Abstract:
A method and apparatus for controlling multi-fluid flow in a micro channel is disclosed. The apparatus has a first inlet for a first fluid; a second inlet for a second fluid; a first outlet; and a second outlet. The micro channel is operatively and fluidically connected to the first inlet, the second inlet, the first outlet and the second outlet. The micro channel is for receiving the first fluid and the second fluid under pressure-driven flow; there being an interface between the first fluid and the second fluid when in the micro channel. The apparatus also includes a pair of electrodes for having a first electric field applied thereto for a controlling the fluid flow velocity of the first fluid along the micro channel.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS  
       [0001]     This application claims priority from U.S. Provisional Patent Application No. 60/618,603 filed Oct. 15, 2004, which is hereby incorporated herein in its entirety for all purposes. 
     
    
     FIELD OF THE INVENTION  
       [0002]     This invention relates to a method and apparatus for controlling multi-fluid flow in a micro channel and refers particularly, though not exclusively, to such a method and apparatus that operates on electrokinetic and hydrodynamic principles. In a preferred aspect the present invention relates to a method and apparatus for controlling a position of an interface of fluids in the micro channel for switching, mixing and/or cytometering. In a more preferred aspect the present invention is also for controlling the form and position of the interface.  
       BACKGROUND OF THE INVENTION  
       [0003]     Most solid surfaces acquire an electrostatic charge when in contact with polar liquids. As a result, a difference in potential is developed across the interface between the negative and positive phases. The charged interface attracts ions of opposition charge (counter-ions) and repels ions of like charge (co-ions) in the liquid. The arrangement of charges that occurs near the interface leads to the development of an electric double layer. When a tangential electric field is applied along the capillary along which the liquid flows, liquids are pumped due to electroosmostic flow. The two widely used methods for the transportation of a single fluid in microfluidics are electroosmostic flow, and pressure-driven flow.  
         [0004]     In microfluidics, the Reynolds number is small and fluid flow is laminar. Laminar fluid diffusion interfaces are created when two or more streams flow in parallel within a single micro-structure. Since the flows are laminar, there is no mixing between them. No mixing may be very useful because only diffusion occurs between the different streams of flow. Therefore, it is able to be used for extraction or separation in biological analysis. Diffusion-based microfluidic devices, such as the T-sensor® and the H-filter® have been developed for commercial use by Micronics, Inc. of Redmond, Wash., USA.  
         [0005]     The variable viscosity of biological fluids can be problematic when the two streams of flows have different viscosities. The fluid with higher viscosity will occupy a wider portion of the channel while having a smaller velocity; whereas the fluid with lower viscosity flows at a larger velocity within a narrow portion of the channel. The two fluids will still have the same volumetric flow rate. The unmatched viscosity affects diffusion due to differences in residence time. The average residence time of the more viscous fluid will increase, while that of the less viscous fluid will decrease. To overcome this problem, it has been proposed to measure the viscosity of the fluid, and to add a viscosity-enhancing solute to the less viscous fluid. Another proposal is to control the ratio of the volumetric flow rate of the two fluids. By increasing the flow rate of the less viscous fluid, it is possible to maintain the interface of the two streams at the center of the channel. However, the unmatched average residence time remains unsolved because the less viscous fluid flows even faster, and has even shorter average residence time within the channel.  
       SUMMARY OF THE INVENTION  
       [0006]     In accordance with a first preferred aspect there is provided apparatus for controlling fluid flow in a micro channel, the apparatus comprising:  
         [0007]     (a) a first inlet for a first fluid;  
         [0008]     (b) a second inlet for a second fluid;  
         [0009]     (c) a first outlet;  
         [0010]     (d) a second outlet;  
         [0011]     (e) the micro channel being operatively and fluidically connected to the first inlet, the second inlet, the first outlet and the second outlet; the micro channel being for receiving the first fluid and the second fluid under pressure-driven flow; there being a first interface between the first fluid and the second fluid when in the micro channel; and  
         [0012]     (f) a pair of electrodes for having a first electric field applied thereto for a controlling the first fluid flow velocity along the micro channel.  
         [0013]     According to a second aspect there is provided a method for controlling fluid flow in a micro channel, the method comprising:  
         [0014]     (a) supplying a first fluid through a first inlet under pressure-driven flow;  
         [0015]     (b) supplying a second fluid through a second inlet under pressure-driven flow;  
         [0016]     (c) the first fluid being able to flow along a micro channel to a first outlet;  
         [0017]     (d) the second fluid being able to flow along the micro channel to a second outlet;  
         [0018]     (e) the micro channel being operatively and fluidically connected to the first inlet, the second inlet, the first outlet and the second outlet; there being a first interface between the first fluid and the second fluid when in the micro channel; and  
         [0019]     (f) applying an electric field to a pair of electrodes for controlling the first fluid flow velocity along the micro channel.  
         [0020]     The micro channel has a width, the first electric field may also being for controlling the location of the first interface across the width, and residence time of the first and second fluids in the micro channel.  
         [0021]     The first pair of electrodes may comprise a first electrode and a second electrode, the first electrode being in the first inlet and the second electrode being in the first outlet.  
         [0022]     There may also be a third inlet also for a third fluid, the second inlet being between the first inlet and the third inlet, there being a second interface between the second fluid and the third fluid; and a third outlet; the third inlet and the third outlet being operatively and fluidically connected to the micro channel.  
         [0023]     A second pair of electrodes for having a second electric field applied thereto may be provided for controlling the third fluid flow velocity along the micro channel from the third inlet. The second electric field may also be for controlling the location of the second interface across the width, and residence time of the first, second and third fluids in the micro channel. The second pair of electrodes may comprise a first electrode and a second electrode, the first electrode being in the third inlet and the second electrode being in the third outlet.  
         [0024]     There may also be a fourth outlet operatively and fluidically connected to the micro channel. The second electrode of the second pair of electrodes may be in the fourth outlet.  
         [0025]     There may also be a fifth outlet operatively and fluidically connected to the micro channel. The second electrode of the second pair of electrodes may be in the fifth outlet.  
         [0026]     The first electric field and the second electric field may be able to be controlled for directing the second fluid to at least one of: the first outlet, the second outlet, the third outlet, the fourth outlet and the fifth outlet.  
         [0027]     The method and apparatus may be used for at least one selected from the group consisting of: an electrokinetic flow switch, a micromixer, a micro-flow cytometer, an interface position controller, and an in-channel fluidic lens.  
         [0028]     At least one fourth inlet may be provided that is operatively and fluidically connected to the micro channel and being for a fourth fluid. There may be one fourth inlet between the second and third inlets. Alternatively, there may be a pair of fourth inlets; a first of the pair of fourth inlets may be located between the first and second inlets, and a second of the pair of fourth inlets may be located between the second inlet and the third inlet. The fourth fluid may be a protection fluid for separating the first fluid from the second and third fluids. Alternatively, the fourth fluid may be two sample fluids, the second fluid being a protection fluid for separating the two sample fluids.  
         [0029]     The first and second electric fields may be controlled for narrowing a stream width of the second fluid for flow focusing of the second fluid. The method and apparatus may be for mixing at the micro scale, the first and second electric fields may be used for narrowing the stream width of the second and fourth fluids for controlling diffusion path and diffusion time.  
         [0030]     A controller may be provided for controlling at least one of the first electric field and the second electric field for controlling the location of at least one of the location of the first interface and the location of the second interface.  
         [0031]     There may be provided a pair of additional electrodes axially of the micro channel, and a pair of further electrodes at the top and bottom of the micro channel, the further electrodes being for controlling a curved shape of the first interface, and the additional electrodes being for controlling the focal length and position of the curved shape.  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0032]     In order that the present invention may be fully understood and readily put into practical effect, there shall now be described by way of non-limitative example only preferred embodiments of the present invention, the description being with reference to the accompanying illustrative drawings.  
         [0033]     In the drawings:  
         [0034]      FIG. 1  is a schematic top view of a preferred microchannel arrangement;  
         [0035]      FIG. 2  is an enlarged vertical cross-sectional view along the lines and in the direction of arrows  2 - 2  on  FIG. 1 ;  
         [0036]      FIG. 3  is two graphs of the relationship between NaCl holdup and (a) different applied voltage for the same volumetric flow rates, and (b) volumetric flow rate under the same applied voltage;  
         [0037]      FIG. 4  is a schematic illustration of a second preferred from of flow switch at a first operational state;  
         [0038]      FIG. 5  is a schematic illustration of the second preferred form of flow switch at a second operational state;  
         [0039]      FIG. 6  is a schematic illustration of the second preferred form of flow switch at a third operational state;  
         [0040]      FIG. 7  is a schematic illustration of the second preferred form of flow switch at a fourth operational state;  
         [0041]      FIG. 8  is a schematic illustration of the second preferred form of flow switch at a fifth operational state;  
         [0042]      FIG. 9  is a schematic illustration of the third preferred form of flow switch at a first operational state;  
         [0043]      FIG. 10  is a schematic illustration of the third preferred form of flow switch at a second operational state;  
         [0044]      FIG. 11  is a schematic illustration of a fourth preferred form of flow switch at a first operational state;  
         [0045]      FIG. 12  is a schematic illustration of a fourth preferred form of flow switch at a second operational state;  
         [0046]      FIG. 13  is a schematic illustration of a fourth preferred form of flow switch at a third operational state;  
         [0047]      FIG. 14  is a schematic illustration of a micro mixer;  
         [0048]      FIG. 15  is a schematic illustration of a microflow cytometer;  
         [0049]      FIG. 16  is a schematic illustration of an interface position controller; and  
         [0050]      FIG. 17  is a schematic illustration of an in-channel fluidic lens.  
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0051]     The first embodiment is shown in  FIGS. 1 and 2  and includes an H-shaped micro fluidics structure  10 , syringes  31 ,  32  driven by pumps (not shown), and electrodes  14  for the application of electric field. Preferably the electrodes  14  are of a metal such as, for example platinum. Each syringe  31 ,  32  supplies a single fluid of the two fluids  16 ,  17  with the two fluids  16 ,  17  flowing side-by-side in a straight microchannel  20  from left to right. The flow is under the action of pressure from the syringes  31 ,  32 . A and C are the inlets for the two fluids  16 ,  17  and B and D are the outlets for the collection of the products, or the wastes. Between A and B, electrodes  14  are inserted for the application of the electric field and are supplied by power supply  22 . The electric filed from A to B is positive, and from B to A is negative. The straight portion  20  of the H-shaped structure  10  may have any suitable size and configuration such as, for example, a cross sectional area of 1000 μm×100 μm, and a length of 5 mm. This gives a width to depth rate of 10:1.  
         [0052]     Solution  16  may be, for example, an aqueous NaCl solution (concentration 0.7×10 −3 M) and solution  17  may be, for example, an aqueous glycerol (volume concentration 14%). The solutions  16 ,  17  are introduced through inlets A and C respectively. The schematic cross-sectional view of the two fluids flow inside the straight channel is shown in  FIG. 2 . The widths occupied by the NaCl  16  and aqueous glycerol  17  are denoted as w 2  and w 1  respectively. The holdup of the NaCl  16 , e 2 , is the ratio of the area occupied by the NaCl  16  to the whole area of the cross-section of the channel  20 . As the height is common, this becomes:  
         e   2     =         w   2         w   1     +     w   2         .         
 
         [0053]     Similarly, the holdup of the aqueous glycerol  17  is e 1 =1−e 2 .  
         [0054]     When the two fluids  16 ,  17  are in contact with the wall of the channel  20 , the negatively charged surface  20  will influence the distribution of free ions in the NaCl solution  16  to form an electrical double layer near the channel wall  20 . But the aqueous glycerol  17  will only minimally form an electrical double layer as there are few free ions. Thus the electroosmotic flow will only affect the NaCl solution  16 . When a positive voltage is applied between A and B (A as the positive electrode, B as the negative electrode), the electroosmotic force will force the NaCl solution  16  to flow in the same direction as the pressure-driven flow. If the negative electric field is applied (A is negative, B is positive), an opposite electroosmotic flow will result which is against the pressure-driven flow.  
         [0055]     A fluorescent dye such as, for example, fluorescein disodium salt C 20 H 10 Na 2 O 5 , (also called Acid Yellow 73) may be added to the NaCl solution  16  for image collection. When the fluorescein is illuminated by a mercury lamp, a coupled charge device (CCD) camera or other similar device may be used for image capturing to enable measurements to be taken. The same volumetric flow rates of the two inlet flows A and C may be ensured through the use of identical syringes driven by a single syringe pump.  
         [0056]     The parameters considered in the graphs of  FIG. 3  are inlet volumetric flow rates, and electric voltage applied between A and B. The holdup of the NaCl solution  16  was obtained by normalizing its width w 2  to the whole channel width (w 2+ w 1 ). As shown in  FIG. 3 ( a ), when the electric field changes in magnitude and direction, the holdup of NaCl solution  16  changes accordingly. When no voltage is applied across A and B, the flow is simply a pressure-driven two-phase flow. As the aqueous glycerol  17  is about 1.5 times more viscous than the NaCl solution  16 , the less viscous NaCl solution  16  occupies a smaller portion of the channel  20  width. The NaCl solution has a holdup of 0.35 without an externally applied voltage, as shown in  FIG. 3 ( a ). When a negative electric field is applied across A and B, the holdup of the NaCl solution  16  increases as the electroosmotic flow is against the pressure-driven flow by the use of a negative electric field. One explanation for this is that the NaCl solution  16  is becoming more “viscous” due to the electroosmotic effect. As such it occupies a larger proportion of the width of channel  20 −w 2  increases and w 1  decreases. The holdup of the NaCl solution  16  increases with an increase in the negative electric field.  
         [0057]     Due to the same pressure drop across E and F, in order to achieve the same volumetric flow rates, the more viscous fluid has to spread to a larger width, i.e. a higher liquid holdup. When a positive electric field is applied, the NaCl solution  16  has a lower “viscosity”, since the electroosmotic flow is the same direction as the pressure-driven flow so that the electroosmotic effect aids the flow of the NaCl solution  16 .  
         [0058]      FIG. 3 ( a ) also shows that as the inlet volumetric flow rates of the two fluids increase, the electroosmotic flow effect on the pressure-driven flow weaken. At the flow rate of 1.2 ml/h, the holdup of NaCl, e 2 , remains constant even though the voltage varies from −0.8 kV to 0.6 kV. For typical electroosmotic flows, in which hundreds of volts per centimeter of electric field are applied, the resultant flow rate is of the order 0.1 to a few mm/s. But for pressure-driven flow in microchannels, the flow rate can be controlled over a wider range. When the pressure-driver flow rate is set at 0.4 ml/h, the average velocity for the NaCl solution  16  through the channel  20  is 3.17 mm/s with a no external applied electric field. This is comparable to that from electroosmotic flow.  FIG. 3 ( a ) shows that by adjusting the electric field the position of interface  24  between the two fluids can be controlled. As such, variation of the NaCl solution  16  holdup e 2 , from 0.25 to 0.50 is able to be controlled.  
         [0059]     The relationship between the NaCl holdup, e 2  at different flow rates under the fixed electric field is shown in  FIG. 3 ( b ). Holdup e 2  remains the same (0.35) for different volumetric flow rates in the absence of an externally applied electric field. This is because the volumetric flow rates ratio between the two fluids is kept unchanged at 1:1. As the flow rate increases, holdup e 2  converges to a constant value, 0.35. This is the value without an externally applied electric field. The reason for this is that the larger, pressure-driven flow speed makes the electroosmotic effect virtually negligible.  
         [0060]     Therefore, by adjusting the magnitude and the direction of the applied electric field the position of interface  24  between the two fluids  16 ,  17  can be controlled, as can be the average residence time for the fluids. The H-shaped microfluidics structure  10  can therefore be used as a diffusion-based analysis device as it provides the same average residence time for the two fluids.  
         [0061]     A second preferred from of microfluidic flow switch is shown in a  FIG. 4 . The microfluidics device  400  has three inlets  401 ,  402  and  403  with respective syringes  431 ,  432  and  433 ; and five outlets,  411  to  415 . Inlets  401  and  403  are spaced apart and are for the introduction of control fluids  416  and  418  such as, for example, aqueous NaCl. The sample fluid  417 , which can be a biological fluid of interest, is introduced from inlet  402  between the other two inlets  401 ,  403 . A first pair of electrodes  421  is located between inlet  401  and outlet  411 , and a second pair of electrodes  422 , are located between inlet  403  and outlet  415  for the application of electric fields. The first electrodes  421  are supplied by a first power supply  423 ; and the second electrodes  422  are supplied by a second power supply  424 .  
         [0062]     Without changing the flow rate, the spread widths of the three laminar streams of fluids  416 ,  417  and  418  can be adjusted by adjusting the direction and strength of the electric-field, based on the working principle described above. The sample fluid  417  can therefore be guided into different outlets by controlling the direction and strength of the voltage applied to electrodes  421  and  422 .  
         [0063]     With  FIG. 4 , the electrodes  421  and  422  have electric fields that are applied to them equally so the fluids  416  and  418  will occupy an equal portion of the width of channel  420 . In that way the sample fluid  417  is guided down the centre of the channel  420  and thus exits through the centrally-aligned outlet  413 .  
         [0064]     As shown in  FIG. 5 , if the electrodes  421  have a positive electric field applied to them and electrodes  422  have a negative field applied to them, the fluid  416  will occupy a reduced portion of the width of channel  420 , and fluid  418  will occupy an increased portion of the width of channel  420 , thereby guiding the sample fluid to outlet  412 . A similar effect may be achieved by having a strong, positive electric field applied to electrodes  421  and no electric field applied to terminals  422 . The effect is created by having the field applied to electrodes more positive than that applied to electrodes  422 .  
         [0065]      FIG. 6  is the reverse of  FIG. 5 , so that sample fluid  417  flows to outlet  414 , and  FIG. 7  is the same as  FIG. 5  except that the difference in the applied electric fields is greater so that sample fluid flows to outlet  411 .  
         [0066]     To get a sample fluid of a high purity, the electric fields can be adjusted in such a way that the sample fluid  417  width is slightly larger then the outlet width.  
         [0067]     Besides flow switching, the device can be used for the purposes of flow focusing. It is possible to squeeze the sample fluid  417  into a very thin flow to allow only a single cell or several cells to pass as is shown in  FIG. 8 . This is useful for cell detection. If the electric field is remotely controlled such as, for examples, by using a computer, it may be possible to achieve a programmable sample injection device or programmable dispensing device. The device can also be used as a valve, since the desired outlet can be selected by controlling the electric field.  
         [0068]     To reduce diffusion or reaction between the control fluid  416 ,  418  and the sample fluid  417 , another protection fluid  419  can be introduced to separate the two, as shown in  FIG. 9 . Preferably, the protection fluid  419  is relatively inert with both the control fluid  416 ,  418  and the sample fluid  417 . The protection fluid  419  can be introduced by extra syringes  434 ,  435  and respective inlets  404 ,  405 .  
         [0069]     Also, it is possible to switch more than one sample fluid  417  as shown in  FIG. 10 . Between the two sample fluids  417 ( a ) and  417 ( b ), a buffer fluid or a protection fluid  419  is introduced for separation of the two sample fluids  417 ( a ) and  417 ( b ).  
         [0070]     Other design based on this working principle is possible. FIGS.  11  to  13  show a Y-shaped flow switch under different work modes, e.g. switching sample fluid to one or more outlets. In  FIG. 11 , the Y-shaped microfluidic flow switch has two inlets  401 ,  402  and four outlets  411  to  414 . The control fluid  416  and the sample fluid  417  are introduced from inlets  401  and  402 . The electric field is applied through two electrodes  421  inserted between inlet  401  and outlet  411 . The sample fluid  417  can be directed to the outlets  412 ,  413  and  414 . The flow switch directs the sample fluid to outlet  412  as shown. In  FIG. 12 , the sample fluid is being passed to outlets  412 ,  413  and  FIG. 13  it is passed to all outlets  411  to  414 . This may be simultaneously, or sequentially.  
         [0071]      FIG. 14  shows the use of the device as a micromixer. The diffusion distance, according to the square dependency, affects the diffusion time between the laminar flows of two sample fluids  417 ( a ) and  417 ( b ). As diffusion is the main mechanism through which mixing occurs between the two laminar streams, by adjusting the electric field across the control fluids  416  and  418 , it is possible for the two sample fluids to be squeezed into a narrow stream to thus reduce the diffusion path and diffusion time and increase the mixing efficiency.  
         [0072]      FIG. 15  shows its use as a micro flow cytometer. A conventional micro-flow cytometer uses hydrodynamic focusing. Instead of focusing the sample flow hydrodynamically through the sheath flow rate, by combining the pressure driven and the electrokinetic effects, a micro-flow cytometer capable of focusing the cells in the sample fluid  417  is created. The fluid flow along channel  420  will be smaller in width than the inlet  403 , and is preferably the same as, or only slightly greater than outlet  413 . In this way the focusing takes place along channel  420 .  
         [0073]     Although the electrodes  14 ,  421  and  422  are described and illustrated as being in the inlets and outlets, they may be located in channel  20 ,  420  adjacent the inlets and outlets; or at the junction of the inlets and the channel, and/or the junction of the outlets and the channel.  
         [0074]      FIG. 16  illustrates a controller for determining and controlling the positions of the interfaces. When the fluids in the channel  1620  are excited with a laser  1640 , fluorescent light signals are emitted. A band-gap filter  1642  is placed on the other side of the channel  1620  so that only light of the emitted wavelength is passed to a CCD array  1644 , or other photosensor. The fluorescent signal will detect the presence of the fluid interfaces and thus enable the position of the fluid interfaces to be determined as the output signal  1646  is proportional to the bright area of the channel  1620 . The interface position is compared to the desired position  1648  in a controller  1650 , and, if they are different, the controller  1650  outputs a control signal  1652  that is received by an amplifier  1622 . The power supply to the terminals  1614  is adjusted to adjust the applied electric field to channel  1620  thereby controlling the interface position.  
         [0075]      FIG. 17  illustrates an in-channel fluidic lens. Here two additional electrodes  1760  and  1762  are used for axial control; and two further electrodes  1764  and  1766  are placed at the top and bottom of the channel  1720  at the detection area of the channel  1720 . The electrodes may be made of a transparent material such as, for example, Indium Tin Oxide. The two further electrodes  1764  and  1766  are controlled by an applied potential that, in turn, controls the contact angle  1768 . Therefore, the interface  1770  becomes curved, as shown. The curved interface  1770  acts as a cylindrical lens, and serves to focus the incoming excitation laser  1772  to a sheet with high intensity. This allows for a large fluorescence detection area within channel  1720 , and for the emitted signal  1776  to have a higher intensity. The focal length and position  1774  can be controlled by the potential applied to the additional terminals  1760 ,  1762 . Therefore, by selective excitation of the four terminals,  1760 ,  1762 ,  1764  and  1766  improved performance may result.  
         [0076]     Whilst there has been described in the foregoing description preferred embodiments of the present invention, it will be understood by those skilled in the technology concerned that many variations or modifications in details of design or construction may be made without departing from the present invention.