Abstract:
A microfluidic dispensing tap, such as for use in screening assays, includes a dispensing tube translatable within a sealed reservoir housing. The tube has an outer surface and defines an inner cavity open at a lower end of the tube, and a metering aperture extending through a side wall of the tube between the inner cavity and the outer surface to define a known volume. The tube is movable against a seal at a lower end of the reservoir housing between a first position, in which the metering aperture is disposed below the seal, and a second position, in which the metering aperture is disposed above the seal and exposed to the reservoir for entraining a discrete dose of a sample liquid within the aperture. An injector is configured to inject a known quantity of a diluent into the inner cavity of the tube and into fluidic contact with the dose of sample liquid in the aperture, such that the dose of sample liquid diffuses into the diluent to form a discrete mixture for dispensing from an open end of the tube.

Description:
RELATED APPLICATIONS  
       [0001]    This application is a continuation of PCT Application No. PCT/US02/25653, filed Aug. 13, 2002 and designating the United States, the entire contents of which are hereby incorporated herein by reference. 
     
    
     
       TECHNICAL FIELD  
         [0002]    This invention relates to liquid dispensing devices for mixing and dispensing extremely small quantities of liquids, and arrays of such devices for use in microfluidics and laboratory automation.  
         BACKGROUND  
         [0003]    The science and economics of drug discovery has changed with developments in the areas of genomics, combinatorial chemistry and high-throughput screening. The number of targets has increased as a result of genomics while the number of small molecule compounds (samples) has dramatically increased as a result of combinatorial chemistry. This increase in targets and compounds has an exponential effect on the number of tests that need to be performed to increase the likelihood of finding a new chemical entity using high-throughput screening. Microliter amounts of target and sample must suffice for many screening assays, putting pressure on the automation industry to provide new tools to accurately meter, mix and dispense liquids in doses as low as on the order of 10 nanoliters in many instances. Conventional R&amp;D screening efforts use multiple variations of pipetting to move aliquots of the concentrated liquid sample from storage receptacles, to working receptacles, to dilution receptacles where the sample is diluted with a solvent such as pure dimethylsulfoxide (DMSO), and finally to assay receptacles. This “reformatting” process, or “sample preparation” can waste valuable sample or target and increase time and assay cost. Devices and methods are needed for accurately and efficiently handling these valuable liquids in such minute quantities, to increase screening productivity and accuracy.  
         SUMMARY  
         [0004]    The invention features a microfluidic dispensing tap configured to accurately meter and dilute extremely small amounts of liquids, such as sample fluids for screening assays.  
           [0005]    According to one aspect of the invention, the tap has a dispensing tube having an outer surface and defining an inner cavity open at a lower end of the tube, the tube also defining a metering aperture extending through a side wall of the tube between the inner cavity and the outer surface, the metering aperture defining a known volume. The tap also includes a reservoir housing defining, together with the tube outer surface, a reservoir cavity for holding a quantity of a first liquid, and a seal between the reservoir housing and the tube outer surface at a lower end of the reservoir, the tube being movable against the seal between a first position, in which the metering aperture is disposed below the seal, and a second position, in which the metering aperture is disposed above the seal and exposed to the reservoir for entraining a discrete dose of the first liquid within the aperture. An injector is hydraulically connected to the inner cavity of the tube and configured to inject a known quantity of a second liquid into the inner cavity of the tube and into fluidic contact with the dose of first liquid in the aperture, such that the dose of first liquid diffuses into the quantity of second liquid to form a discrete mixture for dispensing from the open end of the tube, such as into a well.  
           [0006]    Preferably the tap does not contact the well, and the liquid dispensed from each tap breaks contact with the tap before contacting the well aligned with that tap or the contents of the well aligned with that tap. The reservoirs are preferably sealed against air and light. The taps may be configured in an array of reservoir units aligned directly above an array of wells. Each tap may be actuated independently and preferably contains zero dead volume. Examples of suitable multi-well containers are a 96-well microtiter plate, a 384-well microtiter plate and a 1536-well microtiter plate.  
           [0007]    In some embodiments, the aperture is a metering capillary and the first liquid is drawn via capillary forces into the metering capillary.  
           [0008]    In some cases the tap includes means for cycling the solution up and down within the inner cavity of the tube, such as through a mixing orifice, to thoroughly mix the first and second liquids before dispensing. For example, the injector may be configured to perform such cycling pneumatically.  
           [0009]    Some embodiments include means for propelling the mixed solution from the tube utilizing a compressed gas, such as air, nitrogen or argon, that engages an exposed surface of the solution. Alternatively, the fluid can be drawn from the end of the tube by touching the solution to another fluid surface or a solid surface.  
           [0010]    The invention also features a device for storing and dispensing liquid into an array of wells in a multi-well container. The device includes: an array of isolated, sealed, tapped reservoir units, each unit containing an integrated metering tap, each tap including a meter capillary. The meter capillary can be sized to draw in, for example, 5 nanoliters to 20 microliters, preferably from 5 to 200 nanoliters of a liquid. The device also includes suitable instrumentation to pump a diluent in through the inner diameter of the tube so that the lower meniscus edge is below the meter capillary, drawing the liquid into the diluent via diffusion or forced vacuum, mixing the liquid and diluent in the tube by hydraulically moving the diluent up and down inside of the tube, and expelling the mixture from the tube by pumping the diluent to the end of the translatable tube. The array of reservoir units can be arranged so that each tap aligns with one well of a multi-well container such as a 96-well microtiter plate, a 384-well microtiter plate, a 1536-well microtiter plate or a flat plate designed to hold small amounts of fluid. However, with suitable equipment, any particular tap can be positioned to dispense into any chosen well. Some embodiments of the invention include a compressed gas inlet port in fluid communication with the fluid output path when the tube is in the dispense position. In addition, some embodiments include a compressed gas path terminating in an annular opening surrounding the fluid output tip. Some embodiments of the invention feature a single channel device that operates independently or operates as an array by placing multiple single-channel units into a frame.  
           [0011]    According to another aspect of the invention, a microfluidic dispensing tap includes a dispensing tube having an outer surface and defining an inner cavity open at a lower end of the tube. The tube also defines a metering aperture extending through a side wall of the tube between the inner cavity and the outer surface, the metering aperture defining a known volume. A reservoir housing defines, together with the tube outer surface, a reservoir cavity for holding a quantity of a first liquid. A seal extends between the reservoir housing and the tube outer surface at a lower end of the reservoir cavity. The tube is movable against the seal between a first position, in which the metering aperture is disposed below the seal, and a second position, in which the metering aperture is disposed above the seal and exposed to the reservoir cavity for entraining a discrete dose of the first liquid within the aperture. A tap actuator is hydraulically connected to the inner cavity of the tube and configured to introduce a known quantity of a second liquid into the inner cavity of the tube and into fluidic contact with the dose of first liquid in the aperture, such that the dose of first liquid diffuses into the quantity of second liquid to form a discrete mixture for dispensing from the open end of the tube.  
           [0012]    Preferably, the reservoir cavity is sealed against air and light.  
           [0013]    In some embodiments, the aperture is a metering capillary and the first liquid is drawn via capillary forces into the metering capillary.  
           [0014]    The actuator is preferably adapted to cycle the solution up and down within the inner cavity of the tube to mix the first and second liquids before dispensing, such as by cycling through a mixing orifice. The mixing orifice may be defined at (i.e., aligned with) a detent in the outer surface of the tube, for example. The tap actuator may be configured to perform such cycling pneumatically.  
           [0015]    In some cases, the tap also includes means for propelling the mixed solution from the tube utilizing a compressed gas, such as air, nitrogen or argon, that engages an exposed surface of the solution. For example, a compressed gas inlet port may be provided in fluid communication with the inner cavity of the tube when the tube is in a dispense position, or a compressed gas path may terminate in an annular opening surrounding the lower end of the tube.  
           [0016]    In some embodiments, the second liquid is introduced into the inner cavity of the tube by injecting the second fluid into the tube at a point where the metering aperture is between the injected second fluid and said open end of the tube. In some other embodiments, the second liquid is introduced into the inner cavity of the tube by being drawn up from the open end of the tube toward the metering aperture.  
           [0017]    The metering aperture or capillary preferably has a fixed volume of less than about 20 microliters, more preferably between about 5 and 200 nanoliters.  
           [0018]    In some configurations, a multiplicity of the above-described dispensing taps are arranged in an array alignable with an array of wells of a microtiter plate, into each of which the mixed solution is expelled from a corresponding dispensing tap by operating the corresponding tap.  
           [0019]    According to another aspect of the invention, a device is provided for storing and dispensing liquid into an array of wells in a multi-well container. The device includes an array of isolated, sealed, tapped reservoir units, each unit containing an integrated metering tap including a dispensing tube having an outer surface and defining an inner cavity open at a lower end of the tube. The tube also defines a metering capillary extending through a side wall of the tube between the inner cavity and the outer surface, the metering capillary sized to draw in a known volume of a liquid. The device includes instrumentation configured to pump a diluent along the inner cavity of the tube so that a lower meniscus edge of the diluent is below the metering capillary; draw the liquid from the metering capillary into the diluent via diffusion or forced vacuum; mix the liquid and diluent in the tube by hydraulically moving the diluent up and down inside the tube, to form a mixture; and then expel the mixture from the tube by pumping the mixture to the end of the tube.  
           [0020]    In preferred embodiments, the array of reservoir units is arranged so that each tap aligns with one well of a multi-well container such as a 96-well microtiter plate, a 384-well microtiter plate, a 1536-well microtiter plate or a flat plate designed to hold small amounts of fluid.  
           [0021]    According to another aspect of the invention, a method of mixing and dispensing microliter volumes of a sample liquid with a diluent liquid is provided. The method includes:  
           [0022]    (a) providing a sealed, tapped reservoir unit containing an integrated metering tap with a dispensing tube having an outer surface and defining an inner cavity open at a lower end of the tube, the tube also defining a metering capillary extending through a side wall of the tube between the inner cavity and the outer surface;  
           [0023]    (b) drawing a dose volume of sample liquid into the metering capillary by capillary action;  
           [0024]    (c) pumping a volume of liquid diluent along the inner cavity of the tube so that a lower meniscus edge of the diluent is below the metering capillary;  
           [0025]    (d) drawing the dose of sample liquid from the metering capillary into the diluent, such as by diffusion or forced vacuum;  
           [0026]    (e) mixing the sample liquid and diluent in the tube to form a mixture; and then  
           [0027]    (f) expelling the mixture from the tube by pumping the mixture to the end of the tube.  
           [0028]    In some cases the volume of liquid diluent is introduced into the inner cavity of the tube by injecting the diluent into the tube at a point where the metering aperture is between the injected diluent and the end of the tube. In some other cases, the liquid diluent is introduced into the inner cavity of the tube by being drawn up from the end of the tube toward the metering aperture.  
           [0029]    In some applications, mixing includes hydraulically moving the diluent up and down inside the tube, and may include cycling the sample liquid and diluent through a mixing orifice. The diluent may be moved up and down inside the tube pneumatically, for example.  
           [0030]    In some embodiments, expelling the mixture from the tube includes engaging an exposed surface of the mixture with a compressed gas, such as air, nitrogen or argon.  
           [0031]    The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. 
       
    
    
     DESCRIPTION OF DRAWINGS  
       [0032]    [0032]FIG. 1 is a perspective view of a device for integrated storage, integrated dilution and single-channel dispensing of small volumes of liquids, having multiple tap units.  
         [0033]    [0033]FIG. 2 shows a sectional view of two arrayed tap units, with metering tubes in a down position.  
         [0034]    [0034]FIG. 3 shows the tap units with the metering tubes in an intermediate up position.  
         [0035]    [0035]FIG. 4 shows the tap units with metering tubes in an up position.  
         [0036]    [0036]FIG. 4A is an enlarged view of section  4 A of FIG. 4.  
         [0037]    [0037]FIG. 4B illustrates metering during pressure equalization in a second embodiment.  
         [0038]    [0038]FIG. 5 shows the embodiment of FIG. 2 with metering tubes in a down position with filled capillaries for dispensing.  
         [0039]    [0039]FIG. 6 shows the tap units combined with actuation instrumentation and an arrayed assay receptacle.  
         [0040]    [0040]FIG. 7 shows one of the tap units as shown in FIG. 6, viewed from the right side.  
         [0041]    [0041]FIGS. 8-10 sequentially illustrate the positioning of a quantity of diluent in contact with the filled capillary, for diffusion.  
         [0042]    [0042]FIGS. 11-13 sequentially illustrate mixing the diluent and sample, and dispensing the solution into an assay receptacle.  
         [0043]    [0043]FIG. 14 is an enlarged view of the lower seal detail of FIG. 2.  
         [0044]    [0044]FIG. 15 schematically illustrates a system for delivering diluent to multiple tap units.  
         [0045]    [0045]FIGS. 16 and 17 illustrate an alternative embodiment in which diluent is aspirated from a reservoir located below the tap units. 
     
    
       [0046]    Like reference symbols in the various drawings indicate like elements.  
       DETAILED DESCRIPTION  
       [0047]    Referring to FIG. 1, a microfluidic dispensing device  10  is useful for storing and dispensing liquid into a conventional 96-well microtiter plate  12 . The depicted device contains a 96-unit array of integrated reservoir/tap units. The 96 units are arranged so that each of the 96 tubes aligns with one well of a conventional 96-well microtiter plate. Protruding from lower surface  13  of device  10  are 96, 384, 1536 or other configuration of flow tubes  11  arranged so that when device  10  is aligned above a 96, 384, 1536 microtiter plate or other receptacle  12 , each flow tube  11  is above a different one of the 96, 384, 1536, or other number of wells or receptacles  14 . On the upper surface  15  of device  10  are 96, 384, 1536, or other number of mechanical interfaces  16  for tap actuation. Operation of each interface  16  actuates a tap whose flow tube  11  is located beneath that interface  16 . Alternatively, a mechanical interface can be provided on the lower end of each tube  11 , with the flow path of tubes  11  reversed.  
         [0048]    [0048]FIGS. 2 through 5 illustrate sample fluid metering. As shown in FIG. 2, each tap unit  20  contains a reservoir  21  around the outer diameter of its tube  11 , defined by a cylinder wall  22  of reservoir plate  32  between upper and lower seals  23  and  24  providing dynamic sealing against the outer surface of the tube  11 . Seals  23  and  24  may be of any suitable material compatible with the fluids to be contained in reservoirs  21 . For use with DMSO as a solvent, molded silicone coated with polytetrafluoroethylene (PTFE) is a suitable seal material for providing a contacting seal surface against the outer surface of each tube  11 . Non-coated silicone may be employed, but DMSO can pull impurities from silicone, resulting in possible sample contamination. The seals may be individual units held in place by upper and lower seal retaining plates  208  and  210  of polypropylene, as shown, or portions of a common sealing member spanning multiple reservoirs. Each reservoir  21  contains a quantity of sample fluid  30 . Each round tube  11  is hollow, defining a central bore  25 , and has a midsection detent  28  of reduced diameter, defining an inner mixing orifice  204 . Tubes  11  have a nominal outer diameter of about 1.5 millimeters, and a nominal inner diameter of bore  25  of about 0.8 millimeter. A mechanical interface  26  is disposed at the upper end of each tube  11  and held within an interface plate  212 , for hydraulically connecting the tube to an actuation instrumentation manifold block (not shown). Each meter/dilution/dispensing tube  11  also defines a meter capillary  27  hydraulically connecting the outside of the tube  11  with the inside bore  25  of the tube, below the mixing orifice  204 . Capillaries  27  define fixed volumes within the thickness of the side wall of each tube. In the illustrated embodiment, tubes  11  are of polypropylene and capillaries  27  are round holes having a diameter of about 0.28 millimeter and a length (equal to the wall thickness of the tube) of about 0.34 millimeter, defining a capillary volume of approximately 15 nanoliters. The metered amount can be from near zero nanoliters to 20 microliters, preferably from 5 to 200 nanoliters. Mixing orifices  204  need not be at the same position along tubes  11  as necked detents  28 .  
         [0049]    In operation, the metering tubes  11  are first translated up to an intermediary position (FIG. 3) by moving the interface plate  212  away from upper seal plate  208 . In this position, tube detent  28  is aligned with, and fully spans, upper seal  23  to allow nitrogen or other inert gas to enter the reservoir  21  through open channel  29  defined between upper seal  23  and the outer surface of tube  11 , to balance internal reservoir pressure. Detent  28  may be of any other form suitable for performing this pressure-balancing function, such as one or more longitudinal grooves extending a limited distance along the outer surface of the tube. Tubes  11  continue to be pulled upward to an up position (FIG. 4), where meter capillaries  27  are in direct exposure to stored sample fluid  30  in reservoirs  21 . With reservoir pressure having just been established by the temporary spanning of detent  28  across upper seal  23 , a determinable amount of fluid sample  30  will be drawn into each capillary  27  by capillary action, as a function of capillary volume and surface tension effects, forming a metered fluid dose  31  (FIG. 4A). Typically, the inner meniscus of metered dose  31  will not protrude into the inner tube bore  25 . In the tube position shown in FIG. 4, reservoir  21  is now completely sealed from the outside by cylinder wall  22 , upper seal  23  and lower seal  24 .  
         [0050]    Alternately, reservoir pressure equalization may be timed to coincide with metering by repositioning detent  28  with respect to capillary  27 , as shown in FIG. 4B. In the illustrated position of tube  11 , tube detent  28  momentarily spans upper seal  23  to allow nitrogen or other inert gas to enter the reservoir  21  through channel  29  to balance the internal reservoir pressure, while capillary  27  is exposed to sample fluid in reservoir  21 .  
         [0051]    As the outside of the tube  11  (at the site of capillary  27 ) comes in contact with the fluid, capillary forces and the relationship between the surface tension of the fluid and the surface energy of the tube material will draw fluid into the capillary hole  27  until the volume of that capillary hole is substantially filled. A meniscus forms at the inside surface of the tube  11 . A meniscus is often described in the form of a contact angle between the fluid and the material. The contact angle will vary according to the relationship between the surface tension of the fluid and the surface energy of the tube material. A variation in contact angle will cause the volume of the capillary to vary slightly. The surface tension (fluid) and surface energy (solid) relationship is optimized when the fluid has a low surface tension (e.g. 20-70 dynes per centimeter) and the solid has a relatively high surface energy (e.g. 30-100 dynes per centimeter).  
         [0052]    The metering tubes  11  are next moved back to a down position (FIG. 5), with the meter capillaries  27  again beneath lower seals  24  and now containing known volumes  31  of sample fluid separated from the remaining fluid in reservoirs  21  by the wiping action of lower seals  24 .  
         [0053]    [0053]FIGS. 6 through 13 illustrate mixing and dispensing metered sample fluid with a diluent. Referring first to FIG. 6, actuation instrumentation injection block  40  is connected to devices  20  through their mechanical interfaces  26 . Injection block  40  includes means for introducing a known volume of a diluent into each tube  11  and driving the diluent up and down within the tube to engage and mix with the metered sample, as discussed below. Devices  20  have also been connected to an actuation instrumentation manifold block  40  at an opposite end of tubes  11 . A receptacle device  12  is disposed underneath the devices  20  such that each tube  11  is aligned with a corresponding receptacle well  14 , with the capillaries  27  of the tubes each already containing a metered dose  31  of fluid sample. As seen in the side view of FIG. 7, injection block  40  defines both a driving fluid port  50  and a diluent fluid port  51  for each tap unit  20 , hydraulically connected to the bore  25  of tube  11  by an injection sleeve  220  coupled to the upper end of tube  11  at interface  26  to form an air-tight seal. Driving fluid  52  and a discrete plug  53  of diluent fluid of known volume are pumped through injection block  40  to their respective entrances of sleeve  220  (FIG. 8) and then diluent fluid plug  53  is pumped into sleeve  220  (FIG. 9), such as by pneumatic operation. Driving fluid  52  is then forced into sleeve  220  (FIG. 10), hydraulically translating diluent fluid plug  53  down through mixing orifice  204  until the bottom edge or meniscus  55  of diluent fluid  53  is below meter capillary  27 . Driving fluid  52  is either air, or is separated from diluent fluid  53  by air gap  54 , such that the driving fluid  52  never comes in contact with the diluent plug  53 . In the condition illustrated in FIG. 10, diluent plug  53  is in direct fluidic contact with the metered dose  31  of fluid sample contained within the meter capillary  27  (FIG. 6). In an amount of time typically less than about 120 seconds, meter capillary fluid sample  31  diffuses into diluent fluid  53 , and may collect at the bottom meniscus  55  of the diluent fluid plug.  
         [0054]    Referring next to FIG. 11, driving fluid  52  is cycled into and out of injector sleeves  220  to hydraulically translate the diluent fluid plugs  53  (now containing both the diluent and the metered doses of fluid sample drawn from capillaries  27 ) up and down a predetermined number of times within the bores  25  of tubes  11 , through mixing orifices  204 , until the solution is sufficiently mixed. The driving fluid  52  is then advanced to hydraulically translate the mixed solution plugs  53  to the bottom of tube bores  25  until proud droplets  56  of mixed solution  53  appear outside of the open ends of tubes  11  (FIG. 12). Compressed dispensing gas is then delivered through port  57  of actuation instrumentation manifold block  41 , between extrusion director sleeves  58  and the outer surfaces of tubes  11  along coaxial flow paths  59 , to engage the exposed surfaces of proud drops  56 . The dispensing gas breaks the liquid-solid attraction between the solution droplets and their metering tubes  11 , overcoming surface tension effects to enable the droplet to fall free of the tube end. Flow paths  59  need not be coaxial with tubes  11  in all cases. The gas flow pushes the proud drop  56  off of the tube  11  and into the bottom of the receptacle well  14  (FIG. 13). The dispensed solution  60  wets the bottom of the receptacle well  14 . The tubes  11  of the device may now be cleaned and dried for further use.  
         [0055]    Referring to FIG. 14, lower seals  24  forms a fluid-tight seal with reservoir plate  32  and tubes  11 . Seals  24  each have thin cylindrical protrusions  222  of about 0.6 millimeter thickness that extend up and down the tube surface to help maintain a reliable seal against the tube surface under positive and negative pressure differentials between the reservoirs  21  and the outside environment. Alternatively, seals  24  may be molded without such protrusions  222 , or with the protrusions on either top or bottom in tight engagement with seal plate  210 , rather than spaced apart. Seals  24  are molded of silicone having a hardness of between about 30 and 90 shore A, coated with a layer of PTFE. The sealing bore diameter of each seal should be selected to provide a good seal against the tube surface. Seals with higher durometers can be fashioned to provide less interference against the tube, but softer seals need a tight fit to prevent losing metered fluid as the capillary is forced along the seal.  
         [0056]    [0056]FIG. 15 shows a schematic of an eight channel injection manifold for controlling the injection of both diluent and cleaning fluid into multiple tap units along a common injection line  139  for each tap unit. Each line  139  is hydraulically connected to the tube bore  25  (FIG. 2) of a respective tap unit. A standard 96 or 384 pipette system with standard or custom tips is indicated by  130 . Prior to use, diluent fluid lines  133  are purged of air for proper channel operation. The injection sequence begins when parallel or serial pinch valves  138  are closed and diluent fluid valve  132  opens and pipette  130  draws diluent fluid from diluent fluid reservoir  131  through diluent fluid valve  132 , through diluent fluid lines  133  into tap unit drive lines  134 . Diluent fluid valve  132  is then closed followed by parallel or serial pinch valves  138  opening. Pipette  130  pushes the diluent fluid along drive lines  134  until the diluent fluid plugs pass through parallel or serial pinch valves  138  and connecting lines  139  to be mixed with fluid sample in each tap unit.  
         [0057]    The diluent fluid reservoir  131  is positioned such that the upper surface of the fluid is at nearly the same height as the manifold. This positioning prevents the entry of either too much fluid or not enough fluid air into the diluent fluid lines  133  due to the compressible nature of air. The predictability and accuracy of fluid control is thereby maintained.  
         [0058]    The valves  132 ,  136 ,  138  preferably include elastomeric elements made of silicone rubber or similar elastomers. During aspiration by the pipettes  130 , i.e. when the pipettes draw fluid from diluent fluid reservoir  131  into diluent fluid line  133 , a control vacuum deflects elastomeric elements in the diluent and cleaning fluid valves  132 ,  136  away from the individual channel input ports to allow fluid flow into the tap unit drive lines  134 . In the diluent fluid valve  132 , a control pressure forces an elastomeric element onto each seat of the individual channel input port, thereby providing a seal. In the parallel or serial pinch valves  138 , tubes are either pinched so that each channel is closed, or not pinched so that each channel is open.  
         [0059]    To clean the tap unit drive lines  134 , the main connection lines  139 , and the individual tap unit lines, cleaning fluid valve  136  is opened. Cleaning fluid (i.e. solvent, air) is pumped from cleaning fluid reservoir  135  through cleaning fluid valve  136 , through cleaning fluid lines  137 , and into tap unit drive lines  134 . The cleaning fluid then passes through connecting lines  139  into each tap unit to be expelled into a receptacle device (not shown).  
         [0060]    [0060]FIGS. 16 and 17 illustrate an alternative embodiment in which diluent  53  is aspirated from a diluent reservoir  150  defined in a diluent reservoir plate  152  located below the device. Fluid sample metering is identical to that disclosed above with respect to FIGS. 2-5. In this embodiment, a mechanical interface block  154  is first attached to a standard pipettor (e.g., pipettor  130  of FIG. 15) or other aspirating piece of equipment as known in the art. The pipettor mates to the liquid dispensing device  20  through mechanical interface block  154 . A burst of compressed dispensing gas delivered through port  57  blows the metered dose into the center bore  25  of tube  11 .  
         [0061]    A diluent reservoir plate  152  is disposed underneath the devices  20  such that each tube  11  is aligned with a corresponding diluent reservoir well  150 , with the metering capillaries  27  of the tubes already emptied of their respective metered doses of fluid