NL2002862C2

NL2002862C2 - Microfluidic apparatus and method for generating a dispersion.

Info

Publication number: NL2002862C2
Application number: NL2002862A
Authority: NL
Inventors: Koen Cornelis Dijke; Catharina Gerarda Petronella Henrica Schroen; Remko Marcel Boom; Gert Veldhuis; Albert Padt
Original assignee: Friesland Brands Bv
Priority date: 2009-05-08
Filing date: 2009-05-08
Publication date: 2010-11-09
Also published as: CN102458630B; EP2427266A1; CN102458630A; WO2010128858A1

Description

MBX/P86123NL00

Title: Microfluidic apparatus and method for generating a dispersion

The invention relates to a system for generating a dispersion. The invention also relates to a microchannel apparatus for generating a dispersion, comprising a feed openingfor supplying a to-be-dispersed phase first substance, a guide channel having a second depth which may supply for supplying a 5 continuous phasesubstanceproduct, and a connection channel forming a fluid connection between the feed opening and the guide channel, wherein the connection channel mouths into the guide channel.

Background of the invention

Monodisperse emulsions with droplet size of 0.1-100 pm are of great 10 importance in both science and industry. However, conventional emulsification techniques yield wide droplet size distributions with typical coefficients of variation (CV) of around 40%. Moreover, most of the energy put into the product is dissipated as heat.

Recently, several new energy-efficient droplet formation systems 15 have been developed which give more monodisperse emulsions.

One known class of systems for generating a dispersion that are capable of producing highly monodisperse droplets utilizes so-called singledrop technologies such as flow-focusing devices, co-flowing systems, T-, Y- or cross-junctions and microchannels. In these single-drop systems, a feed 20 channel feeds a to-be-dispersed phase substance into a guide channel guiding a continuous phase substance. At the location where the feed channel mouths into the guide channel, the droplets are formed one at a time (sequentially).

Some of these single-drop systems produce droplets in the desired range. However, the volumetric productivity is considered too low to be of 25 practical relevance for larger scale applications.

To realize a higher volumetric production rate it is of benefit to scale up these systems. In the single-drop systems mentioned before, the droplets 2 are formed sequentially, which requires mass parallelization of the droplet formation units (DFU). In shear-based systems such as flow-focusing, coflowing devices, and the different junction types, both to-be-dispersed and continuous phase flows need to be precisely controlled at each DFU as the flow 5 rates have a huge influence on the droplet size. Consequently, up-scaling such shear-based system for generating droplets is complex, since it not only involves combining more droplet formation units, but also the control of the flows in all droplet formation units, which is far from trivial.

Another class of known systems for generating a dispersion is known 10 as so-called microchannel (MC) systems. In a microchannel system an oblong feed channel feeds the to-be-dispersed phase product into a guide channel guiding the continuous phase (product matrix). Droplet formation in microchannels is often referred to as spontaneous droplet formation. In such microchannel systems only the flow of the to-be-dispersed phase needs to be 15 controlled. The continuous flow rate is not a parameter suitable for adjusting droplet generation, since droplet formation is not induced by shear forces but by nozzle geometry inducing instabilities in the surface tension on the droplet being formed. A low flow rate is still applied for droplet transport from the DFU, since otherwise it would be blocked by the droplets.

20 The microchannel systems seem to be more suitable for scale-up; especially the straight-through microchannel devices of Kobayashi and coworkers look promising (I. Kobayashi et al., M. Microfluid Nanofluid 2008, 4, 167). By Kobayashi, monodisperse emulsions with droplet diameters of 4.4 - 9.8 μιη with a CV from 5.5 - 2.7% were successfully produced using straight-25 through MC plates with different channel dimensions. Unfortunately, the channel efficiency, which is the percentage of droplet producing channels, was less than 1% for the plate with the smallest microchannels, and only up to 12.3% for the plates with the larger microchannels. This is probably due to pressure gradients in the system, as was extensively discussed by Abrahamse 30 (A.J. Gijsbertsen-Abrahamse et al., AICHE J. 2004, 50, 1364) for 3 emulsification with microsieves which resemble the system of Kobayashi. Moreover, fabrication inaccuracies could also cause low channel efficiency as mentioned by Kobayashi and co-workers.

Kobayashi also presented submicron channel arrays (I. Kobayashi et 5 al., Colloids & surfaces A 296 (2007), 285) allowing droplets of 1.5 μιη to be generated at a high channel efficiency. This system has the disadvantage that the structure is complex, as very small terraces are required having a width of 7.4-8.8 μιη, length of 3.2-5.5 μπι and height of 0.32-1.4 μιη. These structures are relatively difficult to produce, especially when the dimensions of all 10 terraces in the system need to be substantially identical (for narrow droplet size distribution).

It is an object of the invention to provide a system and/or apparatus for generating a dispersion which is more suitable for scale-up.

Summary of the invention 15 The inventors realised that the above objective may be met by providing a robust system and/or apparatus for generating a dispersion in which a multi-droplet formation mechanism occurs that spontaneously generates many narrowly dispersed droplets simultaneously from one and the droplet formation unit.

20 In order to meet the above objects, according to the invention is provided a microfluidic apparatus for generating a dispersion, comprising a droplet formation unit (DFU) comprising a feed opening for supplying a to-be-dispersed phase first substance to the droplet formation unit, and an oblong droplet formation opening for forming droplets of the to-be-dispersed phase 25 first substance in a continuous phase second substance, the droplet formation opening having a first, smallest dimension, e.g. width, W and a second, largest dimension, e.g. length, L, wherein the second dimension L of the droplet formation opening is more than fifty times the first dimension W of the droplet formation opening, the droplet formation unit having a third dimension, e.g.

30 depth, D in a direction from the feed opening to the droplet formation opening, 4 wherein the third dimension D is more than two and a half (2.5) times the first dimension W, wherein the microfluidic apparatus further comprises a feed structure, in fluid communication with the feed opening for feeding the to-be-dispersed phase first substance to the droplet formation unit, wherein a flow 5 resistance of the droplet formation unit is larger than a flow resistance of the feed structure. In use, the to-be-dispersed phase first substance is supplied to the feed opening of the droplet formation unit via the feed structure while the continuous phase second substance is present at or flows across the droplet formation opening. The droplet formation opening defines the location where, 10 in use, an interface between the to-be-dispersed phase and the continuous phase is present. The droplet formation unit forms the droplets of the first substance in the continuous phase second substance at the droplet formation opening.

The inventor realised that by providing the droplet formation unit 15 with the oblong droplet formation opening with a second, largest dimension being more than fifty times the first dimension of the opening and having the third dimension being more than two and a half times the first dimension, and having the flow resistance being larger than the flow resistance of the feed structure, it is possible to allow a simultaneous multi-droplet formation 20 mechanism to occur that spontaneously generates many narrowly dispersed droplets simultaneously from one and the same droplet formation unit. Herein the droplet formation unit may have a very simple geometry. It will be appreciated that generating a plurality of droplets simultaneously by providing a plurality of droplet formation units, e.g. microchannels, in parallel, 25 e.g. on a single substrate, is also possible, although this will result in a much more complicated geometry than the microfluidic apparatus according to the invention.

It is also possible that the second dimension L of the droplet formation opening is more than eighty times, preferably more than one 30 hundred times, more preferably more than 150 times, most preferably more 5 than 200-500 times the first dimension W of the droplet formation opening. This allows even more droplets to be formed simultaneously from the same feed channel. It will be appreciated that the second dimension L of the droplet formation opening may even be more than 10.000 times the first dimension W 5 provided that the droplet formation unit remains geometrically stable.

Without wishing to be bound by any theory, the inventor found the following. The inventor found that in the microfluidic apparatus according to the invention, in use, droplets are being formed at a minimum mutual distance of approximately two to seven times the diameter of the droplets. Further, the 10 inventor found that in the microfluidic apparatus according to the invention, in use, the formed droplets have a diameter Ddrop of approximately five to eight times the first dimension (Ddrop = 5-W to 8-W).

Without wishing to be bound by any theory, it appears that the microfluidic apparatus is capable of forming multiple droplets simultaneously 15 from one and the same droplet formation unit when the second dimension of the droplet formation opening is more than approximately fifty times the first dimension of the droplet formation opening, i.e. L/W > 50.

It will be appreciated that if the droplet formation unit has a substantially constant rectangular cross section corresponding to the 20 dimensions of the droplet formation opening (L x W), wherein the droplet formation unit has a depth D in a flow direction from the feed opening to the droplet formation opening, the volume of the connection channel is LxWxD.

The flow resistance for such droplet formation unit, Rdfu, can be approximated by Rdfu = KD/(W3L), wherein K is a geometry dependent contant which is 12 25 in this case (see Perry’s 7th edition, equations 6-36 and 6-51). It will be appreciated that the droplet formation unit having the substantially constant rectangular cross section may be manufactured relatively easily.

If the feed structure is chosen to be a channel with a substantially constant rectangular cross section, the feed structure can be defined having a 30 width Wfs in a direction parallel to the width W of the droplet formation 6 opening, a length LfS in a direction parallel to the length L of the droplet formation opening, and a depth Dfs in a direction parallel to the depth D of the droplet formation unit. The feed structure then has a flow resistance Rfs that may be approximated by Rfs = K Dfs/(Wfs3 Lfs). In a preferred embodiment, the 5 width Wfs of the feed structure is substantially equal to the width W of the droplet formation opening. It will be appreciated that in such embodiment the flow resistance Rdfu of the droplet formation unit is larger than the flow resistance Rfs of the feed structure if Dfs/Lfs < D/L. This provides simple design guidelines for possible geometries of the microfluidic apparatus according to 10 the invention.

It will be appreciated that the flow resistance of the droplet formation unit may also simply be made larger than the flow resistance of the feed structure is a cross section of the feed structure is (much) larger than the cross section of the droplet formation unit.

15 Preferably, a feed rate at which the to-be-dispersed phase substance is fed into the connection channel via the feed opening is chosen such that the simultaneous formation of the plurality of droplets does not deplete the connection channel from the to-be-dispersed phase substance. The inventor has found that several, up to hundreds of, droplets may be formed per 20 microsecond by a single droplet formation unit according to the invention, depending on the length of the droplet formation unit. Preferably the feed rate of the to-be-dispersed phase substance is at least one hundred times the volume of the droplet to be formed per microsecond. For instance, for a droplet formation opening having a first dimension W of 1.2 μπι, the feed rate is 25 preferably at least 11 microliter per second, preferably at least 30 μΐ/s. It will be appreciated that the feed rate may be affected by a flow resistance of a feed channel feeding the to-be-dispersed phase substance to the feed opening of the DFU.

It will be appreciated that forming multiple droplets simultaneously 30 from one and the same feed channel markedly increases the droplet yield per 7 DFU, thus making the apparatus according the invention very well suited for scaling up production of droplets. The latter is of benefit for e.g. producing large amounts of dispersions as will be detailed below. Also for the apparatus according to the invention, the flow rate of the continuous phase product is not 5 a ruling parameter for droplet generation, since the shear forces do not play a role and the droplets are generated by instabilities in the surface tension on the forming droplet, possibly induced by the geometry of the droplet formation opening.

In an embodiment, the microfluidic apparatus further comprises a a 10 collection structure for supplying the continuous phase second substance and collecting the formed droplets, wherein the droplet formation opening mouths into the guide structure.

In an embodiment, the droplet formation unit is formed by a plateau having a width corresponding to the first dimension of the droplet formation 15 opening. Hence it is possible to form the microfluidic apparatus having simple geometric construction wherein the feed structure and the collection structure may be connected via the plateau.

Preferably, the first dimension of the droplet formation opening, e.g. the width of the plateau, is more than ten times smaller than the depth of the 20 collection structure in a direction along the first dimension of the droplet formation opening, more preferably more than fifty times. Hence, the process of forming small droplets or bubbles at the droplet formation opening is not disturbed by the presence of physical boundaries of the guide channel.

Preferably, the smallest, first dimension of the droplet formation 25 opening is between 0.05 and 25 pm, more preferably between 0.1 and 2 pm.

The inventor found that the apparatus according to the invention provides droplets having a diameter of between approximately 5 and 8 times the first dimension of the droplet formation opening. Hence, the preferred size range for the first dimension of the droplet formation opening provides droplets within 30 the desired range, e.g. 0.1 to 200 micron.

8

In one embodiment, preferably, the feed structure, collection structure and plateau are covered with a ceiling.

The microfluidic apparatus, e.g.. the feed structure, DFU (e.g. the plateau) and collection structure may be machined, e.g. milled, etched, routed, 5 sand blasted and/or injection moulded, in a substrate, or built using spacers on a, e.g. substantially flat, substrate. Preferably, the feed structure, DFU and collection structure are etched (e.g. in an essentially lithographical process) in a semiconductor substrate, such as a silicon substrate, although other substrate materials are possible, such as glass, metal (e.g. stainless steel) or 10 polymers. The substrate may be covered with a ceiling, such as a glass plate, e.g. bonded to the substrate to close the respective structures. It is also possible to use a first substrate as the ceiling of a second substrate.

Preferably, the droplet forming unit (e.g. the plateau) has a depth D, in a direction perpendicular to the droplet formation opening, such that, in 15 use, the to-be-dispersed phase substance fills the droplet formation unit over substantially the entire second dimension. It will be appreciated that the suitable depth of the droplet formation unit may depend on a surface tension between the to-be-dispersed phase substance and the continuous phase substance optionally including appropriate emulsifiers or stabilisers. It will 20 also be appreciated that the suitable depth D of the droplet formation unit may depend on the second dimension of the droplet formation opening, e.g. corresponding to a width W of the droplet formation unit or plateau, and/or a width Wf of the feed opening in the direction parallel to the second dimension W of the droplet formation opening.

25 It will be appreciated that if the length Lf of the feed opening is substantially equal to, or larger than, the second dimension L of the droplet formation opening (e.g. the length of the plateau) the depth D of the droplet formation unit, e.g. corresponding to a depth of the plateau, may be very short, e.g. in the order of several microns. On the other hand, if the length Lf of the 30 feed opening is much smaller than the second dimension L, the depth D of the 9 droplet formation unit may need to be much longer, e.g. substantially equal to the second dimension L.

The invention also relates to a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention.

5 In an embodiment, the system comprises a substrate having therein a plurality of microfluidic apparatus according to the invention. Preferably, the feed structures of the respective apparatus are in fluid communication. Preferably, the collection structures of the respective apparatus are in fluid communication. Preferably, the droplet formation units of the respective 10 apparatus are arranged such that the to-be-dispersed phase substance flows through the respective droplet formation units in parallel. Hence, a system may be obtained having an increased yield. It will be appreciated that also a plurality of such substrates may be connected in series and/or in parallel.

15 Brief description of the drawings

The invention will now be further elucidated by means of, nonlimiting, examples referring to the drawing, in which

Fig. 1 shows a schematic representation of a microfluidic apparatus according to the invention; 20 Fig. 2 shows a schematic representation of an alternative microfluidic apparatus according to the invention;

Figs. 3a-3e show a top plan view of a microfluidic apparatus according to the invention at various stages during its operation;

Fig. 4a and 4b show schematic representations of examples of 25 systems according to the invention;

Fig. 5a shows a schematic representation of an alternative apparatus according to the invention;

Fig. 5b shows a schematic representation of an alternative apparatus according to the invention; 10

Fig. 6 shows size distributions for emulsions produced with exemplary microfluidic systems, the small picture in the corner is a produced emulsion visualized via microscope;

Figs. 7a-7h show a typical shape of an interface between the oil and 5 water phases during droplet formation; and

Fig. 8 shows a graphic representation of droplet diameter as a function of pressure applied to the feed structure.

Detailed description of the invention 10 Fig. 1 shows a schematic representation of a microfluidic apparatus 1 according to the invention. In Fig. 1 the apparatus 1 comprises a droplet formation unit (DFU) 3. The droplet formation unit 3 comprises a feed opening 2. The droplet formation unit 3 also comprises a droplet formation opening 14. In Fig. 1 the droplet formation opening 14 is oblong, more specifically 15 rectangular. The droplet formation opening 14 has a first, smallest dimension or width W. The droplet formation opening 14 has a second, largest dimension or length L.

In Fig. 1 the droplet formation unit 3 is designed as a connection channel 6 forming a fluid connection between the feed opening 2 and the 20 droplet formation opening 14. In this example, the connection channel 6 is designed as a slot 8’ with a substantially constant cross section. The cross section of the connection channel 6 in this example corresponds to the dimensions L and W of the droplet formation opening 14. Hence, the width of the droplet formation unit 3 is in this example equal to the width W of the 25 droplet formation opening 14. Also, the length of the droplet formation unit 3 is in this example equal to the length L of the droplet formation opening 14. The connection channel 6 has a depth D, defined as the length in the direction from the feed opening 2 to the droplet formation opening 14. In this example, the depth of the droplet formation unit 3 is equal to the depth D of the 30 connection channel 6. Although in Fig. 1 the feed opening 2 is smaller than the 11 droplet formation opening 14, it will be appreciated that the feed opening 2 may also be equal to or larger than the droplet formation opening 14.

Note that Fig. 1 is schematic and is not drawn to scale. In this example, the length L of the droplet formation opening 14 may for instance be 5 5500 μηι, the width W of the droplet formation opening 14 may be 2.6 μπι and the depth D of the connection channel 6 may be 25 μηι. The second, largest dimension L of the droplet formation opening 14 is, hence, much larger, here more than 4500 times larger, than the first dimension W of the droplet formation opening 14. The third dimension D of the droplet formation unit 3 is, 10 hence, larger, here more than nine times larger, than the first dimension W of the droplet formation opening 14.

In the example of Fig. 1 the length Lfs of the feed structure 2’ may for instance be 5500 μπι, and the width Wfs of the feed structure 2’ may for instance be 2.6 μπι, while the depth Drs of the feed structure 2’may be 5 μπι.

15 In the example of Fig. 1 the flow resistance of the droplet formation unit 3, Rdfu, can be approximated by Rdfu = K-D/(W3L), wherein K is a geometry dependent constant which is 12 in this case (see Perry’s 7th edition, equations 6-36 and 6-51). Hence, the flow resistance of the droplet formation unit 3 of Fig. 1 is approximately 3.1 nr3. The flow resistance Rfs of the feed 20 structure may be approximated by Rfs = K Dfs/(Wfs3 Lfs). Hence the flow resistance of the feed structure 2’ of Fig. 1 is approximately 0.62 nr3. Hence, the flow resistance of the droplet formation unit 3 is larger than the flow resistance of the feed structure 2’ in this example.

The droplet formation unit 3, i.e. the feed opening 2, the droplet 25 formation opening 14 and the connection channel 6, is in this example provided in a substrate 10. In this example the feed opening 2 is in fluid connection with a feed structure 2’ for supplying a to-be-dispersed phase first substance to the droplet formation unit 3. Further, in use, the apparatus 1 of Fig. 1 may be arranged such that the droplet formation opening 14 is in fluid 30 communication with a collection structure in which a continuous phase second 12 substance is present, such that the continuous phase second substance is present at or flows across the droplet formation opening 14.

The microfluidic apparatus 1 as described thus far with respect to Fig. 1, may be operated as follows.

5 A to-be-dispersed phase first substance Pd is supplied to the feed opening 2. The feed rate at which the to-be-dispersed phase substance Pd is supplied to the feed opening 2 may in this example be approximately 340 μΐ/s. A continuous phase second substance Pc is supplied to the collection structure to be present at the droplet formation opening 14. In this example the 10 continuous phase may be an aqueous phase. In this example the to-be- dispersed phase may be a fat or gas phase. A pressure difference is applied such that the to-be-dispersed phase substance Pd is at an overpressure with respect to the continuous phase substance Pc. The overpressure may be approximately 0.01-10 bar.

15 The to-be-dispersed phase substance Pd flows via the feed opening 2 into the droplet formation unit 3. The to-be-dispersed phase substance Pd will displace continuous phase substance Pc present in the droplet formation unit 3, here in the connection channel 6, until the droplet formation unit 3 is substantially entirely filled with the to-be-dispersed phase substance.

20 When the to-be-dispersed phase substance Pd continues to be fed into the feed opening 2, droplet formation will occur at the droplet formation opening 14. Droplet formation may occur at many locations along the length L of the droplet formation opening 14 simultaneously. The size of the droplets formed at the droplet formation opening 14 will be very homogeneous. Upon 25 formation, the droplets will be forced out of the droplet formation unit 3 into the (flow of) the continuous phase substance Pc.

Fig. 2 shows a schematic representation of an alternative microfluidic apparatus 1 according to the invention. In Fig. 2 the apparatus 1 comprises a feed structure 2’. The feed structure 2’ has a depth Drs and a first 30 width Wfs. In Fig. 2 the apparatus 1 further comprises a collection structure 4.

13

The collection structure has a depth Dcs and a second width Wcs. In Fig. 2 the apparatus 1 further comprises a droplet formation unit 3 designed as the connection channel 6 forming a fluid connection between the feed structure 2’ and the collection structure 4. In this example, the droplet formation unit 3 is 5 designed as a plateau 8. The droplet formation unit 3 and the feed structure 2’ are in fluid communication at the feed opening 2.

The feed structure 2’, collection structure 4 and droplet formation unit 3 are in this example provided in a substrate 10. Towards a top side the structures 2, 4, 6 are closed by a cover 12, shown in phantom in Fig. 2. It will 10 be appreciated that instead of a separate cover 12, also a further substrate may be placed on top of the substrate 10 to close the top side of the structures 2, 4, 6.

In Fig. 2, the connection channel 6 mouths into the collection structure 4 at the oblong droplet formation opening 14.

15 It will be appreciated that a first, smallest dimension or width W of the droplet formation opening 14 in this example corresponds to the width, WP, of the plateau 8. It will be appreciated that a second, largest dimension or length L of the droplet formation opening 14 in this example corresponds to the length, Lp, of the plateau 8.

20 Note that Fig. 2 is schematic and is not drawn to scale. In this example, the length L of the droplet formation opening 14 may for instance be 500 pm, the width W of the droplet formation opening 14 may be 1.2 pm and the depth D of the connection channel 6 may be 200 pm. The second, largest dimension L of the droplet formation opening 14 is, hence, much larger, here 25 more than 190 times larger, than the first dimension W of the droplet formation opening 14. More in general, the second, largest dimension L of the droplet formation opening 14 is much larger, i.e. more than fifty times larger, than the first dimension W of the droplet formation opening 14. It has been found that better results may be achieved if the second dimension L is more 30 than eighty, preferably more than one hundred, times the first dimension W.

14

The third dimension D of the droplet formation unit 3 is larger, here more than 166 times larger, than the first dimension W of the droplet formation opening 14. More in general, the third dimension D of the droplet formation unit is larger, i.e. more than two and a half times larger, than the first dimension W 5 of the droplet formation opening 14. It has been found that better results may be achieved if the third dimension D is more than five, preferably more than ten, times the first dimension W.

In the example of Fig. 2 the width Wfs of the feed structure 2’ is substantially equal to the width W of the droplet formation unit 3. The length, 10 LfS of the feed structure 2’ is in this example 300 μκα. The depth DfS of the feed structure 2’ is in this example 40 μπι.

In the example of Fig. 2 the flow resistance of the droplet formation unit 3, Rdfu, can be approximated by Rdfu = K-D/(W3 L), wherein K is a geometry dependent contant which is 12 in this case (see Perry’s 7Lh edition, 15 equations 6-36 and 6-51). Hence, the flow resistance of the droplet formation unit 3 of Fig. 2 is approximately 2.78 nr3. The flow resistance Rfs of the feed structure may be approximated by Rfs - K Dfs/(Wfs3 Lfs). Hence the flow resistance of the feed structure 2’ of Fig. 2 is approximately 0.93 m3. Hence, the flow resistance of the droplet formation unit 3 is larger than the flow 20 resistance of the feed structure 2’ in this example.

In Fig. 2 the first, smallest dimension W of the droplet formation opening 14 is smaller than the width Wcs of the collection structure 4. Preferably, the first dimension W is more than ten, preferably more than fifty times smaller than the width WCSg of the collection structure 4.

25 The microfluidic apparatus 1 as described thus far with respect to

Fig. 2, may be operated as follows.

A to-be-dispersed phase first substance Pd is supplied to the droplet formation unit 3 via the feed structure 2’ in the direction of arrow F (see Fig. 3a). The feed rate at which the to-be-dispersed phase substance Pd is supplied 30 to the feed opening 2 may in this example be approximately 11 μΐ/s. A

15 continuous phase second substance Pc is supplied to the collection structure 4 in the direction of arrow G (see Fig. 3a). In this example the continuous phase may be an aqueous phase. In this example the to-be-dispersed phase may be a fat or gas phase. A pressure difference is applied such that the to-be-dispersed 5 phase substance Pd is at an overpressure with respect to the continuous phase substance Pc. The overpressure may be approximately 0.01-10 bar.

The to-be-dispersed phase substance Pd flows through the feed opening 2 onto the plateau 8 (see Fig. 3b). The to-be-dispersed phase substance Pd will displace continuous phase Pc product present on the plateau 8 until the 10 plateau is substantially entirely covered with the to-be-dispersed phase substance (see Fig. 3c). It is noted that the corners of the plateau 8 may be free of to-be-dispersed phase substance due to Laplace pressure differences. The droplet formation unit 3 will then be substantially entirely filled with the to-be-dispersed substance.

15 When the to-be-dispersed phase substance Pd continues to be fed into the feed opening 2, droplet formation will occur at the edge 16 of the plateau 8 (see Fig. 3d). Droplet formation may occur at many locations at the edge 16 of the plateau 8 simultaneously. A size of the droplets formed at the edge 16 of the plateau 8 will be very homogeneous. Again, the corners of the 20 plateau 8 may be not used due to Laplace pressure differences.

Upon formation, the droplets will enter the collectyion structure 4 and will be forced out of the apparatus 1 by the flow of the continuous phase substance Pc (see Fig. 3e).

The width difference between plateau 8 (Wp) and collection structure 25 4 (Wes) is believed to play a role in spontaneous droplet generation. Preferably the width Wcs of the collection structure 4 is at least ten times larger than the width WP of the plateau 8, more preferably at least fifty times larger, most preferably at least eighty times larger.

In the example of Fig. 1 the volume V of the connection channel 6 of 30 the DFU 3 is approximately 3.575· 105 pm3. Further, the volume Vdrop of the 16 droplets to be formed is at least approximately 1150 μηα3 (65-W3). Hence, the volume of the connection channel is approximately 310 times the volume of the droplet to be formed.

In the example of Fig. 2 the volume V of the connection channel 6 of 5 the DFU is approximately 1.2-105 μηι3. Further, the volume Vdrop of the droplets to be formed is at least approximately 112 μιη3 (65-W3). Hence, the volume of the connection channel is approximately 1070 times the volume of the droplet to be formed.

More in general, the volume V of the connection channel 6 is 10 preferably chosen such that it is at least one hundred times the volume Vdrop of the droplet to be formed. Thus, the connection channel may contain a sufficient amount of the to-be-dispersed phase substance to supply the to-be-dispersed phase substance to the plurality of droplets being formed simultaneously.

It will be appreciated that in the examples of Fig. 1 and Fig. 2, the 15 feed rate at which the to-be-dispersed phase substance Pd is fed into the connection channel 6 via the feed opening 2 is at least one hundred times the volume Vdrop of the droplet to be formed per microsecond. It will be appreciated that the feed rate thus, is chosen such that the simultaneous formation of the plurality of droplets does not deplete the connection channel from the to-be-20 dispersed phase substance.

The microfluidic apparatus according to the invention is very well suited for scale-up of the process in an efficient way. Manufacturing the slot or plateau is not a serious challenge for the modern etching techniques. In addition, the microfluidic apparatus 1 can be considered as self-regulating; the 25 droplet formation position along the droplet formation opening 14 can be at many places at the same time. Moreover, operation of the microfluidic apparatus is straightforward. After pressurization, the connection channel 6 fills with the to-be-dispersed phase substance, and even if some disturbing factor (e.g., a speck of dust) is present, which influences the flow pattern, the 17 relatively large length L of the droplet formation opening 14 with respect to its width W, causes the connection channel 6 to fill regularly.

It will be appreciated that scale-up may be suitably achieved by placing a plurality of microfluidic apparatus according to the invention in 5 parallel. Additionally, or alternatively, the aspect ratio of the droplet formation opening 14 may be increased to increase the area available for droplet formation. It is for instance possible that the length L of the droplet formation opening is more than 150 times the width W, or even more than 250 times or 500 times. Preferably, the feed structure for the droplet formation unit having 10 such large aspect ratio is designed such that the flow resistance of the feed structure is smaller than the flow resistance of the droplet formation unit.

Fig. 4a shows an example of a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention. In the example of Fig. 4a, a single substrate 10 comprises a plurality of droplet 15 formation units 3.i (i=l,2,3,...) designed as connection channels 6.i connecting a common feed structure 2’ and a common collection structure 4. In this example, each connection channel 6.i of the plurality of connection channels 6.i forms a plateau 8.i. In this example the width WfS of the feed structure 2’ is chosen larger than the width Wp of the plateaus 8.i, while the length Lfs of the 20 feed channel of each apparatus is equal to the length Lp of the plateau of each apparatus. Hence, the flow resistance of the feed structure for each apparatus can easily be chosen to be smaller than the feed resistance of each droplet formation unit.

The system shown in Fig. 4a may comprise a cover 12 as shown in 25 Fig. 2. It is also possible that a plurality of substrates according to Fig. 4a are stacked, each subsequent substrate forming the cover for the next, underlying substrate. If the stacked substrates are removably connected, e.g. clamped together, the substrates may be removed from one another, allowing easy cleaning of the substrates.

18

Fig. 4b shows another example of a system for generating a dispersion comprising a plurality of microfluidic apparatus according to the invention. In the example of Fig. 4b, a single substrate 10 comprises the plurality of droplet formation units 3.i (i=l,2,3,...) designed as connection 5 channels 6.i each ending at a droplet formation opening 14.i. In the example of Fig. 4b, the connection channels 6.i are designed as the slots as in Fig. 1. Also in this example, all connection channels 6.i may be in fluid communication with a common feed structure 2’ and/or mouth into a common collection structure 4.

10 It is noted that in Fig. 4a the length LfS at which the feed structure 2’ opens into the connection channels 6.i is substantially equal to the length Lp, at which the connection channel 6 opens into the collection structure 4. It will be appreciated that hence the entire width of the plateau 8.i can easily be filled with the to-be-dispersed phase substance. Here is referred back to Figs. 2 and 15 3c where it is shown that also in that case, where the length Lrs of the feed structure 2’ at the connection channel 6 is smaller than the length L of the droplet formation opening 14.i at the collection structure 4, the entire width of the plateau is filled with the to-be-dispersed product.

It will be appreciated that if the length Lfs of the feed opening at the 20 connection channel 6 is substantially equal to, or larger than, the second dimension L of the droplet formation opening (e.g. the length Lp of the plateau 8) the depth D of the connection channel, e.g. corresponding to a depth Dp of the plateau 8, may be very short, e.g. in the order of several microns.

On the other hand, if the length Lfs of the feed opening at the 25 connection channel 6 is much narrower than the second dimension L, the depth D of the connection channel 6 may need to be much longer, e.g. substantially equal to the second dimension L, to allow the to-be-dispersed phase substance Pd to fill the entire length L of the connection channel 6.

It will be appreciated that if that if the length Lfs of the feed 30 structure 2’ at the droplet formation unit 3 is substantially equal to, or larger 19 than, the second dimension L of the droplet formation opening (e.g. the length Lp of the plateau 8) the flow resistance of the droplet formation unit 3 can easily be made to be larger than the flow resistance of the feed structure.

It will be appreciated that the system shown in Fig. 4b can be 5 referred to as a plate-like structure 10 having a plurality of slots therein. The length L and width W of these slots is chosen such that the length is more than fifty times the width. The slots can be designed such that the feed opening of each slot is substantially of equal size as the droplet formation opening 14.i. In such case, the depth D of each droplet formation unit is equal to a thickness of 10 the plate-like structure 10. The depth D of each droplet formation unit is chosen such that the depth D is at least two and a half times the width W of the slot. It will be appreciated that the feed structure may be formed by a hollow space provided at the bottom side of the plate-like structure, adjacent to the feed openings 2, in fluid communication with said feed openings. The 15 dimensions of such feed structure can easily be designed such that the flow resistance of the feed structure is smaller than the flow resistance of the combined droplet formation units. Hence, proper filling of the droplet formation units with the to-be-dispersed phase substance can be assured.

Fig. 5a shows another example of a microfluidic apparatus 1 for 20 generating a dispersion. In Fig. 5a the apparatus 1 comprises the droplet formation unit (DFU) 3. The droplet formation unit 3 comprises the feed opening 2. The droplet formation unit 3 also comprises the droplet formation opening 14. In Fig. 5a the droplet formation opening 14 comprises a plurality of sections 15.j ()=1,2,3,...) which are connected to together form the droplet 25 formation opening 14 having a total (unfolded) length which is more than fifty times a width of the droplet formation opening. It will be appreciated that the corners in the droplet formation opening 14, where the respective sections join, may serve as droplet nucleation structure to aid in forming the plurality of droplets simultaneously. More in general, such nucleation structure may be 20 formed by a change in direction of the droplet formation opening in the plane of the droplet formation opening.

Fig. 5b shows yet another example of a microfluidic apparatus 1 for generating a dispersion. In Fig. 5b the apparatus 1 comprises the droplet 5 formation unit (DFU) 3. The droplet formation unit 3 comprises the feed opening 2. The droplet formation unit 3 also comprises the droplet formation opening 14. In Fig. 5b the droplet formation unit 3 comprises a plurality of nucleation structures 17.k (k=l,2,3,...). In this example, such nucleation structure 17.k is designed as a local widening of the width W of the droplet 10 formation unit 3. The nucleation structure acts as a preferential site for droplet generation. Preferably, a distance between two adjacent nucleation structures is chosen to be less than a distance at which droplets would “automatically” be generated without the presence of nucleation structures. As already explained, the formed droplets have a diameter Ddrop of approximately 15 five to eight times the first dimension (Ddrop = 5-W to 8-W). Hence, the distance between two adjacent nucleation structures is preferably chosen to be 8-W or less, more preferably 5-W or less. Preferably the distance between two adjacent nucleation structures is not less than Ddrop.

In the example of Fig. 5b the droplet formation unit 3 is designed as 20 the slot 8’. It will be appreciated that it is also possible to provide the nucleation structures in the droplet formation unit designed as the plateau 8.

The examples shown thus far may have been produced by etching the connection channels 6, and optionally the feed structure 2’and collection structure 4, into the substrate 10 from the top side. Hence in the example of 25 Fig. 2, the top side of all structures 2’,4,6, may extend in one plane (e.g. the bottom plane of the cover 12) while the bottom side of the structures may extend at different planes due to differences in widths of the respective structures. In the example of Fig. 1 the feed structure 2’ and connection channel 6 are machined through the thickness of the substrate 10. The 30 connection channel 6 mouths into the collection structure 4 at the oblong 21 opening 14. Note that in Fig. 1 the colection structure 4 is partially bounded by a top surface 22 of the substrate. However, different geometries are also conceivable.

In the examples of Figs. 2-4a, the continuous phase product flows 5 through the collection structure 4 in a direction substantially parallel to the largest dimension L of the droplet formation opening 14. In the example of Figs. 1 and 4b, however, the continuous phase product may flow through the collection structure 4 in a direction substantially parallel to the smallest dimension W of the droplet formation opening 14.

10

Example A silicon microchip substrate 10 of 1.5 x 1.5 cm was provided. The structures, also referred to aschannels, 2’, 4, 6 were etched in the silicon microchip with the Deep Reactive Ion Etching (DRIE) technique (Micronit 15 Microfluidics, The Netherlands). A glass plate 12 was bonded on top of the microchip to close the channels. Hydrophilic surfaces needed for oil-in-water emulsion production were formed in the channels 2’, 4, 6, in this way by the silicon and the glass. The microfluidic apparatus comprised an oil feed channel 2’ of 200 pm wide (Wfs) and 100 pm deep (D&). The continuous phase collection 20 channel 4 was also 200 pm wide (Wcs) and 100 pm deep (Dcs). In between the feed channel 2’ and the collection channel 4, there is a plateau 8 with fixed length (Lp = 500 pm) and depth (Dp = 200 pm). The plateaus 8 that were used have either of two widths (WP = 2.6 or 1.2 pm). Thus, the droplet formation opening has a length L of 500 pm and a width W of 2.6 or 1.2 pm, respectively. 25 The plateau 8 functions as droplet formation unit in this system. Two systems have been tested having a plateau width Wp of 1.2 pm (dotted line) and a plateau width Wp of 2.6 pm (solid line) respectively. Figure 2 gives a good impression of the microfluidic apparatus, but is not completely to scale.

The to-be-dispersed phase product Pd, such as oil, in this example 30 hexadecane (viscosity η = 3.34 mPas, as supplied by Merck KGaA, Darmstadt, 22

Germany), is guided to the plateau 8 via the oil feed channel 2’. In this example, a digital pressure controller (Bronkhorst, The Netherlands) was used to set and control the applied pressure. The pressure needed for hexadecane to flow onto the plateau 8 is determined by Laplace's law. If the pressure exceeds 5 this value, the oil flows on the plateau 8 and droplets will be formed at the droplet formation opening 14, where the droplets fall over the edge 16 into the collection channel 4 guiding MilliQ ultra pure water with 1 % SDS as surfactant as the continuous phase product Pc in this example.

Droplet formation at the edge 16 of the plateau 8 occurs at many 10 locations at the edge of the plateau simultaneously, albeit that the corners of the plateau 8 are not used due to Laplace pressure differences. With a constant applied pressure on the oil, monodisperse hexadecane droplets can be formed at frequencies of more than 300 Hz per droplet formation unit. The droplet sizes of emulsions produced with both the tested systems have been analyzed 15 through image analysis and with a Mastersizer 2000 (Malvern Instruments Ltd., United Kingdom). The resulting droplet size distributions are depicted in Fig. 6. The volume weighted average droplet size for the 2.6 μιη plateau depth system is 15.55 μιη with a Span of 0.346 (CV = 16 %). For the 1.2 μηι plateau width system, these values are 7.20 μιη and 0.236 (CV ~ 10 %), respectively. In 20 conclusion, the produced emulsions have a narrow distribution, especially when compared to emulsions made by homogenization.

To study the droplet formation process in more detail, sequential close-up images of a single droplet were made. Figs. 7a-7h show a typical shape of an interface between the oil and water phases during droplet 25 formation. In use the interface between the oil phase and the water phase is present at the droplet formation opening. Each of the Figs. 7a-7h bears an indication of the time at which the image was taken.

The droplet grows in time, which results in a decrease in Laplace pressure in the droplet. The droplet in Figs. 7a-7h is still connected to the 30 plateau through a neck N. Very close to the edge 16 of the plateau 8, the local 23 pressure in the neck N will be approximately equal to the Laplace pressure in the droplet. The pressure on the plateau 8 and also the neck N is determined by two curvatures; in this case, one of them (x-z plane) is fixed at a value of half the width of the plateau (Rpi = WP/2). The curvature in the x-y plane (RP2) 5 can have different values and has to become negative if the droplet radius (Rd) becomes twice as large as the fixed curvature (Rpi) on the plateau 8, due to the decrease of the pressure in the growing droplet. We can describe this with 2σ / Rd(t) = σ / Rpi - σ / RP2(t). While RP2 is very large before a droplet has been formed, it assumes a much smaller value as soon as the droplet is present. The 10 counter-pressure σ / RP2(t) stabilizes the neck N, which therefore can be stable for some time.

It is noted that in general it applies that the dynamics of the interface between the to-be-dispersed phase product and the continuous phase product at droplet formation opening induce the necking, and are different 15 from the dynamics in prior art microchannel systems. In general the interface between the to-be-dispersed phase and the continuous phase is present at the droplet formation opening. It will be clear that the interface bulges outwardly of the droplet formation unit into the continuous phase product at locations where the droplets are formed and may recede adjacent to these droplet 20 formation locations. Nevertheless, on average the interface between the to-be-dispersed phase and the continuous phase is present at the droplet formation opening. Moreover, in the microfluidic apparatus according to the invention droplet formation occurs simultaneously at many locations over the length of the droplet formation opening 14; thus the whole droplet formation opening 25 contributes to the productivity.

In close-up movies that were made, it has been observed that the curvature in the x-y plane indeed becomes more and more negative in time. The curvature RP2 in each of Figs. 7a-7h corresponds to these values, which underpins the explanation of the observed interfacial behavior. Also, further 30 away from the droplet formation position, the local pressure will be higher 24 than in the neck, which follows from the increasing Rpi along the interface further away from the neck. With the forced decrease in RP2 a quasi-static neck near the edge is created. This may be caused by the Laplace pressure in the droplet, and thus neck, not changing very rapid anymore with the growth of 5 the droplet. In this situation, as long as the amount of oil flowing into the droplet does not exceed the amount of oil flowing into the neck from the surrounding area on the plateau, the droplet will remain attached. Evidently, the droplet will detach once the supply is exceeded by the outflow. Although the interface can be seen to slightly recede near the droplet formation location, 10 it is clear that the plateau is not depleted from oil during droplet formation. Thereto, the oil feed rate is chosen to be sufficient to replenish the oil present on the plateau.

An interesting aspect is the dependency of droplet diameter Ddrop on the applied pressure in a system as depicted in Fig. 8. D,]rop has in this 15 example been determined with image analysis software (ImagePro Plus), and 100 droplets have been measured. An increase in applied pressure results in a substantially constant Ddrop (around 7 μηι) at lower pressures. Hence, a broad practical pressure range is available at which a monodisperse emulsion can be formed. In this pressure range, 250-350 mbar in this example, the oil supply 20 over the plateau is small compared to the flow into the droplet. At higher applied pressures, the droplet diameter increases with the applied pressure. It has been found that the pressure range in which the droplet diameter is substantially constant is larger if the difference between the flow resistance of the feed structure and the droplet formation unit is larger. This pressure range 25 may also be enlarged by providing the droplet formation unit having a larger flow resistance at its droplet formation opening than at its feed opening, e.g. a droplet formation unit which has a length L which decreases when going from the feed opening to the droplet formation opening.

It has been found that an important factor that determines the 30 droplet diameter in the pressure independent range (see Fig. 8) is the width of 25 the plateau WP. The droplet diameter appears to scale with the width of the plateau, while being approximately five to eight times, e.g. approximately six times, the width of the plateau.

In the foregoing specification, the invention has been described with 5 reference to specific examples of embodiments of the invention. It will, however, be evident that various modifications and changes may be made therein without departing from the broader spirit and scope of the invention as set forth in the appended claims.

In Figs. 4a and 4b the feed structure 2’ and the collection structure 4 10 are substantially parallel. It is for instance also possible that that the feed structure forms branches and the collection structure circumscribes the branches. In such embodiment the connection channels may be substantially radially oriented or otherwise.

In the example of Fig. 2 the width of the feed structure is 15 substantially identical to the width of the connection channel. In the example of Fig. 4a the width of the feed structure is substantially identical to the width of the collection structure. It will be appreciated that the width of the feed structure may be chosen to suit the application. Preferably, the width of the feed structure is chosen such that the feed structure does not form such flow 20 restriction as to cause an undue pressure drop in the to-be-dispersed phase product.

In the examples the to-be-dispersed phase product is a liquid fat or oil phase product (or air) and the continuous phase product is a liquid aqueous phase product. It will be appreciated that also other products may be used.

25 It is for instance possible that the to-be-dispensed phase is an aqueous substance and the continuous phase is an oil, to form a dispersion of e.g. water in oil. It is also possible to form a dispersion comprising a solid substance in oil (nano suspension) in water, a (biodegradable) polymer solution into water, a solution of a (biodegradable) polymer and a drug into water, a 30 mixture of a lipid (melt) and a drug into water, a monomer (solution) into 26 water, an oligomer (solution) into water, a mixture of oil/solvent, cosolvent, polymer, oil, lipids, actives into water. All of these may additionally be provided with extra ingredients such as pharmaceutical excipients, surfactants, stabilizers, thickeners, (para)magnetic, radioactive, radio 5 labelable, fluorescent or phosphorescent ingredients etc. In general, the dispersion to be formed may e.g. be any lipophilic fluid mixture and/or solution and/or suspension into any hydrophilic fluid mixture and/or solution and/or suspension and vice versa.

It is also possible that droplets formed with the microfluidic 10 apparatus according to the invention are transformed into micro particles or nano particles or capsules. Thereto, various techniques may be applied such as cooling, solvent extraction, solvent evaporation, phase separation, (suspension) polymerization, or other chemical reactions.

The droplets may serve as seed as part of seed swelling techniques 15 for generating particles.

In particular the particles formed out of droplets produced with the microfluidic apparatus according to the invention may be used for controlled release drug delivery and/or for application in separation processes in the life sciences industries. Examples are PLGA microsphere based drug delivery 20 systems, magnetic polymer or glass beads. Particle based contrast agents.

The droplets may also act as reaction chambers in processes such as emulsion PCR.

It is for instance also possible that the to-be-dispersed phase product is a gas (mixture) or vapour, so as to manufacture a dispersion of bubbles in a 25 (liquid) continuous phase product.

Alternatively, it is possible that the continuous phase product is a gas (mixture) or vapour, so as to manufacture a mist of droplets, e.g. in air. Such droplets may e.g. be dried so as to yield a spray dried to-be-dispersed product.

27

It is also possible that the to-be-dispersed phase product already is a dispersion. It is for instance possible that the to-be-dispersed phase product is a dispersion of an aqueous phase product, such as water, in a fat phase product, such as an oil. The microfluidic apparatus may then yield a fine 5 dispersion of water filled oil droplets in e.g. an aqueous continuous phase product, for instance for use in so-called “light” food products. Herein the water within the oil droplets may comprise an additive such as a flavour, colorant and/or medicine.

It is also possible that the to-be-dispersed product is a pre-mix, such 10 as a course dispersion comprising large droplets. Feeding the pre-mix through the droplet formation opening of the microfluidic apparatus according to the invention, causes the large droplets in the premix to be broken up into small droplets dispersed into the continuous phase product. Reducing the droplet size of the pre-mix in this way is herein also considered to constitute 15 generating a dispersion, viz. having smaller droplets and/or a narrower droplet size distribution.

However, other modifications, variations, and alternatives are also possible. The specifications, drawings and examples are, accordingly, to be regarded in an illustrative rather than in a restrictive sense.

20 In the claims, any reference signs placed between parentheses shall not be construed as limiting the claim. The word ‘comprising’ does not exclude the presence of other features or steps then those listed in a claim. Furthermore, the words ‘a’ and ‘an’ shall not be construed as limited to ‘only one’, but instead are used to mean ‘at least one’, and do not exclude a plurality. 25 The mere fact that certain measures are recited in mutually different claims does not indicate that a combination of these measures cannot be used to advantage.

Claims

Microfluidic device for generating a dispersion, comprising a drop-forming unit comprising a feed opening for supplying a phase first substance to be dispersed to the drop-forming unit, and an elongated drop-forming opening for forming drops of the phase first substance to be dispersed in a continuous phase second substance, wherein the drop-forming opening has a first, smallest dimension W and a second, largest dimension L, wherein the second dimension L of the drop-forming opening is more than fifty times the first dimension W of the drop-forming opening, wherein the drop-forming unit is a third dimension D has a direction from the feed opening to the drop-forming opening, the third dimension D being more than two and a half times the first dimension W, the microfluidic device further comprising a feed structure 15, in fluid communication with the feed opening for feeding from d The phase first substance to be dispersed on the drop-forming unit, wherein a flow resistance of the drop-forming unit is greater than a flow resistance of the feed structure.

A microchannel device according to claim 1, wherein the second dimension of the opening is more than eighty times, preferably more than one hundred times the first dimension of the opening.

3. Microfluidic device as claimed in any of the foregoing claims, further comprising: a collecting structure for supplying the continuous phase second substance, wherein the drop-forming opening opens into the guide channel.

Microfluidic device as claimed in any of the foregoing claims, wherein the drop-forming unit has a substantially constant, for instance substantially rectangular, cross-section corresponding to the dimensions of the drop-forming unit.

A microfluidic device according to any one of the preceding claims, wherein the width Wfs of the feed opening is substantially equal to the width W of the drop-forming opening. 10

A microfluidic device according to any one of the preceding claims, wherein a ratio of the depth and length (Dfe / Lfs) of the feed structure is smaller than a ratio of the depth and length (D / L) of the droplet opening. 15

A microfluidic device according to any one of the preceding claims, wherein the drop forming unit is formed by a tray with a width corresponding to the first dimension of the drop forming opening. 20

A microfluidic device according to claim 5, wherein the first dimension of the droplet opening is more than ten times smaller than a depth of the collecting structure, more preferably more than fifty times.

A microfluidic device according to any one of the preceding claims, wherein the first dimension of the droplet opening is between 0.05 and 25 µm, more preferably between 0.1 and 5 µm.

10. Microfluidic device as claimed in any of the foregoing claims, wherein the drop-forming opening and / or the entire drop-forming unit is manufactured, for example, ground, etched, milled, sandblasted and / or injection-molded, in a substrate, and / or built using spacers on a, for example, substantially flat, substrate.

11. Microfluidic device according to any one of the preceding claims, wherein the feed structure and / or the collecting structure is manufactured, for example, ground, etched, milled, sandblasted and / or injection molded, in a substrate, and / or built using spacers on a, for example, substantially flat, substrate.

A microfluidic device according to any one of the preceding claims, wherein the depth D of the drop-forming unit is such that, in use, the phase product to be dispersed fills the drop-forming unit over substantially the entire second dimension.

A microfluidic device according to any one of the preceding claims, wherein the droplet forming unit comprises at least one nucleation structure.

14. Microfluidic device according to claim 13, wherein the nucleation structure comprises a local increase in the width of the droplet opening, and / or a change in direction in the droplet opening.

A system for generating a dispersion comprising a plurality of microfluidic devices according to any one of the preceding claims. 25

A system according to claim 15, comprising a substrate containing a plurality of microfluidic devices according to any one of the preceding claims 1-14.

The system of claim 15 or 16, wherein the microfluidic devices are of claim 3, and wherein the feed structures of the respective devices are in fluid communication, the collection structures of the respective devices are in fluid communication, and the drop forming units of the respective devices are in parallel prepared. 5

18. A method for generating a dispersion, comprising supplying a phase first product to be dispersed to a drop-forming unit through a feed opening thereof, supplying a continuous phase second product to a drop-forming opening of the drop-forming unit, and adding it to the second product allowing the first product to come through a connecting channel and forming a fluid connection between the supply opening and the drop-forming opening, the drop-forming opening being elongated, and a second, largest dimension L of the drop-forming opening more than fifty times a first, smallest dimension W of the drop-forming opening is.