WO2005121780A2 - Methods and apparatus for characterizing, measuring, and dispensing fluids - Google Patents

Methods and apparatus for characterizing, measuring, and dispensing fluids Download PDF

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Publication number
WO2005121780A2
WO2005121780A2 PCT/US2004/041444 US2004041444W WO2005121780A2 WO 2005121780 A2 WO2005121780 A2 WO 2005121780A2 US 2004041444 W US2004041444 W US 2004041444W WO 2005121780 A2 WO2005121780 A2 WO 2005121780A2
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WO
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Patent type
Prior art keywords
pipettor
sensor
controller
tip
configured
Prior art date
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PCT/US2004/041444
Other languages
French (fr)
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WO2005121780A3 (en )
Inventor
Peter R.C. Gascoyne
Jody V. Vykoukal
Christian Girardet
Jamileh Noshari
Ulrich Mueller
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Board Of Regents, The University Of Texas System
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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N35/1009Characterised by arrangements for controlling the aspiration or dispense of liquids
    • G01N35/1016Control of the volume dispensed or introduced
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02Burettes; Pipettes
    • B01L3/021Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02Burettes; Pipettes
    • B01L3/021Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids
    • B01L3/0217Pipettes, i.e. with only one conduit for withdrawing and redistributing liquids of the plunger pump type
    • B01L3/0237Details of electronic control, e.g. relating to user interface
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02Burettes; Pipettes
    • B01L3/0275Interchangeable or disposable dispensing tips
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N15/1031Investigating individual particles by measuring electrical or magnetic effects thereof, e.g. onconductivity or capacity
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/02Identification, exchange or storage of information
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/02Identification, exchange or storage of information
    • B01L2300/025Displaying results or values with integrated means
    • B01L2300/027Digital display, e.g. LCD, LED
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0645Electrodes
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00Investigating characteristics of particles; Investigating permeability, pore-volume, or surface-area of porous materials
    • G01N15/10Investigating individual particles
    • G01N2015/1062Investigating individual particles counting the particles by other than electro-optical means
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/10Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
    • G01N2035/1027General features of the devices
    • G01N2035/1048General features of the devices using the transfer device for another function
    • G01N2035/1062General features of the devices using the transfer device for another function for testing the liquid while it is in the transfer device

Abstract

The invention is directed to methods and an apparatus for characterizing, measuring, and dispensing fluids. Pipettor system (10) is described as including sensors in or near the tip (14) for sensing parameters useful for fluid handling. In a respective embodiment, a pipettor can include an integral impedance sensor useful for counting particles and/or calculating particle concentration. Such information can be used in the dispensing of fluids and avoids the need for additional measuring equipment.

Description

DESCRIPTION

METHODS AND APPARATUS FOR CHARACTERIZING, MEASURING, AND DISPENSING FLUIDS

This application claims priority to, and incorporates by reference, U.S. Provisional Patent Application Serial No. 60/528,091, which was filed December 9, 2003.

Statement as to Rights to Inventions Made under Federally- Sponsored Research and Development Aspects of this invention were made with government support by the Defense Advanced Research Projects Agency through DARPA order No. E934 to issue Navy Contract No. N66001- 97-C-8608. The government may accordingly have certain rights in this invention. Background of the Invention

1. Field of the Invention The present invention relates generally to fluid handling. More particularly, it concerns characterizing, measuring, and dispensing fluids. Even more particularly, it concerns methods and apparatuses involving a pipettor with an associated sensor such as an impedance sensor.

2. Description of Related Art The measurement and dispensing of known fluid volumes is one of the most fundamental operations in chemistry, the life sciences, food science, environmental analysis, pharmaceuticals, perfumery, color science, and numerous other applications. Commonly, pipetting technologies are used to draw up and dispense known volumes of fluid.

In order to measure and dispense small, controlled volumes of fluids, pipetting devices are in common use. In operation, a pipetting device draws a predetermined volume of fluid into a fluid-retaining reservoir. Subsequently, that volume is dispensed into a second receptacle.

Replaceable tips are normally used for drawing up, temporarily retaining, and dispensing the fluids. These tips are usually disposable so that a fresh tip may be installed to handle each new solution. This avoids carryover and cross-contamination between different samples and reagents. Typically, pipettors have a means to set a desired dispensing volume by adjusting a manual setting in the handle. Pipettors such as micro-pipettors may be spring-loaded and operated using manual power or they may be equipped with an electronic controller and an electrical motor that actuates fluid loading and dispensing. Electrical pipettors are typically programmed via one or more push buttons on the handle and can have a liquid crystal display (LCD) or other display to provide user feedback and data. Electrical pipettors provide high reproducibility and can remember programmed operations and pipetting volumes to make measurement operations more convenient for the user.

Frequently, it is desirable to measure one or more properties of a fluid prior to dispensing it. For example, parameters such as electrical conductivity, pH, sugar content, and particle or cell count may be required to be known. It is often necessary to control the amount of fluid to be dispensed on the basis of one of these measured parameters. In such cases, before the volume to be dispensed can be calculated, parameters of interest have to be measured, usually using standalone laboratory machines such as a conductivity meter, pH meter, particle counter, etc.

For example, many applications in the life sciences require that the concentration of cells in a cell suspension be known. It is often necessary to dispense a known number of cells for culture, assaying, drug tests, transfections, or other manipulations. Typical methods of accomplishing this are to count the number of cells within a given volume of suspending medium either microscopically, using a hemocytometer chamber, or automatically by using an electronic counter such as an electrical impedance (Coulter-type) counter or a flow cytometer. Disadvantages of these methods are that specialized, stand-alone equipment such as a microscope, Coulter counter, or a flow cytometer are required and that special samples have to be taken and prepared before the count can be made. Afterwards, calculations are required before the cell count in the starting suspension can be derived and appropriate volumes of the cell suspension needed for a given application can be determined. Accordingly, it would be advantageous to provide technology that can, among other things, count cells without the need for a separate, stand-alone counter and, if desired, to dispense desired numbers of cells based on the determined concentration. The shortcomings of conventional techniques mentioned above are not intended to be exhaustive but, rather, are among many that tend to impair the effectiveness of previously known techniques concerning fluid handling. Other noteworthy problems also exist; however, those mentioned here are sufficient to demonstrate that a significant need exists for the techniques described and claimed here.

Summary of the Invention Shortcomings are reduced or eliminated by the techniques disclosed here. These techniques are applicable to a vast number of applications, including but not limited to applications involving the need to handle fluids in a controlled, precise manner using a pipettor.

As used herein, a "pipettor" generically refers to any type of pipettor, including but not limited to pipettors such as PIPETEMAN (trademark owned by GILSON MEDICAL ELECTRONICS(FRANCE)). In one respect, this disclosure involves combining pipetting and measuring technologies into a single, hand pipetting device so that various measurement and dispensing operations can be accomplished in a single step. This can be accomplished by incorporating one or more sensors and an electronic controller into an electrical pipetting instrument. Parameters of interest are measured as the fluid is drawn into the pipettor, the result of the measurements are displayed, and, if desired, dispensing operations are adjusted in response to the measured parameters.

For example, in one embodiment, an apparatus is presented that is able to count cell concentrations without the need for a separate, stand-alone counter and, if desired, to dispense desired numbers of cells based on the determined concentration.

In one embodiment, the invention involves a pipettor including an integrated impedance sensor. In another embodiment, the impedance sensor can be configured to count particles. In another embodiment, the impedance sensor can be configured to determine a concentration. In another embodiment, the invention involves a pipettor including an integrated pH meter. In another embodiment, the invention involves a pipettor including an integrated conductivity meter. In another embodiment, the invention involves a pipettor including an integrated sensor and controller that intakes and dispenses fluid volume in response to one or more sensed parameters. In another embodiment, the invention involves a pipettor including a wired or wireless link to communicate with a host computer. As used herein, a "host computer" means a computing device such as a PC or laptop, a personal data assistant, or the like that can house instructions or data associated with the pipettor. In another embodiment, the invention involves a pipettor that can be configured to accept user-generated scripts to allow functions of the pipettor to be programmed. In another embodiment, the invention involves a pipettor including a display, audible output, or voice output customizable by the user. In another embodiment, the invention involves a pipettor configured to be programmed to do sequences of dispensing operations according to a user-generated algorithm that changes the volume dispensed. In another embodiment, the invention involves a pipettor configured to calculate a particle concentration. In another embodiment, the invention involves a pipettor configured to display particle counts, viability, pH, or conductivity. In another embodiment, the invention involves a pipettor configured to download data into a host computer for display in a spreadsheet or other application. In another embodiment, the invention involves a computer readable medium including instructions for generating a user interface for programming functions of a pipettor. In another embodiment, the invention involves a computer readable medium including instructions for communicating data to a pipettor. In another embodiment, the invention involves a pipette tip including an embedded impedance sensor, pH sensor, or conductivity sensor. In another embodiment, the invention involves a pipette tip including electrical connections to a pipettor stem. In another embodiment, the invention involves a pipette tip including encoding for functional characteristics. In another embodiment, the invention involves a pipettor including concentric-multiple-plungers to handle different fluid volume ranges. In another embodiment, the invention involves a pipettor including a controller and a motor drive assembly configured to control multiple plungers independently. In another embodiment, the invention involves a pipettor configured to be customized by exchanging a cover or housing according to color, pattern, name, or logo. In another embodiment, the invention involves a pipettor including: a tip including an impedance sensor; a plunger electrically coupled to the tip; a motor; a controller configured to use data from the sensor to calculate particle count or concentration; and a display. In another embodiment, the pipettor can also include an input/output for wireless or wired communications with a host computer. In another embodiment, the invention involves a pipettor that discriminates between particles based on frequency characteristics in their dielectric properties. In another embodiment, the pipettor can discriminate between viable and nonviable cells.

In another embodiment, the invention involves a method of fluid handling, including: using any of the pipettors described above or in this disclosure. In another embodiment, the invention involves a method of fluid handling, including : determining a particle count or concentration using a sensor integrated into a pipettor; and dispensing fluid from the pipettor. In another embodiment, the dispensing of fluid can be based on the particle count or concentration. In another embodiment, the invention involves a method of fluid handling, including : determining a pH using a sensor integrated into a pipettor; and dispensing fluid from the pipettor.

In another embodiment, the invention involves a method of fluid handling, including: determining a conductivity using a sensor integrated into a pipettor; and dispensing fluid from the pipettor. In one embodiment, the invention involves a pipettor including an integrated sensor and controller that intakes and dispenses fluid volume in response to one or more parameters sensed by the sensor. The integrated sensor may include an impedance sensor, pH sensor, or conductivity sensor. The controller may be configured to receive user-generated scripts that program dispensing or measurement functions of the pipettor.

In one embodiment, the invention involves a pipettor that includes an orifice, a tip, an impedance sensor, and a controller. The tip is coupled to the orifice. The impedance sensor is coupled to the tip. The controller is coupled to the impedance sensor and is configured to count particles taken up by the pipettor using data from the impedance sensor. The controller may be configured to determine a particle concentration. The controller may be configured to count particles dispensed by the pipettor using data from the integrated impedance sensor. The particles may be cells, and the controller may be configured to discriminate and count viable and nonviable cells. The pipettor may also include a wired or wireless link to one or more host computer systems. The pipettor may transmit information from or derived from the impedance sensor to the one or more host systems. The controller may be configured to discriminate and count particles on the basis of frequency characteristics in the dielectric properties of the particles. The impedance sensor may be a multi-frequency impedance sensor.

In one embodiment, the invention involves a pipettor that includes an orifice, a tip, a pH sensor, and a controller. Tne tip is coupled to the orifice. The pH sensor is coupled to the tip.

The controller is coupled to the pH sensor and is configured to determine a pH of a sample taken up by the pipettor using data from the pH sensor. In one embodiment, the invention involves a pipettor that includes an orifice, a tip, a conductivity sensor, and a controller. The tip is coupled to the orifice. The conductivity sensor is coupled to the tip. The controller is coupled to the conductivity sensor and is configured to determine a conductivity of a sample taken up by the pipettor using data from the conductivity sensor. In one embodiment, the invention involves a pipettor including a tip and a controller.

The tip includes a sensor. The tip is configured to automatically identify the sensor to the controller. The controller may be configured to execute an algorithm corresponding to the identified sensor. The tip may be further configured to automatically identify the size of the tip to the controller.

In one embodiment, the invention involves a pipettor including concentric, multiple plungers configured to dispense different fluid volume ranges and a motor drive assembly configured to control the multiple plungers independently. The pipettor may also include an integrated particle counter, the pipettor being configured to use a first plunger to determine a particle concentration and a second plunger to take up and dispense a desired volume. The pipettor may also include a controller configured to identify a maximum fluid capacity associated with each of the multiple plungers. Other features and associated advantages will become apparent with reference to the following detailed description of specific embodiments in connection with the accompanying drawings.

Brief Description of the Drawings The following drawings demonstrate certain aspects of the invention. The drawings illustrate examples only. Identical element numbers are used for convenience only and signify identical or similar structures or functionality. The use of identical element numbers should not be interpreted as signifying the scope of the invention. FIG. 1 is a block diagram of a pipettor and its systems in accordance with embodiments of the disclosure.

FIG. 2 is a schematic diagram of a pipettor in accordance with embodiments of the disclosure. FIG. 3 is a schematic diagram of a plunger and tip of a pipettor in accordance with embodiments of the disclosure.

FIG. 4 is a schematic diagram of internal workings of a pipettor in accordance with embodiments of the disclosure.

Description of Illustrative Embodiments Techniques of this disclosure are applicable to any fluid handling application. The description below focuses on several, representative embodiments such as cell counting. However, those having ordinary skill in the art will recognize that the techniques find application in other areas as well. Those other areas are also encompassed by this disclosure and the claims.

Particle Counting: A commonly used method of counting cells is to measure electrical impedance changes as cells pass through a small orifice in which an electrical current is passing. Recently, it has become possible to make sensors for such instruments through microfabrication methods, and new configurations of sensors and refined signal analysis methods have made it possible to improve the discrimination of cell impedance sensors while reducing the need to measure fluid flow volumes directly.

These developments make it possible to incorporate a particle counter based on impedance measurements within a device primarily designed for other functions. Furthermore, microfabrication methods make it possible to manufacture impedance sensor elements very inexpensively so that they may be disposable. Finally, the use and analysis of multi-frequency waveforms in impedance sensors makes it possible to discriminate between different particles on the basis of not only size but also other parameters. For example, a loss of viability of mammalian cells suspended in a low conductivity medium is accompanied by leakage of ions from those cells and a corresponding alteration in high frequency electrical impedance. Such impedance changes can be used to discriminate viable from non viable cells. Different cell types may also be identified on the basis of frequency characteristics in their dielectric properties.

Such differences can be recognized by a multi-frequency impedance sensor. Therefore, impedance sensors allow for useful forms of particle discrimination, can be easily microfabricated, and can be disposable. Pipettor To Achieve Particle Counting and Sensing of Parameters: A block diagram showing representative functional components of a combined particle impedance counter and pipettor are shown in FIG. 1. The device may resemble a conventional, hand-held electrical pipettor. A non-linear electrical feedback loop can be included.

FIG. 1 is a block diagram of a pipettor system 10 in accordance with embodiments of the disclosure. Pipettor system 10 includes an orifice 12, a tip 14, a plunger 16, a motor 18, a controller 20, a display 22, a first host system 24, a second host system 26, a battery 28, sensor electronics 30, and input mechanism 32. Arrows and lines in FIG. 1 depict coupling and communication among the components of the pipettor system 10.

Orifice 12, in different embodiments may include one or more sensors at or in proximity to the orifice. For example, in one embodiment, orifice 12 may include one or more impedance sensors that act as fluid passes through, into, or out of orifice 12. In other embodiments, different types of sensors may be used (i.e., for detecting properties other than, or additional to, impedance), and those sensors may be placed according to need — whether it be near the actual orifice or removed from it. In some embodiments, one or more sensors may be placed in or near tip 14, plunger 16, or elsewhere. Orifice 12 may be sized according to knowledge and practice in the art.

Tip 14, in a typical embodiment, is a fluid retaining tip that can take several sizes. Different considerations corresponding to tip 14 are discussed below. Tip 14 may be disposable. Tip 14 may include one or more electrical connectors for transmission of electronic information. Tip 14 may include a quick release mechanism to aid quick removal or attachment.

Plunger 16, in a typical embodiment, couples motor 18 and tip 14 and is responsible for the plunging of samples.

Motor 18 draws power from battery 28 and acts to drive one or more plungers for pipettor operation.

Controller 20 is discussed below and controls various functions and operations associated with the pipettor system 10. Display 22 may display various information. In different embodiments, the display parameters may be customized according to need or preference.

Host systems 24 and 26 signify that one or more different computing devices may communicate with the pipettor system 10. Host systems 24 and 26 may include a wired or wireless connection with pipettor system 10 and may interact with or control pipettor system 10 as described below or according to need.

Battery 28 drives motor 18 and may take the form of any power source known in the art not necessarily limited to batteries per se. For example, battery 28 may involve devices that run on natural gas, electricity from a wall socket, solar energy, or the like. Battery 28 may also drive other electrical components within or associated with pipettor system 10.

Sensor electronics 30 controls or interacts with one or more sensors at or near orifice 12 or located otherwise and may include one or more boards, chips, or structures known in the art for sensor applications. Input mechanism 32, in a typical embodiment, includes buttons, keys, a touchpad, a stylus/screen, or other input devices known in the art. Input mechanism 32 allows a user to input information into pipettor system 10. Information may be input through other mechanisms as well including but not limited to hosts 24 and/or 26.

In use, controller 20 can be programmed from input mechanism 32 (e.g., a manual input, such as a keypad), or via data link from an optional host system (e.g., host system 24 and/or 26) that is connected through a wired or wireless connection.

In counting mode, controller 20 activates motor 18, which draws particle suspending medium through orifice 12 (in this example, an impedance sensor orifice) into tip 14 by moving components of plunger 16. Sensor electronics 30 (in this example, impedance sensor electronics) detect particles that pass through orifice 12 and controller 20 can count the particles and compute the particle concentration in the suspending medium. Controller 20 can be programmed to take up or dispense a predetermined volume of suspending medium or a predetermined number of particles. When taking up a predetermined volume of suspending medium, controller 20 may be programmed to take up that volume without counting particles or programmed to derive the particle concentration in that volume. When programmed to take up a predetermined number of particles, controller 20 can count the particles directly while taking up a volume (which can be a slower process) or use a derived particle concentration to determine the volume of suspending medium that must be taken up to provide the desired particle number in the tip 14 and then actuates motor 18 so as to take up that computed volume.

In impedance applications, particles are drawn through impedance-sensing tip 14 that induces a signal that is detected by impedance sensor electronics 30 inside the apparatus. Information about, for example, the size and dielectric characteristics of each particle are sent to controller 20 where particles are counted and categorized according to programmed criteria.

Programs and criteria can be entered either manually from a human interface on the apparatus, such as via pushbuttons (e.g., by way of input mechanism 32), or, optionally, downloaded to the apparatus from a host computer system via either a wireless or wired connection (e.g., by way of host systems 24 and or 26). Host system 24 or 26 can be, but are not limited to, a laptop or other computer or a personal data assistant (PDA) that may aid in the development or storage of programs for the pipettor system 10. Examples of wired links are RS232, Ethernet, USB, and other serial or parallel data transfer protocols and associated wiring. Examples of wireless links are Bluetooth, 802.11, cell phones, and other protocols and associated radio communication equipment. The link can be used for downloading programs or algorithms and other data to the pipettor system 10 including firmware updates for controller 20 and user customizations such as display and audible output options.

Pipettor system 10 can be programmed using scripting languages, computer languages, "macros," or the like. Customizations such as the ability to play music or speak in different languages may also be downloaded in this way. The ability to download programs offers enormous flexibility to the user and permits any desired criteria, including conditional ones, to be easily programmed on a host system such as host system 24 or 26 and downloaded. Programs can be, for example, serial titrations or other measurement protocols whereby each subsequent dispensing operation involves a different volume of solution. The ability to program such operations in an intuitive, user-friendly environment not only enables complex tasks to be made easier but also eliminates the complexity of trying to program operations directly into the pipettor via pipettor buttons and display. This, in turn, allows the pipettor buttons and display to be kept simple and intuitive, an advantage when operating the pipettor with protective gloves. The two way link can also serve the important function of uploading information from the pipettor to a host system 24 or 26 when pipetting operations are being undertaken. Thus, during an experiment on multiple cell samples, the pipettor may upload data for each cell sample comprising concentration, viability, and microliters dispensed, for example. Such data may be interfaced with spreadsheets, graph packages, or other data handling applications. This capability can assist the user by eliminating the need for the user to stop and write or type each data entry by hand, saving time and possible contamination and preventing user distraction. For example, in operations under a sterile hood, a cytologist may conduct cell counts, measure and dispense cells for culture or transfection, and record data into a nearby computer spreadsheet without ever leaving the sterile environment.

Information in the form of messages may be sent back from the host system 24 or 26 to aid the user. For example, the pipettor may display the measurement number or name or other information that helps the user keep track of a protocol.

Programmable criteria for controlling pipetting operations may include, for example, volume, particle count, cell viability, particle size, particle dielectric properties, or particle frequency responses. Other criteria may be utilized as well, as known in the art of sensor electronics. Controller 20 may be programmed to display accumulated or derived data on the basis of measurements. For example, a total cell count, or percentage of viable cells, or the total volume of fluid containing a desired number of particles can be displayed at display 22 and/or to host system 24 or 26 according to the program.

The pipettor may also be customized to suit user or owner needs by displaying the user's name, instrument number, company name, time, date, or similar information at display 22 and/or to host system 24 or 26. Other customization capabilities can be included. For example, a polymer cover of the pipettor is available in different colors and with or without designs and/or logos, allowing the look and feel of the apparatus to be customized or personalized. Covers can be changed when needed or desired to alter customization. In one embodiment, an image may be uploaded from host system 24 or 26 to display 22, so, for example, a pipettor may display someone's picture on the device. Pipettors may also be customized to capture usage information that can help in maintenance, such as the number of operations or the time since last maintenance, etc. In one embodiment, controller 20 may monitor voltage and charging of battery 28 and provide an estimate of remaining charge or the condition of battery 28. Battery 28 may be internal or external. Battery 28 may be rechargeable and may consist of a NiCad, NiMH, Li ion or similar technology, or may be substituted by any other energy sources such as a small fuel cell.

In one embodiment, controller 20 may use non-volatile (EEPROM or flash) memory so that programming information is not lost even if the battery 28 becomes discharged or fails.

Such memory may be swappable so that, if needed, larger storage may be achieved (e.g., if 512 megabytes of storage are needed a 512 megabyte flash card may be used, while if significantly less storage is needed an 8 megabyte card may suffice).

In one embodiment, controller 20 is connected to a motor controller (not shown) that provides energy to motor 18 that drives components of plunger 16 in the pipettor system 10. In one embodiment, plunger 16 is connected via an airtight interface to tip 14. In this way, controller 20 can send instructions to the motor controller and thereby actuate the drawing in or expulsion of fluid through orifice 12. As controller 20 causes fluid to be drawn into tip 14 through orifice 12, it can collect data on particles and may compute desired parameters. For example, from the number of particles counted in an impedance sensor and the total volume of fluid drawn into orifice 12, particle concentration may be readily derived. Once the particle concentration is derived, the volume of fluid that needs to be drawn up to bring a programmed number of cells into the apparatus can be calculated.

If programmed to do so, controller 20 may automatically take up a desired number of particles. For example, if 1340 cells were counted as the first 1 microliter of fluid was drawn into the pipette, the cell concentration would be calculated by controller 20 as 1.34 x 106 /ml. If the user had programmed the pipettor to automatically draw in 1.0 x 105 cells, controller 20 would calculate that it needs to draw in 74.6 μL of fluid to reach that cell count. Controller 20 would then draw in this volume. Controller 20 may then cause a visible or audible notification to be given to the operator that the desired cell uptake count has been reached. Controller 20 may, in the same or similar manner dispense a desired number of particles.

If a very accurate number of particles is required, controller 20 may draw in fluid and count every particle until the desired count is loaded. Fluid must be drawn into tip 14 slowly during counting operations, and the mode in which every particle is counted individually tends to be slower than the mode in which particle concentration is measured at the beginning of uptake and the total volume required is calculated and then quickly drawn up. In accurate counting applications, controller 20 is able to estimate how long it will take to draw in the required number of particles. A count down of remaining time may be displayed in such cases so that the operator has some indication of progress.

If controller 20 determines that the cell concentration cannot allow the desired number of cells to be reached, it can display an appropriate alert and/or sound an alarm. Such an occurrence results if the cell concentration in the fluid is too low to allow the desired number of cells to be taken up in the available volume of the reservoir of tip 14. An error condition can also be signaled if the cell concentration is so high that the counter cannot operate accurately or the pipettor is unable to take up with sufficient accuracy a required, very small volume. Other parameters may also be used in programming pipettor behavior. For example, if tip 14 is equipped with sensors that detect multiple parameters, controller 20 may be programmed to pick up fluid in accordance with those parameters. A useful application that illustrates this function is when an impedance sensor discriminates between viable and non- viable cells. In this case, controller 20 may be programmed to pick up a known number of viable cells and to ignore non-viable cells, for example. Other criteria such as large versus small cells may be used similarly.

In many applications, it is necessary to use a pipettor for the purpose of dispensing known fluid volumes only. In such cases, the desired dispensing volume may be entered manually, and counting is used only to allow particle concentrations to be determined and displayed. In still other applications, particle counts may not be required at all and controller 20 can be programmed so the apparatus behaves as a conventional pipetting aid whereby preset volumes are measured and dispensed with no counting function. FIG. 2 is a schematic diagram of a pipettor 40 in accordance with embodiments of the disclosure and is similar in respects to FIG. 1. Pipettor 40 of FIG. 2 may include all the block- functionality of pipettor system 10 shown in FIG. 1. Description of similar structure and function will not repeated. In FIG. 2, quick release mechanism 46 is shown. This mechanism may be any known in the art for aiding in the quick removal and/or attachment of tip 14. Associated with tip 14 are electrical connectors 48. In the illustrated embodiment, electrical connectors 48 are attached to tip 14 and plunger assembly 16. As shown, the electrical connectors 48 include three metallic strips. In other embodiments, electrical connectors may take other forms, as is known in the art.

The location of electrical connectors 48 may also vary. In still other embodiments, electrical connectors 48 may be replaced with one or more wireless communication technologies for achieving the same or similar results. For example, a radio frequency identification (RFLD) system may be used between tip 14 and the remaining portions of pipettor 40. In such an embodiment, tip 14 may convey information to pipettor 40, and particularly controller 20, via radio frequency identification.

Element 42 in FIG. 2 indicates a combined display/battery assembly. In different embodiments, a separate battery or energy source may be used to drive a display. Elements 44 in FIG. 2 illustrate manual input keys, which corresponds to the more general input mechanism 32 of FIG. 1.

FIG. 3 is a schematic diagram of a plunger and tip of a pipettor in accordance with embodiments of the disclosure and offers a more detailed view of the lower section of FIG. 2. As illustrated, electrical connection may be made between tip 14 and plunger assembly 16 via electrical connectors 48, and upon making a connection, controller 20 (see FIG. 1 or FIG. 2) can determine which type of tip is in place.

As discussed previously, different types of sensors may be incorporated into the pipettor (e.g., at or around tip 14) including, for example, those for impedance, conductivity, pH, glucose, and ion sensing. Different styles of tip 14 may be used including, for example, those having different volumes and those having various measurement functions associated with different sensor types. In general, electrical connection between the tip 14 and plunger 16 (or other component of pipettor 40) provides electrical communication (one or two way) with, e.g., sensors associated with tip 40 and allows for information associated with the tip 14 or other component to be detected. Electrical connection (through electrical connectors 48 or otherwise) may be encoded or otherwise handled so that the pipettor 40, and particularly controller 20, may identify the style, parameters, or any other data associated with the tip 14 that is being attached or its user. For example, encoding may identify the size of the tip 14, the sensor type associated with that tip 14, data associated with the sensor or sensors of tip 14, and/or data associated with the tip 14 itself (e.g. , number of times the tip has been used, the volume the tip has transferred, the number of cells the tip has transferred, the type of samples transferred, the owner of the tip, the dates on which the tip was used, or any other storable information that a user may find useful).

The up/down arrow of FIG. 3 is meant to signify that tip assembly 14 may form an air tight seal when pressed onto the end of plunger assembly 16 and also make electrical connection.

FIG. 4 is a schematic diagram of internal workings of a pipettor in accordance with embodiments of the disclosure and is similar in respects to the previous figures. Shown, among other things, in FIG. 4 is that outer diameters of a plunger housing may be stepped to accept different tip diameters. In FIG. 4, three steps are illustrated — steps 66a, 66b, and 66c. It will be understood by those having ordinary skill in the art, however, that more or fewer steps can be employed.

The section shown in FIG. 4 also includes display/controls 52, controller board 54, sensor electronics 56, battery pack 58, stepper motor 60, gearbox/clutch 62, drive mechanism 64, large plunger 68, medium plunger 70, small plunger 72, electrical contacts 74, and antenna 76.

Display/controls 52 may display information as discussed above. In one embodiment, it may show the progress of measurement, data derived from one or more sensors (e.g., sensors in or near tip 14), user name, sample number, or custom information.

Controller board 54 is analogous to controller 20 (see FIGS. 1-2) and may be loaded with custom programs and run internally stored programs for interacting with and/or controlling the pipettor. In this disclosure, description of, or reference to, controller 20 applies also to controller board 54.

Sensor electronics 56 interact with or control one or more sensors. In one embodiment, sensor electronics 56 measure output from one or more sensors and communicates data to controller board 54 (or, generally, to controller 20). In one embodiment battery pack 58 may be a rechargeable battery pack. In other embodiments, different energy sources may be used, as discussed above.

Stepper motor 60, in one embodiment works with gearbox/clutch 62 to drive each plunger (plungers 68, 70, and 72) independently.

Drive mechanism 64 transfers the rotary motion of the stepper motor 60 and gearbox/clutch 62 to the plungers, which are shown here as spiral-geared plungers. In other embodiments, the gearing and operation may work according to knowledge in the art.

Plungers 68, 70, and 72 may have spiral gears that interlock into meshing gearways (as shown) on the next outer component. While three plungers are illustrated, those having ordinary skill in the art will appreciate that more or fewer may be employed. Electrical contacts 74 engage with one or more electrical sensors and identification functions (or other functions) in a tip 14 as discussed above. The form and layout of electrical contract 74 may vary — here, they are shown to correspond with the steps 66a, 66b, and 66c.

In the illustrated embodiment, antenna 76 is internal (other embodiments may utilize an external antenna or no antenna) and provides a wireless link to a host system (e.g., host systems

24 or 26 of FIG. 1) for, e.g., downloading programs, data, customization information, or uploading information such as status information or data.

Current pipettors are typically available in a variety of sizes each having a different maximum volume that it can dispense. Commonly used pipette sizes in biology are lOμL, 25μL, lOOμL, 200μL, lmL and 5 mL. The reason for different sizes is that pipette measuring precision is determined by the minimum distance over which plunger travel can be accurately controlled. Furthermore, pipettors are typically operated by thumb pressure and it is therefore necessary to keep the maximum travel distance of the pipette plunger to a distance that the thumb can easily accommodate. Plunger diameters on pipettors therefore increase with increasing maximum dispensing volume. In order to maximize the range of volumes that can be handled accurately with a single pipette, a concentric-multiple-plunger arrangement may be used, such as the arrangement shown in FIG. 4. In order to accurately dispense small volumes, the pipettor may be fitted with a small tip

14 (e.g., see step 66c of FIG. 4) and controller 20 activates the central, slim plunger 72. For intermediate volumes, a larger tip 14 (e.g., see step 66b of FIG. 4) may be used and the small and medium-sized plungers 72 and 70 are operated. For larger volumes, a still larger tip 14 (e.g., see step 66a of FIG. 4) may be used and the small, intermediate, and large plungers 72, 70, and 68 can be operated together. In other embodiments, any different combination of one or more plungers can be operated.

An advantage of this method is that a user no longer needs to carry multiple pipettors but can achieve all dispensing with a single apparatus having a single set of controls. Another advantage of a multiple (e.g. , triple) plunger design is that for particle counting, small plunger 72 may be used initially, no matter how large the tip size or volume to be dispensed may be, to draw particles slowly enough through an impedance sensor orifice (or other orifice including other sensor-equipped orifices) to accomplish particle counting for particle concentration estimation or other functions. Once cell concentration estimation is achieved, controller 20 may activate a larger plunger (e.g., plungers 70 and/or 68) to take up and dispense the desired volume.

The ability of controller 20 to recognize tip volume, in addition to sensor capabilities via electrical connection or other communication, is advantageous in several applications including a concentric-multi-plunger embodiment because controller 20 should be aware of the maximum fluid capacity of a tip 14 so that excursions of plungers are limited to that capacity. Otherwise, fluid could be inadvertently drawn inside the plunger barrel contaminating and possible damaging it.

In another embodiment, a changeable filter may be seated inside an intake port at the bottom of a plunger stem to block fluid and prevent it from entering the plunger compartment.

This embodiment provides an added level of protection to guard against accident or misuse of the apparatus. A sensor for tip volume may be a micro-switch or optical sensor located on tip searings at the bottom of a plunger stem. Switches of this type enable controller 20 to determine which seat is engaged with a tip 14. Different standard sized tips that lack encoding electrodes may thereby be correctly sensed.

In the concentric-multi-plunger embodiment illustrated in FIG. 4, each plunger 68, 70, and 72 may be equipped with individual drive capabilities from stepper motor 60, and each may be sealed by O-rings or another mechanism to ensure air- and water-tight seals. Because different tips may contain different, or no, sensors, the electrical connection of a tip 14 may be encoded so that the pipettor controller 20 is able to read the type of tip (as well as other associated information) that is in place. Program options available to the user may then be tailored to the capabilities of the tip 14, and a warning may be issued if the user attempts to program a function for which the currently installed tip 14 is inappropriate.

The apparatus is also compatible with conventional tips that have no sensors. When a sensorless tip is installed, the program options available may be those of a conventional pipettor. This allows the pipettor to be used for multiple functions and the user does not require different pipettors for each function.

Pipettor To Achieve Sensing of Additional Functions: In addition to cell counting and functionality mentioned above, additional sensing functions may be readily incorporated into interchangeable tips. For example, pH and conductivity are parameters that are commonly of interest, which can be addressed with the techniques of this disclosure. The inclusion of an AC conductivity sensor and/or a pH sensor into or near a tip 14 provides appropriate measurement functionality to the pipettor to allow these parameters to be measured.

By encoding a tip 14 electrically, controller 20 in the pipettor automatically recognizes the measurement functions available for a given tip type. For example, a tip 14 with a pH sensor signals the pipettor to display pH. Then, when the tip 14 is placed into a solution, the pH is displayed. Electrical conductivity is displayed for tips having a conductivity sensing function. As for the examples given above with cell counting, the measurements may be used as criteria for determining the operation of the pipettor. As an example of the utility of this capability, the amount of protein present in a solution may be signaled by the conductivity of that solution. By estimating the protein concentration in a fluid from the fluid conductivity, a pipettor may be programmed to dispense known amounts of protein.

The ability of controller 20 to recognize tip 14 type means that all of these functions can be accomplished by a single pipettor design, allowing the user to efficiently conduct multiple laboratory tests without having to stop the flow of the experiment, waste material, or clean bench-top measurement devices.

While representative embodiments can be directed towards handheld pipetting devices, one of ordinary skill in the art will appreciate that the techniques of this disclosure apply equally to mount pipetting devices having similar operational characteristics and to equipment that accommodates a variety of pipetting needs. For example, robotic devices are often used to assist in drug testing and other applications. An electrical pipetting aid having similar sensing capabilities to the devices disclosed here could easily be adapted to such robotic applications. This disclosure is intended to cover all such alternative embodiments.

Multi-tip Operation: In some applications, such as when 96 well plates are used, an operator needs to pipette measured volumes of solutions into parallel wells. Multichannel pipettors are available for this purpose in which a single handle operates multiple pipette tips simultaneously. It will be understood by those of ordinary skill in the art that the pipetting methods disclosed here may be applied in such multi-tip devices. In such a case, a sensing element may be present in one of the multiple tips, or multiple sensing tips may be used if the sensor electronics is engineered to accommodate them. Various algorithms may be applied to determine how much fluid is taken up and dispensed. For example, a cell concentration determined from one sensing tip may be used to determine the fluid volume taken up and dispensed by the multiple, parallel tips.

With the benefit of the present disclosure, those of ordinary skill in the art will comprehend that techniques claimed and described here may be modified and applied to a number of additional, different applications, achieving the same or a similar result. Elements from the figures and described here can be taken in different combinations, as will be apparent to those having ordinary skill in the art. The claims cover all such modifications that fall within the scope and spirit of this disclosure. For instance, in one embodiment, one may simply build a pipettor that has the ability to recognize, through electrical connection, what type of tip 14 is being used.

REFERENCES Each of the following references is incorporated by reference in its entirety:

U.S. Patent No. 6,703,819 U.S. Patent No. 6,437,551

U.S. Patent No. 6,294,063

U.S. Patent No. 5,871,860

U.S. Patent No. 5,716,437

U.S. Patent No. 5,702,839 U.S. Patent No. 5,531,883

U.S. Patent No. 5,260,192

U.S. Patent No. 5,231,005

U.S. Patent No. 4,829,833

U.S. Patent No. 4,791,355 U.S. Patent No. 4,325,909

U.S. Patent No. 4,496,907

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Claims

1. A pipettor comprising an integrated sensor and controller that intakes and dispenses fluid volume in response to one or more parameters sensed by the sensor.
2. The pipettor of claim 1, where the integrated sensor comprises an impedance sensor, pH sensor, or conductivity sensor.
3. The pipettor of claim 1, where the controller is configured to receive user- generated scripts that program dispensing or measurement functions of the pipettor.
4. A pipettor comprising: an orifice; a tip coupled to the orifice; an impedance sensor coupled to the tip; and a controller coupled to the impedance sensor and configured to count particles taken up by the pipettor using data from the impedance sensor.
5. The pipettor of claim 4, where the controller is configured to determine a particle concentration.
6. The pipettor of claim 4, where the controller is configured to count particles dispensed by the pipettor using data from the integrated impedance sensor.
7. The pipettor of claim 4, where the particles are cells, and the controller is configured to discriminate and count viable and nonviable cells.
8. The pipettor of claim 4, further comprising a wired or wireless link to one or more host computer systems.
9. The pipettor of claim 8, the pipettor being configured to transmit information from or derived from the impedance sensor to the one or more host systems.
10. The pipettor of claim 4, where controller is configured to discriminate and count particles on the basis of frequency characteristics in the dielectric properties of the particles.
11. The pipettor of claim 4, where the impedance sensor is a multi-frequency impedance sensor.
12. A pipettor comprising: an orifice; a tip coupled to the orifice; a pH sensor coupled to the tip; and a controller coupled to the pH sensor and configured to determine a pH of a sample taken up by the pipettor using data from the pH sensor.
13. A pipettor comprising: an orifice; a tip coupled to the orifice; a conductivity sensor coupled to the tip; and a controller coupled to the conductivity sensor and configured to determine a conductivity of a sample taken up by the pipettor using data from the conductivity sensor.
14. A pipettor comprising: a tip comprising a sensor; and a controller; wherein the tip is configured to automatically identify the sensor to the controller.
15. The pipettor of claim 14, where the controller is configured to execute an algorithm corresponding to the identified sensor.
16. The pipettor of claim 14, where the tip is further configured to automatically identify the size of the tip to the controller.
17. A pipettor comprising concentric, multiple plungers configured to dispense different fluid volume ranges and a motor drive assembly configured to control the multiple plungers independently.
18. The pipettor of claim 17, the pipettor further comprising an integrated particle counter, the pipettor being configured to use a first plunger to determine a particle concentration and a second plunger to take up and dispense a desired volume.
19. The pipettor of claim 17, further comprising a controller configured to identify a maximum fluid capacity associated with each of the multiple plungers.
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