 is opened at a specific time so that the air volume in the chamber 224 is not overly (negatively or positively) pressurized by the displacement of the rear plunger 244, and air can be expelled from the rear chamber 224 through the relief port 228. When the pressure relief valve 255 is closed, the rear chamber 224 is sealed from the atmosphere so that a pressure change for the suction or dispensing operation can be generated in the rear chamber 224 by the displacement of the rear plunger 244.

[0347] As described above, the dispensing system 201 sucks the liquid sample by reducing the pressure in the dispensing channel 202 and dispenses the liquid sample by increasing the pressure in the dispensing channel. However, the pressure in the dispensing channel 202 may vary depending on other operations or states in this procedure, as described above for the dispensing system 101 for example.

[0348] In some embodiments, the controller 20 automatically operates the actuators of the pressure relief valve 255 and the linear drive mechanism 258 in a programmed manner to open and close the valve 255 and extend and retract the plunger member 240 as described herein.

[0349] In some embodiments, the controller 20 receives a pressure signal indicating the air pressure in the dispensing channel 202 from the dispensing channel pressure sensor 256. The controller 20 may continuously monitor the pressure in the dispensing channel 202.

[0350] The selection of the aspiration or dispensing mode to be used for a given aspiration or dispensing procedure can also be a function of the conditions or parameters of the aspiration or dispensing procedure, or can be adapted to the conditions or parameters. By employing serial plungers of different sizes, the volume range of the dispenser 200 can be expanded, and the process-specific volume accuracy and precision can be accommodated without the need for multiple dispensing channels.

[0351] For example, if only a relatively small amount of liquid sample is aspirated or dispensed, the dispenser 200 may be configured to operate in a first aspiration mode or a first dispensing mode. Using a smaller front plunger 242 can provide higher resolution, enabling improved accuracy and precision.

[0352] If a relatively large amount of liquid sample is aspirated or dispensed, the dispenser 200 may be configured to operate in a second aspiration mode or a second dispensing mode. Using a larger rear plunger 244 may enable the dispenser 200 to draw in and hold a greater amount of liquid sample at one time. Using a larger rear plunger 244 may enable the dispenser 200 to aspirate or dispense the liquid sample at a higher speed.

[0353] For example, in an exemplary embodiment, in the first part SF1 of the stroke of the front plunger 242, since the stroke distance L6 (FIG. 17) is 25 mm and the front plunger 242 has a diameter D6 (FIG. 18) of 2 mm, it can displace up to 78.5 microliters of air. In an exemplary embodiment, the rear plunger 244 can displace up to 1413 microliters of air since the stroke distance L7 (FIG. 17) is 50 mm and the diameter D7 (FIG. 19) is 6 mm. In the case of operation in the first suction mode, the dispenser 200 can suction a liquid sample of up to 60 microliters. In the case of operation in the second suction mode, the dispenser 200 can suction a liquid sample of up to 1300 microliters.

[0354] 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) in a cross-sectional plane perpendicular to the plunger axis P4 - P4 (i.e., the axis along which the first plunger translates for suction and dispensing). The rear plunger 244 has a cross-sectional area A7 (FIG. 19) in a cross-sectional plane perpendicular to the plunger axis P4 - P4 (i.e., the axis along which the rear plunger 244 translates for suction and dispensing). In some embodiments (such as shown in the figure), the cross-sectional area A7 of the rear plunger 244 is larger 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 A7 ranges from about 3 to 64 times the cross-sectional area A6.

[0355] In some embodiments, the cross-sectional area A6 ranges from about 0.5 to 5 mm 2 and the cross-sectional area A7 ranges from about 5 to 85 mm 2 in range.

[0356] The smaller front plunger 242 displaces the air volume in the front chamber 222 at an air volume displacement rate per first unit translation. The larger rear plunger 244 displaces the air volume in the rear chamber 224 at an air volume displacement rate per second unit translation. Since the larger rear plunger 244 also has a larger cross-sectional area, the air volume displacement rate per second unit translation is larger than the air volume displacement rate per first unit translation. In some embodiments, the air volume displacement rate per second unit translation is at least three times the air volume displacement rate per first unit translation.

[0357] In some embodiments, the air volume displacement rate per first unit translation ranges from about 0.1 microliters / second to 100 microliters / second, and the air volume displacement rate per second unit translation ranges from about 1 microliters / second to 2500 microliters / second.

[0358] In some embodiments, the dispenser 200 is configured such that the maximum air volume displaceable by the rear plunger 244 (when the rear plunger 244 translates over its full stroke) is greater than the maximum air volume displaceable by the front plunger 242 (when the front plunger 242 translates over its full stroke). In some embodiments, the maximum air volume displaceable by the rear plunger 244 is at least ten times the maximum air volume displaceable by the front plunger 242.

[0359] In some embodiments, the maximum air volume displaceable by the rear plunger 244 ranges from about 100 microliters to 5000 microliters, and the maximum air volume displaceable by the front plunger 242 ranges from about 10 microliters to 200 microliters.

[0360] In some embodiments, the volume of the rear chamber 224 is larger than the volume of the front chamber 222. In some embodiments, the volume of the rear chamber 224 is at least 10 times the volume of the front chamber 222.

[0361] Referring to FIGS. 20-24, these illustrate a dispensing system 301 according to other embodiments. The dispensing system 301 may be configured and operable in a manner similar to the dispensing system 201, except as discussed below.

[0362] The dispensing system 301 includes a dispenser 300 instead of the dispenser 200. The dispenser 300 may be configured and operable in a manner similar to the dispenser 200, except as follows. The dispenser 300 further includes an opening mechanism in the form of an inter-chamber valve 360. The inter-chamber valve 360 includes a connection passage 362 and a valve control mechanism 364. The connection passage 362 may be formed in the barrel 310 and fluidly couples the rear chamber 324 to the front chamber 322. The valve control mechanism 364 includes an actuator 364A (e.g., a solenoid) and a valve member 366.

[0363] The actuator 364A is selectively operable to place the valve member 366 in each of a closed position (FIGS. 20, 22, and 23) and an open position (FIGS. 21 and 24). In the closed position, the valve member 366 blocks the connection passage 362 so that the rear chamber 324 is not fluidly connected to the front chamber 322 through the connection passage 362. In the open position, the valve member 366 does not block the connection passage 362 so that the rear chamber 324 is fluidly connected to the front chamber 322 through the connection passage 362.

[0364] In the case of suction or dispensing in the first suction mode or the first dispensing mode as described above with respect to the dispenser 200 (i.e., suction and dispensing using the front plunger 342 and not using the rear plunger 344 as shown in FIG. 23), the valve member 366 is closed. Therefore, in these procedures, the connection 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-sealed from the rear chamber 324. As described above, in these procedures, the pressure relief valve 355 is open.

[0365] Also, by using the dispenser 300, suction or dispensing can be performed in a second suction mode or a second dispensing mode similar to the second suction mode or the second dispensing mode as described above with respect to the dispenser 200.

[0366] In the case of suction in the second suction mode (i.e., suction using both the front plunger 342 and the rear plunger 344 as shown in FIG. 24), the valve member 366 is opened and the pressure relief valve 355 is closed. In the present embodiment, the plunger member 340 is disposed at the first starting position at the beginning of the suction step. That is, the plunger member 340 is disposed such that the front plunger 342 extends through the front seal 352 and occupies the front chamber 322. At the first starting position, the distal end of the plunger member 340 may be at the lowermost position or offset from the lowermost position as described above with respect to the dispenser 200. With the plunger member 340 in this first starting position, the valve member 366 opened, and the pressure relief valve 355 closed, the plunger member 340 then translates in the retraction direction E9 to perform suction. The plunger member 340 translates such that the front plunger 342 moves in the first part SF1 of its stroke and enters the second part SF2 of its stroke. In this case, the rear chamber 324 is fluidly connected to the front chamber 322 (via the connection passage 362) in both stroke parts SF1, SF2, and both plungers 342, 344 contribute in parallel with suction throughout the stroke of the plunger member 340.

[0367] For dispensing in the second dispensing mode (i.e., dispensing using both the front plunger 342 and the rear plunger 344), the plunger member 340 translates in the extension direction E8 with the valve member 366 opened and the pressure relief valve 355 closed. The plunger member 340 translates such that the front plunger 342 moves in the second part SF2 of its stroke and the first part SF1 of its stroke. In this case, the rear chamber 324 is fluidly connected to the front chamber 322 (via the connection passage 362) in both stroke parts SF1, SF2, and both plungers 342, 344 contribute in parallel with dispensing throughout the stroke SF.

[0368] In the second suction and dispensing mode, by fluidly connecting the front chamber 322 and the rear chamber 324, the dispenser 300 can initiate the suction retreat of the plunger member 340 with the front portion 342 disposed in the front chamber 322 and the front seal 352 sealed around the plunger member 340. As a result, the dispenser 300 can reduce the dead volume in the rear chamber 324.

[0369] Referring to FIGS. 25-27, these illustrate a dispensing system 401 according to another embodiment. The dispensing system 401 may be configured and operable in a manner similar to the dispensing system 301, except as discussed below.

[0370] The dispensing system 401 includes a dispenser 400 instead of the dispenser 300. The dispenser 400 may be configured and operable in a manner similar to the dispenser 300, except as follows.

[0371] The dispenser 400 includes a connection valve 460 instead of the inter-chamber valve 360 and the pressure relief valve 355. The connection valve 460 is selectively operable to fluidly connect the rear chamber 424 to the front chamber 422 (via channels 468A, 468B on both sides of the front seal 452) and to the atmosphere (via channel 468C to the relief port 468D). In a first valve state, the connection valve 460 closes the rear chamber 424 from the front chamber 422 and opens the rear chamber 424 to the pressure relief port 468D to the atmosphere. In a second valve state, the connection valve 460 opens the rear chamber 424 to the front chamber 422 and closes the rear chamber 424 from the pressure relief port 468D. The connection valve 460 may be an electronically controlled valve.

[0372] During use, in the case of suction or dispensing in the first suction mode or the first dispensing mode as described above for the dispenser 200 (i.e., suction and dispensing using the front plunger 442 and not using the rear plunger 444 as shown in FIG. 27), the connection valve 460 is set to the first valve state.

[0373] In the case of suction in the second suction mode (i.e., suction using both the front plunger 442 and the rear plunger 444 as shown in FIG. 26), the connection valve 460 is set to the second valve state. Thereafter, with the connection valve 460 set to the second valve state, the plunger member 440 translates in the rearward direction E9 to perform suction. The plunger member 440 translates such that the front plunger 442 moves in the first part SF1 of its stroke and enters the second part SF2 of its stroke. In this case, the rear chamber 424 is fluidly connected to the front chamber 422 (via the connection valve 460) in both stroke parts SF1, SF2, and both plungers 442, 444 contribute in parallel with suction throughout the stroke of the plunger member 440.

[0374] For dispensing in the second dispensing mode (i.e., dispensing using both the front plunger 442 and the rear plunger 444), the plunger member 440 translates in the extending direction E8 with the connection valve 460 set to the second valve state. The plunger member 440 translates such that the front plunger 442 moves in the second part SF2 and the first part SF1 of its stroke. In this case, the rear chamber 424 is fluidly connected to the front chamber 422 (via the connection valve 460) in both stroke parts SF1, SF2, and both plungers 442, 444 contribute in parallel with dispensing throughout the entire stroke SF.

[0375] The dispenser 400 is mounted on the rear plunger 444 and further includes an annular seal (e.g., an O-ring) 453 that moves through the rear chamber 424 together with the rear plunger 444. The seal 453 forms an airtight and pressure-tight seal that slides 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. The dispensers according to other embodiments (e.g., dispensers 200 and 300) may include a seal corresponding to the seal 453.

[0376] According to another embodiment, the dispenser 400 is configured and / or operable such that the front plunger 442 extends through the front seal 452 over the entire first part SF1 and the entire second part SF2 of the stroke (with the front seal 452 maintaining a seal around the front plunger 442 over the entire plunger stroke). That is, even in the second suction mode (when the connection valve 460 is set to the second valve state and fluidly connects the rear chamber 424 to the front chamber 422), the front seal 452 remains blocked by the plunger member 440 over the entire suction strokes SF1, SF2. In this way, the front plunger 442 will always engage within the front seal 452. This avoids any pressure jumps due to deformation of the front seal 452. Since the front seal is hardly subjected to mechanical forces, the stability and reliability of the seal are improved.

[0377] To achieve this effect or function of neither releasing nor disengaging the front plunger 442 from the front seal 452, the front plunger 442 may be extended or elongated compared to that shown in FIG. 25. In some embodiments, the length of the front plunger 442 is at least as long as the second part SF2 of the plunger stroke.

[0378] In other embodiments, a pressure sensor (e.g., pressure sensor 256) can be arranged and configured to detect the air pressure in the rear chamber (e.g., rear chamber 224), and the controller 20 can use the pressure detection data from the rear pressure sensor to control the operation of the dispenser, similar to that described for the front pressure sensor.

[0379] Referring to FIGS. 28-35, these illustrate an exemplary dispensing system 601 according to other embodiments of the present technology. The dispensing system 601 can aspirate and dispense the liquid volume within the liquid processing system. The dispensing system 601 may be adapted to be used in place of the dispensing system 101, for example, in the automated liquid processing system 10 (FIG. 1). However, it is understood that the disclosed methods, systems, and devices are not limited to the liquid processing system 10 or its use therein, and the present disclosure is applicable to other systems and applications where aspiration and / or dispensing of liquid volume is desired.

[0380] The dispensing system 601 is configured to be used in each of the air displacement (AD) mode and the positive displacement (PD) mode. In the AD mode, the dispensing system 601 operates to aspirate and / or dispense liquid using an air displacement pipette tip. In the PD mode, the dispensing system 601 operates to aspirate and / or dispense liquid using a positive displacement pipette tip.

[0381] The dispensing system 601 includes one or more dispensers 600. The dispenser may be mounted on the dispensing module 30. The dispensers 600 may be similarly configured and operate in the same manner. Naturally, the following description of a representative one of the dispensers 600 may equally apply to each of the dispensers 600. If a plurality of dispensers 600 are provided, these dispensers 600 may operate independently of each other or may operate in cooperation. For the purpose of detailed explanation, only a single dispenser will be described below.

[0382] The dispensing system 601 includes a dispenser 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 with respect to the dispenser 600 and may be de facto disposable or consumable parts of the dispensing system 601.

[0383] Referring to FIGS. 28 and 33, as will be discussed in more detail herein, it can be appreciated that the dispenser 600 has a longitudinal axis A-A and a distal end 600A. The dispenser 600 includes a tubular barrel 610, a pressure control system 606, a dispensing channel 602, a dispenser orifice 604, and a tip adapter 614. The barrel 610 extends from a distal end 610A to a proximal end 610B. The barrel 610 includes a shaft 612 that terminates at the distal end 610A. The tip adapter 614 is attached or formed at the distal end 610A. The dispenser orifice 604 is disposed at the distal end 600A and is in fluid communication with the dispensing channel 602.

[0384] The pressure control system 606 includes the barrel 610, a plunger 640, a rear seal 654, a plunger drive mechanism 658, and a pressure sensor 656.

[0385] Referring to FIG. 33, the barrel 610 includes a barrel passage 620. The passage 620 is longitudinally aligned with the axis A-A and extends from a front end 620A to an opposite rear end 620B. The passage 620 terminates at a rear opening 620E at the proximal end 610B of the barrel 610 and is in communication therewith. The barrel passage 620 includes a barrel chamber 621. The rear seal 654 is axially disposed between the barrel chamber 621 and the rear opening 620E at the proximal end 610B. The barrel chamber 621 is in fluid communication with the pressure sensor 656 via a sensor port 656A.

[0386] The rear seal 654 may be an annular seal (e.g., an O-ring).

[0387] The plunger 640 has a front end or tip 640A, an opposite rear end 640B, and a rear plunger portion 644.

[0388] The plunger 640 further includes an integral piston engagement feature 646 at the tip 640A. In some embodiments, as shown in FIG. 33, the piston engagement feature 646 includes a slot 646A. The slot 646A may be configured as a blind hole, for example, as shown. The piston engagement feature may have any suitable configuration and is not limited to slots or openings.

[0389] The plunger 640 is mounted in the passage 620 so as to be slidably translatable with respect to the barrel 610 along the plunger axis P5 - P5 in the extension direction E10 and the opposite retraction direction E11. In some embodiments, the plunger axis P5 - P5 substantially coincides with the shaft axis A - A.

[0390] The plunger 640 is slidable to translate between a fully extended position as shown in FIG. 31 and a fully retracted position as shown in FIG. 30 (by a plunger stroke with respect to the passage 620). Also, as discussed below, the plunger 640 is slidable to an AD mode start position as shown in FIG. 28 or a PD mode start position as shown in FIG. 31.

[0391] In the fully extended position (FIG. 31), a portion of the front plunger portion 642 extends distally beyond the distal end 600A of the dispenser 600. The rear end 640B of the plunger 640 is in front of the rear seal 654 at the first part SF1 (FIG. 31) of the retraction stroke (starting from the fully extended position) such that the passage 620 is open to the rear opening 620E.

[0392] The rear end 640B of the plunger 640 is behind the rear seal 654 in the second part SF2 (Figure 30) of the retraction stroke (following the first part SF1) such that the plunger rear part 644 is disposed within the rear seal 654. In this part of the stroke, the rear O-ring 654 forms an airtight and pressure-tight seal between the outer diameter of the rear plunger part 644 and the barrel 610, sealing the passage 620 from the rear opening 620E. The rear plunger part 644 is slidable through the rear O-ring 654 while maintaining the airtight and pressure-tight seal.

[0393] 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 an electric motor. In some embodiments, the linear drive mechanism 658 includes a spindle and a spindle nut link mechanism driven by an electric motor. In some embodiments, the plunger drive mechanism 658 is manually operable and does not include an actuator. For example, the plunger member 640 may be configured to be pushed and pulled using a manual extension portion, lever, knob, or other feature.

[0394] In use, when the plunger 640 is driven in the extension direction E10 in the stroke portion SF2, an air volume is displaced from the barrel chamber 621, reducing the effective volume of the barrel chamber 621. When the plunger 640 is driven in the retraction direction E11, the air volume is restored to the barrel chamber 621, increasing the effective volume of the barrel chamber 621.

[0395] The plunger 640 may be formed of any suitable material. In some embodiments, the plunger 640 is formed of stainless steel.

[0396] The barrel 610 may be formed of any suitable material. In some embodiments, the barrel 610 is formed of aluminum.

[0397] The chip adapter 614 is configured to removably secure the pipette tips 660 and 670 to the end 600A of the dispenser 600, similar to that described above with respect to the chip adapter 156.

[0398] The AD pipette tip 660 (Figs. 28 - 30 and 34) is an example of a pipette tip that can be used with the dispenser 600 for aspiration and dispensing in the AD mode. However, of course, pipette tips of other designs may be used as alternatives. The AD pipette tip 660 may be a tubular body configured similarly to that described for the AD pipette tip 160, having a distal end 660A, a proximal end 660B, a tip volume or passage 664, a dispensing orifice 662, an interface opening 663, a mounting portion 666, and a liquid collection volume 665 corresponding to the components 160A, 160B, 164, 162, 163, 166, and 165, respectively.

[0399] The PD pipette tip 670 (Figs. 31, 32, and 35) includes a tubular chip body 678 and a piston 680 slidably mounted within the chip body 678. The piston 680 is slidable between an extended or standby position (Fig. 31) and a retracted position (e.g., Fig. 32).

[0400] Referring to FIG. 35, the chip body 678 extends from a distal end 670A to a proximal end 670B. The chip body 678 includes a front portion 678A and a rear portion 678B that integrally define a chip volume or passageway 674. The front portion 678A defines a front chamber 679A, and the rear portion 678B defines a rear chamber 679B, each forming a part of the passageway 674. The rear portion 678B includes an attachment portion 676 and defines an interface opening 673. A dispensing orifice 672 is defined at the distal end 670A. The passageway 674 terminates at the interface opening 673 and the dispensing orifice 672.

[0401] 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 member. In some embodiments, the shaft 682, the base 684, and the plunger engagement feature 686 integrally form a single piece member.

[0402] The shaft 682 extends from a proximal end 682B fixed to the base 684 to an opposite distal end 682A. In some embodiments, the distal end 682A is disposed at or near the dispensing orifice 672 when the piston 680 is in the standby position. The front side of the base 684 may have a convex or reverse undulating shape so as to conform to the opposing profile of the chip body 678.

[0403] The illustrated plunger engagement feature 686 includes two or more opposing legs 686A. The plunger engagement feature 686 is configured to be received in the slot 646A and releasably secure the piston engagement feature 646A to the plunger engagement feature 686. In some embodiments, the legs 686A have a relaxation width greater than the width of the slot 646A and are elastically deflectable.

[0404] The liquid treatment system 10 and the dispensing system 600 may be used to aspirate and / or dispense one or more liquid samples in the following manner according to several methods. As described above, the dispensing system 601 is configured to be used in each of an air displacement (AD) mode and an alternative displacement (PD) mode.

[0405] Generally, in the AD mode, the AD pipette tip 660 is mounted on the dispenser 600. By driving the plunger 640 to displace the air volume in the passage 620, the pressure in the dispensing channel 602 is correspondingly changed to aspirate the liquid sample into the liquid collection volume 665 or dispense the liquid sample from the liquid collection volume 665. In the AD mode, when the plunger 640 is displaced, the air volume in the barrel 614 is displaced or expanded, causing a pressure change, and an air cushion may (usually does) exist and be maintained between the liquid sample in the liquid collection volume 665 and the distal end 640A of the plunger 640.

[0406] Generally, in the PD mode, the PD pipette tip 660 is mounted on the dispenser 600. By driving the piston 680 with the plunger 640 to displace the air volume in the front chamber 679A, the pressure in the front chamber 679A is correspondingly changed to aspirate the liquid sample into the liquid collection volume 675 or dispense the liquid sample from the liquid collection volume 675. In the PD mode, when the piston 680 is displaced, the air volume in the front chamber 679A is displaced or expanded, causing a pressure change. In some embodiments, the distal end 682A of the piston 680 contacts the liquid sample in the front chamber 679A.

[0407] The operator or controller 20 may be configured to select and execute an operation mode (AD mode or PD mode). For example, the operator may use the HMI 22 to instruct the controller 20 that the pipette tip attached to the dispenser 600 or the pipette tip to be attached to the dispenser 600 is an AD type tip 660 or a PD type tip 670. Thereafter, the controller 20 may automatically program the dispensing system 601 to operate according to the type of pipette tip (for example, as described below).

[0408] Hereinafter, the operation of the dispensing system in the AD mode will be described in more detail. As shown in FIG. 28, the AD pipette tip 660 is mounted on the chip adapter 614. For example, the AD pipette tip may be held in a tray, and the controller 20 may operate the actuators 34A, 34B to place the dispenser 600 above the AD pipette tip 660, and then drive the dispenser 600 downward to insert the chip adapter 614, and then lift the dispenser 600 to remove the AD pipette tip 660 from the tray. In this mounting operation, the plunger 640 may be in the AD mode start position.

[0409] Thereafter, the controller 20 may operate the actuators 34A, 34B to place the pipette tip 660 above the liquid sample LS, for example. The sample LS may be disposed in the container 36, for example. If the plunger 640 is not in the AD mode start position, it is placed in the AD mode start position as shown in FIG. 28. Thereafter, the controller 20 may operate the actuator 34B to lower the distal end 660A and thus the dispensing orifice 662 into the sample LS, for example. In some embodiments, the distal end 660A and thus the dispensing orifice 662 are submerged in the sample to at least a defined depth so that the dispensing orifice 662 remains submerged in the sample LS during aspiration.

[0410] With the plunger 640 in the AD mode start position and the dispensing orifice 662 submerged, the drive mechanism 658 displaces the plunger 640 in the retraction direction E11 by a part or all of the stroke portion SF2, thereby operating to pull the plunger 640 away from the dispensing orifice 604. Throughout the entire stroke portion SF2 of the retraction stroke, the dispensing channel 602 is sealed (except for the dispensing orifice 604) by the engagement between the rear seal 654 and the rear portion 644 of the plunger 640.

[0411] Due to the retraction of the plunger 640, the effective air volume of the barrel chamber 621 expands, generating a negative pressure at the dispensing orifice 604. This 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 a desired amount of the liquid sample volume LV is suctioned into the collection volume 665. An air volume or air cushion AC may remain in the tip passage 664 and the barrel chamber 621 between the proximal end of the liquid sample volume LV and the dispenser 600.

[0412] Thereafter, by using the dispenser 600, the liquid sample volume LV may be dispensed from the AD pipette tip 660. The drive mechanism 658 operates to push the plunger 640 toward the dispenser orifice 604 by displacing the plunger 640 in the extending direction E10. Throughout the entire extending stroke, the dispensing channel 602 is sealed (except for the dispenser orifice 604) by the engagement between the rear seal 654 and the rear portion 644 of the plunger 640. Due to the extension of the plunger 640, an air volume is displaced from the barrel chamber 621, generating a positive pressure at the proximal end of the liquid sample volume LV. This positive pressure expels the liquid sample volume LV from the liquid collection volume 665 through the dispensing orifice 662. An air cushion AC may remain between the proximal end of the liquid sample volume LV and the tip 640A of the plunger 640 until the liquid sample volume LV is completely dispensed.

[0413] In the illustrated embodiment, the dispenser 600 is not provided with a front seal corresponding to the front seal 252 (FIG. 17). Accordingly, the front portion of the barrel chamber 621 is not sealed from the rear portion of the barrel chamber 621. In some embodiments or applications, the PD chip 670 is used for a smaller volume and the AD chip 660 is used for a relatively larger volume. However, in other embodiments, the dispenser 600 may be configured to operate in the AD mode as discussed, for example, with respect to the dispenser 200 (FIG. 14).

[0414] In some embodiments, when performing the aspiration or dispensing operation in the AD mode, the controller 20 receives a pressure signal indicating the air pressure in the dispensing channel 602 from the pressure sensor 656. The controller 20 may continuously monitor the pressure in the dispensing channel 602.

[0415] As described above, the dispensing system 601 sucks the liquid sample by reducing the pressure in the dispensing channel 602 and dispenses the liquid sample by increasing the pressure in the dispensing channel 602. However, the pressure in the dispensing channel 602 may vary depending on other operations or states in this procedure, as described above for the dispensing system 101 for example.

[0416] Hereinafter, the operation of the dispensing system in the PD mode will be described in more detail. As shown in FIG. 31, the PD pipette tip 670 is mounted on the chip adapter 614. For example, the PD pipette tip 670 may be held in a tray, and the controller 20 operates the actuators 34A and 34B to place the dispenser 600 above the PD pipette tip 670, for example, and then drive the dispenser 600 downward to insert the chip adapter 614, and then lift the dispenser 600 to remove the PD pipette tip 670 from the tray.

[0417] In this mounting operation, the plunger 640 is disposed at the PD mode start position (FIG. 31). The dispenser 600 is configured such that when the PD pipette tip 670 is sufficiently mounted on the chip adapter 614 and the piston 680 is at its most forward position with respect to the chip body 678, the plunger engagement feature 686 is received in the slot 646A of the plunger 640. Thus, the piston 680 is removably captured or removably fixed to the distal end of the plunger 640.

[0418] Thereafter, the controller 20 may operate the actuators 34A, 34B to place, for example, the PD pipette tip 670 above the liquid sample LS. The sample LS may be disposed, for example, in the container 36. Thereafter, the controller 20 may operate the actuator 34B to lower, for example, the distal end 670A and thus the dispensing orifice 672 into the sample LS. In some embodiments, the distal end 670A and thus the dispensing orifice 672 are submerged in the sample to at least a defined depth so that the dispensing orifice 672 remains submerged in the sample LS during aspiration.

[0419] With the plunger 640 in the PD mode start position and the dispensing orifice 672 submerged, the drive mechanism 658 operates to displace the plunger 640 in the retraction direction E11 by a part or all of the stroke portion SF1, thereby pulling the plunger 640 away from the dispenser orifice 604. Throughout the retraction stroke, since the rear seal 654 does not seal the rear portion 644 from the rear opening 620E, the dispensing channel 602 is not sealed.

[0420] When the plunger 640 retracts, the piston 680 also retracts in the retraction direction E11, as shown, for example, in FIG. 32. Due to the retraction of the piston 680, the effective fluid volume of the front chamber 679A expands, generating a negative pressure at the dispensing orifice 672. This 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 may be further retracted until a desired amount of the liquid sample volume LV is aspirated into the collection volume 675. In some embodiments, there is no air cushion or air volume between the distal end 682A of the piston 680 and the liquid sample volume LV.

[0421] Thereafter, by using the dispenser 600, the liquid sample volume LV may be dispensed from the PD pipette tip 670. The drive mechanism 658 operates to push the plunger 640 toward the dispenser orifice 604 by displacing the plunger 640 in the extending direction E10. Throughout the entire extending stroke, since the rear seal 654 does not seal the rear portion 644 from the rear opening 620E, the dispensing channel 602 is not sealed.

[0422] When the plunger 640 extends, the piston 680 also extends in the extending direction E10. Due to the extension of the piston 680, a fluid volume is displaced from the front chamber 679A, and thus the liquid sample volume LV is expelled from the liquid collection volume 675 through the dispensing orifice 672.

[0423] By using the dispensing system 601 and the dispenser 600, the suction and dispensing procedures as described above can be performed by selectively and interchangeably using the AD pipette tip 660 and the PD pipette tip 670.

[0424] For example, the dispenser 600 may be equipped with the AD pipette tip 660 and be adapted to be used for suction and dispensing in the AD mode. Thereafter, after the AD pipette tip 660 is removed (e.g., discharged) from the dispenser 600, the dispenser 600 may be equipped with the PD pipette tip 670 and be adapted to be used for suction and dispensing in the PD mode. Similarly, after the PD pipette tip 670 is mounted on the dispenser 600 and used for suction and dispensing in the PD mode and then removed, it can be replaced with the AD pipette tip 660 used for suction and dispensing in the AD mode.

[0425] Any number of various pipette tips may be adapted to be used in a series of procedures (for example, the dispensing system 601 may perform aspiration and dispensing in an AD mode (alternatively, a PD mode) using a series of AD pipette tips 660 before switching to aspiration and dispensing in a PD mode (or, an AD mode) using one or more PD pipette tips 670).

[0426] The user need not use the dispensing system 601 and the dispenser 600 that include both the AD pipette tip 660 and the PD pipette tip 670.

[0427] The pipette tips 660, 670 may be adapted to be removed from the dispenser 600 using any suitable technique and hardware. In some embodiments, the dispenser 600 includes an ejector (not shown in FIGS. 28-33, for example, an ejection sleeve) that ejects the pipette tips 660, 670 from the tip adapter 614. The dispenser 600 may include an ejection mechanism corresponding to, for example, the ejection mechanism 151 of the dispenser 100.

[0428] In some embodiments, the PD pipette tip 670 is removed from the dispenser 600 as follows. The plunger 640 is retracted in the direction E11 until the base 684 of the piston 680 abuts the tip adapter 614. Also, the plunger 640 is retracted in the direction E11 until the piston engagement feature 646 is separated or disengaged from the plunger engagement feature 686, thereby releasing the piston 680. Thereafter, the PD pipette tip 670 is removed using any suitable technique or mechanism for removing the tip body 678 from the tip adapter 614.

[0429] Of course, the described dispensing systems and dispensers (for example, the dispensing system 601 and the dispenser 600) are compatible with both positive displacement dispensing and air displacement dispensing in a single dispensing channel. Even when the use of both types of tips is required in one device, no instrument change is necessary.

[0430] Referring to FIG. 36, these illustrate a dispensing system 701 according to other embodiments. The dispensing system 701 corresponds to the dispensing system 601 and is configured and operates in the same manner, except for the points discussed below. The dispensing system 701 includes one or more AD pipette tips 660 (not shown in FIG. 36), a dispenser 700 that corresponds to the dispenser 600 and the PD pipette tip 670 and is configured and operates in the same manner except for the points discussed below, and one or more pipette tips 770.

[0431] In the dispenser 700, the plunger 740 is extended or stretched (compared to the plunger 640) so that the rear part of the plunger 740 maintains an airtight seal with the rear seal 754 throughout the operation of the dispenser 700 in its AD and PD suction and dispensing procedures, even when fully extended (as shown in FIG. 36). Also, the tip body 778 of the PD pipette tip 770 includes a vent port 779C that fluidly connects the rear chamber 779B of the tip passage 774 to the ambient atmosphere. The vent port 779C functions as a pressure relief port or passage from the tip passage 774 between the piston 780 and the dispenser 700. Thus, the vent port 779C can prevent a negative or positive pressure that can interfere with the control of the piston 780 from being generated in the rear chamber 779B due to the translational movement of the piston 780 (in the tip body 778) and the plunger 740 (in the barrel 710).

[0432] As described above, the automated liquid handling system may be adapted to transfer a specific amount of liquid, such as a reagent or a sample, between designated containers. Such a system may use a dispenser for both suction and dispensing of the liquid. Advantages of the automated liquid handling process include improved throughput and efficiency of operation and elimination of human error, but these may depend on the accuracy and reproducibility of the dispensing operation.

[0433] FIG. 37 is a schematic perspective view showing another example of an automatic liquid processing system 901 according to some embodiments. System 901 includes elements similar to the dispensing system 101 and the automatic liquid processing system 10 described above, but the description of similar elements may be omitted for simplicity.

[0434] Referring to FIG. 37, the automatic liquid processing system 901 includes an arm member 912 configured to hold one or more dispensers 900 (which may include one or more of dispenser 100 or any other suitable dispenser), and an actuator mechanism 934 (which may include the dispensing module placement system 34A and actuator 34B of FIG. 1). The actuator mechanism 934 is configured to move the arm member 912 along at least one axis in response to a control signal from a control circuit 920 (which may include the controller 20 of FIG. 1). In the example of FIG. 36, the robotic arm 914 has a first horizontal movement axis (X direction (e.g., front - back)), a second horizontal movement axis (Y direction (e.g., left - right)), and a vertical movement axis (Z direction (e.g., up - down)). The control circuit 920 may include at least one processor 925, a memory 910, and an input / output (I / O) circuit 915 operable to generate a control signal to move the arm member 912 in a direction approaching or away from the surface of the liquid sample LS along at least one axis and transmit it to the actuator mechanism 934. More generally, the memory 910 may be a non - transitory storage medium configured to store computer - readable instructions, and the control circuit 920 may be configured to execute the computer - readable instructions stored in the memory 910 to perform the operations as described herein.

[0435] FIG. 37 shows each of the dispensers 900 to which the pipette tip 960 is attached. 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 dispensing orifice or opening 962 that provides a passage through the tip 960 to the dispenser 900 and that can function as a liquid sample collection volume. The pipette tip 960 may be an air displacement type tip as described herein or a positive displacement type tip. The pipette tip 960 may be automatically removed from the pipette tip holder and moved vertically upward by the robot arm assembly 914 under the control of the control circuit 920.

[0436] Upon aspiration of liquid by the dispenser 900 (in the liquid processing system 901 or the stand-alone dispenser 900), other embodiments described herein may be recalled from the recognition that the volume of liquid in the container is decreasing. For example, when the container is of an unknown size, the placement of the pipette tip 160 can affect whether an accurate amount of liquid is effectively aspirated into the dispenser 900 (i.e., if the pipette tip 160 is positioned too high relative to the liquid level, the desired amount of liquid may not be aspirated). Thus, for effective dispensing, it may be necessary to know variables such as the container from which the liquid is aspirated, the type of liquid, the container to which the liquid is transferred, and the like.

[0437] Capacitive liquid level detection (LLD) can be used to determine the level difference between immersion in and withdrawal from the sample liquid. If the device does not know the level, the use of liquid level detection may be used to detect the fill level at the start of aspiration or dispensing. The aspiration or dispense volume can be calculated from the level difference and the cross-sectional area of the container. However, these methods may be too inaccurate when the volume is small and the cross-sectional area is large. Parasitic capacitance can also cause a decrease in the accuracy of determining the amount of processed sample or liquid volume.

[0438] Embodiments described herein provide a conductive pipette tip 960 configured to provide a control window for axial movement of the dispenser 100. In contrast to some existing techniques that can use a conductive tip capable of detecting the surface of a liquid when in contact with the liquid, embodiments described herein enable dynamic liquid level detection based on a change in capacitance indicated by a signal from the conductive electrode 1002 on the pipette tip 960 and, in some embodiments, are independent of the shape and / or size of the liquid container.

[0439] The conductive pipette tip 960 includes an arrangement of conductive areas 1002 and non-conductive areas 1001. FIG. 38 is an enlarged side view showing the conductive pipette tip 960 according to some embodiments described herein. The pipette tip 960 has a distal end 960A having an opening or orifice 962 sized and configured to aspirate and / or dispense liquid, and an opposite proximal end 960B configured to connect to the dispenser 900 at the end, and comprises a chip member 1000. And the conductive electrodes 1002 extend along the surface of the pipette tip 960 (for example, including on the outer surface of the chip member 1000 and / or a portion integrated with the side wall of the chip member 1000). The chip member 1000 comprises a non-conductive or electrically insulated chip "bottom" or "pod" 1001 at the end 960A of the pipette tip 960 between the dispensing orifice or opening 962 and the conductive electrodes 1002. Also, a learning circuit may be implemented (or the learning circuit may communicate with the control circuit 920) by a control circuit 920 that controls the axial movement of the dispenser 900 (for example, along the Z-axis or depth direction of the liquid being aspirated). The learning circuit may be configured to continuously monitor by detecting changes in capacitance due to the contact between the conductive electrode 1002 and the liquid, as described herein. The inner surface of the chip member 1000 defines a passage through the pipette tip 960 and may function as a liquid sample collection volume. The inner surface of the chip member 1000 may be non-conductive, and in some embodiments, the conductive electrodes 1002 may be configured as a single electrode.

[0440] Referring to FIG. 38, the insulated chip bottom 1001 protrudes from the conductive electrode 1002 or is between the conductive or functional portion of the conductive electrode 1002 and the opening 962 at the end 960A of the pipette tip 960. There may be no conductive material or layer forming the conductive electrode 1002 on the outer surface of the insulated chip bottom 1001. For example, in some embodiments, the lower portion of the conductive electrode 1002 adjacent to the opening 962 may include a non-conductive material coating thereon to provide the insulated chip bottom 1001. In some embodiments, the insulated chip bottom 1001 may be provided by a non-conductive portion of the chip member 1000 that extends beyond the conductive electrode 1002. The insulated chip bottom 1001 may extend for a length or distance D of about 2 millimeters (mm) or more. The opposite end 960B of the chip 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 dispenser 900 (e.g., end 112A of the dispenser 100 described herein).

[0441] The conductive interconnect 1003 extends along the chip member 1000 and electrically connects the conductive electrode 1002 to the conductive element 1004 for signal transmission (e.g., to transmit a signal from the conductive electrode 1002 to the controller circuit 920). The conductive portions 1002, 1003, 1004 of the chip member 1000 may be copper (Cu) or any suitable conductive material.

[0442] FIGS. 39A, 39B, and 39C are cross-sectional views showing embodiments 1000a, 1000b, 1000c of the chip member 1000 of FIG. 38. As shown in the embodiment of FIG. 39A, the conductive electrodes 1002 and the conductive interconnects 1003 extend along the outer surface between the two ends 960A and 960B of the chip member 1000a, defining a conductive "wall" of the chip member 1000a. In some embodiments, however, they may extend on the opposing sidewalls or around the entire circumference of the chip member 1000a. In some embodiments, as shown in FIG. 39B, the conductive interconnects 1003 may be injection molded rather than extending along the outer surface of the chip member 1000b, or may be at least partially integrated or embedded in the sidewalls of the chip member 1000b. In some embodiments, as shown in FIGS. 38 and 39C, the conductive electrodes 1002 and / or the conductive interconnects 1003 may not extend over the entire outer perimeter or circumference of the chip member 1000c. More generally, the chip member 1000 includes one conductive area 1002 at the bottom or distal end 960A, one conductive area 1004 at the top or proximal end 960B (e.g., inside the chip member 1000), and the conductive interconnects 1003 (which may be embedded in the outer surface of the chip member 1000 or may be present on the outer surface).

[0443] The conductive electrodes 1002 adjacent to the end 960A of the chip member 1000 may be provided in a variety of different shapes. FIGS. 40A, 40B, and 40C are cross-sectional views showing embodiments 1002a, 1002b, 1002c of the conductive electrodes 1002 in various "crown" shapes. The crown shapes of the conductive electrodes 1002a, 1002b, 1002c include a plurality of ends that protrude towards the non-conductive chip bottom 1001 such that the conductive surface area can increase with the immersion depth when submerged in the liquid to be dispensed. More generally, the shape of the conductive electrode 1002 may define a surface area that varies with the distance from the opening 962. This feature can accommodate dynamic LLD proportional regulation in the conductive liquid, as described separately in the following examples.

[0444] The contact between the attracted liquid and the conductive electrode 1002 may be detected as capacitance by the controller circuit 920 based on the signal received from the conductive electrode 1002. FIG. 41 is a diagram showing the change in capacitance 900C associated with the vertical position 912Z of the pipette tip 960 including the conductive electrode 1002 and the non-conductive chip bottom 1001 with respect to the surface of the liquid LS according to some embodiments.

[0445] Referring to FIG. 41, the capacitance 900C indicated by the signal from the conductive electrode 1002 is substantially constant when the end 960A of the chip member 1000 moves toward the surface of the liquid LS (indicated by the vertical position 912Z). When the non-conductive chip bottom 1001 contacts the liquid surface at time t = 1 (as shown by (1)), the capacitance 900C maintains a substantially unchanged state. The capacitance 900C remains substantially constant until the conductive electrode 1002 of the chip member 1000 contacts the surface of the liquid LS at time t = 2 (as shown by (2)), but at this point, a substantially instantaneous increase in the capacitance 900C is indicated by the signal from the electrode 1002. The increase in the capacitance 900C remains substantially constant despite the increase in the immersion depth of the conductive electrode 1002 below the surface of the liquid LS at time t = 3 (as shown by (3)).

[0446] Referring further to FIG. 41, when the contact between the conductive electrode 1002 and the surface of the liquid LS is lost at time t = 6 (for example, as shown in (4), as the liquid level rises and falls due to suction or dispensing, the movement of the robot arm 912 is insufficient to maintain contact between the conductive electrode 1002 and the liquid, so that the liquid level falls below the conductive electrode 1002), a substantially instantaneous decrease in the capacitance 900C is indicated by a signal from the electrode 1002. That is, the contact (or non-contact) between the conductive electrode 1002 and the surface of the liquid LS can be indicated as a sharp change or jump in the detected capacitance. The detected capacitance can vary or fluctuate over a range of several picofarads (pF). For example, the change or difference in the detected capacitance between the contact and the loss of contact between the conductive electrode 1002 and the surface of the liquid LS can vary over a range of about 0.1 to 15 pF (for example, about 0.5 to 10 pF or about 1 to 3 pF). In the example of FIG. 40, the variation in the detected capacitance is about 1.4 pF with respect to the contact and loss of contact between the conductive electrode 1002 and the liquid LS.

[0447] In some embodiments, the capacitance indicated by a signal from the electrode 1002 may not vary based on the depth to which the conductive electrode 1002 is submerged below the surface of the liquid LS (as indicated by a substantially constant capacitance 900C between times t = 3 and t = 6). That is, since the detected capacitance does not substantially depend on the contact area between the conductive electrode 1002 and the liquid LS, the measured or indicated capacitance cannot change due to variations in the depth of immersion.

[0448] In other embodiments, the capacitance indicated by a signal from the conductive electrode 1002 can vary or fluctuate more gradually based on the depth to which the conductive electrode 1002 is submerged below the surface of the liquid, due to the shape of the conductive electrode 1002a, 1002b, 1002c, for example, as shown in the examples of FIGS. 40A - 40C, where the surface area increases with the depth of immersion.

[0449] Therefore, the configuration of the conductive electrode 1002 and the non-conductive chip bottom 1001 in the exemplary chip member 1000 described herein can implement a capacitance sensor as an integrated circuit connected to the pipette tip 960. For example, the capacitance sensor may be integrated on a printed wiring board (which may include, for example, a controller circuit 920 and related motor drive circuits, readout circuits, etc. as well), and may also be routed to the chip adapter of the dispenser 900 for connection to the conductive contact 1004 of the pipette tip 960 via a single conductive wire or cable. In some embodiments, the capacitance sensor may be configured to exhibit capacitance at a resolution of up to about 1 femtofarad (fF) at a desired data acquisition rate (e.g., about 1000 samples / second). The amplitude and time resolution may enable accurate detection of the liquid level.

[0450] Thus, the controller circuit 920 may be configured to dynamically detect and continuously monitor changes in the liquid level based on changes in the detected capacitance due to contact (or loss of contact) between the conductive electrode 1002 and the liquid. The detected capacitance from the conductive electrode 1002 on the chip member 1000 may be used as a feedback signal or control loop that provides dynamic liquid level detection and liquid level tracking without losing contact between the dispensing 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 may be configured to generate a control signal and transmit it to the actuator mechanism 934 of the robot arm assembly 914. The control signal varies based on changes in the detected capacitance indicated by the signal from the conductive electrode 1002, causing the arm member 912 that holds the dispenser 100 to move in a direction approaching or away from the surface of the liquid along at least one axis (e.g., the Z-axis), so as to maintain contact between the pipette tip 960 and the liquid such that the non-conductive chip bottom 1001 of the chip member 1000 can achieve a constant immersion regardless of changes in the liquid level.

[0451] To provide dynamic liquid level detection (LLD) and tracking, the non-conductive chip bottom 1001 of the chip member 1000 is sized to be larger than the desired control window, for example, extending by a length or dimension D of about 2 mm or more. Thereby, the insulated chip bottom 1001 functions as a buffer between the conductive electrode 1002 and the surface of the aspirated liquid, so that the conductive electrode 1002 is submerged before contacting the surface of the liquid. For this reason, the insulated chip bottom 1001 shifts the jump of the capacitance 900C beyond the initial immersion of the chip bottom 1001 (as shown at (1) in FIG. 40) to the immersion of the conductive electrode 1002 or contact with the conductive electrode 1002 (as shown at (2) in FIG. 40).

[0452] The delay in the change of the capacitance 900C due to the protrusion distance D of the non-conductive chip bottom 1001 can be used to maintain the immersion of the pipette tip 960 in the liquid. When the liquid level in the container drops, the loss of contact between the liquid and the conductive electrode 1002 is identified based on the change in the detected capacitance 900C before the contact between the opening 962 and the liquid surface is lost. In response to this, the arm member 912 is controlled to move the dispenser 100 along the Z-axis so that the pipette tip 960 follows the liquid level during aspiration or dispensing while maintaining the immersion state of the opening 962 in the liquid.

[0453] For this reason, the control signal applied to the actuator mechanism 934 can 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 can be either stepwise or continuous. For example, based on past movement along the Z-axis, the controller circuit 920 can be controlled so that the movement along the Z-axis is more continuous or smooth.

[0454] In some embodiments, the direction of movement of the arm member 912 along the Z-axis is determined by the mode, whereby vibration can be further suppressed and the movement can be made smoother. For example, in the suction mode, the arm member 912 may be restricted to allow movement of the pipette tip 960 only downward toward the liquid. On the other hand, in the dispensing mode, the arm member 912 may be restricted to allow movement of the pipette tip 960 only upward away from the liquid. That is, the actuator mechanism 934 may have a first operation mode in which the arm member 912 is restricted to a movement approaching the liquid surface along at least one axis during suction, and a second operation mode in which the arm member 912 is restricted to a movement away from the liquid surface along at least one axis during dispensing.

[0455] In some embodiments, the controller circuit 920 may calculate or estimate the suction or dispensing volume of the liquid based on the movement distance of the arm member 912 along the Z-axis, and may also control the subsequent movement of the arm member 912 along the Z-axis based on the calculated or estimated suction or dispensing volume. That is, the controller circuit 920 may estimate the amount of liquid dispensed or suctioned by utilizing the capacitance variation in conjunction with the past movement of the arm member 912 along the Z-axis, and in response thereto, may generate a control signal to the actuator mechanism 934 to move the arm member 912 predictively.

[0456] In this way, the controller circuit 920 measures or determines the capacitance using the signal from the conductive electrode 1002, monitors the capacitance variations, and predicts that the non-conductive tip bottom 1001 of the pipette tip 960 will soon lose contact with the liquid (for example, from a jump or sharp change in the detected capacitance due to loss of contact between the conductive electrode 1002 and the liquid), thereby continuously and dynamically monitoring the changing liquid level. In response, the controller circuit 920 sends a control signal to the actuator mechanism 934 to move the arm member 912 holding the dispenser 100 along the Z-axis (for example, downward / toward the liquid in the aspiration mode or upward / away from the liquid in the dispensing mode), enabling dynamic liquid level tracking.

[0457] According to the extension of the non-conductive tip bottom 1001 below or beyond the portion of the conductive electrode 1002 that provides the signal for capacitance detection, the controller can move the arm member 912 to follow the liquid level while the opening 962 of the pipette tip 960 maintains its immersion state in the liquid (by means of a buffer provided by the distance D between the conductive electrode 1002 and the opposite end of the non-conductive tip bottom 1001).

[0458] Dynamic liquid level detection and tracking as described herein may be used with various liquid solutions (including conductive and non-conductive liquids) without depending on the shape or size of the liquid container. For example, the embodiments described herein may be used with ethanol, milli-Q water, and phosphate buffer (but not limited thereto). The control signal provided to the actuator mechanism 934 may be continuously adjusted (for example, for non-conductive liquids) or may be adjusted stepwise (for example, in the case of highly conductive liquids).

[0459] During or after suction of a liquid in a dispensing or other liquid handling system, since a portion of the liquid evaporates in the channel, the volume of air taken in increases, and it may be recognized that the amount of liquid sucked in may be less than the intended amount, and thus other embodiments described herein may be envisioned. Ensuring the accuracy and precision of dispensing performance is considered impossible without compensating for evaporation.

[0460] Accordingly, the embodiments described herein provide a method for detecting, for example, whether evaporation is occurring in a dispensing channel during or after suction of a liquid. When an increase in pressure in the channel is detected, the system described herein is configured to automatically deploy measures to prevent (or reduce the rate of) evaporation. In some prior arts, analysis and development of liquid classes may be required, and for each developed liquid class, determination and updating of compensation parameters in software may be required. In contrast, in some embodiments described herein, distinction between liquid classes and / or the amount of evaporation expected for each liquid class is not required for quantification and / or compensation of evaporation.

[0461] FIG. 42, FIG. 43A, and FIG. 43B schematically show evaporation detection in a pipette tip of an automatic dispensing system 1101 according to some embodiments described herein. System 1101 includes elements similar to the dispensing systems 101, 901 and the automatic liquid handling system 10 described above, but the description of similar elements may be omitted for simplicity.

[0462] Referring to FIGS. 42 and 43A, system 1101 includes dispenser 1100, one or more pressure sensors 1156 coupled to channel 1102 of dispenser 1100, and a controller or control circuit 1120. Controller circuit 1120 may include controllers 20, 920 and associated processors 925, memories 910, and I / O circuits 915 described herein. Pressure sensor 1156 is fluidly coupled to dispensing channel 1102. In some embodiments, pressure sensor 1156 is an in-line pressure sensor (similar to or including pressure sensor 256 of FIG. 14) disposed in or along dispensing channel 1102, or an in-line pressure sensor disposed in pipette tip 1160 attached to the distal end of dispenser 1100. In other embodiments, channel 1102 is in fluid communication with pressure sensor 1156 via a sensor port. Pipette tip 1160 may be removable or replaceable (such as pipette tips 160, 960 described herein) or may be integrated with dispenser 1100. More generally, dispenser 1100 may be of any suitable type or design and may include any suitable plunger configuration (including any of the dispensers and plunger configurations described herein). By operating drive mechanism 1128 (including one or more actuators) to drive plunger 1140, suction, dispensing, and / or compensation operations as described herein may be performed in response to control signals from controller circuit 1120. Drive mechanism 1128 may be any of the drive mechanisms described herein (e.g., 128, 148) and / or may operate similarly thereto.

[0463] The operations described herein can be executed by the controller circuit 1120 or through the controller circuit 1120. The controller circuit 1120 receives a pressure signal from the pressure sensor 1156 indicating the pressure in the dispensing 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 difference) in the channel 1102. The pressure measurement result may indicate the air pressure or the pressure of one or more other gases in the channel 1102. The controller circuit 1120 may execute the aspiration, dispensing, and / or compensation operations described herein by controlling the movement of the plunger 1140 in response to a signal from the pressure sensor 1156 (e.g., via the feedback loop 1150) by operating the drive mechanism 1128.

[0464] Referring to FIG. 43A, the controller circuit 1120 can detect the evaporation of the liquid in the channel based on the pressure indicated by the signal from the pressure sensor 1156. For example, after the aspiration of the liquid, at the initial pressure P1 in the channel 1102, the volume V1 (along with the filling level h1) in the pipette tip 1160 attached to the distal end of the dispenser 1100 can be occupied by the liquid sample LS. The controller circuit 1120 controls the movement of the arm member 912 away from the container containing the liquid volume, for example, as described herein via the actuator mechanism 934, to remove the pipette tip 1160 from the container containing the liquid volume. When evaporation occurs, the number of molecules in the gas phase in the channel 1102 (and the volume between the plunger 1140 and the liquid sample LS) increases. As a result, a part of the liquid sample LS is pushed through the opening 1162 of the pipette tip 1160, forming beads LB, and as a result, the volume V2 (and the filling level h2) occupied by the liquid sample LS in the pipette tip 1160 decreases. Also, due to the surface tension of the surface of the beads LB, the internal pressure P2 in the channel 1102 increases.

[0465] Figure 43B shows an example of bead LB formation due to evaporation of the EtOH solution LS for a target volume of 1 μl with a chip volume of 10 μl. As shown in Figure 43B, after removal of the pipette tip 1160 from the liquid volume, but before evaporation occurs, the liquid sample LS is completely contained in the pipette tip 1160. With the pipette tip 1160 removed from the liquid volume, the opening 1162 is sealed by the effect of surface tension, so a change in pressure in the channel 1102 can be caused by evaporation. When evaporation occurs, the pressure in the channel 1102 can increase, so the liquid sample LS is pushed out from the opening 1162 of the tip 1160, and bead LB is formed as long as the radius of the bead decreases. As evaporation continues, the bead reaches the shape of a hemisphere (indicated by radius r1), and at this point, while the bead radius begins to increase (indicated by radius r2), the pressure inside the channel 1102 decreases again.

[0466] The controller circuit 1120 measures the pressure inside the channel and the displacement volume using the signal from the pressure sensor 1156. More specifically, by using the signal from the pressure sensor 1156, it is possible to monitor the change in pressure inside the channel 1102 after aspiration, which is caused by changes in volume due to evaporation and bead formation (for example, from volume V1 before evaporation to volume V2 after evaporation has continued for some time).

[0467] Hereinafter, with reference to the graphs of FIGS. 44A and 44B and the flowchart of FIG. 45, the operations that the controller circuit 1120 can perform to control the position and aspiration of the dispenser 1100 and to detect a change in pressure in the channel 1102 to detect evaporation will be described. In the graphs of FIGS. 44A and 44B, line 4401 indicates the gauge pressure (Pascal (Pa)) determined by the signal from the pressure sensor 1156, and line 4402 indicates the volume (microliter (μl)) displaced by the plunger 1140.

[0468] Referring to FIGS. 44A, 44B, and 45, the dispenser 1100 moves so as to contact the liquid volume from which the pipette tip 1160 is aspirated (e.g., by the arm member 912 in response to a control signal applied to the actuator 934) as shown in step 1111. In response to the contact, due to capillary action, the liquid can be pushed into the dispensing orifice 1162 (thereby increasing the pressure in the dispensing channel 1102 as shown in step 1112). As shown in step 1112a, the liquid sample LS is aspirated into the dispenser 1100 by driving the plunger 1140 in response to a control signal from the controller circuit 1120. In step 1113, the aspiration is completed, and in step 1114, the pipette tip 1160 is removed from the liquid volume (e.g., by the arm member 912 and the actuator 934). When the pipette tip 1160 is in air, the orifice 1162 can be substantially sealed by the surface tension of the liquid sample LS, so a change in pressure in the channel 1102 can be caused by evaporation. With the chip 1160 in air or removed from the liquid volume, as shown in step 1115, the pressure change dp / dt over time is monitored based on a signal from the pressure sensor 1156. Also, in step 1116, a relatively small distance or displacement ΔV Dis is caused by the plunger 1140 moving in the channel 1102, and the elasticity of the system (e.g., a combination of air cushion elasticity and surface tension) may be explored. The volume change ΔV Dis due to the displacement of the plunger 1140 is considered to be small enough to avoid dripping of the liquid beads LB from the chip 1160.

[0469] When the signal from the pressure sensor 1156 indicates an increase in pressure over time (e.g., from 1114 to 1116), evaporation of the liquid sample LS can be detected. This pressure may be monitored in step 1115 immediately after removal of the chip 1160 from the liquid volume (i.e., before bead formation LB) in order to ensure accuracy.

[0470] In addition to detection of evaporation, in step 1118, in some embodiments, the evaporation rate is calculated along with an estimation of the suction error due to evaporation. For example, the evaporation rate may be calculated based on the change in pressure (i.e., the slope of line 4401) indicated by the pressure signal over time as monitored in step 1115, and in some embodiments, it involves the measurement result of the pressure change as a result of the movement of the plunger 1140 in step 1116. The evaporation rate may be proportional to the change in pressure dp / dt over time. As shown in FIG. 44A, the measurement result of the rate of change of pressure (and thus the evaporation rate) can be determined by a line that fits the pressure curve between the removal of the pipette tip 1160 from the liquid volume in step 1114 and the displacement of the piston or plunger in step 1116.

[0471] As described above, in some embodiments, the evaporation rate may also be calculated using, in addition, the measurement result of the pressure change as a result of the movement of the plunger 1140 in step 1116. In particular, in step 1117, the volume change ΔV Dis due to (indicated by the pressure signal from the pressure sensor 1156) the pressure change ΔP Dis is measured and used in the calculation of the evaporation rate in step 1118. That is, as shown in FIG. 44B, the small volume change ΔV Dis resulting from the movement of the plunger 1140 in the channel 1102 causes a pressure response ΔP Dis By using this, the evaporation rate E = dVe / dt may be calculated from the measurement result of the rate of change of pressure using the following equation. [Number] Note that in the described method, it is not necessary to know in advance the suction liquid class for determining the evaporation rate. The dependence on the liquid class is eliminated because in the proposed formula, the surface tension dependencies of the ΔV Dis / ΔP Dis term and the dPe / dt term cancel each other out.

[0472] The evaporation rate may 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 is maintained substantially constant. Under the condition of constant pressure, the evaporation rate is directly given by the displacement rate of the plunger 1140 as shown by the following formula. [Number]

[0473] Therefore, the system 1101 can detect that evaporation has occurred based on the pressure (or pressure change) in the channel 1102 or the chip 1160 as indicated by the signal from the pressure sensor 1156. The graphs of FIGS. 44A and 44B show exemplary operations from experimental data using EtOH as the liquid sample LS, but it is understood that the detected pressure changes (and the calculated evaporation rates) can vary significantly based on the material of the liquid sample LS. For example, H 2When O is used as the liquid sample LS, in response to the operation of FIG. 45, the pressure change and the calculated evaporation rate may be significantly reduced. In some embodiments, a comparison of the pressure change and / or the difference in the evaporation rate may be used to identify the liquid sample LS in the pipette tip 1160. However, in the exemplary operations described herein, the evaporation rate can be calculated independently of the surface tension or type of the liquid of the aspirated liquid sample LS. That is, the evaporation detection and the calculation of the evaporation rate as described herein can be performed based on the measurement result of the pressure change rate without determining the surface tension of the liquid sample LS or prior knowledge of the liquid class of the liquid sample LS.

[0474] By using the evaporation rate E (calculated in step 1118) and the aspiration time (i.e., the duration of aspiration between steps 1112 and 1113), the additional gas or vapor volume generated by evaporation during aspiration (also referred to herein as the evaporation volume (Vevap)) can be estimated. The evaporation volume Vevap may be equal to or indicative of the under-aspiration amount due to evaporation. Thus, in the embodiments described herein, by using the estimated evaporation volume Vevap as a relevant parameter, it can be determined whether the evaporation rate is acceptably low or the evaporation is greater than a predetermined threshold (TH) for its reduction or compensation. Such a determination threshold may vary based on the desired accuracy. For example, for a particular dispensing application, if an accuracy of 5% is within the acceptable range, an evaporation volume less than 5% of the target volume may be acceptable, but an evaporation volume exceeding 5% of the target volume may require compensation.

[0475] Referring again to FIG. 42, for example, a feedback loop 1150 may be used to automatically or programmatically perform a compensation operation based on, for example, the calculation of the evaporation rate from a pressure signal and the comparison to a threshold evaporation rate. For example, when the evaporation rate E exceeds the threshold TH, one or more countermeasures may be initiated by the controller circuit 1120 (e.g., by adapting the suction by the plunger 1140 by repeating the suction and operating the drive mechanism 1128) to compensate for the detected evaporation.

[0476] FIGS. 46A and 46B are flowcharts showing respective evaporation compensation operations during suction (e.g., between blocks 1112 and 1113 of FIG. 45) and after chip removal (e.g., after block 1114 of FIG. 45) according to some embodiments. The compensation may include a plurality of operations performed by the controller circuit 1120 based on a pressure signal from the pressure sensor 1156 to compensate for evaporation. For example, the evaporation compensation operation may include performing a pre-wetting operation (where an amount of liquid is suctioned and dispensed prior to suction of liquid for delivery), adapting one or more suction parameters (e.g., by over-suctioning another amount of liquid volume to compensate for under-suction due to evaporation), and / or controlling the movement of the plunger 1140 in the dispensing channel 1102 (e.g., to maintain a defined or predetermined constant pressure in the dispensing channel 1102 and / or pipette tip 1160 to avoid dripping).

[0477] Referring to FIG. 46A, aspiration (e.g., at or during step 1112 of FIG. 45) may include calculating, at step 1119a, the aspiration volume (Va) of the liquid sample LS. In calculating the aspiration volume Va at step 1119a, the expansion of the air cushion (AC in FIG. 16) may be taken into account. For example, the aspiration volume Va may change by an amount equal to or proportional to the change in the air cushion volume. In some embodiments, the aspiration 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 cushion volume, A is the cross-sectional area of the plunger, and Δx represents the movement distance of the plunger.

[0478] In step 1121, the calculated aspiration volume Va is compared with a desired or target volume (Vtarget). In some embodiments, the use of a control loop may be employed to reduce or minimize the difference between the aspiration volume Va and the target volume Vtarget. For example, the controller circuit 1120 may use a control loop mechanism that employs feedback, continuously calculates an error value as the difference between the desired target volume Vtarget and the aspiration volume Va, and includes a proportional-integral-derivative controller (PID controller) that applies a correction to the plunger movement. In particular, when the comparison of the aspiration volume Va to the target volume Vtarget exceeds a desired error threshold (i.e., when Va - Vtarget > errorTH), a compensation operation may be performed in step 1123a. For example, one or more aspiration parameters may be adapted to suppress the aspiration error, and based on the adapted parameters, the aspiration may be changed or repeated. The operations of FIG. 46A, which calculates the aspiration volume Va in step 1119a, compares the aspiration volume Va with the target volume Vtarget in block 1121a, and uses the comparison result (Va - Vtarget) as an input to a control loop for controlling or correcting the plunger movement, may be continuously performed during aspiration to reduce or minimize the difference between the calculated aspiration volume Va and the target volume Vtarget. The operations of FIG. 46A are performed with the chip immersed (e.g., prior to step 1114 of FIG. 45). The calculation in step 1119a is based on a known plunger position and the expansion (or contraction) of the air volume derived from the measured gauge pressure. The operations of FIG. 46A may be independent of evaporation and thus may be performed even if the evaporation rate was not evaluated in past dispensing steps.

[0479] As an addition or alternative, in FIG. 46B, after removing the pipette tip 1160 from the liquid volume (e.g., in step 1114 of FIG. 45), the aspiration volume Va may be calculated in step 1119b (or recalculated if the operation of FIG. 46A has been performed in the past) based on the change in pressure indicated by the signal from the pressure sensor 1156. At this point, the influence of the unintended liquid inflow during the extraction of the chip, which is considered to be due to the effect of surface tension, is reflected in the aspiration volume Va. In step 1121b, if the (recalculated) aspiration volume Va is less than the target volume Vtarget by a sufficient margin, one or more aspiration parameters are adapted in step 1123b and aspiration is repeated. For example, by over-aspirating another amount of liquid (based on the calculated or estimated evaporation rate) to compensate for the initial under-aspiration due to evaporation, a desired amount of liquid may be delivered. In some cases, it may be sufficient to simply report or record the aspiration error (Va - Vtarget).

[0480] In step 1122, the calculated evaporation rate E (or evaporation volume Vevap) is compared with a threshold TH. For example, the threshold TH may be volume-based for comparison with the calculated evaporation volume Vevap. If the evaporation volume or evaporation rate is below the threshold TH, no action may be taken. If the evaporation rate or evaporation volume exceeds the threshold TH, one or more compensation operations are performed in step 1123b and the aspiration volume Va is recalculated in step 1119b. Thus, the evaporation rate may be considered in the calculation of Va. Based on the aspiration volume Va recalculated in step 1119b, the system can improve accuracy by determining and performing compensation measures in step 1123b (e.g., repeating the dispensing step, pre-wetting, adapting parameters, or simply recording or reporting the deviation from the target volume Vtarget).

[0481] The operations shown in FIGS. 46A and 46B may be executed in combination or may be executed independently of each other. That is, the operations of FIGS. 46A and 46B may be executed sequentially, or the operation of FIG. 46A may be executed during suction without separately executing the operation of FIG. 46B after chip extraction, or the operation of FIG. 46B may be executed after chip extraction without executing the operation of FIG. 46A during suction.

[0482] As described above, the evaporation compensation operations in steps 1123a and 1123b may include, but are not limited to, pre-wetting, adaptation of suction parameters, and / or control of plunger movement. For example, in steps 1123a and 1123b, evaporation in the chip 1160 may be suppressed or prevented by performing a pre-wetting operation. Pre-wetting can suppress or prevent evaporation in the chip airspace by increasing the humidity inside the pipette tip 1160, and can improve the accuracy of suction. Therefore, according to the pre-wetting of the pipette tip, the pressure change indicated by the signal from the pressure sensor 1156 can be suppressed or eliminated.

[0483] As an addition or alternative to this, as described above, in steps 1123a and 1123b, one or more suction parameters may be adapted (for example, for over-suction to compensate for under-suction or vice versa). For example, when sucking water, although inflow into the chip 1160 measurable by the surface tension of the water may occur during withdrawal in step 1114, this can be corrected by suppressing the suction volume.

[0484] As an addition or alternative to the above, in step 1123b, the plunger 1140 in the channel 1102 may be controlled to move a sufficient distance to maintain a defined or predetermined constant pressure in the pipette tip 1160 and / or the dispensing 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 such that the pressure in the channel 1102 and / or the tip 1160 is maintained substantially constant. This constant pressure may be a predetermined pressure or may be based on the measured pressure in the channel immediately after removal of the pipette tip from the liquid volume (e.g., in step 1114). In this way, by keeping the pressure constant (after liquid aspiration and removal of the tip 1160 from the liquid volume) or by moving the plunger 1140 to aspirate a small amount of air, dripping from the bead formation LB at the orifice 1162 of the pipette tip 1160 may be suppressed or avoided. The pressure sensor 1156 may be provided in the channel 1102 or the pipette tip 1160 to provide a pressure signal with a (sufficiently high level of accuracy to address chip bead formation LB) even with a small amount of air being aspirated, as described herein with reference to embodiments of, for example, a dual plunger dispenser (e.g., dispenser 100), a serial plunger dispenser (e.g., dispenser 200), and / or a dual metering dispenser (e.g., dispenser 1200).

[0485] It should be understood that the adaptation of the dispensing parameters and / or other compensation operations in steps 1123a and 1123b is 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 also enables compensation for hydrostatic pressure and capillary pressure. Also, these compensation operations may include (for example, adapting the aspiration rate based on the pressure change ΔP indicated by the signal from the pressure sensor 1156 with respect to the target pressure change ΔPtarget) viscosity-dependent dispensing rates and / or (for example, starting pre-wetting when the temperature of the liquid falls below the minimum temperature) heat transfer compensation. By using such operations, it is possible to effectively compensate for differences in the liquid density, surface tension, wettability, and / or viscosity of the liquid sample LS.

[0486] From the recognition that in conventional dispensing or other liquid handling systems, an accurate piston or plunger control system is typically used to control the displacement of air, other embodiments described herein may be envisioned. For example, in some dispensing systems, a liquid is aspirated into a disposable tip with an air cushion AC between the liquid sample LS and the dispensing channel and dispensed into another container, which is also referred to as an air displacement pipette or pipette tip. This can avoid cross-contamination of the dispenser by different liquid samples. The dispensing performance may mainly result from the shape of the plunger control motor that operates the plunger (i.e., based on the internal volume of the pipette or the distance of movement or stroke of the piston or plunger within the bore) and the accuracy and / or precision, but the higher the accuracy and precision of the arrangement (for example, with respect to over-aspiration or under-aspiration), the higher the dispensing performance. Thus, conventional dispensing performance may be limited by the resolution of the encoder of the plunger control motor.

[0487] The embodiments described herein provide a dual metering dispensing system configured to control a plunger position based on a displacement air volume in a dispensing channel as a determination from a sensor signal (e.g., as an output from a flow sensor coupled to the dispensing channel). The system may also include a negative or positive pressure source coupled to a valve and / or a flow restriction mechanism. The amount of air displaced in the channel (i.e., the displacement air volume) can be determined by the use of an air flow (flow rate) over time indicated by the sensor signal. The flow sensor may have sufficient sensitivity for a wide range of flow rates (e.g., over a measurement range of one digit or more) that are difficult to achieve with conventional encoders and plunger control motors.

[0488] In some embodiments, the flow sensor can be implemented by a pressure sensor with sufficient sensitivity to provide a feedback loop for controlling the channel pressure / air displacement volume. For example, the flow sensor can be implemented by two pressure sensors in parallel arrangement across a flow restriction mechanism (also referred to herein as a dual metering sensor or a dual flow sensor). Thus, the flow sensor, valve, and pressure source can provide a control loop for controlling the liquid flow inside the dispensing channel, and because an in-line measurement is provided by the flow sensor, accurate and precise control of the liquid flow becomes possible. Since the plunger position can be determined based on the air displacement volume calculated from the measurement results of the flow rate or pressure change, it is not necessary to make the movement of the plunger very accurate, and thus the accuracy requirements for the plunger control motor and / or encoder can be relaxed.

[0489] FIG. 47 is a side view showing a dual metering dispenser that can be used in an automatic dispensing system according to some embodiments. FIG. 48 is an enlarged schematic view showing the dual metering dispenser of FIG. 47 with the pipette tip removed. The automatic dispensing system (e.g., 101, 901, 1101) may include one or more of the illustrated dispensers 1200. When a plurality of dispensers 1200 are provided, these dispensers 1200 may be configured to operate independently of each other or may be configured to operate in cooperation. For purposes of detailed explanation, only a single dispenser will be described below.

[0490] Referring to FIGS. 47 and 48, the dispenser 1200 includes a mechanical interface 1207, a frame 1208, an electrical interface 1209 (shown as a printed circuit board), a pressure control system 1206, a chip attachment feature or adapter 1276, and a manifold 1275. The pressure control system 1206 includes sensors 1279A, 1279B, 1280, a plunger 1240 in a dispensing channel 1202 controlled by a drive mechanism 1228, and an air flow control system 1271 including a valve 1278 and a switching type flow restriction mechanism 1277 (see FIG. 53) operable to couple the channel 1202 to a pressure source. The chip adapter 1276 is attachable to a pipette tip 1260, which includes a dispensing orifice 1262 and a liquid collection volume LV that is in fluid communication with the dispensing channel 1202 via a passage 1274 in the manifold 1275. As used herein, the dispensing channel 1202 may generally include features that communicate between a chamber or barrel including the chip 1260 / adapter 1276 and the plunger 1240.

[0491] The plunger mechanism is operable to suck or dispense a liquid volume by translating the plunger 21240 in response to a control signal applied to the drive mechanism 1228 to change the pressure in the dispensing channel 1202. The drive mechanism 1228 may be a linear drive system including a plunger actuator and an encoder. Also, it may be configured such that a linear sensor 1229 (e.g., having a resolution of about 1 μm) measures the deflection by the chip 1260 contacting the side wall of the container.

[0492] The components of the dispenser 1200 may be mounted on the frame 1208. The mechanical interface 1207 may couple the dispenser 1200 to an automatic dispensing system as described herein (e.g., 101, 1101). For example, the mechanical interface 1207 may mechanically couple between the frame 1208 (including the components of the dispenser 1200) and an arm member (e.g., 912) of a robot arm assembly (e.g., 914) to control the movement of the dispenser 1200 along one or more axes (e.g., the Z-axis) as described herein.

[0493] The electrical interface 1209 may include one or more control circuits 1220 (which may include any of the control circuits 20, 920, 1120 described herein) including an input / output (I / O) circuit (e.g., 915), a memory (e.g., 910), a processor / microcontroller (e.g., 925), and a drive circuit for the motor / drive mechanism 1228. Also, the electrical interface 1209 may be configured to perform the reading and preprocessing functions of the sensors 1279, 1280. More generally, the memory may be a non-transitory storage medium configured to store computer-readable instructions, and the controller circuit 1220 may be configured to execute the computer-readable instructions stored in the memory to perform operations as described herein.

[0494] Accordingly, the dispensing control operation described herein can be executed by the controller circuit 1220 or through the controller 20. The controller circuit 1220 receives sensor signals from one or more of the sensors 1279A, 1279B, 1280 coupled to the dispensing channel 1202. These sensors include the dispensing channel pressure sensors 1279A, 1279B (which may include the pressure sensor 179 described herein), and the sensor 1280 configured to output a sensor signal capable of determining the air displacement in the channel 1202, which is mainly referred to as the flow sensor 1280 herein. The dispensing channel pressure sensors 1279A, 1279B may include the pressure sensor 179 described herein. The flow sensor 1280 may be configured to output a sensor signal indicating the flow rate in the channel 1202 that is detected or identified based on, for example, pressure change data of air (or other gas) in the channel 1202.

[0495] Based on the sensor signal from the sensor 1280, the controller circuit 1220 may determine the displaced air volume in the channel 1202. The controller circuit 1120 may transmit one or more control signals (e.g., to a pressure source) for performing the suction and / or dispensing operations described herein by controlling the position of the plunger 1240 in the channel 1202 based on the displaced air volume in the channel 1202 or in response to signals from the pressure sensors 1279A, 1279B, 1280. The control signals may include, but are not limited to, a plunger actuator signal that directly operates the drive mechanism 1228, related control signals such as a flow rate control signal that operates or controls the operating state of the flow rate or restriction mechanism 1277 (see FIG. 53), and / or a valve control signal that operates or controls the operating state of the valve 1278. Accordingly, as a pressure source for providing a pressure difference to drive the flow, the plunger 1240 / actuator 1228, the pressure reservoir 1290 (see FIG. 53), or other pump mechanisms are possible.

[0496] Valve 1278 is operable to couple channel 1202 to pipette tip 1260 mounted on chip adapter 1276 and / or a pressure source (see FIG. 53) in response to a valve control signal from controller circuit 1220. As will be described in more detail below, the pressure source can include a negative pressure source and a positive pressure source, which can be selected to control the direction of air flow in channel 1202 (in response to the operation of valve 1278 and switching flow restrictor 1277).

[0497] FIG. 49 is a simplified schematic view showing plunger 1240 and manifold assembly 1275 of the dual metering dispenser of FIG. 48. FIG. 50 is an enlarged view of area L in FIG. 49, showing microfluidic manifold 1275 and flow sensor 1280 in more detail. Referring to FIGS. 49 and 50, manifold 1275 interconnects dispense channel 1202 and plunger 1240 with pressure sensors 1279, 1280 and valve 1278. Manifold 1275 includes a plurality of microfluidic passages 1274 configured to couple channel 1202 to chip adapter 1276 in response to the operation of valve 1278. Within area F, a dead volume or ineffective volume (i.e., a residual volume of aspirated liquid that can be lost as waste) may be defined, for example, as arising from connections provided by microfluidic passages 1274 and / or sensor volumes.

[0498] Manifold 1275 shortens the distance of all interconnected fluid channels by compactly integrating the dispensing channel 1274, sensors 1279A, 1279B, 1280, and valve 1278 that are operably coupled to the plunger 1240. In some such embodiments, the manifold 1275 may be configured to reduce or minimize the dead volume (e.g., make the void volume less than about 120 μl) based on one or more dimensions of the internal microfluidic passageways or channels 1274. For example, each passageway 1274 in the microfluidic manifold 1275 may have a diameter in the range of about 0.2 mm to 0.8 mm. In the illustrated embodiment, the flow sensor 1280 is coupled to the microfluidic passageway 1274 to provide the pressure change measurement results described herein. In some embodiments described herein, an accurate measurement result of the pressure change may be provided by a void volume of less than about 50 μl or a volume range of about 50 μl to 100 μl.

[0499] FIG. 51 is a perspective view of a manifold 1275 mounted on a portion of a PCB 1209 that includes pressure sensors 1279A, 1279B and a flow sensor 1280, which is also referred to herein as a manifold assembly. As shown in the manifold assembly of FIG. 51, in some embodiments, the manifold 1275 and sensors 1279, 1280 may be mounted on both sides of the PCB 1209 with the microfluidic passage 1274 routed under and / or inside the PCB 1209 for coupling to the sensors 1279 and / or 1280. The PCB 1209 may include metallized holes to prevent swelling when exposed to moisture. In some embodiments, the air connection and / or sensor connection provided by the microfluidic passage 1274 may result in a dead volume of less than about 50 μl. Also, the manifold 1275 may be adapted for use in some embodiments without the flow sensor 1280 (e.g., in the dual plunger embodiments of FIGS. 2-13), further reducing the dead volume (e.g., less than about 20 μl). That is, since the air displacement is accurately measured based on the integration of two or more pressure sensors 1279A, 1279B in the manifold 1275 as described herein, it is understood that the dual metering dispenser as described herein may be operable in single or dual plunger embodiments.

[0500] FIG. 52 is a schematic circuit diagram showing the connection parts of sensors 1279 and 1280 in manifold 1275. Referring to FIG. 52, valve 1278 is operable to couple channel 1202 (including plunger 1240) to pipette tip 1260 mounted on chip adapter 1276. Manifold 1275 is equipped with a pressure sensor 1279B configured to provide a relatively high range of pressure measurement results (e.g., up to about 350 millibar or more), which is coupled to channel 1202 via microfluidic passage 1274, and this can define a relatively large stroke volume (including, for example, a plunger 1240 with a relatively large diameter (about 6 mm)). Manifold 1275 is equipped with a pressure sensor 1279A configured to provide a relatively low range of pressure measurement results (e.g., up to about 10 millibar or more), which is coupled to pipette tip 1260 on chip adapter 1276 via microfluidic passage 1274. In some embodiments, an additional pressure sensor 1256 (such as pressure sensors 256 and 1156 described herein) may be included in or coupled to pipette tip 1260. Also, a relatively small dead volume may be defined by the connection provided by microfluidic passage 1274 and / or the sensor volume within area F.

[0501] The flow sensor 1280 is coupled to the dispensing channel 1202 (e.g., between the dispensing channel 1202 and the pipette tip 1260 or the chip adapter 1276), and is configured to output a sensor signal indicating the air flow rate in the channel 1202 based on, for example, the detected pressure or pressure change data. For example, the flow sensor 1280 may be a dual metering sensor or a differential pressure sensor including first and second pressure sensors 1280A and 1280B coupled to the channel 1202 in parallel arrangement via a microfluidic passage 1274. The first and second pressure sensors 1280A and 1280B may output respective signals including first and second pressure data indicating the first and second flow rates. In some embodiments, the measurement range of the second pressure sensor 1280B may be wider than that of the first pressure sensor 1280A by, for example, one digit or more, thereby enabling flow rate measurement with an expanded dynamic range. For example, flow rate changes close to zero can result in extremely small pressure differences, making it difficult or impossible to detect using a pressure sensor configured to detect larger pressure fluctuations in the channel 1202.

[0502] Therefore, in some embodiments, the first pressure sensor 1280A may be highly sensitive to detect sub - Pascal (Pa) fluctuations at low pressure (e.g., less than about 50 Pa). On the other hand, the second pressure sensor 1280B may have a wide measurement range to detect fluctuations at high pressure (e.g., up to about 5000 Pa). The first and second pressure data indicated by the respective outputs of the first and second pressure sensors 1280A and 1280B may be combined by the controller circuit 1220. That is, the controller circuit 1220 may include a signal processing function that combines the respective pressure data provided by the first and second pressure sensors 1280A and 1280B to expand the dynamic range of the flow rate measurement.

[0503] Referring to FIGS. 47 and 48, the controller circuit 1220 may be configured to determine a displacement air volume in channel 1202 based on the flow rate in channel 1202 indicated by the output signal from sensor 1280 (e.g., indicated by a change in pressure), and based on this displacement air volume, may output a plunger actuator control signal to drive mechanism 1228, whereby the accuracy of suction and / or dispensing can be improved. The plunger actuator control signal may continuously vary based on a change in the displacement air volume in channel 1202 (as indicated by the varying output from sensor 1280) to dynamically control the position and / or speed of the movement of plunger 1240 in channel 1202. For example, the controller circuit 1220 may execute a control loop, whereby (i) the controller circuit 1220 transmits a plunger actuator control signal to drive mechanism 1228 to move plunger 1240 in channel 1202 to perform suction or dispensing, and (ii) the flow sensor 1280 outputs a signal indicating a pressure change in channel 1202 (e.g., based on first and / or second pressure data indicated by sensor signals from first and second pressure sensors 1280A, 1280B) as a result of the movement of plunger 1240, and (iii) the controller circuit 1220 determines the air displacement in channel 1202 from the pressure change (or the flow rate it indicates) and transmits another plunger actuator control signal to drive mechanism 1228 to move plunger 1240 based on the determined air displacement. Thus, in contrast to some conventional motor / encoder assemblies that may determine the displacement air volume based on tracking the movement distance of the plunger in the dispensing channel, the controller circuit 1220 may continuously monitor the pressure in channel 1202 and generate a plunger actuator control signal based on the output of sensor 1280 without relying on the determination of the past position or movement of plunger 1240 in channel 1202.

[0504] Referring again to FIG. 52, the flow rate limiting mechanism 1277 is coupled to the channel 1202, for example, via the microfluidic passage 1274 of the manifold 1275. The flow rate limiting mechanism 1277 can be switched between states that allow different ranges of flow rates in response to a flow rate limiting control signal from the controller circuit 1220 and may be configured to increase or decrease the flow rate, for example, based on the outputs of the dual pressure sensors 1280A and 1280B. The valve 1278 is coupled to the channel 1202, for example, between the flow rate limiting mechanism 1277 and the channel 1202. In some embodiments, the flow rate limiting mechanism 1277 and the valve 1278 may be configured to couple the channel 1202 to the pressure source 1290 as described with reference to the example of FIG. 53.

[0505] FIG. 53 is a schematic diagram showing in more detail the operation of various components of the dual metering dispenser 1200 according to some embodiments. Referring to FIG. 53, the dual metering dispenser 1200 includes a flow sensor 1280 coupled to the dispensing channel 1202 and the switching flow restriction mechanism 1277 via an in-line valve 1278 as described above with reference to FIG. 52. The flow sensor 1280 is implemented by a dual metering sensor including first and second pressure sensors 1280A and 1280B, and measures the flow rate inside the dispensing channel 1202, for example, based on the pressure difference or change across the variable flow restriction mechanism 1277. The first pressure sensor 1280A may be configured to measure a first narrow pressure range (e.g., about 0 - 25 Pa or ΔP = about 0.0036 psi) for low flow rates, while the second pressure sensor 1280B may be configured to measure a second wide pressure range (e.g., about 0 - 500 Pa or ΔP = about 0.0725 psi) for high flow rates. In some embodiments, the second wide pressure range may be two or more orders of magnitude higher than the first pressure range. By utilizing two parallel (narrow and wide range) pressure sensors 1280A, 1280B across the flow restriction mechanism 1277, a dual metering dispenser 1220 having sufficient sensitivity to measure a wide range of flow rates is provided. For example, the differential pressure sensors 1280A, 1280B may be operable to provide a flow rate measurement range of about 1 μl / s to 1000 μl / s.

[0506] The flow rate limiting mechanism 1277 is configured to provide a variable flow rate in channel 1202 over a corresponding range of, for example, about 1 μl / s to 1000 μl / s. In the embodiment of FIG. 53, the flow rate limiting mechanism 1277 is coupled between channel 1202 and a pressure source 1290. The pressure source 1290 may comprise 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 rate limiting mechanism 1277 and / or valve 1278 may be coupled between the positive pressure reservoir 1290A and the negative pressure reservoir 1290B and configured to apply a positive or negative pressure (and thus control the direction of air flow) in channel 1202, for example, in each of dispensing or aspiration, by switching between them.

[0507] Referring more specifically to FIG. 53, the flow rate limiting mechanism 1277 is switchable between each flow rate limiting state that provides a different range of flow rates in response to a flow rate limiting control signal from the controller circuit 1220 and is configured to increase or decrease the flow rate, for example, based on the measurement range of sensors 1280A and / or 1280B. For example, the switchable flow rate limiting mechanism 1277 may include three flow rate limiting states A, B, and C, each of which progressively reduces the flow rate limitation. That is, state B has less flow rate limitation than state A, and state C has less flow rate limitation than state B. However, this progressive flow rate limiting mechanism is merely illustrative, and it is understood that the flow rate limiting mechanism 1277 may have fewer or more flow rate limiting states than shown, or may include continuously varying (rather than progressive) ones. Thus, the switchable flow rate limiting mechanism 1277 and valve 1278 may be operable to provide (i) a switchable flow rate (provided by the plurality of flow rate limiting states A, B, C) and (ii) a switchable flow direction (provided by the positive and negative pressure reservoirs 1290A and 1290B).

[0508] In some embodiments, the control circuit 1220 may be configured to send a valve control signal to the valve 1278 to stop the flow when the displacement air volume indicated by the flow sensor 1280 exceeds a threshold air displacement volume, and may effectively function to stop the movement of the plunger 1240 in other embodiments described herein. The threshold air displacement volume may be determined from the target volume and may be calculated to compensate for various secondary effects during the dispensing operation.

[0509] The range of the flow rate in the channel 1202 may be based on the pressure provided by the pressure sensor 1290 and the switchable limits of the flow rate limiting mechanism 1277 (for example, a low pressure source may be able to switch between flow rates ranging from about 1 μl / s to 100 μl / s, while a high pressure source may be able to switch between flow rates ranging from about 10 μl / s to 1000 μl / s), which is within the range of the dynamic range of the flow rate measurements provided by the dual pressure sensors 1280A and 1280B. In some embodiments, the response time of the flow sensor 1280 may be less than 5 ms, and the in-line valve 1278 may be switchable between an open state and a closed state in less than about 1 ms (for example, about 200 μs or less).

[0510] As described above, the controller circuit 1220 may improve the accuracy of over-suction and / or under-suction by implementing a control mechanism or loop based on the pressure data from the pressure sensors 1280A, 1280B. Also, by using the pressure data indicated by the signals from the pressure sensors 1280A, 1280B, the speed or the plunger position (i.e., the end position of the plunger 1240 in the channel 1202) can be dynamically controlled. For this reason, the end position of the plunger 1240 may be controlled based on the change in the pressure data indicated by the sensor 1280, rather than tracking the movement distance of the plunger. That is, the position of the plunger 1240 in the channel 1202 may be dynamically controlled based on the change in the flow rate or the displacement air volume in the channel 1202 as indicated by the signal from the sensor 1280, without depending on the past position and / or the movement distance of the plunger 1240. In some embodiments, as shown in FIG. 53, the pressure sensors 1279A, 1279B are distributed along the channel, and the pressure sensor 1279A may be included in the pipette tip 1260 (e.g., instead of the pressure sensors 256, 1156 described herein) or may be coupled to the pipette tip 1260, and the pressure sensor 1279B may be further arranged along the channel. The chip pressure sensor 1279A may output a pressure signal, and the controller circuit 1220 may use this to determine the volume of the liquid LV in the pipette tip 1260 based on the pressure signal, and may also control the position of the plunger 1240 based on the determined volume of the liquid in the pipette tip 1260.

[0511] Referring to FIGS. 54-59, these show an exemplary positive displacement (PD) pipette tip 1360 according to other embodiments of the present technology. The PD pipette tip 1360 can form a dispensing system when used in combination with a dispenser. An exemplary dispensing system 1301 according to an embodiment of the present technology is shown in FIGS. 54-59, which includes the PD pipette tip 1360 and a dispenser 1300.

[0512] The dispensing system 1301 can aspirate and dispense the liquid volume within the liquid processing system. The dispensing system 1301 may be adapted to be used in place of the dispensing system 101, for example, in the automated liquid processing system 10 (FIG. 1). However, the disclosed methods, systems, and devices are not limited to the liquid processing system 10 or its use therein, and it is understood that the present disclosure is applicable to other systems and applications where aspiration and / or dispensing of liquid volume is desired.

[0513] The PD pipette tip 1360 is not limited to use with the dispenser 1300. The PD pipette tip 1360 may be adapted to be used with any suitable air displacement type dispenser. The PD pipette tip 1360 may be adapted to be used in place of, for example, the air displacement pipette tip 160.

[0514] The dispensing system 1301 includes one or more dispensers 1300. The dispenser may be mounted on the dispensing module 30 (FIG. 1). Each dispenser 1300 may be configured and operate in the same manner, and of course, the following description regarding a representative one of the dispensers 1300 may equally apply to each of the dispensers 1300. When a plurality of dispensers 1300 are provided, these dispensers 1300 may operate independently of each other or may operate in cooperation. For the purpose of detailed explanation, only a single dispenser will be described below.

[0515] The dispensing system 1301 includes one or more of the dispenser 1300, the controller 20, and the PD pipette tip 1360. The pipette tip 1360 is removable and replaceable on the dispenser 1300 and may also be a de facto disposable or consumable part of the dispensing system 1301.

[0516] Referring to FIGS. 54 and 55, it can be appreciated that the dispenser 1300 has a longitudinal axis A-A and a distal end 1300A. The dispenser 1300 includes a tubular barrel 1310, a pressure control system 1306, a dispensing channel 1302, a dispenser orifice 1304, and a tip adapter 1314. The barrel 1310 includes a shaft 1313 that terminates at the distal end 1300A. The tip adapter 1314 is mounted or formed on the distal end 1300A. The dispenser orifice 1304 is disposed at the distal end 1300A and is in fluid communication with the dispensing channel 1302.

[0517] In some embodiments, the pressure control system 1306 includes a plunger mechanism (such as those described and illustrated hereinafter). The dispenser 1300 may be configured and operable in a manner similar to that described herein with respect to any one of the dispensers 100, 200, 300, 400, 600.

[0518] However, the pressure control system 1306 is not limited to a plunger mechanism and may include and use any suitable type of mechanism for controlling the pressure in the tip 1360 as discussed herein. For example, other suitable pressure control mechanisms may include one or more pumps of other designs that are incorporated into the dispenser 1300 or are remote from the dispenser 1300 and are fluidly connected to the dispenser 1300.

[0519] An exemplary pressure control system 1306 includes a barrel 1310, a plunger 1340, a plunger drive mechanism 1358 (shown schematically in FIGS. 54 and 55), and a pressure sensor 1356 (shown schematically in FIGS. 54 and 55).

[0520] Referring to FIG. 55, the barrel 1310 includes a barrel passage 1320. The passage 1320 is longitudinally aligned with the axis A-A and extends rearwardly from a front end 1320A to an opposite rear end.

[0521] 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 the extending direction E12 and the opposite retracting direction E13.

[0522] The plunger drive mechanism 1358 is selectively operable to drive the plunger 1340 in each of the extending direction E12 and the retracting direction E13. The plunger drive mechanism 1358 may be a linear drive mechanism. The plunger drive mechanism 1358 may comprise an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes an electric motor. In some embodiments, the plunger drive mechanism 1358 is manually operable and does not include an actuator. For example, the plunger member 1340 may be configured to be pushed and pulled using a manual extension, lever, knob, or other feature.

[0523] The tip adapter 1314 is configured to removably secure the pipette tip 1360 to the end 1300A of the dispenser 1300, similar to that described above with respect to the tip adapter 156.

[0524] Referring to FIGS. 54 and 56, the PD pipette tip 1360 comprises a tubular tip body 1362 and a piston unit 1380 slidably mounted within the tip body 1362. The piston unit 1380 is slidable between an extended or standby position (FIG. 54) and a retracted position (e.g., FIG. 55). In some embodiments, the pipette tip 1360 further comprises an indexing mechanism 1375.

[0525] Referring to FIG. 56, the chip body 1362 extends from a distal end 1362A to a proximal end 1362B. The chip body 1362 includes a front portion 1364A and a rear portion 1364B that integrally define a combined volume or body passageway 1370. The front portion 1364A defines a front chamber or chip passageway 1370A. The rear portion 1364B defines a rear chamber 1370B (FIG. 54) and an intermediate chamber 1370C (FIG. 54) between the chip passageway 1370A and the rear chamber 1370B. The chip passageway 1370A and the chambers 1370B, 1370C each form a part of the passageway 1370. The rear portion 1364B includes an attachment portion 1364D and defines an interface opening 1368. A chip or dispensing orifice 1366 is defined at the distal end 1362A. The passageway 1370 terminates at the interface opening 1368 and the dispensing orifice 1366.

[0526] Also, a pressure relief port 1372 is provided in fluid communication with the intermediate chamber 1370C. The pressure relief port 1372 may be adapted to vent to the ambient atmosphere.

[0527] The piston unit 1380 includes a piston 1382 and a seal member 1388. The piston 1382 and the seal member 1388 may be configured as a single member forming the piston unit 1380 as a single member, or may be separate components joined to form the piston unit 1380 as an assembly of components.

[0528] 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 member. In some embodiments, the base 1384, the shaft 1385, and the rear extension 1386 integrally form a single piece member.

[0529] 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 disposed at or near the dispensing orifice 1366 when the piston 1382 is in the standby or extended position. The front side of the base 1384 may have a convex or undulating shape so as to conform to the opposing profile of the chip body 1362. A pressure relief passage 1384A is defined in the base 1384.

[0530] The exemplary seal member 1388 is a generally disk-shaped body or portion. The seal member 1388 is fixed (i.e., attached or integrated) to the piston 1382 at the proximal end 1382B of the extension 1386. The seal member 1388 has an annular outer peripheral sealing edge 1388A.

[0531] The piston 1382 and the seal member 1388 may be integrally formed (e.g., molded or co-molded), or may be formed separately and then attached to each other. In some embodiments, the piston 1382 and the seal member 1388 form a single member or assembly. In some embodiments, the piston 1382 and the seal member 1388 integrally form a single unitary member.

[0532] In some embodiments, the piston 1382 and the seal member 1388 are formed of the same material. In some embodiments, the piston 1382 and the seal member 1388 are formed of different materials. In some embodiments, the piston 1382 is formed of a material harder than the material of the seal member 1388. For example, while the seal member 1388 may be formed of an elastomer or a thermoplastic elastomer, the piston 1382 may be formed of a thermoplastic resin. Suitable materials for the piston 1382 include, but are not limited to, polyethylene (PE). Suitable materials for the seal member 1388 include, but are not limited to, silicone. As an alternative or addition to the seal member 1388, other types of seals (e.g., O-rings) may be used.

[0533] Referring to FIGS. 54 and 58, the outer peripheral sealing edge portion 1388A slidably engages with the inner wall surface 1362D of the rear portion 1364B to form a sliding seal 1389 between the piston unit 1380 and the chip body 1362. The sliding seal 1389 is axially slidable along the axis P6-P6 with respect to the chip body 1362. The seal member 1388 and the seal 1389 divide, separate, and fluid-seal the rear chamber 1370B from the intermediate chamber 1370C.

[0534] In use, the seal 1389 translates with the body 1362 together with the seal member 1388 and the piston 1382. Naturally, when the seal 1389 translates parallel to the body 1362 along the axis P6-P6, correspondingly, the boundaries and volumes of the intermediate chamber 1370C and the rear chamber 1370B change. That is, when the piston unit 1380 translates in the direction E12, the volume of the rear chamber 1370B increases and the volume of the intermediate chamber 1370C decreases. When the piston unit 1380 translates in the direction E13, the volume of the rear chamber 1370B decreases and the volume of the intermediate chamber 1370C increases.

[0535] Referring to 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 chip body 1362, and a second indexing feature in the form of protrusions or annular ribs 1387 formed on the base 1384. The grooves 1377 and the ribs 1387 are relatively arranged and configured such that the rib 1387 can be received in each groove 1377 to hold the piston 1382 in a corresponding axial position relative to the chip body 1362, while (upon application of sufficient force) disengaging from the groove 1377 to axially reposition the piston 1382 relative to the chip body 1362. For example, the chip body 1362 and / or the rib 1387 may be formed of an elastically deformable material.

[0536] The grooves 1377 are continuously distributed along the axis P6 - P6. In some embodiments, the grooves 1377 have a substantially uniform pitch W14 (FIG. 57) between adjacent grooves 1377. In some embodiments, the grooves 1377 have a pitch W14 in the range of 0.05 mm to 0.5 mm.

[0537] In some embodiments, the set 1377A of grooves includes at least 10 grooves 1377. In some embodiments, the number of grooves 1377 in the set 1377A is in the range of about 10 to 400.

[0538] Of course, the first and second indexing features may be in other forms. For example, an annular groove may be provided in the base 1384 instead of the rib 1387, and a series of annular ribs may be provided on the chip body 1362 to be received in the annular groove of the base 1384. The grooves 1377 may be defined between upright annular ribs 1377B or may be in the same plane as the inner diameter of the inner wall 1362C.

[0539] The liquid treatment system 10 and the dispensing system 1301 may be used as follows according to some methods to aspirate and / or dispense one or more liquid samples.

[0540] Generally, the PD pipette tip 1360 is mounted on the dispenser 1300. The chip body 1362 forms an airtight and pressuretight seal with the chip adapter 1314 such that the rear chamber 1370B is airtight and pressuretight sealed.

[0541] By driving the plunger 1340 to displace the air volume in the dispenser passage 1320, correspondingly, the pressure in the dispensing channel 1302 and the rear chamber 1370B (which is in fluid communication with the dispensing channel 1302) is changed. Due to the change in the pressure in the rear chamber 1370B, the piston unit 1380 is pulled in the retraction direction E13 (in response to the negative pressure change in the rear chamber 1370B), or the piston unit 1380 is pushed in the extension direction E12 (in response to the positive pressure change in the rear chamber 1370B). The piston assembly 1380 is shown in its standby or fully extended position in FIG. 54 and in the retracted position in FIG. 55.

[0542] When the piston unit 1380 is pulled in the retraction direction E13, the shaft 1385 is displaced in the direction E13 with respect to the front portion 1364A, so that the fluid volume in the chip passage 1370A expands. Due to this expansion, a negative pressure is generated in the chip passage 1370A, and the liquid volume LV of the liquid sample LS is sucked into the chip passage 1370A through the orifice 1366.

[0543] When the piston unit 1380 is pushed in the extension direction E12, the shaft 1385 is displaced in the direction E12 with respect to the front portion 1364A, so that the fluid volume in the chip passage 1370A is displaced or contracted. Due to this contraction, a positive pressure is generated in the chip passage 1370A, and the liquid volume LV of the liquid sample LS is expelled or dispensed from the chip passage 1370A through the orifice 1366.

[0544] Therefore, in response to the negative pressure in the rear chamber 1370B, the piston 1382 moves parallelly away from the chip orifice 1366 rearward (in the direction E13), thereby generating a negative pressure at the chip orifice 1366 and sucking the liquid through the chip orifice 1366 into the positive displacement pipette tip 1360.

[0545] In response to the positive pressure in the rear chamber 1370B, the piston 1382 moves parallelly forward (in the direction E12) toward the chip orifice 1366, thereby generating a positive pressure in the chip passage 1370A and expelling the liquid from the positive displacement pipette tip 1360 through the chip orifice 1366.

[0546] Naturally, the piston unit 1380 is operatively coupled to the drive mechanism of the dispenser 1300 not by a direct mechanical engagement or linkage between the plunger and the piston 1382, but via the air cushion AC in the dispensing channel 1302 and the rear chamber 1370B. This intervening air cushion AC exists and is maintained between the distal end 1300A of the dispenser 1300 and the piston unit 1380.

[0547] The pressure relief passage 1384A allows air to flow in and out of the intermediate chamber 1370C in front of the base 1384 when the base 1384 moves parallelly. The pressure relief port 1372 allows air to flow in and out of the intermediate chamber 1370C when the seal 1389 moves parallelly. In this way, the pressure in the intermediate chamber 1370C can be maintained substantially constant (e.g., ambient pressure) so that the pressure fluctuations in the intermediate chamber 1370C do not prevent the displacement of the piston unit 1380.

[0548] During operation, the indexing system 1375 serves to stop the displacement of the piston 1380 at a defined axial discrete position relative to the chip body 1362. That is, the indexing system 1375 moves the piston 1380 stepwise along the axis P6 - P6 from one groove 1377 to the next. This stepwise movement can make it possible or certain for the pipette tip 1360 to dispense or aspirate a known discrete volume for each step. The resolution or accuracy of the dispensed volume can be determined by the number of provided steps (e.g., grooves). In some embodiments, the grooves 1377 are equidistantly spaced so that the discrete volumes for each step are substantially equal.

[0549] When an indexing system 1375 as disclosed herein is provided in the pipette tip 1360, the pressure change applied by the dispenser 1300 to displace the piston 1382 needs to be sufficient to resolve the engagement or interlock between the indexing features (e.g., ribs 1387 and the grooves 1377 in which the ribs 1387 are received). In some embodiments, the controller 20 operates the dispenser 1300 to deliver pressure pulses to the rear chamber 1370B that are each sufficient to move the piston 1382 by one step.

[0550] 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 dispensing channel 1302. The controller 20 may continuously monitor the pressure in the dispensing channel 1302. In some embodiments, the controller 20 uses a dual metering flow sensor (e.g., dual metering flow sensor 1280) as described herein to monitor the pressure in the dispensing channel 1302.

[0551] As described above, the dispensing system 1301 sucks a liquid sample by reducing the pressure in the dispensing channel 1302 and dispenses the liquid sample by increasing the pressure in the dispensing channel 1302. However, the pressure in the dispensing channel 1302 may vary depending on other operations or states in this procedure, for example, as described above with respect to the dispensing system 101.

[0552] Referring to FIGS. 60-75, these illustrate an exemplary positive displacement (PD) pipette tip 1440 according to other embodiments of the present technology. The PD pipette tip 1440 can form a dispensing system when used in combination with a dispenser. An exemplary dispensing system 1401 according to an embodiment of the present technology is shown in FIGS. 60-75, which includes a PD pipette tip 1440 and a dispenser 1400.

[0553] The dispensing system 1401 can suck and dispense a liquid volume within a liquid processing system. The dispensing system 1401 may be adapted to be used in place of the dispensing system 101, for example, in an automated liquid processing system 10 (FIG. 1). However, it is understood that the disclosed methods, systems, and devices are not limited to the liquid processing system 10 or its use therein, and the present disclosure is applicable to other systems and applications where the sucking and / or dispensing of a liquid volume is desired.

[0554] The PD pipette tip 1440 is not limited to use with the dispenser 1400. The PD pipette tip 1440 may be adapted to be used with any suitable positive displacement type dispenser. The PD pipette tip 1440 may be adapted to be used, for example, in place of the air displacement pipette tip 160.

[0555] Referring to FIG. 60, the dispensing system 1401 includes one or more dispensers 1400. The dispenser may be mounted on the dispensing module 30 (FIG. 1). The dispensers 1400 may be similarly configured and operate in the same manner. Naturally, the following description regarding a representative one of the dispensers 1400 may equally apply to each of the dispensers 1400. When a plurality of dispensers 1400 are provided, these dispensers 1400 may operate independently of each other or may operate in cooperation. For the purpose of detailed explanation, only a single dispenser will be described below.

[0556] The dispensing system 1401 includes one or more of the dispenser 1400, the controller 20, and the PD pipette tip 1440. The pipette tip 1440 is removable and replaceable with respect to the dispenser 1400 and may be a virtually disposable or consumable part of the dispensing system 1401.

[0557] The dispenser 1400 may be configured and operable in the same manner as described herein with respect to, for example, the dispenser 600.

[0558] Referring to FIGS. 60 and 66, it can be understood that the dispenser 1400 has a longitudinal axis A-A and a distal end 1400A. The dispenser 1400 includes a dispensing orifice 1404, a tubular barrel 1410, a tubular tip adapter 1416, a driver 1420 (in the form of a plunger), a plunger drive mechanism 1424, and a discharge system 1431. The barrel 1410 includes a dispensing shaft 1414 that terminates at the distal end 1400A. The tip adapter 1416 is mounted or formed at the distal end 1400A. The dispensing orifice 1404 is disposed at the distal end 1400A.

[0559] Referring to FIG. 66, the barrel 1410 includes a barrel passage 1414. The passage 1412 is longitudinally aligned with the axis A-A and extends rearward from the distal end 1400A to the opposite rear end.

[0560] The plunger 1420 functions as a driver and is mounted in the passage 1412 so as to be slidably translatable with respect to the barrel 1410 along the plunger axis P7 - P7 in the extending direction E14 and the opposite retracting direction E16 (FIG. 66).

[0561] The plunger 1420 includes an integral piston engagement or coupling feature 1422 (FIG. 66) at its tip 1420A. In some embodiments, as shown, the piston coupling feature 1422 includes a slot 1422A. The piston coupling feature 1422 may be configured and operable in a manner similar to that described herein with respect to, for example, the piston coupling feature 646.

[0562] The plunger drive mechanism 1424 is selectively operable such that the plunger 1420 is driven to translate in the extending direction E14 and the retracting direction E16, respectively. The plunger drive mechanism 1424 may be a linear drive mechanism. The plunger drive mechanism 1424 may comprise an actuator and may be any suitable type of linear drive mechanism. In some embodiments, the actuator includes an electric motor. In some embodiments, the plunger drive mechanism 1424 is manually operable and does not include an actuator. For example, the plunger member 1424 may be configured to be pushed and pulled using a manual extension portion, lever, knob, or other feature.

[0563] The tip adapter 1416 is configured to removably secure the pipette tip 1440 to the end 1400A of the dispenser 1400, similar to that described above with respect to the tip adapter 156.

[0564] Referring to FIGS. 60 and 66, the discharge system 1431 includes a discharge member or sleeve 1430 and a discharge drive mechanism 1432. The discharge sleeve 1430 is attached around the barrel 1410 so as to be slidably translatable with respect to the barrel 1410 along the discharge axis P8-P8 in the extending direction E18 and the opposite retracting direction E20. The discharge axis P8-P8 may be coaxial with the plunger axis P7-P7.

[0565] Referring to FIGS. 61 to 65, the PD pipette tip 1440 includes a tubular tip body 1450, a piston 1460 slidably mounted in the tip body 1450, and an integral piston restraint mechanism 1471. The piston restraint mechanism 1471 includes an interlock insert 1470.

[0566] Referring to 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 portion 1452A, an intermediate portion 1452B, and a rear portion 1452C. The front portion 1452A defines a front chamber or tip passage 1455A. The rear portion 1452C defines a rear chamber 1455C. The intermediate portion 1452B defines an intermediate chamber 1455B between the tip passage 1455A and the rear chamber 1455C. The tip passage 1455A and the chambers 1455B, 1455C together form a combined volume or tip body passage 1455.

[0567] The rear portion 1452C includes a mounting portion 1455D and defines an interface opening 1458. A tip or dispensing orifice 1456 is defined at the distal end 1450A. The passage 1455 terminates at the interface opening 1458 and the dispensing orifice 1456.

[0568] The chip body 1450 may be formed of any suitable material. In some embodiments, the chip body 1450 is formed of a polymer. In some embodiments, the chip body 1450 is formed of a thermoplastic resin. Suitable materials for the chip body 1450 include, but are not limited to, polyethylene (PE). In some embodiments, the chip body 1450 is a rigid single member. In some embodiments, the chip body 1450 is a single member.

[0569] The piston 1460 is slidable relative to the chip body 1450 along the piston axis P9 - P9 (FIG. 62) in the extending direction E22 and the opposite retracting direction E24 between the extended or standby position (FIGS. 62 and 66) and the retracted position (e.g., FIG. 70).

[0570] The piston 1460 (FIG. 64) extends from a distal end 1460A to a 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 interlock feature or flange 1466, and an integral plunger engagement or coupling feature 1468.

[0571] The piston shaft 1462 extends rearward from the distal end 1460A. The annular sealing rib 1462A is disposed at the distal end 1460A and forms a moving seal with the inner diameter of the front passage 1455A. In some embodiments, the distal end 1460A is disposed at or near the dispensing orifice 1456 when the piston 1460 is in the standby or extended position.

[0572] The intermediate portion 1463 extends rearward from the proximal end of the piston shaft 1462. In some embodiments, the outer diameter of the intermediate portion 1463 is larger than the outer diameter of the piston shaft 1462.

[0573] The rear extension portion 1464 extends rearward from the proximal end of the intermediate portion 1463. In some embodiments, the outer diameter of the rear extension portion 1464 is larger than the outer diameter of the intermediate portion 1463.

[0574] The plunger coupling feature 1468 is disposed or formed at the proximal end of the rear extension portion 1464. The plunger engagement feature 1468 is received in the slot 1422A and is configured to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468. The illustrated plunger coupling feature 1468 includes two or more opposing elastically deformable legs 1468A that are received in the slot 1422A and are configured to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468. However, any suitable structure that allows for a releasable coupling of the plunger coupling feature 1468 to the piston coupling feature 1422 can be used for the plunger coupling feature 1468.

[0575] For example, the plunger coupling feature 1468 may include two or more opposing elastically deformable legs 1468A that are received in the slot 1422A and are configured to releasably secure the piston coupling feature 1422 to the plunger coupling feature 1468.

[0576] The flange 1466 is annular and is axially disposed between the plunger coupling feature 1468 and the intermediate portion 1463. The flange 1466 projects radially outward from the rear extension portion 1464. In some embodiments, the flange 1466 is substantially concentric with the axis P9-P9. In some embodiments, the flange 1466 has a width W20 (FIG. 64) in the range of about 0.5 mm to 3 mm.

[0577] Piston 1460 may be formed of any suitable material. In some embodiments, piston 1460 is formed of a polymer. In some embodiments, piston 1460 is formed of a thermoplastic resin. Suitable materials for piston 1460 may include plastics, thermoplastic resins, or heat-resistant thermoplastic resins (e.g., polyetheretherketone (PEEK)). In some embodiments, piston shaft 1462, intermediate portion 1463, rear extension 1464, flange 1466, and plunger coupling feature 1468 form a rigid single member. In some embodiments, piston shaft 1462, intermediate portion 1463, rear extension 1464, flange 1466, and plunger coupling feature 1468 integrally form a single member.

[0578] As shown in FIG. 62, interlock insert 1470 is housed in rear chamber 1455C. Interlock insert 1470 is fixed in rear chamber 1455C to prevent relative axial displacement between interlock insert 1470 and chip body 1450.

[0579] Interlock insert 1470 (FIG. 65) has a distal end 1470A and an opposite proximal end 1470B. Interlock insert 1470 is tubular and includes a front portion 1472A (at end 1470A) that defines a front opening 1474A, and a rear portion 1472B (at end 1470B) that defines a rear opening 1474B. Also, a passage 1474 extends from opening 1474A to opening 1474B. Also, a pair of opposing slots 1475 extend through front portion 1472A from rear portion 1472B towards distal end 1470A.

[0580] The interlock 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. Also, each proximal end 1476B is connected to the rear portion 1472B such that the legs 1476 are cantilevered from the rear portion 1472B, and each distal end 1476A is a free end. The legs 1476 are circumferentially spaced from each other about axis P9 - P9 and are circumferentially aligned with the slot 1475.

[0581] The interlock insert 1470 may be formed of any suitable material. In some embodiments, the interlock insert 1470 is formed of a polymer and / or a synthetic polymer. In some embodiments, the interlock insert 1470 is formed of a thermoplastic resin. Suitable materials for the interlock insert 1470 include, but are not limited to, polyvinyl chloride (PVC). In some embodiments, the interlock insert 1470 is a rigid single member. In some embodiments, the interlock insert 1470 is a single piece member.

[0582] The interlock insert 1470 may be fastened or joined to the chip body 1450 (e.g., by an adhesive or co - molding). In other embodiments, the interlock insert 1470 is integrally formed with the chip body 1450. In some embodiments, the interlock insert 1470 and the chip body 1450 form an integral single member or a single piece member. In other embodiments, the interlock insert 1470 is fixed to the chip body 1450 by cooperating mechanical features on the interlock insert 1470 and the chip body 1450.

[0583] The piston restraint mechanism 1471 is operable to selectively limit movement between the piston 1460 and the chip body 1450. The piston restraint mechanism 1471 includes a flange 1466 and a latch leg 1476 of the interlock insert 1470. The latch leg 1476 is positionable in each of a latch position (as shown in FIGS. 62 and 66) and a non-latch position (as shown in FIG. 68). The piston restraint mechanism 1471 is positionable in each of a restraint configuration (as shown in FIGS. 62 and 66) and a release configuration (as shown in FIG. 68).

[0584] When the piston restraint mechanism 1471 is in the restraint configuration, the latch leg 1476 is in the latch position and, in conjunction with the flange 1466, prevents axial displacement of the piston 1460 in the retraction direction E24 beyond a defined position relative to the chip body 1450.

[0585] When the piston restraint mechanism 1471 is in the release configuration, the latch leg 1476 is not in conjunction with the flange 1466, thus permitting axial displacement of the piston 1460 in the retraction direction E24 beyond a defined position relative to the chip body 1450. In some embodiments, as shown, the piston restraint mechanism 1471 does not limit movement between the piston 1460 and the chip body 1450 when in the release configuration.

[0586] In the latch position, the legs 1476 are angled, tapered, or angled radially inward such that the axis P10 - P10 of each leg 1476 forms an angle AL (FIG. 65) with respect to the chip axis P9 - P9. In the latch 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 ranges from about 2 to 30 degrees.

[0587] In some embodiments, the insert 1470 is configured such that at the latch position, the legs 1476 are elastically bent, folded, or deflected outwardly (i.e., in the direction E28 (FIG. 65)) from their relaxed positions. As a result, the legs 1476 continuously load the rear portion 1464 of the piston 1460, so that the distal end 1470A of the legs 1476 maintains alignment with the flange 1466.

[0588] In some embodiments, the legs 1476 are elastic along their lengths so as to be elastically bent, folded, or deflected from the latch position to the non-latch position. In some embodiments, the proximal end 1476B is elastically connected to the rear portion 1472B such that the legs 1476 can be elastically deflected around the connection portion from the latch position to the non-latch position.

[0589] The liquid processing system 10 and the dispensing system 1401 may be used as follows according to some methods to aspirate and / or dispense one or more liquid samples.

[0590] First, as shown in FIGS. 62 and 66, the PD pipette tip 1440 is disposed in a constrained configuration. The tip 1440 may be held, for example, in a pipette tip supply rack.

[0591] If the plunger 1420 has not yet retracted, it retracts (as shown in FIG. 66). As shown in FIG. 66, the dispenser shaft 1414 moves in the insertion direction I to insert the distal end 1400A of the dispenser into the attachment portion 1455D. As shown in FIG. 67, the dispenser shaft 1414 is further inserted into the chip body 1450 until the chip adapter 1416 engages the leg portion 1476. As shown in FIG. 68, the dispenser shaft 1414 is similarly further inserted until the chip adapter 1416 reaches a specified depth within the rear chamber 1455C. As shown in FIG. 68, the plunger 1420 may be retracted relative to the dispenser shaft 1414 to provide a gap between the piston 1460 and the distal end of the plunger 1420. When the chip adapter 1416 translates to the specified depth, the outer diameter of the chip adapter 1416 displaces or pushes the leg portions 1476 to pivot, fold, or deflect in the radially outward opposite direction E28 to their unlatch positions. Thus, as shown in FIG. 68, the chip 1440 is placed in its released configuration.

[0592] During insertion of the dispenser shaft 1414, the discharge sleeve 1430 is positioned far from the distal end 1400A or displaced in the retraction direction E20 relative to the barrel 1410 to create space for the chip body 1450. For example, the discharge sleeve 1430 may be driven in the retraction direction E20 by the chip body 1450 upon insertion of the dispenser shaft 1414.

[0593] Thereafter, as shown in FIG. 69, the plunger drive mechanism 1424 drives the plunger 1420 to translate in the extension direction E14 until the piston coupling feature 1422 interlocks or couples with the plunger coupling feature 1468. Thereby, the plunger 1420 is mechanically coupled to the piston 1460.

[0594] With the chip 1440 in the released configuration and the plunger 1420 and piston 1460 coupled, suction and dispensing can be performed using the dispenser 1400 and the chip 1440, for example, as described herein with respect to the pipette tip 670 (FIG. 32). While the chip 1440 is maintained in the released configuration, the plunger 1420 is driven in directions E14 and E16 by the plunger drive mechanism 1424 to translate the piston 1460 in the chip passage 1455A.

[0595] When the piston 1460 is pulled in the retraction direction E24 by the plunger 1420, the piston shaft 1462 translates in the direction E24 relative to the front portion 1452A (for example, as shown in FIG. 70), so that the fluid volume in the chip passage 1455A expands. This expansion generates a negative pressure in the chip passage 1455A, and the liquid volume LV of the liquid sample LS is sucked into the chip passage 1455A through the orifice 1456.

[0596] When the piston 1460 is pushed in the extension direction E22 by the plunger 1420, the piston shaft 1462 translates in the direction E22 relative to the front portion 1452A (for example, as shown in FIG. 71), so that the fluid volume in the chip passage 1455A is displaced or contracted. This contraction generates a positive pressure in the chip passage 1455A, and the liquid volume LV of the liquid sample LS is discharged or dispensed from the chip passage 1455A through the orifice 1456.

[0597] If the use of the pipette tip 1440 is no longer required in the dispenser 1400, it may be removed from the dispenser 1400 as follows by using the piston restraint mechanism 1471.

[0598] Starting from the chip 1440 of the decompose structure and the plunger 1420 and piston 1460 coupled as shown in FIG. 71, while the plunger drive mechanism 1424 drives the plunger 1420 in the direction E14 with respect to the dispenser shaft 1414, the discharge drive mechanism 1432 translates the discharge sleeve 1430 in the extending direction E18 parallel to the dispenser shaft 1414. As a result, as shown in FIG. 72, the chip body 1450 and the piston 1460 are pushed forward F with respect to the dispenser shaft 1414. Consequently, since the chip adapter 1416 slides out from between the legs 1476, the legs 1476 can elastically return radially E30 (by bending, pivoting, or folding, as shown in FIGS. 72 and 73).

[0599] In this way, until the chip 1440 and the dispenser 1400 reach the configuration shown in FIG. 73, the discharge sleeve 1430 and the plunger 1420 are driven. Thereby, the legs 1476 are returned to their latch positions and the chip 1440 is in its constrained configuration. In some embodiments, the plunger 1420 translates in the extending direction E14 together with the discharge sleeve 1430 such that the distal end 1476A of the legs 1476 closes around the piston 1460 behind the flange 1466 to maintain the relative axial arrangement between the flange 1466 and the distal end 1476A.

[0600] With the chip 1440 in the constrained configuration and the plunger 1420 and piston 1460 coupled as shown in FIG. 73, the plunger drive mechanism 1424 drives the plunger 1420 to translate it in the retracting direction E16 with respect to the dispenser shaft 1414 and the chip body 1450, as shown in FIG. 74. The engagement between the legs 1476 and the flange 1466 prevents the piston 1460 from translating in the direction E24 (FIG. 70) with respect to the chip body (i.e., the legs 1476 hold the piston 1460 in place). As a result, as shown in FIG. 74, the piston coupling feature 1422 is separated from the plunger coupling feature 1468 (i.e., the plunger 1420 is detached from the piston 1460).

[0601] Thereafter, as shown in FIG. 75, the discharge drive mechanism 1432 moves the discharge sleeve 1430 parallel to the dispensing shaft 1414 in the extending direction E18 with respect to the dispensing shaft 1414, thereby pushing out the chip body 1450 (and thus the chip 1440) from the dispenser 1400 forward in the F direction.

[0602] In other embodiments, the latch leg 1476 is integrally formed with the chip body 1450. In some embodiments, integral latches or latch features other than the latch leg 1476 are provided on the pipette tip to selectively restrain the piston 1460. Each latch may be configured as a tab, a protrusion, or a sleeve.

[0603] Other designs of piston coupling features and plunger coupling features may be used instead of the piston coupling feature 1422 and the plunger coupling feature 1468 to releasably join the plunger to the piston.

[0604] In some embodiments, the interlock features 1466, 1476 may be provided with other designs or configurations.

[0605] In some embodiments, the PD pipette tip 1440 is provided with a vent orifice 1452V (FIG. 63) or other vent passage to prevent overpressure (positive or negative pressure) in the rear chamber 1455C that could interfere with the operation of the dispenser or cause damage to the dispenser (e.g., a pressure sensor).

[0606] In this specification, the present technology has been described with reference to the accompanying drawings showing exemplary embodiments of the present technology. In the drawings, the relative sizes of regions or features may be exaggerated for clarity. However, the present technology can be implemented in many different forms and should not be construed as limited to the embodiments described 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.

[0607] In this specification, terms such as first, second, etc. may be used for the description of various elements, components, regions, layers, and / or sections. However, it should be understood that these elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only 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 described below may also be referred to as the second element, component, region, layer, or section without departing from the teachings of the present technology.

[0608] In this specification, spatially relative terms such as "beneath", "below", "lower", "above", "upper", etc. may be used to facilitate the description of the relationship between one element or feature and another element or feature as shown in the drawings. It should be understood that the spatially relative terms are intended to include different orientations of the device during use or operation in addition to the orientation shown in the drawings. For example, if the device in the drawing is turned over, an element described as "below" or "beneath" another element or feature will be oriented "above" the other element or feature. Therefore, the exemplary term "below" may include both upward and downward orientations. In this specification, the device may have different orientations (such as other orientations like a 90° rotation), and accordingly, the spatially relative descriptions may be interpreted accordingly.

[0609] As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly dictates otherwise. As used herein, the terms "include" and / or "including" and / or "comprise" and / or "comprising" specify the presence of the stated features, integers, steps, operations, elements, and / or components, but are not to be construed as precluding the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof. When reference is made herein to an element being "connected" or "coupled" to another element, it is understood that the element can be directly connected or coupled to the other element or intervening elements may be present. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0610] The term "automatically" means that the operation is substantially performed and may be fully performed without human or manual input and may be directed or executed by a program.

[0611] The term "programmatically" represents an operation that is electronically directed and / or primarily executed by a computer program module, code, and / or instructions.

[0612] The term "electronically" includes both wireless and wired connections between components.

[0613] Those skilled in the art will be able to make many changes and improvements without departing from the spirit and scope of the present disclosure, given the benefits thereof. Therefore, it should be understood that the illustrated embodiments are described for illustrative purposes only and should not be construed as limiting the present invention as defined by the following claims. For this reason, the following claims should be construed to include not only the literal combinations of elements described, but also all equivalent elements for performing substantially the same function in substantially the same way to obtain substantially the same result. From the above, it is understood that the claims include, in addition to the specifically illustrated and described ones, those conceptually equivalent and those incorporating the essential ideas of the present invention.

Claims

1. Dispensing channel and A first plunger mechanism capable of operating to aspirate or distribute liquid by changing the pressure in the dispensing channel, A second plunger mechanism capable of operating to change the pressure in the dispensing channel to aspirate or distribute the liquid, Dispenser including An automated dispensing system equipped with the following features.

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

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

4. The dispensing system includes a dispensing orifice and a liquid collection volume. The automatic dispensing system according to claim 1, wherein the first plunger mechanism and the second plunger mechanism are operable to change the pressure in the dispensing channel to draw the liquid into the liquid collection volume through the dispensing orifice or to distribute the liquid from the liquid collection volume through the dispensing orifice.

5. The automated dispensing system according to claim 4, comprising a pipette tip detachably coupled to the dispenser, wherein the pipette tip includes the liquid collection volume and the dispensing orifice.

6. The first plunger mechanism includes a first chamber and a first plunger, and the first plunger mechanism is operable to move the first plunger in the first chamber to change the pressure in the dispensing channel. The automatic dispensing system according to claim 1, wherein the second plunger mechanism includes a second chamber and a second plunger, and the second plunger mechanism is operable to move the second plunger in the second chamber to change the pressure in the dispensing channel.

7. The first plunger mechanism includes a first plunger actuator that is operable to move the first plunger in the first chamber, The second plunger mechanism includes a second plunger actuator that is operable to move the second plunger in the second chamber, The automatic dispensing system according to claim 6, wherein the automatic dispensing system includes a controller configured to automatically programmatically control the first plunger actuator and the second plunger actuator.

8. The first plunger mechanism is configured to move the first plunger in parallel along the first plunger axis, The second plunger mechanism is configured to move the second plunger in parallel along the second plunger axis, The first plunger has a first cross-sectional area in a plane perpendicular to the axis of the first plunger, The second plunger has a second cross-sectional area in a plane perpendicular to the axis of the second plunger, The automatic dispensing system according to claim 6, wherein the second cross-sectional area is larger than the first cross-sectional area.

9. The first plunger mechanism is configured to move the first plunger in parallel within the first chamber, The second plunger mechanism is configured to move the second plunger in parallel within the second chamber. The first plunger displaces the air volume in the first chamber at a first air volume displacement rate per unit translation, The second plunger displaces the air volume in the second chamber at a second air volume displacement rate per unit translation, The automatic dispensing system according to claim 6, wherein the second air volume displacement rate per unit translation is greater than the first air volume displacement rate per unit translation.

10. The automatic dispensing system according to claim 6, wherein the dispenser includes a valve for selectively controlling fluid communication between the second chamber and a port to the atmosphere.

11. The automatic dispensing system according to claim 6, wherein the dispenser includes at least one valve for selectively controlling fluid communication between the second chamber and the dispensing channel.

12. The automatic dispensing system according to claim 1, further comprising a controller configured to automatically control the first plunger mechanism and the second plunger mechanism by program.

13. The automatic dispensing system according to claim 12, comprising a pressure sensor coupled to the dispensing channel, wherein the controller is configured to receive a dispensing channel pressure signal from the pressure sensor indicating the pressure in the dispensing channel.

14. The dispenser includes a valve that selectively controls the fluid communication between the second plunger mechanism and the dispensing channel, The automatic dispensing system according to claim 12, wherein the controller is configured to automatically control the valve by program.

15. The first plunger mechanism includes a first chamber and a first plunger, The first plunger mechanism is operable to move the first plunger within the first chamber in order to displace or restore the air volume within the first chamber and thereby change the pressure in the dispensing channel. The second plunger mechanism includes a second chamber and a second plunger, The second plunger mechanism is operable to move the second plunger within the second chamber in order to displace or restore the air volume within the second chamber and thereby change the pressure in the dispensing channel. The first plunger mechanism and the second plunger mechanism are capable of operating independently of each other to move the first plunger and the second plunger in order to change the pressure in the dispensing channel. The dispenser includes a valve that can be operated to selectively control the fluid communication between the second chamber and the port to the atmosphere. The automated dispensing system according to claim 1.

16. A controller configured to control the valve between a first valve state in which the valve prevents the flow of fluid between the second chamber and the dispensing channel, and a second valve state in which the valve allows the flow of fluid between the second chamber and the dispensing channel, The controller is configured to operate the dispenser in each of the first and second aspiration modes. In the first suction mode, the controller sets the valve to the first valve state, and while the valve remains in the first valve state, operates the first plunger mechanism to move the first plunger in the first chamber, thereby generating negative pressure in the dispensing channel. In the second suction mode, the controller sets the valve to the second valve state, and while the valve remains in the second valve state, operates the second plunger mechanism to move the second plunger in the second chamber, thereby generating negative pressure in the dispenser. The automated dispensing system according to claim 15.

17. The first plunger mechanism includes a first chamber and a first plunger, The first plunger mechanism is operable to move the first plunger in the first chamber in order to change the pressure in the dispensing channel. The second plunger mechanism includes a second chamber and a second plunger, The second plunger mechanism is operable to move the second plunger in the second chamber in order to change the pressure in the dispensing channel. The first plunger mechanism and the second plunger mechanism are capable of operating independently of each other to move the first plunger and the second plunger in order to change the pressure in the dispensing channel. The aforementioned dispenser is Port to the atmosphere, A valve that selectively controls the fluid communication between the second chamber and the port so as to selectively expel the air transferred from the second chamber by the second plunger into the atmosphere through the port, The automatic dispensing system according to claim 1, comprising:

18. The automatic dispensing system includes a controller configured to automatically control the first plunger mechanism and the second plunger mechanism by program, The first plunger mechanism and the second plunger mechanism are capable of operating independently of each other to change the pressure in the dispensing channel. The controller is configured to aspirate a liquid sample volume. The first plunger mechanism is automatically controlled by a program to aspirate the first portion of the liquid sample volume, and The second plunger mechanism is automatically controlled by a program to aspirate the second portion of the liquid sample volume. The automated dispensing system according to claim 1.

19. A method for operating an automated dispensing system, With at least one control circuit, The first plunger mechanism of the dispenser of the automatic dispensing system is operated to change the pressure in the dispensing channel of the dispenser to aspirate or distribute liquid, The second plunger mechanism of the dispenser is operated to change the pressure in the dispensing channel and aspirate or distribute the liquid, A method that includes performing an action that includes an action.

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