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Invited Feature Article Continuous Microfluidic Reactors for Polymer Particles Minseok Seo, Zhihong Nie, Shengqing Xu, Michelle Mok, Patrick C. Lewis, Robert Graham, and Eugenia Kumacheva* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada Received February 25, 2005. In Final Form: June 13, 2005 This article provides an overview of our work in the area of the synthesis of polymer particles in continuous microfluidic reactors. The method includes (a) the generation of highly monodisperse monomer droplets in a microfluidic flow-focusing device and (b) in-situ solidification of these droplets by means of photopolymerization. We discuss the effect of monomer properties on the emulsification process, the effect of the polymerization rate on the production of high-quality particles, the role of the material of the microfluidic device in droplet formation, and the synthesis of particles with different shapes and compositions. We also demonstrate the production of highly ordered arrays of polymer particles achieved by photopolymerization of the dynamic lattices of monomer droplets in microfluidic channels. The article is concluded with a summary of future research directions in the production of polymer colloids in microfluidic reactors.
I. Introduction Polymer colloids with dimensions in the range of 10100 µm are extensively used in ion-exchange and chromatography columns, in various biological and medicinal applications, and as calibration standards, toners, coatings, and supports for catalysts.1 In many of these applications, the particle size and size distribution are of key importance. The preparation of monodisperse submicrometer-sized polymer beads with a predetermined surface and bulk properties is a well-established procedure.2,3 By contrast, the synthesis of larger particles with a narrow size distribution is a synthetic challenge: it is either material-specific or time-consuming (that is, it is accomplished in several stages) or it does not provide a sufficiently narrow size distribution of the resulting particles. Moreover, the control of microbead shapes in conventional polymerization reactions is generally limited by the preparation of spherical particles. Recent progress in developing new microfabrication techniques and microreaction technologies has raised exciting opportunities in reaction engineering.4 Microreactors provide high heat and mass-transfer rates, safe and rapid synthesis, and the possibility to develop new reaction pathways that are too difficult for conventional * Corresponding author. alchemy.chem.utoronto.ca.
E-mail:
ekumache@
(1) (a) Ugelstadt, J.; Berge, A.; Elingsen, T.; Smid, R.; Nielsen, T. N. Prog. Polym. Sci. 1992, 17, 87-161. (b) Sugimoto, T. Adv. Colloid Interface Sci. 1987, 28, 65-108. (2) (a) Becher, D. Z.; Becher, P.; Breuer, M. M.; Clausse, D.; Davis, S. S.; Hadgraft, J.; Jaynes, E. N.; Krog, N. J.; Lasson, K.; Menson, V. B.; Palin, K. J.; Riisom, T. H.; Wasan, D. T. Encyclopedia of Emulsion Technology; Mercel Dekker: New York, 1985; Vol 2. (b) Ugelstadt, J.; Mfutakamba, H. R.; Mork, P. C.; Ellingsen, T.; Berge, A.; Schmidt, R.; Hom, L.; Jorgedal, A.; Hansen, F. K.; Nustad, K. J. Polym. Sci., Polym. Symp. 1985, 72, 225-240. (c) Merkel, M. P.; Dimonie, V. L.; El-Aasser, M. S.; Vanderhoff, J. W. J. Polym. Sci., Part A: Polym. Chem. 1987, 25, 1219-1233. (3) (a) Hora´k, D. Acta Polym. 1996, 47, 20-28. (b) Landfester, K. Macromol. Rapid Commun. 2001, 22, 896-936. (4) Jensen, K. F. Chem. Eng. Sci. 2001, 56, 293-303.
reactors.5,6 The literature is burgeoning with reports on microreaction syntheses of various organic, bioorganic, and inorganic materials.7-12 Several years ago, our group initiated research aimed at the development of continuous microfluidic reactors for the synthesis of polymer particles with controlled size, shape, morphology, and composition. This work was inspired by progress in the production of highly monodisperse droplets and bubbles by using various microfluidic devices and methods. The present article provides an overview of our work in the area of continuous microfluidics-based synthesis of polymer colloids. The described strategy is applicable to the production of both hydrophobic and hydrophilic particles, including microgels. Here, however, we describe the production of hydrophobic beads. Some of the results presented herein have been reported in coauthorship with Professors G. M. Whitesides and H. A. Stone (Harvard University);13 most of the results, however, were obtained after a joint paper was published. Herein, we describe important factors that govern the synthesis of polymer microbeads: (i) emulsification of monomers with different (5) (a) Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999, 10, 883-884. (b) Nisisako, T.; Torii, T.; Higuchi, T. Lab Chip 2002, 2, 2426. (6) Ehrfeld, W.; Golbig, K.; Hessel, V.; Lo¨we, H.; Richter, T. Ind. Eng. Chem. Res. 1999, 38, 1075-1082. (7) Cheng, J.; Schoffner, M. A.; Mitchelson, K. R.; Kricka, L. J.; Wilding, P. J. Chromatogr., A 1996, 732, 151-158. (8) Kopp, M. U.; de Mello, A. J.; Manz, A. Science 1998, 280, 10461048. (9) Chan, E. M.; Mathies, R. A.; Alivisatos, A. P. Nano Lett. 2003, 3, 199-201. (10) Khan, S. A.; Gunther, A.; Schmidt, M. A.; Jensen, K. F. Langmuir 2004, 20, 8604-8611. (11) Fortt, R.; Wootton, C. R.; de Mello, A. J. Org. Process Res. Dev. 2003, 7, 762-768. (12) Kobayashi, J.; Mori, Y.; Okamoto, K.; Akiyama, R.; Ueno, M.; Kitamori, T.; Kobayashi, S. Science 2004, 304, 1305-1308. (13) Xu, S.; Nie, Z.; Seo, M.; Lewis, P. C.; Kumacheva, E.; Garstecki, P.; Weibel, D.; Gitlin, I.; Whitesides, G. M. Angew. Chem., Int. Ed. 2005, 44, 724-728.
10.1021/la050519e CCC: $30.25 © 2005 American Chemical Society Published on Web 08/09/2005
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viscosities; (ii) effect of hydrodynamic conditions (that is, flow rates of continuous and droplet phases) on the dimensions of monomer droplets; (iii) importance of the selection of an appropriate material of microfluidic devices; (iv) photopolymerization of emulsified monomers; and (v) production of microspheres with different shapes and compositions. With an eye toward the potential applications of the arrays of particles produced in microfluidic devices, we have also explored the assembly of monomer droplets in periodic arrays. The article is concluded with a summary and our perspective on future research in the field. The experimental details are available as Supporting Information. II. Background: Related Work on the Generation of Polymer Colloids by Means of Microfluidics To the best of our knowledge, prior to 2004 the preparation of polymer particles with the assistance of microfluidic methods had been accomplished via a twostage process. In the first stage, a monomer or a liquid polymer was emulsified to obtain droplets with a narrow size distribution. In the next stage, the resulting droplets were hardened in a batch (that is, a noncontinuous) process. Emulsification has been achieved by various methods (e.g., by forcing fluids into the bulk continuous medium through a nozzle,14 a membrane,15 or a vibrating orifice16). In other approaches, emulsification was accomplished solely in microfluidic devices at T junctions,17 by flow-focusing in a narrow orifice,18 or by using microchannel terraces.19 The advantage of these emulsification methods was their ability to control droplet size and produce highly monodisperse droplets. The chemical nature of the droplet phase determined the next step in which the droplets were solidified. Droplets of polymer solutions were hardened by solvent evaporation, by physical (e.g., ionic) cross linking,20 by photoinitiated cross linking,13b,16b or by means of chemical reactions (e.g., by condensation of carbonyl chloride and amine groups).21 Droplets of monomers were solidified by means of thermally initiated15a,19,22 or UV-initiated batch polymerization.23 Particle production via two-stage processes did not realize the full potential of continuous microfluidics-based (14) (a) Berkland, C.; Kim, K.; Pack. D. W. J. Controlled Release 2001, 73, 59-74. (b) Loscertales, I. G.; Barrero, A.; Guerrero, I.; Cortijo, R.; Marquez, M.; Ganan-Calvo, A. M. Science 2002, 295, 1695-1698. (15) (a) Omi, S.; Katami, K.; Taguchi, T.; Kaneko, K.; Iso, M. J. Appl. Polym. Sci. 1995, 57, 1013-1024. (b) Yuyama, H.; Yamamoto, K.; Shirafuji, K.; Nagai, M.; Ma, G.-H.; Omi, S. J. Appl. Polym. Sci. 2000, 77, 2237-2245. (16) (a) Partch, R. E.; Nakamura, K.; Wolfe, K. J.; Matijevic, E. J. Colloid Interface Sci. 1985, 105, 560-569. (b) Esen, C.; Schweinger, G. J. Colloid Interface Sci. 1996, 179, 276-280. (17) (a) Thorsen, T.; Roberts, R. W.; Arnold, F. H.; Quake, S. R. Phys. Rev. Lett. 2001, 86, 4163-4166 (b) Link, D. R.; Anna, S. L.; Weitz, D. A.; Stone, H. A. Phys. Rev. Lett. 2004, 92, art 054503. (c) Tice, J. D.; Lyon, A.; Ismagilov, R. F. Anal. Chim. Acta 2004, 507, 73-77. (18) Anna, S. L.; Bontoux, N.; Stone, H. A. Appl. Phys. Lett. 2003, 82, 364-366. (19) (a) Sugiura, S.; Nakajima, M.; Itou, H.; Seki, M.; Nisisako, T.; Torii, T.; Higuchi, T. Macromol. Rapid Commun. 2001, 22, 773-778. (b) Sugiura, S.; Nakajima, M.; Iwamoto, S.; Seki, M. Langmuir 2001, 17, 5562-66. (c) Sugiura, S.; Nakajima, M.; Kumazawa, N.; Iwamoto, S.; Seki, M. J. Phys. Chem. B 2002, 106, 9405-9409. (d) Kobayashi, I.; Mukataka, S.; Nakajima, M. J. Colloid Interface Sci. 2004, 279, 27780. (20) Smidsrod, O.; Skjak-Brek, G. Trends Biotechnol. 1990, 8, 7178. (21) Cohen, I.; Li, H.; Hougland, J. L.; Mrksich, M.; Nagel, S. R. Science 2001, 292, 265-267. (22) (a) Sugiura, S.; Nakajima, M.; Seki, M. Ind. Eng. Chem. Res. 2002, 41, 4043-4047. (b) Wu, T.; Mei, Y.; Cabral, J. T.; Xu, C.; Beers, K. L. J. Am. Chem. Soc. 2004, 126, 9880-9881. (23) Nisisako, T.; Torii, T.; Higuchi, Chem. Eng. J. 2004, 101, 23-29.
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Figure 1. (a) Schematic of droplet formation in the microfluidic flow-focusing device. The height of the channels varied from 25 to 100 µm, and the width of the orifice was from 15 to 120 µm. The orifice had a rectangular shape. Fluid A: aqueous 2 wt % SDS solution. Fluid B: monomer liquid or silicone oil. (b) Serpentine channel for the photopolymerization of monomer droplets. Channel width and length are 640 µm and 17.6 cm, respectively.
synthesis, that is, the possibility of the fast and reproducible generation of polymer beads (in contrast to substantial batch-to-batch product variation in batch processes). In addition, batch polymerization of monomer droplets required their stabilization against coalescence. We note that several communications reported the continuous production of polymer colloids via polycondensation16a or photopolymerization16b of aerosol droplets generated with the assistance of vibrating-orifice generators. These methods, however, could not be ascribed to the microfluidics-based synthesis. In 2004-2005, several papers reported the rapid continuous scalable emulsification and synthesis of polymer particles accomplished in microfluidic reactors. “On the fly” synthesis of microscale fibers and tubes was demonstrated by Beebe and Jeong.24 Highly monodisperse polymer particles with different compositions were obtained in the collaborative work of Whitesides, Stone, and Kumacheva.13 In the latter work, photopolymerization of acrylate-based droplets in the constrained geometry of microfluidic devices allowed for the production of nonspherical particles such as polymeric disks, ellipsoids, and rods. A similar approach was used by Doyle et al.,25 who obtained polymer particles from Norland Optical Adhesive. The feasibility of preparation of polymer capsules (liquid droplets engulfed with a polymer shell) has been demonstrated by carrying out interfacial polycondensation26 or free-radical polymerization.27 In situ photopolymerization of 2D lattices of monomer droplets has led to the formation of arrays of polymer disks with a high degree of order and symmetry. 41 III. Design of the Microfluidic Reactor Figure 1 shows the design of the microfluidic laminar flow reactor used in the present work: a microfluidic flowfocusing device (MFFD)18 in which the monomer droplets were formed (Figure 1a) and a wavy channel in which these droplets were exposed to UV irradiation (Figure 1b). The microfluidic devices were fabricated in poly(dimethylsiloxane) (PDMS) or polyurethane (PU) elastomer (synthesized in our laboratory) using a standard soft lithograpy procedure.28 Photolithographic masters were prepared with SU-8 photoresist on silicon wafers. The height of the microfluidic channels varied from 25 to 100 µm (Figure 1a). (24) Jeong, W.; Kim, J.; Kim, S.; Lee, S.; Mensing, G.; Beebe, D. J. Lab Chip 2004, 4, 576-580. (25) Dendukuri, D.; Tsoi, K.; Hatton, T. A.; Doyle, P. S. Langmuir 2005, 21, 2113-2116. (26) Takeuchi, S.; Garstecki, P.; Weibel, D.; Whitesides, G. M. Adv. Mater. 2005, 17, 1067-1072. (27) Nie, Z.; Xu, S.; Seo, M.; Lewis, P. C.; Kumacheva, E. J. Am. Chem. Soc. 2005, 127, 8058-8063. (28) Xia, Y.; Whitesides, G. M. Annu. Rev. Mater. Sci. 1998, 28, 153184.
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Figure 2. Breakup of the TPGDA thread in 2 wt % aqueous SDS solution in the PU MFFD. (a) Regime 1: Qm ) 0.04 mL/h, Qw ) 0.04 mL/h. (b) Regime 2: Qm ) 0.03 mL/h, Qw ) 0.30 mL/h. (c) Regime 3: Qm ) 0.2 mL/h, Qw ) 4.0 mL/h.
Two immiscible liquids (a monomer and an aqueous phase) were supplied to the MFFD by two digitally controlled syringe pumps. Unless specified, a monomer was supplied to the central channel, and a 2 wt % aqueous solution of sodium dodecyl sulfate was supplied to the two outer channels. The monomer droplets were photopolymerized in the serpentine channel of the MFFD (Figure 1b). The length of the wavy channel was 17.6 cm. The time of residence of droplets in the wavy channel (that is, the time of photopolymerization) depended on their velocities, and it could be varied from 20 s to 15 min. IV. Emulsification of Monomers in Microfluidic Devices In the microfluidics-based emulsification methods17-19,29,30 for a particular combination of continuous and dispersed phases the size of the droplets and their size distribution are conveniently controlled by varying the flow rates of the continuous and droplet phases and the design of the microfluidics device. Generally, the variation in droplet size is a function of a dimensionless Reynolds number, Re ≡ FRU/µ, and a capillary number Ca ≡ µU/γ12, where U is the average velocity of the liquid, γ12 is the interfacial tension, F and µ are the density and viscosity of the liquid, respectively, and R is the characteristic length scale of the system. Because the objective of our work was the synthesis of polymer particles, here we discuss only the details of emulsification that are pertinent to the production of droplets from polymerizable fluids (that is, liquid monomers). We studied the emulsification of four multifunctional acrylates: ethylene glycol dimethacrylate (EGDMA), tri(propylene glycol) diacrylate (TPGDA), pentaerythritol triacrylate (PETA-3), and pentaerythritol tetraacrylate (PETA-4). Figure 2 illustrates three major regimes in the formation of monomer droplets in the microfluidic flow-focusing device. The low flow rate of the continuous water phase, (29) (a) Ganan-Calvo, A. M. Phys. Rev. Lett. 1998, 80, 285-288. (b) Ganan-Calvo, A. M.; Gordillo, J. M. Phys. Rev. Lett. 2001, 87, art. 274501. (30) Cramer, C.; Fischer, P.; Windhab, E. J. Chem. Eng. Sci. 2004, 59, 3045-3058.
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Figure 3. (a) Variation in droplet diameter vs capillary number, Ca, of the continuous water phase for a constant water-tomonomer flow rate ratio, Qw/Qm ) 60. For Ca > 0.028, a thread of PETA-4 did not break up into droplets. (b) Variation in viscosity of monomers plotted as a function of shear rate. (a and b) PETA-4 (]), PETA-3 (4), TPGDA (0), and EGDMA (O). (c) Distribution of diameters of TPGDA droplets (average diameter 103.9 µm, CV ) 0.94%, Qm ) 0.035 mL/h, Qw ) 2.1 mL/h) and PETA-3 droplets (average diameter 187.5 µm, CV ) 0.9, Qm ) 0.06 mL/h, Qw ) 3.6 mL/h).
Qw, and low ratios of flow rates of water to monomer phases, Qw/Qo, resulted in a weak shear force exerted on the monomer thread. The monomer droplets formed in the dripping regime (Figure 2a): the monomeric thread broke up behind the orifice into the droplets with a diameter that was significantly larger than the orifice width. For the moderate values of Qw and Qw/Qo, the droplets were generated by breaking up the monomer thread in or behind the orifice. In this regime, a monomer thread was focused in the orifice by the continuous phase, where the former broke up, released a droplet, and retracted back into the upstream (Figure 2b). At high flow rates of the continuous phase and large values of Qw/Qo, a transition to the jetting mode occurred:31 the monomer thread remained behind the orifice, breaking up into droplets due to the Rayleigh plateau hydrodynamic instability (Figure 2c). Under particular conditions, small satellite droplets accompanied the formation of the main population of droplets. Qualitatively, the generation of oil-in-water emulsion droplets shown in Figure 2 was analogous to the preparation of oil-in-water emulsions in a similar MFFD.18 In the rest of this article unless specified, we will focus on monomer emulsification in regime 2: the generation of droplets by flow focusing of the monomer thread in the orifice. For a particular width and height of the orifice, the size of droplets was governed by the properties of the monomer liquid and the flow rates of the continuous and droplet phases. Figure 3a shows the variation in diameter of monomer droplets plotted as a function of capillary number Ca of the continuous phase. Generally, at low values of Ca all monomers produced large droplets. By constrast, for intermediate and large values of Ca we observed different trends for the bifunctional monomers (EGDMA and TPGDA) and the tri- and tetrafunctional monomers (31) Eggers, J. Rev. Mod. Phys. 1997, 69, 865-929.
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Table 1. Properties of Monomers Emulsified in MFFD
monomer
density F(g/cm3)
viscosity µ(cP)
interfacial tension γ (dyn/cm)
EGDMA TPGDA PETA-3 PETA-4 MAOP-DMS
1.05 1.03 1.18 1.19 0.93
3.5 14 586 1813 19.6
1.0 2.8 3.1 3.4 2.7
(PETA-3 and PETA-4). With increasing Ca, the diameters of EGDMA and TPGDA droplets decreased until they became almost invariant. The difference in the formation of droplets from EGDMA and TPGDA was caused by the difference in their viscosity and interfacial tension of the monomer fluid with the water phase (Table 1). The results were in agreement with previous reports on the relationship between viscosity- and interfacial tension-driven forces on one hand and droplet size on the other hand.32 By contrast, with increasing Ca the dimensions of droplets formed by PETA-3 and PETA-4 first slightly increased and then remained almost invariant. We verified the Newtonian behavior of the monomers: the viscosity of all monomer liquids (including PETA-3 and PETA-4) did not change with increasing shear rate (Figure 3b). Thus we ascribe the unusual variation in the dimensions of droplets formed from PETA-3 and PETA-4 to the high viscosity of these fluids. In contrast to low-viscosity monomers, the generation of droplets of PETA-3 or PETA-4 occurred through the formation of a long, narrow neck in a monomer thread. The breakup of the neck occurred in the orifice or behind (but quite close to) the orifice at moderate values of Qw and Qw/Qo, and after releasing a droplet, the monomer thread retracted into the upstream, thus the generation of droplets of PETA-3 and PETA-4 occurred in regime 2. The “tail” resulting from necking contributed to the increase in droplet volume. The width of the droplet size distribution depended on the type of monomer used and the flow rates of water and monomer. However, for each monomer a particular window of Qw and Qo existed in which the droplets featured an extremely narrow size distribution. Figure 3c shows the distribution in dimensions of TPGDA and PETA-3 droplets. Generally, the coefficient of variance (CV) of the droplets, defined as standard deviation divided by average droplet diameter, was below 2% for a broad range of hydrodynamic conditions. We stress that despite the high viscosity of PETA-3 and especially PETA-4 these monomers were successfully emulsified in droplets with a narrow size distribution. In addition to the variation in hydrodynamic conditions of the generation of droplets, further control of droplet dimensions was achieved by varying the design of MFFD: a decrease in the width and height of the orifice resulted in the production of droplets with diameters as small as ca. 18 µm. V. Material of the Microfluidic Reactor The selection of an appropriate material for the MFFD is a vital stage in the generation of monomer droplets. Several groups reported that the affinity of the droplet phase for the material of the microfluidic device (e.g., glass, silicon, and PDMS33-35) can cause “phase inversion” (32) Garstecki, P.; Gitlin, I.; DiLuzio, W.; Whitesides, G. M.; Kumacheva, E.; Stone, H. A. Appl. Phys. Lett. 2004, 85, 2649-2651. (33) Dreyfus, R.; Tabeling, P.; Williams, H. Phys. Rev. Lett. 2003, 90, art. 144505. (34) Umbanhowar, P. B.; Prasad, V.; Weitz, D. A. Langmuir 2000, 16, 347-351.
Figure 4. Optical microscopy images of droplets obtained in MFFDs fabricated in PU (a, b) and PDMS (c, d). The water phase contained 2 wt % SDS. (a) MAOP-DMS was supplied to the central channels, and the water phase was forced to the outer channels. (b) The water phase labeled with methylene blue dye was supplied to the central channel, and MAOP-DMS was supplied to the outer channels. Phase inversion occurred because of the higher affinity of the water phase for the PU mold. (c) The dye-labeled water phase was supplied to the central channel, and MAOP-DMS was delivered to the outer channels. (d) MAOP-DMS was supplied to the central channel, and the water phase was forced into the outer channels. Phase inversion occurred because of the higher affinity of MAOP-DMS for PDMS. Flow rates are (a) Qw ) 1.00 mL/h, Qo ) 0.05 mL/h, (b) Qw ) 0.20 mL/h, Qo ) 0.05 mL/h, (c) Qw ) 0.02 mL/h, Qo ) 0.50 mL/h, and (d) Qw ) 0.50 mL/h, Qo ) 0.20 mL/h. Scale bar is 200 µm.
when the liquid to be emulsified becomes a continuous phase. We examined the emulsification of the monomer methacryl oxypropyl dimethylsiloxane in the MFFDs that were fabricated from poly(dimethylsiloxane) (PDMS) and polyurethane (PU). The wetting angles of water on PDMS and PU were 109 and 86°, respectively. A monomer phase showed an affinity for the PDMS mold that was stronger than that of water, whereas the water phase showed a stronger affinity for the PU mold. Figure 4a-d shows typical optical microscopy images of the droplets formed in the MFFDs fabricated from PU (Figure 4a and b) and PDMS (Figure 4c and d). The MFFDs had the same design as shown in Figure 1. In both cases, the liquid supplied to the central channel was expected to form droplets, whereas the liquid forced into the outer two channels was supposed to form a continuous phase. When methacryl oxypropyl dimethylsiloxane was delivered to the central channel and the water phase (a 2 wt % aqueous solution of SDS) was supplied to the side channels of the PU MFFD, the monomer avoided contact with the PU walls and formed a cylindrical plug that broke up into droplets dispersed in the continuous aqueous phase (Figure 4a). In Figure 4b, the water phase was supplied to the central channel, and MAOP-DMS was supplied to the side channels of the same MFFD. By contrast with the previous case, droplets were formed by the monomer (35) (a) Stone, H. A.; Strook, A. D.; Ajdari, A. Annu. Rev. Fluid Mech. 2004, 36, 381-411. (b) Beers, K. L.; Wu, T. In FY 2004 Programs and Accomplishments in Materials Science and Engineering Laboratory Polymer Division in National Institute of Standard and Technology; Amis, E. J., Ed.; NIST: Gaithersburg, MD, 2004; pp 12-13. (c) Harrison, C. J.; Cabral, T.; Stafford, C. M.; Karim, A.; Amis, E. J. J. Micromech. Microeng. 2004, 14, 153-158.
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supplied to the side channels, whereas water formed a continuous phase. Phase inversion occurred because the water phase had a higher affinity for the PU mold: it adhered to the wall of the orifice (Figure 4b) and squeezed out methacryl oxypropyl dimethylsiloxane to the second wall. The monomer thread was sheared off at the corner of the orifice, breaking up into droplets. The monomer droplets were formed in an “oscillating” regime by periodically breaking up a monomer thread at the two different corners of the orifice. Thus, in the PU MFFDs regardless of the type of liquid induced in the central channel, we obtained direct methacryl oxypropyl dimethylsiloxane emulsions. Emulsification of water in the PDMS microfluidic devices produced inverse emulsions when the water phase was supplied to the central channel and methacryl oxypropyl dimethylsiloxane was forced into the side channel (Figure 4c), which is similar to the experiments of Anna and Stone.18 When, however, the order of delivery of the liquids to the central and the side channels was changed, that is, when MAOP-DMS was supplied to the central channel (and expected to form droplets), phase inversion occurred in a manner similar to that shown in Figure 4b. The monomer wet the wall of the orifice, squeezing out the water solution to the other wall. The thread of water breaking up at the corner of the orifice generated droplets dispersed in methacryl oxypropyl dimethylsiloxane. Thus in the PDMS MFFD, inverse water-in-monomer emulsions were obtained. The described phenomenology is under investigation. Here, however, we stress several important observations: (a) Direct emulsions of moderately hydrophobic monomers such as multifunctional acrylates (e.g., TPGDA)36 could be obtained in both PDMS and PU microfluidic devices. (b) In the case of methacryl oxypropyl dimethylsiloxane and 2 wt % SDS aqueous solution, phase inversion was favored in an MFFD with a wide orifice. (c) Surface modification of PDMS and PU MFFDs by the adsorption of surfactants (e.g., cetyl trimethylammonium bromide (CTAB)) suppressed the phase inversion illustrated in Figure 4b; however, the effect disappeared after several hours of emulsification VI. Photopolymerization of Monomer Droplets Efficient polymerization of the monomer droplets generated in MFFD is a critical stage of the continuous microfluidics-based synthesis of polymer particles. To increase the productivity of the “lab on a chip”, we foresee placing on a single chip several microfluidic reactors acting in parallel. Therefore, it is imperative to reduce the dimensions of the MFFD device. The limiting factor, however, is the time of flow of the monomer droplets through the wavy microchannel (Figure 1b): the time of residence of the droplets in this part of the MFFD has to be sufficiently long for monomer conversion into polymer. For a particular monomer and a UV-light source, we controlled the rate of monomer polymerization by varying the concentration of photoinitiator in the monomer liquid. In photoinitiated free-radical polymerization, the rate of chain propagation (Rp) is related to the concentration of photoinitiator, cin, as Rp ∝ [1 - exp(-lcin)]0.5 where l is the sample thickness and is the absorptivity of the initiator.37 We found that for TPGDA for cin ) 2 wt % monomerto-polymer conversion was low: the particles that collected (36) The contact angle of water on poly(TPGDA) is ca. 57°. (37) (a) Decker, C. Polym. Int. 1998, 45, 133-141. Decker, C. Polym. Int. 2002, 51, 1141-1150. (b) Decker, C. Macromol. Rapid Commun. 2002, 23, 1067-1093.
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Figure 5. Typical SEM images of polyTPGDA polymer particles produced by continuous polymerization in PU MFFD at concentrations of photoinitiator HPCK, cin, of (a) 2, (b) 4, and (c) 6 wt %. (d) SEM image of particles obtained via polymerization of PETA-3. Qw ) 4 mL/h, Qm ) 0.1 mL/h, and cin ) 4 wt %. Scale bar is 100 µm.
at the exit of the serpentine channel had a rigid polymer “skin” and a liquid monomer core. Such morphology resulted in particle collapse under the vacuum in the SEM experiments (Figure 5a). The optimized concentration of photoinitiator in the preparation of TPGDA beads was from 3.5 to 4.5 wt %, whereas the conversion of TPGDA to polymer achieved at cin ) 4.0 wt % was 95-97%.38 PolyTPGDA microspheres had a smooth surface and a mean diameter that was 5-8% smaller than that of the corresponding droplets. The polydispersity (CV) of the microbeads was below 2%, similar to that of the corresponding droplets.39 For a higher content of photoinitiator of ca. 6 wt. %, fast polymerization of TPGDA led to particle “explosion” due to the large amount of heat released during the polymerization reaction (Figure 5c). Similar to TPGDA continuous polymerization of multifunctional monomers (e.g., PETA-3 at cin ) 4.0 wt %), monodisperse spherical microbeads with ca. 97% conversion (Figure 5d) were produced. VII. Synthesis of Particles with Various Shapes Many interesting applications of polymer particles are governed by their shapes in morphologies. Typically, conventional batch polymerization of homopolymers leads to the production of spherical particles.1 In our work, the emulsification and polymerization of monomers in the constrained geometry of the microfluidic reactor allowed for the preparation of particles with nonspherical shapes.13 We generated droplets with different volume by varying (38) Polymer conversion was determined by weighing polymer beads prior to and after extraction of unreacted monomer with acetone. (39) According to the standards of the National Institute of Standards and Technology (NIST) “particle distribution may be considered monodisperse if at least 90% of the distribution lies within 5% of the median size” (Particle Size Characterization Special Publication 960961, January 2001). We fit the experimental histograms of the size of the particles with Gaussian distributions. The standard deviations were typically on the order of 1-2% of the mean size, complying with the NIST definition of monodispersity.
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VIII. Synthesis of Particles with Different Compositions
Figure 6. Schematic (a-c) and optical microscopy (a′-c′, d) images of polyTPGDA particles with different shapes: microspheres (a, a′), disks (b, b′), (c, c′) rods, and (d) ellipsoidal polyTPGDA particles obtained via photopolymerization of droplets produced at Qw ) 8 mL/h, Qm ) 0.1 mL/h, and cin ) 4 wt %. Scale bar is 50 µm.
the flow rates of the continuous and droplet phases. The shape of the droplets was determined by the relationship between the diameter (d) of an undeformed droplet and the dimensions of the wavy channel in which polymerization took place (Figure 1b). Figure 6a-c shows the schematics of the generation of droplets with various shapes. Droplets with nonspherical shapes formed when the value of d was larger than at least one of the dimensions of the wavy channel. For w > d and h > d (where w and h are the width and the height of the channel, respectively), the droplets minimize their surface energy by acquiring a spherical shape (Figure 6a). For w < d, h > d and w < d, h < d, droplet confinement suppresses the relaxation of their shapes, and they assume a discoid and a rod shape, respectively, as shown in Figure 6b and c, respectively. In this approach, the aspect ratio of the nonspherical droplets can be conveniently varied by changing the ratio between the droplet volume and dimensions of the microchannel. Figure 6a’-c’ shows the nonequilibrium droplet shapes trapped in the solid state in the microfluidic reactor by photopolymerizing TPGDA, following the schematics of Figure 6a-c. The reduction of particle size accompanying polymerization prevented microbead clogging in the serpentine channel. We also obtained ellipsoidal particles by using the rate of flow of the water phase exceeding 8 mL/h. Under these conditions, the spherical liquid droplets flowing through the serpentine channel transformed into ellipsoids. The polymerization of such droplets produced “egg-like” TPGDA particles, as shown in Figure 6d.
The synthesis of liquid crystal/polymer particles, microbeads labeled with fluorescent dyes, polymer particles doped with inorganic nanoparticles (e.g., quantum dots), and porous microbeads has been demonstrated in our previous work.13 Prior to emulsification, a host monomer was mixed with an additive. If the concentration of the latter was not too high and it was compatible with the host monomer (that is, no aggregation or macroscopic segregation of the additive occurred), then subsequent polymerization of the monomer-additive mixture led to the functionalized microbeads. By contrast, the synthesis of copolymer microbeads was less straightforward. We obtained two types of copolymer microspheres carrying surface carboxyl and amino groups. The former particles were obtained by mixing TPGDA (a host monomer) with various amounts of acrylic acid (AA). The functionalization of the microbeads with -NH2 groups was achieved by polymerizing droplets of TPGDA mixed with amino ethyl methacrylate (AEMA). To achieve mixing, we shook an aqueous solution of AEMA (pH 10) and TPGDA for ca. 30 min. Here, we demonstrate the synthesis of copolymer particles carrying surface -COOH groups, molecules and cells. Such particles have important applications40 in the detection, immobilization, and isolation of biological molecules and cells. The introduction of a hydrophilic co-monomer into the host droplet phase had several important consequences. For example, efficient emulsification of the TPGDA/AA monomer mixture was achieved for the concentration of AA, CAA, not exceeding 5.0 wt % (Figure 7a, left). For 8.0 < CAA < 15 wt %, the resulting droplets showed a tendency to adhere to the orifice wall (Figure 7a, middle) or to the top surface of the MFFD fabricated in PU; the latter effect was more pronounced at the low flow rates of the continuous phase. Although this problem could, in principle, be solved by using a MFFD fabricated in PDMS, we found that for CAA > 15 wt % the monomer thread did not break up into droplets (Figure 7a, right). For 0 < CAA e 8.0%, mixing AA with TPGDA led to the reduction in interfacial tension between the monomer mixture and the water phase and to a weak increase in the viscosity of the host monomer. The resulting 6-7% reduction in the capillary number Ca led to a small reduction in the size of the droplets with increasing concentration of AA, as shown in Figure 7b. The TPGDA/AA droplets (CAA ) 5 wt %) were photopolymerized in the manner similar to that described above. Figure 7 shows a typical SEM image of the resulting poly(TPGDA-AA) particles with CV < 2%. The surface composition of the microspheres was examined by using X-ray photon spectroscopy (XPS). We found that the surface concentration of AA was 12.3 mol %, that is, ca. 66% of the amount expected from the weight ratio AA/ TPGDA in the monomer mixture. We speculate that a reduction in AA content occurred because of monomer diffusion from the droplets into the continuous phase. We bioconjugated poly(TPGDA-AA) particles synthesized in the microfluidic reactor with bovine serum albumin covalently labeled with a fluorceine isothiocynate (FITC-BSA). The bioconjugation was achieved by (a) attaching the FITC-BSA to the surface of polymer beads for 1 h at 30 °C in a phosphate buffer at pH 6.0 and (b) adding 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) to the dispersion of poly(TPGDA(40) (a) Slomkowski, S. Prog. Polym. Sci. 1998, 23, 815-874. (b) Kawaguchi, H. Prog. Polym. Sci. 2000, 25, 1171-1210.
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Figure 7. (a) Flow focusing of TPGDA mixed with different amounts of AA. (CAA, from left to right): 5, 8, and 15 wt %, respectively. (b) Variation of droplet size vs CAA. (c) SEM image of poly(TPGDA-AA) particles obtained by photopolymerization of TPGDA droplets with 5 wt % AA. (d) Fluorescence microscopy image of copolymer beads conjugated with FITC-BSA, cAA ) 5 wt %. For the emulsification of the TPGDA/AA mixture, we used T Qm ) 0.01 mL/h and Qw from 0.5 to 2.0 mL/h. Scale bar is 100 µm.
AA) particles bearing FITC-BSA at 30 °C.41 Control experiments were conducted by heating poly(TPGDA/AA) microbeads with FITC-BSA or EDC. The attachment of fluorescent FITC-BSA to the microbead surface occurred only when both EDC and FITC-BSA were used. Figure 7d shows a fluorescence microscopy image of the copolymer microbeads synthesized using an MFFD reactor and conjugated with FITC-BSA. IX. Periodic Arrays of Polymer Particles High monodispersity of the droplets generated in the MFFD and their geometric confinement in the downstream microchannel led to the dynamic assembly of droplets into 2D lattices with a high degree of order and symmetry. We first explored the formation of lattices by droplets of silicone oil (SO) dispersed in a 2 wt % aqueous solution of SDS. We varied the volume of droplets to produce circular liquid disks with a diameter from 87 to 880 µm. Under typical operating conditions, the coefficient of variance in disk diameters was below 2.5%. The rates of flow of the oil and aqueous phases determined the total volume of droplets generated per unit time and the rate of droplet evacuation from the downstream channel. The velocity of droplets in the downstream channel of the MFFD was slower than the speed of the continuous aqueous phase,42 and the discoid droplets assembled in the dynamic 2D close-packed lattices filling the entire volume of the downstream microchannel. Figure 8a-c shows typical optical microscopy images of the lattices of circular discoid oil droplets. The number of columns, n, aligned parallel to the microchannel walls decreased with increasing dimensions of droplets. In our experiments, the number of columns varied from 1 to 15. With increasing size of droplets, a transition between the lattices with a different number of columns occurred (41) Desai, M. C.; Stramiello, L. M. S. Tetrahedron Lett. 1993, 34, 7685-7688. (42) (a) Wong, H.; Radke, C.; Morris, S. J. J. Fluid Mech. 1995, 292, 71-94. (b) Wong, H.; Radke, C.; Morris, S. J. J. Fluid Mech. 1995, 292, 95-110. (c) Garstecki, P.; Gitlin, I.; DiLuzio, W.; Whitesides, G. M.; Kumacheva, E.; Stone H. A. Appl. Phys. Lett. 2004, 85, 26492651.
Figure 8. Optical microscopy images of 2D lattices of circular (a-c) and hexagonal (d-f) liquid disks of silicone oil dispersed in a 2 wt % SDS aqueous solution in PU MFFD. Average volume of the disks × 10-6 cm3: (a) 1.12, (b) 0.74, (c) 0.53, (d) 2.73, (e) 2.01, (f) 1.52. Binary 2D lattices (g-h) produced by the assembly of large and small SO droplets (viscosity 5 and 10 cP), respectively. (i) Droplets of dye-labeled hexadecane surrounded by SO droplets (viscosity 10 cP). Scale bar is 200 µm.
through the deformation of circular disks: because of confinement, the circular disks acquired pentagonal and, more frequently, hexagonal shapes (Figure 8d-f). The lattices of hexagonal disks retained a high degree of order and symmetry. Using a modified MFFD, we also produced droplets with a bimodal size distribution. Each population of droplets had a coefficient of variance of ca. 2.5%. The droplets were obtained from silicone oil dispersed in an aqueous SDS solution or from droplets of silicone oil and hexadecane
Microfluidic Reactors for Polymer Particles
Figure 9. Optical microscopy images of 2D lattices of MAOPDMS disks in PU MFFD prior to (a, c) and after (b, d) in situ photopolymerization. A 3.5 ( 0.5 wt % mixture of HPCK and MAOP-DMS was used to generate droplets in a 2 wt % aqueous solution of SDS. (a) Qw ) 0.02 mL/h, Qm ) 0.04 mL/h; (c) Qw ) 0.1 mL/h, Qm ) 0.2 mL/h. Scale bar is 200 µm.
dispersed in the SDS solution. By changing the relative flow rates of the nonpolar and aqueous liquids, we achieved control over the number ratio and the size ratio of the droplets with different sizes and compositions. Figure 8g-i shows several representative images of the binary dynamic lattices of discoid droplets formed in MFFD. The droplets with different sizes acquired complicated shapes; however, they assembled in strikingly ordered gliding arrays. We produced periodic arrays of polymer disks by trapping the structure of droplet lattices in the solid state. The discoid droplets were obtained from methacryl oxypropyl dimethylsiloxane mixed with 4.0 ( 0.5 wt % of photoinitiator HCPK. Figure 9 shows the structure of the lattice of methacryl oxypropyl dimethylsiloxane droplets with n ) 2 and 7 prior to (Figure 9a and c) and following polymerization (Figure 9b and d). Following solidification, the droplets shrank by ca. 5%. Weaker confinement led to the relaxation of droplet shapes and the transformation from hexagonal to close-to-circular droplets (Figure 9d); nevertheless, highly ordered lattices were preserved during polymerization. X. Summary and Outlook This work provides an overview of research conducted in our laboratory over the past several years that has focused on the use of microfluidic laminar flow reactors in continuous (“on the fly”) synthesis of polymer colloids. The resulting particles featured extremely narrow size distribution and a large versatility in dimensions, shapes, and compositions. The production of polymer particles included the emulsification of monomer droplets in MFFD and their in-situ free-radical photopolymerization. Our results show that microfluidics-based synthesis is an efficient strategy for the production of highly monodisperse polymer particles in the range of sizes from ca. 20 to 200
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µm. The size of microbeads is controlled by varying the flow rates of the continuous and droplet phases, the design of the microfluidic device, and the composition of dispersed and continuous phases, that is, their viscosities and interfacial tension. Other properties of monomers such as their solubility in the continuous medium or viscosity have to be taken into consideration to achieve efficient microbead production. Our results demonstrate that the selection of an appropriate material for the fabrication of microfluidic reactors is vital in the production of polymer beads: the droplet phase should have lower affinity for the material of the MFFD than the continuous phase does. Close-tocomplete conversion of monomer to polymer is achieved by optimizing the concentration of photoinitiator in monomer droplets and providing a sufficient time of residence of droplets in the microfluidic reactor. The use of multifunctional monomers is an alternative to increasing the photopolymerization rate and producing highly cross-linked particles. Although the production of polymer colloids in microfluidic reactors resembles the batch polymerization of monomers, it has several useful features distinguishing it from suspension polymerization, the polymerization of monomer droplets obtained by membrane emulsification, or the Bibette process. The polydispersity of particles produced in microfluidic reactors is typically below 2-2.5%, that is, it is significantly narrower than in the methods listed above. No stabilization against coalescence or Ostwald ripening of monomer droplets is required because their collisions in the microfluidic device are suppressed and the time prior to monomer polymerization is on the order of seconds. Polymerization in the constrained geometry of the microfluidic device allows for the production of rods, disks, and ellipsoids or particles with more complicated shapes (e.g., L or Π shapes). Polymer colloids produced in microfluidic reactors have all of the applications of polymer particles synthesized by conventional methods. In particular, we foresee the use of bioconjugated microbeads in medical diagnostics, bioseparation applications, and microcarriers of cells. These particles can be doped with magnetic nanoparticles or different populations of quantum dots. The extremely narrow size distribution of microbeads allows their use as the building blocks of materials with periodically modulated structures and compositions. The possibility of encapsulating liquid ingredients will enable the application of polymer capsules in mucosal and oral drug delivery or in cosmetic applications. Porous microbeads have potential applications in separation and sensing technologies. Very recently, we showed that the combination of more than two immiscible liquids can be successfully used for the production of polymer capsules with single or multiple liquid cores and particles with nonconventional shapes.27 The further development of the microfluidics-based synthesis of polymer colloids will obviously require the demonstration of scaling up in particle production. The productivity of the lab on a chip can be increased by using highly reactive monomers and/or by placing several microfluidic reactors on a single chip. Given that a single MFFD device produces approximately 100-500 polymer particles/s, we expect that a 10-device chip will produce up to 1.6 × 107 particles/h. The synthesis of smaller particles (in the size range from ca. 3 to 25 µm) is highly desirable. Preliminary experiments showed that the reduction of the width and height of the rectangular orifice (Figure 1a) is the most
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efficient route to the reduction of microbead diameter below 20 µm. Further efforts in the microfluidics-based synthesis of polymer particles will seek to extend the range of materials used in particle generation. Photoinitiated cross linking of liquid oligomers or polymers will allow for the production of particles from “nonconventional” polymers. In particular, our group collaborates with Professor Ian Manners (University of Toronto) in the production of polyferrocenebased microbeads. The emulsification of aqueous solutions of biopolymers accompanied by hardening of the droplets will lead to the production of biomicrogels. Furthermore, the generation of particles with unique morphologies will allow the production of new materials with structuredependent properties.
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Acknowledgment. This research was funded by the Canada Research Chair Fund. Discussions with Professors Howard A. Stone and George M. Whitesides, and Dr. Piotr Garstecki are greatly appreciated. We also thank Professor David James for his assistance with measurements of monomer viscosity. Supporting Information Available: Experimental details of materials, monomer and particle characterization, and droplet emulsification. This material is available free of charge via the Internet at http://pubs.acs.org. LA050519E
