Patent Publication Number: US-6911181-B1

Title: Self-dispensing storage device

Description:
FIELD OF THE INVENTION 
     The present invention relates in general to a dispensing system for dispensing a sample. More particularly, the present invention relates to a self-dispensing system including having a storage device, a dispensing mechanism, and a drive mechanism for driving the dispensing mechanism, wherein the storage device and the dispensing mechanism that form an integral unit with the dispensing mechanism in dispensing communication with the storage device. 
     BACKGROUND OF THE INVENTION 
     Various industries require automated systems for the precise dispensing of samples from one storage device to a workstation or another storage device. For example, in typical pharmaceutical research laboratory processes, labs may be involved in genetic sequencing, combinatorial chemistry, reagent distribution, high throughput screening, and the like. A dominant thread that is present in each of these processes is that, if one ignores the incubation or reaction periods (which in properly designed automation, should not tie up the other devices), the vast majority of time is spent dealing with individual sample handling (e.g., dispensing). 
     Individual samples refer to the samples that get distributed to a storage device, such as a well, as opposed to those samples that get distributed over, for example, multiple wells forming a whole plate. In sequencing, for example, these may include the picked bacteria and templates; in combinatorial chemistry, for example, it may include the building blocks that define the next step in the reaction, and in high throughput screening, for example, it may include the test compounds. The reason that this is such a time consuming process is that a tip wash or replacement is typically required between every transfer operation. Both washing and changing tips take a good deal of time, often as long as 15 or more seconds. 
     Conventional dispensing devices include, for example, pipette devices which are separate devices intended for dispensing a known quantity of a sample (e.g., biological or chemical reagents) from a source storage device to a destination storage device for use in various processes. Traditionally, these pipettes can be activated either manually or automatically. The same pipette device may draw a different sample from any number of different storage devices. Accordingly, conventional pipettes also require a tip wash or replacement between every sample transfer operation. 
     What is needed by various sample handling and manipulation industries, such as, for example, the pharmaceutical discovery, clinical diagnostics, and manufacturing industries, is a precise sample dispensing system and method that overcome the drawbacks in the prior art. Specifically, a system and method having a dispensing mechanism formed as part of a storage device for precisely dispensing samples from the storage device to a workstation or another storage device. What is also needed is an inexpensive dispensing mechanism that does not require a tip change or wash between each handling of a sample. Therefore, a need exists for an accurate sample dispensing system and method that overcome the drawbacks of the prior art. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to a self-dispensing system and method having a dispensing mechanism contained within or formed as part of a storage device for precisely and reproducibly dispensing a measured volume of a sample. The dispensing mechanism is in dispensing communication with an opening in the storage device for dispensing a measure quantity of a sample from the storage device. Preferably, the system and method of the present invention provide a disposable dispensing mechanism that never has to be changed, washed, or cleaned. The resulting combination of the individual storage device having a dispensing mechanism is what is referred to as “a self-dispensing storage device.”Since the storage device is already “contaminated” by the substance and destined for disposal it is the ideal place to put the dispensing mechanism. 
     In certain application having a plurality of storage devices and using automation, samples are typically stored and manipulated in, for example, 96-well microtiter plates. The resulting combination of the plurality of wells of the microtiter plate each having its own dispensing mechanism (e.g., one dispensing mechanism per well) which is in dispensing communication with an opening in the well is what is referred to as “a self-dispensing plate.” The self-dispensing plate includes a plurality of individual wells or reservoirs preferably arranged at evenly spaced centers. The system and method of the present invention provide the improved efficiency and throughput due to the fact that a tip wash or replacement is not required between every sample transfer operation. 
     In a preferred embodiment, the dispensing mechanism can reproducibly eject drops (e.g., is reproducible in volume) having a predetermined size, such as for example, about 5 microliters, about 1 microliters, about 0.5 microliters, and about 0.1 microliters in size. The dispensing mechanism preferably ejects the drops cleanly and reproducibly and does not clog when left in the air for extended periods. The self-dispensing storage device or plate, with its sample, is preferably freezable to at least −20° C., ideally to −80° C. The self-dispensing storage device and its sample are capable of being thawed and then dispensed. 
     The storage device includes a reservoir defining a volume for holding a predetermined amount of a sample. The storage device is where the sample to be dispensed is stored until it is dispensed by the dispensing mechanism. The reservoir can include any suitable shape and construction, including a tube, a balloon, a well, or any other kind of reservoir or container capable of containing and holding the sample to be dispensed. The storage device may be a rigid structure or alternative, may include a collapsible structure that collapses as the sample is dispensed from it. The storage device can be made of any suitable material or may include a coating material that is compatible with the sample, including, for example, polypropylene, polystyrene, polyethylene, silicon rubber, PEEK, glass, vinyl, porcelain, metal, or the like. The sample storage device can also be made from a transparent material so that the level of the sample remaining in the sample storage device may be ascertained. 
     The sample includes any compound, material, reagent, serum, specimen, and the like, including but not limited to samples in liquid, powdered, pasty, viscous, or other flowable or disposable form. In an exemplary pharmaceutical research laboratory having multiple processes, the samples may include, for example: the picked bacteria and templates, in sequencing; the building blocks that define the next step in the reaction, in combinatorial chemistry; the test compounds, in high throughput screening; etc. 
     The dispenser or dispensing mechanism can include a time and pressure type dispensing mechanism, a positive displacement type dispensing mechanism, or any other suitable dispensing device capable of dispensing the sample in precise and repeatable measured amounts or volumes. The dispensing mechanism should be capable of reproducibly dispensing the required quantity or volume of sample from the self-dispensing storage device. The life-time of the dispenser should be at least sufficient to fire enough drops to empty the well. Since the well and dispenser are preferably disposed after use, the dispenser can be made inexpensively. Preferably, the dispenser is a positive displacement type dispensing mechanism. A positive displacement type dispensing mechanism typically includes an inlet valve, an actuator, and an outlet valve. Generally, the actuator moves in one direction to draw a quantity of the sample in from the reservoir of the storage device, and moves the other direction to push the sample out a tip opening formed in a tip of the dispensing mechanism. The outlet valve prevents air from the outside from being drawn in when the actuator makes the first, or suction, move. The inlet valve prevents the sample tom being pushed back into the storage device when the actuator makes the second, or discharge, move and dispenses the sample. 
     The dispenser can include a cow udder type, a membrane pump type, an embedded balls type, a two-dimensional pump type, a rotary valve type, and a steam engine type of dispensing mechanism. 
     The system and method include a drive mechanism for driving the dispensing mechanism. The drive mechanism can be positioned internal or external to the dispensing mechanism. Also, the driving mechanism can be operated manually or automatically. Preferably, the driving mechanism is positioned external to the dispensing mechanism and does not come into contact with the sample, and therefore the driving mechanism is not contaminated by the sample. However, the drive mechanism can also be positioned internal to the dispensing mechanism and can be replaced along with the storage device and the dispensing mechanism. 
     The self-dispensing system preferably includes a filter or screen disposed between the storage device and the dispensing mechanism to prevent solids from jamming or clogging the dispensing mechanism. 
     The storage device also preferably includes some means to prevent contamination and evaporation of the sample contained therein. The means for preventing contamination and evaporation can include a sealed storage device or a storage device having a lid. In addition, the storage device preferably includes a means of replacing the volume of the reservoir corresponding to the dispensed sample with, for example, air, so that a vacuum is not created. The means of replacing the volume of the dispensed sample can include, for example, a removable lid, a valve, or the like. 
     A further embodiment within the scope of the present invention is directed to a method of dispensing a sample from a storage device using a self-dispensing mechanism that is in dispensing communication with the storage device. The method includes driving the dispensing mechanism with a driving mechanism such that highly accurate and reproducibly measured volumes are dispensed. 
     The system and method of the present invention provide for improved processing time through the use of a self-dispensing storage device and/or a self-dispensing plate that do not require a tip change or wash between each sample handling or transfer operation. They also provide for reduced waste due to less liquid being left, unused at the bottom of the sample storage device. They also reduce wasted sample containers and time because separate dilution steps can often be avoided. Preferably, the self-dispensing storage device and/or a self-dispensing plate include a disposable storage device and dispensing mechanism. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The foregoing and other aspects of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there is shown in the drawings embodiments that are presently preferred, it being understood, however, that the invention is not limited to the specific methods and instrumentalities disclosed. In the drawings: 
         FIG. 1  is a schematic diagram of an exemplary self-dispensing system in accordance with the present invention; 
         FIGS. 2A through 2F  are schematic diagrams of several exemplary embodiments of the storage device of  FIG. 1 ; 
         FIGS. 3A through 3C  are schematic diagrams illustrating several exemplary embodiments for filling the storage device of  FIG. 1 ; 
         FIG. 4  is a schematic of an exemplary time and pressure type dispensing mechanism that can be used with the self-dispensing system of  FIG. 1 ; 
         FIGS. 5A and 5B  are schematic diagrams of exemplary cow udder type embodiments of the dispensing mechanism of  FIG. 1 ; 
         FIG. 6  is a plan view of an exemplary mold for making the cow udder type dispensing mechanism of  FIGS. 5A and 5B ; 
         FIGS. 7A through 7E  are schematic diagrams of exemplary membrane pump type embodiments of the dispensing mechanism of  FIG. 1 ; 
         FIG. 8  is a schematic diagram of exemplary embedded balls type embodiment of the dispensing mechanism of  FIG. 1 ; 
         FIGS. 9A and 9B  are a side view and top view of an exemplary two-dimensional pump type embodiment of the dispensing mechanism of  FIG. 1 ; 
         FIGS. 10A through 10F  are schematic diagrams of exemplary rotary valve embodiments of the dispensing mechanism of  FIG. 1 ; 
         FIGS. 11A and 11B  are schematic diagrams of exemplary steam engine type embodiments of the dispensing mechanism of  FIG. 1 ; 
         FIG. 12  is a schematic diagram of an exemplary self-dispensing plate in accordance with the present invention; 
         FIG. 13  is a side view of an exemplary robot carrying a single self-dispensing storage device of the present invention in an automated system; 
         FIG. 14  is a schematic diagram of an exemplary layout of an automated sample positioning system that can be used with the self-dispensing system of the present invention; 
         FIG. 15  is an exemplary grid type track system that can be used with the self-dispensing storage device of the present invention for movement of sample carrying robots between stations in an automated system; 
         FIG. 16  is a top view of an exemplary robot carrying a self-dispensing plate of the present invention in an automated system; and 
         FIG. 17  is a flowchart of an exemplary method of precisely and reproducibly dispensing a sample using a self-dispensing storage device or plate in accordance with the present invention. 
     
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     The present invention is directed to a highly accurate and repeatable self-dispensing system and method for the precise dispensing of a sample. The system for self-dispensing a sample includes a storage device and a dispensing mechanism that form an integral unit in which the dispensing mechanism is in dispensing communication with the storage device containing the sample to be dispensed. The present invention reduces or eliminates the risk of contamination of the sample or of the dispensing mechanism due to the fact that the storage device and the dispensing mechanism are formed as an integral unit. A single dispensing mechanism is used with a single storage device. 
     The resulting combination of the individual storage device having an individual dispensing mechanism is what is referred hereinafter as “a self-dispensing storage device”. In applications having a plurality of storage devices, such as a multiple-well microtiter plate (e.g., a 96-well microtiter plate), the resulting combination of the plurality of storage devices each having its own dispensing mechanism (e.g., one dispensing mechanism per well) is what is referred hereinafter as “a self-dispensing plate”. Since each storage device is already “contaminated” by the substance and is destined for disposal, it is the ideal place to put the dispensing mechanism. The system and method of the present invention provide the improved efficiency and throughput due to the fact that a tip wash or replacement is not required between every sample transfer operation. They also provide for reduced waste due to less liquid being left, unused at the bottom of the sample storage device. They also reduce wasted sample containers and time because separate dilution steps can often be avoided. 
     For purposes of clarity, the term “sample”, as used herein, is intended to encompass any compound, material, reagent, serum, specimen, and the like, including but not limited to samples in liquid, powdered, pasty, viscous, or other flowable or disposable form. In an exemplary pharmaceutical research laboratory having multiple processes, the samples may include, for example: the picked bacteria and templates, in sequencing; the building blocks that define the next step in the reaction, in combinatorial chemistry; the test compounds, in high throughput screening; etc. 
       FIG. 1  shows an exemplary self-dispensing system  1  in accordance with the present invention. As shown in  FIG. 1 , the self-dispensing system  1  includes a storage device  2 , a dispensing mechanism  3 , and a drive mechanism  4 . The dispensing mechanism  3  is in dispensing communication with the storage device  2  making it a self-dispensing storage device. Each dispensing device  3  is used with a single storage device  2 . The storage device  2  defines a volume  5  for holding a sample  6 . The dispensing mechanism  3  is connected to an opening in the storage device  2  and receives the sample  6  to be dispensed from the storage device  2 . The dispensing mechanism  3  is acted upon by the drive mechanism  4  to dispense a measured amount or volume of the sample  6 , in the form of, for example, one or more drops  7 , from the dispensing mechanism  3  to a destination workstation or another storage device  8 . 
     Preferably, the storage device  2  and the dispensing mechanism  3  are adapted to directly contact the sample  6  being dispensed. This provides for high accuracy in dispensing. During operation, the storage device  2  and the dispensing mechanism  3  contact the sample  6  and are therefore contaminated by the sample  6 . For this reason, the storage device  2  and the dispensing mechanism  3  are preferably disposable. In this case, the dispensing mechanism  3  only needs to last long enough to dispense the volume total in the storage device  2 . Since the dispensing mechanism is integral with the storage device, it only comes into contact with the sample  6  that is contained therein and accordingly, no tip wash or replacement is required between each sample transfer. Once the sample  6  has been expended or used up (e.g., the storage device  2  is empty) or after some predetermined time period (e.g., at the end of the shelf life of the sample), then the dispensing mechanism  3  and the storage device  2  are disposed. This eliminates the need for a tip change or wash between each handling of the sample  6 . 
     Preferably, the driving mechanism  4  does not contact the sample  6  and is thus insulated from contamination by the sample  6  being dispensed. The driving mechanism  4  can be internal or external to the dispensing mechanism. In embodiments having an internal drive mechanism, the internal drive mechanism would also be disposed along with the sample storage device  2  and the dispensing mechanism  3 . For embodiments having an external drive mechanism, the sample  6  preferably never comes into contact with the external drive mechanism and therefore this component need not be disposable. 
     The self-dispensing storage device or plate can be used for dispensing stored samples in a variety of applications including, for example, pharmaceutical research laboratory processes and the like. Exemplary processes include, for example, sequencing, genetic sequencing, genotyping, functional genomics, combinatorial chemistry, reagent distribution, high throughput screening, clinical diagnostics, industrial compound testing, and the like. The self-dispensing storage device or plate can be used as part of an automated system. In this type of application, the self-dispensing system  1 , including the storage device  2  and its corresponding dispensing mechanism  3 , is moved about by, for example, a robot in a robotic system, to different workstations or other sample storage devices  8  where a measured quantity or volume of the sample  6  may be dispensed. 
     As shown in  FIG. 1 , the storage device  2  includes a reservoir  8  defining a volume  5  for holding a predetermine amount of a sample  6 . The storage device  2  is where the sample  6  to be dispensed is stored until it is dispensed by the dispensing mechanism  3 . As shown, the storage device  2  includes a top  9 , a bottom  10 , and at least one sidewall  11 . The reservoir  8  can include any suitable shape and construction, including a tube, a balloon, a well, or any other kind of reservoir or container capable of containing and holding the sample  6  to be dispensed. The storage device  2  may be a rigid structure or alternative, may include a collapsible structure that collapses as the sample is dispensed from it. The storage device  2  can be made of any suitable material or may include a coating material that is compatible with the sample  6 , including, for example, polypropylene, polystyrene, polyethylene, silicon rubber, PEEK, glass, vinyl, porcelain, metal, or the like. The sample storage device  2  can also be made from a transparent material so that the level of the sample remaining in the sample storage device  2  may be ascertained. 
     The storage device  2  can include a single storage device or a plurality of storage devices.  FIG. 1  shows a single storage device  2  having a dispensing mechanism  3  which is referred to as a self-dispensing storage device. The present invention also includes a self-dispensing plate which is a storage plate having a plurality of individual wells or reservoirs preferably arranged at evenly spaced centers (e.g., a 96-well microtiter plate at 9 mm centers), as shown in  FIGS. 10F and 16 . Each well in the self-dispensing plate has a dispensing mechanism formed integral with it and arranged in dispensing communication with it. 
     Preferably, the dispensing system  1  includes a filter or screen  12 . The filter or screen  12  is optional and is preferred for application where the dispensing mechanism  3  draws the sample  6  from the bottom of the storage device in order to get all the sample, and also for those application where the sample to be dispensed may contain solids particles. The filter or screen  12  helps to keep the solids from jamming or clogging the dispensing mechanism  3 . 
     The storage device  2  also preferably includes some means to prevent contamination and evaporation of the sample  6  contained therein. The means for preventing contamination and evaporation can include a sealed storage device or a storage device having a lid. In addition, the storage device  2  preferably includes a means of replacing the volume of the reservoir corresponding to the dispensed sample  6  with, for example, air, so that a vacuum is not created. The means of replacing the volume of the dispensed sample can include, for example, a removable lid, a valve, or the like. 
       FIGS. 2A through 2F  shows a variety of mechanisms that can be employed to prevent contamination and evaporation, and also allow replacement of the displaced sample  6 . The mechanisms for preventing contamination and evaporation, and also allowing replacement of the displaced sample resulting from a dispensing operation can include one or more of the following features. A loose fitting lid  13  can be used that covers the storage device, while at the same time, allows air to replace the displaced volume of the dispensed sample, similar to the styrene lids currently used with microtiter plates for cell assays, as shown in FIG.  2 A. Alternatively a tight fitting lid  13 , like a silicon rubber “cap mat”, which is removed in order to allow the sample to be dispensed can be used. Alternatively, as shown in  FIGS. 2B and 2C , a non-stretching membrane  14  can be used that is expanded when full and collapsed when empty, like, for example, wine in a box, full-scale aircraft fuel tanks, or the like. The membrane  14  can be a thin flexible material, such as poly-propylene, polyethylene, or Mylar. This “blister-type” of storage device collapses as it dispenses, thus allowing no air. This design and method may be preferred because the sample is never exposed to air during storage or dispensing. Alternatively, as shown in  FIG. 2D , a stretching membrane  15  such as, for example, a balloon, a pressurized fuel tank in model airplane, or the like can be used.  FIG. 2D  shows the stretching member  15  in a non-stretched state  15   a  wherein the reservoir of the storage device is empty, and in a stretched state  15   b  wherein the reservoir of the storage device is filled with a sample  6 . This method is also preferred because the sample  6  is not exposed to air during storage or dispensing. Also, as shown in  FIG. 2E , a slot  16  in the top of a rubbery or flexible storage device  2  that would be closed at rest, but leak (e.g., allow air to enter) when a vacuum is formed by a dispensing action. The top could be made from a silicon rubber material and the slot  16  would allow the displaced sample replacement member  16  to be self sealing/opening. In addition, a solid top with a one-way valve  17 , such as a check valve, can be used to let air in, but not let the sample out, as shown in FIG.  2 F. 
       FIGS. 3A-3C  show several exemplary processes that may be used to fill the storage device  2 . The method used for initially filling the storage device  2  with a sample  6  to be dispensed will typically depend on the particular type of storage device that is being used and the application. For example, if removable lids  13  are employed, as shown in  FIG. 3A , the storage device  2  can be filled by removing the lid  13  and adding the sample  6  from a sample supply  18  through the open top  9 . The sample supply  18  can include a conventional dispensing device, such as a pipette, a self-dispensing storage device, a self-dispensing storage plate, or any other suitable sample source. Alternatively, if a stretching or non-stretching membrane type storage device  14  or  15  is used, the storage device could be filled from a temporary tube  19  extending from the bottom  10 , as shown in FIG.  3 B. The tube could be a conventional pipette tip attached to the bottom of the storage device or plate. The tube  19  could be dipped in the sample source  18 , and a vacuum could be applied to the back of the storage device  2  to pull the sample  6  into the reservoir. A valve (not shown), such as a check valve for example, could be built into an aspiration tube, or it could be simply pinched off with a hot tool, melting it closed and removing it in one step. As shown in  FIG. 3C , a separate aspiration tube  19  can be provided for filling the storage device  2  through aspiration. Once the storage device is filled, the aspiration tube  19  could be pinched-off as indicated. Once the fill or aspiration tube  19  is pinched off, it may forever remove the ability of the storage device from loading anything else. Another possible method of filling the storage device is that a disposable tip can be temporarily added in a manner that forces the valves open, or the valves can be held open by a mechanism. Alternatively, the slot  16  in the top  9  of a rubbery or flexible storage device could be pulled open or opened by pushing on the side, like, for example, a rubber coin purse. The slot  16  would seal when left alone. 
     The dispenser or dispensing mechanism  3  can include a time and pressure type dispensing mechanism, a positive displacement type dispensing mechanism, or any other suitable dispensing device capable of dispensing the sample in precise and repeatable measured amounts or volumes. The dispensing mechanism  3  should be capable or reproducibly dispensing the required quantity of sample from the self-dispensing storage device. The life-time of the dispenser  3  should be at least sufficient to fire enough drops  7  to empty the well. Since the well  2  and dispenser  3  are preferably disposed after use, the dispenser  3  can be made inexpensively.  FIG. 4  shows an exemplary time and pressure type of dispenser  3  having a valve that is closed until opened, then opened for a fixed amount of time, and a pressure upstream of the valve forces the sample through the valve. As shown in  FIG. 4 , an exemplary time and pressure type dispensing mechanism can include, for example, a solenoid valve  25  wherein the storage device  2  is pressurized through a pressure connection  27  from a pressure source (not shown) and a normally closed valve  26  is actuated for short, carefully measured period of time thereby dispensing a measure quantity of the sample  6 . The solenoid valve  25  may be actuated using conventional techniques, including mechanically, electrically, electro-magnetically, piezo, and the like. 
       FIGS. 5A through 11B  show several exemplary positive displacement type dispensing mechanisms  3 . As shown in the Figures, a positive displacement type dispensing mechanism typically include an inlet valve  31 , an actuator  32 , and an outlet valve  33 . Generally, the actuator  32  moves in one direction to draw a quantity of the sample  6  in from the reservoir  8  of the storage device  2 , and moves the other direction to push the sample  6  out a tip opening  23  formed in a tip  24  of the dispensing mechanism  3 . The outlet valve  33  prevents air from the outside from being drawn in when the actuator  32  makes the first, or suction, move. The inlet valve  31  prevents the sample  6  from being pushed back into the storage device  2  when the actuator  32  makes the second, or discharge, move and dispenses the sample  6 . 
     The inlet valve  31  and outlet valve  33  can either be passive or active valves. An example of a passive valve is a passive check valve and an example of an active valve is an actively actuated valve. The volume of the sample to be dispensed with each stroke of the actuator is determined be the cross sectional area and stroke distance of the actuator, or the equivalent measure. Another type of positive displacement type dispensing mechanism  3  that can be used with the present invention that has a slightly different configuration is a rotating valve type of positive displacement pumps. 
     Positive displacement dispensing mechanisms  3  are preferred over time and pressure type valves because the samples to be dispensed may vary in viscosity and surface tension, and thus, the best way to be ensure of a precise measured volume is to dispense by volume. Preferred materials for the dispensing mechanism  3  include polypropylene, polystyrene, polyethylene, silicon rubber, PEEK, stainless steel, and the like. 
     Generally, samples  6  are required to be dispensed in precise and repeatable measured amounts, quantities, or volumes. For example, depending on the particular application, individual samples  6  may be dispensed from about 0.5 to about 100 microliters for typical assays and operations. Therefore, a drop dispenser that is reproducible in volume, at for example, about 5 microliters, about 1 microliters, and about 0.5 microliters, is capable of dispensing any needed amount by dispensing multiple drops  7 . Alternatively, smaller measured quantities or volumes may be dispensed using dispensing mechanisms having the desired dispensing or drop rate. The drop rate can be about 0.1 μl or smaller, depending on the application. Preferably, the dispensing mechanism is capable of being accurate and reproducible within plus or minus  10  percent. Preferably, the dispensing mechanism is capable of being accurate and reproducible within plus or minus 5 percent. The drop rate or capacity of the dispensing mechanism  3  is preferably tailored to the particular application. Preferably, the drop rate and measured amount dispensed during each firing of the dispensing mechanism (e.g., the measured amount of each drop  7 ) are highly reproducible. 
     The dispensing mechanism  3  is preferably constructed such that drops  7  are ejected cleanly so that no tip touch-off is required. Small amounts of the sample  6  should not be allowed to accumulate to a large drop  7  that will fall randomly. The tip  24  may include a wiper (not shown) or the like to wipe off any excess sample from the tip  24 . 
     Preferably, the dispensing mechanism  3  is rinsed after use, or even more preferably, it is not exposed to air after use. If the dispensing mechanism  3  is exposed to air, and evaporation is allowed to occur between uses, then any remaining solids could destroy or adversely affect the future operation of the dispensing mechanism  3 . 
     Preferably, the entire self-dispensing system  1  is capable of being frozen and thawed one or more times. This would include the storage device, the dispensing mechanism, the sample, and, in the case of an internal driving mechanism, the driving mechanism. The dispensing system  1  should still operate reliably and accurately when thawed. 
     The drive or driving mechanism  4  can be disposed external or internal to the dispensing mechanism  3 . The driving mechanism  4 , whether it be mechanically, electrical, or electro-magnetically actuated, can be positioned external to the dispensing mechanism in, for example, a non-disposable element or machine. Preferably, the driving mechanism  4  is constructed and designed so that each sample storage device  2  and its corresponding dispensing mechanism  3  can be addressed and dispensed individually. Alternatively, some applications could have a plurality of storage devices dispensed simultaneously, such as one or more rows or columns, or all wells of a multi-well plate  21  being dispensed at once (see FIG.  10 E). The external driving mechanism  4  should not come in contact with the sample  6  in order to avoid cross-contamination. Alternatively, the dispensing mechanism  4  can be positioned internal to the dispensing mechanism  3 . 
       FIGS. 5A and 5B  show embodiments of the dispensing system  1  having a “cow udder” type dispensing mechanism  3   a  As shown in  FIGS. 5A and 5B , the cow udder type dispensing system  1  includes storage device  2  containing a sample  6  to be dispensed and a dispensing mechanism  3   a . As shown, the dispensing mechanism  3   a  is connected to the bottom  10  of the storage device  2  and is in dispensing communication with an opening  22  formed in the storage device  2 . 
       FIGS. 5A and 5B  show the cow udder type dispensing mechanism  3   a  including a body  30  having an inlet valve  31 , an actuator  32 , and an outlet valve  33 . In the cow udder type of dispensing mechanism  3   a , the body  30  is preferably made of a resilient member. The inlet valve  31  and the outlet valve  33  can be active and/or passive valves. As shown in  FIG. 5A , the inlet valve  31  is an active valve and the outlet valve  33  is a passive valve. The passive outlet valve  33  can be, for example, a ball valve, a resilient material with a pinhole poked in it after molding, or the like. 
     As shown in  FIG. 5A , the self-dispensing system  1  includes a driving mechanism  4   a  having an inlet valve drive member  34  for driving the inlet valve  31  and an actuator drive member  35  for driving the actuator  32 . In this embodiment, there is no outlet valve drive member because the outlet valve  33  is a passive valve. 
       FIG. 5B  shows another cow udder type self-dispensing system  1  having both a passive inlet valve  31  and a passive outlet valve  33 . Alternatively, the dispensing mechanism could be formed having an active outlet valve (not shown). Where an active outlet valve is used, the drive mechanism includes an outlet valve drive member (not shown) for driving the outlet valve  33 . 
     In all forms of the cow udder type of dispensing mechanism  3   a , actuation is achieved by squeezing the resilient material of body  30 . When it is squeezed, the sample  6  is pushed out the outlet valve  33 . When it is released, the resilient material expands and draws sample  6  in through the inlet valve  31 . The dispensing mechanism operates by pinching the resilient material above and below the actuator  32 . As shown, the top valve is the inlet valve  31 , and the bottom valve is the outlet valve  33 , and the actuator  32  is positioned between the inlet valve  31  and the outlet valve  33 . 
       FIG. 5A  shows a hybrid approach including a passive outlet valve  33  and an active inlet valve  33 . Under normal operation, the normally closed outlet valve  33  opens when internal pressure is applied. To actuate this self-dispensing system  1 , the active inlet valve  31  is first closed by squeezing the resilient body  30  near the top. Next the actuator  32  is squeezed. The sample  6  cannot go out the top, because of the inlet valve  31  is closed, so the sample  6  goes out the outlet valve  33  (e.g., the pinhole opening  23 ) in the bottom. After dispensing, the inlet valve  31  is opened while the actuator  32  remains closed, then the actuator  32  opens, drawing sample  6  in through the inlet valve  31 . The inlet valve  31  can be actuated by a separate pincher  34  from the actuator driver  35 , or alternatively, they can be combined. The volume or quantity of sample  6  dispensed can be set by the resting volume of the resilient dispensing mechanism. For example, the size and shape of the resilient body  30  and the location of the inlet-valve  31 , the actuator  32 , and the outlet valve  33 , with respect to one another, all contribute to determine the volume of sample  6  dispensed during each cycle of the dispensing mechanism  3   a.    
     Advantages of the cow udder design and construction include low manufacturing cost, simple, and reliable operation. It also is difficult to plug because the actuation pressure can be very high, forcing it to unplug. 
       FIG. 6  shows a mold  37  that can be used to form the resilient body  30 . The mold  37  can have a notch  38  that makes a ridge on the molded body part. This feature can be used to reduce the actuating motion of the inlet valve  31 . This can also make for a higher dispensed volume with better reproducability. 
       FIGS. 7A through 7E  show alternative embodiments having a membrane pump type dispensing mechanism  3   b . As shown in  FIGS. 7A through 7E , the membrane pump type dispensing mechanism  3   b  includes an inlet valve  41 , an actuator  42 , and an outlet valve  43 . As shown, the inlet valve  41  and the outlet valve  43  are active valves having a flexible membrane  44  and a valve body  45 . The flexible membrane fits over the end of the cylindrical or tube shaped valve body  45 . The actuator  42  includes a flexible membrane  44  and an actuator body  47 . The flexible membrane  44  fits over the end of the cylindrical or tube shaped actuator body  47 . Preferably, this is the same membrane as is used for the inlet and outlet valves, although it need not be. The inlet valve  41 , actuator  42 , and outlet valve  43  are operated using a drive mechanism  4   b , such as a pneumatic system. 
     As shown in  FIGS. 7A through 7E , the membrane type of dispensing mechanism  3   b  includes a plurality of tube or channels  48  for forming a dispensing communication between a storage device  2  containing a sample  6  and the dispensing exit hole  49 . The channels  48  are disposed between and connecting the storage device  2  to the inlet valve  41 , the inlet valve  41  to the actuator  42 , the actuator  42  to the outlet valve  43 , and the outlet valve  43  to an exit hole  49 . 
     This design and construction is preferably made of a rigid lower plate  50  with a flexible membrane  44  attached over the top surface. The flexible membrane  44  may be attached to the plate  50  using conventional techniques, including gluing, heat sealing, welding (sonic, or optic), or the like. The inlet valve  41  and outlet valve  43  are made by creating the channels  48  in the lower plate through which the sample  6  to be dispensed flows. At the site of each valve  41 ,  43 , a dam  51  is placed in the path of the channel  48 , such that when the membrane  44  lays flat, the sample  6  cannot flow. In the closed position of each valve  41 ,  43 , the tubular body  45  is placed over the membrane  44  and the membrane  44  is pressed down to form a seal with the top surface of the plate  50  and the dam  51 . The valves  41 ,  43  are opened by evacuating the tubular body  45 , thereby pulling up on the flexible membrane  44 , forming an opening or bubble between the flexible membrane  44  and the dam  51 . When this happens, the sample  6  can pass from the inlet channel, over the top of the dam  51 , and into the outlet channel, and continues down the channels  48  toward the exit hole  49 . 
     The actuator  42  has a similar construction and design, except that the actuator tube  47  preferably has a thicker side wall and is shaped to physically limit the upward travel of the membrane  44 , thereby setting the positive displacement volume. As shown in  FIG. 7E , the actuator body  47  includes a stop  52  that functions to limit the movement of the flexible membrane  44  and set the positive displacement volume of the dispensing mechanism. As shown, the stop  52  can be a shaped surface. The membrane type dispensing mechanism  3   b  operates in the sequence of any active valve actuator. Alternatively, instead of a single membrane being disposed over the plate, a separate membrane may be used between the inlet and outlet valve bodies  45  and the plate  50  and the actuator body  47  and the plate  50 . 
     Advantages of a membrane type dispensing mechanism  3   b  include the fact that the same membrane  44  used to form the inlet valve  41 , the actuator  42 , and the outlet valve  43  can form the collapsible well  2  (e.g., wine in a box style). These can also be made very cheaply, and can have a filter  53  built in. 
       FIG. 8  shows an alternative embodiment having an embedded balls type dispensing mechanism  3   c . As shown in  FIG. 8 , the embedded balls type dispensing mechanism  3   c  includes an inlet valve  61 , an actuator  62 , and an outlet valve  63 . The inlet and outlet valves  61 ,  63  can be active or passive valves. For example, the valves can be spring operated or magnetically operated. The actuator  62  preferably includes a magnetic ball  64  within a cylinder  65  (plastic or Teflon coated). The magnetic ball  64  slides in a cylindrical section  65  molded or machined into the plate  66 . The drive mechanism  4   c  includes a magnetic system  67  that moves the ball  64  by applying an externally applied magnetic field. When the ball  64  moves, it displaces the sample  6  to be moved. Preferably, a sliding seal  68  is formed ball  64  and the cylinder  65  in which the ball  64  sides. Active valves may be made and operate in the same way. The back side of the actuator cylinder  65  may be connected by a passage to the storage device to prevent any sample  6  that leaks past the seal  68  from escaping the device. 
       FIGS. 9A and 9B  show an alternative embodiment having a two-dimensional type dispensing mechanism  3   d .  FIG. 9A  shows a side view and  FIG. 9B  shows a top view of the tow-dimensional pump type embodiment for the dispensing mechanism  3   d . As shown in  FIGS. 9A and 9B , the two-dimensional type dispensing mechanism  3   d  includes an inlet valve  71 , an actuator  72 , and an outlet valve  73 . As shown, a center plate  74  is sandwiched between two flat surfaces  75 . The center plate  74  is preferably a springy material, such as, for example, stainless steel, peek plastics, or the like and the two flat surfaces  75  can be made of, for example, Teflon or the like. Holes or cavities in the top and/or bottom plates  75  form inlet and outlet channels  76   a ,  76   b . One of the two flat surfaces  75  has a exit hole  79 . The center plate  74  has the channels, valves, and actuator. These features are preferably created by photo-etching, laser cutting, water or conventional milling, molding, or the like. The inlet and outlet valves  71 ,  73  can be passive or active. A check valve shape can be formed, and then slit open in a second operation so that it springs closed. The device components are preferably made flat enough so that the sample  6  is forced to pass through the valve, not over or under the features. 
     Preferably, the actuator  72  is made by building a piston  77   a  on a bellows  77   b . The bellows  77   b  keeps fluids from going around the piston  77   a  without requiring a sliding seal on the sides (e.g., one on top and one on bottom). One way to actuate the actuator  72  is to create a lever arm  78   a  pivotable about a hinge  78   c  with an imbedded magnetic component  78   b  that can be moved from side to side by application of an external field. 
     One advantage of the two-dimensional pump embodiment is that components can be made extremely small using photolithography and etching techniques. It can also be made multilayer and combined with other micro-fluidics. Filters (not shown) can also be incorporated. 
       FIGS. 10A through 10E  show alternative embodiments having a rotating valve type dispensing mechanism  3   e . As shown in  FIG. 10A through 10E , the rotating valve type dispensing mechanism  3   e  includes a rotating rod  81  is placed between the inlet channel and outlet channel. The rod  81  rotates in a cylinder  82  with a very close fit to prevent leaking out the sides. In one embodiment shown in  FIGS. 10A through 10C , the cylinder has a hole  84  drilled through it. In one position shown in  FIG. 10B  it connects the inlet to a waste channel. In this position a small pulse of pressure is placed on the storage device  2  to force the sample  6  through the hole  84  in the rod  81 . Next, the rod  81  rotates to its second position as shown in  FIG. 10A , which connects the outlet channel to an air pressure source. This air pressure forces the small, measured, quantity or volume of sample  6  contained in the hole  84  in the rod  81  out the outlet channel. The rod  81  continues to rotate, repeating the process. 
     In another type of the rotating valve embodiment shown in  FIGS. 10D and 10E , the rod  81  has a small slot  85  milled on its side. The slot  85  gets filled with sample when exposed to the inlet. An optional wiper  86  may be used to dislodge any air bubble (not shown)that may be left after the dispense. As the rod  81  rotates, the slot  85  comes to a position where it connects a channel with pressurized air to the outlet channel, as shown in FIG.  10 E. When this occurs, the pressurized air forces the small quantity of sample  6  out of the slot  85  and out the outlet channel. The rod  81  continues to rotate in the direction of arrow  87 , and the process continues. An advantage of this method is that the dispensed sample  6  volume is replaced by the same quantity of air each time, eliminating the need for any check valves in the storage device lid, or lid removal. Another advantage is that it can be operated relatively quickly by continuously rotating the rod  81 . In both cases, the volume dispensed is set by the size of the hole  84  or slot  85  in the rod  81 . 
       FIG. 10F  shows a 96-well plate having a valve rod  81  connecting the wells in each column (or row). The rod  81  can be driven externally and the self-dispensing system  1  can be set up to dispense one or more of the columns at a time, or all of the wells in the plate at the same time. 
       FIGS. 11A and 11B  show an alternative embodiment having a steam engine type dispensing mechanism  3   f . Generally, a steam engine type dispensing mechanism  3   f  works by having a cylinder pushed alternately on one side, then the other by expanding steam. The steam is switched from side to side by a valve that alternately switches the inlet and outlet pipes. Typical steam engines use either D valves or piston valves that swap channels as they move from side to side, covering and uncovering ports. If the steam were replaced by pressurized water, a measured quantity of water would be dispensed with each stroke. 
     As shown in  FIGS. 11A and 11B , the steam engine type dispensing mechanism  3   f  includes an inlet and outlet valve  91 ,  93 , an actuator  92 , and an outlet opening  94 . The steam engine type self-dispensing storage device could be created with the both the two-dimensional and ball pump mechanisms described herein above. The main piston  91  could be a ball  95  sliding in a cylinder  96  (as shown), a bellows mounted piston sandwiched between to flat plates, a hinged bar sweeping out an arc, etc. Similarly, both a reciprocating and a wankel rotary style four-stroke internal combustion engine could be used. 
     In addition, these processes that typically require precision and reproducible dispensing also typically require automated systems for the general movement of one or more samples between workstations and other storage devices where the precision dispensing of the sample at each workstation or storage device takes place. For example, for pharmaceutical research and clinical diagnostics, there are several basic types of automation systems used. Each of these conventional approaches is essentially a variant on a method to move samples from one container or storage device to another, and may perform other operations on theses samples, such as optical measurements, washing, incubation, and filtration. Some of the most common automated liquid handling systems include systems such as those manufactured by Beckman, Tecan, and Hamilton. 
     These conventional automation systems share the characteristic that sample transfer and manipulation operations are carried out by workstations, or devices, of some kind. These workstations can be used separately for manual use, or alternatively, can be joined together in automated systems so the automation provider can avoid having to implement all possible workstation functions. Another shared characteristic is that samples are often manipulated on standardized “microtiter plates.” These plates come in a variety of formats, but typically contain 96 “wells” in an 8 by 12 grid on 9 mm centers. Plates at even multiples or fractions of densities are also used. 
       FIG. 12  shows the precision sample dispensing system of the present invention being used as part of an automated sample positioning system  100 . As shown in  FIG. 12 , the automated sample positioning system  100  can include a positioning mechanism for the movement of one or more samples along a pathway between various destinations, or stations. The samples  6  can be contained within, for example a self-dispensing plate  21 . Once at a destination or station  103 , the samples  6  to be dispensed is first positioned with respect to the station  103 . The automated sample positioning system  100  can receive samples from an input stack  108  and delivery the samples to an output stack  109  once the dispensing operation has been completed. Once at the station  103 , the sample  6  may be dispensed or transferred to a destination device or another storage device  8  such as a reaction block or the like. The self-dispensing system  1  dispensing a precise and reproducible quantity of the sample  6  in more or more drops  7  until a measured quantity or volume of the sample  6  has been dispensed. 
       FIG. 13  shows an exemplary automated system wherein the self-dispensing system  1  of the present invention is carried on one or more robots  101  that travel on tracks  102 . The track system  102  is preferably multi-dimensional having multiple levels, such that one portion of the track may travel over another portion of the track. As shown, one robot  101  may travel over another robot  101  and dispensing a measured quantity or volume of the sample  6  to the storage device under it using the onboard self-dispensing system  1 . 
     One suitable automated system  100  that the self-dispensing system  1  of the present invention can be used with is the “SYSTEM AND METHOD FOR SAMPLE POSITIONING IN A ROBOTIC SYSTEM”, U.S. patent application Ser. No. 09/411,748, filed Oct. 1, 1999. This patent application describes an automated sample positioning system having robot to robot transfer and/or robot to workstation transfer, wherein the storage device or devices are included as part of the robot. This patent application is incorporated by reference in its entirety. 
       FIG. 14  shows an exemplary automated system  100  in which the self-dispensing system  1  of the present invention may be used. As shown in  FIG. 14 , the automated system  100  includes a positioning system having one or more robots  101  that travel along a track system  102  that defines one or more predetermined pathways disposed between various stations  103 . Each station has a device  104  or another storage device (e.g., a source  2  and/or destination  8  sample storage device) for interacting in some way with the self-dispensing system  1  that is carried on the robot  101 . One or more intersections  105  are formed along the various pathways where the pathways diverge and converge, and where workstations are located. One or more siding  106  can be provided at each station  103  for allowing a robot  101  to exit a pathway onto the siding  106 . The siding  106  for a station  103  allows other robot  101  traffic to pass while the self-dispensing system  1  on the robot  101  interact with a device  104  or another storage device  2  at the station  103 . An indicator device (not shown) can be provided at each intersection  105  and at each station  103  which can be detected by a sensor device (not shown) on each robot, for determining when a robot  101  is at an intersection  105  or station  103 . The sample transfer station could also be composed of two or more tracks arranged in a multi-level configuration wherein individual robots  101  may travel over or below a sample transfer station  103  or another sample storage device, such as shown in FIG.  13 . 
       FIG. 15  shows a grid-type, or array-type, track system  110  which is designed to create an arbitrarily large work surface on which robots  101  carrying self-dispensing plates  21  holding a sample  6  are set to be moved between workstations  103  or destination plates  111 . Once at the destination plate  111  the self-dispensing system  1  on the robot  101  dispenses a measured quantity of a sample to the destination plate  111 . The self-dispensing plates  21  are moved from one location  103  to another location  103  by robots  101  which can travel in X or Y directions along the grid system  110 . Because these robots  101  have self-dispensing systems  1  onboard, the time required to perform the dispensing process is reduced and the through put of the automated system  100  can be improved. Also, no tip change or wash is required between each sample transfer. 
       FIG. 15  shows the basic layout of these robots  101  on the grid-type track system  10 . Rails  102  are provided upon which the robots  101  run. As shown, each robot has a set of “X” wheels and a set of “Y” wheels. If the robot  101  is centered on a grid location and either changing direction or interacting with a plate, both sets of wheels are raised and the robot rests on, for example, indexing feet (not shown). If the robot  101  wants to move on the “X” direction, it lowers its “X” wheels and rolls in that direction. If it wants to change to travel in the “Y” direction, it raises the “X” wheels while at an intersection  105 , then lowers the “Y” wheels. Note that this also realigns the robot ensuring that the new wheel set will properly engage. 
     In an automated system, the drive mechanism  4  is preferably controlled and operated using conventional techniques. For example, the control and operation function can be onboard (local) the robot  101  or can be located in a central controller (not shown) that communicates with each individual robot  101  to move the robots  101  around the automated system  100  and to also control the dispensing operation. 
     Two models for the control and operation of an automated system having self-dispensing storage device or plate include a first embodiment wherein the source and destination wells are placed in a workstation  103  that contains the drive mechanism  4 . The drive mechanism  4  is then given the command to fire a predetermined number ‘n’ of drops from the source storage device  2  to the destination device  8 . The workstation could have stackers, and the source and destination wells could be on 96 well plates, such as shown in FIG.  12 . In this embodiment, the workstation  103  could stand alone, or be part of an automated system  100  with a separate mechanism to move samples. If in an automated system, the central controller (not shown) could send the commands to the workstation, otherwise the operator would do it through, for example, a front control panel (not shown). 
     Alternatively, the wells  2  can be on robots  101  that travel on tracks  102  so that the source storage device  2  is positioned over the destination device  8 . The two robots can communicate with each other or a third computer (e.g., a central controller) that can coordinates their activities. When all is in alignment, the top robot fires the actuator pump ‘n’ times to dispense the desired volume. 
     Also, in an automated system, the dispensing operation can be powered using a mechanical, electrical, electromagnetic, or air driven power source. The power source would depend on several factors, including whether the drive mechanism is internal or external, etc. 
       FIG. 16  shows an exemplary robot  101  having a self-dispensing system  1  in accordance with the present invention. As shown in  FIG. 16 , the robot  101  includes a body  115 , a self-dispensing plate  21 , a propulsion mechanism  116 , and track engagement mechanism  117 . Alternatively, the robot  101  could include a single self-dispensing storage device  20 . Preferably, each robot  101  also includes a controller  118 , a drive system  119 , and a power supply  120 . The robot  101  can include various displays (not shown) and/or indicators (not shown) for showing a state of the robot  101 . In addition, the robot  101  can include an identification system, a collision avoidance system, and an error correction system (not shown). 
     As shown, the self-dispensing plate  21  can be located on top of the robot  101  and can include, for example, any standard microtiter plate format, such as a 4-well plate, a 24-well plate, a 96-well plate, a 384-well plate, a 1536-well plate, a 9600-well plate, etc. The wells  119  may be varying depths, such as shallow or deep well. The wells  119  may have a variety of shapes based on the application and the samples that they will carry and the wells can have a flat, a U-shaped, or a V-shaped bottom. Preferably, the self-dispensing well plates  21  meet SBS standards, are made from optically quality polystyrene to allow direct sample observation, and have raised rims (not shown) to prevent cross-contamination. Alternatively, robot  101  can include a single self-dispensing storage device  20 , as shown in  FIG. 13 , or any other size or type of container or platform depending on the particular application, such as standard or non-standard sizes of, for example, a vial, a test tube, a pallet, a cup, a beaker, a matrices, etc. 
     This robotic sample positioning system  100  having robots  101  with self-dispensing systems  1  is conceived to be implemented in multiple scales. For example, in a first embodiment of the invention, the scale can be designed to work with standard size microtiter plates. These standard plates are approximately 125 mm by 85 mm. The wells of a 96-well plate are on about 9 mm centers and hold from about 30 μl to about 1500 μl depending on the plate depth. In another embodiment of the invention, the scale could be significantly smaller. For example, a 96-well plate could be approximately 16 mm by 12 mm, with wells on about 1 mm centers. These wells would hold approximately 1 μl. The sample  6  contained within the well would be transferred by the onboard dispensing mechanism  3 , such as describe herein above. 
       FIG. 17  shows an exemplary method for precisely dispensing a sample using a self-dispensing storage device or a self-dispensing plate. As shown in  FIG. 17 , the method includes providing one or more storage devices each having one or more reservoirs for holding a sample, at step  200 . Connecting a dispensing mechanism capable of precisely and reproducibly dispensing a measured volume of a sample in dispensing communication with each of the one or more reservoir, at step  205 . The dispensing mechanism and the storage device form a self-dispensing storage device. Positioning the self-dispensing storage device in dispensing relationship with a destination device or another self-dispensing storage device capable of receiving the measured volume of the dispensed sample, at step  210 . Driving the dispensing mechanism using a driving mechanism to dispense measured quantity or volume of sample, at step  215 . The self-dispensing method dispenses the sample in one or more measured drops until the measured quantity has been dispensed by the dispensing mechanism. The measured drops are precisely measured and reproducible in volume. 
     The present invention comprising a system and method for accurately and precisely dispensing a sample to be worked on or manipulated using a dispensing mechanism  3  that is formed integral with and in dispensing communication with a sample storage device  2  (e.g., connected to the storage device), preferably in an automated or robotic system, and has significant value in those situations where there are compelling needs for no tip washes or changes, less daughter plates are required, minimal cross contamination, and the like. 
     Although illustrated and described herein with reference to certain specific embodiments, it will be understood by those skilled in the art that the invention is not limited to the embodiments specifically disclosed herein. Those skilled in the art also will appreciate that many other variations of the specific embodiments described herein are intended to be within the scope of the invention as defined by the following claims.