Abstract:
A method of controlling fluid flow in a channel in a microfluidic flow control device by introducing fluid to the channel, with the fluid flowing in a flow direction and controllably deforming material defining the channel in a direction perpendicular to the flow direction to control fluid flow in the channel. The channel is formed between a first plate and a second plate and controllably deforming material defining the channel comprises deforming at least one of the first and second plates. Material defining the channel extends continuously between an inlet port and an outlet port. Controllably deforming material defining the channel preferably comprises deforming the first plate into contact with a seat formed in the second plate to close the channel. The seat may be formed by a ridge having a smoothly changing profile in section across the channel. The method may be operated to generate a pumping, filtering, trapping or mixing function. Apparatus for carrying out the method is also disclosed.

Description:
BACKGROUND OF THE INVENTION 
     This invention relates to the design and use of microfluidic devices, particularly microfluidic valves, pumps and mixers. 
     Microfluidic devices are used extensively in biotechnology and health industries for the manipulation and analysis of small quantities of fluid samples. Various devices have been proposed for use as valves and pumps, such as described in U.S. Pat. No. 6,146,103 to Lee et al issued Nov. 14, 2000, and U.S. Pat. No. 6,056,269 to Johnson et al issued May 2, 2000. The Lee et al device provides a valve for a microfluidic device, but the design described requires a somewhat complicated structure and as shown does not show how to prevent leakage. The Johnson et al device provides a device that blocks flow by movement of a plate parallel to fluid flow. Again this device has a somewhat complicated design. This invention is directed to an improved microfluidic control device that is easy to make and use, while ensuring a tight fluid seal in a microfluidic flow control structure. 
     SUMMARY OF THE INVENTION 
     There is therefore provided according to an aspect of the invention, a method of controlling fluid flow in a channel in a microfluidic flow control device. The method may comprise introducing fluid to the channel, with the fluid flowing in a flow direction and controllably deforming material defining the channel in a direction perpendicular to the flow direction to control fluid flow in the channel. The channel is preferably formed between a first plate and a second plate and controllably deforming material defining the channel comprises deforming at least one of the first and second plates. Preferably, material defining the channel extends continuously between an inlet port and an outlet port. Controllably deforming material defining the channel preferably comprises deforming the first plate into contact with a seat formed in the second plate to close the channel. The seat may be formed by a ridge having a smoothly changing profile in section across the channel. 
     A pumping action may be obtained by deforming the channel at successively at spaced apart positions along the channel to drive fluid along the channel. Alternatively, a pumping action may be obtained by closing the channel at a first position by deformation of the channel, compressing the channel in a compression region adjacent the first position to drive fluid in the channel along the channel away from the first position past a second position in the channel, closing the channel at the second position by deformation of the channel to prevent fluid flow past the second position into the compression region while the compression region is decompressed; and opening the channel at the first position to allow fluid to flow into the compression region while the compression region is decompressed. 
     A filtering action may be obtained, for particular use when the fluid contains particles, by controllably deforming material defining the channel to restrict the channel sufficiently to selectively prevent and allow the particles to move with the fluid in the channel. 
     According to a further aspect of the invention, there is provided a microvalve, comprising a first plate and a second plate placed together to form a channel between them, valve seat formed in the first plate on one side of the channel, the valve seat having a valve seat profile, and the second plate being deformable opposite to the valve seat into a deformation profile that matches the valve seat profile. Preferably, the valve is actuated by an actuator positionable against one of the first plate and the second plate for deforming the one of the first plate and the second plate. The valve seat is preferably formed by a ridge extending transversely across the channel. Preferably, the ridge drops in height to be flush with the channel at the center of the channel. 
     According to a further aspect of the invention, the channel may be formed partly in a top plate and partly in a bottom plate. Preferably, the bottom plate contains a weir. Controllably deforming material defining the channel may comprise deforming material of the top plate across from the weir. 
     According to a further aspect of the invention, there is provided a microvalve, comprising a first plate and a second plate placed together to form a channel between them, a valve seat formed in the first plate on one side of the channel, the valve seat having a valve seat profile, the valve seat profile being U-shaped, deformable material in the second plate opposite to the valve seat, the deformable material being deformable into a deformation profile that matches the valve seat profile; and an actuator positionable against one of the first plate and the second plate for deforming the one of the first plate and the second plate. The microvalve may include a bypass channel is formed in one or both of the first plate and the second plate on at least one side, and preferably both sides, of the valve seat. 
     According to a further aspect of the invention, there is provided a microfluidic trapping device, comprising a body having a channel extending through the body, the channel having a first end and a second end, a first gate at the first end of the channel, a first gate actuator operably connected to the first gate, a second gate at the second end of the channel and a second gate actuator operably connected to the second gate. Preferably, the body comprises a first plate and a second plate, with the channel being formed between the first plate and the second plate, and the first gate is actuated by moving the first plate towards and away from the second plate. The second gate may be actuated by moving the first plate towards and away from the second plate. 
     According to a further aspect of the invention, there is provided a method of controlling fluid flow in a channel in a microfluidic flow control device, the method comprising the steps of merging a first fluid stream and a second fluid stream in the channel; and forcing fluid in the first fluid stream into the second fluid stream by repeatedly blocking and unbiocking the first fluid stream. There may also be provided the step of merging a third fluid stream with the first fluid stream and the second fluid stream, the first fluid stream being located between the third fluid stream and the second fluid stream; and forcing fluid in the first fluid stream into the third fluid stream by repeatedly blocking and unblocking the first fluid stream. Preferably, blocking and unblocking the first fluid stream comprises the step of deforming material defining the channel to close a portion of the channel. Preferably, the first fluid stream has a width and the portion of the channel extends widthwise beyond the width of the first fluid stream. 
     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 shows a basic chip layout, top plan view, with inlet and outlet ports, and a weir which prevents flow through the channel when external pressure is applied; 
     FIG. 2 is a section along the channel along the line  2 — 2  in FIG. 1; 
     FIG. 3 is a section across the channel along the line  3 — 3  in FIG. 1, with valve open; 
     FIG. 4 is a section across the channel along the line  3 — 3  in FIG. 1, with valve closed; 
     FIG. 5 shows a weir top view, with mask outline (solid), etch undercut (dashed line) and glass; 
     FIG. 6 is a section along the line A-A′ in FIG. 5; 
     FIGS. 6A and 6B are views of different manners of ramping the surface of the channel up to a weir in a valve structure according to the invention; 
     FIGS. 7,  8  and  9  are cross-sections of the weir along the lines B-B′, C-C′ and D-D′ respectively in FIG. 6; 
     FIG. 10 is a top view of a basic chip layout in a pump configuration, showing the inlet and outlet valves, with a compression zone in between. 
     FIG. 11 is a cross-sectional view of the micro-machined pump of FIG. 10; 
     FIGS. 12A,  12 B,  12 C and  12 D show the four steps required for operation of the pump of FIG. 10; 
     FIG. 13 shows a filtering device in section, with open weir and unhindered flow; 
     FIG. 14 shows the device of FIG. 13 with closed weir, particles are filtered from the flowing liquid; 
     FIG. 15 shows the device of FIG. 13 showing a flow of concentrated particles after opening the weir; 
     FIG. 16 shows a basic chip layout of a trapping device, with inlet and outlet ports, and a weir at each end of the zone where beads are trapped; 
     FIG. 17 shows a side view detail of the weir in the device of FIG. 16, beads trapped between weirs; 
     FIG. 18 shows a side view detail of the weir in the device of FIG. 16, with the first weir opened to allow beads to load into the chamber; 
     FIG. 19 shows a side view detail of the weir in the device of FIG. 16, both weirs open; 
     FIG. 20 shows actuation forces for the device of FIG. 16; 
     FIG. 21 is a top plan view of a mixer device with flow pattern for 2 fluids (labeled A and B) through a mixing weir; 
     FIGS. 22A and 22B are details of the device of FIG. 21, showing valve cross section, open and closed respectively; 
     FIG. 23 is a top view of the device of FIG. 21, steady state flow with valve closed; 
     FIG. 24 is a top view of the device of FIG. 21, steady state flow with valve open; 
     FIG. 25 is a top view of the device of FIG. 21, valve opening and closing to extend the fluid interface and enhance fluid mixing; and 
     FIGS. 26A and 26B are respectively perspective views of a top and bottom plate of a further embodiment of a valve structure according to the invention; and 
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
     In this patent document, “comprising” means “including”. In addition, a reference to an element by the indefinite article “a” does not exclude the possibility that more than one of the element is present. 
     Referring to FIGS. 1-4, a channel  10 , formed between two plates  12 ,  14 , for example by etching a groove in one or both plates  12 ,  14 , in conventional manner, extends between an inlet  16  and an outlet  18  of a microchip  22 . The inlet  16  and outlet  18  may be made by conventional methods such as etching and drilling. A valve seat is formed by a weir  20  protruding from plate  12  on one side of the channel. The plates  12 ,  14  are bonded together in conventional manner, and the groove allows a small gap between the plates  12 ,  14  to form the channel  10  and allow fluids to flow between the inlet  16  and outlet  18 . The microchip  22  may have multiple channels, ports and chambers, with the valve structures describe here controlling fluid flow between them. 
     As shown particularly in FIG. 2, the material of the top plate  14  at the location of the valve structure and extending on either side of the weir  20 , as for example to the ports  16 ,  18  is made sufficiently thin to be deformable into contact with the weir  20 . The weir  20 , together with the material of the opposing plate adjacent the weir  20  and extending a distance on either side of the weir to allow for bending without fracture of the plate  14 , is described herein as a valve structure. As shown in FIGS. 3 and 4, the profile of the weir  20  matches the deformation profile of the top plate  14  at the location of the valve structure when the plate  14  is acted on by a force applicator  21 . Deformation the cover plate  14  can open or close the channel and thus have a valve action. The force required to activate the valve structure is a function of the thickness of the top plate  14  and the unsupported width of the channel at the weir  20 . The direction of movement of the plate  14  is perpendicular to the fluid flow direction in the channel  10 . 
     Referring to FIGS. 5-9, leakage through the valve structure is minimized by matching the profile of the weir  20  to the deformed shape of the top plate  14  when the closing force is applied. If the material of the bottom plate  12  is removed to form the weir  20  using isotropic etching techniques, the matching deformation profile can be achieved by giving an etch mask  24  a gradual taper  28  which, after etching, will produce a weir  20  having the form of a knife-edged ridge. As shown in FIGS. 6-9, the height of the weir  20  diminishes towards the center of the channel  10  until it is flush with the channel defining material of the bottom plate  12  (FIG.  9 ). The shape of the taper on the mask  24  can be chosen to give the desired height profile of the weir  20 . The sharpness of the knife-edge of the weir  20  will be a function of the etch isotropy. As shown in FIG. 6A a weir  20 A has a steep slope between channel bottom and the face of the weir. In FIG. 6B, an alternative design is shown in which a weir  20 B has a gradual transition between the bottom of the channel  10  and the top of the weir  20 B. 
     Various force applicators  21  and equivalent methods may be used to apply the force to open and close the valve and all other microfluid structures described in this patent document. For example, pressurization of the channel  10  could push the plates  12 ,  14  apart and open the valve. Any other sort of force external to the plate surfaces applied by a representative force applicator  21  could also be used. Some examples are pneumatic, electromagnetic, piezo-electric, or mechanical. Another example is thermal control of the channel width, either heating the surface of one or both of the plates, or by heating one plate and not the other. The term “force applicator” covers any of these techniques and their equivalents. 
     The plates may be made of any suitable material, such as glass, silicon dioxide, or plastic, depending on the desired application. The applications for these devices typically have channel heights from 1 μm to 100 μm. As shown in FIG. 1, to accommodate bending of the top plate  14 , the channel has a breadth that far exceeds its height, in ratios greater than 10 to 1. In an example of a glass plate used as the top plate  14 , the ridge and channel were 7 mm wide at the valve structure, the glass was 0.5 mm thick with 5 μm movement transverse to the channel under a differential pressure of 100 psi. 
     The valve structure may be used to control fluid flow. When fluid is introduced into the channel, the fluid flow in the channel may be controlled by controllably deforming material defining the channel. A complete block may be achieved when the material of the top plate  14  is urged into direct contact with the weir  20  across the channel width. Partial blocking, or restricted flow, may be achieved with a lower degree of deformation. 
     Deformation of the material defining the channel  10  may also be used to pump fluid. Referring to FIGS. 10 and 11, a basic pump  31  is made from glass plates  32 ,  34  bonded together to form a channel  30  out of an etched depression on the surface of plate  32 . The top plate  34  is made sufficiently thin to be deformable. External force on the plate  34  can cause deformation of the upper channel surfaces. Optionally, the bottom plate  32  may also or may only be made deformable. A structure for pumping fluid uses two independently operating valves  36 ,  38 , separated by a volume or chamber  40  from which fluid can be forced by compression of the plates  32 ,  34 . Pumping can be achieved by having the inlet closed and outlet open while compressing the central region, and having the inlet open and outlet closed during de-compression. 
     Referring to FIG. 12A, the valve  36  is first closed preferably by deformation of the plate  34  at the valve location. Valve  38  is open. In FIG. 12B, the plate  34  is deformed over the compression chamber  40  to close the chamber  40  and force fluid out of the chamber  40  past the open valve  38 . In FIG. 12C, valve  38  is closed and valve  36  is opened. In FIG. 12D, the compression zone is decompressed, enlarging chamber  40  and allowing fluid to flow into the chamber  40 . Repetition of these steps causes fluid to be pumped through the channel  30 . In another embodiment, the location of the deformation region may be moved along the channel  30  to pump fluid through the channel  30 . 
     The valve structure of FIG. 1 may also be used as a variable orifice inside a channel, for filtering particles from a solution flowing through the channel. When the weir  20  has a surface profile matching that of the deformed top plate  14 , a very small gap can be maintained uniformly across the entire channel width. The gap size may be chosen to filter sizes ranging from the molecular scale up to 30-50 μm. Concentration of the particles occurs after flowing a large amount of fluid past the filter, and the concentrated particles could then be released as desired into the fluidic channel. Some materials of particular interest would be DNA, proteins, and biological cells. 
     As shown in FIG. 13, the valve is open allowing unhindered flow of fluid carrying particles  42  through the channel  10 . In FIG. 14, the channel has been selectively restricted by partially closing the valve to trap the particles  42  behind the weir  20 . In FIG. 15, concentrated particles  42  trapped behind the weir  20  are released to flow through the channel  10 . 
     Referring to FIG. 16, there is shown a structure  50  for control of bead loading and unloading in a micro-channel. The channel structure  50  allows movement of beads into a channel  52  having an inlet  56  and outlet  58 , trapping of the beads in a specific zone  54  defined between two weirs  60 ,  61 , and then opening of the channel  52  for flushing the beads. 
     Referring to FIG. 17, the channel  52  is made in a plate  62 , for example made from glass, by etching a groove in the surface of the plate  62  using conventional methods. The inlet  56  and outlet  58  are formed in a top plate  64  using conventional methods. Beads  66 , which may for example have chemically active surface coatings, are shown trapped in the zone  54 , with both valve structures defined by the weirs  60 ,  61  sufficiently restricted that the beads  66  cannot exit the trapping zone  54 . Performing multiple analyses in the same channel with beads with chemically active surface coatings may require flushing out of used beads and bringing in new ones. Loading of the trapping zone  54  may be accomplished as shown in FIG. 18 by opening weir  61  and closing weir  60  sufficiently to trap beads  66  carried by fluid flowing within the channel  50 . Unloading of the trapping zone  54  is accomplished by opening the weir  60  and allowing the fluid and beads  66  to flow out of the trapping zone  54 . Preferably, the gap between the weirs  60  and  61  and the undeformed surface of the plate  64  at the weirs  60 ,  61  has a height close to the bead diameter so that under a small deformation the plate  64  opens or closes the channel  50 . The force required to change the opening size is determined by the thickness of the plate  64  and the unsupported width of the channel  50  at the weirs  60 ,  61 . 
     Actuation of the valve structures defined by the weirs  60 ,  61  may be controlled by pessurization of the channel  50  to cause deformation of the plate  64  at both weirs  60 ,  61 . The inlet weir  61  may be made to open at a low pressure by making the channel  50  wider at the inlet weir  61  as shown in FIG.  18 . Higher pressure opens both the inlet weir  61  and outlet weir  60  as shown in FIG.  19 . Any mechanical or pneumatic force can be applied directly to the plate  64  above or below each of the weirs  60 ,  61  as illustrated at  67  in FIG.  20 . 
     The valve structure of the invention may also be used to enhance the mixing of two fluids in a micro-fabricated channel. As shown in FIGS. 21,  22 A and  22 B, a micro-chip  68  has grooves etched in a bottom plate  82  that is covered by a top plate  84  to form three channels  72 ,  74 ,  76  through which three streams flow and merge to form a mixing stream in a single channel  80 . A valve structure  86  is formed in the single channel  80  as shown in FIGS. 22A and 22B. At the valve structure  86 , the plate  82  is etched so that a weir  90  has a central section that matches the deformation profile of the plate  84  opposite the weir  90 , and side channels  92 ,  94  that allow flow of fluid even when the central section of the weir  90  is closed. Mixing of fluid is enhanced by merging the streams in the channels  72 ,  74  and  76 , then forcing fluid in the central fluid stream into streams on either side of the central fluid stream by repeatedly blocking and unblocking the central fluid stream using the valve structure  86 . 
     When two different flowing fluids, one for example in channels  72 ,  76  and the other in channel  74 , are merged into a single channel  80 , the characteristics of laminar flow mean that the only mixing occurs at the interface between the two fluids. Increasing the interface length speeds the mixing of the two fluids. In the design shown in FIGS. 21,  22 A and  22 B, the interface between the two fluids is extended by opening and closing the valve structure  86 . The valve structure  86  forces the central fluid to flow to the channel edge when the valve is closed, but to pass through the central area when open. 
     Opening and closing the valve structure  86  causes pulses of fluid to flow as illustrated in FIGS. 23,  24  and  25 . In FIG. 23, the valve structure  86  is closed and the fluids flowing in the channel  80  are spread out across the central portion of the weir  90  and diverted into the channels  92 ,  94 . When the valve structure  86  is opened, the fluid is free to flow across the entire channel as shown in FIG.  24 . By opening and closing the valve structure  86 , pulses of backed up fluid flow down the channel  80  as illustrated in FIG. 25, thus increasing the contact area between the fluids and enhancing mixing. 
     Another way to make a weir for a valve structure is shown in FIGS. 26A and 26B. A channel plate  102  with a full channel-height weir  104  and channel  105  is bonded to a cover plate  106  (shown upside down) with a groove  108  having shallow, linearly ramped, sidewalls  110 ,  111 . When bonded together with the groove  108  and channel  105  together form a channel through the micro-structure, with a small gap above the weir  104  that may be opened or closed with external force. Unlike the weir  20  with the curved contact surface, the shape of the opening would be three straight-line segments. 
     The main advantage of the design of FIGS. 26A and 26B is that the valve seat contact area is defined by the width of the un-etched weir  104  in the channel plate  102 . With the design of FIGS. 1-9, the contact is only along the line defining the top of the weir  20 , which may be non-ideal due to either manufacturing flaws or damage during operation. The larger contact area of the embodiment of FIGS. 26A and 26B provides a more reliable valve-seat surface quality. 
     Immaterial modifications may be made to the invention described here without departing from the essence of the invention.