Abstract:
A pipette receiver and its variations are discussed for use in a multi-channel pipetting device typically used for medical, biological or biochemical research and development. There is a plurality of individual positive air displacement channels that are fitted to individual disposable pipette tips intended to pipette into associated “plates”. These “plates” may be Micro-titer plates, wells or vials each typically containing 96 wells in an 8×12 array usually spaced 9 mm apart. Other common plates contain 384 wells 4.5 mm apart in the same footprint of the 96, or a 1536 well plate fitting the same footprint.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority to U.S. provisional patent application Ser. No. 61/215,769 titled “Multi-Channel Aspirating and Dispensing Instrument”,” filed on May 11, 2009, and U.S. provisional patent application Ser. No. 61/294,122 titled “Alternative Multi-Channel Liquid Aspirating &amp; Dispensing Instrument”, filed on Jan. 12, 2010, the disclosures of both of which are herein incorporated by reference in their entireties. 
    
    
     TECHNICAL FIELD 
     The present invention relates generally to multi-channel aspirating and dispensing pipettors, and in particular, those having repositionable tip fittings or mounting shafts for disposable pipette tips. 
     BACKGROUND 
     In laboratory work, multi-channel pipettors are designed to enable laboratory workers to transfer multiple samples or reagents from one series of containers to another series of containers, such as from one set of wells in a micro titer plate to another micro titer plate. Multichannel liquid aspirating &amp; dispensing instruments, or pipettors, capable of aspirating and dispensing single or multiple channels at a time, typically 1, 8, 12, 96, 384 &amp; 1536 channels at a time and moving to a plurality of microplate stations. Many multi-channel pipettors rely on electronically controlled stepper motors to control piston movement for aspirating and dispensing. 
     The spacing between individual channels is fixed to accommodate the ANSI SBS microplate standards. Precision and accuracy, especially in dispensing, are the basic driving specifications required by those in the biological sciences laborites. Values of &lt;10% at volumes down to 1 micro liter are considered good. 
     Thus the market is left with single row manual or powered units, or instruments that are big, heavy &amp; expensive as they are intended to be used in an automated environment. What is required is a portable, semi or fully automated multi-channel pipettor that overcomes the many complications and limitations of the previous systems. 
     SUMMARY OF THE INVENTION 
     This section is for the purpose of summarizing some aspects of the present invention and to briefly introduce some preferred embodiments. Simplifications or omissions may be made to avoid obscuring the purpose of the section. Such simplifications or omissions are not intended to limit the scope of the present invention. 
     In one aspect, the invention relates to fittings and receivers for holding pipettes on aspirating and dispensing systems. In one embodiment, to a pipette holding apparatus comprising a proximal annular shape designed to make continuous contact with a pipette&#39;s internal surface at the proximal end of said pipette, one or more annular shapes designed to make continuous contact along the length of a pipette&#39;s internal surface, said annular shapes being of sequentially reduced diameter, with the one at the distal end having the smallest diameter, and a cavity between said sequential annular shapes designed to avoid contact with a pipette&#39;s internal surface. 
     In one embodiment, to an apparatus where two or more annular shapes are arranged as substantially continuous horizontal bulges, and the cavity between them forms a in a gradual spool-like shape. In one embodiment, to an apparatus with two or more annular shapes arranged as substantially continuous horizontal loops, with significantly sharp walls, and the cavity between them forms a significantly sharp walled air gap between them. In another aspect, to an apparatus wherein the walled air gap between the two continuous horizontal loops is divided into two or more sections by the addition of one or more barrier travelling along the length of the axis of insertion, and the barrier diameter matches that of the two or more annular shapes they connect. 
     In another aspect, the invention relates to a pipette holding apparatus comprising a proximal annular shape designed to make significantly continuous contact with a pipette&#39;s internal surface at the proximal end of said pipette, one or more compressible vanes of a diameter slightly larger than the pipette&#39;s inner orifice diameter, arranged so that the vanes travel significantly in the direction of the axis of insertion, and one or more cavities between the vanes. 
     In another aspect, the invention relates to a pipette holding apparatus comprising a Ferro fluidic taper expansion with a magnetic field and magnetic means to radially expand said Ferro fluidic filled lower tapered fitting so that an annular shape is formed in said taper that makes continuous contact with a pipette&#39;s internal surface at the proximal end of said pipette. 
     In another aspect, to a pipette holding apparatus comprising an upper stationary fitting, a pull/push rod having axial movement in/out of the fitting, a compliant tapered head, mechanical means for pulling on said rod, so that when the rod pushes on the head, its diameter expands outward into the pipettes&#39; internal surface, forming a continuous annular seal; and mechanical means for pushing on said rod. 
     In one aspect, the invention relates to a pipette holding apparatus comprising an upper stationary fitting, a pull/push rod having axial movement in/out of the fitting, a compliant tapered head receiver, mechanical means for pulling on said rod, so that when the rod pushes on the head, its diameter expands outward into the pipettes&#39; internal surface, forming a continuous annular seal and mechanical means for pushing on said rod. In one embodiment, the apparatus comprises a compliant tapered head receiver has one or more slits cut along a portion of its side, and the pull/push rod has a tapered head at one end. 
     In one aspect, the invention relates to a multi-channel aspirating and dispensing system comprising a single motor to drive the pump and the pipette ejecting mechanism, electronic means for controlling the aspiration and dispensing functions, a multilevel stepped plate that eject smaller groups of tips at a time. In one embodiment, there is an adaptor to accommodate 384 well micro titer plates with a 96 channel pipetting head, said adaptor requiring three easy manual X-Y movements to target all 384 wells. In another embodiment, the X-Y movements are halved, allowing the adaptor to accommodate 384 channel pipettor and a 1536 well micro titer plate. 
     Other features and advantages of the present invention will become apparent upon examining the following detailed description of an embodiment thereof, taken in conjunction with the attached drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a perspective view of the multi-channel aspiration and dispensing system, according to an illustrative embodiment of the invention. 
         FIG. 2  is a close-up view of the fitting and pipette, according to an illustrative embodiment of the invention. 
         FIG. 3  is a cross-section of the conventional fitting, according to an illustrative embodiment of the invention. 
         FIG. 4  is a cross-section of a proposed spool-like fitting, according to an illustrative embodiment of the invention. 
         FIGS. 5A-5C  are views of proposed improved fittings, according to an illustrative embodiment of the invention. 
         FIGS. 6A-6C  are views of proposed fittings, according to an illustrative embodiment of the invention. 
         FIGS. 7A-7B  are views of a proposed magnetic fitting, according to an illustrative embodiment of the invention. 
         FIG. 8  is a view of a compressible fitting, according to an illustrative embodiment of the invention. 
         FIGS. 9-14  are views of a tapered compressible fitting, according to an illustrative embodiment of the invention. 
         FIGS. 15-18  area isometric perspectives of the system components, according to an illustrative embodiment of the invention. 
         FIG. 19-26  are various isometric perspectives of the system, according to an illustrative embodiment of the invention. 
     
    
    
     DETAILED DESCRIPTION 
     To provide an overall understanding of the invention, certain illustrative embodiments will now be described, including apparatus and methods for displaying images. However, it will be understood by one of ordinary skill in the art that the systems and methods described herein may be adapted and modified as is appropriate for the application being addressed and that the systems and methods described herein may be employed in other suitable applications, and that such other additions and modifications will not depart from the scope hereof 
       FIG. 1  is an isometric view of a multi-channel liquid aspirating &amp; dispensing instrument, according to an illustrative embodiment of the invention. The design provides a lightweight, portable instrument that can fit into a standard lab hood or be moved around the lab with ease, yet have the same accuracy and precision standards found in semi-automated and high end fully automated pipettors. The design uses a single motor which drives the pump &amp; eject pipette tips. This is accomplished using a smaller, low cost motor &amp; linear rail assembly  1502 . Motion to the three dimensions of movement is manual, eliminating motors &amp; controls to lower cost &amp; weight. It also simplifies operation as no external software, controller or computer is required. 
     Mechanically this instrument provides easy &amp; precise horizontal and vertical motion using guided rails and shafts  104 . All manual motion is intended to be done effortlessly. The vertical motion carries the weight of the mechanical components using a precisely counterbalanced gas spring. The base of the instrument is heavier than everything above to eliminate the tendency to tip. In one embodiment, an optional LED light is available to light up the area above the active plate position  106 . 
     In one embodiment, the horizontal &amp; vertical dimensions are designed to fit into any typical laboratory fume hood without modifications. The general dimensions for a 3-station model are 17.78 cm wide×45.72 cm long×40.64 cm high. This footprint can easily fit on top of available counter space. A user can now bring the pipettor to the work area rather than having the work area brought to the pipettor. 
     As seen in an isometric close-up 200 (in  FIG. 2 ), the disposable pipette tip  202  needs to be inserted and sealed onto the individual pipette fitting channel  204 . When doing  96  or  384  tips at a time, the manual force required to press these all on at the same time is significant. In one embodiment, the invention is capable of doing the above at speed and with minimal effort through the unique fitting design  206  and  208 . 
     In previous inventions, as shown in ( FIG. 3 ) a straight cross sectional view  300  of a standard fitting  302  has a line-to-line fit with the pipette tip  202 , which is typically pressed over a complementary similar shaped parallel surface. This provides an air tight seal. The force to insert this is in the range of one to two kilograms-force. For a typical 96 style configuration as described previously, the cumulative force would be 96 to 192 Kgs-force, and would be too much for most people to achieve. 
     As seen in  FIG. 4 , in one embodiment  400 , the proposed new fitting requires less than ¼ Kg-force per tip, equating to less than 24 Kgs-force. This reduced force is accomplished by the spool-like surface of the fitting  402 , limiting the contact area between the traditional straight inside wall of the pipette tip  404  and the two smaller areas at the top  208  and another at the bottom  206 . This makes the pressure required to make an airtight seal between the inside wall of the tip  404  and fitting  402  is accomplished with less force. Mathematically explained, pressure=force/area, with a constant pressure a lower contact area yields a lower force. Further force reduction is accomplished by using a fitting material having low friction properties. Further force reduction is accomplished by the mechanical advantage of the pivotal linkage and handle  1910 . 
     The contact area is split into two regions  206  and  208 , in one embodiment spread apart as far as possible to provide tip stability. If the reduced contact area were localized, then the tip would tend to act more like a pivotal joint. Having two contact areas spread apart stabilizes the tip against perpendicular forces, such as the bottom distal tip end touching the side of the plate well. The two points of contact further apart provide increased lateral stability. 
       FIGS. 5A-5C  illustrate a number of alternate exemplary embodiments to accomplish the same goal by modifying a fitting to create air gaps, and variations of the gap seen in the fitting  402 , creating low force fittings. The two or more horizontal rings  502  provide one or more interposed air gaps  504  that limit contact area with the pipette tip  506 . This limited contact requires less force to insert said pipette tip  506  onto any fitting. In an alternate embodiment, spool designs  508 ,  510  having sharper transitions also accomplish a low insertion force. As seen in  FIGS. 6A-6C  in alternate embodiment  600 , vertical gaps  602  traveling significantly along the direction of the axis of insertion create the air gaps  604  and provide a stable surface for a pipette tip  606 . In an alternate embodiment, the air gaps may travel in a spiral direction. 
       FIGS. 7A-7B  illustrate an exemplary illustration of an alternate embodiment  700 , where a Ferro fluidic taper expansion utilizing a magnetic field is used to radially expand the Ferro fluidic filled lower tapered fitting  702 . The taper expansion would be powered by the fitting impale command generated by the user interface. The lower fluid fitting  702  is bonded to the upper fitting  704  to form a permanent assembly of the two parts  706 . The magnetic field required to change the lower fitting  702  may be generated by using either a movable permanent magnet or energizing an electromagnet. The field is then passed through a “tuned” iron rod within the upper fitting, or it may be the entire upper fitting is iron with a protective coating. 
       FIG. 8  illustrates an exemplary illustration of an alternate embodiment  800 . In it, a flexible compressible fitting  800  is comprised of rubber (be it natural or synthetic), silicone or such other similar compliant material having many vertical vanes or slices  802  (in one embodiment significantly in the direction of the axis of insertion) will allow an easy pipette tip insertion by conforming to the exact taper then giving-way or bending in areas where the press-fit is not uniform. This is especially useful when using a variety of pipette tips from various manufactures where the taper varies. In an alternate embodiment, the vanes have a spiral orientation along the axis of insertion. 
       FIGS. 9-11  illustrate exemplary illustrations of alternate embodiments of a mechanically expanding and contracting taper fitting. The fitting assembly parts  900  look like the standard fitting except it is comprised of three parts, an upper stationary fitting  902 , a pull/push rod  904 , having axial movement in/out of the fitting and a compliant taper section  906 . The pull/push rod  904  when pulled toward the taper section  906  compresses the compliant material making the tapered diameter expand outward  1002 . When a non compliant pipette tip is in place, the expanding compliant taper forms a tight seal. To eject the tip the rod  904  moves away from the taper  906  that is fixed to one or two ends. In one embodiment, the pull/push rod movement would be controlled by movement of the rod in connection to the piston assembly  1504  under command of the electronic user interface. 
     This motion stretches the taper  906 , reducing the diameter  1004  and forming a slip fit with the pipette tip  1102 . Now the tip can be removed with much ease. Likewise, and more importantly, when in this last position where the taper diameter is less than the pipette tip diameter, one can easily insert a series of 96 tips manually with less than ¼Kg-force of force per tip. This ability to manually insert and pick up a series of 96 pipette tips is a key feature that makes this instrument desirable. Once the tips are in place the push/pull rod will move toward the taper forming a press fit making a seal &amp; adding positional stability with the entire pipette tip ID in contact with the fitting. This concept applies to all the fittings discussed throughout this provisional patent. 
     More importantly, when in this last position where the taper diameter is less than the pipette tip diameter, one can easily insert a series of 96 tips, manually with less than ¼Kg-force of force per tip. This ability to manually pick up a series of 96 pipette tips is the key feature that makes this instrument desirable. Once the tips are in place the push/pull rod will move toward the taper forming a press fit making a seal &amp; adding positional stability with the entire pipette tip in contact with the fitting. In one embodiment, the split taper can be made of two or more splits. 
       FIGS. 15-18  illustrate exemplary embodiments of the mechanism for tip ejection. In one embodiment, Tip Ejection off the fitting is done using the same motorized linear rail assembly  1502  used for pipetting, which moves the ejector plate  1602  up/down. The ejector plate is multileveled and stepped  1604  in order stagger the push of the tips into smaller sections or groups of tips at a time. This results in a reduction in the force to eject, thus requiring a less expensive linear rail assembly, and lowers manufacturing costs. 
     The plate  1602  is connected to two push rods  1606  that travel up through the cylinder block  1608  and protrude a given distance beyond the top surface of the cylinder block. Two springs  2302  urge the pushrods in an upward direction. The piston block  1612  contacts the two push rods  1606  thus transferring the ejection force to the ejector plate. The piston block triggers a sensor just before touching the push rods, and the electronics deliver a message to travel a precise distance required to remove all tips. This motion is preset and performed at a slow speed to produce a greater force from the electromechanical assembly. Using the electromechanical assembly for ejection also eliminates those forces required by the user, reducing or eliminating potential fatigue as well as potential injuries from repetitive motions, such as carpal tunnel syndrome. 
     Pipetting accuracy and precision are critical, and usually the most important factors of purchasing a pipettor. In one embodiment, this design uses a precision step motor driven linear rail assembly  1502  with precisely controlled electronics to operate the positive displacement pump chambers. These pump chambers are made by the openings in the cylinder block  1608  being filled by the individual pistons  1800  of the piston block  1612 , sealed with O-rings  1616  are compressed between the upper O-ring plate  1618  and the cylinder block  1608  creating the piston assembly  1504 . The precise up/down motion of the assembly is key to the repeatability and consistent accuracy of fluid dispense. In operation, the displacement of the piston block up/down is controlled by the motor/rail assembly  1502  (in turn controlled by the system electronics). The controlled motion of the piston block  1612  generates motion of each piston  1800  within each channel  1614  created by the individual openings in the cylinder block  1608 . An up motion aspirating fluid into the pipette tip, whereas a down motion compresses air dispensing fluid out of the tip. 
     In operation, a user starts with a unit  100  having no tips at the fittings  204 , and the pistons  1800  at their lowest (all in) position within each channel  1614 . The pipette tips are held within a pipette box that slides into and is retained by the pipette box retainer  1912 . The complete assembly  1914  is lowered, inserting each pipette  202  into each channel fitting  204 . In one embodiment, mechanical means within the channel operate to expand the channel fitting ( FIGS. 9-14 ). In an alternate embodiment the special fitting shape accomplishes the compression  400 . In on embodiment, the tip is energized via electromagnetic means to expand the fitting  204  end and hold the tip. 
     With the tips held, the assembly  1914  is translated along a linear bearing rail  104  to a position with a tray under it whose openings are holding a fluid. The assembly is lowered so the tips are within it, and the aspiration is engaged by the separation of the piston block  1800  from the cylinder block  1608  via the motor/rail displacement. The assembly is again translated, one or more trays are set under it as the fluid is displaced via the lowering of the piston block  1800  into the cylinder block  1608  under the precise control of the electronics. 
     The operation is repeated until a new set of tips is deemed necessary. At that time, the assembly  1914  is placed on a tip assembly, and the tips ejected via the reverse of the embodiments used. 
     All the pipetting channels upon which each individual piston  1800  actuates provides the precision or the consistency of dispense between each channel fitting  204 . The quality of the electronics and the mechanical linear rail directly coupled to the piston assembly  1504  give this instrument the same accuracy and precision found in much more expensive instruments. 
     In one embodiment ( FIG. 19 ), electronic controls  1900  provide the embedded step motor controls, a user interface  1902  for programmability and a display area  1904  to visually see commands. In one embodiment, a rotary knob in the center of the control panel turns to select menus, programs, to enter aspirate/dispense volumes and such. Without moving fingers off the knob, a user can push either of the surrounding buttons. This provides an easier method of programming by not having to move your hand away from the center of the panel. The display area provides real time feed back to either programming or running a program. There is an option to choose languages on the display and the control panels are engraved with the associated language. 
     The overall operation of this instrument is intended to provide continuous easy hands-on motion. Much like an automotive steering wheel having controls built in to keep the drivers hands on the wheel. This instrument has the ability to move horizontally and vertically with little effort without removing your hands from the handle  1910 . Once a program is entered and a series of plates are positioned below then one can seamlessly perform desired steps with minimal hand motion. 
     In one embodiment, a single handle  1910  allows the up/down operation of the pipette assembly for aspirating and dispensing between the tray positions  1908  and  1918 . A special tip box holder  1912  may be used to ease operation when picking or ejecting tips, as well as when aspirating and dispensing fluids from one tray to another. 
     The instrument is intended to be built as a 96 or 384 channel model. However, as seen in ( FIG. 20 ) the less costly 96 channel model can accommodate a 384 well plate by using a 96/384 adaptor  1916 . This adaptor&#39;s station well is 4.5 mm longer and wider than the ANSI_SBS — 4-2004 footprint described in detail in the attached specifications. Since a 384 well is spaced 4.5 mm apart and the 96 is 9.0 mm apart the difference is 4.5 mm. When a 96 channel pipettor is directly over the center of an 384 well, the next well is achieved by sliding the 384 plate from one right edge of the adaptor all the way over to the adjacent left edge (or vice versa). Now the pipettor is directly over the next well in that row. To get to the row below, move the 384 plate from the bottom edge all the way up to the top edge, then repeat the left-right motion to get the last well. Three simple movements allow the 96 channel pipettor to reach all of the 384 wells. 
     Another method of designing the 96/384 adaptor  2100  is to make the bottom footprint of the adaptor 4.5 mm smaller in both the X &amp; Y directions, see  FIG. 21 . This way both the adaptor &amp; plate move together while sliding in the standard station well below. This design will move exactly like the first design to access the four wells in the 384 plate, except this time the adaptor moves and the plate is an exact fit on the top side of the adaptor. 
     Using the concept of the two adaptor designs described above, but this time with a 384 channel pipettor, one can adapt to a 1536 plate. This adaptor has a 2.25 mm offset to allow travel from one 1536 well to the other. Refer to the attached ANSI_SBS — 4 “Microplate Well Positions” for details and illustrations of the 96, 384 &amp; 1536 plates. 
     A rotating handle is used to move the upper portion up and down with extreme ease and precision. The upper head assembly may be in the upper or lower positions. The lower is called the “positive stop position”. The two illustrated adjustable stops ( 1920 ,  1922 ) allow the user to either screw the knurled portion up or down to set a repeatable height at which the upper unit will stop at every time. This allows the user to quickly pull the head down until it stops against the stop, thus eliminating the need to visually gauge the proper lower height. 
     The handle rotates about a fixed axis to give the user a smooth mechanical advantage when adjusting the upper height position. The pivoting handle transfers vertical motion (force) nearly directly over the two vertical fixed shafts, thus eliminating a moment force that tends to bind with motion. Furthermore, this handle provides a mechanical advantage to reduce force needed to move the upper unit up and down. Also the handle is now positioned further away from the three position wells below, eliminating potential contamination from the users hand to the product being pipetted into below. 
     The custom “pivoting arm &amp; wheel”  2602  provides positive yet smooth feedback to the user to center the upper unit directly over the desired well  2604  below. Three position can be used, where a microplate, reservoir, tip box or whatever may appear, sliding the upper unit to a precise position over each position below is easily accomplished by the self centering wheel engaging with the mating detent. 
     Various embodiments and features of the present invention have been described in detail with a certain degree of particularity. The utilities thereof can be appreciated by those skilled in the art. It should be emphasized that the above-described embodiments of the present invention merely describe possible examples of the implementations to set forth a clear understanding of the principles of the invention, and that numerous changes, variations, and modifications can be made to the embodiments described herein without departing from the spirit and scope of principles of the invention. Also, such variations and modifications are intended to be included herein within the scope of the present invention, as set forth in the appended claims. The scope of the present invention is defined by the appended claims, rather than the forgoing description of embodiments. Accordingly, what is desired to be secured by Letters Patent is the invention as defined and differentiated in the following claims, and all equivalents