Abstract:
Described are pipetting systems that automatically track the dispensing and extracting of reagents to and from arrays of well locations. The systems track the position of a pipette with respect to the well locations, and selectively illuminate those locations to indicate the progress of pipetting operations. Control logic can shepherd pipetting processes, indicating errors and guiding the user.

Description:
FIELD 
       [0001]    The present invention relates to method and systems for pipetting reagents for use in various kinds of analysis, such as immunoassays and DNA analysis. 
       BACKGROUND 
       [0002]    Transferring reagents to, from, or between vials—a process commonly referred to as “pipetting”—is a basic function for most life science and chemical labs. Vials, also called “tubes” or “wells,” can be small and are commonly arrayed in considerable numbers. Pipetting large numbers of samples is repetitive and prone to human error. Unfortunately, such errors can result in grave consequences, especially in clinical diagnostic and forensic labs. 
         [0003]    A number of companies have commercialized semi-automated pipetting tracking devices to reduce pipetting errors. For example, some pipetting systems position arrays of wells over similar arrays of visible light-emitting diodes (LEDs) to selectively illuminate the wells from beneath. Other systems employ an LCD screen in lieu of an array of LEDs for the same purpose, as detailed in U.S. Patent Publication No. US 2006/0188406 to James Dahle Frost III. Users of such devices can use this lighting to keep track of which wells will be subjected to the next pipetting step. These systems require the user to select an illumination pattern specifying a pipetting order. The user then manually advances to a next well or set of wells after each pipetting step, or advances to the next well or set of wells responsive to a preset timer. The manual step can include pressing a button, a foot switch, or passing a sensor outside the pipetting zone. These manual steps add to the workload and are also subject to human error. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0004]    The subject matter disclosed is illustrated by way of example, and not by way of limitation, in the figures of the accompanying drawings and in which like reference numerals refer to similar elements and in which: 
           [0005]      FIGS. 1A and 1B  depict a system  100  for tracking the position of a pipette  105  with respect to a well plate  110 . 
           [0006]      FIG. 2  depicts an embodiment of pipette  105 , which includes a pipette body  200  and a thumb-activated plunger  205 . 
       
    
    
     DESCRIPTION 
       [0007]      FIGS. 1A and 1B  depict a system  100  for tracking the position of a pipette  105  with respect to a well plate  110  that includes an array of well locations  115  defining an X axis and a Y axis. System  100  includes a well designator  120  that selectively directs light to one or more well locations responsive to control signals Ctrl. Illuminated well locations  115  are highlighted using cross-hatching, which illumination indicates e.g. that the respective location was the subject of a prior pipetting operation. 
         [0008]    A sensor  125  along the periphery of well plate  110  is positioned above well locations  115 , from a perspective along a Z axis normal to the X and Y axes, to detect positions of pipette  105  with respect to the well locations. Well plate  110  is a microplate with integrated vials in this example, but other types of well plates (e.g., microplates or racks that support discrete vials) can also be used. 
         [0009]    Control logic  130 , such as a central processing unit (CPU) or microcontroller, receives sensory signals Snc from sensor  125 . Control logic  130  derives control signals Ctrl from the sense signals and feeds them to a display driver  135 . Display driver  135 , in turn, issues conventional display signals Dsp to control well designator  120 . 
         [0010]    Sensor  125 , in this embodiment, includes arrays of infrared photodiodes  140  that produce beams of light  145  to photoreceptors  150 . In one embodiment sensor  125  is a light-based touch screen of the type detailed in U.S. Patent Publication No. US 2009/0189878 to Goertz et al., which is incorporated herein by reference. Such screens employ light beams that can be used to detect the presence of pipette  105  or e.g. a user&#39;s finger. Sensor  125  can determine the position of a pipette or finger relative to the X and Y axes, and consequently relative to well locations  115 . Some embodiments may support different arrangements of sensors, such as to support parallel planes of light  145 , to provide a measure of pipette angle. Angle sensitivity can be used to more precisely locate the tip of pipette relative to the well locations. Some embodiments may only determine the position of a pipette or finger relative to the Z axis, without determining the accurate position to the X and Y axes. The Z axis detection can be used to advance illumination to a next well or set of wells based on the preselected illumination pattern specifying a pipetting order. 
         [0011]    System  100  additionally includes alignment mechanisms  142  that may double as well spacers to establish a desired spacing between light beams  145  and the tops of well locations  115 . Closer spacing renders system  100  less susceptible to location errors due to pipette angle. 
         [0012]    In the depicted embodiment, well designator  120  is a touch-screen display, which can double as a user interface for e.g. calibrating and issuing user input to control logic  130 . Display  120  can react to sensor  125 , some other sensor (e.g., capacitive sensors in the display), or both. In still other embodiments control logic  130  is equipped with an antenna  155  or wired connection that allows control logic  130  to communicate with pipette  105 . As discussed in more detail in connection with  FIG. 2 , antenna  155  allows control logic  130  to receive user input and other information from pipette  105  (e.g., dosage amounts, number of pipette channels, completion of a pipetting operation, and error messages), and can allow control logic  130  to communicate information to pipette  105 . System  100  can also include e.g. a microphone and speaker to facilitate interaction between a user and control logic  130 . 
         [0013]    With reference to  FIG. 1A , each cross-hatched well location  115  may be assumed to indicate a well that has been subjected to a pipetting operation, such as receiving a dose of a reagent, and that has consequently been illuminated (e.g., by green light). The next well location  115 , at Cartesian coordinate A12, is not illuminated, or may be illuminated with a different color than the other well locations, to identify it as a “next” well location to receive a pipetting operation. The user would thus place the pipette in proximity to the next well location and e.g. provide the dose of reagent. System  100  would sense the proximity of pipette  105  to the well location  115  at location A12 and change the corresponding illumination to indicate receipt of the reagent. The illumination parameters can be modified to suit different needs. For example, some assays may be sensitive to certain lights. It will be desirable to illuminate wells that have not received the reagent, and turn off illumination on wells that have received the reagent. Users can also illuminate only the wells subject to next pipetting step to minimize the overall light exposure, or choose certain light colors that will not interfere with the assays. 
         [0014]    The user may miss a well location, or may subject the same well location to multiple pipetting operations. In either case system  100  uses the sensed coordinate of pipette  105  to identify the error and provide appropriate user feedback. In embodiments in which pipette  105  is capable of transmitting indicia of a pipetting operation, such as a signal indicating depression of a plunger, control logic  130  can use this information along with the location information to identify a pipetting operation. 
         [0015]    Well designator  120  is a touch screen in this embodiment, but may be e.g. a standard display or an array of lights (e.g. light-emitting diodes). In other embodiments well designator  120  can uniquely designate wells or collections of wells using by reference to row(s), column(s), or both. For example, the text “B12,” or icons or lights adjacent row B and column 12, may designate the next well location  115  in  FIG. 1A . Other means of uniquely designating well locations or collections of well locations will be evident to those of skill in the art. 
         [0016]    In still other embodiments the well designator can transmit light to well plate  110  from above, as by projecting an image or light beams that selectively illuminate well locations  115 . Such illumination preferably impinges well plate  110  at an angle with respect to the Z axis so the pipette does not overly interfere with the illumination. Well designator  120  may be calibrated with control logic  130  for different sizes, numbers, and spacing of well locations  115 . Illumination patterns specifying a pipetting order can then be illuminated to guide the user. Other embodiments omit such calibration, as the sensing of pipetting operations automatically identifies the well locations. 
         [0017]      FIG. 2  depicts an embodiment of pipette  105 , which includes a pipette body  200  and a thumb-activated plunger  205 . Pipette  105  additionally includes a sensor  210  that communicates with plunger  205  to sense a pipetting operation and control logic  215  (e.g., a microcontroller) that receive input from sensor  210 . Pipette  105  additionally includes a transmitter/receiver TxRx and an antenna  220  to facilitate communication between pipette  105  and control logic  130  ( FIG. 1B ). Pipette  105  can thus communicate pipette signals to controller  130  to indicate e.g. completion of a pipetting operation, an amount of reagent, or an error signal (e.g., that a plunger operation failed to take on or release a desired reagent volume). Pipette  105  can also receive information from controller  130 ; in one embodiment, for example, controller  130  issues user feedback to pipette  105  to indicate completion or errors in pipetting operations. Pipette can alert the user in such instances using e.g. light, sound, or vibration. In still other embodiments controller  130  may prohibit or initiate delivery or extraction of reagents from well locations based on the sensed proximity of pipette  105 . 
         [0018]    System  100  detects the tip of pipette  105  in the foregoing examples, but may similarly detect the reagent. In embodiments in which a stream of reagent is detected, sensor  125  can be used to time the stream to obtain a measure of volume. Moreover, solid reagents, such as pills, can be counted for each well location. 
         [0019]    While the present invention has been described in connection with specific embodiments, variations of these embodiments are also envisioned. For example, when a multi-channel pipette is used, system  100  can detect and illuminate multiple locations or an area of locations. The system  100  can also detect multiple well plates with different styles e.g. 96-well or 384-well for plate-to-plate reagent transfer. These examples are in no way exhaustive, as many alternatives within the scope of the claims will be obvious to those of ordinary skill in the art. Therefore, the spirit and scope of the appended claims should not be limited to the foregoing description. Only those claims specifically reciting “means for” or “step for” should be construed in the manner required under the sixth paragraph of 35 U.S.C. Section 112.