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Controlled production of emulsions and particles by milli- and microfluidic techniques
Current Opinion in Colloid & Interface Science 13 (2008) 206 – 216 www.elsevier.com/locate/cocis
Controlled production of emulsions and particles by milli- and microfluidic techniques ☆ W. Engl a , R. Backov b,1 , P. Panizza c,⁎ a
c
Department of Chemical Engineering, Yale University, P.O. Box 208284 New-Haven Connecticut 06520, USA b Centre de Recherche Paul Pascal, UPR CNRS 8641, 115 Avenue A. Schweitzer, 33600, Pessac, France Groupe Matière Condensée et Matériaux, UMR CNRS 6626, Université Rennes 1, Campus Beaulieu, 35000, Rennes, France Received 14 July 2007; received in revised form 10 September 2007; accepted 19 September 2007 Available online 26 September 2007
Abstract The recent developments of soft lithography and microfluidic techniques now permit the manipulation of small quantities of fluids with very good control and reproducibility. These advances open a new “bottom-up” route to emulsification that paves the way to the fabrication of calibrated hierarchically organized emulsions and particles. In this article, we describe the microfluidic techniques elaborated for engineering emulsions and new dispersed materials and discuss their advantages over “top-down” approaches. We review and comment the high potentialities these techniques offer to emulsion and colloid science, to the development of high-throughput set-ups for chemistry, physics and biology. We illustrate them through a few examples taken from the current literature. © 2007 Elsevier Ltd. All rights reserved.
1. Introduction Emulsions are metastable dispersions of one fluid in another immiscible. They are ubiquitous to our daily life since they concern many areas, as different as the food, paints, pharmaceutical, polymers, colloids or oil industry, where they occur either as end products or during the processing of products [1,2]. As end products, emulsions enable to avoid using organic solvents when processing hydrophobic coatings for paints, to vehicle viscous dispersed phases or to encapsulate, transport and vectorize active molecules. In product processing, emulsion droplets can also be used as reactors to engineer hierarchically organized dispersed materials such as for instance mesoporous silica capsules, polymer and ceramic spherical particles. Since most physical properties of these materials are size dependent, controlling their monodispersity as well as their uniformity in shapes and composition is a ☆ Major recent advances: Microchannel technology is a new “bottom-up” approach for emulsification and colloid science. Recent advances in scaling up droplet production and dimensions of microdevices yield promising prospects for transposing this technique into Industry. ⁎ Corresponding author. Tel.: +33 223235700; fax: +33 223236717. E-mail addresses: [email protected] (W. Engl), [email protected] (R. Backov), [email protected] (P. Panizza). 1 Tel.: +33 556845630; fax: +33 556845000.
1359-0294/$ - see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cocis.2007.09.003
necessity. From a practical point of view, monodispersity also enhances emulsion stability. As a result of many years of research, several emulsification techniques that produce emulsions with narrow droplet size distributions now exist. The proper choice of the process conditions is dictated by the value of the droplet mean size to reach. Thus, well calibrated fine (50 nm to 1 μm) emulsions are industrially produced by high-pressure microfluidic injection [3], whereas droplets of intermediate sizes (1 to several μm) are obtained using narrow gap shear devices [4]. All these “top-down” techniques handle huge quantity of droplets at the same time. In contrast, the recent advents made in microtechnologies and in microfluidics [5] these last few years, now open a new “bottomup” approach to emulsification. The goal of this review is to 1) describe and understand the numerous advantages such a methodology presents, and 2) discuss the numerous prospects it opens for material science and science. We first describe the various microfluidic devices and their flow configurations used to produce calibrated droplets. 2. Microfluidics: a new “bottom-up” approach to emulsification The high potentialities of the microfluidic fabrication approach stem from the possibility to generate highly monodisperse
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droplets, one at a time with an incomparable degree of control over size. This method leads to extremely narrow-sized distribution since no stabilization over coalescence is needed as collisions between droplets are suppressed during the droplet formation process and the transport in the channels. 2.1. Droplet production Several microchannel techniques exist to generate calibrated droplets depending on the type of technology used for the fabrication of the microfluidic devices. They are depicted in Fig. 1. With planar chips, designed using soft lithography or laser etching fabrication methods, two main configurations are now commonly used. Periodic trains of monodisperse droplets can form by colliding two immiscible fluids streams at a T-shaped junction (Fig. 1a) [6,7] or by using a flow focusing microdevice (FFD) where a 2D planar co-axial stream is forced to flow through a small orifice (Fig. 1b) [8]. With both configurations, experiments can be performed either by imposing the flow rates or the pressure drop of the various streams. In each case, the mechanism of droplet formation which results from a subtle interplay between confinement, viscous and capillary stresses leads to the production of periodic trains made of monodisperse droplets with extremely narrow size distribution. The mean droplet size can be fine-tuned by adjusting the flow parameters of the various streams from 10 μm, typically the lateral size of the channels used for the experiment, up to a few hundreds of microns. It decreases with the flow rate and
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viscosity of the continuous phase and increases with the flow rate of the dispersed phase [9–11]. The dispersion in droplet size is extremely low as the coefficient of variation (CV) defined as the ratio of the standard deviation of the droplet size over the mean size is typically lower than 5%. To decrease the droplet size, one may break the drops into controlled daughter droplets at a simple T junction [12] or at a junction of any arbitrary angle [13]. This passive method of break-up is very powerful since the size ratio of daughter droplets can be adjusted by modifying the hydrodynamic resistances of the two junction's outlets. It can be carried out in succession without increasing the polydispersity of the droplets until their dimensions are larger than the channel dimensions. A drawback of planar devices is that prior to droplet formation, both the to-be-dispersed and the continuous phases are in contact with the channel walls. It follows that the wetting properties of the materials constituting the channels play a key role since they control the nature and stability of the droplets with respect to phase inversion [14,15]. Thus, when oil preferentially wets the channels, as for instance with polydimethylsiloxane (PDMS) based microdevices, stable O/W droplets cannot be prepared. To avoid this problem, it is necessary to modify the wetting properties of the channels at the location where droplet are formed for instance by applying a specific surface treatment [16,17]. Droplets with comparable narrow size distribution can also be generated with non-planar microfluidic devices which do not necessitate any expensive technologies such as soft lithography
Fig. 1. Shown are different strategies used to generate monodisperse emulsions droplets one by one and images of the droplets obtained with these techniques: a) T junction in planar microfluidic devices, b) flow focusing microfluidic device and c) double capillary millifluidic set-up.
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or laser etching techniques for their design. One may thus extend the flow focusing method to 3D, by injecting the disperse fluid with a syringe pump through a capillary tube with an inner diameter of typically a hundred microns, inside a chamber pressurized by a continuous supply of another immiscible fluid [18,19]. When the tip of the feeding capillary tube faces the small exit orifice of the chambers, the outer fluid stream focuses and forces the injected disperse fluid to exit the chamber through the orifice producing a microjet. As a result of a capillary instability, the microjet then breaks up into a chain of nearly monodisperse droplets, much smaller than the exit orifice. Monodisperse drops in larger sizes can also be generated using double capillary devices, by injecting the disperse phase through the co-flowing matrix fluid (Fig. 1c) [20–23]. The setup consists of a blunt calibrated needle with a diameter φ of typically a few hundreds of micrometers, centred to a cylindrical glass capillary with a diameter of D ≥ φ.Using independent syringe pumps, two immiscible fluids are respectively infused through both the needle and the annular gap between it and the internal capillary wall. The flow rates are independently controlled and adjusted in order to form monodisperse droplets of the dispersed phase in the continuous one. Both W/O and O/W droplets can be prepared provided that the wetting properties of the internal capillary wall are compatible with the continuous phase. With glass surfaces, this can easily be done. Such devices
then allow the extension of the preparation of well calibrated emulsions up to sizes of a few millimeters. Emulsions with smaller sizes (typically a few tens micrometers) can be generated by using a double capillary device which consists of a cylindrical capillary tubes co-axially nested within a square glass [24••]. 2.2. Fabrication of double emulsions Microfluidic emulsification techniques offer a promising route to the fabrication of monodisperse double emulsions and to the tailoring of complex architecture. It is the only technique which enables to encapsulate 100% of an active product in a single step and to control the nature of the encapsulated objects. To illustrate this, let us consider the fabrication of double emulsions, which consists of emulsion drops containing smaller droplets inside. In batches, the fabrication process usually requires two step processes: an emulsification of the inner droplets in the middle fluid followed by a second emulsification for dispersion [2]. In microfluidic planar devices, calibrated double emulsions can be generated with a mere succession of two T junctions as depicted in Fig. 2a [25••]. Aqueous droplets of uniform size are formed at a T junction by colliding water and oily flows. The resulting periodic train of W/O droplets is then directed towards another T junction placed downstream, to form monodisperse organic drops containing aqueous droplets within
Fig. 2. Shown are illustrations of the different microfluidic techniques used to produce double emulsions and corresponding images of emulsion droplets. I, M and O stand respectively for the inner, middle and outer fluids. a) The two steps drop break-up method using a planar device. Photograph of the droplet formation mechanism are reprinted from “Production of monodisperse double emulsions by two steps drop break-up in microfluidic devices”, Okushima S., Langmuir, 2004, 20:9905–9908. with permission from ACS. b) 3D equivalent of the double step drop break-up technique using double capillary devices. Images of the droplets are reprinted from “Controlled production of hierarchically organized large emulsions and particles using assemblies on line of co-axial flow devices”, Panizza P. et al., Colloids Surf. A: Physicochem. Eg. Aspects (2007), doi:10.1016/j.colsurfa.2007.06.026 with permission from Elsevier and c) microcapillary device used to break-up concentric streams and form monodisperse double emulsions or core-shells (images are reprinted from “Monodisperse double emulsions generated from a microcapillarydevice”, Utada A.S. et al., Science, 2005, 308:537–541 with permission from AAS.
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an external aqueous phase. The sizes of drops and inner droplets can be fine-tuned independently by adjusting the flow rate values of the various streams. Moreover, the number of encapsulated droplets can also be monitored independently from their size and that of the drops. This can be achieved by performing an additional injection or withdrawing of the continuous phase between the two T junctions using another T junction. This enables to dilute or concentrate the initial W/O droplet train before its encapsulation without altering the droplet size. From a practical point of view, double W/O/W emulsions can only be prepared provided that the upstream and downstream T junctions, used to form droplets and drops are respectively hydrophobic and hydrophilic. O/W/O emulsions are prepared by inverting the wetting properties of these two junctions. This method is very versatile. It can successfully be transposed to 3D as shown in Fig. 2b and extended to more than two steps [26••]. W/O/W/O macroemulsions can then be prepared using an assembly of glass double capillary devices connected to each other by means of Plexiglas home-made modules. A promising feature of this multiple steps emulsification technique is the possibility to encapsulate in a same drop, droplets of various compositions and to control their sizes and respective ratio (Fig. 2a). When two droplet trains having the same continuous phase but droplets of different composition meet at a T junction, they form a periodic alternated train [27]. Monodisperse drops containing droplets of different composition are generated by injecting this droplet train through the needle of another double capillary device placed downstream. The size of the internal droplets, their respective number as well as the size of the drops can be tuned continuously and independently by changing the flow conditions [25••, 26••]. Double emulsions can also be generated in a single step process using a different strategy. The idea consists of destabilizing a liquid thread of two or more parallel co-flowing streams in order to form monodisperse drops containing droplets (Fig. 2c). This can be achieved for instance in planar microfluidic devices by forcing this liquid thread through the small orifice of a flow focusing geometry [28 •• ]. A similar approach has successfully been transposed to 3D by Utada et al. Their device consists of two cylindrical glass capillary tubes co-axially nested within an outer square glass tube and tapered at their facing ends as depicted in Fig. 2c [24 •• ] Three different fluids are simultaneously injected in the system at controlled flow rates. The innermost fluid is pumped through one of the inner tube, whereas the middle fluid is injected through the outer square capillary region, in the same direction. Since the outermost fluid is pumped through the outer co-axial region of the opposite direction, all fluids are forced through the exit orifice formed by the other inner cylindrical tube. The thread breaks up to produce double emulsion in the collecting tube. The size of the inner and outer droplets as well as the number of inner droplets can be monitored and varied with a very good degree of control. This technique offers an incomparable step forward for the production of core-shell droplets with a control over both droplet size and shell thickness [29]. For instance, core-shell droplets with a ratio of shell over size as low as 3% have been
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prepared. By photopolymerizing a polymer in the intermediate fluid, these structures can be used to form capsules. They can also be transformed into polymer vesicles by using for the middle phase a volatile fluid where diblock co-polymers are dissolved [30]. 2.3. Towards the tailoring of complex dispersed materials Synthesis of solid particles in planar microfluidic reactors is an excellent route to particles with unconventional shape and morphologies. In batches, dispersed materials obtained by using droplets as microreactors are generally spherical systems since the minimization of interfacial energy leads to spherical shapes during most syntheses, whether they are polymer latexes formed through emulsion polymerization or droplets formed using shear flows in microfluidic devices. This inherent difficulty can however be circumvented by using a microfluidic scheme which permits good controls of the droplets geometrical and concentration environments. In 2004–2005, several papers have thus demonstrated the possibility to generate non-spherical particles, such as disks, ellipsoids or rods by photopolymerizing monomer droplets on the “fly” while flowing in constrained geometries as illustrated in Fig. 3 [31–33]. Monodisperse monomer droplets with different volume are first produced using a flow focusing device by varying the flow rates of the continuous and droplet phases. These droplets are then forced to flow through a narrow channel in which polymerization takes place. Because of confinement, droplets adopt a non-spherical shape, dictated by a relationship between w and h, the two lateral dimensions of the channel and d, the diameter of an undeformed droplet. At low capillary numbers, for w N d and h N d, the droplets minimize their surface energy by taking a spherical shape whereas for h N d N w, and for situations where d N w and d N h, confinement suppresses the relaxation of their shape into spheres, and the droplets respectively deform into discoid or rod shapes. With this approach, the aspect ratio of the non-spherical droplets can be conveniently monitored by changing the ratio between the droplet volume and the dimensions of the microchannels. The fabrication of solid particles using continuous microfluidic reactors exhibit many features that distinguish it from batch polymerization of monodisperse emulsions produced by “top-down” emulsification methods [2–4]. The polydispersity of the solid particles obtained using microfluidic tools is comparable to that of the droplets prior to hardening, typically below 3%. This value is therefore much narrower than in the batch methods, where coalescence and Oswald ripening occur. In microfluidic reactors, no stabilization against coalescence of monomer droplets is necessary since their collisions are suppressed. Furthermore, polymerization in a confined geometry allows for the production of non-spherical shapes such as disks, rods or tubes with an independent and very good control over volume, shapes and aspect ratio. The ability to generate and to control composition gradients with microfluidic devices offers a unique route to synthesize colloids with complex architectures. A good illustrative example of this concept concerns the production of Janus particles obtained by breaking up a liquid thread of two parallel co-flowing streams of monomer
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Fig. 3. Schematic (a–c) and optical microscopy (a′–c′) images of particles obtained from with polymerization of deformed monomer droplets with different shapes: microspheres (a, a′), disks (b, b′) and rods (c, c′). Reprinted from “Continuous microfluidic reactors for polymer particles”, Seo M. et al., Langmuir, 2005, 11614–11622 with permission from ACS.
of two immiscible polymer solutions that is forced through a narrow orifice (Fig. 4). The resulting droplets present a Januslike structure, with an approximate flat interface between the adjacent polymer phases that can be solidified with an UV exposition, performed downstream [34•]. This synthesis method gives a precise control over the volume ratio of the constituent of the particles as well as their size. It can also be extended to generate ternary particles by breaking up a three parallel coflowing monomer streams. The possibility to perform independent operations on individual dispersed objects and to integrate them opens incomparable broad prospects for engineering new materials. Complex architectures prepared along these lines are now flourishing in literature. They include the fabrication of colloid-filled hydrogel Janus granules of tunable size, geometry and composition, the encapsulation of solid particles in liquid drops or the production of non-spherical objects with liquid compartments. Consider for instance, the fabrication of colloid-filled non-spherical Janus granules reported by Shepherd et al. [35]. It necessitates several operations. To start, monodisperse colloid-filled hydrogel Janus droplets are produced with a flow focusing device according to the method previously described, the two hemispheres of the droplets differing by their composition in colloids. These spherical droplets are then deformed, by flowing through a constrained geometry, while being photopolymerized.
2.4. Turning microfluidic emulsion technology into an industrial tool Microfluidic technology paves the way to a bottom-up approach to emulsion science that offers numerous prospects compared to the “top-down” techniques that handle large populations of droplets at each step of an industrial process. However, its impact in industry relies on the ability to generate high throughput. So far, it is limited because of the extremely small flow rates involved (typically of the order of 0.1 ml/h) in such devices. The formation rate of monodisperse droplets in a single FFD is only a few tens of droplets/s. The necessity to parallelize droplets generators such as FFD or T junctions is therefore the central issue for potential industrial applications. From a practical point of view, this issue turns out to be a real difficult task which raises numerous theoretical questions. By parallelizing devices with multiple nodes, branches and crossflows, one couples non-linear fluidic oscillators. At low Reynold numbers, monophasic flows of Newtonian fluids in a network made of channels are governed by linear equations since the flow rate of a fluid flowing through a channel is proportional to the pressure drop applied to the extremities of this channel. Such interconnected flows can be solved using an analogy with resistors electrical circuits and do not present any difficulty. In contrast, multiphase flows of immiscible fluids are highly non-
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Fig. 4. (a) Sheath-flow microfluidic device used to produce monodisperse colloid-filled hydrogel granules. b) Schematic representation of the granules shapes and composition. c) View of the parallel two streams prior to their dispersion in droplets. d) Formation of Janus droplets. Reprinted from “Microfluidic assembly of homogeneous and Janus colloid-filled hydrogel granules”, Shepherd R.F., Langmuir 2006, 22:8618–8622 with permission from ACS.
linear. Understanding such flows in hydrodynamic networks is a challenging problem in the field of hydrodynamics and nonlinear physics. Take for instance, a situation where a train of droplets or bubbles is directed towards a T junction and ask how the droplets and carrier phase divide between the two outlets [23]. When a droplet reaches the junction, two directions are possible if it does not break. The selection is triggered by the dominant stream so that the droplet flows into the outlet characterized by the lower hydrodynamic resistance. Since the presence of droplets in conducts increase the resistance to flow, there is a hydrodynamic feedback between choices of successive droplets. The outcome turns out to be a complex non-linear dynamical problem which may lead to chaos or quasiperiodicity. With such effects, producing droplets in parallel microfluidic devices yields to emulsions with large polydispersity [36]. A possible way to circumvent this difficulty of parallelization is to generate droplets without applying cross-flows. In the last two years, large efforts have been undertaken along this line by Nakajima's group in Japan [37•• ,38]. They have conceived and developed two different microchannel array devices able to generate monodisperse droplets with a production rate increased by a factor 100 and more with respect to single channel devices. The first device is a silicon microchannel (MC) array plate with a multilevel structure. The method consists of forcing the to-be-dispersed phase through an array made of several hundreds of parallel channels into a shallow well, filled with the continuous phase as depicted in Fig. 5 [37•• ]. This MC array plate is capable of generating monodisperse discoid droplets of O/W or W/O types without applying a forced cross-flow of the continuous phase, up to a thousand droplets per second. The other device consists of a silicon array of about 10 4 asymmetric straight through-holes
vertically microfabricated on a plate surface of a liquid chamber to supply the to-be dispersed phase [38]. Each asymmetric through-hole is composed of a slit (with typical length, width and depth values of respectively 100, 10 and 20 μm) and a cylindrical channel (typically 10 μm in diameter and 5 μm in depth). These through-holes are uniformly arranged with intervals of typically 100 μm across the asymmetric straightthrough MC. The phase to disperse is injected through the array of vertical channels into the horizontal module filled with the continuous phase. This device can be applied to the preparation of monodisperse emulsions as well as microparticles and microcapsules. Since the formation rate of droplets from each active through-hole is typically a few tens of droplets/s, this apparatus can produce up to 10 5 droplets per second. 2.5. Scaling up microfluidics Scaling up these microdevices into millimetric ones presents some considerable advantages. Recently, a continuous co-axial flow scheme to engineer and industrially produce at low cost hierarchically organized structures of larger sizes with an incomparable degree of control over their size, shape and internal structure has been developed (Fig. 6) [26••]. The method consists of using an assembly of capillaries or flexible tubes (with diameters ranging from 50 μm to a few mm) put together with elementary home-made modules. This synthesis method is based on the association of three different elements able to achieve the basic following four functions used in microfluidic devices: (1) form periodic trains of monodisperse droplets with very good control over their size, (2) dilute–concentrate these trains while keeping the volume of droplets unchanged,
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Fig. 5. Schematic illustrations of the two techniques based on microchannel arrays developed by M. Nakajima's group to scale up production of monodisperse droplets and photographs of produced emulsions. a) The two level structures conceived to scale up droplet production is made of an array of several hundreds of parallel channels. The to-be-dispersed phase is injected through the microchannels into the shallow well filled with the continuous phase. (Left) Images of successfully generated O/W discoid droplets. Reprinted from “Controlled generation of monodisperse discoid droplets using microchannel arrays”, Kobayashi I. et al., Langmuir, 2006, 22:10893–10897 with permission from ACS. b) Mechanism of droplet formation using an asymmetric straight through-holes MC plate. (Right) An microscopic photographs of the resultant droplets. Reprinted from “Novel asymmetric through-hole array microfabricated on a silicon plate for formulating monodisperse emulsions”, Kobayashi I. et al., Langmuir, 2005, 21:7629–7632 with permission from ACS.
(3) generate periodic trains made of alternated droplets and (4) deform droplets in a controlled manner. Modular millifluidic set-ups can then be designed to produce newly controlled integrated architectures limited only by the number of combinations possible and one's creativity. The great versatility of this method is already illustrated through the encapsulation of droplets or solid particles of various shapes, composition and size, in liquid or solidified drops, the formation of large organic or inorganic cylindrical particles as well as the generation of double and triple emulsions. This strategy presents several advantages over microfluidic synthesis while keeping its specificities. Since no lithography, glass etching techniques or specific equipment are necessary for the design of the devices, their fabrication costs are low. The connecting capillary tubes and the various modules can assemble and disassemble easily so that modular set-ups can be designed on demand in a short time. This modularity is also considerable advantage from a practical point of view since modifying a hydrodynamic circuit on a planar microfluidic chip demands starting over at the lithography or glass etching level. Combined with the ability to modify very simply the wetting properties of the glass capillary tubes used for connection it offers the opportunity to fabricate multiple emulsions of
different nature with a same device. The use of such devices pave the way to an industrial integrative formulation of dispersed materials with very large characteristic sizes ranging from typically 100 μm to several mm and new complex architectures [39]. This should lead to the rapid emergence of new products in cosmetics or food where the texture and visual aspect plays a key role for sale. 3. Miniaturizing the laboratory using droplet-based microfluidic devices Monodisperse droplets generated by microfluidic devices can serve as microreactors to compartmentalize reactions and control the reaction time precisely [40]. One of the key properties of droplet-based high-throughput microfluidic devices stems from the uniform constant speed motion of droplets in the channel allowing equivalence between distance and reaction so that one can perform a stationary measurement of a kinetic process along the flow. Using this property, microfluidic platforms to perform kinetic measurements of fast and very fast reactions with better than millisecond resolution using very small volumes of reagents have recently
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Fig. 6. (a) Sketches of the different elementary tubular millifluidic modules and their corresponding basic functions. b) Shown are schematic representations of the different modular set-ups used to fabricate triple and double emulsions and images of emulsions produced with different number of internal droplets reprinted from “Controlled production of hierarchically organized large emulsions and particles using assemblies on line of co-axial flow devices”, Panizza P. et al., Colloids Surf. A: Physicochem. Eng. Aspects (2007), doi:10.1016/j.colsurfa.2007.06.026 with permission from Elsevier.
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been developed [40]. This microreactor technology is a very efficient alternative to batch chemical procedure, because of the rapidity of analysis and the low consumption of reagents. Furthermore, other advantages results from the high heat and mass transfer rates provided by microfluidic reactors which induce safe and fast syntheses and therefore may open new chemical reactions [41]. Briefly, the droplets are usually formed at a T junction by using the to-be-disperse phase, streams of the various reagents separated from each other by buffer streams in order to avoid premixing. Rapid mixing of the reagent inside the droplet is necessary since it determines the starting time of the reaction. This is achieved by chaotic advection when the droplets flow through a winding channel [42]. The composition of the reaction mixture at the reaction time, t, is then determined with spectroscopic techniques (UV–vis, Raman or Flurorescence) by analyzing the composition inside the droplets at the distance d = tU (where U is the velocity of the droplet) within the channel. Since the composition of reagents within each droplet carrier can be changed by simply varying the flow rates of the reagent streams, this technique can be used for screening of a target. Using droplets as microreactors is not limited to chemical reactions, but can apply to other fields such as for instance enzyme kinetics, DNA analysis, synthesis of nanoparticles or protein crystallization. We advise the reader to refer to the reviews written by R.F. Ismagilov to get more information and precision on the use of droplets in these various fields [43••]. Another interesting specificity of droplet-based microfluidic devices is the possibility to rapidly carry out many experiments (typically a few hundred per second) under the same controllable conditions. These features are well suited to study stochastic processes where many experiments are necessary to accurately measure the probability of a single event. A good example of this approach concerns, a dropletbased set-up recently developed by Laval et al. to investigate crystal nucleation kinetics [44•]. Monodisperse droplets of a solution are produced, convected along a channel and then rapidly submitted to a temperature quench so that nucleation may occur. The nucleation rate is then determined by measuring the probability that a droplet contains a nucleus at different positions along the channel on a large number of droplets. This technique presents numerous advantages over the classical droplet methods using emulsions. They include the production of monodisperse droplets of tunable size with no surfactant molecule which may induce heterogeneous nucleation, the rapidity of the temperature quench, the possibility to eliminate interactions between multiple nuclei by choosing small enough droplets and a fast and direct measurement of the proportion of crystallized droplets. This continuous method yields to rapid and reliable statistical measurements of the nucleation kinetics, and offers the opportunity to carry out high-throughput crystallization conditions [45]. The ability of microfluidic technology to produce, handle and manipulate single droplet in a very controlled way opens new prospects to study the physical properties and stability of emulsions, at the scale of an individual or two droplets. Along this line, a microfluidic interfacial tensiometer has been
conceived [46]. The method is based on quantitative real time observation and analysis of drop shape dynamics in microchannels. Drops of controlled diameter and spacing are produced at a T junction of two immiscible fluids and injected in a wider downstream channel where they become spherical. They are then deformed by flow constrictions. Measurements are performed at the exit or entrance of a constriction where the flow is respectively accelerating or decelerating, producing an extensional flow that deform the drops. This tensiometer gives very accurate and precise results, with very low reagent consumption and rapidity. Because of the equivalence between time and position along the channel, the age of the interface is known, so that information on the dynamic surface tension and kinetics of adsorption surfactant at the interface can be gained by using multiple constrictions along the channel. With no doubt, in the near future, microfluidic tools will be used to investigate the coalescence between two droplets. Such a study could for instance be performed by forming in a capillary tube an alternating train of small and large droplets using a T junction. Since in the downstream channel, the small droplets are convected faster than the large ones, coalescence events could therefore be observed and quantified. An important research field now deals with developing active techniques and new tools to handle droplets in microfluidic devices. 4. Conclusion and prospects Microfluidic technology offers a new “bottom-up” approach to emulsification which shows much promise in the emulsion field. By contrast to the “top-down” approach of other emulsification techniques, which operate on a very large number of droplets at each step, microfluidic generates one single droplet at a time with incomparable results in terms of size control. Its abilities to create chemical gradient and to handle each produced droplet individually lay the foundation of a new concept in colloidal science, that of Continuous Integrative Chemistry. The novelty and originality of this approach consists of using monodisperse droplet as individual chemical reactor and operating “on line” on each reactor to successively add a chemical or physical function at each step of a process. This integrative approach is based on several elementary functions that microfluidic tools can accomplish. These basic operations include formation of parallel streams with different composition, generation of monodisperse droplet trains, dilution and concentration of these trains, formation of alternated trains with droplet of different compositions, asymmetric droplet breaking-up, fusion of two droplets, controlled deformation of the droplets, and encapsulation. By combining and integrating these various functions with polymerization, solidification or any other chemical process, it then becomes possible to synthesize new dispersed materials with complex architecture. This methodology yields to a very good control of the size, shape, and internal structure of the manipulated objects, at each step of the process. It is for instance the only technique that can ensure encapsulation of an active product at 100% in a single step. Illustrative examples of the
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high potentialities of this approach are now numerous in literature. They concern for instance double emulsions with internal droplets of different composition, triple emulsions, nonspherical particles, Janus or ternary particles and core-shells. With no doubt, the further step to make is to combine microfluidic and millifluidic formulation methods to generate multiscale structured materials. By integrating these tools with classical emulsification techniques, the fabrication of multiple emulsions with four or five degrees of multiplicity and hierarchical sizes ranging from the micrometer for the innermost droplets up to typically a millimeter for the size of the outer drops should in principle be feasible. However, despite its numerous advantages, the microfluidic technology is not yet suitable as a production tool for industry because of the very small flow rate involved (typically of the order of a few hundreds of microliters per hours) in this type of devices. Consequently, a very important and active research work must now be devoted to overcome this limitation since both industrial and financial stakes are tremendous. Generating monodisperse droplets with controllable sizes and shapes and being able to manipulate them individually and reproductively in networks of small channels give the opportunity to miniaturize a laboratory down to a few inches per square [47, 48•]. This is the lab-on chip concept. Using droplets as individual microcarriers and reactors in such devices is very promising for developing high-throughput applications since reaction conditions can easily be compartmentalized and addressable [44•]. This approach enables to considerably increase and accelerate the number of tests up to a few tens per seconds, using very small amounts of materials. The prospects are numerous for many scientific fields where one target must be tested against a large number of reaction conditions. In chemical engineering, this continuous screening approach permits for instance to explore the conditions of a reaction, to optimize it and consequently to orientate the synthesis of new materials. For biology, it permits to efficiently and rapidly test the effect of a drug on viruses. The possibility with droplet-based microdevices to rapidly perform many experiments (typically a few hundred per second) under the same controllable conditions also opens many opportunities to address fundamental issues. These tools are thus well suited to study stochastic processes which necessitate a statistical analysis such as for instance coalescence phenomena or crystallization nucleation. In biology, such a digital highthroughput technique may give access to the statistical distribution of a population as a function of a stress [49]. Finally, on another level, flows of droplets occurring in microfluidic devices raise challenging questions in the field of hydrodynamics and non-linear physics [23,50]. To conclude, the recent progresses made in the production of droplets of controllable size and in their individual manipulation lead to novel approaches of emulsification and synthesis of complex materials, and the foundation of new scientific methods and applications in many different fields. Recent advances in scaling up droplet production and the dimensions of microdevices now allow to transpose these promising techniques into industry.
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• ••
Of special interest. Of outstanding interest.
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[25] Okushima S, Nisisako T, Torii T, Higushi T. Controlled production of •• monodisperse double emulsions by two-step droplet break-up in microfluidic devices. Langmuir 2004;20:9905–8. An outstanding paper that describes the continuous generation of calibrated double emulsions using microfluidics. [26] Panizza P, Engl W, Hany C, Backov R. Controlled production of •• hierarchically organized large emulsions and particles using assemblies on line of coaxial flow devices. Colloids Surf, A Physicochem Eng Asp 2007, doi:10.1016/j.colsurfa.2007.06.026. An important paper describing how to produce hierarchically organised large emulsions using an integrative synthesis approach based on the combination of modular millifluidic devices. [27] Zheng B, Tice JD, Ismagilov RF. Formation of droplets of alternating composition in microfluidic channels and applications to indexing of concentrations in droplet-based assays. Anal Chem 2004;76:4977–82. [28] Nie Z, Xu S, Seo M, Lewis PC, Kumacheva E. Polymer particles with •• various shapes and morphologies produced in continuous microfluidic reactors. J Am Chem Soc 2005;127:8058–63.A key paper describing and illustrating the background principles of the synthesis of non-spherical particles using microfluidics. [29] Kim JW, Utada AS, Fernandez-Nieves A, Hu Z, Weitz DA. Fabrication of monodisperse gel shells and functional microgels in microfluidic devices. Angew Chem Int Ed 2007;46:1819–22. [30] Lorenceau E, Utada AS, Link DR, Cristobal G, Joanicot M, Weitz DA. Generation of polymerosomes from double emulsions. Langmuir 2005;21:9183–6. [31] Jeong W, Kim J, Kim S, Lee S, Mensing G, Beebe DJ. Hydrodynamic microfabrication via “on the fly” photopolymerization of microscale fibers and tubes. Lab on a Chip 2004;4:576–80. [32] Seo M, Nie Z, Xu S, Mok M, Lewis PC, Graham R, et al. Continuous microfluidic reactors for polymer particles. Langmuir 2005;21:11614–22. [33] Xu S, Nie Z, Seo M, Lewis P, Kumacheva E, Stone HA, et al. Generation of monodisperse particles by using microfluidics: control over size, shape and composition. Angew Chem Int Ed 2005;44:724–8. [34] Nie Z, Li W, Seo M, Xu S, Kumacheva E. Janus and ternary particles • generated by microfluidic synthesis: design, synthesis and self-assembly. J Am Chem Soc 2006;128:9408–12. A key article to understand the microfluidic fabrication of Janus particles. [35] Shepherd RF, Conrad JC, Rhodes SK, Link DR, Marquez M, Weitz DA, et al. Microfluidic assembly of homogeneous and Janus colloid-filled hydrogel granules. Langmuir 2006;22:8618–22. [36] Barbier V, Willaime H, Tabeling P, Jousse F. Producing droplets in parallel microfluidic systems. Phys Rev E 2006;74:046306–9.
[37] Kobayashi I, Uemura K, Nakajima M. Controlled generation of •• monodisperse discoid droplets using microchannel arrays. Langmuir 2006;22:10893–7. An important paper that describes a way to scale-up droplet microfluidic production. [38] Kobayashi I, Mukataka, Nakajima M. Novel asymmetric through-hole array microfabricated on a silicon plate for formulating monodisperse emulsions. Langmuir 2005;21:7629–32. [39] Tachibana M, Engl W, Panizza P, Deleuze H, Lecommandoux S, Ushiki H, et al. Combining sol–gel chemistry and millifluidic toward engineering microporous silica ceramic final sizes and shapes: an integrative chemistry approach. Chem Eng Process 2007, doi:10.1016/j. cep.2007.04.010. [40] Song H, Ismagilov RF. Milliseconds kinetics on a microfluidic chip using nanoliters of reagents. J Am Chem Soc 2003;125:14613–9. [41] Brivio M, Verboom W, Reinhoudt DN. Miniaturized continuous flow reaction vessels: influence on chemical reactions. Lab on a Chip 2006;6:329–44. [42] Song H, Bringer MR, Tice JD, Gerdts CJ, Ismagilov RF. Experimental test of scaling of mixing by chaotic advection. Appl Phys Lett 2003;83: 4664–6. [43] Ismagilov RF. Reactions in droplets in microfluidic channels. Angew Chem •• 2006;45:7336–56. An up-to-date review describing the principles and recent advances of droplet-based microfluidics, for high through-put. [44] Laval P, Salmon JB, Joanicot M. A microfluidic device for investigating • crystal nucleation kinetics. J Cryst Growth 2007;303:622–8.An important paper showing how droplets produced by microfluidic tools can be used to investigate ad characterize stochastic processes. [45] Zheng B, Roach LS, Ismagilov RF. Screening of protein crystallization conditions on a microfluidic chip using nanoliter-size droplets. J Am Chem Soc 2003;125:11170–1. [46] Hudson SD, Cabral JT, Goodrum WJ, Beers KL, Amis EJ. Microfluidic interfacial tensiometry. Appl Phys Lett 2005;87:081905(1)–3). [47] DeMello AJ. Control and detection of chemical reactions in microfluidic systems. Nature 2006;442:394–402. [48] Janasek D, Frankze J, Manz A. Scaling and the design of miniaturized • chemical analysis systems. Nature 2006;442:374–80. An interesting paper to understand the advantages of miniaturization for Chemistry. [49] Elowitz MB, Levine AJ, Siggia ED, Swain PS. Stochastic gene expression in a single cell. Science 2002;297:1466–70. [50] Garstecki P, Fuerstman MJ, Withesides GM. Oscillations with uniquely long periods in a microfluidic bubble generator. Nature Physics 2005;1:168–71.
Controlled production of emulsions and particles by milli- and microfluidic techniques ☆ W. Engl a , R. Backov b,1 , P. Panizza c,⁎ a
c
Department of Chemical Engineering, Yale University, P.O. Box 208284 New-Haven Connecticut 06520, USA b Centre de Recherche Paul Pascal, UPR CNRS 8641, 115 Avenue A. Schweitzer, 33600, Pessac, France Groupe Matière Condensée et Matériaux, UMR CNRS 6626, Université Rennes 1, Campus Beaulieu, 35000, Rennes, France Received 14 July 2007; received in revised form 10 September 2007; accepted 19 September 2007 Available online 26 September 2007
Abstract The recent developments of soft lithography and microfluidic techniques now permit the manipulation of small quantities of fluids with very good control and reproducibility. These advances open a new “bottom-up” route to emulsification that paves the way to the fabrication of calibrated hierarchically organized emulsions and particles. In this article, we describe the microfluidic techniques elaborated for engineering emulsions and new dispersed materials and discuss their advantages over “top-down” approaches. We review and comment the high potentialities these techniques offer to emulsion and colloid science, to the development of high-throughput set-ups for chemistry, physics and biology. We illustrate them through a few examples taken from the current literature. © 2007 Elsevier Ltd. All rights reserved.
1. Introduction Emulsions are metastable dispersions of one fluid in another immiscible. They are ubiquitous to our daily life since they concern many areas, as different as the food, paints, pharmaceutical, polymers, colloids or oil industry, where they occur either as end products or during the processing of products [1,2]. As end products, emulsions enable to avoid using organic solvents when processing hydrophobic coatings for paints, to vehicle viscous dispersed phases or to encapsulate, transport and vectorize active molecules. In product processing, emulsion droplets can also be used as reactors to engineer hierarchically organized dispersed materials such as for instance mesoporous silica capsules, polymer and ceramic spherical particles. Since most physical properties of these materials are size dependent, controlling their monodispersity as well as their uniformity in shapes and composition is a ☆ Major recent advances: Microchannel technology is a new “bottom-up” approach for emulsification and colloid science. Recent advances in scaling up droplet production and dimensions of microdevices yield promising prospects for transposing this technique into Industry. ⁎ Corresponding author. Tel.: +33 223235700; fax: +33 223236717. E-mail addresses: [email protected] (W. Engl), [email protected] (R. Backov), [email protected] (P. Panizza). 1 Tel.: +33 556845630; fax: +33 556845000.
1359-0294/$ - see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.cocis.2007.09.003
necessity. From a practical point of view, monodispersity also enhances emulsion stability. As a result of many years of research, several emulsification techniques that produce emulsions with narrow droplet size distributions now exist. The proper choice of the process conditions is dictated by the value of the droplet mean size to reach. Thus, well calibrated fine (50 nm to 1 μm) emulsions are industrially produced by high-pressure microfluidic injection [3], whereas droplets of intermediate sizes (1 to several μm) are obtained using narrow gap shear devices [4]. All these “top-down” techniques handle huge quantity of droplets at the same time. In contrast, the recent advents made in microtechnologies and in microfluidics [5] these last few years, now open a new “bottomup” approach to emulsification. The goal of this review is to 1) describe and understand the numerous advantages such a methodology presents, and 2) discuss the numerous prospects it opens for material science and science. We first describe the various microfluidic devices and their flow configurations used to produce calibrated droplets. 2. Microfluidics: a new “bottom-up” approach to emulsification The high potentialities of the microfluidic fabrication approach stem from the possibility to generate highly monodisperse
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droplets, one at a time with an incomparable degree of control over size. This method leads to extremely narrow-sized distribution since no stabilization over coalescence is needed as collisions between droplets are suppressed during the droplet formation process and the transport in the channels. 2.1. Droplet production Several microchannel techniques exist to generate calibrated droplets depending on the type of technology used for the fabrication of the microfluidic devices. They are depicted in Fig. 1. With planar chips, designed using soft lithography or laser etching fabrication methods, two main configurations are now commonly used. Periodic trains of monodisperse droplets can form by colliding two immiscible fluids streams at a T-shaped junction (Fig. 1a) [6,7] or by using a flow focusing microdevice (FFD) where a 2D planar co-axial stream is forced to flow through a small orifice (Fig. 1b) [8]. With both configurations, experiments can be performed either by imposing the flow rates or the pressure drop of the various streams. In each case, the mechanism of droplet formation which results from a subtle interplay between confinement, viscous and capillary stresses leads to the production of periodic trains made of monodisperse droplets with extremely narrow size distribution. The mean droplet size can be fine-tuned by adjusting the flow parameters of the various streams from 10 μm, typically the lateral size of the channels used for the experiment, up to a few hundreds of microns. It decreases with the flow rate and
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viscosity of the continuous phase and increases with the flow rate of the dispersed phase [9–11]. The dispersion in droplet size is extremely low as the coefficient of variation (CV) defined as the ratio of the standard deviation of the droplet size over the mean size is typically lower than 5%. To decrease the droplet size, one may break the drops into controlled daughter droplets at a simple T junction [12] or at a junction of any arbitrary angle [13]. This passive method of break-up is very powerful since the size ratio of daughter droplets can be adjusted by modifying the hydrodynamic resistances of the two junction's outlets. It can be carried out in succession without increasing the polydispersity of the droplets until their dimensions are larger than the channel dimensions. A drawback of planar devices is that prior to droplet formation, both the to-be-dispersed and the continuous phases are in contact with the channel walls. It follows that the wetting properties of the materials constituting the channels play a key role since they control the nature and stability of the droplets with respect to phase inversion [14,15]. Thus, when oil preferentially wets the channels, as for instance with polydimethylsiloxane (PDMS) based microdevices, stable O/W droplets cannot be prepared. To avoid this problem, it is necessary to modify the wetting properties of the channels at the location where droplet are formed for instance by applying a specific surface treatment [16,17]. Droplets with comparable narrow size distribution can also be generated with non-planar microfluidic devices which do not necessitate any expensive technologies such as soft lithography
Fig. 1. Shown are different strategies used to generate monodisperse emulsions droplets one by one and images of the droplets obtained with these techniques: a) T junction in planar microfluidic devices, b) flow focusing microfluidic device and c) double capillary millifluidic set-up.
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or laser etching techniques for their design. One may thus extend the flow focusing method to 3D, by injecting the disperse fluid with a syringe pump through a capillary tube with an inner diameter of typically a hundred microns, inside a chamber pressurized by a continuous supply of another immiscible fluid [18,19]. When the tip of the feeding capillary tube faces the small exit orifice of the chambers, the outer fluid stream focuses and forces the injected disperse fluid to exit the chamber through the orifice producing a microjet. As a result of a capillary instability, the microjet then breaks up into a chain of nearly monodisperse droplets, much smaller than the exit orifice. Monodisperse drops in larger sizes can also be generated using double capillary devices, by injecting the disperse phase through the co-flowing matrix fluid (Fig. 1c) [20–23]. The setup consists of a blunt calibrated needle with a diameter φ of typically a few hundreds of micrometers, centred to a cylindrical glass capillary with a diameter of D ≥ φ.Using independent syringe pumps, two immiscible fluids are respectively infused through both the needle and the annular gap between it and the internal capillary wall. The flow rates are independently controlled and adjusted in order to form monodisperse droplets of the dispersed phase in the continuous one. Both W/O and O/W droplets can be prepared provided that the wetting properties of the internal capillary wall are compatible with the continuous phase. With glass surfaces, this can easily be done. Such devices
then allow the extension of the preparation of well calibrated emulsions up to sizes of a few millimeters. Emulsions with smaller sizes (typically a few tens micrometers) can be generated by using a double capillary device which consists of a cylindrical capillary tubes co-axially nested within a square glass [24••]. 2.2. Fabrication of double emulsions Microfluidic emulsification techniques offer a promising route to the fabrication of monodisperse double emulsions and to the tailoring of complex architecture. It is the only technique which enables to encapsulate 100% of an active product in a single step and to control the nature of the encapsulated objects. To illustrate this, let us consider the fabrication of double emulsions, which consists of emulsion drops containing smaller droplets inside. In batches, the fabrication process usually requires two step processes: an emulsification of the inner droplets in the middle fluid followed by a second emulsification for dispersion [2]. In microfluidic planar devices, calibrated double emulsions can be generated with a mere succession of two T junctions as depicted in Fig. 2a [25••]. Aqueous droplets of uniform size are formed at a T junction by colliding water and oily flows. The resulting periodic train of W/O droplets is then directed towards another T junction placed downstream, to form monodisperse organic drops containing aqueous droplets within
Fig. 2. Shown are illustrations of the different microfluidic techniques used to produce double emulsions and corresponding images of emulsion droplets. I, M and O stand respectively for the inner, middle and outer fluids. a) The two steps drop break-up method using a planar device. Photograph of the droplet formation mechanism are reprinted from “Production of monodisperse double emulsions by two steps drop break-up in microfluidic devices”, Okushima S., Langmuir, 2004, 20:9905–9908. with permission from ACS. b) 3D equivalent of the double step drop break-up technique using double capillary devices. Images of the droplets are reprinted from “Controlled production of hierarchically organized large emulsions and particles using assemblies on line of co-axial flow devices”, Panizza P. et al., Colloids Surf. A: Physicochem. Eg. Aspects (2007), doi:10.1016/j.colsurfa.2007.06.026 with permission from Elsevier and c) microcapillary device used to break-up concentric streams and form monodisperse double emulsions or core-shells (images are reprinted from “Monodisperse double emulsions generated from a microcapillarydevice”, Utada A.S. et al., Science, 2005, 308:537–541 with permission from AAS.
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an external aqueous phase. The sizes of drops and inner droplets can be fine-tuned independently by adjusting the flow rate values of the various streams. Moreover, the number of encapsulated droplets can also be monitored independently from their size and that of the drops. This can be achieved by performing an additional injection or withdrawing of the continuous phase between the two T junctions using another T junction. This enables to dilute or concentrate the initial W/O droplet train before its encapsulation without altering the droplet size. From a practical point of view, double W/O/W emulsions can only be prepared provided that the upstream and downstream T junctions, used to form droplets and drops are respectively hydrophobic and hydrophilic. O/W/O emulsions are prepared by inverting the wetting properties of these two junctions. This method is very versatile. It can successfully be transposed to 3D as shown in Fig. 2b and extended to more than two steps [26••]. W/O/W/O macroemulsions can then be prepared using an assembly of glass double capillary devices connected to each other by means of Plexiglas home-made modules. A promising feature of this multiple steps emulsification technique is the possibility to encapsulate in a same drop, droplets of various compositions and to control their sizes and respective ratio (Fig. 2a). When two droplet trains having the same continuous phase but droplets of different composition meet at a T junction, they form a periodic alternated train [27]. Monodisperse drops containing droplets of different composition are generated by injecting this droplet train through the needle of another double capillary device placed downstream. The size of the internal droplets, their respective number as well as the size of the drops can be tuned continuously and independently by changing the flow conditions [25••, 26••]. Double emulsions can also be generated in a single step process using a different strategy. The idea consists of destabilizing a liquid thread of two or more parallel co-flowing streams in order to form monodisperse drops containing droplets (Fig. 2c). This can be achieved for instance in planar microfluidic devices by forcing this liquid thread through the small orifice of a flow focusing geometry [28 •• ]. A similar approach has successfully been transposed to 3D by Utada et al. Their device consists of two cylindrical glass capillary tubes co-axially nested within an outer square glass tube and tapered at their facing ends as depicted in Fig. 2c [24 •• ] Three different fluids are simultaneously injected in the system at controlled flow rates. The innermost fluid is pumped through one of the inner tube, whereas the middle fluid is injected through the outer square capillary region, in the same direction. Since the outermost fluid is pumped through the outer co-axial region of the opposite direction, all fluids are forced through the exit orifice formed by the other inner cylindrical tube. The thread breaks up to produce double emulsion in the collecting tube. The size of the inner and outer droplets as well as the number of inner droplets can be monitored and varied with a very good degree of control. This technique offers an incomparable step forward for the production of core-shell droplets with a control over both droplet size and shell thickness [29]. For instance, core-shell droplets with a ratio of shell over size as low as 3% have been
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prepared. By photopolymerizing a polymer in the intermediate fluid, these structures can be used to form capsules. They can also be transformed into polymer vesicles by using for the middle phase a volatile fluid where diblock co-polymers are dissolved [30]. 2.3. Towards the tailoring of complex dispersed materials Synthesis of solid particles in planar microfluidic reactors is an excellent route to particles with unconventional shape and morphologies. In batches, dispersed materials obtained by using droplets as microreactors are generally spherical systems since the minimization of interfacial energy leads to spherical shapes during most syntheses, whether they are polymer latexes formed through emulsion polymerization or droplets formed using shear flows in microfluidic devices. This inherent difficulty can however be circumvented by using a microfluidic scheme which permits good controls of the droplets geometrical and concentration environments. In 2004–2005, several papers have thus demonstrated the possibility to generate non-spherical particles, such as disks, ellipsoids or rods by photopolymerizing monomer droplets on the “fly” while flowing in constrained geometries as illustrated in Fig. 3 [31–33]. Monodisperse monomer droplets with different volume are first produced using a flow focusing device by varying the flow rates of the continuous and droplet phases. These droplets are then forced to flow through a narrow channel in which polymerization takes place. Because of confinement, droplets adopt a non-spherical shape, dictated by a relationship between w and h, the two lateral dimensions of the channel and d, the diameter of an undeformed droplet. At low capillary numbers, for w N d and h N d, the droplets minimize their surface energy by taking a spherical shape whereas for h N d N w, and for situations where d N w and d N h, confinement suppresses the relaxation of their shape into spheres, and the droplets respectively deform into discoid or rod shapes. With this approach, the aspect ratio of the non-spherical droplets can be conveniently monitored by changing the ratio between the droplet volume and the dimensions of the microchannels. The fabrication of solid particles using continuous microfluidic reactors exhibit many features that distinguish it from batch polymerization of monodisperse emulsions produced by “top-down” emulsification methods [2–4]. The polydispersity of the solid particles obtained using microfluidic tools is comparable to that of the droplets prior to hardening, typically below 3%. This value is therefore much narrower than in the batch methods, where coalescence and Oswald ripening occur. In microfluidic reactors, no stabilization against coalescence of monomer droplets is necessary since their collisions are suppressed. Furthermore, polymerization in a confined geometry allows for the production of non-spherical shapes such as disks, rods or tubes with an independent and very good control over volume, shapes and aspect ratio. The ability to generate and to control composition gradients with microfluidic devices offers a unique route to synthesize colloids with complex architectures. A good illustrative example of this concept concerns the production of Janus particles obtained by breaking up a liquid thread of two parallel co-flowing streams of monomer
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Fig. 3. Schematic (a–c) and optical microscopy (a′–c′) images of particles obtained from with polymerization of deformed monomer droplets with different shapes: microspheres (a, a′), disks (b, b′) and rods (c, c′). Reprinted from “Continuous microfluidic reactors for polymer particles”, Seo M. et al., Langmuir, 2005, 11614–11622 with permission from ACS.
of two immiscible polymer solutions that is forced through a narrow orifice (Fig. 4). The resulting droplets present a Januslike structure, with an approximate flat interface between the adjacent polymer phases that can be solidified with an UV exposition, performed downstream [34•]. This synthesis method gives a precise control over the volume ratio of the constituent of the particles as well as their size. It can also be extended to generate ternary particles by breaking up a three parallel coflowing monomer streams. The possibility to perform independent operations on individual dispersed objects and to integrate them opens incomparable broad prospects for engineering new materials. Complex architectures prepared along these lines are now flourishing in literature. They include the fabrication of colloid-filled hydrogel Janus granules of tunable size, geometry and composition, the encapsulation of solid particles in liquid drops or the production of non-spherical objects with liquid compartments. Consider for instance, the fabrication of colloid-filled non-spherical Janus granules reported by Shepherd et al. [35]. It necessitates several operations. To start, monodisperse colloid-filled hydrogel Janus droplets are produced with a flow focusing device according to the method previously described, the two hemispheres of the droplets differing by their composition in colloids. These spherical droplets are then deformed, by flowing through a constrained geometry, while being photopolymerized.
2.4. Turning microfluidic emulsion technology into an industrial tool Microfluidic technology paves the way to a bottom-up approach to emulsion science that offers numerous prospects compared to the “top-down” techniques that handle large populations of droplets at each step of an industrial process. However, its impact in industry relies on the ability to generate high throughput. So far, it is limited because of the extremely small flow rates involved (typically of the order of 0.1 ml/h) in such devices. The formation rate of monodisperse droplets in a single FFD is only a few tens of droplets/s. The necessity to parallelize droplets generators such as FFD or T junctions is therefore the central issue for potential industrial applications. From a practical point of view, this issue turns out to be a real difficult task which raises numerous theoretical questions. By parallelizing devices with multiple nodes, branches and crossflows, one couples non-linear fluidic oscillators. At low Reynold numbers, monophasic flows of Newtonian fluids in a network made of channels are governed by linear equations since the flow rate of a fluid flowing through a channel is proportional to the pressure drop applied to the extremities of this channel. Such interconnected flows can be solved using an analogy with resistors electrical circuits and do not present any difficulty. In contrast, multiphase flows of immiscible fluids are highly non-
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Fig. 4. (a) Sheath-flow microfluidic device used to produce monodisperse colloid-filled hydrogel granules. b) Schematic representation of the granules shapes and composition. c) View of the parallel two streams prior to their dispersion in droplets. d) Formation of Janus droplets. Reprinted from “Microfluidic assembly of homogeneous and Janus colloid-filled hydrogel granules”, Shepherd R.F., Langmuir 2006, 22:8618–8622 with permission from ACS.
linear. Understanding such flows in hydrodynamic networks is a challenging problem in the field of hydrodynamics and nonlinear physics. Take for instance, a situation where a train of droplets or bubbles is directed towards a T junction and ask how the droplets and carrier phase divide between the two outlets [23]. When a droplet reaches the junction, two directions are possible if it does not break. The selection is triggered by the dominant stream so that the droplet flows into the outlet characterized by the lower hydrodynamic resistance. Since the presence of droplets in conducts increase the resistance to flow, there is a hydrodynamic feedback between choices of successive droplets. The outcome turns out to be a complex non-linear dynamical problem which may lead to chaos or quasiperiodicity. With such effects, producing droplets in parallel microfluidic devices yields to emulsions with large polydispersity [36]. A possible way to circumvent this difficulty of parallelization is to generate droplets without applying cross-flows. In the last two years, large efforts have been undertaken along this line by Nakajima's group in Japan [37•• ,38]. They have conceived and developed two different microchannel array devices able to generate monodisperse droplets with a production rate increased by a factor 100 and more with respect to single channel devices. The first device is a silicon microchannel (MC) array plate with a multilevel structure. The method consists of forcing the to-be-dispersed phase through an array made of several hundreds of parallel channels into a shallow well, filled with the continuous phase as depicted in Fig. 5 [37•• ]. This MC array plate is capable of generating monodisperse discoid droplets of O/W or W/O types without applying a forced cross-flow of the continuous phase, up to a thousand droplets per second. The other device consists of a silicon array of about 10 4 asymmetric straight through-holes
vertically microfabricated on a plate surface of a liquid chamber to supply the to-be dispersed phase [38]. Each asymmetric through-hole is composed of a slit (with typical length, width and depth values of respectively 100, 10 and 20 μm) and a cylindrical channel (typically 10 μm in diameter and 5 μm in depth). These through-holes are uniformly arranged with intervals of typically 100 μm across the asymmetric straightthrough MC. The phase to disperse is injected through the array of vertical channels into the horizontal module filled with the continuous phase. This device can be applied to the preparation of monodisperse emulsions as well as microparticles and microcapsules. Since the formation rate of droplets from each active through-hole is typically a few tens of droplets/s, this apparatus can produce up to 10 5 droplets per second. 2.5. Scaling up microfluidics Scaling up these microdevices into millimetric ones presents some considerable advantages. Recently, a continuous co-axial flow scheme to engineer and industrially produce at low cost hierarchically organized structures of larger sizes with an incomparable degree of control over their size, shape and internal structure has been developed (Fig. 6) [26••]. The method consists of using an assembly of capillaries or flexible tubes (with diameters ranging from 50 μm to a few mm) put together with elementary home-made modules. This synthesis method is based on the association of three different elements able to achieve the basic following four functions used in microfluidic devices: (1) form periodic trains of monodisperse droplets with very good control over their size, (2) dilute–concentrate these trains while keeping the volume of droplets unchanged,
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Fig. 5. Schematic illustrations of the two techniques based on microchannel arrays developed by M. Nakajima's group to scale up production of monodisperse droplets and photographs of produced emulsions. a) The two level structures conceived to scale up droplet production is made of an array of several hundreds of parallel channels. The to-be-dispersed phase is injected through the microchannels into the shallow well filled with the continuous phase. (Left) Images of successfully generated O/W discoid droplets. Reprinted from “Controlled generation of monodisperse discoid droplets using microchannel arrays”, Kobayashi I. et al., Langmuir, 2006, 22:10893–10897 with permission from ACS. b) Mechanism of droplet formation using an asymmetric straight through-holes MC plate. (Right) An microscopic photographs of the resultant droplets. Reprinted from “Novel asymmetric through-hole array microfabricated on a silicon plate for formulating monodisperse emulsions”, Kobayashi I. et al., Langmuir, 2005, 21:7629–7632 with permission from ACS.
(3) generate periodic trains made of alternated droplets and (4) deform droplets in a controlled manner. Modular millifluidic set-ups can then be designed to produce newly controlled integrated architectures limited only by the number of combinations possible and one's creativity. The great versatility of this method is already illustrated through the encapsulation of droplets or solid particles of various shapes, composition and size, in liquid or solidified drops, the formation of large organic or inorganic cylindrical particles as well as the generation of double and triple emulsions. This strategy presents several advantages over microfluidic synthesis while keeping its specificities. Since no lithography, glass etching techniques or specific equipment are necessary for the design of the devices, their fabrication costs are low. The connecting capillary tubes and the various modules can assemble and disassemble easily so that modular set-ups can be designed on demand in a short time. This modularity is also considerable advantage from a practical point of view since modifying a hydrodynamic circuit on a planar microfluidic chip demands starting over at the lithography or glass etching level. Combined with the ability to modify very simply the wetting properties of the glass capillary tubes used for connection it offers the opportunity to fabricate multiple emulsions of
different nature with a same device. The use of such devices pave the way to an industrial integrative formulation of dispersed materials with very large characteristic sizes ranging from typically 100 μm to several mm and new complex architectures [39]. This should lead to the rapid emergence of new products in cosmetics or food where the texture and visual aspect plays a key role for sale. 3. Miniaturizing the laboratory using droplet-based microfluidic devices Monodisperse droplets generated by microfluidic devices can serve as microreactors to compartmentalize reactions and control the reaction time precisely [40]. One of the key properties of droplet-based high-throughput microfluidic devices stems from the uniform constant speed motion of droplets in the channel allowing equivalence between distance and reaction so that one can perform a stationary measurement of a kinetic process along the flow. Using this property, microfluidic platforms to perform kinetic measurements of fast and very fast reactions with better than millisecond resolution using very small volumes of reagents have recently
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Fig. 6. (a) Sketches of the different elementary tubular millifluidic modules and their corresponding basic functions. b) Shown are schematic representations of the different modular set-ups used to fabricate triple and double emulsions and images of emulsions produced with different number of internal droplets reprinted from “Controlled production of hierarchically organized large emulsions and particles using assemblies on line of co-axial flow devices”, Panizza P. et al., Colloids Surf. A: Physicochem. Eng. Aspects (2007), doi:10.1016/j.colsurfa.2007.06.026 with permission from Elsevier.
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been developed [40]. This microreactor technology is a very efficient alternative to batch chemical procedure, because of the rapidity of analysis and the low consumption of reagents. Furthermore, other advantages results from the high heat and mass transfer rates provided by microfluidic reactors which induce safe and fast syntheses and therefore may open new chemical reactions [41]. Briefly, the droplets are usually formed at a T junction by using the to-be-disperse phase, streams of the various reagents separated from each other by buffer streams in order to avoid premixing. Rapid mixing of the reagent inside the droplet is necessary since it determines the starting time of the reaction. This is achieved by chaotic advection when the droplets flow through a winding channel [42]. The composition of the reaction mixture at the reaction time, t, is then determined with spectroscopic techniques (UV–vis, Raman or Flurorescence) by analyzing the composition inside the droplets at the distance d = tU (where U is the velocity of the droplet) within the channel. Since the composition of reagents within each droplet carrier can be changed by simply varying the flow rates of the reagent streams, this technique can be used for screening of a target. Using droplets as microreactors is not limited to chemical reactions, but can apply to other fields such as for instance enzyme kinetics, DNA analysis, synthesis of nanoparticles or protein crystallization. We advise the reader to refer to the reviews written by R.F. Ismagilov to get more information and precision on the use of droplets in these various fields [43••]. Another interesting specificity of droplet-based microfluidic devices is the possibility to rapidly carry out many experiments (typically a few hundred per second) under the same controllable conditions. These features are well suited to study stochastic processes where many experiments are necessary to accurately measure the probability of a single event. A good example of this approach concerns, a dropletbased set-up recently developed by Laval et al. to investigate crystal nucleation kinetics [44•]. Monodisperse droplets of a solution are produced, convected along a channel and then rapidly submitted to a temperature quench so that nucleation may occur. The nucleation rate is then determined by measuring the probability that a droplet contains a nucleus at different positions along the channel on a large number of droplets. This technique presents numerous advantages over the classical droplet methods using emulsions. They include the production of monodisperse droplets of tunable size with no surfactant molecule which may induce heterogeneous nucleation, the rapidity of the temperature quench, the possibility to eliminate interactions between multiple nuclei by choosing small enough droplets and a fast and direct measurement of the proportion of crystallized droplets. This continuous method yields to rapid and reliable statistical measurements of the nucleation kinetics, and offers the opportunity to carry out high-throughput crystallization conditions [45]. The ability of microfluidic technology to produce, handle and manipulate single droplet in a very controlled way opens new prospects to study the physical properties and stability of emulsions, at the scale of an individual or two droplets. Along this line, a microfluidic interfacial tensiometer has been
conceived [46]. The method is based on quantitative real time observation and analysis of drop shape dynamics in microchannels. Drops of controlled diameter and spacing are produced at a T junction of two immiscible fluids and injected in a wider downstream channel where they become spherical. They are then deformed by flow constrictions. Measurements are performed at the exit or entrance of a constriction where the flow is respectively accelerating or decelerating, producing an extensional flow that deform the drops. This tensiometer gives very accurate and precise results, with very low reagent consumption and rapidity. Because of the equivalence between time and position along the channel, the age of the interface is known, so that information on the dynamic surface tension and kinetics of adsorption surfactant at the interface can be gained by using multiple constrictions along the channel. With no doubt, in the near future, microfluidic tools will be used to investigate the coalescence between two droplets. Such a study could for instance be performed by forming in a capillary tube an alternating train of small and large droplets using a T junction. Since in the downstream channel, the small droplets are convected faster than the large ones, coalescence events could therefore be observed and quantified. An important research field now deals with developing active techniques and new tools to handle droplets in microfluidic devices. 4. Conclusion and prospects Microfluidic technology offers a new “bottom-up” approach to emulsification which shows much promise in the emulsion field. By contrast to the “top-down” approach of other emulsification techniques, which operate on a very large number of droplets at each step, microfluidic generates one single droplet at a time with incomparable results in terms of size control. Its abilities to create chemical gradient and to handle each produced droplet individually lay the foundation of a new concept in colloidal science, that of Continuous Integrative Chemistry. The novelty and originality of this approach consists of using monodisperse droplet as individual chemical reactor and operating “on line” on each reactor to successively add a chemical or physical function at each step of a process. This integrative approach is based on several elementary functions that microfluidic tools can accomplish. These basic operations include formation of parallel streams with different composition, generation of monodisperse droplet trains, dilution and concentration of these trains, formation of alternated trains with droplet of different compositions, asymmetric droplet breaking-up, fusion of two droplets, controlled deformation of the droplets, and encapsulation. By combining and integrating these various functions with polymerization, solidification or any other chemical process, it then becomes possible to synthesize new dispersed materials with complex architecture. This methodology yields to a very good control of the size, shape, and internal structure of the manipulated objects, at each step of the process. It is for instance the only technique that can ensure encapsulation of an active product at 100% in a single step. Illustrative examples of the
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high potentialities of this approach are now numerous in literature. They concern for instance double emulsions with internal droplets of different composition, triple emulsions, nonspherical particles, Janus or ternary particles and core-shells. With no doubt, the further step to make is to combine microfluidic and millifluidic formulation methods to generate multiscale structured materials. By integrating these tools with classical emulsification techniques, the fabrication of multiple emulsions with four or five degrees of multiplicity and hierarchical sizes ranging from the micrometer for the innermost droplets up to typically a millimeter for the size of the outer drops should in principle be feasible. However, despite its numerous advantages, the microfluidic technology is not yet suitable as a production tool for industry because of the very small flow rate involved (typically of the order of a few hundreds of microliters per hours) in this type of devices. Consequently, a very important and active research work must now be devoted to overcome this limitation since both industrial and financial stakes are tremendous. Generating monodisperse droplets with controllable sizes and shapes and being able to manipulate them individually and reproductively in networks of small channels give the opportunity to miniaturize a laboratory down to a few inches per square [47, 48•]. This is the lab-on chip concept. Using droplets as individual microcarriers and reactors in such devices is very promising for developing high-throughput applications since reaction conditions can easily be compartmentalized and addressable [44•]. This approach enables to considerably increase and accelerate the number of tests up to a few tens per seconds, using very small amounts of materials. The prospects are numerous for many scientific fields where one target must be tested against a large number of reaction conditions. In chemical engineering, this continuous screening approach permits for instance to explore the conditions of a reaction, to optimize it and consequently to orientate the synthesis of new materials. For biology, it permits to efficiently and rapidly test the effect of a drug on viruses. The possibility with droplet-based microdevices to rapidly perform many experiments (typically a few hundred per second) under the same controllable conditions also opens many opportunities to address fundamental issues. These tools are thus well suited to study stochastic processes which necessitate a statistical analysis such as for instance coalescence phenomena or crystallization nucleation. In biology, such a digital highthroughput technique may give access to the statistical distribution of a population as a function of a stress [49]. Finally, on another level, flows of droplets occurring in microfluidic devices raise challenging questions in the field of hydrodynamics and non-linear physics [23,50]. To conclude, the recent progresses made in the production of droplets of controllable size and in their individual manipulation lead to novel approaches of emulsification and synthesis of complex materials, and the foundation of new scientific methods and applications in many different fields. Recent advances in scaling up droplet production and the dimensions of microdevices now allow to transpose these promising techniques into industry.
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• ••
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