Patent Application
20090197977
The present invention relates to a device and a method for producing a mixture of two phases that are insoluble in each other, for example of emulsions or foams.
Emulsification is a central step in a plurality of production processes in the fields of food industry, cosmetic industry and pharmaceutical industry. For emulsification, two liquids that are insoluble in each other, for example oil and water, are mixed so as to produce a mixture wherein one liquid is distributed in the other in the form of small droplets.
Equipment used for producing emulsions may be classified into two large groups, namely turbulence-inducing systems and systems with controlled drop generation.
With regard to the turbulence-induced systems, for example rotor/stator systems are used, for industrial application, wherein a rotor is used to stir the liquids so as to produce the mixture. Such systems are available, for example, from Microtec Co., Ltd. (http://nition.com/en). In addition, high-pressure homogenizers, for example from Niro Inc. (http://www.niroinc.com”), or ultrasound-based systems, e.g. Dr. Hielscher GmbH (http://www.hielscher.com), are used. This equipment may be used universally for dispersing several immiscible phases. To this end, high shearing forces are induced in the phase boundaries so as to achieve a mixture. With this method, however, the size distribution of the disperse phase strongly varies since stochastically distributed break-away effects in turbulent flows are responsible for the drop generation. A further disadvantage of these mechanical dispersing processes is the energy input into the phase mixture. Because of it, the temperature of the emulsion is increased, and heat-sensitive components as are often found in pharmaceutical production may be destroyed.
The disadvantages of the turbulence-inducing systems, namely wide drop size distribution as well as a temperature rise in the emulsion, may be circumvented by systems wherein structures of the order of magnitude of the drops to be produced are employed for geometrically controlled drop generation.
A known example of producing monodisperse emulsions is a membrane reactor as is disclosed, for example, by Fraunhofer Institut für Grenzflächen und Bioverfahrenstechnik (http://www.igb.fraunhofer.de). An example of such a membrane reactor is depicted in
Recently, the production of stable microemulsions, which comprise distributions with small droplet sizes, by microfluidic systems has been disclosed, see T. Thorsen, R. W. Roberts, F. H. Arnold and S. R. Quake, Phys. Rev. Lett. 86, pp. 4.163-4.166 (2001). The creation of double emulsions by microfluidic systems has also been disclosed, see A. S. Utada, E. Lorenceau, D. R. Link, P. D. Kaplan, H. A. Stone, D. A. Weitz, Science, 308, pp. 537-541 (2005). In the event that the droplet size is adjusted to the range of the channel dimensions, a continuous flow is subdivided into separate liquid departments, each of which represents a minute reaction vessel, where fast diffuse and even convection-aided mixing occurs, see A. Günther, M. Jhunjhunwala, M. Thalmann, M. A. Schmidt and K. F. Jensen, Langmuir, 21, pp. 1.547-1.555 (2005), and L. S. Roach, H. Song, R. F. Ismagilov, Anal. Chem., 77, pp. 785-796 (2005).
By means of such methods, it is possible to produce emulsions comprising a very narrow-band distribution of the drop sizes, so-called monodisperse emulsions.
Such sub-millimeter range fluidic structures produced by means of microtechnology, referred to as microfluidic systems, enable controlled production and manipulation of individual drops, so that emulsions comprising a very narrow-band distribution of the drop sizes and, thus, highly monodisperse emulsions may be produced.
T. Nisiako, T. Toru and H. Toshiro, “Rapid Preparation Of Monodispersed Droplets With Confluent Laminar Flows”, in Proceedings of the sixteenth annual international conference on micro electro mechanical systems—MEMS 2003, pp. 331-334, describe a T-shaped channel structure as is depicted in
Q. Y. Xu and M. Nakajima, “The generation of highly monodisperse droplets through the breakup of hydrodynamically focused microthread in a microfluidic device”, Applied Physics Letters, vol. 85, no. 17, pp. 3.726-3.728, 2004, disclose an alternative channel structure for droplet generation. Such a channel structure is depicted in
For the physical principles of droplet formation in the channels shown in
Irrespective of the methods mentioned for producing emulsions, one has known microfluid systems which use centrifugal forces for handling liquids, see J. Ducrée, H-P. Schlosser, S. Haeberle, T. Glatzel, T. Brenner, R. Zengerle, Proc. of μTAS 2004, Malmö, Sweden, pp. 554-556. Droplet-based analytical chemistries and corresponding microprocessing techniques are further described, for example, by S. Okushima, T. Nisisako, T. Torii, T. Higuchi, Proc. of μTAS 2004, Malmö, Sweden, pp. 258-260.
According to an embodiment, a device for producing a mixture of two phases that are insoluble in each other may have: a first fluid channel leading into a contact region; a second fluid channel leading into the contact region; a third fluid channel leading into the contact region; and a rotation imparter configured to impart a rotation on the first fluid channel, the second fluid channel and the third fluid channel, a first phase being centrifugally supplied to the contact region through the first fluid channel, and a second phase, insoluble in the first phase, being supplied to the contact region through the second fluid channel, compressive and/or shearing forces in the contact region which are centrifugally/hydrodynamically induced by the rotation causing drops to break away in one of the phases supplied in order to produce the mixture of the first and second phases.
According to another embodiment, a method for producing a mixture of two phases that are insoluble in each other may have the steps of: centrifugally supplying a first phase to the contact region through a first fluid channel; supplying a second phase to a contact region through a second fluid channel, the centrifugal supplying being effected by a rotation of the first fluid channel, the second fluid channel and the contact region, compressive and/or shearing forces in the contact region which are centrifugally/hydrodynamically induced by the rotation causing drops to break away in one of the phases supplied in order to produce the mixture of the first and second phases; and centrifugally draining off the mixture from the contact region through a third fluid channel.
The present invention provides a device for producing a mixture of two phases that are insoluble in each other, comprising:
a first fluid channel leading into a contact region;
a second fluid channel leading into the contact region;
a third fluid channel leading into the contact region; and
means configured to impart a rotation on the first fluid channel, the second fluid channel and the third fluid channel, a first phase being centrifugally supplied to the contact region through the first fluid channel, and a second phase, insoluble in the first phase, being supplied to the contact region through the second fluid channel, compressive and/or shearing forces in the contact region which are centrifugally/hydrodynamically induced by the rotation causing drops to break away in one of the phases supplied in order to produce the mixture of the first and second phases.
The present invention further provides a method for producing a mixture of two phases that are insoluble in each other, comprising:
centrifugally supplying a first phase to a contact region through a first fluid channel;
supplying a second phase to the contact region through a second fluid channel,
the centrifugal supplying being effected by a rotation of the first fluid channel, the second fluid channel and the contact region, compressive and/or shearing forces in the contact region which are centrifugally/hydrodynamically induced by the rotation causing drops to break away in one of the phases supplied in order to produce the mixture of the first and second phases; and
centrifugally draining off the mixture from the contact region through a fluid channel.
As compared to known methods, the present invention is thus based on exploitation of the centrifugal force so as to contact at least two immiscible phases in a rotating system to produce emulsions, if the two phases are liquids. Here, liquid phases are supplied to the contact region in a centrifugal manner by means of the rotation.
In accordance with the invention, foams, for example monodisperse liquid/gas phase dispersions, may also be produced if one phase is a liquid, and one phase is a gas. Supplying a gas phase to a liquid phase is not possible directly by means of centrifugal pumping, since in the presence of the liquid phase, which is considerably more dense, the gas phase would be pumped radially inward instead of outward. In order to produce liquid/gas dispersions, embodiments of the invention therefore provide for a means which enable supplying the gas via the associated fluid channel(s). Such means could be formed, for example, by a co-rotating pump (on-board pump). In addition, the gas could be sucked in, in accordance with the waterjet pump principle, at high speed of the liquid flow at a radially outer location of the channel.
Thus, the present invention addresses the production of drops or emulsions in rotating channels, and the processing of immiscible phases in rotating modules. In accordance with the invention, at least one, and—in the event of two liquids—both phases are transported in fluid channels by centrifugal forces, and the phases are joined at at least one location, drops breaking away in a controlled manner from at least one phase. This process may occur in a repeated manner, serially or in parallel.
The inventive pumping by means of the centrifugal force enables continuous operation, i.e. a pulse-free field of force on the interacting fluids. Here, the rotational frequency in the continuous rotary motion is stabilized as against speed variations of the drive via the rotor's moment of inertia. In this manner, oscillations as occur in a drive by means of syringe pumps or positive-displacement pumps are avoided.
This ensures consistent conditions for all drop breakaway processes, and, thus reproducibility of the processes or the drops produced. Here, pumping of highly viscous media by means of the centrifugal force is also possible. In advantageous embodiments, the phases are continually apportioned into an inlet region of the fluid channels, it being possible for such an inlet region to be formed, for example, by a reservoir on a top face of a rotor. Via suitable guidance structures within the rotor, the liquids may then be fed to closed channels which represent the fluid channels whose radially outer ends lead into the contact region. Further embodiments of the invention may comprise continual, radial ejection of the processed liquid from the rotor into a collector. Alternatively, the liquid may be collected within a cavity on the rotor, possibly in combination with targeting draining off of same. Thus, no pressure-tight fluid interfaces are needed in accordance with the invention, since media to be processed may be led into the process module in an open jet, and may possibly be led out of same.
In advantageous embodiments, the inventive channel structure includes three supply channels in the form of a sheath-flow structure, wherein the phase to be dispersed is contacted, at a contacting point, with the continuous phase from two opposite sides. In addition, the present invention enables the production of multi-phase drops, at least two miscible or immiscible phases being included in one drop. To achieve this, a mixture of two miscible or immiscible phases may be supplied via one of the supply channels. The production of 2-phase drops is possible, in accordance with the sheath-flow principle, also by means of adding further inflow channels, which provide further phase boundaries in the contacting region. In addition, double emulsions may also be produced in accordance with the sheath-flow principle in that still further phases are added to the contacting region in, for example, two further supply channels. These may serve, for example, to encapsulate an inner phase from the continuous medium (vesicle).
The channel structures necessary for implementing the invention may be formed either directly within a rotor, for example a disc, or may be formed within a module inserted into a rotor. Further processing of the drops on the rotor, or the rotating module, for example repeated splitting of the drops, is also possible. In addition, new process sequences may be enabled by means of integrated extraction of the phases, for example by means of sedimentation and/or decanting. In addition to producing emulsions, the present invention also enables producing dispersions of gasses and liquids, i.e. foams.
The inventive utilization of the centrifugal force for producing a mixture of two phases that are insoluble in each other enables precise control and reproducibility of the drop size by means of hydrodynamic boundary conditions specified by geometric structures. In addition, identical structures may be operated in parallel, which leads to a parallelization on the process module. In the invention, there are new “centrifugal” conditions of the drop breakaway, which enables access to new areas of experimental parameters, for example the drop size, the drop frequency, the drop spacing at specified viscosities, densities and surface/interfacial tensions of the liquids to be dispersed. Finally, heat input into the liquids may be fully avoided by centrifugal pumping.
To enable centrifugal transport of liquid, in each case radially outer ends of the channels via which the liquids are supplied to a contact region lead into the contact region, whereas radially inner ends of the channel or channels serving to drain off liquids or a liquid/gas emulsion lead into the contact region. A “radially outer” end is understood to mean an end which is radially further out than another end of the respective channel, so that a centrifugally driven transport of liquids from the other end to the radially outer end is possible. Similarly, a “radially inner” end is understood to mean an end which is radially further in than another end of the respective channel, so that a centrifugally driven transport of liquid is possible from the radially inner end to the other end. These designations thus represent no absolute condition in that the channels could not comprise arches whose arch regions are located, in sections, radially further out or in than the respective confluences, as long as a centrifugal transport of liquid as was described above is possible.
The present invention thus provides a novel centrifugal microfluidic method for continuous production of highly monodisperse mixtures of two phases that are insoluble in each other, for example of water droplets in a flow of oil. The present invention may readily be integrated on centrifugal platforms with further processing methods, for example centrifugal droplet sedimentation, which allows novel applications in the field of droplet-based analysis and microprocessing technology.
Embodiments of the present invention will be detailed subsequently referring to the appended drawings, in which:
With reference to
The embodiment of the present invention depicted in
At least one channel structure enabling creation of a mixture of two phases that are insoluble in each other is provided within the rotational body 102. In advantageous embodiments, however, a plurality of respective channel structures 110 are advantageously provided which are arranged, within the rotational body, in a star-shaped manner and extend outward in a radial manner, and which may be fed via separate or common reservoirs. In the embodiment represented, the rotational body 102 consists of a substrate 102 which may be formed from any suitable material, for example plastic, silicon, glass or the like. The channel structures 110 are structured within the substrate 102. The substrate 102a is provided with a cover 102b comprising openings 112 for fluid connection with fluid reservoirs 114 and 116, which are formed on the rotational body 102. The reservoirs 114 and 116 are formed on the rotational body 102 in an annular manner, so that they enable continuous replenishment via the fluid injection means 104 and 106 during a rotation. In addition, the reservoirs are shaped such that centrifugal overflow is avoided up to a certain rotational speed which should exceed the speed necessitated for the drop production.
The channel structures 110 are open toward the outside in a radial manner so that liquid may be radially ejected from same to the outside into the collector 108 by centrifugal force. The collector 108 may further be provided with suitable outlet means so as to drain off the produced mixture from same, as is indicated by an arrow 120. Also, the dispersion may be collected in a co-rotating reservoir.
During operation, a first liquid is continually introduced into the reservoir 114 by the fluid injection means 104, whereas a second liquid is continually introduced into the reservoir 116 by the fluid injection means 106. The reservoirs 114 and 116 are configured to keep the liquids within the reservoirs during rotation of the rotational body 102 about the axis of rotation Z perpendicular to same. During the rotation of the rotational body 102 about the axis Z, the liquids pass into the channel structures 110 by centrifugal force, supported by gravitational force, where they are driven radially outward by the centrifugal force FZ. At a radially outer end, the fluid channels branching off from the reservoirs 114 and 116 each lead into a contact region into which also a radially inner end of a third fluid channel leads. At the location where the liquids meet within the contact region, compressive and/or shearing forces which are centrifugally/hydrodynamically induced by the rotation cause drops to break away in one of the liquids supplied, so that an emulsion of the two liquids is centrifugally driven outward through the third channel and is ejected into the collector 108 at the radially outer end of the rotational body.
The device described with reference to
In the example depicted in
In the embodiment depicted in
As was set forth, the fluids, in the advantageous embodiment liquids that are insoluble in each other, are fed via vertical collecting channels or openings 112 in the cover 102b on the substrate, and are coupled into the microchannels of the channel structure which causes the creation of an emulsion. During rotation, the fluids are centrifugally transported outward, the phases to be dispersed being transported to a contacting point in separate and differently shaped microchannels.
An embodiment of such a channel structure for inducing a suspension or a mixture of two phases that are insoluble in each other is shown in
The different designs, i.e. lengths and cross-sections, of the channels define the hydrodynamic resistances Rd and Rc of the supply channels as well as the hydrodynamic resistance Rout of the drain channel 138, as is indicated on the left-hand side of
Merely schematically, in this context
Four phases of the drop breakaway are depicted in a stroboscopic frame sequence in
As was described, the disperse phase supplied through the fluid channel 130 by centrifugal force Fv is contacted, from two sides, with flows of the continuous phase supplied by the channels 134 and 136, and is transported into a shared channel 138. This occurs at a defined attack angle so as to achieve a constricting effect of the two side streams on the disperse phase coming from the central channel 130, and so as to promote the breaking away of drops at the contacting point.
In addition to the channel arrangement, the wetting properties of the channels are also significant. The continuous phase Φc, preferentially wets the channels, as compared to the dispersive phase Φd. Thus, the dispersive phase must be actively drawn from the central channel 130 by means of the centrifugal force Fz. From a specific size of the front of the dispersive phase Φd projecting into the contacting region, the constricting action of the side streams Φc and of the interfacial tension between the two phases causes drops to break away, as may be seen in
Both the drop size and the type of the multi-phase stream may be adjusted by targeted changes in the geometric parameters of the channel structure and in the rotational frequency. In this respect,
d-7f, respectively, show the same channels as do
The microchannels may be formed within a polymer substrate, for example made of COC (cyclic olefin copolymer), wherein the continuous phase (for example non-polar oil) exhibits more intense wetting properties than the phase to be dispersed (for example water). Thus, the water plug must be actively drawn from the central channel 130 by means of centrifugal force, against the force Fσ of the surface tension. At smaller rotational frequencies, the water plug thus rests in the central channel, so that the work area above which a drop formation takes place comprises a lower cut-off frequency νlow. Above this lower cut-off frequency, the water plug exits the central channel and breaks away as soon as the mass of the droplet exceeds a critical mass. The upper boundary of the work area νhigh is determined by the point where the drops begin to touch one another and to intergrow because of the drop diameter d and the drop spacing Δ. In this respect, in
With regard to drop generation, one may establish that the droplet generation process is influenced by the hydrodynamic resistances Rc, Rd and Rout, the radial positions of the supply channels and of the outlet channel, as well as by the geometry of the drop-carrying channel and the rotational speed. The channel geometries and rotational speeds which are to be used for different fluids for producing emulsions or foams may be readily determined by appropriate calculations or simulations on the part of those skilled in the art.
An example of a possibility of further processing the generated drops on the rotating platform is depicted in
The inventive method for droplet formation was examined using surfactant-free sunflower oil and ink-dyed water (2% by volume).
Two parameters, a characteristic droplet surface area A and the droplet spacing Δ, the latter being a measure of the droplet production rate, were evaluated experimentally. The diameters d as well as the volumes of the droplets were partially approximated from A, since the droplets were squeezed between the upper and lower channel walls, partly to an unknown extent, the channel comprising a depth of about 200 μm.
By varying the design of the structure, it was possible to realize three different functions. In this respect, fully free-flowing and isolated droplets may be produced using a high Φc and a low Rout. Vertically squeezed droplet trains may be realized using a low flow rate Φc and a high Rout, while a segmented flow may be implemented by a narrowing in the droplet-carrying channel. As was already set forth, it is also the frequency of the rotation, in addition to the channel geometry, which influences the spacing and the diameter of the droplet, the droplet generation rate increasing, and its size decreasing, as the rotational frequencies increase. The pertinent results for the droplet diameter d and the droplet spacing Δ are shown in
Thus, the present invention provides a device and a method enabling the production of monodisperse droplet trains (CV<2%). The experiments conducted enable droplet generation with droplet volumes between 5 and 22 nL within one work area, it being possible for their sizes and spacings to be controlled by channel geometry and rotational frequency. In addition, the present invention enables a further important operation, namely hydrodynamic division of droplets. The centrifugal platform also enables new functions in multiphase-microfluid applications, particular emphasis being placed on sedimentation in this context.
Exemplary post-processing of mixtures produced in accordance with the invention may include polymerization of dispersed drops, which may lead to solid/liquid emulsions having monodisperse solid-phase particles.
Advantageous embodiments were explained above with reference to a so-called sheath-flow channel structure. However, the present invention is not limited to such a channel structure, but may also be implemented using alternative channel structures which enable detachment of droplets, for example by a T-shaped channel structure as is depicted in
While this invention has been described in terms of several embodiments, there are alterations, permutations, and equivalents which fall within the scope of this invention. It should also be noted that there are many alternative ways of implementing the methods and compositions of the present invention. It is therefore intended that the following appended claims be interpreted as including all such alterations, permutations and equivalents as fall within the true spirit and scope of the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 10 2005 048 259.7 | Oct 2005 | DE | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/009099 | 9/19/2006 | WO | 00 | 9/5/2008 |
