Abstract:
A microfluidic device operates as a pump for pumping fluid along a channel in a microchip by moving a drive fluid in the channel under the influence of a force field that is generated externally to the channel. The drive fluid is preferably a ferrofluid, and the force field is preferably a variable magnetic field. Drive fluid, driven by variation of the magnetic field, drives driven fluid through the channel. The drive fluid is recirculated, in one case by rotating the drive fluid within an enlargement in the channel, and in another case by returning the drive fluid along a return channel. A valve is formed by using a ferrofluid plug as a movable barrier for fluids in a channel. The microfluid device may be formed between two plates forming a microchip. The channels may be as small as 1 μm to 100 μm. Methods of pumping fluids by using an in channel drive fluid and exterior drive are also disclosed.

Description:
FIELD OF THE INVENTION 
     This invention relates to fluidic devices, and particularly microfluidic devices. 
     BACKGROUND OF THE INVENTION 
     Microfluidic devices are becoming increasingly critical to biochemical analysis. These devices may have channels whose cross-sections are in the order of 1 μm to 1000 μm A fluid containing a sample to be analyzed and a reagent for activating the sample are delivered along channels to a reaction zone in the microchip. Pumping of the fluid is often carried out with external pumps, or electrical pumps that rely upon principles such as electroosmosis, electrophoresis and dielectrophoresis. When external pumps are used, problems can arise in both sample and reagent delivery. 
     For example, in sample delivery, transfer of sample to the chip may result in pressure differentials in excess of the pumping capacity, with resulting pressure fluctuations. In reagent delivery, the channels in the chip must be manually primed with reagent, with risk of cross-contamination. 
     SUMMARY OF THE INVENTION 
     There is thus a need for an on chip pump for use with microchips. 
     The invention provides a device that provides isolation and sample delivery in a microchip while not introducing large dead volumes. In addition, the use of the micropump in the channel allows pre-priming of the microchip, thus reducing the time in which the microchip is exposed to contaminants. 
     According to a first aspect of the invention, a pump pumps fluid along a channel by moving a drive fluid in the channel under the influence of a force field that is generated externally to the channel. The drive fluid is preferably a ferrofluid, and the force field is preferably a variable magnetic field. Drive fluid, driven by variation of the magnetic field, drives driven fluid through the channel. The drive fluid is recirculated, in one case by rotating the drive fluid within an enlargement in the channel, and in another case by returning the drive fluid along a return channel. The channel is preferably a microchannel in a microchip. The channel and pump may be formed between two plates forming a microchip. The channel may be as small as 1 μm to 100 μm in its cross-sectional dimensions. A valve is formed by using a ferrofluid plug as a movable barrier for fluids in a channel. Methods of pumping fluids by using an in channel drive fluid and exterior drive are also disclosed. 
     These and other aspects of the invention are described in the detailed description of the invention and claimed in the claims that follow. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     There will now be described preferred embodiments of the invention, with reference to the drawings, by way of illustration only and not with the intention of limiting the scope of the invention, in which like numerals denote like elements and in which: 
     FIG. 1 is an exploded view showing a first embodiment of the invention; 
     FIG. 1A is a section through the embodiment of FIG. 1 along the line  1 A— 1 A; 
     FIG. 2 is an exploded view showing a second embodiment of the invention; 
     FIG. 2A is a section through the embodiment of FIG. 2 along the line  2 A— 2 A; 
     FIG. 3 is an exploded view showing a third embodiment of the invention; 
     FIG. 3A is a section through the embodiment of FIG. 3 along the line  3 A— 3 A; 
     FIGS. 4A-4C show the manner of operation of the first embodiment of the invention; 
     FIGS. 5D-5C show the manner of operation of the second embodiment of the invention; 
     FIGS. 6A-6D show the manner of operation of the third embodiment of the invention; and 
     FIGS. 7A and 7B show operation of an exemplary valve for use with the invention; 
     FIG. 8 shows an embodiment of the invention as applied to pumping with a reciprocal motion in a microchip; 
     FIG. 8A shows how a plug may be stretched to provide differential pumping in opposite directions; 
     FIGS. 9A-9E show schematically embodiments of the invention in which drive fluid is recirculated around a recirculation channel; and 
     FIGS. 10A-10E show magnetic drives for the embodiments of FIGS. 9A-9E respectively, with FIG. 10F showing in addition a permanent magnet that forms part of the drive shown in FIG.  10 E. 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     Referring to FIG. 1, a channel  10  extends through a body  12  and may be formed such as by etching or laser ablating the channel in a base plate  11  and covering  10  the base plate  11  with a cover plate or lid  13 . The channel  10  may have cross-sectional dimensions in the order of 1 μm to 1000 μm, preferably in the range 1 μm to 100 μm. Such devices are known as microchips, and conventional micromachining methods may be used to make the channels. The channel  10  may be straight, but it is preferred to form a reservoir in the channel  10  for a drive fluid plug  14  such as by forming a cylindrical enlargement  16  as in FIG.  1 . In another preferred embodiment, a channel  20  in body  22  formed of base  21  and lid  23  may be split into two branch channels  20 A and  20 B separated by a wall  26  as shown in FIG.  2 . In a further embodiment shown in FIG. 3, the wall  26  may have passages  27 A- 27 D connecting the channel branches  20 A and  20 B in several places. 
     Referring as well to FIGS. 4A-4C and  5 A- 5 D, a drive fluid plug  14  or  24  occupies the enlargement  16  or channel  20 B respectively. The drive fluid plug  14  has interfaces  14 A,  14 B with driven fluid in respective spaced apart portions  30 ,  32  of the channel  10 . The drive fluid plug  24  has interfaces  24 A,  24 B with driven fluid in respective spaced apart portions  40 ,  42  of the channel  20 . The portions  30 ,  32  of channel  10  and  40 ,  42  of channel  20  are spaced sufficiently to form an adequate stroke for the pump, such as 1 cm. 
     The drive fluid may be any fluid that is capable of being moved by forces applied by a drive exterior to the channel. For example, the drive fluid is preferably a ferrofluid. A ferrofluid is any fluid that is capable of being moved around under the influence of a magnetic field. When the drive fluid is a ferrofluid, the body  12  should be made of a non-magnetic material at least in areas adjacent to the enlargement  16  or branch channels  20 A and  20 B. 
     Drives  50 ,  60  for the drive fluid are mounted exterior to the channels  10 ,  20  respectively. The drives  50 ,  60  may be attached such as by clamps to the bodies  12 ,  22 , or each may be held in a separate frame. The drives  50 ,  60  should be close enough to the bodies  12 ,  22  that the force field may drive the drive fluid. The drives  50 ,  60  are configured to isolate a driven fluid segment from the portions  30 ,  40  respectively of the channels  10 ,  20  and drive the driven fluid segment to the portions  32 ,  42  of the channels  10 ,  20 . When the drive fluid is a ferrofluid, the drives  50 ,  60  are magnetic field generators such as electromagnets. 
     In the example shown in FIG. 1, the drive  50  is a rotatable magnet or electromagnet with an initially weakly magnetized area  52  and an initially more strongly magnetized area  54 , the remainder of the magnet being moderately magnetized. The drive  50  may be mounted on a shaft  18  of a conventional stepper motor  17 . Power and control for the electromagnetic areas  52  and  54  may be supplied by a power control module  19 . 
     To facilitate the variability of the magnetization of the areas  52  and  54 , it is preferably that they be elecromagnets. When the magnet  50  is located over the cylindrical enlargement  16  in the channel  10  with the weakly magnetized area adjacent the portion  30  of the channel  10 , drive fluid is pulled away from the weakly magnetized area to alter the interface  14 A and form a pocket in the drive fluid as shown in FIG.  4 B. Driven fluid enters the pocket from the channel  10 . The driven fluid segment  56  in the pocket is isolated from the driven fluid in the portion  30  of the channel  10  as shown in FIG. 4C with a drive fluid barrier  58  between the driven fluid segment  56  and driven fluid in the portion  30  of the channel  10 . When the magnet  50  is rotated, the drive fluid barrier  58  rotates with the magnet  50  and along with the fluid in the grip of the magnet  50  drives the driven fluid segment  56  around the cylindrical enlargement  16  from the portion  30  of the channel  10  to the portion  32  of the channel  10 . The weakly magnetized area is then magnetized to release the driven fluid segment  56  into the portion  32  of the channel  10 . Preferably, when the pocket is formed, the area  54  is energized to draw fluid towards that end of the magnet. When the pocket is released, the strongly magnetized area  54  is preferably deenergized, weakening the field, to allow drive fluid to flow towards the pocket and drive the driven fluid into the channel  10  at area  32 . As the magnet  50  continues to rotate, the area  54 , which is strongly magnetized during the initial part of the rotation (first 180° of rotation), is made weak, thus forming a pocket that is occupied by a driven fluid segment from portion  30  of the channel  10 . Similarly, area  52  is strengthened, thus attracting the drive fluid towards the end  32 . The magnet  50  may then be continuously rotated to form a flow of driven fluid along the channel, with the degree of magnetization of areas  52  and  54  switching after each half rotation. 
     In the example shown in FIG. 2, the drive  60  includes a permanent magnetic strip  70  which is placed exterior to the body  22  over the channel  20 A and individual magnets  61 - 64  over the channel  20 B. This magnetic strip  70  holds the driven fluid in the channel  20 A. A series of electromagnets  61 - 64  are placed exterior to the body  22  between the portions  40  and  42  of the channel  20 B. The operation of the pump shown in FIG. 2 may then be understood from the explanation that follows and FIGS. 5A-5C. 
     In FIG. 5A, the electromagnet  61  is strengthened, and the other electromagnets weakened to pull drive fluid into the channel  20 B and form a drive fluid barrier  66  in the channel, which isolates a driven fluid segment  68  from drive fluid in the portion  40  of the channel  20 B. The electromagnets  61 - 64  are then strengthened sequentially so that a localized strong magnetic field moves along the channel  20 B from the portion  40  to the portion  42  of the channel  20 B. This localized strong magnetic field drives the drive fluid barrier  66  along the channel  20 B, separating it from the main drive fluid reservoir in the channel  20 A. As the electromagnets  61 - 64  are successively strengthened, the drive fluid barrier  66  reaches the end of the pump stroke and returns to the drive fluid reservoir in channel  20 A at the interface  24 B. As the series of electromagnets  61 - 64  are repeatedly strengthened in succession, a flow of driven fluid is formed along the channel. 
     In the embodiment of the invention shown in FIGS. 6A-6D, instead of moving the drive fluid plug along the channel  20 B, the drive fluid is brought out from the cross-channels  27 A- 27 B and returned to the drive fluid reservoir through the same channel. Referring to FIGS. 3 and 6A, magnet  61  is energized to force drive fluid into the channel  20 B at portion  67  through channel  27 A. This forms a barrier between drive fluid in the channel at  69  and  71 , and drives some fluid along the channel towards cross-channel  27 B. Instead of moving the drive fluid along the channel from portion  67 , the magnet  62  is energized to force fluid along channel  27 B into the portion  71 . This displaces driven fluid further along the channel. The process is repeated for channel  27 C. Magnet  63  is energized to force fluid into channel  20 B at location  73 . At the same time, magnet  61  is deenergized, and fluid in portion  67  is returned by attraction of the magnetic strip  70  to the drive fluid reservoir. This process is repeated for magnet  64 , which is energized while magnet  62  is deenergized, as shown in FIGS. 6C and 6D. Finally, the process is repeated again by energizing magnet  61 . The effect of moving the drive fluid from channel  20 A into channel  20 B through cross-channels  27 A- 27 D in succession is to drive driven fluid along the channel  20 B. 
     In the embodiments shown in FIGS. 2 and 3, filters may be provided in the return path (eg channel  27 D in FIG. 3) to prevent driven fluid from mixing with the drive fluid, to enhance stability of the colloidal suspension or to remove any contamination of the drive fluid with the driven fluid. 
     The drive fluid is preferably immiscible in the driven fluid. A range of immiscible ferrofluids are available commercially available, as for example from Ferrofluidics Inc. of Nashua, N.H. USA. If ferrofluids are used, they should not have ferromagnetic particles larger than the channel size. Ferrofluids available from Ferrofluidics Inc. can withstand  1  atmosphere pressure differential, which is adequate for the intended application. Ferrofluids are colloidal suspensions of ultramicroscopic magnetic particles in a carrier liquid, usually used as lubricants or damping fluids. If the ferrofluid is not immiscible in the driven fluid, then some means must be used to maintain the ferromagnetic particles in a stable colloidal suspension. 
     The drive fluid may also be a dielectric fluid, and the drive is then provided by a strong electric field, preferably oscillating at high frequency. 
     As shown in FIGS. 7A and 7B, a valve may be formed at a junction between three microchannels  70 ,  72  and  74  by placing a ferrofluid plug  76  at the junction as shown in FIG.  7 A and moving the ferrofluid plug  76  with a magnetic drive (not shown) into one of the microchannels as shown in FIG.  7 B and allow free fluid flow between the other microchannels. 
     Referring to FIG. 8, a drive fluid plug  80  may also be reciprocated to force fluid along a channel  82  in a microchip. Channel  82  intersects with channel  84 , which has branch channels  86  and  88  connected with it at intersections  87  and  89 , the channels  86  and  88  being located on either side of the intersection between channels  82  and  84 . Ferrofluid plugs  76  operate as valves in the manner described in relation to FIGS. 7A and 7B. If the intersection  87  is open while plug  80  is moved towards channel  84 , with intersection  89  closed, fluid in channel  84  will be moved in the direction from intersection  89  to  87  and thus pumped along the channel  84 . If the intersection  89  is open while plug  80  is moved away from channel  84 , with intersection  87  closed, fluid in channel  84  will be moved into channel  82  ready for pumping into channel  84  on the next pump stroke of plug  80 . 
     In a further example shown in FIG. 8A, a pump may be formed by moving the plug  76  in channel  82  in one direction, with the plug sealing the channel, and then expanding the plug  76  lengthwise along the channel as shown at  85 , thus thinning it and unsealing it from the channel walls, so that on the return stroke, less fluid is driven. 
     Referring to FIGS. 9A-9E, embodiments of the invention in which drive fluid is recirculated around a loop channel that intersects with the flow channel are shown. The loop channel in each of FIGS. 9A-9E is shown as circular, but it may have any arbitrary shape that allows the drive fluid to be re-circulated. 
     In FIG. 9A, main channel  90  carries the driven fluid. A loop channel  92  intersects with the channel  90  along a path between points  94  and  96 . A magnetic drive  110  as shown in FIG. 10A has electromagnets  112  spaced around the circumference of the magnetic drive. A strongly magnetized electromagnet is indicated by the dark shading in each of FIGS. 10A-10E, and a weakly magnetized electromagnet is indicated by light shading. Each electromagnet may be energized and deenergized. In FIG. 9A, at the intersection  94  between the loop channel  92  and the main channel  90 , a nozzle is formed by a series of obstructions  98  in the channel  92 . Drive fluid fills the part of loop channel  92  that does not intersect with the channel  90 . All the electromagnets  112  over the loop channel  92  are strongly magnetized. The electromagnets  112  that are situated over the channel  90  are initially weakly magnetized and when it is desired to pump are sequentially activated, with the first electromagnet  112  to be energized being the one over the region  94 . This draws drive fluid from the drive fluid reservoir into the flow channel  90 . As the electromagnets of the magnetic drive that are located over the flow channel  90  are sequentially activated, drops of drive fluid are forced between the obstructions  98  and moved along the main channel  90  from point  94  to  96 , dragging driven fluid by frictional contact. The drive fluid is pulled by the sequential activation of the electromagnets in the magnetic drive into the loop channel  92  while the momentum of the driven fluid forces the driven fluid along the channel  90 , tangentially to the channel  92 . It is preferred to have strong magnetization in the loop channel  92  just beyond the point  96  to ensure recirculation of drive fluid around the loop channel  92 . 
     In FIG. 9B, a similar device to the device shown in FIG. 9A is shown, except the injector obstructions  98  are replaced by a restriction or nozzle  99 , from which large fluid drops  101  are pulled by a localized strong magnetic field, moved along the channel  90  to point  96  and returned to the loop channel  92  for recirculation. The large drops have a size similar to the channel width. Again, the localized strong magnetic field is created by sequential activation of the electromagnets over the flow channel  90 , as illustrated in FIG.  10 B. 
     In FIG. 9C the same loop channel  92  and main channel  90  are used. However, fluid in the loop channel  92  is continuously moved around the loop channel as a series of segments  103  by several spaced locally strong magnetic fields. As shown in FIG. 10C, the magnetic drive is again a series of sequentially activated electromagnets  112 . In this case, the electromagnets  112  are activated sequentially to attract the drive fluid and move it anticlockwise around the loop  92 . Over the loop channel  92 , the electromagnets may alternate in relative magnetic strength. Care must be taken to coordinate activations so that drive fluid does begin moving clockwise. Over the flow channel  90 , the spacing between the activated electromagnets  112  is increased to create suction and pull more driven fluid along the flow channel  90  to be pumped. 
     In FIG. 9D, the loop channel  92  and flow channel  90  are the same as in FIG. 9A. A magnetic drive  114  is formed by several magnets  116  mounted for rotation on a ring or disc  118  driven for example by a stepper motor (not shown in FIG.  9 D). Four permanent magnets  116  may be used. Each electromagnet should be strongly magnetized. As the drive  114  rotates, drive fluid drops  105  are pulled around the loop channel  92  and through the flow channel  90  to drive driven fluid in the flow channel along the flow channel  90 . In FIG. 9D, it is preferred that channel  90  be slightly wider than channel  92  to accommodate volume changes due to the pressure exerted by the drive fluid. 
     In FIG. 9E, loop channel  92  and main channel  90  are the same as shown in FIG.  9 A. In this case, a strong ring shaped magnetic field is formed by a magnetic drive to shape the drive fluid into a ring on the inside of the loop channel  92  with multiple barriers or cogs  107  spaced around the loop channel  92 . The cogs  107  may be continuous around the loop channel  92  or may be generated only in the flow channel  90 . The magnetic drive in this instance is formed by a disc magnet  109  centered in the middle of the circle formed by the loop channel  92  and flow channel  90  with spaced satellite magnets  111  around the periphery of the disc magnet  109 . To create a reservoir of drive fluid in the loop channel  92 , a permanent magnet  113  may be placed over the loop channel  92 . As the magnetic drive rotates (driven for example by a stepper motor), the cogs  107  drive driven fluid along the channel  90 . 
     The magnets or electromagnets require an active field area commensurate with the size of the channel, but may be larger. For example, magnetic drivers for use with a microchip may be provided by coils with ferromagnetic cores having a diameter of in the order 100 μm. When the magnets are rotated, commercially available stepper motors may be used. The size of the apparatus outside the channels is not a factor in the operation of the pumps. A varying magnetic field may also be created in the channel by varying the distance of a permanent magnet from the channel. 
     In the embodiment of FIG. 1, several pockets could be formed in the driven fluid plug by several weak field areas in the magnet, but the more driven fluid that has to be moved in a single rotation, the more drive fluid has to be displaced. An additional reservoir to take drive fluid overflow may be required in this instance. 
     The pumps shown in FIGS. 1,  2  or  3  may be connected to a chamber having a small closeable opening at one end. The chamber may be evacuated with the pump to form a vacuum chamber, and samples may be drawn in through the opening for analysis within the chamber, such as by using a mass spectrometer. 
     A person skilled in the art could make immaterial modifications to the invention described in this patent document without departing from the essence of the invention that is intended to be covered by the scope of the claims that follow.