Patent Publication Number: US-7219567-B2

Title: Combinatorial pipettor device

Description:
FIELD OF THE INVENTION 
   The present invention relates to devices for the separation and/or transfer of particles or liquids. More specifically, the present invention relates to a multi-collector combinatorial pipettor device for the separation and/or transfer of magnetic particles or liquids that can be used with microtiter plates of different sizes. 
   BACKGROUND OF THE INVENTION 
   Magnetic particles are used for a variety of separation, purification, and isolation techniques in connection with chemical or biological molecules. In those techniques, a magnetic particle is coupled to a molecule capable of forming a specific binding (“affinity binding”) with a molecule in a biological sample, which is to be isolated, purified or separated. The biological sample is then brought into contact with the magnetic particle and those biological molecules which bind to the magnetic particles are then isolated by application of a magnetic field. 
   Magnetic microparticles or nanoparticles are used to bind DNA molecules, proteins, cells, and sometimes subcellular fragments. In recent years, magnetic microparticles have been used as solid phase for chemical synthesis. Microparticles are in the size of 0.5-10 micron while nanoparticles are 0.05-0.3 micron. 
   Various devices and methods have been developed in order to separate and transfer magnetic particles. Generally, the available methods fall under two categories. In the first method, a specialized magnetic suspension vessel is contacted with a magnet, and particles move towards the magnet, thus becoming attached to the side of the vessel. The remaining liquid is removed out of the vessel via decantation or aspiration. 
   In the second method, cylindrical magnetic rods covered with protective plastic sleeves or tips are brought into direct contact with a magnetic suspension. Particles are captured on the rod while the liquid remains in vessel. The rod with captured particles is moved into another vessel. When the magnet is withdrawn out of the protective sleeve, particles detach from the tip into the vessel. 
   The second method is advantageous with respect to the first, since a stronger magnetic field is applied directly on the particles, and therefore, nearly all of the particles are captured. Another advantage is that since the particles are readily transferred to a second vessel, removal of liquid in the source vessel is not needed, and one step has been saved. 
   Patent No. EP 0787296 to Tuunanen describes a magnetic rod device for the separation of microparticles. The tip of the device is shaped like a cone for transferring particles from large volumes into smaller volumes. The device, however, is only useful for separating one sample at a time. 
   U.S Pat. No. 6,409,925 to Gombinsky et al. describes a system of magnetic rod devices wherein each device in the system is independently controlled. Thus, any desired combination of magnetic rods can be operated. The magnets in this system are operated via pneumatic forces that are automatically controlled. The system permits transfer of specific combinations of magnetic particles and thus it can be used for combinatorial chemical synthesis. A magnetic plate is provided beneath the microtiter plates for facilitating separation of the magnetic particles from the tip into liquid in the well. 
   U.S. Pat. No. 6,468,810 to Korpela describes a similar rod device for capturing and releasing magnetic microparticles. The magnets in this device are operated via springs. An extendible membrane is provided as well as means for joining and separating the magnet with the first side of the membrane such that in operation the magnet is releasably pressed against the first side of the membrane, thereby stretching the membrane so that microparticles become fixed, by magnetic attraction, to the second side of the membrane. When the magnet is separated from the first side of the membrane, the particles become released from the second side. 
   In all of the aforementioned references, the magnetic rod moves inside of a static tube either electrically, pneumatically, or manually. The protective sleeve or tip covering the magnet is attached to the end of the static tube, and is detached or released from the tube by an outside mechanism, usually a manual arm attached to the outside surface of the tube. 
   U.S. Pat. No. 5,970,806 to Telimaa et al. relates to a multi-cylinder pipette comprising 16 4.5 mm spaced channels. The pipette is thus suitable only for use with a plate comprising 16×24, or 384 wells. 
   U.S. Pat. No. 6,235,244 to Allen et al. relates to a uniformly expandable multi-channel pipettor having a plurality of tip fittings whose spacing can be adjusted so that the spacing between each adjacent tip fitting is substantially identical. The device is known as the Equalizer 384 ™ by Matrix, and it allows the user to switch between microtiter plates of different sizes. The tip fittings are attached one to another by a linkage such as a pantographic linkage. The spacing is limited by an adjustable, slidable stop. Uniformly increasing and decreasing the spacing is accomplished by pulling and pushing a rod attached to one tip fitting. However, the Equalizer is a highly complicated device, and it is very expensive. 
   A disadvantage of prior art devices is that they cannot be used with microtiter plates of different sizes, only with one-size plates. Pipettor devices with eight connectors are for use with 96-well plates and pipettor devices with sixteen connectors are for use with 384-well plates. Patent EP 0787296 allows for the transfer of particles between microtiter plates having different sizes, but this is with the use of a single magnetic rod, and thus it cannot be used in combinatorial applications. 
   In light of the above, it would be desirable to provide a combinatorial device for the separation and transfer of magnetic particles or liquids that can be used with microtiter plates of different well sizes, and that would allow the user to determine the exact combination of samples that are to be separated and transferred. 
   SUMMARY OF THE INVENTION 
   Accordingly, it is a principal object of the present invention to provide a combinatorial pipettor device that is adapted for use with microtiter plates (also known as “Micro-well plates” or “Nano plates” or “deep well plates”) of different sizes, for example 96-well (8×12 wells) and 384-well (16×24 wells), though other size microtiter plates could also be possible. The device can be used for the separation of magnetic particles or for the collection and transfer of liquids. The device is adapted for being set by the user according to the exact number and positioning of the samples that are to be processed. 
   In accordance with a preferred embodiment of the present invention, there is provided a combinatorial device for the collection of a sample, adapted for use with microtiter plates of different sizes, comprising;
         (a) an upper plate comprised of a first half and a second half, wherein each of the halves is independently movable between at least an upper position and a lower position;   (b) a lower plate having a plurality of tip connectors coupled thereto for facilitating attachment of at least one collecting tip;   (c) a plurality of sample collector members each having a proximal end and a distal end;   (d) a mechanism for moving at least one of the first half and the second half of the upper plate between the upper position and the lower position;
 
wherein the proximal ends of the sample collector members are held by the first and second halves of the upper plate and wherein the distal ends of the sample collector members are adapted for being engaged by the lower plate such that when at least one half of the upper plate is moved from the upper position to the lower position, the corresponding sample collector members are lowered with respect to the lower plate, thereby facilitating collection of at least one sample into a collecting tip attached to one of the connectors.
       

   According to preferred embodiments of the present invention, each of the first half and the second half of the upper plate is adapted for accommodating eight sample collector members, for a total of sixteen sample collector members. By moving the first upper plate half (8 sample collector members), the second upper plate half (8 sample collector members) or both halves together (16 sample collector members), the user is able to transfer magnetic particles or liquids from 96-well-plates (having 12 rows of 8) to a 384-well-plates (having 24 rows of 16). 
   Alternatively, according to preferred embodiments of the present invention, each of the first half and the second half of the upper plate is adapted for accommodating twelve sample collector members, for a total of twenty-four sample collector members. 
   Further according to preferred embodiments of the present invention each of the first half and the second half of the upper plate comprises a plurality of projections, the projections of the first half being complementary in shape to the projections of the second half such that the two plate halves fit together, and wherein each of the projections comprises an opening for receiving the proximal end of a sample collector member. 
   Still further according to preferred embodiments of the present invention, the sample collector members comprise pins and the lower plate comprises a plurality of pump units, the connectors defining the lower portions of the pump units and the pins being adapted for engaging with and activating the pump units when at least one half of the upper plate is moved to the lower position such that a liquid can be collected into a collecting tip attached to one of the connectors. 
   Additionally according to preferred embodiments of the present invention, the sample collector members comprise rod-shaped magnetic elements. 
   Moreover according to preferred embodiments of the present invention, the lower position corresponds to a position in which the distal ends of the magnetic elements extend through the lower plate and into the tip connectors such that when a collecting tip is attached to a tip connector, a magnetic force is exerted by the distal end of the magnetic element onto the end of the collecting tip such that magnetic particles can be collected onto the collecting tip due to the magnetic force. 
   Further according to preferred embodiments of the present invention, the mechanism comprises an actuator button comprising a first button half adapted for enabling moving the first half of the upper plate and a second button half adapted for enabling moving the second half of the upper plate. 
   Still further according to preferred embodiments of the present invention, at least a portion of the tip connectors are switchable between an inactivated position and an activated position, the activated position corresponding to a position in which the tip connectors can be employed for collection of a sample when at least one collecting tip is attached thereto. 
   Additionally according to preferred embodiments of the present invention, the lower plate comprises a first lower plate half and a second lower plate half, the first lower plate half having a plurality of tip connectors coupled thereto, the tip connectors on the lower plate half being provided in the activated position. 
   Moreover according to preferred embodiments of the present invention, the second lower plate half comprises a plurality of tip connectors provided in the inactivated position, and the device further comprises means for switching the tip connectors to the activated position. Preferably, the means comprises a lock button. Unlocking the lock button causes the second lower plate half to move downward, thus causing the corresponding tip connectors to switch from the inactivated position to the activated position. 
   Further according to preferred embodiments of the present invention, the device also includes a release button for enabling release of used tips from the device. 
   Still further according to preferred embodiments of the present invention, the release button operates by enabling the upper plate halves to be lowered such that the distal ends of the magnetic elements push against attached collecting tips, causing the collecting tips to become released from the tip connectors. 
   It is a feature of the present invention that individual tip connectors are adapted for being inactivated by at least partially pushing the individual tip connector inward towards the lower plate. In one embodiment, individual tip connectors are adapted for being inactivated by disconnection of the individual tip connector from the lower plate. In other embodiments, a plurality of tube members are provided that are adapted for being connected to the tip connectors. The added length provided by the tube members produces an effect that only those tip connecters with tube members attached thereto will become connected to a collecting tip. In yet another embodiment, the tip connectors are adapted for being partially or completely pushed into the main body of the device. The user simply pushes in those tip connectors which are not needed. Thus, the step of having to remove unnecessary tips from the tip box by hand has been saved. 
   It is a further feature of the present invention that a mechanism can be provided for activating individual tip connectors wherein lowering of an individual magnetic element into a tip connector causes the tip connector to switch to the activated position. In one embodiment, a slide mechanism is provided whereby, in the inactivated state, the connector is positioned inside of the main body of the device. When a magnetic element is lowered into the connector, it pushes against the connector, causing it to extend from the main body of the device by a predetermined measured amount. 
   According to preferred embodiments of the present invention, there is also provided a method for collecting and transferring a sample from a microtiter plate, comprising providing a combinatorial device for the collection and transfer of a sample, the device being adapted for use with microtiter plates of different sizes, and the device comprising:
         (a) an upper plate comprised of a first half and a second half, wherein each of the halves is independently movable between at least an upper position and a lower position;   (b) a lower plate having a plurality of tip connectors coupled thereto for facilitating attachment of at least one collecting tip;   (c) a plurality of sample collector members each having a proximal end and a distal end;   (d) a mechanism for moving at least one of the first half and the second half of the upper plate between the upper position and the lower position;       

   wherein the proximal ends of the sample collector members are held by the first and second halves of the upper plate and wherein the distal ends of the sample collector members are adapted for being engaged by the lower plate, and the method further comprising moving at least one half of the upper plate from the upper position to the lower position such that the corresponding sample collector members are lowered with respect to the lower plate, thereby facilitating collection of at least one sample into a collecting tip attached to one of the connectors. 
   Further features and advantages of the present invention will become more readily apparent and understood from the detailed description of the invention provided below. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
     For a better understanding of the invention with regard to the embodiments thereof, reference is made to the accompanying drawings, in which like numerals designate corresponding elements or sections throughout and in which: 
       FIG. 1  represents a perspective view of a first preferred embodiment of the combinatorial device of the present invention, with the cover of the device removed; 
       FIG. 2  represents a side view of the device of  FIG. 1 , with the cover of the device removed and with half of the upper plate of the device partially lowered; 
       FIG. 3  represents a side view of the device of  FIG. 1 , with the cover of the device removed and with half of the upper plate of the device lowered such that magnetic elements extend from the tip connectors; 
       FIG. 4  represents a side view of the device of  FIG. 1 , with the cover of the device removed and with half of the upper plate of the device further lowered such that used tips are released from the device; 
       FIG. 5  represents a side view of the device of  FIG. 1 , with the lock button in the locked position; 
       FIG. 6  represents a side view of the device of  FIG. 1 , with the lock button in the unlocked position; 
       FIG. 7  represents a side view of the device of  FIG. 1 , with the cover removed and with all tip connectors in the activated position; 
       FIG. 8  represents a side view of the device of  FIG. 1 , with the cover removed and with both halves of the upper plate in the lowered position; 
       FIG. 9   a  represents a schematic side view of a second preferred embodiment of the combinatorial device of the present invention.  FIG. 9   b  represents a schematic view of a single pump unit of the device of  FIG. 9   a;    
       FIG. 10   a  is the same as  FIG. 9   b , except that half of the upper plate of the device have been lowered; 
       FIG. 10   b  is the same as  FIG. 9   b , except that the pump unit is illustrated in a different configuration; 
       FIG. 11  represents a further side view of the device of  FIG. 9   a , illustrating how a plurality of used tips are released from the device; 
       FIG. 12  represents a perspective view of a third preferred embodiment of the combinatorial device of the present invention, with the cover removed; 
       FIG. 13  represents a side view of the device of  FIG. 12 , with the cover removed; 
       FIG. 14  represents a top view of the upper plate of the device of  FIG. 12 ; 
       FIGS. 15   a - 15   d  represent schematic views of various preferred embodiments for a magnetic element employed in certain preferred embodiments of the combinatorial device of the present invention; and 
       FIGS. 16   a  and  16   b  represent schematic views of sequential steps in the activation of a single tip connector via a magnetic element, according to certain preferred embodiments of the present invention. 
   

   DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
   Reference will first be made to  FIGS. 1-8 , which illustrate various views of a combinatorial pipettor device  12  for the separation and transfer of magnetic particles, according to a preferred embodiment of the present invention. 
   Device  12  comprises two plates: an upper plate, comprised of a first upper plate half  20   a  and a second upper plate half  20   b  each of which are movable between an upper position and a lower position; and a lower plate, comprised of a first lower plate half  22   a  and a second lower plate half  22   b . In  FIG. 14 , it is possible to see the upper plate as a complete unit whereas in  FIG. 1-4 , one half of the upper plate has been moved down with respect to the other half. Upper plate halves  20   a ,  20   b  are complementary in shape with one another, as shown in  FIG. 14 , which will be further described below. Upper plate halves  20   a ,  20   b  have a plurality of openings  24  for holding the proximal ends  26   a  of a plurality of magnetic elements  26 , such that when one or both halves  20   a ,  20   b  move down, magnetic elements  26  which are maintained thereon move down correspondingly. It will be appreciated that magnetic elements do not move independently; they move only in conjunction with the upper plate. 
   An actuator button having two halves  90   a ,  90   b  is provided for operating device  12 . Actuator button half  90   a  is operably coupled to upper plate half  20   a ; actuator button half  90   b  is operably coupled to upper plate half  20   b . When activated, upper plate halves  20   a ,  20   b  slide downward along two pairs of poles  10 . 
   Lower plate halves  22   a ,  22   b  are complementary in shape to one another in a manner similar upper plate halves  20   a ,  20   b . Openings in lower plate halves  22   a ,  22   b  are for receiving the distal ends  26   b  of magnetic elements  26 . A plurality of connectors  34  are located on lower plate halves  22   a ,  22   b  for facilitating connection of at least one collecting tip to device  12 . 
   In  FIG. 1 , eight sample collector members, associated with the first half of the upper plate, have been lowered; the second half of the upper plate, and thus the eight sample collector members associated therewith, remain in the upper position. 
   Preferably, first lower plate half  22   a  is non-movable; and connectors  34  located on the lower boundary of lower plate half  22   a  are provided in the activated position (“activated position” refers to a position in which a connector, in combination with an attached collecting tip, can be used for collection of a sample). Second lower plate half  22   b , however, is movable; connectors  34  located on the lower boundary of lower plate half  22   b  are initially provided in the non-activated position (non-activated or inactivated position refers to a position in which a connector cannot be employed for collection of a sample), in which the connectors  34  are at least partially located within the main body  100  of device  12 . When lower plate half  22   b  is lowered, connectors  34  attached thereto become lowered, thereby assuming the activated position. 
   A lock button  92  is provided whereby connectors  34  located on lower plate half  22   b  can be switched by the user from the non-activated to the activated position and vice-versa.  FIGS. 5 and 6  clearly illustrate lock button  92 . When in locked position a, only connectors  34  from the first lower plate half  22   a  are in the activated position outside of the main body  100  of the device  12  ( FIG. 5 ). When switched by the user to unlocked position b ( FIG. 6 ), connectors  34  from the second lower plate half  22   b  also become activated, and thus can be seen outside of the device main body  100 . Switching of lock button  92  from position a to position b causes lower plate half  22   b  to become lowered, thereby extending connectors  34  associated therewith by a predetermined amount from the device body. 
   Unlocking of lock button  92  also allows for actuator button half  90   b  to be used. When in locked position a, only actuator button half  90   a  may be pressed, and thus only upper plate half  20   a  can be lowered. When in unlocked position b, both button halves  90   a    90   b  can be pressed for lowering both upper plate halves  20   a    20   b . In unlocked position b, a channel  94  engages lock button  92 , thereby allowing for downward movement of actuator button half  90   b  whereas in locked position a, movement is prevented by lock button  92 . 
   According to the number and positioning of samples that are to be processed, the user determines whether only one or both halves of device  12  are to be employed. In  FIGS. 1-4 , lock button  92  is in locked position a and thus only upper plate half  20   a  and lower plate half  22   a  are being used. In  FIGS. 7 and 8 , lock button  92  is in unlocked position b and thus both upper plate halves  20   a ,  20   b  and both lower plate halves  22   a ,  22   b  are being employed. 
   In the device illustrated, each upper plate half  20   a ,  20   b  can accommodate up to 8 magnetic elements, for a total of sixteen. In situations where between 1-8 samples need to be processed, only actuator button half  90   a  needs to be employed. When 8-16 samples need to be processed, both actuator button halves  90   a ,  90   b  a re employed, thus activating both halves of the upper plate. It will be appreciated that device can be designed to accommodate other combinations of magnetic elements as well, for example, 12 on each upper plate half. 
   Each lower plate half is aligned with the corresponding upper plate half so as to receive the distal ends of magnetic elements held by the upper plate. Thus, each lower plate half has the same number of openings as the corresponding upper plate half. 
   In  FIG. 2 , upper plate half  20   a  is partially lowered. Eight connectors  34  associated with lower plate half  22   a  a re seen activated outside of the device main body  100 . When upper plate half  20   a  is fully lowered, eight magnetic elements  26  connected at the proximal end  26   a  to upper plate half  20   a  extend through connectors  34  on lower plate half  22   a  ( FIG. 3 ). Tips  32  (not shown in  FIG. 3 ) can then be attached to connectors  34  and magnetic particles can be collected onto the tip  32  due to the magnetic force of the distal end  26   b  of magnetic element  26  onto the tip (in  FIG. 4 , only one collecting tip  32  is illustrated, for purposes of example only). 
   It will be appreciated that for the collection of magnetic particles, a specialized collecting tip is employed which has a thin membrane having a thickness of about 30 microns or less at the very tip portion thereof. A membrane of such size maximizes the magnetic force on the sample, creating a “button” of nearly all of the magnetic particles on the membrane. This was disclosed previously in U.S. Pat. No. 6,409,925 to the same inventor. 
   Thus, in operation of the device, when eight or fewer samples are to be processed, the user presses down on actuator button half  90   a , thus causing upper plate half  20   a  and associated magnetic elements  26  to become lowered. While button  90   a  is pressed, magnetic particles can be collected, for example by lowering of attached collecting tips into wells containing magnetic particles suspended in a liquid. Magnetic particles are attracted to the tips as a result of the magnetic force of the distal ends  26   b  of magnetic elements  26  on the collecting tips  32 . The device is then transferred to the target vessel and actuator button half  90   a  is released, thus removing the magnetic force from the tips via raising of the magnetic elements to their original location. The magnetic particles can thus be released from the tips. 
   To release used tips, a release button  96  is provided on device  12  which, when pressed inward, enables the user to press down on actuator button half  90   a  to a further extent than previously ( FIG. 4 ). Upper plate half  20   a  thus becomes lowered further than it was during collection of the magnetic particles, and magnetic elements  26  are correspondingly lowered. Due to this action, the distal ends  26   b  of magnetic elements  26  press onto the ends of the tips  32 , causing them to be released from connectors  34 . 
   In  FIGS. 7 and 8 , lock button  92  is in unlocked position b. Sixteen connectors  34  are activated, eight from each half of lower plate  22   a ,  22   b . When both halves of actuator button  90   a ,  90   b  are pressed, both halves of upper plate  20   a    20   b  become lowered, and, in the example illustrated, sixteen magnetic elements  26  extend through connectors  34  ( FIG. 8 ) for collection of sixteen magnetic particle samples. Used tips are released in the same manner as described above, with both halves of the actuator button  90   a ,  90   b  being pressable to a further extent than previously. 
   It will be appreciated that the user can choose the number and combination of connectors that are to be employed according to the number of samples and their positioning in the microtiter plate. When eight or less samples are being separated, only the first side of the device needs to be used. When between nine and sixteen samples are being processed, the second half of the device is used as well. 
   In order to provide the user with the ability to collect any number and combination of samples, the device of the present invention is preferably provided with at least a portion of tip connectors that can be inactivated by the user. In this case, prior to attachment of collecting tips, the user disconnects individual connectors which are not required, as determined by the number of samples to be processed and their position in the plate. As an example, if only three samples need to be processed, then five out of the eight connectors located on the first half of the lower plate are inactivated by the user (connectors from the second half of the lower plate are initially provided in the inactivated state and thus do not require deactivation). The remaining combination of three connectors are then used for attachment of collecting tips to the device. 
   Detachment of the connectors from the device can be accomplished, for example, by a screw mechanism, wherein each connector can be screwed and unscrewed from the lower plate, or by any other appropriate means. Alternatively, the tip connectors may be adapted for being partly or completely pushed inside of the main body of the device. The user pushes in connectors which are not needed. The connectors can be pulled out when they are required. 
   In some embodiments, magnetic elements are provided separate from the rest of the device and the user inserts magnetic elements into the device according to the number and combination of samples to be processed. In  FIG. 1 , for example, only one magnetic element  26  is present on the second upper plate half  20   b , whereas the first upper plate half  20   a  has eight magnetic elements  26 . In  FIGS. 2-8 , all sixteen magnetic elements are present. 
   A second preferred embodiment for the combinatorial pipettor device  14  of the present invention will now be described with reference to  FIGS. 9   a ,  9   b ,  10   a ,  10   b , and  11 . This embodiment operates in a manner similar to the previous embodiment, and only those features that differ have been illustrated and will be discussed below. 
   Device  14  is adapted for use for the transfer of liquids and comprises a plurality of pump units, each of which includes: a pin  70  having a proximal end  70   a  held by the upper plate  20  and a distal end  70   b ; a plurality of suction tubes  72  maintained by lower plate  22 ; a piston  74  movably disposed within each suction tube  72 . It will be appreciated that the pump unit described is well known in the art and is readily available. In this embodiment, connectors  34  are defined by the lower portion of the suction tubes  72 . 
   It will be appreciated that though only “half” of the device is illustrated, this embodiment, like the previous one, preferably includes an upper plate comprising two complementary halves which can be independently operated. Thus, though only eight pump units are shown, the device preferably has sixteen pump units, eight of which are activated by each half of the upper plate. Likewise, only one half of the upper plate can be seen, though the reference numeral used is  20 . A simplified version has been illustrated for the purposes of clarity only. It is noted however, that this embodiment, and other ones described, could be readily modified so as to include an upper plate having only one main movable part, instead of two, and thus the device would resemble  FIG. 9   a . Such a device would be simpler but it could not be used for combinatorial purposes. 
   Upper plate  20  is switchable between an upper position ( FIG. 9   a ) and a lower position ( FIG. 10   a ) via an actuator button (not shown) operating in a similar manner as the actuator button of the previous embodiment. In the upper position, distal ends  70   b  of pins  70  are located at the top of suction tubes  72  (see  FIG. 9   b ). When upper plate  20  is lowered, pin  70  pushes against piston  74 , causing piston  74  to move downward inside of suction tube  72  ( FIGS. 10   a  and  10   b ). When the actuator button is released, upper plate  20  moves up, pin  70  is raised and piston  74  moves back up correspondingly. The extent to which each of these events takes place is determined by the amount of liquid that is to be drawn into collecting tip  32  attached to connector  34 . 
   When a liquid is to be drawn into collecting tips  32 , the actuator button is pressed such that piston  74  becomes lowered inside of tube  72 . The tips are then inserted into the liquid and then the actuator button is released, thereby effecting drawing in of a predetermined amount of liquid. When the liquid is to be released into a target vessel, the actuator button is again pressed, causing pistons  74  to move downward and thus expelling liquid in the collecting tips. 
   The mechanism for releasing used tips differs from that of the previous embodiment. In this embodiment, to release used tips  32 , upper plate  20  is raised such that the distal ends  70   b  of pins  70  clear suction tubes  72  ( FIG. 11 ). This could be accomplished, for example, by raising the actuator button or by an external switch coupled to upper plate  20 . Next, lower plate  22  is raised, for example, via an external switch, such that connectors  34  enter inside of the device main body  100 . As connectors  34  are raised, tips  32  press against device main body  100 , thereby causing them to be released from device  14 . 
   A third preferred embodiment of the combinatorial device of the present invention is shown in  FIGS. 12 ,  13 , and  14 . This embodiment is for a device for the separation and transfer of magnetic particles and it is similar to the first embodiment described, with the exception that the mechanism for the collection of magnetic particles is different. This difference will be further described below. 
   Certain features of the first embodiment described above will be better understood and appreciated with reference to  FIGS. 12 ,  13 , and  14 . For example, it is now possible to see the complementary nature of the two halves of both the upper plate and the lower plate with one another. Each half of each plate comprises a plurality of projections  60 ,  84  which contain openings  24 ,  28  for receiving the proximal and distal ends  26   a ,  26   b  of magnetic elements  26 . As seen in  FIG. 14 , the two plate halves  20   a ,  20   b  are complementary in shape to one another, and the projections of each half fit the projections of the other half along curved interface edge  102 . All of openings  24  are thus located along the same longitudinal axis. Aside from openings  24  which are located at either end of the plate, each opening  24  is neighbored by a pair of openings (one on each side) from the opposite plate half. 
   In the embodiment illustrated in  FIGS. 12 and 13 , each half of upper plate  20  is switchable from an upper inactivated position to a lower activated position. Preferably, one or two external switches is provided for switching one or both halves of the upper plate to the activated position. In the activated position, the distal ends  26   b  of magnetic elements  26  are located inside of openings  28  of lower plate  22 . Each half of upper plate  20  is adapted for moving along two pairs of poles  19 . 
   Lower plate  22  is switchable between three positions: a lower pre-collecting position, a middle collecting position, and an upper tip-releasing position, to be described further below. Mechanism  16  is provided for switching one or both halves of lower plate  22  between the three positions. 
   Prior to operation of mechanism  16 , one or both halves of upper plate  20  is activated such that the corresponding magnetic elements  26  become lowered. Initially, lower plate  22  is in the pre-collecting position. One or both halves of lower plate  22  is then raised slightly to the middle collecting position. Raising of one or both halves of lower plate  22  is effected by pressing on one or both halves of an actuator button coupled to mechanism  16  that pushes down on a pair of gears  30  coupled to a pair of supports  18 . 
   When gears  30  are lowered, supports  18  become raised, thus raising the half of lower plate  22  which is coupled thereto. Since lower plate  22  has been raised with respect to magnetic elements  26 , the distal ends  26   b  of magnetic elements  26  now extend through connectors  34  located on the bottom of lower plate reaching the end of attached collecting tips  32  so as to exert a magnetic force of the end of collecting tips  32 . Thus, magnetic particles can be collected on the collecting tips. 
   In  FIG. 12 , only one magnetic element and collecting tip have been illustrated, for the purposes of simplicity and clarity only. In  FIG. 13 , three magnetic elements and collecting tips  32  are shown. When the magnetic particles are to be released into the target vessel, the actuator button or button half is released and the lower plate  22  or lower plate half is returned to the pre-collecting position, thereby positioning said lower plate  22  or lower plate half downward and displaced from the distal ends  26   b  of magnetic elements  26  and thus removing the magnetic force from the tips. When used tips are be released, the actuator button is pressed to a further extent than previously, such that the distal ends  26   b  of the magnetic elements  26  press against the collecting tips, causing their release. 
   It will be appreciated that a single mechanism serves both to collect and release the sample and also to release the used tips. This is highly advantageous since it contributes to the simplicity in design and ease-of-use of the device, and also lowers costs. This is also in contrast to regular pipettor, in which a separate mechanism needs to be used in order to release a used tip from the pipettor. 
     FIG. 13  illustrates a way for preventing the attachment of collecting tips to the device in positions which are not required. In this case, a tube member  50  is placed onto those connectors  34  to which the user desires that a collecting tip be attached, according to the number and position of magnetic particle samples that are be separated. Due to the added length, when the user presses the device into the tip box, collecting tips  32  will only become attached to those connectors  34  which have tube members  50  attached thereto. It will be appreciated that by not using extra tips, the separation process is simplified, tips are not wasted, and the user can more easily keep track of samples. 
   It will be appreciated that during operation of the device, the magnetic elements are fixed with respect to the upper plate, and they only move when the upper plate is moved. It will be appreciated that this feature facilitates usage of the device in microtiter plates having different numbers of wells. Various preferred embodiments for the magnetic elements employed in the present invention will now be described with respect to  FIGS. 15   a - 15   d.    
   In certain embodiments of the present invention, specifically those where magnetic elements are provided already loaded in the device, the magnetic element preferably has the design illustrated in  FIG. 15   a . In this case, magnetic element  26  comprises a magnetic segment  40  located at the distal end  26   b  of magnetic element  26 . The middle portion of magnetic element  26  is formed from a non-magnetic material such as aluminum. Magnetic element  26  also comprises a cap  42  located at the proximal end  26   a  that facilitates maintaining of magnetic element  26  on the upper plate of the device. To connect between magnetic segment  40  and the non-magnetic portion, a stainless steel (or other suitable material) sleeve (not seen) is preferably used. 
   In another preferred embodiment, illustrated in  FIG. 15   b , magnetic element  26  comprises a magnetic segment  40  located at the distal end  26   b  thereof, as well as a second magnetic segment  44  located at the proximal end  26   a  thereof. The two magnetic segments have the same size. In this case, the upper plate comprises an upper plate cover formed from a magnetizable material. Thus, when a magnetic element is inserted into the device (for example, through the tip connectors at the bottom of the device), the second magnetic segment of the magnetic element contacts the cover and is held in place on the upper plate due to the magnetic force exerted by the second magnetic segment  44  onto the cover. 
   The preferred embodiment illustrated in  FIG. 15   c  is similar to that of  FIG. 15   b , with the exception that instead of a second magnetic segment, magnetic element  26  is provided with a magnetizable segment  46  at the proximal end  26   a . In this case, the upper plate is provided with a cover formed from a magnetic material or the upper plate itself is formed from a magnetic material, so as to create a magnetic force between the magnetizable segment and the upper plate. The magnetizable segment can be formed, for example, from iron. 
   In yet another preferred embodiment, the entire magnetic element  26  is formed from a magnetic material. In this case, the upper plate is formed from a magnetizable material or the upper plate has a cover that is formed from magnetizable material. 
   The device of the present invention can be provided with means whereby individual connectors are activated in an automatic manner, according to the presence or absence of a magnetic element at a specific device location. This is illustrated in  FIGS. 16   a  and  16   b . Initially, connector  34  is positioned inside of the device main body  100  ( FIG. 16   a ). When a magnetic element  26  is lowered, it enters inside of connector  34  and contacts the inner sidewalls of connector  34 , whose diameter is slightly smaller than the width of magnetic element  26 . 
   Magnetic element  26  thus pushes against connector  34 , and causes it to be lowered out of device main body  100 . The upper portion  104  of the distal end  26   b  of magnetic element  26  then engages with the upper portion  106  of connector  34 , inhibiting further downward movement of magnetic element  26 . The distance which the magnetic elements are allowed to move, and the extent to which the connectors are lowered is pre-set such that the magnetic elements and connectors extend by an exact amount from the main body of the device in order to allow for collection of a sample. 
   Alternatively, in other embodiments, a pressable ring is provided within the connector. In this case, as the magnetic element is lowered, it presses against and expands the ring against the inner walls of the connectors. As the magnetic element is lowered, the connector is lowered along with it. Only those connectors where a magnetic element has entered are activated. 
   In the aforementioned cases, at least a portion of the magnetic elements are provided separate from the device, and the user inserts the appropriate number of magnetic elements into the device at required positions, according to the number and position of the samples on the micro-titer plate. In other preferred embodiments, magnetic elements are provided already housed within the device, and connectors can be activated or inactivated in one of the manners previously described. 
   It will be appreciated the device of the present invention could be designed and adapted for use with microtiter plates of any size, including, but not limited to, 96-well microtiter plates, 384-well microtiter plates, and 1536-well microtiter plates. Plates of any other size, such as 5×5 well PCR plates, could also be accommodated. The present invention provides a simple and easy-to-use solution for transferring liquids or magnetic particles between microtiter plates of different sizes. Moreover, the user has the ability to determine the specific number and combination of samples that are to be processed. 
   It will also be appreciated that using the device of the present invention, magnetic particles or liquids can be transferred from wells in a standard 96 well microplate to smaller wells in a standard 384 well plate and vice versa. There are 2 conditions necessary for such a transfer: the size and diameter must fit the smaller well and the number and combination of tips must fit the size and arrangement of wells in both microtiter plates. This is why 8 tips, or any combination ranging from 1 to 8, can be dipped into both microtiter plates, while 16 tips fit only the 384 well microplate. This also applies for 12 tips, that fit both microtiter plates even at any combination and number tips ranging from 1 to 12, but using both sets of 12 tips by activating both halves of the upper plate results in 24 tips that fit only a 384 well microplate. 
   The device of the present invention can be operated as described above either manually or electrically via a stepper motor or an electric actuator. In one embodiment, a separate motor or motors is provided for each half of each plate. In cases where it is operated electrically, it may still be a manual device with a suitable holder though optionally it can be part of an automatic machine controlled via computer. 
   Having described the invention with regard to certain specific embodiments thereof, it is to be understood that the description is not meant as a limitation, as further modifications will now become apparent to those skilled in the art, and it is intended to cover such modifications as are within the scope of the appended claims.