Abstract:
A sample treatment system for automated extraction of compounds is disclosed. The system includes a housing defining an enclosure including a top cover having open ended chambers to receive sample plates on an interposed carriage frame, an automated shuttle means for lateral transportation and vertical lifting of the carriage frame to selectively address the chamber below the sample plate for the throughpassage of fluid from the sample plate and urged by a vacuum pump for evacuating air from a chamber to a degree below atmospheric pressure for through passage of fluid from the sample plate to either a waste plate or a collection plate. The shuttle means includes motor drives for precisely laterally and vertically positioning the carriage frame.

Description:
FIELD OF THE INVENTION 
     The instant invention relates generally to a robotic sample treatment system and, in particular, to a variably controllable vacuum extraction system including a vacuum manifold with both waste and collection sites communicating with a vacuum pump. 
     BACKGROUND OF THE INVENTION 
     Sample preparations in medical diagnostics, the pharmaceutical industries, chemical industries as well as people doing DNA work require many precise liquid handling steps, such as: transfer of samples, dilutions, additions of reagents, transfer of reaction mixtures, etc. Automated liquid handling systems have been developed and are commercially available in the form of programmable pipetting work stations. These automated systems reduce the manual labor involved in the liquid handling and processing of samples. See for example, U.S. Pat. No. 6,033,911, owned by applicant. 
     However, these systems are not completely automatic and still require manual manipulation and user intervention, especially when using a manual vacuum manifold system with the pipetting work station. The processing of liquids still requires human intervention and manual manipulation. Typically, the user is required to place a filter plate on top of the manual vacuum box and then the filter plate is filled with a plurality of samples. Once the filter plate is filled with samples, the user has to manually manipulate the vacuum during the wash steps of the extraction process. Once the wash step of the extraction process is completed, the user carefully removes the filter plate containing the remaining constituents which are being collected. The user then places a collection plate into the vacuum box and then places the filter plate on top of the collection plate and then manually manipulates the vacuum to extract the constituent of interest. Thus, the user is constantly interacting with the system during the collection of samples. 
     Thus, existing systems have short comings that limit their efficiency. For example, some analytical laboratories process hundreds of samples using solid phase extraction or other techniques. Since the steps are highly repetitive, automated systems are needed to reduce the manual labor involved in the liquid handling and processing steps. In addition, user intervention and manual operations reduce the efficiency of an otherwise automated analytical system. 
     Therefore, there is a need for an apparatus and method for performing analytical procedures without the need for operator intervention and minimizing the manual tasks before, during and after the analytical procedures. 
     In addition, there is a need for an apparatus and method which provides automated vacuum control to enhance flow rates through the sorbing media or frit, thus providing good recoveries and throughput of flow rate dependent compounds. In addition, a system having an automated variable vacuum control would mitigate well to well cross talk tendencies. 
     The following prior art reflects the state of the art of which applicant is aware and is included herewith to discharge applicant&#39;s acknowledged duty to disclose relevant prior art. It is stipulated, however, that none of these references teach singly nor render obvious when considered in any conceivable combination the nexus of the instant invention as disclosed in greater detail hereinafter and as particularly claimed. 
     
       
         
               
               
               
             
           
               
                   
               
               
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     OTHER PRIOR ART—NON PATENT LITERATURE DOCUMENTS 
     Applied Biosystems, “6700 Automated Nucleic Acid Workstation”, November 2000, entire brochure. 
     D&#39;Autry discloses a moveable carriage (120) which enables a waste receptacle or individual tubes to be placed beneath an orifice of a cartridge. 
     SUMMARY OF THE INVENTION 
     U.S. Pat. No. 6,133,045, also owned by applicant, resolved many of these problems. However, the present invention takes this technology to a new level. 
     The instant invention provides an automated sample treatment system for automated extraction of genomic and plasmid DNA or simultaneous solid phase extraction of compounds. The sample treatment system is integrated with an automated pipetting work station and a robotic arm which automatically transfers treatment plates into and out of the system. The system includes an automated shuttle means for lateral transportation and vertical lifting of treatment plates over stationary waste and collection sites. 
     In a preferred form, the sample treatment system of the instant invention is integrated with the liquid handling capabilities of a programmable pipetting work station. The sample treatment system includes a vacuum manifold apparatus having a shuttle mechanism, a vacuum control apparatus and an electronic control system. 
     A robotic arm delivers sample treatment plates with respect to the vacuum manifold extraction system for further automation. A vacuum box has two distinct chambers defining two areas to individually receive vacuum: an elution area and a waste area. Each area has a vacuum port. 
     The vacuum control apparatus includes a vacuum pump which is operatively coupled to the vacuum areas via vacuum lines extending from the vacuum pump to each port of the vacuum box. Thus, when the vacuum pump is turned on, the vacuum area of one chamber is depressurized and the vacuum power will pull the liquid from a sample treatment plate during at least two processes detailed below. A liquid waste bottle is coupled to a drain in the vacuum box and a waste pump removes and stores waste liquid in the waste bottle. 
     A transport carriage is operatively coupled to a lift and transport mechanism all of which are disposed exteriorly of both chambers. Thus, the lift and transport mechanism is not exposed to the chemicals used in the system&#39;s chambers. The lift and transport mechanism moves to and from the elution chamber and waste chamber and is preferably dimensioned to cover only one chamber. This allows outside access to the exposed treatment plate (for example by pipetting station or robotic arm). As a consequence, when the chamber receiving the transport carriage is being “processed” (e.g., receiving vacuum) the other chamber is available for further external processing (e.g., removal/insertion via robotic arm, waste removal or pipetting). By sequestering the vacuum box into discrete, separate vacuum areas, the vacuum chamber volume is smaller and therefore requires a smaller vacuum pump. 
     Whereas U.S. Pat. No. 6,133,045 teaches pulling a vacuum through the waste bottle, the present invention utilizes a separate waste circuit, powered by its own pump. By having the vacuum pump on its own circuit, vacuum pump requirements are further lessened. Adjusting the vacuum pressure is also easier since the waste circuit is no longer an element. 
     OBJECTS OF THE INVENTION 
     Accordingly, a primary object of the instant invention is to provide a new, novel and useful sample treatment system: apparatus and method. 
     A further object of the instant invention is to provide a sample treatment system as characterized above which includes a vacuum manifold apparatus with both waste and collection sites. 
     Another further object of the instant invention is to provide a sample treatment system as characterized above which includes an automated vacuum based extraction apparatus. 
     Another further object of the instant invention is to provide a sample treatment system as characterized above which includes a computer interface system including a communication interface and in system programmability. 
     Another further object of the instant invention is to provide a sample treatment system as characterized above which is a stand alone functional module. 
     Viewed from the first vantage point, it is an object of the present invention to provide a sample treatment device, comprising in combination: a housing having plural chambers; a sample plate; means to expose said sample plate to one chamber in said housing; extraction means operating on the sample plate addressing the sample plate to the one chamber and in fluid communication, and shuttle means to selectively present the sample plate to one of the plural chambers for the throughpassage of fluid from the sample plate. 
     Viewed from the second vantage point, it is an object of the present invention to provide a method for treating a sample, the steps including: providing a housing with plural chambers; nesting a sample plate to address one of the chambers wherein the sample plate is in open fluid communication with both an interior area of the one chamber and exteriorly; evacuating air from the one chamber to a degree below atmospheric pressure for throughpassage of a fluid from the sample plate to the chamber; shuttling the sample plate to selectively address another chamber. 
     Viewed from the third vantage point, it is an object of the present invention to provide a sample treatment device, comprising in combination: a housing having plural chambers including means for receiving a sample plate in open fluid communication with both an interior of one said chamber and exteriorly; means for moving the sample plate to said plural chambers; and means for evacuating air from any of the plural chambers to a degree below atmospheric pressure for throughpassage of a fluid from the sample plate to the chamber presented with the sample plate. 
     Viewed from the fourth vantage point, it is an object of the present invention to provide a sample treatment device, comprising, in combination: housing having plural chambers, each including means for receiving a sample plate in open fluid communication both with an interior of one said chamber and exteriorly; said plural chambers including a waste chamber and a collection chamber; means for shuttling said sample plate to either said waste chamber or said collection chamber; and means for evacuating air from said chamber to a degree below atmospheric pressure to pull a fluid from the sample plate to either said waste or collection chamber when said sample plate is adjacent thereto. 
     Viewed from the fifth vantage point, it is an object of the present invention to provide a device to move fluid from a sample plate having plural samples oriented in open bottomed vertical tubes to a collection plate having a complemental number of open topped vertical tubes as the sample plate, comprising, in combination: a chamber to support the collection plate substantially horizontally; said sample plate supported on means to move said sample plate vertically to said chamber and adjacent said collection plate; a vacuum means in said chamber to draw fluid from said tubes in the sample plate; said vacuum means drawing samples from a bottom of said sample plate into said collection plate such that each sample in said sample plate is directed to a corresponding said vertical tube in said collection plate without cross-talk between adjacent tubes once said sample has been moved vertically proximate to said collection plate. 
     Viewed from the sixth vantage point, it is an object of the present invention to provide a method for treating samples, the steps including: placing a sample treatment plate on a sample support; robotically addressing the sample treatment plate with a pipetting mechanism; eluting and washing preparations contained in said sample treatment plate including applying a vacuum; and robotically removing the sample treatment plate. 
     Viewed from the seventh vantage point, it is an object of the present invention to provide a sample treatment workstation, comprising, in combination: a robotic pipetting means; a sample support for receiving a sample treatment plate and addressing said pipetting means; said sample support including eluting and washing means and a robotic arm having means to transfer sample treatment plates to and from said sample support. 
     These and other objects will be made manifest when considering the following detailed specification when taken in conjunction with the appended drawing figures. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a from elevational view of the robotic sample processor and the robotic arm. 
         FIG. 2  is a front elevational view of the vacuum manifold apparatus shown disposed on the robotic sample processor adjacent the robotic arm. 
         FIG. 3  is a conceptual flow chart of two vacuum box layouts, plumbed to a common vacuum pump, waste disposal and control system. 
         FIG. 4  is an upper perspective view of the vacuum manifold apparatus. 
         FIG. 5  is a lower perspective view of that which is shown in FIG.  4 . 
         FIG. 6  is a side view of the  FIG. 4  shuttle mechanism in a first motion. 
         FIG. 7  is a side view of the shuttle mechanism in a second motion. 
         FIG. 8  is a side view of the shuttle mechanism in a third motion. 
         FIG. 9  is a top plan view of the shuttle mechanism. 
         FIG. 10  is a sectional view of the shuttle mechanism taken along lines  10 — 10  of FIG.  9 . 
         FIG. 11  is a perspective view of the waste container shown in FIG.  10 . 
         FIG. 12  is a perspective view of waste side isolation plate shown in  FIGS. 9 and 10 . 
         FIG. 13  is a perspective view of the elution side collection plate positioner shown in  FIGS. 9 and 10 . 
     
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
     Referring to the drawings, wherein like reference numerals denote like parts, numeral  300  ( FIG. 2 ) is directed to the sample treatment workstation according to the present invention. In its essence, the workstation  300  includes a pipette station  100 , a robotic arm  200  and a vacuum box  10 . 
     The pipette station  100  includes a work table  140  ( FIG. 1 ) upon which the vacuum box  10  is placed. In addition, the pipette station  100  includes a probe assembly  150  which has three degrees of freedom as shown in  FIG. 1  to include latitudinal translation along the direction of the arrow “X”, longitudinal translation along the arrow “Y” and vertical translation along the arrow “Z” so that the probe assembly  150  can move along the length and width of the table and up and down. A source of fluid  120  is operatively coupled to a pump  130  which delivers the fluid to the probe assembly  150  by means of a fluidic network comprised of a series of tubes  125 , valves  135  and discreet delivery units  145 . The probe assembly  150  includes a multiplicity of individual probe tips  155  each of which can carry same or different fluids as dictated by the valves  135  and discrete delivery units  145  for urging fluid through the probe assembly  150 . The probe assembly  150  is shown as having 96 tips  155  oriented in an 8×12 array. Other probe arrays and tip populations are possible. Control for the various fluids that pass through the probe assembly is controlled by a computer  110  which can also control the robotic arm  200  and vacuum box  10  and its sequencing protocols. 
     The robotic arm  200  includes a base  202  having a slot  204  extending along its length upon which a mast  206  is vertically disposed and adapted to slide within the slot  204  along the Y direction shown in  FIGS. 1 and 2 . In addition, the mast  206  is adapted to rotate about the double ended arrow “W” by virtue of its coupling to a stem  207  of the mast  206  via a swivel  220 . The mast  206  includes a vertical slot  208  to allow vertical translation of a transversely oriented arm  210  along the direction of the double ended arrow “Z”. The arm  210  is capable of telescopic extension along the direction of the double ended arrow “Y” by means of a telescopic rod  211  extensible within the arm  210 . A free end of the telescopic rod  211  attaches to engaging fingers  214 . The engaging fingers  214  are formed as two substantially L-shaped brackets which face each other to form a substantially “U” shaped structure. Each bracket has a leg proximate the rod  211  fitted with a slot  215 . The slots  215  are in overlapping registry and held by pins  218  (one pin per leg fixed, the other pin slideably disposed in the other&#39;s slot  215 ) which inwardly allow the two opposed free ends of the L-shaped fingers to move along the double ended arrow “X”. Thus, the spacing between the two pairs of L-shaped fingers  214  can be manipulated to grasp side edges of a sample plate  40  to be described. In order to assist in the engagement, each of the engaging fingers  214  includes retention pins  216  on their facing sides to nest within corresponding recesses  41  ( FIG. 4 ) on the sample plate  40 . 
     The sample plate  40  is dimensioned to lie atop vacuum box  10 . Specifically, a carriage frame  2  ( FIG. 4 ) is interposed between the sample plate  40  and a housing  20  of the vacuum box  10 . The carriage frame  2  defines one component of a lift and transport carriage assembly which moves between a first and second position. In a first position, the carriage frame addresses a first (waste) chamber  4  formed within the housing  20 . In a second position, the carriage frame addresses a second (elution) chamber  6  also formed in the housing  20 . 
     The housing  20  overlies a substantially box-shaped interior  21  ( FIGS. 5 and 10 ) having the first and second chambers  4 ,  6  disposed in substantially side by side relationship, interrupted one from the other by a dividing wall  8 . Each chamber is a substantially box-shaped hollow enclosed by three sidewalls  12  and the common dividing wall  8  and includes a floor  14 . A top surface of the housing interior  21  includes a relief area  16  circumscribing each of the chambers, the relief area  16  dimensioned to receive a gasket  18  carried on the lower periphery of carriage frame  2 . The carriage frame  2  is substantially a rectangular construct having four sides  22  leaving an open top and an open bottom. The open top includes a peripheral chamfer  24  to insure tight nesting of the sample plate  40  and a seal which will support a vacuum. 
     The first chamber  4  is regulated to waste as from system washing or purging and includes a drain line  26  passing through its bottom wall  14 . An opening  28  extends through a sidewall  12  from which to draw a vacuum. In addition, the first (waste) chamber  4  receives both a waste container  30  resting on its floor  14  and an isolation plate  32  resting on the waste container  30 . The waste container  30  is essentially an opened top box having a bottom wall  34  and peripheral sidewalls  36  in which the bottom wall  34  includes an opening  38  which communicates with a drain opening in the first chamber  4  and mates therewith by means of a drain stem  42  extending between the drain line  26  and opening  38  to allow waste material to be collected in the waste container  30  and subsequently pumped therefrom into a waste bottle  44  ( FIG. 3 ) via pump  46 . As shown in  FIG. 3 , the drain line  26  communicates via a conduit  48  to the waste pump  46  which transfers waste from the waste container  30  to a waste bottle  44  which is provided with an integrated float and sensor  50  so that when the waste bottle  44  nears being filled, the sensor coupled to the float communicates with control electronics  52  to provide a signal on the screen of the computer  110  to denote that it is time to empty or replace the waste bottle  44 . 
       FIG. 12  reflects details of the bottom surface  56  of the waste isolation plate  32  which in effect provides isolation of each open end of the sample plate  40  when the open ends  72  penetrate within wells  54  of the isolation plate for their washing. As shown in  FIG. 12 , the isolation plate  32  includes a downwardly extending peripheral skirt  58  dimensioned to depend within the waste container  30  upon a shelf  60  formed on a top surface of plate  32 . The number of wells  54  and their dimension are calculated to each receive one open end of the sample plate  40 . The wells have sidewalls  55 . By having the lowermost portion of each open end isolated within one well on the isolation plate, the fluid in the sample plate can be vacuum-pulled downward with minimal concern of “cross-talk” (i.e., splatter) between each open end  72  which could otherwise introduce error during subsequent operations. 
     The second (elution) chamber  6  is a similarly dimensioned well having a floor  14  and peripheral walls  12  (FIG.  10 ). A positioner  62  is located on the floor  14  of the second chamber  6  and maintains a collection plate  64  ( FIG. 4 ) in a fixed position. As shown in  FIGS. 10 and 13 , the collection plate positioner  62  includes a base  66  of substantially rectangular planar configuration having truncated corners  68  such that these corners are mitered at a substantially forty-five degree angle. Adjacent each of these mitered corners are vertically upstanding marginal portions  70  which project above the base  66  and are fashioned to somewhat parallel the interior sidewalls  12  of the second chamber  6 . These marginal portions  70  are on all four sides of the base  66  and include latitudinal and longitudinal margins. The longitudinal margins have interruptions  67  medially disposed. Two holes  69  pass through the base  66 , equispaced from a transversely disposed centerline with respect to the longitude of the collection plate positioner  62 . In one form of the invention, the marginal portions  70  have inwardly chamfered top surfaces  71  sloping down from the peripheral sidewalls  8 ,  12  of the second chamber. These marginal portions  70  subsequently accurately position the collection plate  64  since its orientation within the elution chamber  6  is important to assure vertical registry when the sample plate  40  is held in overlying relationship. It is important to note that the sample plate  40  typically includes downwardly projecting open ends  72  ( FIG. 4 ) corresponding in number to each of the probe tips  155  associated with the probe assembly  150 . Thus, it is important that each open end  72  on the sample plate  40  have a corresponding well opening  74  within the collection plate  64  in vertical alignment therewith to assure a minimal cross-talk between adjacent specimens represented by tips  155  and open end  72 . One feature of the instant invention is that various collection plate positioners  62  may have different vertical dimensions (as by the height of marginal portions  70 ) so that the positioner  62  can control the distance that exists between the collection plate  64  and the sample plate  40 . It is desired that this relationship between the collection plate  64  and the sample plate  40  be held within close tolerances so that the lowermost extremity of each open end  72  of the sample plate  40  resides at least partially within a corresponding well opening  74  of the collection plate  64  to guarantee accurate deployment of the fluid therewithin without migration to an adjacent well opening. A site window  78  ( FIG. 4 ) is provided passing through the lid  22  so that upon assembly, the proper relationship between the collection plate  64  and the sample plate  40  can be assured. The second chamber  6  is similarly provided with a vacuum portal  80  ( FIG. 10 ) to draw fluid down from the sample plate  40  into the collection plate  64 , similar to the first chamber  4 . The second chamber  6  preferably does not, but may also include a drain  82  similar to the first chamber  4 . 
     As mentioned, the carriage frame defines one component of a lift and transport carriage assembly which allows the carriage frame to move between the first and second chambers. 
     Specifically, and with reference to  FIGS. 5 through 10 , the carriage frame  2  is shown as including at least one gasket  18  along its bottom peripheral edge. The carriage frame is defined by a circumscribing wall  22  of substantially rectangular shape open at its bottom and top and provided with a chamfer  24  around its top inner periphery so that the sample plate  40  can nest securely therewithin. 
     The carriage frame  2  has, on two opposed sides thereof, first and second lift rods  84  that are pivoted adjacent corners of the frame  2 . Each of the four lift rods  84  has a remote end which terminate in a cam link  86  at each end thereof. The cam links  86  in turn are connected to gear pairs  88  which are held in meshing engagement. Thus, when the gears rotate as shown in  FIG. 8 , the carriage frame moves from the upward position shown in  FIG. 6  downwardly to the position shown in FIG.  8 . Conversely, when the gears shown in  FIG. 8  rotate in a direction opposite from the arrows as shown thereat, the carriage frame moves upwardly as shown in FIG.  6 . The carriage frame is held stable by means of two slide rods  90 , medially disposed between the lift rods  84  and on the sides of the carriage frame that receive the lift rods  84 . Two bores  92  ( FIG. 4 ) pass through the carriage frame  2  to receive the slide rods  90  so that when the carriage frame is in its lowermost position (FIG.  8 ), a free end of the slide rod  90  projects upwardly from the carriage frame (FIG.  8 ). Each slide rod  90  is attached at its opposite end to a support plate  93  ( FIG. 5 ) through which gears&#39; shafts  94  project and fix to the cam links  86 . The support plates  93  depend from a trolley  102  at extremities thereof. These gear shafts  94  ( FIG. 5 ) extend between the support plates  93  and drive the gear pair  88  to move the transport carriage assembly. One of the gear shafts includes a driven gear  96  which is driven by a drive motor  98  depended from an underside of the trolley  102 , intermediate the support plates  93 . As the drive motor  98  rotates, its drive gear  104  rotates the driven gear  96  on one of the two shafts  94  as shown, which in turn drives the gear pair  88  to effect motion of the lift rods  84  as described. 
     In addition, the lift and transport carriage assembly includes a drive belt  105  spanning the length of the vacuum box and transverse to the long axis of the drive gear shafts  94 . The drive belt  105  is held in position at remote extremities by means of pulley tabs  106 , pairs of which each have an interposed pulley  108  therebetween. The drive belt  105  is looped over each pulley  108  and a portion of the drive belt is operatively coupled to the trolley  102 . When the drive belt  105  is driven by means of a belt motor  112  shown in  FIG. 5 , the trolley can move from over the first chamber  4  to the second chamber  6  and back as suggested by the horizontal arrow in FIG.  7 . Note that it is preferred that the carriage frame  2  be in the uppermost  FIG. 6  position prior to linear translation. The drive motor  112  for the belt  105  is fixed on an underside of the vacuum box and operatively coupled to the belt  105  or one pulley  108 . 
     The computer  110  is operatively coupled to control the robotic arm  200  in grasping, inter alia, sample plates  40  and operating the vacuum pump and waste pump as well as powering the transport mechanism and the pipette operation. 
     Moreover, having thus described the invention, it should be apparent that numerous structural modifications and adaptations may be resorted to without departing from the scope and fair meaning of the instant invention as set forth hereinabove and as described hereinbelow by the claims.