Abstract:
A device for mixing at least one first fluid and one second fluid in a micro-flow system, comprising at least two flow restrictors, a first transfer conduit in fluid communication the first og said fluids and a recipient, at least one second transfer conduit in fluid communication with the second of said fluids, the second transfer conduit having at least two fluid outlets in fluid communication with said first transfer conduit, where each of said outlets of said second transfer conduit is downstream and in fluid communication with the outlet of one of said flow restrictors, and wherein the flow restrictors are bubble-tolerant, being formed to prevent fragmentation of bubbles entering the flow restrictor, into a bubble train consuming the pressure difference between the source and the recipient. Pumping means may be attached to the flow system, possibly being constant-pressure pumps of the kind, where elastomer bladders squeeze a fluid into the channels.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is entitled to the benefit of and incorporates by reference essential subject matter disclosed in International Patent Application No. PCT/DK2005/000775 filed on Dec. 8, 2005 and Danish Patent Application No. PA 2004 01901 filed Dec. 8, 2004. 
       FIELD OF THE INVENTION 
       [0002]    The present invention relates to mixing of fluids in a micro-flow system, without any risk of bubbles clogging the flow paths and thereby destroying the reliability of the mixing. The mixer comprises transfer conduits like capillary tubes or channels engraved on the surface of a plate. The fluids are merged in a laminated manner. Flow restrictors are inserted into the transfer conduits to ensure stable flow rates, but also possess the ability to segment gas bubbles passing the flow restrictors into sizes unable to clog the flow paths. 
       BACKGROUND OF THE INVENTION 
       [0003]    Systems with flows in the order of micro-litres per minute are often realized by connecting a source of pressurized liquid to transfer conduits like capillary tubes or channels engraved into the surface of a plate. In the following the transfer conduits shall freely be referred to as channels. This system of channels often comprises changing internal dimensions like a very abrupt narrowing to regulate the flow rates. 
         [0004]    It is a known practical problem of such small-scale flow systems, that gas dissolved in a liquid may form into bubbles of gas in the liquid, and such bubbles may have a serious impact on the pressure difference or pressure drop required to drive the fluid at a given flow rate, and in the worst case bubbles may lead to an effective blocking of the channels. This is due to the phenomenon of fragmentation of a (larger) bubble into a plurality of small bubbles within the channel, a phenomenon being especially pronounced at the inlet of an internal narrowing of the channel. 
         [0005]    Plugs of liquid separate the small bubbles from each other, and each small bubble requires a certain pressure difference between its ends to move along the channel. That pressure difference is largely independent of bubble length. Bubbles shorter than a critical length have a tendency to situate themselves into the channels thereby blocking the flow. This critical length depends on elements like the viscosity of the liquid, the dimensions of the channels and of the flow. 
         [0006]    Whether actual clogging will occur depends, of course, on the pressure margin, which is available for driving the flow. Clogging will occur only if the total pressure differential between the source and the recipient is consumed by the sum of pressure drops from a train of bubbles and liquid plugs. 
         [0007]    For many applications it is desirable to mix fluids in the system. This would be the case when a reagent fluid is added to give some change indicative of the concentration of some species in the fluid, like a shift in colour detectable by an optical apparatus. One application is to analyse for glucose in human tissue for diabetics, where it may be a matter of life and death to give a fast and reliable measurement. 
         [0008]    Therefore, a number of micro-mixers has been suggested based on lamination of the fluids to enhance the mixing by diffusion, like adding a first fluid to the second from the top and the bottom letting the diffusion occur across two contact areas, or the more complicated lamination described in DE 195 36 856, where the fluids are cut into a plural of small sections. 
         [0009]    Such mixing by lamination may suffer severely if a bubble places itself so as to restrict the flow of one of the fluids, thereby changing the relative flow rates of the fluids. This would lead to a reduced mixing efficiency of the fluids, possibly mixing the fluids in the wrong relative quantities. 
         [0010]    To minimize the effect of the bubbles on the flow rates in general microflow-systems one can insert flow restrictors of a substantially large resistance, making the relative effect of a bubble less pronounced. They may be chosen as small pieces of glass capillary tubes with a smaller internal diameter than the channels. The flow rates in capillary tubes have a well-defined relation to the length and diameter of the capillary, and to the pressure drop along the inside of the capillary. For a given pressure drop the flow rate may thus be fixed at a desired value by choosing a capillary of suitable length and diameter. A disadvantage of this practice is that such flow restrictors themselves tend to fragment the bubble, each fragmented bubble adding to the total flow resistance. 
       SUMMARY OF THE INVENTION 
       [0011]    This invention relates to simple mixing by laminating layers of fluids together, where a first fluid is merged to a second fluid from two sides, leading to a laminated flow structure of the fluids, a lamination process that may naturally be repeated to increase the number of laminated layers of fluids. The laminated fluids then follow a channel section of such a length, that diffusion ensures a sufficient mixing of the fluids, at least in the ideal situation. 
         [0012]    However, if the fluids contain bubbles the flow rates may be affected as described previously, in a way that makes the mixing unpredictable and unreliable. 
         [0013]    Based on this, it has now been found that, by suitably widening the inlet of the flow channel dependent on the desired flow rate, it is possible to control the timing of perturbation growth of the liquid film around gas bubbles in the channel, in such a manner that any bubble fragmentation is controlled to bubble lengths only longer than the critical length and thus posing no risk of blocking the capillary. 
         [0014]    The objective of this invention is to create a reliable micro-mixer, where the fluids are laminated and mixed by simple diffusion, without the drawbacks of bubbles affecting the flow rates and thereby the laminations and the mixing. 
         [0015]    This is achieved by a device for mixing at least one first fluid and one second fluid in a micro-flow system, comprising 
         [0016]    at least two flow restrictors 
         [0017]    a first transfer conduit in fluid communication the first og said fluids and a recipient, 
         [0018]    at least one second transfer conduit in fluid communication with the second of said fluids, the second transfer conduit having at least two fluid outlets in fluid communication with said first transfer conduit, 
         [0000]    where each of said outlets of said second transfer conduit is downstream and in fluid communication with the outlet of one of said flow restrictors, and wherein the flow restrictors are bubble-tolerant, being formed to prevent fragmentation of bubbles entering the flow restrictor, into a bubble train consuming the pressure difference between the source and the recipient. 
         [0019]    Pumping means may be attached to the flow system, possibly being constant-pressure pumps of the kind, where elastomer bladders squeeze a fluid into the channels. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0020]      FIG. 1  shows a simple mixing configuration of two fluids in a micro flow system, and with an air-bubble inside one of the channels. 
           [0021]      FIG. 2  shows a narrowing of a flow channel cutting an air-bubble into a plural of smaller bubbles. 
           [0022]      FIG. 3  shows mixing of two fluids by laminating them into respectively two and three parallel sheets. 
           [0023]      FIG. 4  shows a train of air-bubbles blocking the flow-passage of one of the channels. 
           [0024]      FIG. 5  shows a flow restrictor with a tapered fluid-inlet. 
           [0025]      FIG. 6  shows a preferred embodiment of the invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0026]      FIG. 1  illustrates the channel  100  receiving fluid from the reservoir  105 , where the reservoir may be an elastomer bladder squeezing out the fluid, it may be a flexible reservoir placed in a pressurized container, or it may be any other means for storing a fluid and creating a flow. 
         [0027]    A second channel  101  is communicating a second fluid from the reservoir  106 , reservoir  106  in the preferred embodiment of the invention being identical to the reservoir  105 , but this is not essential to the invention. 
         [0028]    The first channel  100  is split at the point  102  into the branches  100   a  and  100   b  merging with the second channel  101  at a merging point  103  from the left and the right sides, respectively. The pressure drops by a factor DP=P 102 -P 103 , where P 102  is the pressure in channel  100  just before the point of branching point  102 , and P 103  is the pressure in channel  101  just after the merging  103 . 
         [0029]    In the preferred embodiment of the invention, each of the two channels  100   a ,  100   b  has the same internal flow resistance R, and with the same drop in pressure DP, the flow rates are identical in the two channels  100   a  and  100   b , so that Q 100   a /Q 100   b =1, where Q 100   a  and Q 100   b  are the flow rates in channels  100   a  and  100   b  respectively, being Q 100   a =DP/R=Q 100   b.    
         [0030]    When a bubble  104  enters, for example the channel  100   a , the resistance is affected by the perturbation DR lowering the flow rate Q 100   a ,DR=DP/(R+DR), so that Q 100   a /Q 100   b =R/(R+DR)&lt;1, since the perturbation DR is positive. Keeping constant flow conditions may often be vital when mixing fluids in analysis-systems, since, as described, bubbles of gas may have a predominant effect on the flow rates, when the internal resistance R is relatively small, but such fluctuations could be minimized by inserting substantially larger flow restrictors into the flow channels. If the perturbation is small compared to the resistance R, the relation Q 100   a ,DR/Q 100   b  approaches 1 since the two flow rates Q 100   a  and Q 100   b  becomes almost identical. 
         [0031]    However, it is a well known phenomenon in the field of micro fluid systems with laminar flow that a structural change of the flow communicating means may lead to the formation or fragmentation of air-bubbles into sizes, where they will possibly clog the system.  FIG. 2  illustrates a flow channel  1  having an inlet  4  to a narrowing section  3 . At the inlet the section  3  forms an inlet face  7 . 
         [0032]    The liquid  2  may contain bubbles of gas  8 . The bubble  8  is shown as being driven into the inlet  4  of the channel section  3  by the pressure difference between source and recipient. Often the presence of the bubble causes two-phase flow at the channel inlet  4 . Liquid flows in a thin layer  9 , which adheres to the inner surface of the channel  3 . The liquid layer  9  coaxially surrounds a flow  10  of gas, which fills the remaining core of the channel  3 . 
         [0033]    The two-phase flow in the flow channel  3  exhibits a phenomenon of instability, which frequently leads to fragmentation of the gas flow into separate bubbles  11  of gas, separated by plugs  12  of liquid. This is due to the surface tension of the liquid-gas interface of the film  9 . The surface tension causes a tendency of the liquid film to reduce its surface and may grow until a bubble is pinched off as indicated at  13  and  14 . Such fragmentation is frequently observed, although in practice its onset has turned out to be largely unpredictable. 
         [0034]    When sections of capillary tubes are inserted into the channels as flow restrictors, there will be a narrowing as illustrated on  FIG. 2 , which itself causes a bubble fragmentation, thereby adding to the problem of possible clogging. 
         [0035]    For relatively large flows, more than a few micro-litres per minute, it is often sufficient to mix two fluids by simple diffusion, where the intermixing is often helped by a relative turbulent nature of the flows will exist post to the joining. In micro-system however, the conditions often are for the flows to be laminar, without such turbulent behaviour. So when the two flows  30 , 31  meet as illustrated on  FIG. 3   a , they will flow in a relatively laminated structure for a while, limiting the mixing to the surface of contact  32 , thereby slowing down the mixing by diffusion. To increase the mixing times, the flows may be laminated into a plural of sheets, on  FIG. 3   b  one of the fluids is split into two such sheets  30   a ,  30   b , layered on the top and bottom of the first fluid  31  respectively. This doubles the contact area to  32   a  and  32   b , and further reduces the depth of the diffusion, since the thickness of two of the layers  30   a  and  30   b  is smaller than the layer  31 . 
         [0036]      FIG. 4  illustrates what may happen when a train of bubbles  40  of a critical dimension enter a joining zone of two or more channels, where the two fluids  41 ,  42  merge from separate flow channels  43 ,  44  into a common mixing channel  45 . If the total pressure differential between the source and the recipient is consumed by the sum of pressure drops from the train of bubbles  40 , or almost consumed, then the bubbles  40  may be trapped in the channel  43 , thereby preventing full flow of fluid  41  into the mixing channel  45 , resulting in unreliable flows and mixing in the system. 
         [0037]    Investigation has shown, however, that the flow restrictor geometry may be modified to suppress the generation of bubbles below critical length. Shown in  FIG. 5 , on a larger scale than in  FIG. 1 , is the inlet end of a flow restrictor of a similar overall construction as in  FIG. 1 . There is a difference, however, in that the flow channel  3  has been smoothly and gradually widened at the inlet to form the trombone-shaped inlet mouth. Near the inlet face  7 , the channel is wide. Further away from the inlet face the channel narrows down toward the original internal diameter D. In terms of the coordinate z set at zero at the inlet face  7  and pointing in the direction of flow as indicated at 22, at z=D the channel has an internal diameter D(z)=3.5 D, and at z=10.5 D the channel has an internal diameter D(z)=D. 
         [0038]    A first rule for the widening of the channel  3  may be derived from the condition that the inlet geometry should at least allow the formation of bubbles long enough to avoid blocking of the channel  3 . Letting N denote the number of bubbles present in the flow restrictor, flow will not be blocked if 
         [0000]      NΔP d &lt;ÄP 
         [0039]    wherein ΔP d  denotes the deformation pressure drop of each bubble as defined in (3) above. Considering the pinch-off of a bubble in the widened part of the flow channel  3  at a point where the channel has an internal diameter D*&gt;D, it has been calculated, that if 
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         [0000]    and if the inlet of the channel  3  is widened to a diameter slightly above D*, this at least creates the possibility that bubbles produced by fragmentation will be long enough to not completely stop the flow through the channel, even if the channel is filled up completely by such bubbles. In the equation Q is the flow rate of liquid through the channel  3 , η is the viscosity of the liquid and α is a frictional surface tension parameter, which must be established empirically. 
         [0040]    Turning now to the fragmentation process itself,  FIG. 2  shows a bubble  16  of gas  15  entering the channel  3 . At the front  23  of the bubble, liquid is displaced by the gas to form a thin film  17  of thickness h(z) on the inner surface of the channel  3 . Due the surface tension at the gas-to-liquid interface  24 , the film  17  is unstable. The surface tension exerts a pumping action causing a tendency of the liquid to flow both radially and axially, as shown at  25 , which is a well-known phenomenon in the field of hydrodynamics. This causes local accumulation of liquid, which may eventually lead to the formation of a plug of liquid, which fills the channel  3 . Thus a smaller bubble  18  (not shown in  FIG. 2 ) may be pinched off from the bubble  16 . 
         [0041]    Investigations indicate that it is largely a matter of local surface curvature and timing, whether pinch-off will actually occur or not. If the bubble  16  passes a site  25  of beginning local accumulation of liquid but the liquid film  17 , however, not reach sufficient thickness to form a liquid plug while the bubble passes, pinch-off will not happen. On the other hand, if the liquid film  17  grows thick enough to coalesce at the centre of the channel  3  to form a liquid plug, while the bubble  16  flows past the site  25 , pinch-off will be the result. 
         [0042]    Based on this, it has now been found that by suitably widening the inlet of the flow channel dependent on the desired flow rate, it is possible to control the timing of perturbation growth of the liquid film around gas bubbles in the channel  3  in such a manner that any bubble fragmentation will lead to bubbles, which are either longer than the limiting length of equation 6, thus posing no risk of blocking the capillary, or short enough to reduce the flow, but not numerous enough to stop the flow of liquid through the capillary. 
         [0043]    It is calculated that bubbles shorter than a limiting bubble length L bl , 
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         [0000]    where η g  is the viscosity of the gas, lead to a risk of clogging the flow channel because the gain from lower viscosity of the gas is offset by the loss due to deformation; bubbles longer than L bl  will flow freely along the flow channel because the gain from lower viscosity of the gas dominates. 
         [0044]    It has been found that within the tapered channel portion, instabilities will typically cause a liquid film to coalesce at the centre of the flow channel, and thereby to pinch off a bubble, and investigations indicate that the smallest of these local time periods, referred to as τ*, governs the time scale of bubble segmentation within the widened part of the channel  3 . 
         [0045]    It is desired to prevent bubble fragmentation into bubbles shorter than the limiting bubble length L bl , and the characteristic (minimum) transit time τ bl  of such bubbles is 
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         [0000]    where v* is characteristic (maximum) value of bubble velocity at some coordinate z along the channel  3  where the internal diameter is at its minimum. A channel slope designed such that 
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         [0000]    will prevent the formation of bubbles having a length L b &lt;L bl . 
         [0046]    Relations (1) and (2) may then be combined in the design of the widened inlet to the channel  3  to form a flow restrictor which is tolerant to bubble fragmentation, as follows: 
         [0047]    In a first section of the channel  3  between the inlet face  7  and a first z-coordinate z 1 , the channel diameter D should be kept larger than the value D* given by relation (1) above. In this connection, the coordinate z 1  is defined as the first location along the channel where the channel diameter narrows down to D*. This will ensure that any bubble segmentation within the first section does not generate bubbles, which are so short as to block the flow completely. 
         [0048]    In a second section of the channel, between the first z-coordinate z 1  and a second z-coordinate z 2 , the channel should be designed to narrow down gradually towards the original channel diameter D in accordance with the relation (2) above. The second z-coordinate z 2  is defined as the first location along the channel, where the channel narrows down to its original, overall diameter D. In practical terms this means that the geometry should be designed to minimize the change in surface curvature as the channel narrows down. This will ensure that bubbles which have reached z 1  unfragmented, or which have been fragmented at z 1  into bubbles of non-critical length, will not be further fragmented during their passage along the second channel section, and will enter into the remaining, straight section of channel  3  unfragmented and remain unfragmented also there. 
         [0049]      FIG. 6  shows the preferred embodiment of the invented micro-mixer. The two fluids  50 ,  51  are contained in the reservoirs  52 ,  53 . The fluids are lead into the channels  54  and  55  respectively, where the tube is split into two branches  54   a ,  54   b . The fluids flow at rates mainly regulated by the pressure difference driving the fluids, and the flow restrictors  56 ,  57  inserted into the channels (an additional flow restrictor may be inserted into channel  55 ). The flow restrictors have the property of being bubble restraining, like the pieces of capillary tubes with and tapered inlets as described above. This ensures that bubbles of gas arriving in the tubes  54   a ,  54   b , are changed into sizes unable to clog the flow-path, like at the merging point  59  of the channels  54   a ,  54   b ,  55 . 
         [0050]    While the present invention has been illustrated and described with respect to a particular embodiment thereof, it should be appreciated by those of ordinary skill in the art that various modifications to this invention may be made without departing from the spirit and scope of the present invention.