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Fabrication of Highly Porous non-Spherical Particles and Their Optical Properties Using Stop Flow Lithography Minggan Li, Dehi Joung, Janusz A. Kozinski, and Dae Kun Hwang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.6b03358 • Publication Date (Web): 09 Dec 2016 Downloaded from http://pubs.acs.org on December 10, 2016

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Fabrication of Highly Porous non-Spherical Particles and Their Optical Properties Using Stop Flow Lithography Minggan Li1,2,3†, Dehi Joung1,2,3†, Janusz A. Kozinski4, and Dae Kun Hwang1,2,3* 1

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Department of Chemical Engineering, Ryerson University 350 Victoria Street, Toronto, Ontario, M5B 2K3, Canada * Corresponding author e-mail: [email protected]

Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada

Institute for Biomedical Engineering, Science and Technology (iBEST), A partnership between Ryerson University and St. Michael’s Hospital, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada 4

Lassonde School of Engineering, York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3, Canada †

These authors contributed equally to this work

Abstract A microfluidic flow lithography approach is investigated to synthesize highly porous nonspherical particles and janus particles in a one-step and high-throughput fashion. In this study, using common solvents as porogen, we were able to synthesize highly porous particles with different shapes by the UV polymerization-induced phase separation in a microfluidic channel. We also studied the pore-forming process using operating parameters such as porogen type, porogen concentration and UV intensity to tune the pore size and increase the pore size to submicron. By simply co-flowing multiple streams in the microfluidic channel, we are able to create porous janus particles; we show their anisotropic swelling/deswelling exhibiting a unique optical shifting. The distinctive optical properties and enlarged surface area of the highly porous particles can improve their performance in various applications, such as wettability optical sensor and drug loading. 1 ACS Paragon Plus Environment

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INTRODUCTION For decades, porous polymeric particles have attracted enormous attention and have been utilized in a broad range of applications owing to their porous structures and crosslinking degree providing enhanced functionality for hosting various solvents with different polarity.1 In particular, particles with macropores, because of its large pore size and enhanced mass transportation, have been applied in a broad range of applications such as catalyst supports,2 ion exchange resins and sorbents;3 and recently as biomaterials for enzymes immobilization,4 protein seperation,5 tissue culture,6 enhanced cell embolization7-9 and regulation of pharmaceutical drug release.10

Conventionally, suspension and swelling polymerization methods have been used for synthesis of macroporous polymer particles. In the suspension polymerization, macroporous polymer particles are formed via the agitation of a prepolymer solution containing monomer, initiator and inert solvent in an immiscible continuous liquid phase and subsequent free radical polymerization.3,11 The swelling method also yields macroporous particles by seeding swollen template and subsequent template washing.12-15 However, these methods can only produce spherical particles and they have difficulties in achieving shape versatility and size uniformity of particles because of the batch process nature.1

The shape control and size uniformity of porous particles is increasingly critical in biomaterial design for emerging biomedical applications.16 For example, in drug delivery, particles with nonspherical shape can provide enlarged space for drug loading by increasing core volume;17 greatly

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improve therapeutic targeting efficacy in local injection by influencing transport property;18 and binding efficiency of drug carriers that are associated with targeted drug delivery.19

To better control the shape design and size uniformity of macroporous polymeric particles, a microfluidic approach in combination with polymerization-induced phase separation (PIPs) has been adapted for the particle fabrication as an alternative to conventional methods.20 Microfluidic emulsification offers precise fluid control and thus produces highly monodispersed particles with controlled porous structures. However, the emulsion processing nature of current droplet-based microfluidics for the particle production 21,22 limit the particle to spherical and spheroidal shapes. Additionally, the remaining immiscible phase is difficult to be fully removed from the resulting polymeric particles in the post-collecting process.12-15 Moreover, the formation of a thin, dense surface layer with sparse and small pores (non-porous), called “skin,” has been reported by several groups. This skinning effect confines molecular permeating to the interior of macroporous particles through the pores of the surface,20,23 thus subsequently limiting mass transport.

Microfluidic flow-lithography techniques, established by Doyle and coworkers, have been developed to overcome these challenges in microfluidic particle fabrication.24-27 The flow lithography has offered unparalleled control over particle size and shape, which are precisely determined by UV dose, objective magnification and photomask during UV polymerization.28 This technique has been widely used in various applications for microparticle fabrication.24-31 Recently, the improved flow lithography called stop-flow lithography (SFL) has been developed, which not only synthesizes porous particles without the skinning effect, but also efficiently


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enlarges their pore size ranging from ~ 100 to 200 nanometers by simply adding polymeric porogens.32-36 However, increasing the molecular weight of porogens to enlarge particle pores might have certain limitations because they cause a significant decrease in the structural strength of resulting polymer particles.37 For example, polyacrylamide hydrogel containing more than 6% of typically inert PEG1000 as a porogen cannot be fabricated.37 High molecular weight porogens, which are not covalently bound, can interrupt the polymerization process leading to weakening the structural strength of porous polymers.37 Also, their excess use to create larger pores can be costly.37,38 Moreover, using high-molecular polymers as a porogen for microfluidic channel can be problematic to operate because of their high viscosity.

Here we demonstrate a flow lithography synthesis of highly porous non-spherical particles, alternatively using commonly available low-cost solvents. In this route, a simple integration of UV polymerization-induced phased-separation (UV PIPS) and stop-flow lithography enables us to fabricate highly porous non-spherical particles with pore size in a range of approximately 100 nm to 500 nm. As UV is projected to the channel through a photomask to polymerize maskdefined particle shapes, the UV PIPS occurs during the polymerization to generate pores in the particles, synthesizing porous non-spherical particles in a single UV projection. More interestingly, the resulting particles from our fabrication are partially opaque because of their discrete pore morphology attenuates a substantial amount of visual light.39 Given the swelling ability of resulting highly porous particles and their inherited optical feature, we also demonstrate the modulation of their opacity in a timely manner with a simple solvent evaporation process.


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RESULTS AND DISCUSSIONS Porous particle fabrication. Our microfluidic fabrication of porous polymeric particles is illustrated in Figure 1a. We introduced a prepolymer solution containing ethanol as a porogen, and Darcur 1171 as a photoinitiator into a PDMS channel (100 µm height and 6.5 mm width) and stops the flow. Then we project the UV light through a photomask to polymerize the UV curable prepolymer solution to form mask-defined particles. The polymerization is inhibited near the top and bottom PDMS walls because of oxygen diffusion through the PDMS from the surroundings, known as oxygen inhibition (Figure 1a). This oxygen inhibition layer, which acts as a lubrication layer at the top and bottom wall of the PDMS channel, enables us to flush out the fabricated porous particles from the channel by simply resuming the flow. The porous particles can be synthesized in a continuous fashion by repeating this process. Their size and thickness are determined by the height of a given PDMS channel, the dose of an applied UV and the magnification of a selected objective lens. Desired non-spherical shapes of particles are attained using designed photomasks that shape projected UV light during the SFL process (Figure 1b-d). More importantly, the resulting particles show no “skin layer” as expected from the one-phase fluid system. The surface of circular porous particles (Figure 1e) shows no “skin layer” formation when compared to its cross-section microstructure (Figure 1f). Moreover, the rapid polymerization kinetics and homogeneous environment, expected from the microfluidic device associated with UV polymerization, allow us to polymerize particles with highly uniform internal pore structures (Figure 1f and Figure S1).


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Controlling the pore size. The porous structures and pore sizes are controlled by several parameters including porogen type, porogen concentration and UV intensity. For instance, different porogen types determine the morphological characteristics of porous particles. Figure 2 shows the comparison of pore size associated with different porogens used at a fixed 70% volumetric fraction of these porogens in the PEG-DA monomer mixture. These differences in pore size and polymer microstructure are mainly dependent on the different solubility between the porogens and monomer. When a porogen has a similar solubility to the monomer, particles with small pores are produced.40 In contrast, a larger incompatibility between the porogen and monomer empowers its phase separation to occur before the gel point resulting in a cluster formation with a larger pore size during the polymerization.3,6,41,42 The solubility parameters of porogens we used can be found in our previous study.42

In addition to the solubility difference of porogen type, porogen concentration has a large impact on pore size development. Figure 3 explicitly shows that PEG-DA monomer with 40% ethanol develops a denser microstructure with small pore sizes compared to PEG-DA monomer with 70% ethanol that generate a more porous and globule-like pore microstructure. As we increase the porogen concentration, the porogen phase dominates its space more than the PEG-DA phase during the polymerization process, and leaves a larger gap in the structure and greater porosity after its removal (Figure S2).

The pore size can also be manipulated by applying different UV intensities. Figure 4 shows the effect of various UV intensities on the morphological properties including pore size and polymer microstructure. Photoinitiators stimulated by a high UV intensity release a large number of free


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radicals leading to a rapid photo-polymerization. This rapid process is, however, unstable43 and forms a connected-globule microstructure since UV PIPS occurs in the advance of the gel point of the polymer (Figure 4c).3,6,20,41,44 As UV intensity declines, larger clusters comprised of the globules are formed because of a slow photopolymerization rate and less effective phase separation.42 The differences in particle body size also appear along with different UV intensities used despite using the same photomask. This body size difference is mainly caused by the competition between oxygen and UV intensity during the polymerization process.

Synthesis of janus particles and their opacity change. Our resulting porous polymer particles are optically opaque (dark brown color, Figure 1 b-d). Their discrete pore microstructures (gradual-like) with large pore sizes induce light attenuation and influence their opacity, while the enlarged porosity can significantly improve the infiltration of solvent into the particles, offering an enhanced swelling/deswelling capacity and rate.1,45 Thus, such highly porous particles can undergo an opacity shifting during a swelling/deswelling transition because of their structural change. To demonstrate this concept, we fabricate janus particles by co-flowing two streaming of prepolymer solutions including without porogen, non-porous (corresponding to transparent part) and with porogen, porous (corresponding to opaque part) as shown in Figure 5a-f. During the polymerization process, the porogen diffuses from the high-to-low concentration streams and forms a transitional zone (Figure 5e) at the interface between the streams. To induce an optical shifting, we use ethanol as the solvent and let the solvent evaporate (Figure 6 a-d). While the porous region shows a dark brown color, the nonporous part is transparent at the fully emerging state in the solvent (Figure 6a). As ethanol evaporates, the color darkness in the porous region reduces as a result of change in the microstructure and pore size by the solvent-induced


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deswelling (Figure 6b-d); however, the non-porous region remains transparent because of its low swelling capability (Figure 6a-d). This optical transition can be clearly seen in a transmitted light plot (Figure 6e) during the full evaporation process. Interestingly, at close to the fully dried state, the porous region displays an opposite optical transition, a sudden shift from being transparent to opaque (Figure 6e). This transition might be caused by the refractive index changing from ethanol to air during the last evaporation. This optical feature can be used as a dynamic opacity sensor to monitor a solvent-driven wettability change based on its refractive index,46 because a highly enlarged surface area from nonspherical particles and their discrete interconnected microstructures can enhance the range of swelling-dependent-opacity color shift by diffusing solvent facilely within the structures.46 Moreover, the surface of pores can be further modified and functionalized to measure refractive index selectively towards various solvent infiltration.46 This swelling/deswelling-triggered opacity transition can be used for pH-detection. One can induce swelling/deswelling of porous particles in response to the pH change by surface modification. This pH-induced swelling/deswelling of particles might result in porous structural changes, which leads to their opacity attenuations. One can then correlate this optical attenuation to the pH value. Furthermore, the Janus particle configuration in Figure 6 has a great advantage for optical signal detection. The porous section of the particle will change its opacity, while the non-porous section remains transparent.

Because the transparent section carries imaging

background noise, by subtracting this noise, one can recover the true opacity change under different imaging conditions. This ability will offer repeatable and reliable measurements. ■ Materials and Methods Slit Microfluidic Channel Fabrication


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Polydimethyl-siloxane elastomer (PDMS, Sylard 184, Dow Corning) were well mixed with a curing agent at a ratio of 10:1 for fabricating the microfludic channels. The mixture was loaded onto a SU-8 patterned silicon wafer (SU-8 photoresist, Microchem) and baked in an oven at 65 °C for 1 hour in order to mold the PDMS mixture with the patterns. As partially cured PDMS coated glass were prepared at 65°C for 20 minutes, this molded patterned PDMS was attached to the glass and baked for another 1 hour to strengthen the bonding between the molded PDMS and the coated glass forming complete channel.

Photopolymerization Setup Polymeric particles were synthesized using microfluidic PDMS channel-based stop-flow lithography. UV light was generated from an A metal arc lamp (Lumen 200, Prior Scientific, Rockland, MA, USA) connected to the Axio Observer inverted microscope, and UV exposure time was regulated by UV shutter (Lambda SC, Sutter Instruments, Novato, CA, USA) installed in the UV light path. A PDMS channel was linked to the pneumatic solution feeding system including a pressure regulator (type 100LR, ControlAir, Amherst, NH, USA) via a three-way solenoid valve (model 6014, Burkert, Germany). A digital controller of a program in Labview (National Instruments, Austin, TX, USA) manipulated the UV shutter and the solenoid valve to coordinate and repeat the polymerization process cycle by stopping and resuming the flow. A used Axio Observer inverted microscope (Carl Zeiss, Jena, Germany) consisted of 5×/0.13, 10×/0.3, and 20×/0.4 objectives (N-Achroplan, Ec plan-Neoﬂuar and korr LD Plan- Neoﬂuar, Carl Zeiss, Jena, Germany) and equipped with a UV filter set (11000v3, Chroma, VT, USA) that was used for attaining the desired UV irradiation for particle fabrication. AUTOCAD 2011 was


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used for designing the transparent photomask. The designed photomask was printed at a resolution of 25 000 dpi (CAD/Art Services, OR, USA).

Porous Particle Synthesis In porous particle synthesis, microfluidic channel with 100µm depth and 6.5mm width were used (shown in Figure 1). Porous particles were synthesized using presolutions composed of 29.5% poly(ethylene glycol)diacrylate (PEG-DA 250, Sigma-Aldrich), 0.5% 2-hydroxy-2methylpropiophenon photoinitiator (Darocur 1173, Sigma-Aldrich) and 70% porogen. The following solvents were used as a porogen: Mixture of ethanol and water at ratio of 1:1, ethanol and poly(ethylene glycol) (PEG200, Sigma-Aldrich) (Figure 2a-c). The prepolymer solution flowing through the PDMS channel was paused and exposed to UV light through designed photomask and 20X objective lens for one second. During UV polymerization, the desired shape and size of particles were obtained by photomask-shaped UV light, whereas porosity of particles was attained through UV polymerization-induced phase separation. Then the flow was resumed to flush out polymerized porous particles to the outlet without sticking to the wall of channels because of oxygen inhibition. Porous polymer particles can be continuously produced by repeating this process. Prepolymer solution of 0.5% 2-hydroxy-2-methylpropiophenon photoinitiator (PI) (Darocur 1173, Sigma-Aldrich) and different concentration of ethanol (40%,50%,60% and 70%) in poly(ethylene glycol) (250) diacrylate (PEG-DA 250, SigmaAldrich) was used to synthesize the porous particles shown in Figure 3. Various UV intensities were applied to synthesize the porous particles shown in Figure 4 with the 70% Et presolution.

Janus particle synthesis


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A slit PDMS channel with two inlets was used to synthesize heterogeneous porous particles. One inlet supplied prepolymer solution with a porogen consisted of 70% PEG200, 29.5% PEGDA250 and 0.5% PI, while the other inlet supplied presolution without porogen consisted of 99.4% PEGDA250 and 0.6% PI. Janus particles with heterogeneous porosities were formed from the co-flow streams in the presence of one-second UV exposure through a design photomask and 10x objective lens.

SEM Samples were transferred onto SEM specimen tubs covered by aluminum foil. The mounted samples were sputtered coated in 5 nm platinum and observed by a field emission scanning electron microscopy (Quanta 3D FEG SEM, FEI Co., OR) at HV 20.00 kV with a ETD detector.

Opacity change measurement Sequence images of opacity change of a janus particle were captured by a Go imaging camera and saved as a video format by QCapture software. The image J software was used to calculate mean value of light, transmitting the intensity difference of each side measured by drawing straight horizontal lines in the middle from the interface to each end. CONCLUSIONS We have demonstrated a straightforward “skin” free method to fabricate highly porous particles with designed non-spherical shape and size, and tunable pore size via the combination of UV polymerization-induced phased separation with microfluidic-based stop flow lithography. In the absence of the skinning problem, we also showed the various pore morphologies with notably uniform internal structures. We also report that the commonly available low-cost porogens can 11 ACS Paragon Plus Environment

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be alternatively used for the creation of large pore size ranging from nano to submicron level. Resulting janus particles with heterogeneous porosities reveal unique optical properties depending on inherited highly porous microstructures. These findings may be beneficial to a broad range of potential biomedical uses, where big pore size is desired for large molecule permeability, such as immobilizing enzyme,4 separating proteins5 and culturing tissue cell.6

Supporting Information Porous structures of particles and a video-janus particles.mpg Acknowledgment The authors acknowledge the Natural Sciences and Engineering Research Council of Canada (Discovery grant no. 386092 and 170464) for supporting this research.

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REFERENCES

Gokmen, M. T.; Du Prez, F. E. Porous Polymer particles—A Comprehensive Guide to Synthesis, Characterization, Functionalization and Applications. Progress in Polymer Science 2012, 37 (3), 365–405. Sherrington, D. C. Preparation, Structure and Morphology of Polymer Supports. Chem. Commun. 1998, No. 21, 2275–2286. Okay, O. Macroporous Copolymer Networks. Progress in Polymer Science 2000, 25 (6), 711–779. Okay, O.; Gürün, Ç. Synthesis and Formation Mechanism of Porous 2-Hydroxyethyl Methacrylate–ethylene Glycol Dimethacrylate Copolymer Beads. J. Appl. Polym. Sci. 1992, 46 (3), 401–410. Paredes, B.; González, S.; Rendueles, M.; Dı́az, J. M. Particulate Poly(glycidyl Methacrylate-Co-Ethylene Dimethacrylate) Material for Protein Separation by AnionExchange Chromatography. Separation and Purification Technology 2004, 40 (3), 243– 250. Horák, D.; Lednický, F.; Řehák, V.; Švec, F. Porous polyHEMA Beads Prepared by Suspension Polymerization in Aqueous Medium. J. Appl. Polym. Sci. 1993, 49 (11), 2041–2050. Horák, D.; šeksvec, F.; Kálal, J.; Adamyan, A. A.; Volynskii, Y. D.; Voronkova, O. S.; 12 ACS Paragon Plus Environment

Page 12 of 27

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(8)

(9)

(10) (11) (12)

(13) (14) (15) (16) (17) (18) (19) (20) (21) (22)

(23)

Kokov, L. S.; Gumargalieva, K. Z. Hydrogels in Endovascular Embolization. II. Clinical Use of Spherical Particles. Biomaterials 1986, 7 (6), 467–470. Horák, D.; Švec, F.; Adamyan, A.; Titova, M.; Voronkova, O.; Trostenyuk, N.; Vishnevskii, V.; Guseinov, E.; Gumargalieva, K. Poly(2-Hydroxyethyl Methacrylate) Beads for the Preoperative Endovascular Occlusion of Branches of the Hepatic Artery in Focal Alterations of the Liver. Clinical Materials 1990, 6 (4), 287–297. Horák, D.; Švec, F.; Isakov, Y.; Polyaev, Y.; Adamyan, A.; Konstantinov, K.; Shafranov, V.; Voronkova, O.; Nikanorov, A.; Trostenyuk, N. Use of poly(2-Hydroxyethyl Methacrylate) for Endovascular Occlusion in Pediatric Surgery. Clinical Materials 1992, 9 (1), 43–48. Robert, C. C. R.; Buri, P. A.; Peppas, N. A. Influence of the Drug Solubility and Dissolution Medium on the Release from poly(2-Hydroxyethylmethacrylate) Microspheres. Journal of Controlled Release 1987, 5 (2), 151–157. Švec, F.; Hradil, J.; Čoupek, J.; Kálal, J. Reactive Polymers I. Macroporous Methacrylate Copolymers Containing Epoxy Groups. Angew. Makromol. Chem. 1975, 48 (1), 135–143. Ugelstad, J.; Kaggerud, K. H.; Hansen, F. K.; Berge, A. Absorption of Low Molecular Weight Compounds in Aqueous Dispersions of Polymer-Oligomer Particles, 2. A Two Step Swelling Process of Polymer Particles Giving an Enormous Increase in Absorption Capacity. Makromol. Chem. 1979, 180 (3), 737–744. Ugelstad, J.; Söderberg, L.; Berge, A.; Bergström, J. Monodisperse Polymer Particles — a Step Forward for Chromatography. Nature 1983, 303 (5912), 95–96. Cheng, C. M.; Micale, F. J.; Vanderhoff, J. W.; El-Aasser, M. S. Synthesis and Characterization of Monodisperse Porous Polymer Particlesko. J. Polym. Sci. A Polym. Chem. 1992, 30 (2), 235–244. Cheng, C. M.; Vanderhoff, J. W.; El-Aasser, M. S. Monodisperse Porous Polymer Particles: Formation of the Porous Structure. J. Polym. Sci. A Polym. Chem. 1992, 30 (2), 245–256. Mitragotri, S.; Lahann, J. Physical Approaches to Biomaterial Design. Nat Mater 2009, 8 (1), 15–23. Geng, Y.; Discher, D. E. Hydrolytic Degradation of Poly(ethylene Oxide)-BlockPolycaprolactone Worm Micelles. J. Am. Chem. Soc. 2005, 127 (37), 12780–12781. Toy, R.; Peiris, P. M.; Ghaghada, K. B.; Karathanasis, E. Shaping Cancer Nanomedicine: The Effect of Particle Shape on the in Vivo Journey of Nanoparticles. Nanomedicine (Lond) 2014, 9 (1), 121–134. Chen, J.; Clay, N. E.; Park, N.; Kong, H. Non-Spherical Particles for Targeted Drug Delivery. Chemical Engineering Science 2015, 125, 20–24. Dubinsky, S.; Park, J. I.; Gourevich, I.; Chan, C.; Deetz, M.; Kumacheva, E. Toward Controlling the Surface Morphology of Macroporous Copolymer Particles. Macromolecules 2009, 42 (6), 1990–1994. Dendukuri, D.; Tsoi, K.; Hatton, T. A.; Doyle, P. S. Controlled Synthesis of Nonspherical Microparticles Using Microfluidics. Langmuir 2005, 21 (6), 2113–2116. Xu, S.; Nie, Z.; Seo, M.; Lewis, P.; Kumacheva, E.; Stone, H. A.; Garstecki, P.; Weibel, D. B.; Gitlin, I.; Whitesides, G. M. Generation of Monodisperse Particles by Using Microfluidics: Control over Size, Shape, and Composition. Angewandte Chemie 2005, 117 (5), 734–738. Benson, J. R. Highly Porous Polymers. American laboratory 2003, 35 (10), 44–52. 13 ACS Paragon Plus Environment

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(24) Dendukuri, D.; Gu, S. S.; Pregibon, D. C.; Hatton, T. A.; Doyle, P. S. Stop-Flow Lithography in a Microfluidic Device. Lab Chip 2007, 7 (7), 818–828. (25) Dendukuri, D.; Hatton, T. A.; Doyle, P. S. Synthesis and Self-Assembly of Amphiphilic Polymeric Microparticles. Langmuir 2007, 23 (8), 4669–4674. (26) Jang, J.-H.; Dendukuri, D.; Hatton, T. A.; Thomas, E. L.; Doyle, P. S. A Route to ThreeDimensional Structures in a Microfluidic Device: Stop-Flow Interference Lithography. Angewandte Chemie 2007, 119 (47), 9185–9189. (27) Pregibon, D. C.; Toner, M.; Doyle, P. S. Multifunctional Encoded Particles for HighThroughput Biomolecule Analysis. Science 2007, 315 (5817), 1393–1396. (28) Dendukuri, D.; Pregibon, D. C.; Collins, J.; Hatton, T. A.; Doyle, P. S. Continuous-Flow Lithography for High-Throughput Microparticle Synthesis. Nat Mater 2006, 5 (5), 365– 369. (29) Bong, K. W.; Bong, K. T.; Pregibon, D. C.; Doyle, P. S. Hydrodynamic Focusing Lithography. Angewandte Chemie International Edition 2010, 49 (1), 87–90. (30) Haghgooie, R.; Toner, M.; Doyle, P. S. Squishy Non-Spherical Hydrogel Microparticles. Macromol. Rapid Commun. 2010, 31 (2), 128–134. (31) Panda, P.; Yuet, K. P.; Hatton, T. A.; Doyle, P. S. Tuning Curvature in Flow Lithography: A New Class of Concave/Convex Particles. Langmuir 2009, 25 (10), 5986–5992. (32) Chapin, S. C.; Doyle, P. S. Ultrasensitive Multiplexed MicroRNA Quantification on Encoded Gel Microparticles Using Rolling Circle Amplification. Anal. Chem. 2011, 83 (18), 7179–7185. (33) Chapin, S. C.; Appleyard, D. C.; Pregibon, D. C.; Doyle, P. S. Rapid microRNA Profiling on Encoded Gel Microparticles. Angew. Chem. Int. Ed. 2011, 50 (10), 2289–2293. (34) Srinivas, R. L.; Chapin, S. C.; Doyle, P. S. Aptamer-Functionalized Microgel Particles for Protein Detection. Anal. Chem. 2011, 83 (23), 9138–9145. (35) Appleyard, D. C.; Chapin, S. C.; Doyle, P. S. Multiplexed Protein Quantification with Barcoded Hydrogel Microparticles. Anal. Chem. 2011, 83 (1), 193–199. (36) Choi, N. W.; Kim, J.; Chapin, S. C.; Duong, T.; Donohue, E.; Pandey, P.; Broom, W.; Hill, W. A.; Doyle, P. S. Multiplexed Detection of mRNA Using Porosity-Tuned Hydrogel Microparticles. Anal. Chem. 2012, 84 (21), 9370–9378. (37) Lee, A. G.; Arena, C. P.; Beebe, D. J.; Palecek, S. P. Development of Macroporous Poly(ethylene Glycol) Hydrogel Arrays within Microfluidic Channels. Biomacromolecules 2010, 11 (12), 3316–3324. (38) Lee, A. G.; Beebe, D. J.; Palecek, S. P. Quantification of Kinase Activity in Cell Lysates via Photopatterned Macroporous Poly(ethylene Glycol) Hydrogel Arrays in Microfluidic Channels. Biomed Microdevices 2011, 14 (2), 247–257. (39) Wu, Y.-H.; Park, H. B.; Kai, T.; Freeman, B. D.; Kalika, D. S. Water Uptake, Transport and Structure Characterization in Poly(ethylene Glycol) Diacrylate Hydrogels. Journal of Membrane Science 2010, 347 (1–2), 197–208. (40) Dušek, K.; Chompff, A. J.; Newman, S. Polymer Networks: Structure and Mechanical Properties. Plenum, New York 1971. (41) Okay, O.; Gürün, Ç. Formation and Structural Characteristics of Porous Ethylene Glycol Dimethacrylate Networks. J. Appl. Polym. Sci. 1992, 46 (3), 421–434. (42) Li, M.; Humayun, M.; Hughes, B.; Kozinski, J. A.; Hwang, D. K. A Microfluidic Approach for the Synthesis and Assembly of Multi-Scale Porous Membranes. RSC Adv. 2015, 5 (121), 100024–100029. 14 ACS Paragon Plus Environment

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Luo, K. The Morphology and Dynamics of Polymerization-Induced Phase Separation. European Polymer Journal 2006, 42 (7), 1499–1505. (44) Dubinsky, S.; Zhang, H.; Nie, Z.; Gourevich, I.; Voicu, D.; Deetz, M.; Kumacheva, E. Microfluidic Synthesis of Macroporous Copolymer Particles. Macromolecules 2008, 41 (10), 3555–3561. (45) Kita, R.; Svec, F.; Fréchet, J. M. J. Hydrophilic Polymer Supports for Solid-Phase Synthesis: Preparation of Poly(ethylene Glycol) Methacrylate Polymer Beads Using “Classical” Suspension Polymerization in Aqueous Medium and Their Application in the Solid-Phase Synthesis of Hydantoins. J. Comb. Chem. 2001, 3 (6), 564–571. (46) Phillips, K. R.; England, G. T.; Sunny, S.; Shirman, E.; Shirman, T.; Vogel, N.; Aizenberg, J. A Colloidoscope of Colloid-Based Porous Materials and Their Uses. Chem. Soc. Rev. 2016, 45 (2), 281–322.


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Figure 1 Porous particle synthesis using stop flow lithography (a) Schematic of SFL. A prepolymer solution with porogen flowing in PDMS slit channel is stopped and polymerized by UV light through a photomask and 20X objective lens. Then, flow is resumed to flush out polymerized porous particles. Porous particles can be produced continuously by repeating this process. The oxygen inhibition is shown in the red layer. (b-d) Porous particle with designed non-spherical shapes attained from this method. (e, f) SEM image of surface and cross section of the polymerized porous particle, respectively. Scale bars are 50µm (b-d) and 2 µm (e, f).


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Figure 2 Effects of different porogen types on particle morphology. A mixture of 0.5% photoinitiator, 29.5% PEG-DA 250 and 70% porogen at 1 sec UV exposure with full UV intensity was used. Disk-shape particles were made with the following porogens: a) Ethanol and water, b) Ethanol and c) PEG200. Lower SEM images of surface of porous particle correspond to each porogen type, respectively. Scale bars are 40 µm (upper) and 500 nm (lower).


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Figure 3 Effects of porogen concentration on particle morphology using Ethanol. A mixture of 0.5% photoinitiator and various concentrations of Et (porogen) in PEG-DA 250 at 1 sec UV exposure with full UV intensity was used. (a-d) SEM images of Et concentration-dependent surface morphology of porous particle. The following concentrations of Et were used: a) 40% Et, b) 50% Et, c) 60% Et and d) 70% Et. Lower SEM images show more details about surface morphology of porous particle corresponding to each Et concentration, respectively. Scale bars are 2µm (upper) and 500nm (lower).


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Figure 4 Effects of UV intensity on particle morphology using Ethanol. Different UV intensities were introduced to mixture of 0.5% photoinitiator, 29.5% PEG-DA 250 and 70% Et at 1 sec UV exposure. Disk-shape particles were made with the following UV intensities: a) 50% UV, b) 75% UV, and c) 100% UV. Lower SEM images show the surface of porous particles corresponding to each UV intensity, respectively. Scale bars are 40 µm (upper) and 500 nm (lower).


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Figure 5 Porous janus particle. (a) Schematic of heterogeneous porous janus particle synthesis. Presolution with 70% PEG200 progen(green) injected into one inlet, presolution without porogen (blue) injected into the other inlet. (b) Bright filed image of rectangular shape janus particles in presolution mixture. (c-f) SEM images of porous janus particle with corresponding details about surface of each side and interface of particle. Scale bars are 100 µm (b), 50 µm (c) and 1 µm (df).


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Figure 6 Opacity shifting of macroporous janus particle during Et evaporation. (a-d) Bright field images show opacity changes in section with porogen because of change in microstructure and pore size during Et dependent swelling/deswelling process. Whereas the section without porogen is not affected much by Et evaporation remaining transparent. (e) Transmittance of microporous particle is measured in a timely manner during Et evaporation. Transmittance is calculated by dividing the average gray value of the particle by the average gray value of the surrounding background using Image J. As Et evaporates, the porogen-induced section becomes brighter. However, its opacity dramatically increases as the refractive index is changed from Et to air. In contrast, the non-porogen-induced part does not show any significant change in transmittance throughout the evaporation process. The scale bar is 100 µm (a-d).


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