Abstract:
A device and related method for dispensing liquid. The device includes a housing configured to contain a plurality of liquid dispensing members containing a liquid and configured to contain a receiving member in a receiving position to receive the liquid from the plurality of liquid dispensing members. The housing defines a first pressure chamber and a second pressure chamber. The first pressure chamber is capable of being sealed relative to the second pressure chamber. The device also includes a differential pressure generator operably connected to one of the first and second pressure chambers. The generator is capable of generating a pressure differential between the first and second pressure chambers to cause the plurality of liquid dispensing members to dispense liquid to the receiving member.

Description:
RELATED APPLICATIONS  
       [0001]    This application is a continuation of U.S. application Ser. No. 09/426,708, filed on Oct. 26, 1999, which is incorporated herein by reference in its entirety. 
     
    
     
       BACKGROUND OF THE INVENTION  
         [0002]    1. Field of the Invention  
           [0003]    The present invention relates to a device and related method for dispensing small volumes of liquid, and more specifically to such a device and method for simultaneously dispensing liquid from a plurality of liquid dispensing members into a receiving plate.  
           [0004]    2. Discussion of the Related Art  
           [0005]    Currently, screening programs identify potential compounds for use as drugs. Specifically, drug discovery often depends on high throughput screening (HTS) techniques to screen compounds, such as liquid analytes, as potential drug candidates. In HTS, an increasingly high number of compounds, most often organized in libraries, are tested simultaneously. Simultaneous testing of a high number of compounds is due, at least in part, to technological developments, such as automated testing, combinatorial chemistry, and the polymerase chain reaction. An increased demand for new and better drugs for a variety of diseases also drives the simultaneous testing of a high number of compounds.  
           [0006]    The standard library, or plate, for use in HTS has a 96 well per plate format. Thus, HTS systems typically have been developed for use with this format. For increasing throughput requirements and simultaneous testing of more compounds, HTS has been using higher density plates with, for example, 384, 864, 1536, and 9600 wells. These increased density plates present new problems. Particularly, the transfer of compounds into the plate often limits the testing process, as the compounds have to be brought into a high density often at a different geometry. Subsequent dispensing of solutions onto these high density plates during the testing process also poses difficulties. In addition, the introduction of robots and other forms of automation in drug discovery has led to new concerns, such as, for example, concerns regarding the speed, parallelization, volume, and reliability of robotic systems.  
           [0007]    Current transfer and dispensing systems often rely on glass pipettors with plungers (such as the Hydrasystem™ of Robin Scientific Inc.), needles or pins, or piezo-electric pipettors. Each such system has drawbacks. For example, current pipetting systems include the relatively high cost of pipet tips, which can be substantial in automated testing. The use of needles and pins for liquid dispensing, although less expensive, lacks control over the dispensed volume and does not provide for multiple replicas to be made. Current piezo-electric pipettors usually provide increased control over dispensed volume but typically are relatively large, difficult to miniaturize, and not suitable for massive parallel dispensing due to their relative expense. Current glass pipettors, although not as expensive, share many of the disadvantages of current piezo-electric pipettors and may not dispense liquid in volumes as small as 100 nanoliters.  
         SUMMARY OF THE INVENTION  
         [0008]    To overcome the drawbacks of conventional systems and in accordance with the purpose of the invention, the invention comprises a device for dispensing liquid. The device includes a housing configured to contain a plurality of liquid dispensing members containing a liquid and configured to contain a receiving member in a receiving position to receive the liquid from the plurality of liquid dispensing members. The housing defines a first pressure chamber and a second pressure chamber. The first pressure chamber is capable of being sealed relative to the second pressure chamber. The device also includes a differential pressure generator operably connected to at least one of the first and second pressure chambers. The generator is capable of generating a pressure differential between the first and second pressure chambers to cause the plurality of liquid dispensing members to dispense liquid into the receiving member.  
           [0009]    According to an embodiment of the inventive device, the first pressure chamber is in fluid communication with ambient environment. According to another embodiment, the device includes a plug to selectively seal the second pressure chamber from the ambient environment. The plug may include a valve in fluid communication with the second pressure chamber.  
           [0010]    According to a further embodiment of the device, the housing is configured to hold a first end of each of the plurality of liquid dispensing members in the first pressure chamber and a second end of each of the plurality of liquid dispensing members and the receiving member in the second pressure chamber.  
           [0011]    In an even further embodiment of the device, the differential pressure generator is in communication with the second pressure chamber and is capable of creating a pressure in the second pressure chamber that is lower than a pressure in the first pressure chamber.  
           [0012]    In another embodiment of the inventive device, the differential pressure generator is in communication with the second pressure chamber and includes a movable member capable of altering a volume of the second pressure chamber to alter a pressure within the second pressure chamber. In an embodiment, the movable member seals the second pressure chamber from ambient environment. The movable member may include a flexible member between a pair of movable plates.  
           [0013]    In another embodiment, the device of the present invention includes a support adjacent to the housing and capable of supporting a plurality of receiving members. The support may be movable relative to the housing to position a receiving member in the housing. In an embodiment, the support is moveable relative to the housing to sequentially position receiving members in the housing, one receiving member at a time.  
           [0014]    In a further embodiment of the device, the second pressure chamber is configured to contain the receiving member and the device includes a positioning device within the second pressure chamber capable of positioning the receiving member in the receiving position. The positioning device may include a movable element having an end capable of gripping the receiving member.  
           [0015]    According to another aspect, the invention comprises a device for dispensing liquid that includes a holder having a plurality of liquid dispensing members mounted therein. Each of the plurality of liquid dispensing members is configured to contain a liquid between first and second ends of the dispensing member. In an embodiment, each of the members is configured to contain a different liquid between the first and second ends. A receiving member is capable of receiving liquid dispensed from the plurality of liquid dispensing members. A housing defines a first pressure chamber and a second pressure chamber. The first pressure chamber is capable of being sealed relative to the second pressure chamber. A differential pressure generator is operably connected to at least one of the first and second pressure chambers. The generator is capable of generating a pressure differential between the first and second pressure chambers. The housing is configured to contain the holder in a dispensing position and the receiving member in a receiving position so that the generation of the pressure differential causes the plurality of liquid dispensing members to dispense liquid onto the receiving member.  
           [0016]    In an embodiment of the inventive device, the holder seals the first pressure chamber from the second pressure chamber.  
           [0017]    In another embodiment, the first pressure chamber is in fluid communication with ambient environment and the second pressure chamber is capable of being selectively sealed from the ambient environment.  
           [0018]    In a further embodiment, each of the plurality of liquid dispensing members is a capillary. In an even further embodiment of the inventive device, the housing is configured to contain the holder so that the first end of each capillary is in the first pressure chamber and the second end of each capillary is in the second pressure chamber.  
           [0019]    In yet another embodiment of the inventive device, the differential pressure generator is in communication with the second pressure chamber and capable of creating a pressure in the second pressure chamber that is lower than a pressure in the first pressure chamber. According to an embodiment, the differential pressure generator includes a movable member capable of altering a volume of the second pressure chamber to create the pressure within the second pressure chamber. The movable member may seal the second pressure chamber from ambient environment. The movable member also may include a flexible member. According to an embodiment, the flexible member is between a pair of movable plates.  
           [0020]    Another embodiment of the inventive device further includes a support adjacent to the housing and capable of supporting a plurality of receiving members. In another embodiment, the support is movable relative to the housing to sequentially position receiving members in the housing one receiving member at a time.  
           [0021]    According to a further embodiment of the inventive device, the second pressure chamber is configured to contain the receiving member, and the device further includes a positioning device within the second pressure chamber capable of positioning the receiving member in the receiving position. In an embodiment, the positioning device includes a movable element having an end capable of gripping the receiving member.  
           [0022]    According to a further aspect, the invention comprises a method of dispensing liquid from a plurality of liquid dispensing members onto a receiving plate. The method includes the steps of positioning a plurality of liquid dispensing members into a dispensing device so that a first end of each dispensing member is contained in a first pressure chamber of the dispensing device and a second end of each dispensing member is contained in a second pressure chamber of the dispensing device; positioning a receiving plate in the second chamber relative to the second ends of the dispensing members; and creating a pressure differential between the first and second pressure chambers so that the dispensing members dispense liquid into the receiving plate.  
           [0023]    According to an embodiment of the method, the creating step includes lowering a pressure in the second pressure chamber. In an embodiment, lowering the pressure in the second pressure chamber includes increasing a volume of the second pressure chamber. The volume may be increased by moving a movable member.  
           [0024]    According to another embodiment, the inventive method further includes sealing the first pressure chamber from the second pressure chamber. The sealing step may include positioning a holder of the plurality of liquid dispensing members between the first pressure chamber and the second pressure chamber.  
           [0025]    In another embodiment of the inventive method, the first pressure chamber is exposed to an environment, and the method further includes sealing the second pressure chamber from the environment prior to the creating step.  
           [0026]    In yet another embodiment, the method further includes, subsequent to the pressure differential creating step, the step of equalizing pressures within the first and second pressure chambers.  
           [0027]    An embodiment of the method further includes the steps of removing the receiving plate from the second chamber, and repeating the receiving plate positioning step, the pressure differential creating step, and the pressure equalizing step to dispense liquid onto a subsequent receiving plate.  
           [0028]    In a further embodiment of the method each of the plurality of dispensing members is a capillary, the first end is an open top end, and the second end is an open bottom end.  
           [0029]    It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0030]    The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of the specification, illustrate preferred embodiments of the invention, and, together with a description, serve to explain the principles of the invention.  
         [0031]    [0031]FIG. 1 is a cross-sectional view of a dispensing device according to an embodiment of the present invention;  
         [0032]    [0032]FIG. 2 is a cross-sectional view of capillaries dispensing liquid onto a receiving plate in a dispensing device according to an embodiment of the present invention;  
         [0033]    [0033]FIG. 3 is a graph of displacement of plate elements within the dispensing device of FIG. 1 and a graph of pressure differential in chambers of the dispensing device of FIG. 1;  
         [0034]    [0034]FIG. 4 is a cross-sectional front view of a dispensing device according to another embodiment of the present invention;  
         [0035]    [0035]FIG. 5 is a cross-sectional side view of the device of FIG. 4;  
         [0036]    [0036]FIG. 6 is a cross-sectional front view of the device of FIG. 4 with a portion of its print head displaced vertically upwards;  
         [0037]    [0037]FIG. 7 is a partial cross-sectional front view of the device of FIG. 4 with a receiving plate positioned to receive liquid from capillaries;  
         [0038]    [0038]FIG. 8 is a cross-sectional front view of the device of FIG. 4 with a receiving plate positioned to receive liquid from capillaries;  
         [0039]    [0039]FIG. 9 is a top view of the device of FIG. 4;  
         [0040]    [0040]FIG. 10 is a front view of capillaries and a holder for use in a dispensing device according to embodiments of the present invention;  
         [0041]    [0041]FIG. 11 is a top view of the capillaries and holder of FIG. 10;  
         [0042]    [0042]FIG. 12 is a front view of the holder of FIG. 10;  
         [0043]    [0043]FIG. 13 is a top view of a bottom plate of the holder of FIG. 10;  
         [0044]    [0044]FIG. 14 is a bottom view of the top plate of the holder of FIG. 10 showing insertion of side plates;  
         [0045]    [0045]FIG. 15 is a front view of larger side plates of the holder of FIG. 10;  
         [0046]    [0046]FIG. 16 is a front view of other smaller side plates for the holder of FIG. 10;  
         [0047]    [0047]FIG. 17A is an enlarged partial front view of side plates for the holder of FIG. 10, showing two lip types;  
         [0048]    [0048]FIG. 17B is an enlarged front view of a lip type of a side plate, before and after the lip type is bent;  
         [0049]    FIGS.  18 - 21  respectively are bottom, side, cross-sectional front, and top views of an upper housing of the device of FIG. 4, with FIG. 20 taken at line A-A in FIG. 21;  
         [0050]    [0050]FIG. 22 is a bottom view and a cross-sectional side view of an upper round plate element of the print head of the device of FIG. 4;  
         [0051]    [0051]FIG. 23 is a bottom view and a cross-sectional side view of a lower round plate element of the device of FIG. 4;  
         [0052]    FIGS.  24 - 26  respectively are bottom, cross-sectional front, and top views of an upper plate of the print head of the device of FIG. 4, with FIG. 25 being taken at line A-A of FIG. 26;  
         [0053]    [0053]FIG. 27 is a partial cross-sectional view of the upper plate of FIGS.  24 - 26 , showing a groove for an O-ring, taken at either line B-B or line C-C of FIG. 24;  
         [0054]    FIGS.  28 - 30  respectively are bottom, cross-sectional front, and top views of a middle plate of the print head of the device of FIG. 4, with FIG. 29 taken at line A-A of FIG. 30;  
         [0055]    [0055]FIG. 31- 33  respectively are bottom, cross-sectional front, and top views of a lower plate of the print head of the device of FIG. 4, with FIG. 32 taken at line A-A of FIG. 33;  
         [0056]    [0056]FIG. 34 is a partial cross-sectional view of the lower plate of FIGS.  31 - 33 , showing a groove for an O-ring, taken at line B-B of FIG. 31;  
         [0057]    FIGS.  35 - 39  respectively are bottom, cross-sectional side, cross-sectional front, side, and top views of a pneumatically driven element of the device of FIG. 4, with FIG. 37 taken at lines A-A of FIGS. 35 and 39, and with FIG. 36 taken at line B-B of FIG. 37;  
         [0058]    [0058]FIG. 40 is a partial cross-sectional view of the element of FIGS.  35 - 39 , showing a groove for an O-ring, taken at line C-C of FIG. 39;  
         [0059]    FIGS.  41 - 42  respectively are front and top views of a gripper of the device of FIG. 4; and  
         [0060]    FIGS.  43 - 44  respectively are cross-sectional front and top views of a mounting plate of the print head of the device of FIG. 4, with FIG. 44 taken at line A-A of FIG. 43. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0061]    The present invention relates to a device and related method for simultaneous dispensing of liquid from a plurality of liquid dispensing members into a receiving plate. The device and related method apply to liquid dispensing of very small volumes at high densities, i.e., number of dispensings per area, in parallel. The device and method are particularly suitable for use in automated drug screening or combinatorial chemistry. However, the principles of the device and the related method may be used in other applications requiring controlled dispensing of very small amounts of liquid in any specific format, or arrangement. The invention also relates to dispensing any liquid, including liquid with or without cells and viscous solutions such as gels in liquid state.  
         [0062]    Another advantage of the inventive device and related method includes miniaturization of parts, including the liquid dispensing members, so that disposable capillaries may be used. The smaller parts, and specifically capillaries, results in the ability to dispense very small volumes of liquid, reducing the costs from use of rare or expensive chemicals or analytes. The dispensed volume can range from one microliter to as low as ten nanoliters.  
         [0063]    The device and related method also have flexibility in the density of the dispensed volumes and in the type and size of the specific geometries of dispensing. For example, the device may dispense liquid or print liquid spots at densities ranging from the present standard of 1-4 per cm 2  up to 100 per cm 2  or higher in any geometric pattern, such as round, square, or an irregular shape. The device and method also may be used to print multiple identical prints from a single set of capillaries, or other liquid dispensing members, so that numerous tests may be performed on the same analytes. A further advantage of the device and method of the present invention includes the massive dispensement of liquid in parallel. For example, in automatic drug screening, the device may dispense liquid onto receiving plates with much higher than the conventional 96 wells per plate. Instead, dispensing can occur onto plates having hundreds or thousands of wells with the same footprint dimensions. As a further example, in combinatorial chemistry, standard parallel synthesis typically occurs in a maximum of 48 vials at a time with liquid transferred from one needle. The inventive device and method may be used for parallel liquid dispensing to support simultaneous synthesis in a much higher number of wells.  
         [0064]    In addition, the inventive device and related method may be fully automated, and is preferably computer controlled. This increases the speed of dispensing liquid into multiple receiving plates and minimizes human operation and error.  
         [0065]    The device and its related method operate under rapid, controlled relative changes in pressure above and below the liquid dispensing members. More specifically, a dispensing member such as a glass capillary holds a column of liquid by surface tension forces between open top and bottom ends. A rapid, controlled relative pressure drop at the bottom end will force liquid to be dispensed from the bottom of the capillary. Depending on various possible factors, including the type of capillary (its size, shape, and configuration), the viscosity of the liquid therein, and the relative pressure change, a drop of liquid may be released from the capillary or a drop may be suspended from the bottom end. If the former, the drop may be received by a receiving plate that may include wells corresponding to the number and arrangement of capillaries. If the latter, a receiving plate with or without wells may be accurately positioned relative to the bottom end of the capillaries to receive a printed spot of liquid from each capillary in a predetermined arrangement. The optimal gap between the receiving plate and the end of the capillary will depend on, among other things, the width of the capillary, the volume of liquid in the capillary, the pressure differential generated across the capillary, the properties of the liquid in the capillary, for example the viscosity of the liquid, and the properties of the receiving plate, for example the adhesive characteristic of the plate material. Through appropriate experimentation, one skilled in the art may determine the optimal size of the gap according to these and other various factors to result in the desired liquid print.  
         [0066]    The accompanying Figures and the following description refer to the present preferred and exemplary embodiments of the inventive device and related method. Like reference numerals refer to like parts in the various Figures.  
         [0067]    [0067]FIG. 1 shows a dispensing device  100  according to an embodiment of the present invention. Device  100  includes a housing having a top  102 , a bottom  104 , and sides  106  that define a pressure chamber  108 . A support  116  extends from the bottom surface of housing top  102 . Support  116  supports a holder  117  that contains a plurality of liquid dispensing members, for example, capillaries  114 . The plurality of capillaries may be a grid of, for example, eight rows of twelve capillaries per row. Each capillary  114  contains a liquid solution to be dispensed. Capillaries  114  are affixed to holder  117  preferably by an ultraviolet-cured glue on the outside of each capillary  114  or by any other suitable adhesive or fixing means. The liquid dispensing members may take forms other than capillaries for dispensing small volumes of liquid, for example micropipettes.  
         [0068]    Housing top  102  and support  116  with holder  117  therein define another pressure chamber  110  hermetically sealed from pressure chamber  108 . Chamber  110  is in fluid communication with ambient surroundings through opening  111 . A valve  112  couples to housing top  102  and is in fluid communication with chamber  108  via port  109 . Valve  112  is preferably a fast-responding, pneumatically-operable valve. However, the scope of this invention includes other suitable types of valves for altering the pressure within chamber  108  in a manner described below.  
         [0069]    A receiving plate  118  mounts onto a mounting plate  119  within chamber  108 . Receiving plate  118  is positioned at a right angle relative to capillaries  114  for receiving the liquid solution in each capillary  114 . Receiving plate  118  may be separated from the bottom ends of capillaries  114  by an optimal distance, as discussed above. A bolt  132  or other like fastening mechanism may be used to fix receiving plate  118  to mounting plate  119 . Alternatively, receiving plate  118  may sit loosely in position on mounting plate  119 . Mounting plate  119  connects to an end of a linear servodrive  120  through a rod  121  and shaft  123 . A seal  122 , such as an O-ring, seals around rod  121  to seal chamber  108  from ambient conditions. Servodrive  120  rotatably and vertically positions receiving plate  118  relative to capillaries  114 . Various types of suitable actuators may be used to accurately position receiving plate  118  relative to capillaries  114  and still be within the scope of this invention.  
         [0070]    Housing bottom  104  couples to a bottom plate  128 . Housing bottom  104  and bottom plate  128  each include a central throughhole. Top and bottom round plates elements  127  and  129  float within the central throughholes of bottom  104  and plate  128  by provision of a thin, circular flexible membrane  126 . Round plate elements  127 ,  129  and membrane  126  act as a differential pressure generator, as will be described. Flexible membrane  126  is firmly positioned between housing bottom  104  and bottom plate  128  and extends into the throughholes of bottom  104  and plate  128  to be firmly sandwiched between top and bottom round plate elements  127  and  129 . The portion of membrane  126  within the throughholes and not sandwiched between elements  127 ,  129  separates chamber  108  from ambient environment. This membrane portion, identified by reference numeral  126 ′, also has some gather (i.e. fold or wrinkle), as shown in FIG. 1, that permits floating plate elements  127 ,  129  to move vertically. That vertical movement alters the volume of chamber  108  and creates a pressure differential between chambers  108  and  110 , as will be described. A linear servodrive  124  couples to bottom round plate element  129  via a shaft  130  to control vertical displacement of plates  127 ,  129  and flexible membrane  126 . Once again, other types of suitable actuators may be used to accurately displace these elements vertically and still be within the scope of this invention.  
         [0071]    In operation, housing top  102  may be lifted or otherwise separated from housing sides  106  to position receiving plate  118  onto mounting plate  119  and to position holder  117  with capillaries  114  onto support  116 . Housing top  102  then may rejoin sides  106 . Servodrive  120  then rotatably and vertically positions receiving plate  118  under capillaries  114 . An open top of each capillary  114  is exposed to chamber  110 , whereas as open bottom of each capillary  114  is exposed to chamber  108 . At this point, because of equal pressures within chambers  108  and  110 , equal pressures exist at the ends of capillaries  114  and a column of liquid, for example a buffer solution, is held within each capillary  114  by surface tension forces. This state is shown in capillary  114  at the right in FIG. 2.  
         [0072]    A print cycle then begins by actuating servodrive  124  to move plates  127  and  129  vertically upwards. Chamber  108  then is plugged at port  109  via valve  112 . While chamber  110  remains at ambient pressure due to opening  111 , a pressure drop is created in chamber  108  by servodrive  124  displacing plates  127 ,  129  vertically downwards. That vertical displacement downwards increases the volume of chamber  108  to create the pressure drop. The pressure drop is preferably sudden and brief and performed in a controlled manner, as explained below, for example, in connection with FIG. 3. Thus, a lower pressure will exist in chamber  108  relative to chamber  110 . A top of each capillary  114  therefore will be exposed to a greater pressure than a bottom of each capillary  114  and a difference in pressure results across the liquid in each capillary  114 . This difference in pressure causes a microdroplet of liquid  142  to form at the bottom tip of each capillary  114 , as shown in FIG. 2. Droplet  142  touches receiving plate  118  and accurate vertical positioning of receiving plate  118  relative to capillaries  114  forms an oblate (flattened) liquid spheroid  144  between the capillary tip and receiving plate  118 , as also shown in FIG. 2. Liquid spheroid  144  leaves a printed spot on receiving plate  118 . As explained above, depending on various factors, the capillary instead may release a drop of liquid.  
         [0073]    After the brief, sudden pressure drop (which creates the printed spots), valve  112  is actuated to increase the pressure within chamber  108  and equalize the pressures within chambers  108  and  110 . Valve  112  may perform these functions by opening port  109  and exposing chamber  108  to ambient surroundings. Servodrive  124  also may return plates  127 ,  129  and flexible member  126  to their original positions. At this point, capillary forces (surface tension) will dominate once again and microdroplet  142  will return into capillary  114 . If desired, receiving plate  118  may be rotatably repositioned relative to capillaries  114  to print another copy of liquid solution onto receiving plate  118  from the same set of capillaries  114 . When the desired number of print copies has been made onto plate  118 , plate  118  may be removed from dispensing device  100  for use in chemical testing. Holder  117  and its capillaries  114  may be removed after printing the desired number of print copies and/or all the liquid within capillaries  114  is used.  
         [0074]    The top graph in FIG. 3 shows an exemplary position curve as a function of time for plates  127 ,  129  and membrane  126 . The bottom graph in FIG. 3 shows the absolute difference in pressure ΔP in chambers  108  and  110  as a function of time. Reference numeral  160  of the top graph (displacement v. time) represents the initial upwards displacement of plates  127 ,  129  and membrane  126  at the beginning of the print cycle. This upwards displacements occurs at approximately constant velocity until a time t 1 . Between times t 1  and t 2 , represented by reference numeral  162 , plates  127 ,  129  and membrane  126  stay in position as chamber  108  is closed to ambient surroundings. Up until time t 2 , the pressures within chambers  108  and  110  are equal, i.e. ΔP=0.  
         [0075]    From times t 2  to t 3  (reference numeral  164 ), plates  127 ,  129  and membrane  126  are moved downwards to create a pressure drop in chamber  108 . The downwards displacement occurs at approximately constant velocity (angle α represents the displacement velocity) and the absolute difference in pressure between chambers  108  and  110  is shown in the bottom graph of FIG. 3 (angle β represents the pressure drop speed). Printing occurs during this time. The optimal displacement velocity and pressure drop speed are functions of, for example, the properties of the liquid to be dispensed and the capillary containing the liquid. An exemplary pressure drop may be in the range of approximately 20 to 30 mm H 2 O in a fraction of a second.  
         [0076]    At time t 3 , valve  112  is actuated to increase pressure within chamber  108 . Pressure is increased until time t 3 ′ when the pressures within chambers  108  and  110  once again are equalized. Also beginning at time t 3 , plates  127 ,  129  and membrane  126  initially stay in position (from times t 3  to t 4 ; reference numeral  166 ), and then return to their initial position (from times t 4  to t 5 ; reference numeral  168 ). The return to initial position occurs at approximately constant velocity and completes the print cycle.  
         [0077]    [0077]FIG. 3 shows exemplary position and differential pressure curves. The present invention encompasses curves varying from those shown in FIG. 3. For example, during the stages represented by numerals  160 ,  164 , and  168 , velocity of the components can vary. Also, the relative times and displacements shown may be modified according to the preferred characteristics of the print cycle. It is also to be understood that a complete print cycle occurs rapidly, and preferably within seconds, and more preferably within a range of ten seconds or less. As a further modification from the curves shown in FIG. 3, increases in differential pressure may be achieved over time in a stepwise fashion for multiple dispensing. In such a case, at time intervals, the differential pressure may be increased rapidly in equal or unequal amounts so that dispensement occurs at each time interval.  
         [0078]    FIGS.  4 - 9  and FIGS.  18 - 43  illustrate another preferred embodiment of a dispensing device  200  according to the present invention. FIGS.  10 - 17  illustrate a preferred embodiment of a holder and capillaries for use in device  200 . Dispensing device  200  and the holder and capillaries for its use operate under very similar principles as dispensing device  100  described above. Much more detail of device  200  and its holder, however, are provided.  
         [0079]    For purposes of describing its many components, dispensing device  200  can be thought of as having a turntable  310  in which one or more receiving plates  318  rest, a top portion above turntable  310 , and a bottom portion below turntable  310 . The top portion includes a print head  201 . As shown in FIGS.  4 - 8 , the main components of the top portion, including print head  201 , include: an upper housing  202 ; upper and lower round plates  204  and  206  respectively; a flexible member  208 ; a mounting plate  218 ; upper, middle, and lower plates  220 ,  222 , and  224  respectively; a linear servopositioner  214 ; a linear ball bush guide  226 ; a mounting block  228 ; and an air cylinder  230 . Of these components, round plates  204  and  206 , flexible member  208 , and plates  218 ,  220 ,  222 , and  224 , comprise print head  201 . All of these components and their relationship and connection to each other will now be described in detail.  
         [0080]    Upper housing  202  is shown in detail in FIGS.  18 - 21 . FIG. 18 is a bottom view of housing  202 , whereas FIGS.  19 - 21  are side, cross-sectional front, and top views respectively. Upper housing  202  includes a hole  203  to receive a shaft  215  of linear servopositioner  214 . Servopositioner  214  mounts to upper housing  202  at points  217   a  via screws, bolts, or other like suitable connection means. The bottom portion of hole  203  receives upper and lower round plate elements  204 ,  206  between which a portion of flexible member  208  is sandwiched. Shaft  215  connects to upper round plate element  204 . Upper housing  202  also includes a hole  225  to receive linear ball bush guide  226  to which housing  202  fixedly mounts. Mounting block  228  mounts to a top of upper housing  202  at mounting points  229  via pins, bolts, or other suitable fastening means.  
         [0081]    Mounting plate  218 , shown in detail in FIGS. 43 and 44, is fixed to upper housing  202  at mounting points  219   a  (see FIG. 18) and mounting points  219   b  (see FIG. 43). Another portion of flexible member  208  is sandwiched between upper housing  202  and mounting plate  218 . Mounting plate  218  includes a central hole  256  to receive upper and lower round plate elements  204 ,  206 . A plurality of fixing points  223  (see FIG. 43) surround hole  256  and receive bolts or other suitable fastening means to secure flexible membrane  208  between housing  202  and mounting plate  218 .  
         [0082]    [0082]FIGS. 22 and 23 show details of upper and lower round plate elements  204 ,  206 . Elements  204 ,  206  include center holes  210  and  212 , respectively, for receiving a bolt, pin, or other fastening means to couple to shaft  215  of servopositioner  214 . The bottom of upper round plate element  204  includes a central area  205  that is slightly recessed to help achieve an optimal seal.  
         [0083]    Flexible member  208  extends between upper housing  202  and mounting plate  218  and between upper and lower round plate elements  204 ,  206 . As in the first embodiment described above, and as shown most clearly in FIG. 7, the portion of membrane  208  not sandwiched between these structural components, identified by reference numeral  208 ′, has some gather (i.e. fold or wrinkle). The gather  208 ′ permits plate elements  204 ,  206  to move vertically and ultimately create a pressure differential between upper and lower pressure chambers, as will be described. Member  208  is preferably circular, relatively thin, and manufactured from a rubber or other like flexible material.  
         [0084]    Upper plate  220 , shown in detail in FIGS.  24 - 27 , is located below and fixed to mounting plate  218 . Upper plate  220  includes a pair of O-ring seals  238 ,  240  that sit within grooves  242  at the bottom of upper plate  220 . Seal  240  surrounds a pressure chamber  245  defined by upper plate  220  and the top of the holder of the capillaries, to be described. Seal  240  seals pressure chamber  245  (which remains at ambient pressure) from L-shaped passages  243   a.  Passages  243   a  provide a fluid connection between a cavity  251  (defined by the top of plate  220  and the bottom of plates  216 ,  218  and flexible member  208 —see FIG. 7) and another pressure chamber  247  (defined primarily by middle and lower plates  222  and  224 —see FIGS. 7 and 28- 33 ). Seal  238  surrounds passages  243   a  and seals passages  243   a  from ambient environment. Upper plate  220  also includes an orifice  244  providing a fluid connection between the ambient environment and pressure chamber  245  (see FIG. 5) to maintain chamber  245  at ambient pressure. Upper plate  220  connects to points  219   b  of mounting plate  218  at mounting points  219   c.    
         [0085]    Middle plate  222 , shown in detail in FIGS.  28 - 30 , is located below upper plate  220  and couples to points  219   c  of upper plate  220  at mounting points  219   d.  Middle plate  222  includes an orifice  246  in fluid connection with pressure chamber  247 . Orifice  246  provides a fluid connection between a valve  249  and chamber  247 , as shown in FIG. 5, to alter the pressure within chamber  247 . More specifically, valve  249  raises the pressure within chamber  247  at the end of a print cycle by exposing chamber  247  to ambient conditions and aerating chamber  247 , as will be described. Middle plate  222  also includes L-shaped passages  243   b  that (along with passages  243   a ) provide a fluid connection between pressure chamber  247  and cavity  251 . Middle plate  222  also includes a circular hole  248  for receiving linear ball bush guide  226 .  
         [0086]    A lower plate  224 , shown in detail in FIGS.  31 - 34 , is located beneath middle plate  220 . Lower plate  224  includes an O-ring  250  seated within groove  252 . O-ring  250  surrounds and seals chamber  247  from ambient surroundings. Lower plate  224  further includes a circular hole  254  to accommodate linear ball bush guide  226 . Lower plate  224  mounts to points  219   d  of middle plate  222  at mounting points  219   e.    
         [0087]    As described, the connection between housing  202  and plates  218 ,  220 ,  222 , and  224  occurs at mounting points  219   a, b, c, d, e.  As shown most clearly in FIG. 7, the preferable means of connecting these five components includes a pin or bolt  221  extending between each of points  219   a, b, c, d, e.  Each pin or bolt  221  is configured to permit upper plate  220  to separate from middle plate  222  for insertion and removal of a holder  232  of capillaries, as shown in FIG. 6. The scope of the present invention includes other means of connecting these components to achieve this purpose.  
         [0088]    As shown most clearly in FIGS. 6 and 7, mounting block  228  fixedly couples to an upper portion of upper housing  202  via mounting pins  231 . As shown in FIG. 21, mounting pins  231  mount at points  229  of upper housing  202 . Air cylinder  230  mounts above mounting block  228 . Mounting block  228  includes a throughhole through which air cylinder  230  couples to linear ball bush guide  226 . That coupling preferably includes a floating joint  233  and other suitable connection means, including, for example, bolts or pins. Air cylinder  230  controls the vertical movement of housing  202  and plates  218 ,  220  to separate plates  220  and  222  and permit insertion of a holder of capillaries, as will be described.  
         [0089]    The bottom portion of dispensing device  200  includes the following main components: a mounting block  258 ; a bottom support plate  259 ; a pneumatically driven element  260 ; a gripper  280 ; a pair of ball bush guides  300 ; an air cylinder  302 ; a linear servodrive  304 ; and a servodrive  312 . These components and their relationship and connection to each other will now be described in detail.  
         [0090]    Mounting block  258  connects the top portion of dispensing device  200  to the bottom portion of device  200 . Mounting block  258  connects to lower plate  224  at points  261  on plate  224  (see FIGS.  31 - 33 ) via bolts  263  (see FIG. 7) or other suitable fastening means. Mounting block  258  also connects to bottom support plate  259  which supports various components of the bottom portion of device  200 .  
         [0091]    Pneumatically driven element  260  is shown in detail in FIGS.  35 - 40 . FIG. 35 is a bottom view, whereas FIGS.  36 - 39  are cross-sectional side, cross-sectional front, side, and top views, respectively. The top of element  260  includes an O-ring  262  within a groove  264 . O-ring  262  surrounds a cavity  265 , also at the top of element  260 . During operation, cavity  265  is in fluid connection with pressure chamber  247  and O-ring  262  sits between element  260  and a plate holder  314  (to be described). O-ring  262  seals cavity  265  (and thereby pressure chamber  247 ) from ambient surroundings. Element  260  also includes two circular throughholes  266  to accommodate linear ball bush guides  300 . A bottom cavity  268  in element  260  accommodates linear servodrive  304 . Servodrive  304  extends through a hole in plate  259  and couples to element  260  at mounting holes  272  via bolts  274  (see FIG. 7) or other suitable fastening means. Linear servodrive  304  also couples to a center mounting point  281  of gripper  280  by a shaft  284  (FIG. 7). Shaft  284  extends through a throughhole  270  in element  260 . Linear servodrive  304  moves gripper  280  vertically. Suitable O-rings or other sealing structure may be included between shaft  284  and element  260  to seal cavity  265  (and thereby pressure chamber  247 ) from ambient surroundings during operation.  
         [0092]    Gripper  280 , shown in detail in FIGS. 41 and 42, mounts within cavity  265  of element  260 . Gripper  280  includes a plurality of bellows  282  with suction cups at a top of bellows  282 . FIGS. 41 and 42 show gripper  280  having four bellows  282  and corresponding suction cups at 90 degree intervals. It is to be understood that more or less bellows may be used as appropriate and still be within the scope of the present invention. Gripper  280  includes a manifold throughhole  283  for connecting the suction cups to a vacuum source. Shaft  284 , connecting servodrive  304  to gripper  280 , also includes a vacuum throughhole  283 . The vacuum throughhole of shaft  284  also connects, via servodrive  304 , to external vacuum tubing  305  extending from servodrive  304 , as shown in FIG. 4. Vacuum tubing  305  connects to an external vacuum source  307 , such as, for example, a pneumatically-driven, multi-stage ejector. External vacuum source  307  provides a vacuum through external tubing  305 , servodrive  304 , throughhole shaft  284 , manifold throughhole  283 , and to the suction cups. The vacuum at the suction cups permit gripper  280  to securely engage receiving plate  318  for accurate displacement of receiving plate  318 .  
         [0093]    Air cylinder  302  mounts to bottom plate  259 . As best shown in FIG. 7, a shaft of air cylinder  302  extends through a throughhole  303  of plate  259  and mechanically couples to element  260 . The coupling occurs via a floating joint  309  and a pin, bolt, or other like device extending to point  276  in element  260  (see FIG. 35). When actuated, air cylinder  302  raises or lowers element  260 .  
         [0094]    Two linear ball bush guides  300 , best shown in FIG. 5, ensure vertical alignment when element  260  is moved vertically. Each guide  300  mounts to bottom plate  259 , extends through plate  259 , and is received within a hole  266  of pneumatically driven element  260 .  
         [0095]    Turntable  310  mounts between the top and bottom portions of dispensing device  200 . As shown most clearly in FIGS. 6 and 9, turntable  310  includes a plurality of throughholes each to receive a plate holder  314 . Each plate holder  314  has a frustoconical shape corresponding to the shape of the throughhole in turntable  310 . These corresponding shapes retain each plate holder  314  within turntable  310 . FIG. 9 shows turntable  310  with four plate holders  314  arranged at 90 degree intervals around turntable  310 . It is to be understood that any number of plate holders  314  preferably spaced at equal intervals within turntable  310  may be used and be within the scope of the present invention.  
         [0096]    Each plate holder  314  includes a central cavity  315  and a seat  316  for supporting a receiving plate  318 . Plate  318  lies loosely within holder  314 . Receiving plate  318  may be a flat plate made of glass, plastic, or other suitable material, or may be a plate with a plurality of wells to receive liquid from the liquid dispensing members.  
         [0097]    A servodrive  312  couples to turntable  310  to rotatably position turntable  310  and thereby accurately position a receiving plate  318  relative to a matrix of capillaries, to be described. As shown in FIG. 6, servodrive  312  extends through a throughhole in plate  259  and is coupled to a bottom portion of a bellows coupling  319 . The top portion of bellows coupling  319  is coupled to a bottom portion of a bearing  324 . The top portion of bearing  324  is coupled to turntable  310  via a bolt  321  or other suitable like fastening means. Through these connections, servodrive  312  mechanically couples to turntable  310 .  
         [0098]    Bellows coupling  319  is contained within a housing  322 . Housing  322  rigidly connects at its bottom to plate  259  via bolts  320  or other suitable like fastening means. Housing  322  rigidly connects at its top to bearing  324  via bolts  326  or other suitable like fastening means.  
         [0099]    A holder  232  of liquid dispensing members, preferably capillaries  330 , mounts within and separates pressure chambers  245 ,  247  of dispensing device  200 . FIGS.  10 - 17  show details of holder  232 . Holder  232  includes a top plate  332 , a bottom plate  334 , and side plates  336   a,b,c,d  to connect top and bottom plates  332 ,  334 . Side plates  336  include lips  338  and  340  that slide within slots  342  of top and bottom plates  332 ,  334 . Lips  338  are in the form of a flat planes and ensure alignment of top and bottom plates  332 ,  334 . As shown in FIG. 17B, each lip  340  includes a hook that may be bent at, for example, a 45 degree angle, once lip  340  inserts within a slot  342 . This creates tension to draw top and bottom plates  332 ,  334  towards side plates  336  and create a stable, rigid holder  232 . More specifically, and with reference to FIG. 17B, top and bottom plates  332 ,  334  each have a thickness S2. Each hook of a lip type  340  is a distance S1 from a top edge of its side plate  336   a, b, c, d.  Distance S1 is less than thickness S2. Thus, when lip type  340  extends through a slot  342  of top or bottom plate  332 ,  334 , the hook may be bent to engage a surface of top or bottom plate  332 ,  334 , as shown by reference numeral  346  in FIG. 17B. This creates pressure on the surface of top or bottom plate  332 ,  334  at the bend, creating a rigid holder  232 .  
         [0100]    Top and bottom plates  332 ,  334  and side plates  336  are preferably made of copper and are preferably manufactured from a photochemical etching process to make wafer-thin sheets. Each of top and bottom plates  332 ,  334  includes a grid  344  of etched perforations. In an embodiment, grid  344  includes twelve rows of eight perforations to accommodate 96 capillaries  330 . Grid  344 , however, can have any number of rows of varying number of perforations to accommodate much higher numbers of capillaries. The grids  344  of plates  332  and  334  are accurately aligned to ensure alignment of capillaries  330  mounted therein. A thin coat of adhesive, preferably UV-sensitive glue, spread between capillaries  330  along top plate  332  fixes capillaries  330  in holder  232  and ensures that the bottom tips of capillaries  330  are in the same vertical position. The adhesive also acts to seal pressure chamber  245  above top plate  332  from pressure chamber  247  below top plate  332  when holder  232  is placed within dispensing device  200 .  
         [0101]    As shown in FIG. 6, holder  232  inserts within dispensing device  200  when top plate  220  is separated from middle plate  222 . An outer rim of top plate  332  of holder  232  rests on a top surface of middle plate.  222 . More particularly, the outer rim of top plate  332  rests within a slightly recessed surface  253  of middle plate  222 . The amount of recess of surface  253  is approximately the thickness of top plate  332  so that top plate  332  lies flush with the top surface of middle plate  222 . When plates  220  and  222  close and sandwich the outer rim of top plate  332  therebetween, pressure chamber  245  is separated from pressure chamber  247 . Chamber  245  is in fluid communication with the ambient environment via orifice  244 , as shown in FIG. 5, and contains the open top of each capillary  330 . Chamber  247  contains an open bottom of each capillary  330 . Chambers  245  and  247  are sealed from one another by holder  232 , and specifically top plate  332  and the sealing adhesive around capillaries  330 . Whereas top plate  332  serves this sealing function, bottom plate  334  aids in aligning holder  232  and capillaries  330  therein.  
         [0102]    Operation of dispensing device  200  will now be described in connection with FIGS.  4 - 9 . Prior to operation of dispensing device  200 , a liquid solution is aspirated into a plurality of capillaries  330 , or other disposable dispensing members such as micropipettes. The aspirated liquid is retained inside capillaries  330  by capillary surface tension forces. Next, filled capillaries  330  are assembled into the etched perforations of holder  232  to form a high density grid of a plurality of filled capillaries  330 . Capillaries  330  are assembled into any predetermined geometric distribution and preferably packed at a high density, for example twelve rows of eight capillaries. Capillaries  330  are then fixed into holder  232  by, for example, UV-sensitive glue, so that the bottom tip of each capillary  330  is at the same vertical position. The filling of the capillaries and assembly of capillaries into a holder may be done by any suitable method, including that described in PCT International Application No. PCT/IB 98/01399 entitled “Method for the Rapid Screening of Analytes” and filed Sep. 8, 1998, the entire disclosure of which is incorporated herein by reference.  
         [0103]    Holder  232  with capillaries  330  then may be assembled into dispensing device  200 . To do so, air cylinder  230  is actuated to move upwards and thereby lift housing  202  and a portion of print head  201 , specifically plates  218  and  220 . This causes top plate  220  to separate from middle plate  222 . Upper housing  202  and its connected components, including plates  218 ,  220 , servopositioner  214 , round plates  204 , 206 , are then swung clear to expose the upper surface of middle plates  222 . These components swing about the axis of guide  226 . An outer rim surface of top plate  332  of holder  232  then is set on plate  222 . Housing  202  and its connected components then are swung back in place and air cylinder  230  is actuated to move downwards to lower housing  202  and rejoin plates  220  and  222 . At this point, chamber  245  is hermetically sealed from chamber  247 .  
         [0104]    [0104]FIG. 9 shows four stations in turntable  310  of device  200 . These stations are loading L, printing P, inspection and/or identification I, and unloading U. Turntable  310  rotates clockwise, as shown by arrow A in FIG. 9, to move a receiving plate  318  between stations. Plate  318  first is loaded onto turntable  310  at loading station L. Printing onto receiving plate  318  occurs at printing station P. Receiving plate  318  may be inspected for quality and/or marked for identification purposes at station I. Receiving plate  318  then may be unloaded from turntable  310  at station U. All of these stations and their operations may be controlled by suitable computer software derived by one skilled in the art. As an alternative, a manual control panel may be provided at each station for control of the operations at each station. Moreover, robots or other peripherals may be provided at each station to perform the functions of that station. In addition, peripherals may be added between stations to perform appropriate additional functions. For example, a sensor may be provided between loading station L and printing station P to determine if a receiving plate  318  is located on turntable  310  prior to the printing operation.  
         [0105]    Once receiving plate  318  has been loaded onto turntable  310  at station L, turntable  310  is rotated 90 degrees clockwise so that receiving plate  318  is positioned at printing station P. This situation is shown in FIGS. 4 and 5. Next, air cylinder  302  is actuated to displace element  260  upwards and force plate holder  314  upwards against bottom plate  224 . The meshing of element  260 , plate holder  314 , and bottom plate  224  is shown in FIG. 7. FIG. 7 also shows the next step of the printing process, wherein servodrive  304  has been actuated to displace gripper  280  vertically so that its bellows  282  with suction cups engage receiving plate  318  and force receiving plate  318  vertically. Receiving plate  318  is moved vertically to a position just under the bottom tips of capillaries  330 , as shown in FIG. 7. The optimal gap between the bottom tip of capillaries  330  and the top surface of plate  318  will depend on a variety of factors, as mentioned above.  
         [0106]    The structural components of dispensing device  200  are now in position to begin a print cycle. The print cycle begins by actuating servodrive  214  to move plates  204  and  206  vertically downwards. It will be apparent that the movement of plates  204  and  206  downwards is optional, as a pressure differential between chambers  245  and  247  may be created without this movement. Next, pressure chamber  247  is plugged at orifice  246  by valve  249 . While chamber  245  remains at ambient pressure due to orifice  244 , a pressure drop is created in pressure chamber  247  by servodrive  214  displacing plates  204 ,  206  vertically upwards. The pressure drop is preferably sudden and brief and performed in a controlled manner similar to that described above in connection with FIGS.  1 - 3 . Thus, a lower pressure will exist in pressure chamber  247  relative to pressure chamber  245 . A top of each capillary  330  therefore will be exposed to a greater pressure than a bottom of each capillary  330  and a difference in pressure results across the liquid in each capillary  330 . Similar to that described above in connection with FIGS.  1 - 3 , a printed spot of liquid from each capillary  330  will form on receiving plate  318 .  
         [0107]    After the brief, sudden pressure drop, valve  249  is opened to expose pressure chamber  247  to ambient conditions and aerate chamber  247 . This increases the pressure within pressure chamber  247  and equalizes the pressures within chambers  247  and  245 . Servodrive  214  also may be actuated to return plates  204 ,  206  to their original position. As described earlier, capillary forces will dominate once again, forcing liquid to remain within each capillary  330 .  
         [0108]    At the same time, servodrive  304  is actuated to displace gripper  280  vertically downwards and reposition receiving plate  318  onto plate holder  314 . Air cylinder  302  then is actuated to lower element  260  and thus lower plate holder  314  back into its original position within turntable  310 . Next, turntable  310  is rotated clockwise so that receiving plate  318  enters inspection/identification station I, where any number of suitable inspection, identification, or other post-printing functions may be performed. Receiving plate  318  then is rotated to unloading station U, where plate  318  may be unloaded.  
         [0109]    This process may be repeated for any number of receiving plates  318  until liquid in the capillaries  330  has been used, resulting in a number of replica prints of the liquid within capillaries  330 .  
         [0110]    It will be apparent to those skilled in the art that various modifications and variations can be made to the dispensing device and related method of the present invention without departing from the scope or spirit of the invention. For example, the described embodiments employ a pressure drop in the chamber below the capillaries. Instead, the printing device may be configured so that a differential pressure generator creates a pressure rise in the chamber above the capillaries to result in a similar print cycle. In such a case, the upper chamber may be connected to the external environment to equalize the pressures in the chambers, as necessary.  
         [0111]    As a further example, the present invention also encompasses moving the holder with capillaries toward a stationary receiving plate. Moreover, the described embodiments include various servodrives and air cylinders to perform many of the mechanical movements during printing. Any suitable actuation mechanisms may be used for these movements. In addition, any of various suitable elements for fastening the structural components of the dispensing device together may be used, and any suitable sealing element may be used in place of each described O-ring.  
         [0112]    As an even further modification of the described device and method, the dispensing of liquid from the capillaries may be performed through controlled vibration of the liquid or the holder of the capillaries. In such a case, the differential pressure generator creates well-defined combinations of repeated pressure changes. These pressure changes, and the use of particular shaped capillaries, including a narrow open bottom end, can create standing waves in the liquid column inside the capillary. This can result in dispensing a stream of droplets.  
         [0113]    The present invention covers all of these modifications and variations of this invention provided they come within the scope of the appended claims and their equivalents.