Patent Publication Number: US-2003223910-A1

Title: Pipettor systems and components

Description:
CROSS REFERENCE TO RELATED APPLICATIONS  
     [0001] This application claims priority from U.S. Provisional Application Serial No. 60/356,684, filed Feb. 12, 2002, U.S. Provisional Application Serial No. 60/409,786, filed Sep. 11, 2002, and U.S. Provisional Application Serial No. 60/417,681, filed Oct. 10, 2002, the disclosure of each of which is incorporated herein by reference in its entirety.  
     [0002] This application hereby incorporates by reference in their entirety for all purposes the following patents and patent applications: U.S. Pat. No. 5,355,215, issued Oct. 11, 1994; U.S. Pat. No. 6,097,025, issued Aug. 1, 2000; U.S. patent application Ser. No. 09/478,819, filed Jan. 5, 2000; U.S. patent application Ser. No. 09/777,343, filed Feb. 5, 2001; U.S. patent application Ser. No. 10/061,416, filed Feb. 1, 2002; and U.S. patent application Ser. No. 09/703,472, filed Sep. 19, 2000. 
    
    
     
       BACKGROUND OF THE INVENTION  
       [0003] 1. Field of the Invention  
       [0004] This invention is in the field of fluid transfer systems. More particularly, the invention relates to single- or multi-channel pipettors useful for aspirating and/or dispensing of fluids.  
       [0005] 2. Description of the Related Art  
       [0006] Pipettes are used for transferring precise amounts of a fluid from one container to another. A pipette is filled with the desired volume of fluid, by air displacement, positive displacement or capillary action, then the fluid is dispensed by positive or air displacement. Positive or air displacement are generally achieved with a plunger that slides within the barrel to the pipette. Commonly, a disposable plastic pipette tip is mounted on the pipette end to avoid having to clean or sterilize the remainder of the pipette. The pipette can be operated manually or by automated equipment.  
       [0007] Microplates are common containers for dispensed fluids in life science research. Microplates have multiple wells for fluid arranged in an array with, for example, 6, 24, 48, 96, 384, 864, or 1536 wells per plate. Most microplates conform to a standard footprint with well density increasing with increasing number of wells (e.g. 96-well plates have wells at a 9 mm spacing while 1536-well plates have wells at a 2.25 mm spacing). Liquid dispensing devices having a number of parallel pipettes have been developed to allow simultaneous operation of the pipettes for applications such as transferring fluid to and from microplates. Simultaneous pipetting is essential to such applications as initiating a reaction in every well of a microplate simultaneously. For such applications it is important to have a multichannel pipettor with the same number of channels as microplate wells. Even when it is not essential to the application, when using a lower number of pipettors than microplate wells, one must resort to multiple dispense (or aspirate) operations per plate leading to inefficient use of time. Just assembling conventional pipettors with the appropriate density is not enough to ensure a reliable simultaneous multichannel pipettor. Multichannel pipettors generally utilize individual plungers and seals and are not easily adaptable to higher density well format receptacles such as a 1536-well microplates because of size, reliability or both. Examples of prior art dispensing devices are described in U.S. Pat. Nos. 4,215,092 and 5,343,909. A need exists for a reliable pipetting system that can simultaneously transfer fluids to, from and/or between wells of higher density microplates.  
       [0008] In contrast to liquid transfer, as described above, dispensing of a liquid, such as a buffer solution, from a reservoir to a receptacle is often conducted using a needle through which the liquid from the reservoir (e.g., a syringe) is pumped into the receptacle. The same device often can be used for removing a liquid from the receptacle into the reservoir.  
       [0009] Transfer of a liquid between receptacles, therefore, requires different equipment from that used for dispensing of a liquid from a reservoir into a receptacle. Use of different equipment for transferring liquids and dispensing liquids is inefficient, especially when the transfer and dispensing are to the same receptacle. A need also exists, therefore, for devices that can be used for both liquid transfer and liquid dispensing.  
       [0010] In general, the accuracy of pipettors is limited at least in part by the ability of the barrel and plunger to form a seal. If the seal is poor, the system may lose vacuum or pressure, thereby altering the volume of fluid aspirated or dispensed. These alterations may lead to inaccuracies in the volume of a particular sample and inaccuracies and differences in the volumes of different samples, whether prepared by the same or different pipettors. The magnitude of the alterations may depend on the volume of fluid being transferred, for example, a larger volume of fluid may put larger stress on the seal, causing a larger loss of vacuum and a larger alteration in volume. These shortcomings may require different apparatus for different applications, or lead to missed hits, limited research capabilities, lower throughput, and/or increased costs for compounds, assays and reagents.  
       [0011] The accuracy problems caused by poor seals may be addressed by positioning a compliant element such as an O-ring or grease between the plunger and the barrel. Such an element forms a permanent sliding seal. However, compliant elements are only limited solutions because they may be sensitive to wear, variations in plunger and aperture sizes, and changes in temperature and/or materials, among others. Thus, a further need exists for new sealing aids that address one or more of these shortcomings, particularly for dispensing to multiple sample sites.  
       BRIEF SUMMARY OF THE INVENTION  
       [0012] In one embodiment, this invention provides pipetting systems that can be used to transfer a controlled volume of fluid to, from, and/or between a plurality of wells of a microplate or other fluid reservoir or receptacle. The pipette system is particularly suitable for high-density microplates such as those with 1536 wells. The pipette system comprises: a displacement actuator; a flexible membrane; and a pipette tip array comprising one or more pipette tips, each pipette tip having an end for receiving a fluid, and a base for connection to the flexible membrane, wherein the flexible membrane is positioned between the displacement actuator and the pipette tip array and wherein the flexible membrane forms a static seal with the base of each pipette tip. The pipette tip array may optionally be individual elements, i.e., one tip for each aspirate/dispense location, or a single or group of elements that comprise multiple tips.  
       [0013] In another embodiment, this invention provides pipetting systems wherein a flexible membrane may form a part of the plunger or barrel interior thus providing an improved seal between the plunger and the barrel. In this embodiment, pressurized fluid or a vacuum within the plunger or barrel expands the membrane and reversibly forms a seal between the plunger and barrel. Thus, in this embodiment, the invention provides a pipette system for aspirating and/or dispensing small volumes of fluid. The pipette system comprises: a displacement actuator comprising one or more plungers; a pipette barrel through which the displacement actuator travels, a reversible seal element comprising a flexible membrane positioned on the plunger or in the barrel, and a pipette tip array comprising one or more pipette tips.  
       [0014] A further embodiment of the this invention are pipetting systems wherein a reversible seal element formed of a flexible membrane allows the pipettor to dispense fluid from a reservoir to a receptacle such as a microplate, or the reverse, alleviating the need for separate liquid transfer and dispensing equipment. Fluid can be dispensed around the reversible seal element (when the seal is not engaged) or through a hollow pin or plunger. In this embodiment, the pipette system comprises: a displacement actuator comprising one or more hollow pins; a pipette barrel through which the displacement actuator travels; a reversible seal element positioned on the hollow pin or in the pipette barrel; a pipette tip array comprising one or more tips; a fluid flow channel connected to either the pipette barrel or hollow pin; and a valve to open or close the fluid flow channel. 
     
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
     [0015]FIG. 1 is a schematic diagram of an embodiment of a pipette system of the invention showing a displacement actuator, flexible membrane and a pipette tip array.  
     [0016]FIG. 2 is a schematic diagram showing a pipette tip array.  
     [0017]FIG. 3 is a cross-sectional schematic diagram showing a pipette tip in which the membrane is biased by a plunger of the displacement actuator.  
     [0018]FIG. 4 is a cross-sectional schematic diagram showing a pipette tip containing fluid.  
     [0019]FIG. 5 is a cross-sectional schematic diagram showing fluid being expelled from a pipette tip.  
     [0020]FIG. 6 shows a portion of a plunger having a reversible seal element, in accordance with aspects of the invention.  
     [0021]FIG. 7 shows a portion of a pipettor head assembly having a plunger with a reversible seal element, all in accordance with aspects of the invention.  
     [0022]FIG. 8 is a cross-sectional view of a pipette system of the invention useful for both transfer of a liquid and dispensing of a liquid from a reservoir.  
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT  
     [0023] This invention includes pipetting systems that can be used to simultaneously transfer a controlled volume of fluid to, from, and/or between the wells of a microplate or other fluid reservoir or receptacle. The pipette system is particularly suitable for high-density microplates such as those with  1536  wells. The system is simple, inexpensive to manufacture and reliable. The pipette system can be used with manual and automatic pipettor devices. It is one of the advantages of the invention that the system provides an adjustable pipettor, i.e., a pipettor capable of aspirating and dispensing varying amounts of fluids.  
     [0024] The pipettor system may include one or more pipettor elements. A pipettor element, as used here, is an element suitable for dispensing to a single site. In some embodiments, each pipettor element may include its own barrel, plunger, and seal element. In other embodiments, each pipettor element may share one or more of these components with other pipettor elements.  
     [0025] The number and arrangement of pipettor elements may be determined by a number of factors, including pipetting strategy. For example, the pipettor may include a linear array of 8, 16, 32, or any other number of appropriately spaced pipettor elements to correspond to a single row of a 96-well, 384-well, 1536-well, or any other number of well microplate, respectively. The pipettor also may include a linear array of 12 or 24 or 48 appropriately spaced pipettor elements to correspond to a single column of a 96-well or 384-well or 1536-well microplate, respectively. The pipettor also may include a number and arrangement of pipettor elements to correspond to a portion of a row or column, or two or more rows or columns, or another type of sample holder. Pipettor head assemblies may be easily interchangeable on an appropriate driver to accommodate microplates and other sample holders with different numbers and/or densities of wells.  
     [0026] In an exemplary embodiment, the pipettor assembly is capable of pipetting (aspiration and dispense) small fluid volumes, less than about 20 microliters, within a 1536-well format, with speed and accuracy acceptable for high-throughput applications. Toward this end, the device overcomes inherent tolerance accumulation due to the large quantity of well locations. In other embodiments, the volumes pipetted may be less than about 500 microliters, 100 microliters, 50 microliters, 20 microliters, 10 microliters, 5 microliters, or 2 or fewer microliters, depending on the application. The spacing and movement of pipettor elements may be selected to facilitate interaction with a rack of pipette tips (or other dispense elements), for example, as described in the following U.S. patent application, which is incorporated herein by reference: Ser. No. 10/061,416, filed Feb. 1, 2002. In particular, the speed with which the pipette tips are loaded and/or the spacing between the pipettor elements may be selected to correspond to the number of and/or spacing between pipette tips in the rack.  
     [0027] Alternatively, or in addition, the spacing of pipettor elements may be adjustable, during operation, to facilitate interaction with a rack of pipette tips (or a sample holder), for example, by varying the relative pitch of the pipettor elements and dispense elements (or sample sites), as described in U.S. patent application Ser. No. 09/777,343, filed Feb. 5, 2001, which is incorporated herein by reference.  
     [0028] The dispense strategy for a multi-element pipettor assembly may be coordinated with a suitable detection strategy, including time-tagging or other strategies, for example, as described in the following U.S. patent applications, which are incorporated herein by reference: Ser. No. 09/777,343, filed Feb. 5, 2001; and Ser. No. 10/061,416, filed Feb. 1, 2002.  
     [0029] The pipette system may be capable of simultaneously and/or sequentially dispensing fluid in uniform and/or nonuniform aliquots at one or more sample sites. The system optionally may include additional components, such as (1) a loading and/or unloading system for loading and/or unloading pipette tips, respectively, (2) a thermal regulation system for controlling the temperature of the assembly and/or ancillary components, such as pipette tips and/or samples (e.g., to reduce bubble formation), (3) a driver system for moving the pipettor head assembly between aspirating and dispensing positions, and/or sample preparation and/or sample analysis positions, among others, (4) a processor for controlling aspiration and/or dispensing, and so on. More generally, the assemblies may include and/or interface with any element, apparatus, and/or sample holder described in the patents and patent applications listed above under Cross-References and incorporated herein by reference.  
     [0030] An embodiment of the pipette system of the invention is depicted in FIG. 1. Referring now to FIG. 1, a pipette system  10  comprises a displacement actuator  50 , a pipette tip array  100 , and a flexible membrane  110 .  
     [0031] Displacement actuator  50  comprises one or more plungers  70  attached to a stem  80  for simultaneous control of all pipetting channels. In an optional embodiment, each plunger  70  may have its own stem  80  for individual control of pipetting channels.  
     [0032] Preferably, stem  80  and plunger  70  are formed of a unitary piece of rigid material. The rigid material can be a rigid plastic or metal. Suitable plastics include, but are not limited to, polypropylene, polystyrene and polyethylene. The tip  72  of each plunger  70  is preferably rounded to prevent puncture or excessive stretching of the flexible membrane  110  on the pipette tip array  100 .  
     [0033] The displacement actuator  50  can be manually or automatically driven through stem  80  (not shown). Alternatively the displacement actuator  50  may comprise a fluid (e.g., hydraulic or air) that is pressurized to displace flexible membrane  110 . In another alternative, displacement actuator  50  may comprise a vacuum to displace flexible membrane  110 .  
     [0034] The pipette tip array  100  comprises one or more pipette tips  120 . Each pipette tip  120  comprises a pipette tip body  122  defining an interior cavity and having an open end  124  for receiving a fluid, and a base  126  for sealing the flexible membrane  110 . The pipette tip  120  is attached at its base  126  to flexible membrane  110  in an essentially fluid tight relationship. When a plurality of pipette-tips  120  are used, the tips can be formed as part of a single plastic piece, with the tips arranged in the desired configuration. Alternatively, the tips can be metal and formed as a metal tip block.  
     [0035] Flexible membrane  110  is an elastic material that can reversibly stretch when biased with plungers  70 . Preferably, the flexible membrane  110  is essentially flat. Preferred materials for the flexible membrane  110  include gum rubber, neoprene, hypalon, silicone, santoprene, tygon, latex, norprene, and the like. Flexible membrane  110  is preferably a thin membrane with its thickness dependend upon the material used. For example membranes of latex have a preferred thickness of 0.001 to 0.010 inches, more preferably 0.003 to 0.005 inches.  
     [0036] Each pipette tip  120  can be attached at its base  126  and form a seal with the flexible membrane  110  in a variety of ways. For example, pipette tip  120  can be attached to the membrane  110  by a clamp  140  or simply by the pressure of the displacement actuator  50  on the flexible membrane  110  over the base of the pipette tip. The combination of a clamp  140  and the pressure of the displacement actuator  50  can also be used. The attachment or connection can also be made using a sealing or bonding agent such as a glue or grease. A lubricant, such as silicone oil, preferably Dow Coming 200 silcone fluid, can be applied to the surface of the membrane, to the base  126 , or both, to improve the seal between the flexible membrane  110  and the base  126  of the pipette tip  120 . The edge  128  of the base  126  of the pipette tip  120  can be raised to a smooth ridge to improve sealing by concentrating the downward pressure of the membrane onto base  126  of pipette tip  120 . The attachment of pipette tip  120  to the membrane  110  can also be effected by using a sealing ring  130  to secure flexible membrane  110  to base  126  of pipette tip  120 , as depicted in FIG. 2. A sealing ring can also be used to secure the membrane to the base of groups of pipette tips. A groove in clamp  140  can be used as a mating feature for sealing ring  130 , thus further improving sealing of membrane  110 .  
     [0037] In one aspect of this invention, a plurality of pipette tips  120  are formed as a one piece pipette tip array (unitary tip block). The unitary tip block can be a singe piece of plastic, or it can comprise a metal base having a plurality of holes and a plurality of tips attached to the metal base at the holes. If the unitary tip block is formed of difficult to clean materials such as most plastics, it is preferably a disposable item. Injection molding is one method to create plastic parts that are economical enough to be disposable.  
     [0038] In this aspect, flexible membrane  110  is positioned on base  126  of the tip block and sealed by a clamp  140  or simply the pressure of displacement actuator  50  pressing the membrane  110  over the base of the pipette tip, the seal being optionally aided by lubricant, preferably silicone oil. Alternatively membrane  110  is attached to the unitary tip block by gluing membrane  110  at base  126  of each pipette tip  120 . Generally, the tips are arranged to be used with microplates, such as a 1536-well, 384-well, 96-well, 24-well or other density microplate.  
     [0039] In the above aspects of this invention, the displacement actuator  50  preferably comprises a plurality of plungers  70  arranged as an array. Plungers  70  are arranged in an array that matches the array of pipette tips and they may be arranged such that tip  72  of each plunger  70  is located adjacent to base  126  of each pipette tip  120 , with flexible membrane  110  therebetween.  
     [0040] Displacement actuator  50  and pipette tip array  100  can be connected to each other by conventional methods. Such methods include, but are not limited to, a clamping mechanism.  
     [0041] In operation, displacement actuator  50  is coupled to an automatic or manual pipettor device and the pipette tip array  100 , with the flexible membrane positioned on the base of the array, connected to the displacement actuator  50 . Activation of the displacement actuator  50  causes plunger  70  to bias flexible membrane  110  towards pipette tip  120 , pushing air out of pipette tip  120 , as shown in FIG. 3. Fluid is aspirated into the pipette tip by open end  124  of tip  120  below the level of a fluid in the well of a microplate or other fluid container. Moving displacement actuator  50  away from flexible membrane  110  causes membrane  110  to return to its relaxed position and thus pulls fluid into the pipette tip, as shown in FIG. 4. The fluid captured in the pipette tip is expelled into a receptacle, such as a microplate, by activating displacement actuator  50 , which causes plunger  70  to bias flexible membrane  110  above pipette tip  120 , expelling the fluid out of pipette tip  120 , as shown in FIG. 5.  
     [0042] The pipette tip array  100  of the invention can be used with plungers other than the displacement actuator described above. For instance, a multitude of individually actuated plungers can be arrayed over the pipette tip array. With the addition of an appropriate mechanism, random access to any single well or combination of wells is possible. Furthermore the flexible membrane may be formed such that a negative pressure in the actuator is required to aspirate and a positive pressure is required to dispense.  
     [0043] In another embodiment of pipetting systems of the present invention, the flexible membrane is used as a reversible seal between the plunger and barrel. Thus, in this embodiment, the invention provides a pipettor system for aspirating and/or dispensing small volumes of fluid. The system generally comprises any mechanism for aspirating and/or dispensing fluid from, into, and/or onto a reservoir or other sample holder that employs the membrane as a reversible seal element to assist in the formation of vacuum and/or pressure used to aspirate or dispense fluid. The membrane may be part of the plunger or barrel interior. In this embodiment, pressurized fluid or a vacuum within the plunger or barrel expands (or contracts) the membrane and reversibly forms a seal between the plunger and barrel. The pipette system of this embodiment of the invention comprises: a displacement actuator comprising one or more plungers, a pipette barrel through which the displacement actuator travels, a reversible seal element that comprises a flexible membrane either on the plunger or in the barrel, and a pipette tip array comprising one or more tips.  
     [0044]FIGS. 6 and 7 show portions of a pipettor system constructed in accordance with this embodiment of the invention. The system includes a barrel  310 , a plunger  320 , and a reversible seal element  330 .  
     [0045] Barrel  310  generally comprises any void or volume in a suitable block or other support configured to receive plunger  320 . In the embodiment of FIGS. 6 and 7, barrel  310  (or a part of the barrel) is at least substantially cylindrical, with a first end portion for receiving the plunger  320 , a second end portion (directly or indirectly) connected to a pipette tip  340 , and an interior portion  345  for engaging the seal element  330  such that vacuum or pressure may be created.  
     [0046] The plunger generally comprises any body configured to engage the barrel by sliding, so that relative movement of the barrel and plunger will create (or tend to create) vacuum and/or pressure for aspirating and/or dispensing fluid, respectively. In FIGS. 6 and 7, plunger  320  is at least substantially cylindrical; with an outer diameter that is slightly smaller than the inner diameter of the engaged portions of barrel  310 .  
     [0047] Seal element  330  provides a reversible seal between barrel  310  and plunger  320  and comprises any mechanism for forming a seal between the barrel and plunger. Thus, seal element  330  may be used to initiate, terminate, and/or alter contact between barrel  310  and plunger  320 . In particular, the alteration in contact may include an alteration in the extent (i.e., area) of contact, the geometry of contact, and/or the strength of contact, among others. Seal element  330  may be a portion of plunger  320 , a portion of barrel  310 , or a portion of both, depending on the embodiment. In the embodiment of FIGS. 6 and 7, seal mechanism  330  is a portion of plunger  320 .  
     [0048] Seal element  330  typically functions through a change in volume, for example, by inflation and/or deflation of at least a portion of the seal element to increase and/or decrease, respectively, contact between the aperture and plunger  320 . Typically, seal element  330  will include an adjustable portion having a volume that may be changed using any suitable mechanism, such as the application of vacuum and/or pressure, using any suitable medium, including air and/or fluid. In the embodiment of FIGS. 6 and 7, the volume of the adjustable portion is changed by a change in air pressure, in analogy with a balloon. Specifically, the adjustable portion includes a flexible member  350  such as rubber or a similar polymer bonded or molded onto plunger  320  such that a middle sealed circumferential region acts as a radial plenum that expands or contracts to adjust the extent of contact with aperture  310  upon a change in air pressure effected through channels inside the plunger  320 . Air or vacuum is supplied through vent  370 . In other aspects, a seal element can be similarly formed about the inside of barrel  310 , such that it acts as a plenum that engages the plunger.  
     [0049] A reversible seal element, including a balloon-tipped plunger  320  as shown in FIGS. 6 and 7, may provide a number of advantages over O-rings and molded rubber plunger tips. In particular, the reversible seal element may maintain a more uniformly distributed seal over a large range of circumferential size tolerance and over a large number of tips/wells. Moreover, a reversible seal element may make syringe plunger alignment within the barrel cylinder less critical for sealing than with O-ring designs, and may even make the plunger somewhat self aligning.  
     [0050] The seal element may be selected and/or coated to affect or alter friction between the aperture and plunger. This friction should generally be high enough to promote a good seal but low enough so that the aperture and plunger may slide past one another, easily, reproducibly, and with minimal wear.  
     [0051] In the embodiment of FIG. 6, the pipettor assembly includes a molded single, multi-cavity tip block  380  that may be press mounted onto a head base  390 . In use, the deflated ballooned tube/plenum assembly is lowered into position, the balloon is inflated, and the plunger then acts to create vacuum and/or pressure to aspirate and/or dispense, respectively. The balloon-tipped plunger may provide a high degree of compliance for sealing. Air or fluid for inflation is provided through vent  370 .  
     [0052] In a related embodiment of the invention, the reversible seal element can form part of a pipettor useful for dispensing a fluid from a reservoir to a receptacle, such as a microplate, or the reverse, thus alleviating the need for separate liquid transfer and dispensing equipment. Fluid can be dispensed around the reversible seal element (when the seal is not engaged) or through a hollow plunger or pin. In this embodiment, the pipette system comprises a displacement actuator comprising one or more hollow pins, a pipette barrel through which the displacement actuator travels, a reversible seal element, a pipette tip array that comprises one or more tips, a fluid flow channel connected to either the pipette barrel (opposite the tip array) or hollow pins, and a valve to open or close the fluid channel. Preferably, the reversible seal element is a flexible membrane located either on the hollow pin or in the barrel. Also preferably, the fluid flow channel is connected to the hollow pins. This embodiment of the pipette system of the invention is shown in FIG. 8.  
     [0053] Referring now to FIG. 8, the pipette system  200  shown comprises a plunger  230 , a hollow pin  240 , a flexible membrane  250 , a fluid flow channel  260 , and a pipette barrel  270  defining a piston chamber  280 .  
     [0054] Hollow pin  240  is housed in piston chamber  280 . Hollow pin  240  is open at both ends and can be made of various materials including metal, plastic or rubber. The upper end  242  of pin  240  is provided with a pin mounting plate  244 . Pin  240 , along with pin mounting plate  244 , are axially movable within piston chamber  280 . A sealing ring  246  is provided within piston chamber  280 . Preferably, sealing ring  246  is an o-ring which provides an air-tight seal but other mechanisms such as lubricant or grease also can work. The upper portion of the pipettor (comprising elements  240 ,  244 ,  260 ,  250 ,  230 , and  290 ) is moved relative to the lower portion by many possible mechanisms including manually (such as with a conventional pipetman), via linear stage (motor or manually actuated) or solenoid. If operated manually in the preferred manner, a return mechanism such as a spring (not shown) is used to bias the piston&#39;s position to one end of its travel. This biasing spring can be located in various places, such as between the mounting plate  244  and the top of the pipette barrel  270 .  
     [0055] The hollow pin  240  is fluidically connected to a valve and fluid source or drain. The valve is preferably a flexible membrane  250  located between plunger  230  and the upper end  242  of the hollow pin  240 . Membrane  250  can be made of various compliant materials including plastics rubbers, or latexes. Preferably membrane  250  is rubber.  
     [0056] A fluid flow channel  260  is defined by the upper end of the hollow pin  240  and plate  244  and the lower surface of membrane  250 , as shown in FIG. 8. The fluid flow channel  260  is the connection point between the hollow pin  240  and various fluid dispensing or aspirating hardware, such as pumps, gas sources, valves or channels for introducing or removing fluid through the hollow pin  240 .  
     [0057] When actuated, plunger  230  pushes membrane  250  onto top opening  247  of hollow pin  240 . Plunger  230  can be actuated by an actuator  290 , which may be mechanical or manual. Actuator  290  is rigidly connected to the hollow pin, for instance at the pin mounting plate  244  as shown in FIG. 6. When used for transferring fluids (discussed below) the plunger and its actuator are moved with hollow pin  240  to displace air within the pipette tip  294 .  
     [0058] In one embodiment, actuator  290  is a solenoid device that causes the plunger to bias compliant membrane  250  onto top opening  247  of hollow pin  240 , thereby sealing it closing the valve. The pipettor functions as a transfer pipettor when the valve is closed.  
     [0059] In transfer pipettor operation, the membrane  250 , the plunger  230 , and the top of the hollow pin  240  together function as a valve to open and close the flow channel  260 . Alternatively a valve could be located at the beginning of channel  260  instead of the end. When plunger  230  biases the membrane  250  and therefore blocks the opening of the hollow pin, i.e., the valve formed by the plunger and the membrane is closed, the pin acts as a piston. Thus, with the valve closed, the pipettor functions as a fluid transfer pipette, by aspirating and ejecting a fluid from the optional pipette tip  294 . When the membrane  250  is not biased by the plunger  230 , the valve formed by the plunger  230  and the membrane  250  is open. With the valve open, the pipettor functions as a fluid dispenser and any fluid, including liquid or gas, that is pumped through the flow channel will flow through the hollow pin and out of the optional pipette tip  294 . Thus, when the valve is open, the pipettor can be used to dispense fluids, including reagents, from, for example, a fluid reservoir. If suction is applied to the flow channel, fluid flows through the hollow pin into the flow channel.  
     [0060] The pipette system of this embodiment of the invention can be used for several functions. For instance, when the valve formed by the plunger and the membrane is open, the pipettor can be used as a dispenser, with or without a pipette tip, allowing for example, repetitive dispensing of a reagent from a large reservoir. Similarly, wash solution can be dispensed through the tip when the valve is open. In fact, more than one wash solution can be used by appropriate selection of an upstream valve. Further, with the valve open, wash solution can be aspirated through the tip or dry and/or heated air can be used to dry the tip and the interior of the pipette. With the valve closed, the device can be used as a transfer pipettor, by moving the hollow pin and the plunger/membrane valve up and down together relative to the barrel.  
     [0061] The various embodiemnts of the pipette systems of the invention described herein can be used independently of or in conjunction with each other.  
     [0062] The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.