Patent Description:
In general, conventional liquid handling systems comprise a plurality of pipette modules and associated processor-controlled, motor-driven mechanical sub-assemblies. The mechanical sub-assemblies include pipette supporting frames that move along a z-axis raising and lowering one or more pipette tips relative to the containers holding the liquid to be aspirated. Due to these interrelated mechanisms, the structure of liquid handling systems is very complex. The pipette modules need to move in the z-axis to find the liquid level as well as aspirate and dispense liquids (during which the liquid level changes). Since the mass of the pipette modules are large in general, and since there is backlash between moving parts due to manufacturing tolerances, longitudinal movements produce considerable strain on the mechanisms.

<CIT>), hereafter referred to as "Colin" is directed to an apparatus and method for aspirating a biological fluid contained in a specimen holder. More specifically, Colin discloses a pipette having a cylindrical body containing a piston, the movement of which provides for both the suction and discharge of the fluid to be aspirated. In use, as a mechanism to which the pipette is attached brings a tip of the free end of the pipette close to the surface of the biological fluid, movement of the piston expels from the tip a continuous and constant flow of air. When an over-pressure of the air in the tip is determined to be greater than a predetermined threshold as the tip approaches the liquid surface, the tip end is deemed to be in flush contact with the liquid surface, the flow of air from the tip is stopped as is movement of the tip, and aspiration of the fluid is initiated. An inherent and undesirable feature of the Colin device and method is that movement of the inlet and outlet air flow for the liquid surface detection is set independent of the speed at which the pipette tip moves.

<CIT>,), hereafter referred to as "Jessop", is directed to an apparatus and method for aspirating a liquid contained in a sample container and dispensing the aspirated liquid thereafter. More specifically, Jessop discloses an aspiration control system for a liquid dispensing apparatus comprising a probe for receiving a liquid to be aspirated from the sample container and a piston chamber movable with the probe. A pressure line in fluid communication with the probe and the piston chamber provides a partial vacuum or a partial pressure, relative to atmospheric pressure, to the probe in response to movement of a piston in the piston chamber. The aspiration control system coordinates the actuation of a motor driving the movement of the probe and another motor driving the movement of the piston in response to the change in pressure sensed in the probe. Detection of the penetration of the air-liquid interface by the probe is achieved by repeated incremental aspiration of air and movement of the probe until a pressure drop of the air in the probe is determined to be greater than a predetermined threshold at which time the probe is deemed to have penetrated the liquid. An inherent and undesirable feature of the Jessop apparatus and method is that the elapsed time required by the repeated incremental aspiration and probe movement to detect and penetrate the liquid surface may limit the speed at which aspiration and dispensation of the liquid is achievable.

<CIT>), a liquid handling system (LHS) is disclosed. The machine includes a vertically (in Z axis direction) translatable integrated "fusion" head <NUM>, positioned above a Y axis direction translatable table <NUM>. The machine also shows a rotatable sample carrier of carousel <NUM> which can serially bring a plurality of samples into the position for processing by the fusion head <NUM>. The LHS is comprised of a pipette module in the form of x-y head <NUM> attached to the fusion head <NUM>. The x-y head is translatable in X axis direction by motor <NUM>. The x-y head can pick up disposable tip <NUM> from the carousel <NUM> and detect the liquid meniscus of the sample in the testing tube <NUM> located in the carousel <NUM>. The detection of the liquid meniscus is fulfilled by the pressure-sensor-approach under the control of a computer <NUM>.

The x-y head <NUM> is driven by motor <NUM> up and down along Z axis and horizontally by motor <NUM>. The piston block <NUM> is driven by motor <NUM> up and down for certain amount of aspiration or dispense of liquid. There is solenoid of <NUM> and plate <NUM> for tip removal of the x-y head. The x-y head is fully featured pipette that can pick up/remove tip and can detect the liquid meniscus of sample in a tube and can aspirate and dispense given amount of liquid.

There is a ganged pipette subassembly <NUM> in the fusion head <NUM>(multichannel head). The plunger rod <NUM> of the ganged pipettes is actuated by bar <NUM> simultaneously. The pipettes <NUM> are arranged in a row transverse to the axis of translation of table <NUM> (in X axis direction). It includes removable pipette tips <NUM>. The multiple pipettes in the subassembly <NUM> are not fully featured pipette. They cannot work independently because they are not translatable in Z direction independently.

It should be noted that the liquid handling in this device is a two steps approach. Firstly, the carousel <NUM> brings the sample serially to the fusion head <NUM>. The sample liquid in the testing tube <NUM> is aspirated by the x-y head <NUM> and then is transferred horizontally on the guide rails of <NUM> and <NUM> by means of stepper motor <NUM> to the vessels on mixing plate of <NUM> (with bar code) beneath the tip <NUM> of multichannel head <NUM> one by one. Secondly, the samples in the vessels are then processed by the pipette <NUM> arranged in a row transverse to the axis of the translation of table <NUM> (in X direction) simultaneously.

According to Leath's device, a fully featured pipette, i.e., the pipette in x-y head, needs a motion along Z axis driven by an actuator and a motion for piston driven by another actuator. The ganged pipettes <NUM> in the multichannel head <NUM> use less actuator in the price of losing some of the functionality as a pipette apparatus. For example, no independent Z axis direction for the ganged pipettes <NUM> makes it impossible to detect liquid meniscus independently. Therefore, ganged pipette <NUM> can only aspirate liquid from the tubes where the liquid levels must be all the same to each other.

The parallel use of the multiple fully featured independent pipettes (<NUM> pipettes or <NUM> pipettes), i.e., the pipette in x-y head, are not disclosed in this device. An independent Z axis is inevitable for an independent pipette module. For parallel use the multiple pipette (for examples, <NUM> or <NUM> pipette) design, multiple Z axis must be implemented. This is expensive and complicated.

Accordingly, for the reasons set forth above, there is a need in the art for precision control of the plurality of pipette modules and associated processor-controlled, motor-driven mechanical sub-assemblies comprising liquid handling systems.

The present invention is defined by a pipette module according to claim <NUM> and a liquid handling system according to claim <NUM>.

The foregoing summary, as well as the following detailed description of preferred embodiments of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, the drawings show embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown.

Reference will now be made in detail to embodiments of the invention, examples of which are illustrated in the accompanying drawings. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

As used in the description of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The words "and/or" as used herein refers to and encompasses any and all possible combinations of one or more of the associated listed items. The words "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

The words "right," "left," "lower" and "upper" designate directions in the drawings to which reference is made. The words "inwardly" and "outwardly" refer to directions toward and away from, respectively, the geometric center of the needle safety shield, and designated parts thereof. The terminology includes the words noted above, derivatives thereof and words of similar import.

Although the words first, second, etc., are used herein to describe various elements, these elements should not be limited by these words. These words are only used to distinguish one element from another. For example, a first cylinder could be termed a second cylinder, and, similarly, a second cylinder could be termed a first cylinder, without departing from the scope of the present invention.

As used herein, the words "if" may be construed to mean "when" or "upon" or "in response to determining" or "in response to detecting," depending on the context. Similarly, the phrase "if it is determined" or "if [a stated condition or event] is detected" may be construed to mean "upon determining" or "in response to determining" or "upon detecting [the stated condition or event]" or "in response to detecting [the stated condition or event]," depending on the context.

The following description is directed towards various embodiments of a integrated pipetting apparatus in accordance with the present invention.

Referring to the drawings in detail, where like numerals indicate like elements throughout, there is shown in <FIG> and <FIG> a first preferred embodiment of the pipette module, generally designated <NUM>, and hereinafter referred to as the "pipette module" <NUM> in accordance with the present invention. The pipette module <NUM> is for use in a liquid handling system <NUM> including a liquid-handling-system z-axis frame <NUM> and at least one container <NUM> with a container open end <NUM> having a predetermined container-open-end position <NUM> (R<NUM>) relative to the liquid-handling-system z-axis frame <NUM>. A liquid <NUM> in the at least one container <NUM> has a liquid surface <NUM> at an unknown liquid surface level <NUM> (R<NUM>) relative to the position of the container open end.

The pipette module <NUM> has a pipette-module frame <NUM> attachable to the liquid-handling-system z-axis frame <NUM>. A pipette-module translatory-motion frame <NUM> is attached to the pipette-module frame <NUM> and is movable with respect to the pipette-module frame <NUM> by a pipette-module motor <NUM>.

Further, the pipette module <NUM> has a pneumatic aspirator assembly <NUM> comprising a pipette-module cylinder <NUM> having a piston <NUM> movably disposed therein. A tube <NUM> is in fluid communication with the pipette-module cylinder <NUM>. The tube <NUM> terminates in a tip <NUM>. A pressure sensor <NUM> is provided and is in fluid communication with the cylinder <NUM>, the tube <NUM> and the tip <NUM>. The pipette-module cylinder <NUM>, the tube <NUM>, the tip <NUM> and the pressure sensor <NUM> are attached to the pipette-module translatory-motion frame <NUM> and are movable therewith. The piston <NUM> is fixedly attached to the pipette-module frame <NUM> by a piston rod <NUM>.

Still further, the pipette module <NUM> has a pipette-module controller <NUM> in electrical communication with the pipette-module motor <NUM> and the pressure sensor <NUM>. The pipette-module controller <NUM> has a liquid surface detection mode of operation which enables a pressure feedback control algorithm that causes the pipette-module motor <NUM> to move the pipette-module translatory-motion frame <NUM> in a z-axis translatory motion until a change in a pressure in the tip <NUM>, as sensed by the pressure sensor <NUM>, indicates that the tip <NUM> is in contact with the liquid surface <NUM> as further described below.

In some embodiments, the pipette-module translatory-motion frame <NUM> may be attached to the pipette-module frame <NUM> by a linear slider <NUM> and operatively coupled to the pipette-module motor <NUM> by a pipette-module screw <NUM>.

Referring to <FIG>, in some embodiments, the pipette module <NUM> may have a tip remover <NUM> attached to the pipette-module frame <NUM>. The tip remover <NUM> preferably comprises a pair of first and second parallel tip-remover bars <NUM> spaced apart by a tip-remover gap <NUM> greater than an outside diameter of the tube <NUM> and less than an outside diameter of the tip <NUM>. The tip-remover gap <NUM> allows the tube <NUM> to move in z-axis translatory motion between the pair of bars <NUM> and prevents the tip <NUM> from passing therethrough. When the tip <NUM> contacts the pair of bars <NUM>, further z-axis translatory motion of the pipette-module translatory-motion frame <NUM> separates the tip <NUM> from the tube <NUM>.

Referring to <FIG>, in some embodiments the pipette module <NUM> may have another pipette-module translatory-motion frame <NUM> attached to the pipette-module translatory-motion frame <NUM>. The attached another pipette-module translatory-motion frame <NUM> is movable with respect to the pipette-module translatory-motion frame <NUM> by an another pipette-module translatory-motion-frame motor <NUM>. If the pipette module <NUM> has an another pipette-module translatory-motion frame <NUM>, the pneumatic aspirator assembly <NUM> further comprises an another pipette-module cylinder <NUM> having an another pipette-module-cylinder volume greater than the pipette-module cylinder volume of the pipette-module cylinder <NUM>. The another pipette-module cylinder <NUM> is movable with the pipette-module translatory-motion frame <NUM> and is in fluid communication with the pipette-module cylinder <NUM>, the tube <NUM>, the tip <NUM> and the pressure sensor <NUM>. An another pipette-cylinder piston <NUM> is movably disposed in the another pipette-module cylinder <NUM>. The another-cylinder piston <NUM> is fixedly attached to the another pipette-module cylinder translatory-motion frame <NUM> by an another pipette-cylinder piston rod <NUM>. An another pipette-module controller <NUM> is in electrical communication with the another pipette-module cylinder translatory-motion-frame motor <NUM>, the pressure sensor <NUM> and the pipette-module controller <NUM>.

Referring to <FIG>, in a preferred embodiment of the liquid handling system <NUM>, a pipette-module mount <NUM> is attached to the liquid-handling-system z-axis frame <NUM>. The pipette-module mount <NUM> is movable in a z-axis translatory motion with respect to the liquid-handling-system z-axis frame <NUM> by a liquid-handling-system z-axis motor <NUM>. At least one pipette module <NUM> is attached to the pipette-module mount <NUM> and movable therewith. The liquid-handling-system controller <NUM> is in electrical communication with the pipette-module controller <NUM> and the liquid-handling-system z-axis motor <NUM>.

The liquid-handling-system controller <NUM> is operable in a plurality of modes of operation one of which is a container indexing mode of operation, the enablement of which causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in a downward z-axis translatory motion until the tip <NUM> is in register with the container open end <NUM>.

Another mode of operation for the liquid-handling-system controller <NUM> is an aspiration mode of operation the enablement of which causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in an upward z-axis translatory motion while the pipette-module controller <NUM> simultaneously causes the pipette-module motor <NUM> to move the pipette-module translatory-motion frame <NUM> in a downward z-axis translatory motion maintaining the tip <NUM> in contact with the liquid surface <NUM> as the liquid is aspirated into the tip <NUM>.

Another mode of operation for the liquid-handling-system controller <NUM> is a liquid discharging mode of operation the enablement of which causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in an downward z-axis translatory motion while the pipette-module controller <NUM> simultaneously causes the pipette-module motor <NUM> to move the pipette-module translatory-motion frame <NUM> in an upward z-axis translatory motion discharging from the tip <NUM> the liquid <NUM> in the tip <NUM>.

In some embodiments of the liquid handling system <NUM> two or more containers <NUM> are provided and at least two pipette modules <NUM> are provided. The pipette modules may be either single cylinder (see, <FIG>) or two cylinder (see, <FIG>) and are attached to the pipette-module mount <NUM>. Enablement of the container indexing mode of operation causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in a downward z-axis translatory motion until the tip <NUM> of at least one pipette module of the at least two pipette modules is in register with the container open end <NUM> of a corresponding container <NUM>.

Enablement of the liquid surface detection mode of operation of each pipette-module of the at least two pipette modules after completion of the container indexing mode of operation independently detects the liquid surface <NUM> of the liquid <NUM> in the corresponding container <NUM>.

Enablement of the aspiration mode of operation after completion of the liquid surface detection mode of operation of each pipette-module of the at least two pipette modules causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in an upward z-axis translatory motion while the pipette-module controller <NUM> of each pipette-module of the at least two pipette modules simultaneously causes the pipette-module motor <NUM> of each pipette-module of the at least two pipette modules to move the pipette-module translatory-motion frame <NUM> of each pipette-module of the at least two pipette modules in a downward z-axis translatory motion maintaining the tip <NUM> of each pipette-module of the at least two pipette modules in contact with the liquid surface <NUM> of the corresponding container <NUM> as the liquid is aspirated into the tip <NUM> of each pipette-module of the at least two pipette modules.

Enablement of the liquid discharging mode of operation causes the liquid-handling-system z-axis motor <NUM> to move the pipette-module mount <NUM> in an downward z-axis translatory motion while the pipette-module controller <NUM> of each pipette-module of the at least two pipette modules simultaneously causes the pipette-module motor <NUM> of each pipette-module of the at least two pipette modules to move the pipette-module translatory-motion frame <NUM> of each pipette-module of the at least two pipette modules in an upward z-axis translatory motion discharging from the tip <NUM> of each pipette-module of the at least two pipette modules the liquid <NUM> in the tip <NUM> of each pipette-module of the at least two pipette modules.

In operation, the origin of the liquid-handling-system z-axis is defined as the position in which the pipette-module mount <NUM> is in the up-most positon and the pipette-module translatory-motion frame <NUM> is also in the up-most position. As a first step, the liquid-handling-system controller <NUM> enables the container indexing mode of operation, in which the liquid-handling-system z-axis motor <NUM> moves the pipette-module mount <NUM> in a downward z-axis translatory motion until the pipette-module tip <NUM> is in register with the container open end <NUM>.

In the next step, the liquid-handling-system controller <NUM> causes the pipette-module controller <NUM> to activate the pressure feedback control algorithm which encodes the following Proportional, Integral, Derivative (PID) feedback control law: <MAT> where u(t) is a tip speed in mm/sec;.

The target pressure point of the control law is set to the atmosphere pressure P0. Once the pressure drop inside of the tip <NUM> is detected, the target pressure point of the control law is set to a higher value, for example, P0+C, where C is typically equal to <NUM> Pa for water at room temperature. This higher pressure expels the liquid from of the tip <NUM>. The position of the end of the pipette-module tip <NUM> is the position of the liquid surface <NUM> when the pressure P inside the tip equals P0+C.

A schematic of the pressure feedback control system is shown in <FIG>. The pipette-module piston <NUM> is movably disposed in the pipette module cylinder <NUM> and fixedly attached by the piston rod <NUM> to the pipette-module frame <NUM>. The pipette-module motor <NUM> drives the tip <NUM> and the cylinder <NUM> downwardly toward the liquid surface <NUM> in the container <NUM>. The liquid surface level <NUM> in the container <NUM> is unknown and must be detected. The dashed lines show the data flow of the pressure control system. The pipette-module motor <NUM> can be an open loop or closed loop controlled motor. The control system for motor <NUM> is not shown for simplicity, however this motor receives speed commands to make a motion. The pressure controller is preferably the PID controller described above and controls the pressure inside the pipette-module tip <NUM> to the given target values.

Preferably, but not necessarily, the hardware comprising the pressure feedback control system may have the following features: The typical pressure sensor has RMS = <NUM> hPa, Sensitivity = <NUM> LSB per hPa, 24bit resolution. The motor has about <NUM> Pulse per rev. The cylinder <NUM> moves <NUM> when motor rotates <NUM> revolution. The cylinder's volume is <NUM> and the stroke is <NUM>. The inner diameter of the cylinder is <NUM> and the sampling time for the control loop is <NUM> msec. For an initial controller value of U<NUM> = <NUM>/sec, the airflow rate is approximately <NUM>µL/sec.

The operational characteristics of the foregoing control law for detecting an unknown liquid surface <NUM> for water in a container <NUM> where the pipette-module tip <NUM> is initially spaced about <NUM> above the liquid surface, the location of the liquid surface is unknown and the pipette-module tip <NUM> is lowered at velocity of <NUM>/sec is shown in <FIG>. More specifically, the pressure inside the tip and the control error are shown in <FIG>. The motor speed and the motor position are shown in <FIG>.

The motor speed is the output of the pressure feedback controller and the motor position is the output of the pipette module motor <NUM> which drives the pipette-module cylinder <NUM> and pipette-module tip <NUM>. After <NUM> msec, the position of the pipette-module motor <NUM> represents the position of liquid surface <NUM>. After the pipette-module tip <NUM> touches the liquid surface <NUM>, the control error becomes large enough to aspirate the liquid into the pipette-module tip <NUM>. The surface tension between pipette-module tip <NUM> and water is around <NUM> Pa. In the motor speed and position plots in <FIG>, the pipette-module motor <NUM> moves upwardly from a downwardly motion after <NUM> msec.

After the pipette-module tip <NUM> contacts the liquid surface <NUM>, the pipette-module tip <NUM> moves upwardly. Referring to <FIG>which shows the control error of <FIG> and the motor position of <FIG> for the time interval <NUM> msec to <NUM> msec, the pipette-module tip <NUM> moves upwardly about <NUM> after the pipette-module tip <NUM> touches the liquid surface. The control error becomes <NUM> Pa and the tip pressure decreases to <NUM> Pa. The pressure drop is abouat <NUM> Pa The pressure decrease is large enough to aspirate liquid into the pipette-module tip <NUM>. The decrease in control error signifies that the pipette-module tip pressure increases, since the pressure target value is set to P0+C. The liquid inside the tip discharges with the increase of the pipette-module tip pressure, and is completely discharged when the pipette-module tip pressure reaches the target value of P0+C.

Claim 1:
A pipette module (<NUM>) for a liquid handling system (<NUM>) including a liquid-handling-system z-axis frame (<NUM>), at least one container (<NUM>) with a container open end (<NUM>) having a predetermined container-open-end position (<NUM>) (R<NUM>) relative to the liquid-handling-system z-axis frame (<NUM>), a liquid (<NUM>) in the at least one container (<NUM>) having a liquid surface (<NUM>) with an unknown liquid surface level (<NUM>) (R<NUM>), the pipette module (<NUM>) comprising:
a pipette-module frame (<NUM>) attachable to the liquid-handling-system z-axis frame (<NUM>);
a pipette-module translatory-motion frame (<NUM>) attached to the pipette-module frame (<NUM>) and movable with respect to the pipette-module frame (<NUM>) by a pipette-module motor (<NUM>);
a pneumatic aspirator assembly (<NUM>) comprising:
a pipette-module cylinder (<NUM>) having a piston (<NUM>) movably disposed therein;
a tube (<NUM>) in fluid communication with the pipette-module cylinder (<NUM>), the tube (<NUM>) terminating in a tip (<NUM>); and
a pressure sensor (<NUM>) in fluid communication with the cylinder (<NUM>), the tube (<NUM>) and the tip (<NUM>); and
a pipette-module controller (<NUM>) in electrical communication with the pipette-module motor (<NUM>) and the pressure sensor (<NUM>),
characterized in that:
the pipette-module cylinder (<NUM>), the tube (<NUM>) and the tip (<NUM>) are attached to the pipette-module translatory-motion frame (<NUM>) and movable therewith;
the piston (<NUM>) is fixedly attached to the pipette-module frame (<NUM>) by a piston rod (<NUM>); and
the pipette-module controller (<NUM>) has a liquid surface detection mode of operation which enables a pressure feedback control algorithm that causes the pipette-module motor (<NUM>) to move the pipette-module translatory-motion frame (<NUM>) in a z-axis translatory motion until a change in a pressure in the tip (<NUM>) as sensed by the pressure sensor (<NUM>) indicates that the tip (<NUM>) is in contact with the liquid surface (<NUM>).