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 continuousmicrofluidic reactors. The method includes (a) the generation of highly monodisperse monomer dropletsin a microfluidic flow-focusing device and (b) in-situ solidification of these droplets by means ofphotopolymerization. We discuss the effect of monomer properties on the emulsification process, the effectof the polymerization rate on the production of high-quality particles, the role of the material of themicrofluidic 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 byphotopolymerization of the dynamic lattices of monomer droplets in microfluidic channels. The article isconcluded with a summary of future research directions in the production of polymer colloids in microfluidicreactors.
I. Introduction
Polymer colloids with dimensions in the range of 10-100 µm are extensively used in ion-exchange and chro-matography columns, in various biological and medicinalapplications, and as calibration standards, toners, coat-ings, and supports for catalysts.1 In many of theseapplications, the particle size and size distribution are ofkey importance. The preparation of monodisperse sub-micrometer-sized polymer beads with a predeterminedsurface and bulk properties is a well-established proce-dure.2,3 By contrast, the synthesis of larger particles witha narrow size distribution is a synthetic challenge: it iseither material-specific or time-consuming (that is, it isaccomplished in several stages) or it does not provide asufficiently narrow size distribution of the resultingparticles. Moreover, the control of microbead shapes inconventional polymerization reactions is generally limitedby the preparation of spherical particles.
Recent progress in developing new microfabricationtechniques and microreaction technologies has raisedexciting opportunities in reaction engineering.4 Microre-actors provide high heat and mass-transfer rates, safeand rapid synthesis, and the possibility to develop newreaction pathways that are too difficult for conventional
reactors.5,6 The literature is burgeoning with reports onmicroreaction syntheses of various organic, bioorganic,and inorganic materials.7-12
Several years ago, our group initiated research aimedat the development of continuous microfluidic reactorsfor the synthesis of polymer particles with controlled size,shape, morphology, and composition. This work wasinspired by progress in the production of highly mono-dispersedropletsandbubblesbyusingvariousmicrofluidicdevices and methods.
The present article provides an overview of our work inthe area of continuous microfluidics-based synthesis ofpolymer colloids. The described strategy is applicable tothe production of both hydrophobic and hydrophilicparticles, including microgels. Here, however, we describethe production of hydrophobic beads. Some of the resultspresented herein have been reported in coauthorship withProfessors G. M. Whitesides and H. A. Stone (HarvardUniversity);13 most of the results, however, were obtainedafter a joint paper was published. Herein, we describeimportant factors that govern the synthesis of polymermicrobeads: (i) emulsification of monomers with different
(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 EmulsionTechnology; 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.
(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.
viscosities; (ii) effect of hydrodynamic conditions (that is,flow rates of continuous and droplet phases) on thedimensions of monomer droplets; (iii) importance of theselection of an appropriate material of microfluidic devices;(iv) photopolymerization of emulsified monomers; and (v)production of microspheres with different shapes andcompositions. With an eye toward the potential applica-tions of the arrays of particles produced in microfluidicdevices, we have also explored the assembly of monomerdroplets in periodic arrays. The article is concluded witha summary and our perspective on future research in thefield. The experimental details are available as SupportingInformation.
II. Background: Related Work on the Generationof Polymer Colloids by Means of Microfluidics
To the best of our knowledge, prior to 2004 thepreparation of polymer particles with the assistance ofmicrofluidic methods had been accomplished via a two-stage process. In the first stage, a monomer or a liquidpolymer was emulsified to obtain droplets with a narrowsize distribution. In the next stage, the resulting dropletswere hardened in a batch (that is, a noncontinuous)process. Emulsification has been achieved by variousmethods (e.g., by forcing fluids into the bulk continuousmedium through a nozzle,14 a membrane,15 or a vibratingorifice16). In other approaches, emulsification was ac-complished solely in microfluidic devices at T junctions,17
by flow-focusing in a narrow orifice,18 or by using micro-channel terraces.19 The advantage of these emulsificationmethods was their ability to control droplet size andproduce highly monodisperse droplets.
The chemical nature of the droplet phase determinedthe next step in which the droplets were solidified. Dropletsof polymer solutions were hardened by solvent evapora-tion, by physical (e.g., ionic) cross linking,20 by photoini-tiated cross linking,13b,16b or by means of chemical reactions(e.g., by condensation of carbonyl chloride and aminegroups).21 Droplets of monomers were solidified by meansof thermally initiated15a,19,22 or UV-initiated batch po-lymerization.23
Particle production via two-stage processes did notrealize the full potential of continuous microfluidics-based
synthesis, that is, the possibility of the fast and reproduc-ible generation of polymer beads (in contrast to substantialbatch-to-batch product variation in batch processes). Inaddition, batch polymerization of monomer dropletsrequired their stabilization against coalescence.
We note that several communications reported thecontinuous production of polymer colloids via polycon-densation16a or photopolymerization16b of aerosol dropletsgenerated with the assistance of vibrating-orifice genera-tors. These methods, however, could not be ascribed tothe microfluidics-based synthesis.
In 2004-2005, several papers reported the rapidcontinuous scalable emulsification and synthesis of poly-mer particles accomplished in microfluidic reactors. “Onthe fly” synthesis of microscale fibers and tubes wasdemonstrated by Beebe and Jeong.24 Highly monodispersepolymer particles with different compositions were ob-tained in the collaborative work of Whitesides, Stone, andKumacheva.13 In the latter work, photopolymerization ofacrylate-based droplets in the constrained geometry ofmicrofluidic devices allowed for the production of non-spherical particles such as polymeric disks, ellipsoids, androds. A similar approach was used by Doyle et al.,25 whoobtainedpolymerparticles fromNorlandOpticalAdhesive.The feasibility of preparation of polymer capsules (liquiddroplets engulfed with a polymer shell) has been dem-onstrated by carrying out interfacial polycondensation26
or free-radical polymerization.27 In situ photopolymeri-zation of 2D lattices of monomer droplets has led to theformation of arrays of polymer disks with a high degreeof order and symmetry. 41
III. Design of the Microfluidic Reactor
Figure 1 shows the design of the microfluidic laminarflow reactor used in the present work: a microfluidic flow-focusing device (MFFD)18 in which the monomer dropletswere formed (Figure 1a) and a wavy channel in whichthese droplets were exposed to UV irradiation (Figure1b).
The microfluidic devices were fabricated in poly-(dimethylsiloxane) (PDMS) or polyurethane (PU) elas-tomer (synthesized in our laboratory) using a standardsoft lithograpy procedure.28 Photolithographic masterswere prepared with SU-8 photoresist on silicon wafers.The height of the microfluidic channels varied from 25 to100 µm (Figure 1a).
(14) (a) Berkland, C.; Kim, K.; Pack. D. W. J. Controlled Release2001, 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, 277-80.
(20) Smidsrod, O.; Skjak-Brek, G. Trends Biotechnol. 1990, 8, 71-78.
(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.
(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. Langmuir2005, 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, 153-184.
Figure 1. (a) Schematic of droplet formation in the microfluidicflow-focusing device. The height of the channels varied from 25to 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 monomerdroplets. Channel width and length are 640 µm and 17.6 cm,respectively.
Two immiscible liquids (a monomer and an aqueousphase) were supplied to the MFFD by two digitallycontrolled syringe pumps. Unless specified, a monomerwas supplied to the central channel, and a 2 wt % aqueoussolution of sodium dodecyl sulfate was supplied to the twoouter channels.
The monomer droplets were photopolymerized in theserpentine channel of the MFFD (Figure 1b). The lengthof the wavy channel was 17.6 cm. The time of residenceof droplets in the wavy channel (that is, the time ofphotopolymerization) depended on their velocities, and itcould be varied from 20 s to 15 min.
IV. Emulsification of Monomers in MicrofluidicDevices
In the microfluidics-based emulsification meth-ods17-19,29,30 for a particular combination of continuousand dispersed phases the size of the droplets and theirsize distribution are conveniently controlled by varyingthe flow rates of the continuous and droplet phases andthe design of the microfluidics device. Generally, thevariation in droplet size is a function of a dimensionlessReynolds number, Re ≡ FRU/µ, and a capillary numberCa ≡ µU/γ12, where U is the average velocity of the liquid,γ12 is the interfacial tension, F and µ are the density andviscosity of the liquid, respectively, and R is the charac-teristic length scale of the system.
Because the objective of our work was the synthesis ofpolymer particles, here we discuss only the details ofemulsification that are pertinent to the production ofdroplets from polymerizable fluids (that is, liquid mono-mers). We studied the emulsification of four multifunc-tional acrylates: ethylene glycol dimethacrylate (EGD-MA), tri(propylene glycol) diacrylate (TPGDA), penta-erythritol triacrylate (PETA-3), and pentaerythritol tet-raacrylate (PETA-4).
Figure 2 illustrates three major regimes in the formationof monomer droplets in the microfluidic flow-focusingdevice. The low flow rate of the continuous water phase,
Qw, and low ratios of flow rates of water to monomerphases, Qw/Qo, resulted in a weak shear force exerted onthe monomer thread. The monomer droplets formed inthe dripping regime (Figure 2a): the monomeric threadbroke up behind the orifice into the droplets with adiameter that was significantly larger than the orificewidth. For the moderate values of Qw and Qw/Qo, thedroplets were generated by breaking up the monomerthread in or behind the orifice. In this regime, a monomerthread was focused in the orifice by the continuous phase,where the former broke up, released a droplet, andretracted back into the upstream (Figure 2b). At high flowrates of the continuous phase and large values of Qw/Qo,a transition to the jetting mode occurred:31 the monomerthread remained behind the orifice, breaking up intodroplets due to the Rayleigh plateau hydrodynamicinstability (Figure 2c). Under particular conditions, smallsatellite droplets accompanied the formation of the mainpopulation of droplets.
Qualitatively, the generation of oil-in-water emulsiondroplets shown in Figure 2 was analogous to the prepara-tion of oil-in-water emulsions in a similar MFFD.18 In therest of this article unless specified, we will focus onmonomer emulsification in regime 2: the generation ofdroplets by flow focusing of the monomer thread in theorifice.
For a particular width and height of the orifice, the sizeof droplets was governed by the properties of the monomerliquid and the flow rates of the continuous and dropletphases. Figure 3a shows the variation in diameter ofmonomer droplets plotted as a function of capillary numberCa of the continuous phase. Generally, at low values ofCa all monomers produced large droplets. By constrast,for intermediate and large values of Ca we observeddifferent trends for the bifunctional monomers (EGDMAand TPGDA) and the tri- and tetrafunctional monomers(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,
Figure 2. Breakup of the TPGDA thread in 2 wt % aqueousSDS 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 ) 0.30mL/h. (c) Regime 3: Qm ) 0.2 mL/h, Qw ) 4.0 mL/h.
Figure3. (a)Variation indropletdiametervscapillarynumber,Ca, of the continuous water phase for a constant water-to-monomer flow rate ratio, Qw/Qm ) 60. For Ca > 0.028, a threadof PETA-4 did not break up into droplets. (b) Variation inviscosity of monomers plotted as a function of shear rate. (aand b) PETA-4 (]), PETA-3 (4), TPGDA (0), and EGDMA (O).(c) Distribution of diameters of TPGDA droplets (averagediameter 103.9 µm, CV ) 0.94%, Qm ) 0.035 mL/h, Qw ) 2.1mL/h) and PETA-3 droplets (average diameter 187.5 µm, CV) 0.9, Qm ) 0.06 mL/h, Qw ) 3.6 mL/h).
11616 Langmuir, Vol. 21, No. 25, 2005 Seo et al.
(PETA-3 and PETA-4). With increasing Ca, the diametersof EGDMA and TPGDA droplets decreased until theybecame almost invariant. The difference in the formationof droplets from EGDMA and TPGDA was caused by thedifference in their viscosity and interfacial tension of themonomer fluid with the water phase (Table 1). The resultswere in agreement with previous reports on the relation-ship between viscosity- and interfacial tension-drivenforces on one hand and droplet size on the other hand.32
By contrast, with increasing Ca the dimensions ofdroplets formed by PETA-3 and PETA-4 first slightlyincreased and then remained almost invariant. We verifiedthe Newtonian behavior of the monomers: the viscosityof 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 dimensionsof droplets formed from PETA-3 and PETA-4 to the highviscosity of these fluids. In contrast to low-viscositymonomers, thegeneration ofdroplets ofPETA-3 orPETA-4occurred through the formation of a long, narrow neck ina monomer thread. The breakup of the neck occurred inthe orifice or behind (but quite close to) the orifice atmoderate values of Qw and Qw/Qo, and after releasing adroplet, the monomer thread retracted into the upstream,thus the generation of droplets of PETA-3 and PETA-4occurred in regime 2. The “tail” resulting from neckingcontributed to the increase in droplet volume.
The width of the droplet size distribution depended onthe type of monomer used and the flow rates of water andmonomer. However, for each monomer a particularwindow of Qw and Qo existed in which the droplets featuredan extremely narrow size distribution. Figure 3c showsthe distribution in dimensions of TPGDA and PETA-3droplets. Generally, the coefficient of variance (CV) of thedroplets, defined as standard deviation divided by averagedroplet diameter, was below 2% for a broad range ofhydrodynamic conditions. We stress that despite the highviscosity of PETA-3 and especially PETA-4 these mono-mers were successfully emulsified in droplets with anarrow size distribution.
In addition to the variation in hydrodynamic conditionsof the generation of droplets, further control of dropletdimensions was achieved by varying the design of MFFD:a decrease in the width and height of the orifice resultedin the production of droplets with diameters as small asca. 18 µm.
V. Material of the Microfluidic Reactor
The selection of an appropriate material for the MFFDis a vital stage in the generation of monomer droplets.Several groups reported that the affinity of the dropletphase for the material of the microfluidic device (e.g.,glass, silicon, and PDMS33-35) can cause “phase inversion”
when the liquid to be emulsified becomes a continuousphase.
We examined the emulsification of the monomer meth-acryl oxypropyl dimethylsiloxane in the MFFDs that werefabricated from poly(dimethylsiloxane) (PDMS) and poly-urethane (PU). The wetting angles of water on PDMS andPU were 109 and 86°, respectively. A monomer phaseshowed an affinity for the PDMS mold that was strongerthan that of water, whereas the water phase showed astronger affinity for the PU mold.
Figure 4a-d shows typical optical microscopy imagesof the droplets formed in the MFFDs fabricated from PU(Figure 4a and b) and PDMS (Figure 4c and d). The MFFDshad the same design as shown in Figure 1. In both cases,the liquid supplied to the central channel was expectedto form droplets, whereas the liquid forced into the outertwo channels was supposed to form a continuous phase.
When methacryl oxypropyl dimethylsiloxane was de-livered to the central channel and the water phase (a 2wt % aqueous solution of SDS) was supplied to the sidechannels of the PU MFFD, the monomer avoided contactwith the PU walls and formed a cylindrical plug that brokeup into droplets dispersed in the continuous aqueous phase(Figure 4a). In Figure 4b, the water phase was suppliedto the central channel, and MAOP-DMS was supplied tothe side channels of the same MFFD. By contrast withthe previous case, droplets were formed by the monomer
(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.
(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 andAccomplishments in Materials Science and Engineering LaboratoryPolymer 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.
Table 1. Properties of Monomers Emulsified in MFFD
Figure 4. Optical microscopy images of droplets obtained inMFFDs fabricated in PU (a, b) and PDMS (c, d). The waterphase contained 2 wt % SDS. (a) MAOP-DMS was supplied tothe central channels, and the water phase was forced to theouter channels. (b) The water phase labeled with methyleneblue dye was supplied to the central channel, and MAOP-DMSwas supplied to the outer channels. Phase inversion occurredbecause of the higher affinity of the water phase for the PUmold. (c) The dye-labeled water phase was supplied to the centralchannel, and MAOP-DMS was delivered to the outer channels.(d) MAOP-DMS was supplied to the central channel, and thewater phase was forced into the outer channels. Phase inversionoccurred 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.
supplied to the side channels, whereas water formed acontinuous phase. Phase inversion occurred because thewater phase had a higher affinity for the PU mold: itadhered to the wall of the orifice (Figure 4b) and squeezedout methacryl oxypropyl dimethylsiloxane to the secondwall. The monomer thread was sheared off at the cornerof the orifice, breaking up into droplets. The monomerdroplets were formed in an “oscillating” regime byperiodically breaking up a monomer thread at the twodifferent corners of the orifice. Thus, in the PU MFFDsregardless of the type of liquid induced in the centralchannel, we obtained direct methacryl oxypropyl dimethyl-siloxane emulsions.
Emulsification of water in the PDMS microfluidicdevices produced inverse emulsions when the water phasewas supplied to the central channel and methacryloxypropyl dimethylsiloxane was forced into the sidechannel (Figure 4c), which is similar to the experimentsof Anna and Stone.18 When, however, the order of deliveryof the liquids to the central and the side channels waschanged, that is, when MAOP-DMS was supplied to thecentral channel (and expected to form droplets), phaseinversion occurred in a manner similar to that shown inFigure 4b. The monomer wet the wall of the orifice,squeezing out the water solution to the other wall. Thethread of water breaking up at the corner of the orificegenerated droplets dispersed in methacryl oxypropyldimethylsiloxane. Thus in the PDMS MFFD, inversewater-in-monomer emulsions were obtained.
The described phenomenology is under investigation.Here, however, we stress several important observations:(a) Direct emulsions of moderately hydrophobic monomerssuch as multifunctional acrylates (e.g., TPGDA)36 couldbe obtained in both PDMS and PU microfluidic devices.(b) In the case of methacryl oxypropyl dimethylsiloxaneand 2 wt % SDS aqueous solution, phase inversion wasfavored in an MFFD with a wide orifice. (c) Surfacemodification of PDMS and PU MFFDs by the adsorptionof surfactants (e.g., cetyl trimethylammonium bromide(CTAB)) suppressed the phase inversion illustrated inFigure 4b; however, the effect disappeared after severalhours of emulsification
VI. Photopolymerization of Monomer DropletsEfficient polymerization of the monomer droplets gen-
erated in MFFD is a critical stage of the continuousmicrofluidics-based synthesis of polymer particles. Toincrease the productivity of the “lab on a chip”, we foreseeplacing on a single chip several microfluidic reactors actingin parallel. Therefore, it is imperative to reduce thedimensions of the MFFD device. The limiting factor,however, is the time of flow of the monomer dropletsthrough the wavy microchannel (Figure 1b): the time ofresidence of the droplets in this part of the MFFD has tobe sufficiently long for monomer conversion into polymer.
For a particular monomer and a UV-light source, wecontrolled the rate of monomer polymerization by varyingthe concentration of photoinitiator in the monomer liquid.In photoinitiated free-radical polymerization, the rate ofchain propagation (Rp) is related to the concentration ofphotoinitiator, cin, as Rp ∝ [1 - exp(-εlcin)]0.5 where l isthe sample thickness and ε is the absorptivity of theinitiator.37
We found that for TPGDA for cin ) 2 wt % monomer-to-polymer conversion was low: the particles that collected
at the exit of the serpentine channel had a rigid polymer“skin” and a liquid monomer core. Such morphologyresulted in particle collapse under the vacuum in the SEMexperiments (Figure 5a). The optimized concentration ofphotoinitiator in the preparation of TPGDA beads wasfrom 3.5 to 4.5 wt %, whereas the conversion of TPGDAto polymer achieved at cin ) 4.0 wt % was 95-97%.38
PolyTPGDA microspheres had a smooth surface and amean diameter that was 5-8% smaller than that of thecorresponding droplets. The polydispersity (CV) of themicrobeads was below 2%, similar to that of the corre-sponding droplets.39
For a higher content of photoinitiator of ca. 6 wt. %, fastpolymerization of TPGDA led to particle “explosion” dueto the large amount of heat released during the polym-erization reaction (Figure 5c). Similar to TPGDA continu-ous polymerization of multifunctional monomers (e.g.,PETA-3 at cin ) 4.0 wt %), monodisperse sphericalmicrobeads with ca. 97% conversion (Figure 5d) wereproduced.
VII. Synthesis of Particles with Various Shapes
Many interesting applications of polymer particles aregoverned by their shapes in morphologies. Typically,conventional batch polymerization of homopolymers leadsto the production of spherical particles.1 In our work, theemulsification and polymerization of monomers in theconstrained geometry of the microfluidic reactor allowedfor the preparation of particles with nonspherical shapes.13
We generated droplets with different volume by varying
(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.
(38) Polymer conversion was determined by weighing polymer beadsprior to and after extraction of unreacted monomer with acetone.
(39) According to the standards of the National Institute of Standardsand Technology (NIST) “particle distribution may be consideredmonodisperse if at least 90% of the distribution lies within 5% of themedian size” (Particle Size Characterization Special Publication 960-961, January 2001). We fit the experimental histograms of the size ofthe particles with Gaussian distributions. The standard deviations weretypically on the order of 1-2% of the mean size, complying with theNIST definition of monodispersity.
Figure 5. Typical SEM images of polyTPGDA polymerparticles produced by continuous polymerization in PU MFFDat concentrations of photoinitiator HPCK, cin, of (a) 2, (b) 4, and(c) 6 wt %. (d) SEM image of particles obtained via polymer-ization of PETA-3. Qw ) 4 mL/h, Qm ) 0.1 mL/h, and cin ) 4wt %. Scale bar is 100 µm.
11618 Langmuir, Vol. 21, No. 25, 2005 Seo et al.
the flow rates of the continuous and droplet phases. Theshape of the droplets was determined by the relationshipbetween the diameter (d) of an undeformed droplet andthe dimensions of the wavy channel in which polymeri-zation took place (Figure 1b). Figure 6a-c shows theschematics of the generation of droplets with variousshapes. Droplets with nonspherical shapes formed whenthe value of d was larger than at least one of the dimensionsof the wavy channel. For w > d and h > d (where w andh are the width and the height of the channel, respectively),the droplets minimize their surface energy by acquiringa spherical shape (Figure 6a). For w < d, h > d and w <d, h < d, droplet confinement suppresses the relaxationof 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 nonsphericaldroplets can be conveniently varied by changing the ratiobetween the droplet volume and dimensions of themicrochannel. Figure 6a’-c’ shows the nonequilibriumdroplet shapes trapped in the solid state in the microfluidicreactor by photopolymerizing TPGDA, following theschematics of Figure 6a-c. The reduction of particle sizeaccompanying polymerization prevented microbead clog-ging in the serpentine channel.
We also obtained ellipsoidal particles by using the rateof flow of the water phase exceeding 8 mL/h. Under theseconditions, the spherical liquid droplets flowing throughthe serpentine channel transformed into ellipsoids. Thepolymerization of such droplets produced “egg-like” TPG-DA particles, as shown in Figure 6d.
VIII. Synthesis of Particles with DifferentCompositions
The synthesis of liquid crystal/polymer particles, mi-crobeads labeled with fluorescent dyes, polymer particlesdoped with inorganic nanoparticles (e.g., quantum dots),and porous microbeads has been demonstrated in ourprevious work.13 Prior to emulsification, a host monomerwas mixed with an additive. If the concentration of thelatter was not too high and it was compatible with thehost monomer (that is, no aggregation or macroscopicsegregation of the additive occurred), then subsequentpolymerization of the monomer-additive mixture led tothe functionalized microbeads.
By contrast, the synthesis of copolymer microbeads wasless straightforward. We obtained two types of copolymermicrospheres carrying surface carboxyl and amino groups.The former particles were obtained by mixing TPGDA (ahost monomer) with various amounts of acrylic acid (AA).The functionalization of the microbeads with -NH2 groupswas achieved by polymerizing droplets of TPGDA mixedwith amino ethyl methacrylate (AEMA). To achievemixing, we shook an aqueous solution of AEMA (pH 10)and TPGDA for ca. 30 min. Here, we demonstrate thesynthesis of copolymer particles carrying surface -COOHgroups, molecules and cells. Such particles have importantapplications40 in the detection, immobilization, and isola-tion of biological molecules and cells.
The introduction of a hydrophilic co-monomer into thehost droplet phase had several important consequences.For example, efficient emulsification of the TPGDA/AAmonomer mixture was achieved for the concentration ofAA, CAA, not exceeding 5.0 wt % (Figure 7a, left). For 8.0< CAA < 15 wt %, the resulting droplets showed a tendencyto adhere to the orifice wall (Figure 7a, middle) or to thetop surface of the MFFD fabricated in PU; the latter effectwas more pronounced at the low flow rates of thecontinuous phase. Although this problem could, in prin-ciple, be solved by using a MFFD fabricated in PDMS, wefound that for CAA > 15 wt % the monomer thread did notbreak up into droplets (Figure 7a, right).
For 0 < CAA e 8.0%, mixing AA with TPGDA led to thereduction in interfacial tension between the monomermixture and the water phase and to a weak increase inthe viscosity of the host monomer. The resulting 6-7%reduction in the capillary number Ca led to a smallreduction in the size of the droplets with increasingconcentration of AA, as shown in Figure 7b.
The TPGDA/AA droplets (CAA ) 5 wt %) were photo-polymerized 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 surfacecomposition of the microspheres was examined by usingX-ray photon spectroscopy (XPS). We found that thesurface 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 areduction in AA content occurred because of monomerdiffusion from the droplets into the continuous phase.
We bioconjugated poly(TPGDA-AA) particles synthe-sized in the microfluidic reactor with bovine serumalbumin covalently labeled with a fluorceine isothiocynate(FITC-BSA). The bioconjugation was achieved by (a)attaching the FITC-BSA to the surface of polymer beadsfor 1 h at 30 °C in a phosphate buffer at pH 6.0 and (b)adding 1-ethyl-3-(3-dimethylaminopropyl) carbodiimidehydrochloride (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.
Figure 6. Schematic (a-c) and optical microscopy (a′-c′, d)images of polyTPGDA particles with different shapes: micro-spheres (a, a′), disks (b, b′), (c, c′) rods, and (d) ellipsoidalpolyTPGDA particles obtained via photopolymerization ofdroplets produced at Qw ) 8 mL/h, Qm ) 0.1 mL/h, and cin )4 wt %. Scale bar is 50 µm.
AA) particles bearing FITC-BSA at 30 °C.41 Controlexperiments were conducted by heating poly(TPGDA/AA)microbeads with FITC-BSA or EDC. The attachment offluorescent FITC-BSA to the microbead surface occurredonly when both EDC and FITC-BSA were used. Figure 7dshows a fluorescence microscopy image of the copolymermicrobeads synthesized using an MFFD reactor andconjugated with FITC-BSA.
IX. Periodic Arrays of Polymer ParticlesHigh monodispersity of the droplets generated in the
MFFDandtheirgeometric confinement in thedownstreammicrochannel led to the dynamic assembly of droplets into2D lattices with a high degree of order and symmetry. Wefirst explored the formation of lattices by droplets ofsilicone oil (SO) dispersed in a 2 wt % aqueous solutionof SDS. We varied the volume of droplets to producecircular liquid disks with a diameter from 87 to 880 µm.Under typical operating conditions, the coefficient ofvariance in disk diameters was below 2.5%.
The rates of flow of the oil and aqueous phasesdetermined the total volume of droplets generated perunit time and the rate of droplet evacuation from thedownstream channel. The velocity of droplets in thedownstream channel of the MFFD was slower than thespeed of the continuous aqueous phase,42 and the discoiddropletsassembled in thedynamic 2D close-packed latticesfilling the entire volume of the downstream microchannel.Figure 8a-c shows typical optical microscopy images ofthe lattices of circular discoid oil droplets. The number ofcolumns, n, aligned parallel to the microchannel wallsdecreased with increasing dimensions of droplets. In ourexperiments, the number of columns varied from 1 to 15.With increasing size of droplets, a transition between thelattices with a different number of columns occurred
through the deformation of circular disks: because ofconfinement, the circular disks acquired pentagonal and,more frequently, hexagonal shapes (Figure 8d-f). Thelattices of hexagonal disks retained a high degree of orderand symmetry.
Using a modified MFFD, we also produced droplets witha bimodal size distribution. Each population of dropletshad a coefficient of variance of ca. 2.5%. The droplets wereobtained from silicone oil dispersed in an aqueous SDSsolution or from droplets of silicone oil and hexadecane
(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, 2649-2651.
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 dropletswith 5 wt % AA. (d) Fluorescence microscopy image of copolymer beads conjugated with FITC-BSA,cAA ) 5 wt %. For the emulsificationof 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.
Figure 8. Optical microscopy images of 2D lattices of circular(a-c) and hexagonal (d-f) liquid disks of silicone oil dispersedin a 2 wt % SDS aqueous solution in PU MFFD. Average volumeof 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 assemblyof large and small SO droplets (viscosity 5 and 10 cP),respectively. (i) Droplets of dye-labeled hexadecane surroundedby SO droplets (viscosity 10 cP). Scale bar is 200 µm.
11620 Langmuir, Vol. 21, No. 25, 2005 Seo et al.
dispersed in the SDS solution. By changing the relativeflow rates of the nonpolar and aqueous liquids, we achievedcontrol over the number ratio and the size ratio of thedroplets with different sizes and compositions. Figure8g-i shows several representative images of the binarydynamic lattices of discoid droplets formed in MFFD. Thedroplets with different sizes acquired complicated shapes;however, they assembled in strikingly ordered glidingarrays.
We produced periodic arrays of polymer disks bytrapping the structure of droplet lattices in the solid state.The discoid droplets were obtained from methacryl oxy-propyl dimethylsiloxane mixed with 4.0 ( 0.5 wt % ofphotoinitiator HCPK. Figure 9 shows the structure of thelattice of methacryl oxypropyl dimethylsiloxane dropletswith n ) 2 and 7 prior to (Figure 9a and c) and followingpolymerization (Figure 9b and d). Following solidification,the droplets shrank by ca. 5%. Weaker confinement ledto the relaxation of droplet shapes and the transformationfrom hexagonal to close-to-circular droplets (Figure 9d);nevertheless, highly ordered lattices were preservedduring polymerization.
X. Summary and Outlook
This work provides an overview of research conductedin our laboratory over the past several years that hasfocused on the use of microfluidic laminar flow reactorsin continuous (“on the fly”) synthesis of polymer colloids.The resulting particles featured extremely narrow sizedistribution and a large versatility in dimensions, shapes,and compositions. The production of polymer particlesincluded the emulsification of monomer droplets in MFFDand their in-situ free-radical photopolymerization. Ourresults show that microfluidics-based synthesis is anefficient strategy for the production of highly monodispersepolymer particles in the range of sizes from ca. 20 to 200
µm. The size of microbeads is controlled by varying theflow rates of the continuous and droplet phases, the designof the microfluidic device, and the composition of dispersedand continuous phases, that is, their viscosities andinterfacial tension. Other properties of monomers suchas their solubility in the continuous medium or viscosityhave to be taken into consideration to achieve efficientmicrobead production.
Our results demonstrate that the selection of anappropriate material for the fabrication of microfluidicreactors is vital in the production of polymer beads: thedroplet phase should have lower affinity for the materialof the MFFD than the continuous phase does. Close-to-complete conversion of monomer to polymer is achievedby optimizing the concentration of photoinitiator inmonomer droplets and providing a sufficient time ofresidence of droplets in the microfluidic reactor. The useof multifunctional monomers is an alternative to increas-ing the photopolymerization rate and producing highlycross-linked particles.
Although the production of polymer colloids in micro-fluidic reactors resembles the batch polymerization ofmonomers, it has several useful features distinguishingit from suspension polymerization, the polymerization ofmonomer droplets obtained by membrane emulsification,or the Bibette process. The polydispersity of particlesproduced in microfluidic reactors is typically below2-2.5%, that is, it is significantly narrower than in themethods listed above. No stabilization against coalescenceor Ostwald ripening of monomer droplets is requiredbecause their collisions in the microfluidic device aresuppressed and the time prior to monomer polymerizationis on the order of seconds. Polymerization in the con-strained geometry of the microfluidic device allows forthe production of rods, disks, and ellipsoids or particleswith more complicated shapes (e.g., L or Π shapes).
Polymer colloids produced in microfluidic reactors haveall of the applications of polymer particles synthesized byconventional methods. In particular, we foresee the useof bioconjugated microbeads in medical diagnostics, bio-separation applications, and microcarriers of cells. Theseparticles can be doped with magnetic nanoparticles ordifferent populations of quantum dots. The extremelynarrow size distribution of microbeads allows their use asthe building blocks of materials with periodically modu-lated structures and compositions.
The possibility of encapsulating liquid ingredients willenable the application of polymer capsules in mucosaland oral drug delivery or in cosmetic applications. Porousmicrobeads have potential applications in separation andsensing technologies. Very recently, we showed that thecombination of more than two immiscible liquids can besuccessfully used for the production of polymer capsuleswith single or multiple liquid cores and particles withnonconventional shapes.27
The further development of the microfluidics-basedsynthesis of polymer colloids will obviously require thedemonstration of scaling up in particle production. Theproductivity of the lab on a chip can be increased by usinghighly reactive monomers and/or by placing severalmicrofluidic reactors on a single chip. Given that a singleMFFD device produces approximately 100-500 polymerparticles/s, we expect that a 10-device chip will produceup to 1.6 × 107 particles/h.
The synthesis of smaller particles (in the size rangefrom ca. 3 to 25 µm) is highly desirable. Preliminaryexperiments showed that the reduction of the width andheight of the rectangular orifice (Figure 1a) is the most
Figure 9. Optical microscopy images of 2D lattices of MAOP-DMS disks in PU MFFD prior to (a, c) and after (b, d) in situphotopolymerization. A 3.5 ( 0.5 wt % mixture of HPCK andMAOP-DMS was used to generate droplets in a 2 wt % aqueoussolution 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.
efficient route to the reduction of microbead diameterbelow 20 µm.
Further efforts in the microfluidics-based synthesis ofpolymer particles will seek to extend the range of materialsused in particle generation. Photoinitiated cross linkingof liquid oligomers or polymers will allow for the productionof particles from “nonconventional” polymers. In particu-lar, our group collaborates with Professor Ian Manners(University of Toronto) in the production of polyferrocene-based microbeads. The emulsification of aqueous solutionsof biopolymers accompanied by hardening of the dropletswill lead to the production of biomicrogels. Furthermore,the generation of particles with unique morphologies willallow the production of new materials with structure-dependent properties.
Acknowledgment. This research was funded by theCanada Research Chair Fund. Discussions with ProfessorsHoward A. Stone and George M. Whitesides, and Dr. PiotrGarstecki are greatly appreciated. We also thank ProfessorDavid James for his assistance with measurements ofmonomer viscosity.
Supporting Information Available: Experimentaldetails of materials, monomer and particle characterization, anddroplet emulsification. This material is available free of chargevia the Internet at http://pubs.acs.org.
