pNIPAAm Microgels

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Fabrication of shape controllable Janus alginate/pNIPAAm microgels via microfluidics technique and off-chip ionic crosslinking Yuandu Hu, Shibo Wang, Alireza Abbaspourrad, and Arezoo Ardekani Langmuir, Just Accepted Manuscript • DOI: 10.1021/la504422j • Publication Date (Web): 13 Jan 2015 Downloaded from http://pubs.acs.org on January 24, 2015

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Fabrication of shape controllable Janus alginate/pNIPAAm microgels

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via microfluidics technique and off-chip ionic crosslinking

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Yuandu Hu1, Shibo Wang1, Alireza Abbaspourrad3, Arezoo M. Ardekani*1,2

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1 Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre

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Dame, Indiana 46556, USA

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2 School of Mechanical Engineering, Purdue University, 585 Purdue Mall, West Lafayette,

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Indiana 47907, USA

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3 School of Engineering and Applied Sciences, Harvard University, Cambridge,

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Massachusetts 02138, USA

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*Corresponding Author

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E-mail: [email protected]

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ABSTRACT: A novel method to fabricate shape controllable alginate/pNIPAAm

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complex microgels is reported. Monodisperse alginate/pNIPAAm droplets are created

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via microfluidics and crosslinked in different concentrations of hot glycerol/barium

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acetate water solutions. By changing the initial droplet size and glycerol concentration

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of the collecting solution, the resultant microgel shape and surface details can be

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systematically tuned. High-speed imaging is used to visualize and explain the

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microgel formation process.

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INTRODUCTION

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Anisotropic and multicomponent microparticles have been widely investigated in the

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past decades for various applications.1-4 For example, the two distinguishable surface

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areas of Janus particles make them ideal candidates for displays,5-6 target recognition,7

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interfacial stabilizers,8 encoding,9-10 sensors,11-13 cell encapsulation14 and the detection

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of metal ions.15 Anisotropic particles with rough surfaces can be used for Raman

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signal enhancement7 and hydrophobic coatings,16-17 due to their enlarged surface area 1

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compared to that of smooth particles. Droplet-based microfluidic techniques have

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been widely used to fabricate anisotropic microparticles.4,

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polymer microgels with different components has been achieved using water in oil

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(w/o) emulsion droplets combined with UV-induced polymerization or ionic

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crosslinking to solidify droplets. The solidification process mostly occurs inside the

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microfluidic device, known as on-chip solidification method.31 Seiffert et al. have

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developed a double T-junction PDMS-based microfluidic device to fabricate Janus

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pNIPAAm microgels by polymerizing Janus precursor droplets inside the microfluidic

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device.32 The Janus pNIPAAm precursor droplets were formed from two independent

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streams of linear pNIPAAm solutions with photo-chemical reaction groups and

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polymerized using strong UV light32. UV-polymerized anisotropic microgels can also

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be fabricated using stop-flow lithography microfluidic techniques.19,

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coworkers synthesized Janus microgels by injecting NIPAAm-rich and NIPAAm-poor

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phase into a hydrodynamic focusing microfluidic device (HFMD), followed by the

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on-chip polymerization of Janus droplets via UV light.34 Ma et al. prepared concave

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microgels by selectively polymerizing double emulsion droplets template.35 Besides

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UV-induced solidification of polymers, on-chip ionic crosslinking methods can be

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used to fabricate anisotropic microgels. Marquis et al. prepared both homo-Janus and

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hetero-Janus biopolymer microbeads by using a flow-focusing device for

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diffusion-controlled ionic crosslinking system.

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Janus alginate microgels by injecting sodium alginate solutions into a double

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T-junction microfluidic device and used on-chip cross-linking of the sodium alginate

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droplets.37 Lu et al. fabricated Janus-like chitosan-based dimer capsules using a

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T-junction microfluidic chip with four inlets.38 However, all the above-mentioned

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methods are limited to requiring the use of a complicated microfluidic device with

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multiple inlets to inject three or more precursor solutions. To overcome this limitation,

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Choi et al. employed dewetting to induce phase separation, followed by UV

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polymerization, obtaining complex structured microgels through single emulsion

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precursor droplets.39 This approach provides a simple method to fabricate anisotropic

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gel particles, but it is still limited to UV polymerized precursor droplets. To the best of

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The fabrication of

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Kim and

Zhao et al. fabricated magnetic

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our knowledge, there are no reports on the fabrication of anisotropic complex

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microgels by single emulsion droplets through an off-chip ionic crosslinking method.

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In this study, we performed a simple and versatile approach to fabricate

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shape-controllable poly (N-isopropylacrylamide) (pNIPAAm)/sodium alginate (SA)

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microgels using single emulsion droplets. We use a glass capillary microfluidic device

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to generate single water-in-oil emulsions; the monodisperse pNIPAAm/sodium

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alginate emulsions were collected in hot collecting solutions, composed of barium

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acetate (BA) mixed with different concentrations of glycerol aqueous solutions. We

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exploit a non-equilibrium phase separation, crosslinking properties of SA and

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coil-to-globule phase transition of pNIPAAm within the emulsions to fabricate

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microgels of different optical properties, geometries and surface microstructures. We

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control particle morphology, simply by tuning experimental parameters, such as the

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initial droplet diameter and the extent of phase separation, concentration of linear

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pNIPAAm and concentration of glycerol in the collecting solution. These complex

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microgels can potentially be used in the design of stimulus-responsive drug delivery

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vehicles, cell attachment materials, and for building porous three-dimensional tissue

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constructs.

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Materials. Poly (N-isopropyl acrylamide) (carboxylic acid terminated pNIPAAm,

MATERIALS AND METHODS

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average Mn 5000, Sigma-Aldrich),

sodium

alginate

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hexadecane (Anhydrous, 95%), barium acetate (purity > 99%), FeCl3 (Purity >97%),

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FeSO4·7H2O (Purity ≥ 99%), ammonia water (28.0-30.0% NH3 basis) have been

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obtained from Sigma-Aldrich and used without further purification. Glycerol and

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Cetyl PEG/PPG-10/1 Dimethicone Abil EM90 have been supplied by Macron Chem.

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and Evonik Co., respectively.

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Microfluidic setup

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The microfluidic device is composed of coaxially aligned tapered cylindrical glass

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capillaries, inserted into a square capillary and fixed on a glass slide. The schematic of

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the flow-focusing capillary-based microfluidic device is shown in Figure 1. Prior to

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inserting the cylindrical capillaries into the square capillary, we taper them using a 3


(W201502-SAMPLE),

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micropipette puller to create a desired orifice diameter. The square capillary serves as

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a flow channel for the outer fluid stream and also facilitates the alignment of

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cylindrical capillaries. The left and right cylindrical capillaries serve as injection and

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collection tubes, respectively.

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Figure 1 Schematic of a co-flow glass capillary-based microfluidic device. Off-chip

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crosslinking was achieved by keeping the tip of the collecting tube in contact with the

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interface of a hot collecting solution, composed of barium acetate mixed with glycerol

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aqueous solution. Mushroom-like and Janus microgels are fabricated from droplets of

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300 µm and 150 µm diameter, respectively. The droplets were produced within the

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glass capillary microfluidic device at room temperature (~25

) and collected into

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glass beakers containing 4 mL of collecting solutions. The temperature of the

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collecting solution was maintained at 45

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The glass beakers were covered with aluminum foil during this process to minimize

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the evaporation of water.

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Formation of droplets

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Aqueous solutions of pNIPAAm/sodium alginate are emulsified in continuous

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Hexadecane oil phase containing 5 wt% Abil EM 90 that serves as surfactant (Figure

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S1). The collecting aqueous solutions are composed of 10 wt% barium acetate and

using a hot plate for at least 12 hours.

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0-40 wt% glycerol. The flow rates of the dispersed and continuous phases are fixed at

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150 µL/h and 3000 µL/h, respectively.

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Mushroom-like microgels are fabricated from initial droplets of about 300 µm

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diameter. The orifice diameter of the injecting tube is about 80 µm, and the orifice

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diameter of the collecting tube is 310 µm. Experiments are performed for 1 wt%

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pNIPAAm/1wt% SA and 2 wt% pNIPAAm/1wt% SA. Larger concentrations of

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pNIPAAm and sodium alginate lead to higher drop viscosity and formation of

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spherical particles. Droplets are collected in glass beakers containing aqueous solution

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of 10 wt% barium acetate and different glycerol concentrations. The collecting

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beakers are placed on a hot plate, whose temperature is kept at 45 °C. After about 12

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hours, the resultant fully crosslinked microgels are brought to the room temperature

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for further characterization.

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Janus microgels are formed out of initial droplets of 150 µm or smaller. In this case,

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the orifice diameter of the injecting tube is 60 µm and the orifice diameter of the

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collecting tube is 200 µm. The aqueous phase has the same composition as in the case

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of mushroom-like microgels.

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To observe droplet deformation at the air-water interface, we collect droplets in a

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Polystyrene Cuvette (VWR-5ml) containing 2 mL of collecting solution. To perform

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the temperature control experiment, we place the cuvette inside a thermostatic water

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bath with a constant temperature of 45 °C. The high speed camera (SA4 Fastcam,

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Photron) was focused at the interface of air and the collecting solution to monitor the

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droplets evolution process. To investigate the effect of droplet size, we utilize

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microfluidic devices with different injection and collection orifice sizes and we

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operate them under the same flow rates.

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Scanning Electron Microscope (SEM) measurements

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To prepare samples for SEM characterization, we wash and freeze-dried Janus

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microgels. In a typical experiment, we transferred crosslinked 150 µm microgels into

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a 10 mL centrifuge tube and centrifuged them at 2000 rpm for 2 min. The supernatant

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is removed and de-ionized water is added into the centrifuge tube followed by

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redispersion of microgels; the procedure is repeated 3 times. A drop of water 5


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containing purified microgels is put on a cleaned glass wafer (~8 mm×8 mm) and

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freeze-dried for 2 days. The freeze-dried samples are analyzed by a Field

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Emission-Scanning Electron Microscope (FE-SEM, Magellan 400) at a speed voltage

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of 3 KV.

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RESULTS AND DISCUSSIONS

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The monodispersed droplets created inside the microfluidic device and collected in

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collecting solutions are shown in the optical images in Fig. S1. The droplets exiting

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the collecting tube are slowed down at the interface of the collecting solution because

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their density is less than the density of the collecting solution (Table S1). The droplets

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deform and crosslink at the interface, and finally settle to the bottom of the beaker,

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which is in agreement with previous reports.40-42

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Mushroom-like microgels

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The mushroom-like microgels are formed out of 300 µm droplets. The observed

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mushroom shape has been reported for pure alginate hydrogel particles in a previous

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report.40 The shape is generated by the slow transition of the initially spherical

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droplets at the oil/collecting solution interface and by the accompanying crosslinking

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of the alginate via the inwards diffusion of Ba2+.41-42

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to the sodium alginate, droplets are composed of linear pNIPAAm polymer, which is

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one of the most widely used temperature responsive polymers, possessing a low

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critical solution temperature (LCST) of approximately 32°C. When the temperature of

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droplets increases above the LCST, the linear polymer undergo a coil-to-globule

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transition and shrinks, while below the LCST the polymer chain shows a swelling

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state. 43 Use of alcohol can results in pNIPAAm aggregation and limits its diffusivity44.

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Consequently, we employ glycerol within the collection bath to further control the

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morphology of microgels. This approach also enables us to tune the transparency of

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the resultant microgels selectively due to aggregation and formation of pNIPAAm

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microparticles within the main matrix (Figure S2). This indicates that both the

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temperature and glycerol cause the pNIPAAm chains to shrink, and lead to a change

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in the refractive index of the pNIPAAm/SA droplets. When the pNIPAAm/SA

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droplets flow out of the collecting tube and contact the hot collecting solutions, the

In the present study, in addition

6


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pNIPAAm chain instantly shrinks into a globule state, accompanied by a change in

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the refractive index from 1.32 to 1.39. 45 Thus, the collapsed pNIPAAm shows darker

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contrast due to light scattering of the aggregates and the refractive index mismatch

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with water (nwater = 1.33). In addition, the coiled pNIPAAm is gradually entrapped into

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the alginate network undergoing an ionic crosslinking process. Figure 2a shows

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microgels formed using a glycerol-free collecting solution. In this case, the resultant

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microgels exhibit an almost transparent mushroom shape. The transparent microgels

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indicate that little to no coiled pNIPAAm is entrapped in this case. When collected in

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40 wt% glycerol-collecting solutions, the microgels exhibit a mushroom shape with

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large amounts of interior black dots. These black dots in the mushroom microgels are

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pNIPAAm globules that are aggregated due to the addition of glycerol (Figure 2e).

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This phenomenon may be attributed to the diffusion of glycerol into the

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pNIPAAm/SA droplets and increase in the viscosity of the droplet. The inward

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diffusion of glycerol into the droplets limits the mobility of pNIPAAm globules and

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force them to form larger aggregates, resulting in a homogeneous entrapment of

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pNIPAAm particles (3~5 µm) in the resultant microgels. Different concentration of

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glycerol gives rise to different inward diffusion velocities and consequently different

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amount of aggregates. As a result, different features are observed for individual

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microgels collected in different glycerol concentrations. The mushroom microgel

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droplets collected in 10 wt% glycerol solutions display two different optical contrasts

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for each microgel, with one half nearly transparent, while the other half being opaque

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(Figure 2b). The different contrast is attributed to the inhomogeneous distribution of

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pNIPAAm aggregates. With increasing glycerol concentration, the mushroom-like

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microgels gradually show a homogeneous optical contrast (Figure 2c-e). This

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phenomenon suggests that higher glycerol concentration in the collecting solution

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inhibit the migration of pNIPAAm globules in the droplets, and as a result, the

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pNIPAAm particles will be uniformly distributed in the mushroom microgels.

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Not only is the microgels’ optical properties influenced by the collecting solutions,

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but their geometry also changes as a function of glycerol concentration in the

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collecting solutions. The geometric factor is defined here, as the length ratio of the 7


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distance between the poles (defined as L) to the diameter of the equator (defined as B),

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shown in the inset of Figure 2k. Clearly, the geometric factor decreases with the

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increase of glycerol concentration in the collecting solutions. The geometric factor

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falls within the interval 0.70~0.90 (Figure 2k), and continues to decrease with

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increasing glycerol concentration. By increasing the velocity of a continuous phase, a

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Figure 2. (a-e) Optical microscope images of microgels formed out of 300 µm

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diameter droplets, composed of 1 wt% pNIPAAm and 1 wt% sodium alginate and

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collected in collecting solutions with different glycerol concentrations: 0, 10 wt%, 20

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wt%, 30 wt% to 40 wt%. (f-j) Optical microscope images of microgels formed out of

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300 µm diameter droplets, composed of 2 wt% pNIPAAm and 1 wt% sodium alginate,

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collected in solutions with different glycerol concentrations: 0, 10 wt%, 20 wt%, 30

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wt% to 40 wt%. (k) The plot shows the geometric factor for different glycerol

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concentrations. All the samples were heated for 12 hours and then cooled down. All

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the images were taken at the room temperature. 8


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droplet falling into the interface shows greater degree of deformability, which

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provides another level of control to microgel geometry12.

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Similarly, when the concentration of pNIPAAm inside of the droplets was increased to

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2 wt%, more globule pNIPAAm were entrapped inside of the resultant microgels,

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compared to that of 1 wt% pNIPAAm. Figure 2f-j show the optical microscope

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images of microgels obtained from 2 wt% pNIPAAm/1 wt% SA droplets. As shown in

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Figure 2f-j, the microgels collected in the same glycerol collecting solution possesses

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higher contrast value compared to that of Figure 2a-e. The higher contrast was

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attributed to the higher amount of globule pNIPAAm entrapped in the microgels.

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Janus microgels

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By controlling the droplet size, we can also control the microgel morphology and

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obtain Janus shape particles. In the present experiment, when the initial droplet

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diameter is decreased to 175 µm or below, the resultant microgels show Janus

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morphology rather than the mushroom-like morphology formed out of 300 µm initial

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droplets. When the initial droplet diameter is below this critical value, Janus particles

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form, whereas above this value, the resultant microgels show mushroom morphology

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(Figure S4). We attribute this change in the microgel morphology to the combined

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effects of two factors: a) smaller droplets experience a greater extent of phase

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separation between pNIPAAm and SA and possess pNIPAAm-rich and SA-rich

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regions, prior to touching (impacting) the collecting solution interface46-47, and b) the

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viscosity, surface tension and osmotic pressure difference between drops and the

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collecting solution. The collecting solutions with higher glycerol concentrations

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possess higher viscosity and lower interfacial tension, these properties result in a

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greater degree of deformability in drops upon impacting the interface. Smaller

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droplets tend to form Janus particles because they are more difficult to deform due to

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their larger Laplace Pressure difference. The Laplace Pressure difference can be

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calculated by the following equation ∆ =

, where is the interfacial tension

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between the droplet and outer oil phase, and is the droplet radius. We used the

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pendant drop method to measure the surface tension between aqueous solution of 9


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sodium alginate (2 wt%) and pNIPAAm (1 wt%) and hexadecane containing 5 wt. %

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Abil EM90. The measured is 2.35 mN / m , and the ∆ values of the 150 µm and

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300 µm droplets are 31.33 Pa and 15.66 Pa, respectively. Larger droplets are easily

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deformed to a mushroom shape under the driving force of Osmotic pressure

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difference (the minimum osmotic pressure of the collecting solutions is ~ 390 mOsm,

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which is much higher than that of droplet’s osmotic pressure (~ 10 mOsm)) between

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inside and outside of droplets, as shown in Figure 2. Janus microgels collected in

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different glycerol concentrations demonstrate different geometry as shown in Figure 3.

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Figure 3a-e and Figure 3f-j represent the microgels fabricated out of droplets of 1wt%

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pNIPAAm/1wt% SA and 2 wt% pNIPAAm/1 wt% SA, respectively. Both images

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show the resultant microgels with two distinguishable parts: a relatively smaller part,

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which exhibits a darker contrast, richer in pNIPAAm, and a relatively larger

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alginate-rich part. The formation of two different phases is caused by the gradual

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phase separation of pNIPAAm inside the droplets when in contact with the hot

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collecting solutions (Figure S5). Compared to the larger droplets, i.e., 300 µm

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diameter droplets, the pNIPAAm chain in smaller droplets more easily migrate to the

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other side of the droplets and result in Janus morphology. The glycerol and the effect

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of heat could both induce the pNIPAAm chains to shrink into a globule state (Figure

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S2-4). Interestingly, the resultant microgels in glycerol-free collecting solutions only

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show the convex alginate dominant part (Figure 3a and 3f). This is due to the phase

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separation of pNIPAAm and SA within the droplets. However, the size of

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pNIPAAm-rich part gradually decreases with increasing the glycerol concentration of

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the collecting solution due to the entrapment of some of the coiled pNIPAAm in the

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alginate-rich side, as shown in Figure 3b-e and 3 g-j. To quantify the relative volume

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change of the two parts, we define the volume ratio as V1/V2 (V1 and V2 denote the

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volumes of pNIPAAm-rich and alginate-rich parts, respectively). Similar to the

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geometric factor for the mushroom-shaped microgels, the volume ratio of Janus

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particles decreases with increasing the glycerol concentration of the collecting

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solutions (See Figure 3k). The volume ratio decreased from the initial values of 0.20

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and 0.23 for 10 wt% glycerol collecting solutions to the final values of 0.11 and 10


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nearly 0.02 for 40 wt% glycerol collecting solutions. The decrease is attributed to the

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inward diffusion of glycerol from the collecting solutions into the droplets, which

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hinders the pNIPAAm separation from the main droplets and leads to the uniform

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distribution of pNIPAAm globules inside the microgels at high concentrations of

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glycerol collecting solutions. Furthermore, the phase separation process is inhibited

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by higher sodium alginate concentrations in the droplets (Figure S6, S7).

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Figure 3. (a-e). Optical microscope images of microgels formed out of droplets of

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150 µm diameter composed of 1 wt% pNIPAAm and 1 wt% sodium alginate and

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collected in collecting solutions of different glycerol concentrations: 0, 10wt%, 20

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wt%, 30 wt% to 40wt%. (f-j) Optical microscope images of microgels formed out of

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droplets of 150 µm diameter composed of 2 wt% pNIPAAm and 1 wt% sodium

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alginate and collected in collecting solutions of different glycerol concentrations: 0,

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10 wt%, 20 wt%, 30 wt% to 40 wt%. (k) The plot shows the volume ratio for Janus

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particles for different glycerol concentration of the collecting solutions.

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Figure 4. Scanning Electron Microscope (SEM) images of microgels collected in

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different concentrations of glycerol solutions: (a) 0; (b) 10 wt%; (c) 20 wt%; (d) 30

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wt%; (e) 40 wt%.

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Figure 4 represents SEM images of alginate-rich part of microgels formed by using

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collecting solutions of different glycerol concentrations. It can be clearly observed

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that the surface morphology of the microgel changes with glycerol concentration of

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the collecting solutions. As shown in the SEM images, the number of dents on the

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surface increases but their size decreases as the glycerol concentration in the

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collecting solution increases.

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Ultrasonication of Janus microgels

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The present study demonstrates that not only we can controllably fabricate microgels

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of different geometries by carefully adjusting the composition of collecting solution,

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but also we can selectively isolate different part of microgel using ultrasonication.

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Janus microgels formed in collecting solutions containing 10wt% glycerol are purified

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by centrifugation at 2000 rpm to remove the supernatants. This procedure is repeated

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2~3 times. The purified microgels are transferred into a 5 mL centrifuge tube and

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sonicated in an ultrasonicator (VWR, 97043-968) for 1 min. Figure 5 shows the

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breakup process of the initial Janus microgel formed from 10 wt% glycerol collecting

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solution. The Janus microgels breakup when they are placed in an ultrasonicator for 1

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min. The pNIPAAm-rich part is separated from the alginate-rich part due to the weak

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tangling interaction between alginate molecule chains and pNIPAAm molecule

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chains.48 Once further sonicated, the separated pNIPAAm-rich part gradually

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dissolves (as illustrated by red arrows in Figure 5d). The pNIPAAm is a water soluble

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polymer and gradually swells in the aqueous solution and the collapsed pNIPAAm

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chains recover their coil structure. The same behavior is observed when Janus 12


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particles are fabricated using higher glycerol concentrations (such as 50wt% and

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60wt%, corresponding to Figure S5 c and d, respectively) in the collecting solutions.

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Figure 5. (a) and (c) shows the Janus particles (b) and (d) shows that Janus microgels

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are broken to two parts by using external ultrasonication. Red arrows in (d) illustrate

319

disintegrated pNIPAAm. The experiment was conducted at the room temperature.

320

CONCLUSIONS

321

In summary, we report a simple method to fabricate pNIPAAm/sodium alginate

322

microgels through single emulsion generated in microfluidics combined with an

323

external ionic crosslinking process. Monodispersed droplets composed of linear

324

pNIPAAm and sodium alginate are collected in hot collecting solutions of barium

325

acetate and glycerol at different concentrations. Starting out of initial droplets of 300

326

µm and 150 µm in diameter, mushroom-like and Janus microgels can be attained. The

327

geometric factor and optical properties of the mushroom-like microgels can be simply

328

tuned by changing the glycerol concentration of the collecting solutions. Similarly, by

329

varying the glycerol concentration of the collecting solutions, the relative volume

330

ratio and the surface roughness of the Janus microgels can be varied. The Janus

331

microgels can be broken to two parts by using ultrasound and can be potentially

332

extended to other stimulus responsive materials. The resultant microgels may be

333

applied in novel optical materials, superstructure microgels, target drug delivery

334

materials, lock-key particles and highly efficient cell attachment (or regenerative 13


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medicine).

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ASSOCIATED CONTENT

337

Supporting Information

338

Supporting Information including the microfluidic fabrication of droplets and

339

other supplementary data are available free of charge at http://pubs.acs.org.

340

AUTHOR INFORMATION

341

Corresponding Author

342

*E-mail: [email protected]

343

Notes

344

The authors declare no conflict of interest.

345

ACKNOWLEDGEMENTS

346

This work was supported by the NSF Grant No. CBET-1150348. We thank Notre

347

Dame Integrated Imaging Facility Centre for the SEM measurements.

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349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370

1.

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pNIPAAm Microgels

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