Patent Application
20090246086
The present invention relates to a process for producing droplets through a plurality of linked microfluidic devices wherein the formation of the droplets is synchronised by naturally occurring hydrodynamic interactions between the devices.
Microfluidic devices are well known, for example as described in WO-A-2005/058477 and EP-A-1 362 634. The dynamics of droplet formation in such devices has been analysed, for example as described in Billingham J., et al, “Flow Phenomena and Stability of Microfluidic Networks”, 12 May 2005, URL: http://www.smithinst.ac/uk (XP002371235) or in Lung-Hsin Hung et al, Proc. 8th Int. Conf. on Miniaturised System for Chemistry and Life Sciences, Sep. 26-30, Malmö, Sweden.
Micro-fluidic devices have been successfully employed to form emulsion droplets, bubbles, particles, encapsulates, and other complex micro-structures with good control over particle size and composition. By collecting the droplets formed in such devices, one can form novel micro-structured products. In view of the small scale of such devices, the formation of single droplets or similar structures in a micro-device is controlled by a balance of capillary force and viscous or inertial forces, which typically limits the throughput through a single micro-device to a few ml/hr. For practical application requiring production rates in the order of litres/hour, it is therefore necessary to increase the production throughput. This may be done by three means: (1) increasing flow velocity through a micro-device; (2) increasing the size of the micro-device; (3) increasing the number of micro-devices.
In practice, the flow velocity is limited by the break-up mechanism: above a certain flow velocity, depending on viscosity, size, and surface tension of the liquids contacted while remaining in the laminar flow regime, break-up no longer occurs and a stratified flow pattern is formed. Increasing the velocity eventually leads to a turbulent flow, which can break-up the liquid jet. This other type of break-up, however, does not lead to a single drop size and therefore cannot be used to create products with a homogeneous drop size distribution.
The size of droplets is constrained by the size of the channels in the micro-device. Therefore increasing the size of a micro-device, results in an increased drop size. It is therefore not practical to increase the size of a device only to increase throughput.
Parallelisation of multiple micro-devices can achieve the required throughput without any change in the distribution of drop size, and therefore is the preferred way of achieving higher throughput. Several micro-reactors exploit parallelisation of a few 10's or 100's of micro-channels to increase throughput. To limit the complexity of such arrays, a single fluid inlet for each fluid is distributed, via a manifold, to multiple micro-devices. In theory, a perfect manifold distributing the fluids into exactly similar micro-devices could lead to a single droplet size distribution. In practice however, the homogeneity of droplet size distribution coming from an array of parallel emitters is limited by the imbalance of flow rates through each micro-channel, which may arise from small difference in the channel dimension. These differences can be due, e.g., to imperfections in the fabrication of the micro-devices, or to deposits or fouling on the surface of the micro-devices.
Therefore it is an aim of the present invention to provide a method of generating droplets in a parallel microfluidic device which have a much narrower droplet size distribution than was previously possible.
The present inventors have observed that such parallel micro-devices are not independent, as they are linked by the single fluid sources. This can lead to “cross-talk” between the channels, wherein the formation of a drop in one channel creates a pressure imbalance affecting the formation of droplets in a neighbouring channel. It has been observed that such interdependence can be exploited to provide a much narrower droplet size distribution than was previously possible.
A first aspect of the present invention provides a method of producing emulsion droplets from a microfluidic network which comprises a plurality of droplet emitters forming droplets of a first fluid in a second fluid immiscible in the first fluid to produce an outlet stream of the emulsion droplets, each of the emitters being in fluid communication with each other via the network, wherein the emitters have an auto-synchronised droplet formation frequency by hydrodynamic interaction therebetween.
A second aspect of the present invention provides a microfluidic network comprising a plurality of droplet emitters forming droplets of a first fluid in a second fluid immiscible in the first fluid to produce an outlet stream of droplets, wherein each of the emitters are in fluid communication with each other via the network and have an auto-synchronised droplet formation frequency by hydrodynamic interaction between the emitters.
The present invention relates to a microfluidic network of droplet emitters which are auto-synchronised by hydrodynamic interactions.
A droplet emitter is defined herein as a confluence of at least two inlet streams where one fluid stream is immiscible in the other so as to form droplets. The inlet stream which is carrying the fluid which will become the droplet phase is sometimes referred to herein as a dispersed phase inlet stream. In the simplest form, such a junction is made up of two immiscible fluids brought together in a T-junction. Such a droplet emitter is defined herein as a ‘single emitter’ because all of the droplets produced originate from one dispersed phase inlet stream at the junction. The invention also includes networks of double emitters or triple emitters or emitters of even higher order. A good example of a double emitter is given in “Controlled droplet fusion in microfluidic devices”, L.-H. Hung, W.-Y. Tseng, K. Choi, Y.-C. Tan, K. J. Shea, A. P. Lee, Proceedings of the 8th Conference on Miniaturized Systems for Chemistry and Life Sciences, Sep. 26-30, 2004, Malmö, Sweden, p539-541, T. Laurell, J. Nilsson, K. Jensen, D. J. Harrison, J. P. Kutter, Editors (Royal Society of Chemistry: Cambridge). A double emitter produces droplets which originate from two dispersed phase inlet streams at the junction.
For the avoidance of doubt, an emitter is characterised based on the number of inlet streams entering the junction which will form droplets. It is quite possible for example that such a single dispersed phase inlet stream is itself formed by a confluence of a plurality of inlet streams, which may have merged together only a short distance before the emitter. The characterisation comes from the number of dispersed phase inlet streams actually entering the droplet emitter junction, irrespective of the upstream history of the inlets at the emitter.
In one described embodiment, each emitter has a first inlet port and an outlet port arranged along a first axis of symmetry, the first inlet port and the outlet port being interconnected via first and second communicating channels which are substantially symmetrical about the first axis of symmetry.
Second and third inlet ports may be provided at respective positions along the first and second communicating channels. The second and third inlet ports may be provided along a second axis of symmetry substantially orthogonal to the first axis of symmetry.
The first and second communicating channels together may form a square or rectangular shape. However, together they could also form a circular or elliptical, or any other symmetrical shape.
The first, second and third inlet ports may be arranged as respective T junctions with the continuous structure formed by the first and second communicating channels.
When two streams come together to form a droplet of one fluid in another, the drop-forming microfluidic intersection acts as an oscillator with an intrinsic frequency determined by the intersection geometry, fluid viscosity, flow rates, surface tension, and device materials. Coupling between neighbouring emitters originates from the flow rate/pressure variation due to the presence of droplets in the channel network. Indeed the pressure required to push a liquid at a given flow rate in a micro-channel is higher, if the micro-channel contains a droplet of a second liquid, than without a drop. At the manifold point the various micro-channels are connected and fed through. Hence when a droplet forms the flow rate in this channel decreases, which affects the flow in the other channel. As the frequency of droplet formation depends on flow rate, this in turn affects the frequency of droplet formation in the other channel.
When parallelising many such intersections with a common fluid source, such cross-talk between channels leads to dynamic instabilities: each channel is not independent of the other, but is coupled to others via the effect of the drops on the flow. This can be through capillary effects or hydrodynamic effects. The current state of the art does not allow developing a full understanding of the behaviour of two free coupled oscillators.
However, there exists a general theoretical understanding of the behaviour of two coupled oscillators, one of which has a fixed forced frequency [P. Mannevile, Dissipative structures and weak turbulence, Perspective in physics, H. Araki, A. Libchaber, G. Parisi, editors, Academic Press: London, 1990, Chapter 6]. Such a theoretical coupled system presents three different classes of behaviour, depending on the coupling parameter and the difference in the intrinsic frequency of the oscillators:
The homogeneity of drop size distribution in a collection of microdevices depends strongly on the regime of interaction. The inventors have observed that in one example exhibiting a quasi-periodic regime corresponding to a collection of un-coupled oscillators, each emitter presented a drop size variation around the mean of the order of 16%. When the manifold geometry was adjusted, so that the micro-devices became synchronised, total variation of drop size around the global mean fell to 6%. In a chaotic regime, total drop size variation was up to 20%. Therefore it is the attainment of the synchronised state which gives rise to a surprising and highly significant narrowing of droplet size distribution.
The inventors have developed an understanding of the different regimes which enables the skilled person to easily achieve synchronisation through straightforward system tweaking.
Of course it is possible to force each microfluidic device to operate at the same frequency by using a vibrating valve for each device. However, in view of the problem of scale-up this would be a very expensive method of synchronisation for when many thousands of such devices are desired to operate in parallel.
For the avoidance of doubt, the present invention does not preclude the use of forced oscillation. Instead it provides a method of attaining an auto-synchronised state which can allow a vast array of microfluidic devices to operate in synchronisation with a vastly reduced number of forced frequency devices. When the system is operating in an auto-synchronised state, a minority of forced devices will spread their frequency throughout the array.
Thus the present invention relates to a microfluidic network of droplet emitters, each producing droplets of a first fluid into a second fluid immiscible in the first. The streams carrying the formed droplets are referred to as outlet streams. The streams carrying the first and second fluids are referred to as inlet streams.
As discussed above, the microfluidic devices must be in fluid communication. It is preferred that the devices have a common fluid inlet stream, i.e. that they are fed from a manifold having a single fluid inlet.
It is also preferred that a plurality the outlet streams of a plurality of the devices merge together into a common outlet stream.
In an arrangement with common outlet streams the strength of the interaction has been found to be strongly sensitive to the numbers of droplets present in each outlet stream before merging together into the common outlet stream. Preferably therefore the arrangement is such that from 2 to 8 droplets are present in each outlet stream before merging together into the common outlet stream. Preferably the number of droplets is from 2 to 5. With this arrangement the formation of a droplet has a significant impact on the resistance of the outlet stream and therefore affects the flow pattern of the supply streams, the fluctuation of which drives the synchronisation with the other droplet emitters.
In a preferred embodiment, a plurality of emitters have a common supply stream and a common outlet stream. In this arrangement it is preferred that all channels have the same length and width. In this arrangement it is also preferred that a length from the point where the inlet streams for each emitter become individual streams to the point where the droplets are formed is roughly equal to the length from the point where the droplets are formed to a point where the outlet streams merge. This so-called ‘square’ arrangement is thought to be particularly receptive to attainment of synchronisation. Thus the average length of the streams from the common fluid supply point to the droplet formation point to the average length of the streams from the droplet formation point to the common outlet stream are in a ratio of from 3:1 to 1:3. Preferably the ratio is from 2:1 to 1:2, preferably from 1.5:1 to 1:1.5. Preferably also, the fluid resistance of the channels is also in the same ratio.
The inventors have discovered that the coupling strength between the emitters is the main controlling parameter. It indicates how much one oscillator is coupled to a neighbouring oscillator. For low coupling strength, the oscillators are independent and the behaviour is always quasi periodic. For intermediate coupling strength, the oscillators are coupled with large regions of chaotic behaviour and some synchronised states. For large coupling strength, the oscillators are coupled with mostly synchronised states.
In the particular example described below, the coupling strength can be approximated by the following formula:
Where g is the coupling strength, Q the total flow rate in the system, Qo the oil flow rate, RS0 is the resistance of the micro-fluidic element located downstream of the oil manifold and upstream of the junction with the water stream, RO is the resistance of the outlet branch, δR the additional resistance due to the presence of a droplet in a micro-channel, a is a coefficient dependent on viscosity ratio, ω0 the intrinsic frequency of droplet formation in the given conditions of flow rate, and dω/dQO the variation of the intrinsic oscillator frequency with flow rate of oil. Therefore the coupling strength increases by acting on the following parameters:
The invention is further illustrated by reference to the following description of preferred embodiments and examples and with reference to the accompanying drawings, in which:
The experimental system we are considering here is shown in
Water and oil feed two T junctions placed in parallel on the same chip. Droplets are produced at the two junctions. They further move downstream, and are eventually collected in a single canal.
As shown in
Flows are driven by syringe pumps. There is one single entry for oil, and two separate entries for water, connected to two independent syringe pumps. The channels are moulded in PDMS (PolyDimethylSiloxane), using soft lithography technology. They are covered by a glass plate, coated with a PDMS film, so as to expose the fluids to surfaces with homogeneous hydrophobicity. The microchannels have rectangular cross-sections, 50 μm high and 200 μm wide; their lengths are in the centimeter range. The fluids are tetradecane and water labeled with fluorescein and the corresponding flow-rates range between 0 and 20 μl/min for oil and 0 and 10 μl/min for water. The system is observed by using standard epifluorescence microscopy. The emission frequency, drop sizes, water and oil flow rates in each branch are inferred from real time measurements of the light intensity at different places in the channels, at a few hundreds of micrometers beyond the T-junctions. Various treatments of the light intensity signal are applied (FFT, statistical distributions, etc), leading to a detailed characterization of the dynamics of the system.
Each T junction was characterised separately by isolation from the rest of the system. For each emitter, the physical mechanism of the drop formation process is initiated by a water tongue penetrating into the oil channel, forming a neck which elongates under the effect of the oil shear stress, and eventually breaks up; the breakup event quenches the emission of an isolated droplet; this process is periodic in time, as shown by the Fourier analysis of the light intensity signal. Typically, the emission frequencies monotically increase with the water flow-rate and the oil flow-rate, forming a set of curves we call “dispersion curves”.
We now consider three parallelized systems as precedently represented in
In the second example, we consider the “square” channel system as depicted in
Therefore careful selection of geometry and flow rates can lead to synchronised states which leads to narrow size distributions.
| Number | Date | Country | Kind |
|---|---|---|---|
| 05292074.1 | Oct 2005 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2006/009534 | 10/2/2006 | WO | 00 | 4/3/2008 |
