Fabrication of PAA-PETPTA Janus Microspheres with Respiratory

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Interface Components: Nanoparticles, Colloids, Emulsions, Surfactants, Proteins, Polymers

Fabrication of PAA-PETPTA Janus Microspheres with Respiratory Function for Controlled-Release of Guests with Different Sizes Liwei Wang, Liang Yu, Changfeng Zeng, Chongqing Wang, and Lixiong Zhang Langmuir, Just Accepted Manuscript • Publication Date (Web): 25 May 2018 Downloaded from http://pubs.acs.org on May 25, 2018

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Fabrication of PAA-PETPTA Janus Microspheres with Respiratory Function for Controlled-Release of Guests with Different Sizes Liwei Wang, a Liang Yu*, b Changfeng Zeng,c Chongqing Wang, a and Lixiong Zhang*,a a State Key Laboratory of Materials-Oriented Chemical Engineering and College of Chemical Engineering, Nanjing Tech University, Nanjing 210009, PR China b Chemical Technology, Luleå University of Technology, SE-971 87 Luleå, Sweden c College of Mechanical and Power Engineering, Nanjing Tech University, No. 5 Xin Mofan Rd., Nanjing 210009, PR China

KEYWORDS: Janus microspheres; pH stimuli-response; controlled-release; PAA hydrogels; microchannel

ACS Paragon Plus Environment

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ABSTRACT: Polyacrylic acid-poly(ethoxylated trimethylolpropane triacrylate) (PAA-PETPTA) Janus microspheres with “respiratory” function for controlled-release were prepared by polymerization of acrylic acid-ethoxylated trimethylolpropane triacrylate (AA-ETPTA) Janus microdroplets in a continuous oil phase in a simple capillary-based microfluidic device with the assistance of UV radiation. The flow rate ratios of AA and ETPTA phases and surfactant content in the continuous oil phase have a significant effect on the structure of the Janus microspheres. PAA part in the Janus microspheres has respiratory function for loading and release, due to the different stimuli-response to different pH. The hollow structure of PETPTA part with different sizes of opening serve as the host materials for PAA and could control release rate further due to the different opening sizes. The obtained PAA-PETPTA Janus microspheres showed high Rhodamine B (RhB) loading of 860 mg g-1 and different controlled-release behavior in water with different pH. The release rate increase with the increase of pH and the contact area of PAA part with water. The maximum controlled-release time for RhB was about 3 h in water with pH of 5. In addition, the Janus microspheres also showed controlled-release behavior for larger size guests, e.g. 150 nm polystyrene (PS) beads, which indicated a wide range of application. The loading and release behavior for guests, for instance for RhB, has almost no change even after 6 times reuse which indicated a high stability.


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INTRODUCTION Controlled-release technology has gained great interesting due to the importance in drug delivery,1 biotechnology,2 agriculture,3 cosmetics4 etc. fields. Several types of materials, for instance polymers,5 silicon,6 metal oxides,7 hybrid compounds8 and carbonaceous materials9 etc. with different types of controlled-release mechanism, e.g. polymer degradation release,10 stimuliresponsive controlled-release,11 autonomic release5 have been used as the carrier materials for controlled release. In addition, different structures like honeycomb,12 bowl-shaped,13 core-shell,14 yolk-shell,5 Janus,15 hollow microspheres16 for carrier materials also have been investigated. Among them, an open-mouthed hollow capsule with a single hole has stimulated great interest due to the enhanced uptake capacity, diffusivity, and controlled loading/release performance. The Janus type materials with hole or mouth on the shell can provide more versatility for the microparticles by facilitating mass transport through the shell based on the size or functional selectivity of the holes. In addition, controlled-capture of particles, controlled-release of active molecules and small particles, as well as removal of pollutants can be controllable achieved through finer control the size of the holes in the shell.17, 18 For example, an asymmetric eccentric single-hole mesoporous silica nanocages material with a uniform size has been prepared via the anisotropic encapsulation route.19 The obtained material can be used as a dual-sized guest codelivery system by heat and near-infrared (NIR) light induced, respectively. Microscale polymer bottles PS hollow spheres with a hole on its surface have been prepared by swelling and fast freezing method.20 A phase-change material with capable of reversible, solid–liquid transition in response to variation in temperature was used to seal the hole after loading guests materials for temperature controlled-release. Moreover, the hole on the surface allows a quick and efficient loading of small molecules, macromolecules, and even nanoparticles at least 50 nm in size. However, the methods, for instance freeze-drying, templating etc. that can be used for


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preparation of the above materials were complex and therefore highly cost. Therefore, an efficient method for synthesis of open-mouthed hollow capsules or Janus microspheres with controlled-release function is of great interest. Microfluidic technique is particularly appealing for fabrication of such microspherical materials for controlled-release due to its simplicity, good repeatability and high stability.21, 22 Poly(acrylamide)/poly(methyl acrylate) Janus particles with drug loading and controlled-release functions have been fabricated by a side-by-side capillaries microfluidic device with UV-assisted free radical polymerization.23 Weitz et al. reported the synthesis of a single-phase crescentmoon-shaped particles in a capillary microfluidic device by UV induced polymerization of Janus microdroplets with immiscible paired oil microdroplets of fluorocarbon and photocurable monomer.24 Similarly, the acorn-shaped Janus particles with multiple functions have also been prepared by one-step microfluidic approach. In the method, a Janus emulsion was first prepared by emulsifying a dispersed phase containing a water phase (water) and a photocurable oil phase (ETPTA) using a continuous paraffin oil phase with the assistance of glass capillary microfluidic device. The shape of the Janus particles can be controlled easily by tuning the interfacial tension of the dispersed phase and the continuous phase.25 These Janus microspheres or Janus microdroplets derived materials prepared with the assistance of microfluidic technique exhibited high performance as active cargo delivery and controlled-release systems for particles or molecules with different sizes in biology and the environmental field. In addition, water-swellable polymer networks (hydrogels) that are sensitive to external stimuli of temperature, pH, light etc. have found an increasingly large number of applications in the controlled-release system.26 Until now, poly(N-isopropylacrylamide) (PNIPAM) hollow microgel capsules,27 salecan-based pH-sensitive hydrogels,11 polyelectrolyte hydrogel capsules,28


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pH-responsive polyacrylic acid-b-polymethyl methacrylate (PAA-b-PMMA) microcapsules etc.29 have been prepared for controlled-release at different external conditions. However, the major drawback of some of the reported hydrogel materials was the sustainability, i.e. the reuse was difficult because the damage of the hydrogel materials could happen during controlledrelease process.27,28 Therefore, preparation of sustainable hydrogel materials with high stability during regeneration for controlled-release is of great interesting. Incorporation of the waterswellable polymer hydrogels into the acorn-shaped Janus particles could be an efficient solution to improve its sustainability and stability. In the present work, the stimuli-responsive PAA-PETPTA Janus microspheres with breathing function of swelling and contraction of PAA hydrogels were synthesized by combining the advantages of stimuli-response material and the hollow capsule with a single hole. The Janus microspheres were prepared by UV radiation polymerization of Janus AA-ETPTA water–oil emulsions in a simple theta capillary microfluidics. The effect factors of the embedding depth of PAA hydrogel in PETPTA part and the hole size in PETPTA shell were investigated. The pH stimuli-response of the Janus microspheres were examined and the controlled-release behavior for different size of guests were also evaluated. EXPERIMENTAL SECTION Chemicals and Materials Acrylic acid (AA) was purchased from Sinopharm Chemical Reagent Corporation (Shanghai, China). Ethoxylated trimethylolpropane triacrylate monomer (ETPTA) was obtained from Sigma-Adrich (USA). Cetyl dimethicone copolyol surfactant modified polyether-polysiloxane (EM90) was purchased from Evonic industrials (Germany) and liquid paraffin were obtained


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from Shanghai Lingfeng Chemical Reagent Corporation. N, N’-methylene bisacrylamide (MBAM), 2-Hydroxy-4’-(2-hyroxyethoxy)-2-methylproplo phenome (IRGACURE 2959), 2hydroxy-2-methyl-1-phenyl-1-propanone (IRGACURE 1173) and Rhodamine B (RhB) were purchased from Aladdin Industrial Corporation with chemical purity. Polystyrene nanoparticles (PS Nano) beads purchased from Janus New-Materials Co., Ltd. (Nanjing, China). The poly tetra fluoroethylene (PTFE) tubes and rods with different diameters were purchased from Chukoh Chemical Industries, Ltd. The glass capillary was obtained from West China University of Medical Sciences Instrument Industry. Polymethyl methacrylate (PMMA) plate was purchased from Suzhou Yiguan plastic materials Industry. Syringe Pumps (LSP02-1B) used to introduce the solution into the microchannels were purchased from Baoding Longer Precision Pump Corporation.

Figure 1. Schematic illustration of the microfluidic device for the preparation of PAA-PETPTA Janus microspheres. Preparation of Janus Microdroplets in a Microfluidic Channel A co-axial microfluidic device assembled with a theta capillary (inner diameter: 0.05 mm) inserted into a PTFE tube was used for the preparation of Janus microdroplets. The AA aqueous solution was used as the inner water phase, ETPTA as the inner oil phase, and liquid paraffin with various mass fractions of EM90 (surfactant) as the outer continuous oil phase. For easier observations of the Janus morphologies, Sudan Red was added in the inner oil phase to color it red. As shown in Figure 1, the oil phase and water phase flowed through the theta capillary. The


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flow rate of the continuous phase was fixed at 5 ml h-1. The ETPTA oil phase flow rate was fixed at 50 µl h-1, and the AA water phase flow rate was 50, 150 and 250 µl h-1, respectively. Monodispersed Janus microdroplets were formed as a result of the shearing force of the continuous phase. Preparation of Janus Microspheres For preparation of Janus microspheres, 2 wt.% IRGACURE 1173 as photo initiator was added into the ETPTA phase and 5 wt.% IRGACURE 2959 was added into the AA phase, and a UV beam was applied over the downstream of the PTFE tube as shown in Figure 1. ETPTA and AA were polymerized respectively under UV irradiation to convert the above Janus microdroplets to microspheres. The obtained samples were collected in a petri dish. Dye Loading and Controlled-Release For dye loading, Janus microspheres collected for 5 min (4.3 Hz) were put into 5 ml of 50 ppm RhB aqueous solution (pH = 2) for 12 h in dark, subsequent filtration. The dye-loading amount was calculated from the dye concentrations in its solution before and after adsorption. Moreover, the concentration of dye was determined by using an ultraviolet–visible spectrophotometer at a wavelength of maximum absorbance (554 nm). For controlled-release, the RhB-loaded microspheres were dispersed into 5 ml deionized water with pH of 5, 7, 9, 11, and 13 at room temperature, respectively. The pH was adjusted by 0.1 M HCl and NaOH aqueous solution. For more precise results, 7–9 parallel experiments were conducted for each pH at the same time. One of the samples was used to determine the dye concentrations every 5 min. PS Nano Beads Loading and Release


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PS Nano beads with a diameter of 150 nm were loaded into dried hollow-hole Janus microspheres under ultrasonic treatment for 1, 5 and 10 min by mixing dried Janus microspheres with PS Nano beads. The color change of the Janus microspheres with loading time was recorded by optical microscope. The PS Nano beads loaded Janus microspheres were dispersed in pure deionized water for investigation of PS beads release behavior. The change of the Janus microspheres in water was recorded by optical microscope as well. Characterization An optical microscope (BX31, Olympus) was employed to observe the microdroplets and a stereomicroscope

(SHUNYU

SZM45)

equipped

with

a

CCD

camera

(Microview,

MVC610DAC-GE110) was used to film the experiment process, including swelling behavior, loading and release. The morphologies of dried Janus microspheres with PS Nano beads were examined by Hitachi S-4800 scanning electron micros-copy (SEM) using an accelerating voltage of 5 kV, and the samples were coated with gold before measurement. PE UV-2802S ultraviolet– visible spectrophotometer was used to measure the RhB dye concentration. RESULTS AND DISCUSSION Preparation of Oil-Water Janus Microdroplets The stimulus-responsive PAA-PETPTA Janus microspheres with the PAA part embedded in the PETPTA part were prepared by polymerization of AA-ETPTA Janus microdroplets in a microchannel. Figure 1 shows the schematic process for the preparation. As we intended to obtain embedded Janus microspheres, therefore adjust the embedment depth, i.e. the exposure area of AA microdroplets in ETPTA microdroplets was studied first. Previous research revealed that such structure is determined by the coefficient of interfacial tension: γA (between AA and


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liquid paraffin), γE (between ETPTA and liquid paraffin), and γAE (between AA and ETPTA) as illustrated in Figure 2a. The relations of those parameters can be described as: S = γA - (γE + γAE),

(1)

and γ2AE = γ2E + γ2A - 2γEγAcos(π-α).

(2)

where S is spreading coefficient of ETPTA, α is the angle between the interfacial tension of γA and γE.30 When the spreading coefficient S < 0, partial engulfing of AA microdroplet by ETPTA microdroplet occurs, forming an embedded Janus microdroplet with different area of AA microdroplet exposed. The concentration of EM90 in liquid paraffin changes the value of γA, thereby affecting S. The extreme case is that the water phase of AA was engulfed completely by the ETPTA phase.31 The exposure area increases with the increase of the concentration of EM90. Figure 2b-g show the optical microscopic images of the Janus microdroplets prepared from different concentrations of EM90 and the same flow rate of ETPTA and AA solutions, i.e. flow rate ratios of QETPTA:QAA was 1:1. For an easier observation of the Janus morphologies, Sudan Red was added in the inner oil phase to color the ETPTA part red. The transparent part represents the AA water phase. Figure 2b shows that a core/shell structure was formed when no EM90 was used in the liquid paraffin, which indicated that the AA water phase microdroplet was completely engulfed by ETPTA oil phase. In this case, the corresponding γA was 29.13 mN m-1, γE was 3.51 mN m-1, γAE was 6.41 mN m-1 and SE was 19.24 mN m-1. The AA microdroplets moved aside in ETPTA oil phase and AA-ETPTA Janus microdroplets with different structures were formed with the increase of EM 90 content. An eccentric Janus structure was formed at the content of EM90 of 0.01 wt.% (see Figure 2c). Figure 2d shows that the AA water phase started


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moving out from the ETPTA oil phase at the concentration of EM90 of 0.0115 wt.%. The engulfing area of AA microdroplet was reduced in ETPTA phase (Figure 2e) when the surfactant content was 0.0125 wt.%. Most part of AA had been moved out from the ETPTA phase, when the amount of EM90 increased to 0.015 wt.% or higher (Figure 2f and 2g). At EM90 content of 0.030 wt.%, the coefficients of interfacial tension γA, γE and γAE were measured to be 7.59 mN m-1, 3.48 mN m-1 and 6.41 mN m-1. From these, the spreading coefficient of ETPTA (S) and α of microdroplet can be obtained from eq. (1) and (2) with the number of -2.32 mN m-1 and 123°, respectively. As S < 0, Janus microdroplets were also formed with partial engulfing of AA microdroplet in ETPTA microdroplet. The calculation results were consistent with the observation in Figure 2g. Clearly, Janus microdroplets were actually formed at the EM90 contents of 0.010-0.030 wt.% with partial AA water phase microdroplet engulfed by ETPTA oil phase microdroplet. Several parameters were defined to describe the structure of the embedded Janus microdroplets as schematically illustrated in Figure 2a. The depth of AA water phase segment immersed in ETPTA oil phase segment was h, the radius of the AA microdroplet was rA, the radius of ETPTA microdroplet was rE, and the sliced circle diameter was D. For embedded Janus microdroplets, h is larger than rA and D is smaller than 2rE, i.e. h/rA > 1, D/2rE < 1 (see Figure 2a), which indicate that more than half of AA microdroplet embedded in ETPTA part. The AA water phase segment was completely embedded in ETPTA oil phase segment when the concentration of EM90 was 0 in paraffin continuous phase (see Figure 2b). Figure 2h shows h/rA and D/2rE of Janus microdroplets as a function of EM90 content. h/rA decreased coupling with D/2rE increased dramatically with the increase of EM90 content from 0.010 to 0.015 wt.%, which indicate that AA segment moved to the edge of ETPTA segment from inside. Specifically, h/rA was larger


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than 1 and D/2rE deviated from 1 when the content of EM90 increased from 0.010 to 0.0125 wt.%. However, most part of AA segment was still covered by ETPTA segment (Figure 2c, 2d and 2e) in this case. When the content of EM90 increased to 0.015 wt.%, h/rA would be less than 1 and D/2rE was close to 1, the Janus microdroplets did not belong to embedded Janus under this condition, i.e. around half of AA segment was outside of ETPTA segment (see Figure 2f). This situation will change further when the content of EM90 increased from 0.015 to 0.030 wt.%, i.e. most part of the AA segment was out of ETPTA segment as shown in Figure 2g. The above results indicate that the suitable EM90 content should be less than 0.015 wt.% in continuous phase of liquid paraffin to obtain the Janus microdroplets with most of the AA segment engulfed by ETPTA segment.


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Figure 2. (a) An illustration showing interfaces, D, h, and interfacial tensions in a AA-ETPTA Janus microdroplet; (b-g) Optical microscopic images of Janus microdroplets prepared with liquid paraffin containing different amount of EM90: (b) 0, (c) 0.01 wt.%, (d) 0.0115 wt.%, (e) 0.0125 wt.%, (f) 0.015 wt.%, (g) 0.030 wt.%. (h) D/2rE and h/rA of Janus microdroplets as a function of concentrations of EM90. Scale bars represent 200 µm. Figure 2a indicates that increasing the flow rate of the AA water phase can result in the increase in volume of AA, h, D and enlargement of the ETPTA compartment as the resulting Janus microdroplet has to maintain constant α because of constant γA, γE and γAE. Such change enables larger PAA part and larger D, which can facilitate faster PAA swelling32 and higher loading for delivery. Thus, the Janus microdroplets were prepared by keeping the ETPTA oil phase flow rate at 50 µl h-1, EM90 content of 0.010 wt.% and increasing the AA water phase flow rate from 50 to 250 µl h-1. As expected, embedded Janus microdroplets were formed, and the volume of the AA water phase compartment increases, while the ETPTA compartment was enlarged and its thickness became thin with the increase of AA water phase flow rate from 50 to 250 µl h-1, i.e. the flow rate ratios of QETPTA:QAA were 1:1, 1:3 and 1:5, respectively (see Figure 3). Meanwhile, h/rA decreased from 1.73 to 1.05 and D/2rE increased from 0.64 to 0.92. The effect of EM90 content on the structure of the Janus microdroplets at the above AA water phase flow rates can be examined as shown in Figure 3d and 3e. The variation trends of h/rA and D/2rE were obviously different with the change of flow rate ratio of QETPTA and QAA at different concentrations of EM90. h/rA decreased from 1.47 to 1.0, i.e. decreased 32 %, and D/2rE increased from 0.72 to 0.93, i.e. increased 29 %, with the increase of the water phase flow rate at the concentration of EM90 of 0.0115 wt.%. However, h/rA only decreased from 1.09 to 0.93, i.e. decreased 15%, and D/2rE increased from 0.81 to 0.95, i.e. increased 17 %, at the concentration


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of EM90 of 0.125 wt.%. Furthermore, h/rA was completely less than 1 and D/2rE increased from 0.86 to 0.99 at the concentration of EM90 of 0.015 wt.%. All of those results suggested that the depth of the AA compartment embedded by ETPTA (most part of AA was in ETPTA phase) can be adjusted more obviously by changing the AA phase flow rate at lower concentration of EM90, for instance 0.01 wt.%. However, the AA compartment was not embedded by ETPTA (most part of AA was out of ETPTA phase) at too high AA phase flow rate, for instance higher than 150 µl h-1, for all of the studied EM90 concentrations. In addition, the AA compartment was also not embedded by ETPTA at concentration of EM90 of 0.015 wt.% and all studied flow rate ratios.

Figure 3. At the ETPTA flow rate of 50 µl h-1 and EM90 content of 0.01 wt.%, optical images of ETPTA-AA Janus microdroplets prepared at QETPTA:QAA (a) 1:1, (b) 1:3, (c) 1:5; (d,e) h/rA and D/2rE of Janus microdroplets as a function of QETPTA:QAA. Scale bars represent 200 µm. Preparation of pH Stimuli-Responsive Janus Microspheres


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ETPTA and AA were polymerized under UV irradiation to convert the above Janus microdroplets to microspheres. Based on these, a series of Janus microspheres were prepared by using various concentrations of EM90 at an equal flow rate of ETPTA and AA solutions, i.e. QETPTA:QAA was 1:1. Figure 4 shows the optical images of the obtained Janus microspheres. The Janus microspheres inherited the morphology of their parental microdroplets, but with approximately 22 vol.% shrinkage. This was ascribed to the shrinkage of ETPTA after polymerization.16 Figure 4b shows h/rA and D/2rE in Janus microspheres as a function of the concentration of EM90. With the increase of EM90 content, h/rA decreased and D/2rE increased, i.e. the exposure area of PAA increased, which was the same as variation trend of the corresponding Janus microdroplets. In addition, the values of h/rA were generally larger than that of the corresponding microdroplets (see Figure 2h). This was also the reason for the formation of embedded Janus microspheres with h/rA of 1.05 for sample A4 from unembedded Janus microdroplets (see Figure 2f). However, only Janus microspheres with h/rA of 0.83 and D/2rE of 0.86, i.e. most part of PAA was not enwrapped by the PETPTA shell, were obtained when the concentration of EM90 was higher than 0.015 wt.%. Therefore, the above results indicated that the suitable EM90 content should be no more than 0.015 wt.% for preparation of the Janus microspheres with the PAA part mostly enwrapped by the PETPTA shell. Figure 4 also shows the effect of AA phase flow rate on structure of Janus microspheres. Generally, the volume of PAA embedded in PETPTA, the cavity of PETPTA and the hole of PETPTA shell were larger for the Janus microspheres prepared from higher AA water phase flow rate. Figure 4c shows that the value of h/rA decreased, but generally larger than 1, with the increase of AA phase flow rate and EM90 content in continuous phase. Figure 4d shows that the D/2rE value of the Janus microspheres was smaller than that of microdroplets, which indicated


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that the opening of the PETPTA in Janus microspheres was smaller than that of microdroplets due to the shrinkage of ETPTA during polymerization. However, the D/2rE of the microspheres slowly increased with the increase of AA phase flow rate. Therefore, in general, the values of h/rA decreased and the values of D/2rE increased when the flow rate of AA water phase increased, i.e. the size of the PETPTA opening and embedment depth of PAA in the Janus microspheres can be adjusted by changing the flow rate ratios of oil and water phases, which was consistent with that of Janus microdroplets (see Figure 3).


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Figure 4. (a) At the ETPTA flow rate of 50 µl h-1, optical images of PAA-PETPTA Janus microspheres prepared at QETPTA:QAA of 1:1, 1:3, 1:5 and different concentrations of EM90 of 0.01 wt.%, 0.0115 wt%, 0.0125 wt%, 0.015 wt%; (b) D/2rE and h/rA of Janus microspheres as a function of concentrations of EM90 in continuous oil phase; (c, d) h/rA and D/2rE of Janus microspheres as a function of phase flow rate ratio. Scale bars represent 150 µm.


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Figure 5. Optical images of the swelling behavior of PAA-PETPTA Janus microspheres A4 in water with different pH (a) 2.5, (b) 4, (c) 7, (d) 9, (e) 11, (f) 13; (g) Dynamic swelling behavior images of A4 in water with pH of 11; (h) Swelling volume of PAA for Janus microspheres with different D/2rE as a function of pH of water. (i) PAA swelling time at different pH for Janus microspheres with different D/2rE. Scale bars represent 200 µm.


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Swelling Behavior of Janus Microspheres in Water with Different pH Sample A4 was put into water with pH of 2.5, 4, 7, 9, 11 and 13 to examine the swelling behavior, i.e. the breathing out function of PAA part in the Janus microspheres. As expected, Figure 5a shows that no swelling and a slight shrinkage of the PAA part was observed in water with pH of 2.5 due to the shrunken conformation of PAA chains at pH value lower than the pKa of PAA (about 4.5).33 The contracting behavior of PAA could be confirmed further by keeping the swelled PAA-PETPTA Janus microspheres in pH of 2.5 water (See video VS1 in the supporting information). The PAA part swelled out of the PETPTA shell, forming mushroomlike structure in water at pH higher than 4 (see Figure 5b). The swelling behavior of PAA has been investigated experimentally and theoretically.33, 34 The carboxyl groups of the PAA chains are significantly dissociated and negatively charged with the increase of pH, especially from pH value higher than the pKa of PAA. The repulsion between negative charges makes the PAA chains extended, thereby obtaining swelled PAA hydrogel. The volume of the swelled PAA increased with the increase of pH from 7 to 11. Figure 5g shows the swelling process of the Janus microspheres in water with pH of 11. In the first 60s, the gel swelled quickly as if the balloon was inflated, and then the gel volume grew slowly, PAA gel began to deform until 187s. Only slight morphology change happened from 187 to 220s. Janus microspheres were clearly observed as a double-covered mushroom at 300s. Figure 5h summarizes the swelling behavior of Janus microspheres with different D/2rE at different pH. The swelling volume of PAA gel increased slowly with the increase of pH from 2.5 to 11. The swelling volume of PAA gel decreased with further increase of the pH to 13, which is probably resulted from the increased electrolyte concentration in water weakened the interaction between water and PAA hydrogel and the variation trend was consistent with the literature report.35 In addition, the swelling


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volume of PAA of Sample A4 was two times higher than that of Sample A2 due to the larger opening of PETPTA and larger contact area of PAA with water (see Figure 4a). No separation was observed between PAA and PETPTA during the swelling and contracting process as shown in the videos VS2 and VS1 in the supporting information, which indicated that the copolymer could probably be formed in the interface of PAA and PETPTA. The swelling behavior occurred immediately when the microspheres were put into the water and completed in a couple of minutes. However, the completed swelling time was different for microspheres with different D/2rE as well as different pH of the water as shown in Figure 5i. For example, in water with pH of 11, it took 220s for sample A4 to complete the swelling, i.e. breathing out process, while it took 80s for sample A2. The swelling time was the same of 60s in pH of 7 water for different Janus microspheres. All of these results suggested that the swelling volume of PAA could be controlled by swelling time, pH of water and D/2rE, i.e. the contact area of PAA with water.


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Figure 6. Optical images of the swelling behavior in water with pH of 11 for Janus microspheres with D/2rE of (a) 0.51, (b) 0.78, (c) 0.81 at the h/rA >1 and (d) 0.83 at h/rA =0.47. Scale bars represent 200 µm. The influence of the contact area of PAA with water on the swelling volume can be further proved by Janus microspheres with different D/2rE. Figure 6 shows that the swelling volume was larger for the Janus microspheres with higher D/2rE, i.e. larger contact area of PAA with water. Additionally, it is worth noting that the Janus microspheres with different D/2rE are prepared from the same flow rate of ETPTA phase and AA phase (QETPTA:QAA = 1:1), just different concentrations of EM90 in the continuous phase, i.e. the content of PAA in the Janus microspheres is actually the same. PAA hydrogel breathed in when was heated because of dehydration. Therefore, hollow-hole PETPTA microspheres, which can be used for loading of larger size guests, can be obtained by dehydration treatment of the obtained Janus microspheres at higher temperature. Sample B1, which was prepared with 0.010 wt.% EM90 and QETPTA:QAA of 1:3, had a D/2rE value of 0.38, larger than that of Sample A1 (see Figure 4), i.e. the sample B1 has a relatively large cavity, was chose for the further study. Moreover, the large cavity and appropriate openings are favorable to the drug loading and release. A certain amount of liquid paraffin was added to just immersed the Janus microspheres and put into 80 °C oven. After 5 min, the optical images reveal that PAA part shrank into a PETPTA shell with an opening hollow structure. The depth of the hollow cavity was 120 µm and the diameter of opening was 120 µm (see Figure 7a). The PAA part contracted further and the depth of the hollow structure increase to 140, 210 and 240 µm by extending the heating treatment time to 10, 15, 20 min, respectively. After heating for 25 min, PETPTA hollow formed with completely dried PAA inside. The breathing in process of PAA was completed.


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Figure 7b shows the depth of the hollow structure (hA) as a function of the heating time. The depth of the hollow structure slowly increased with the increase of heating time. At 25 min, the depth of the hollow structure was close to 2rA and the dried PAA became a thin curved layer attached to the PETPTA shell (see Figure 7c). No peeling off or cracking from the interface of PAA and PETPTA shell was observed by SEM, which also indicated a strong interaction between those two polymers. Therefore, the results indicated that the method not only can obtain hollow-hole microspheres from PAA-PETPTA Janus microspheres, but also can adjust the hollow size by heating them for different time, which can control the loading amount of larger size guests for even every single Janus microsphere. Figure 7d shows the breathing out behavior of the dried Janus microspheres in pure water. The results clearly show that the dried PAA is reversible, which further proved that the Janus microspheres are suitable for drug loading and release.

Figure 7. (a) Optical images of the dynamic contracting of Janus microspheres (sample B1) in 80 °C oven; (b) Depth of hollow structure for drying Janus microspheres as a function of drying


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time; (c) SEM pictures of dried PAA-PETPTA Janus microspheres: the overview; the single microsphere and the cross-section of Janus microsphere; (d) Optical images of the swelling behavior of the dried Janus microspheres in pure water. Scale bars represent 200 µm. Dye Controlled-Release of Janus Microspheres The loading and release of dye are controllable by breathing in and out function of PAA. Prior to investigation of release behavior, the loading of RhB was firstly investigated by impregnation of the obtained Janus microspheres in pH of 2 RhB aqueous solution (50 ppm) for 12h. RhB will be loaded into the PAA hydrogel due to the electrostatic interaction between the negative carboxylic groups in PAA and positive amino groups in RhB at low pH.36 Obviously, the dye-loaded Janus microspheres exhibit purple color in PAA part (Figure 8a), with a loading amount of 860 mg g-1 for sample B3. Figure 8b shows the adsorbed loading of RhB as a function of impregnation time in pH of 2 RhB aqueous solution. The adsorbed loading of RhB increased dramatically in the first 1 h and reach to equilibrium at 7 h (see Figure 8b). PAA part will breathe in and keep the adsorbed RhB in the Janus microspheres after drying. The high loading in the first 1 h (580 mg g1

) indicated a fast adsorption process, which is a great significance for practical applications.


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Figure 8. (a) Optical images of RhB-loaded Janus microspheres; (b) Adsorption isotherm of RhB in the Janus microspheres; (c) Release curves of RhB in water with different pH; (d) RhB release time in water with different pH for Janus microspheres with different D/2rE; (e) Regeneration of the release behavior of Janus microspheres B3. Scale bars represent 200 µm. The dye cotrolled-release behavior was carried out in water with pH from 5 to 13 by breathing out function of PAA. Figure 8c shows that the release rate increased with the increase of pH. This resulted from the RhB becoming more negatively charged due to the loss of protons in the process, which increased the repulsion with the negative PAA hydrogel.34 The release profiles reveal that RhB was completely released in 10 min in water with pH of 13 and in 180 min in water with pH of 5. This can be ascribed to the quicker breathing out of PAA at higher pH as discussed above. Figure 8c also shows different dye release time in water with different pH, i.e. the release rate was controllable by adjusting the pH of solution. Figure 8d shows the release behavior of Janus microspheres with different D/2rE of 0.28, 0.51, 0.78 and 0.81 for sample A1A4 in water with pH of 11 and 13, respectively. Apparently, the larger D/2rE value, the less time


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it took to complete release, and release time was shorter in water with pH of 13 than that of in water with pH of 11. This could ascribe to the faster proton lost from RhB at higher pH. Sample B3 was employed to demonstrate the regeneration of the release behavior of Janus microspheres. Figure 8f shows the adsorption and release efficiency for six times adsorptionrelease cycles. The regeneration of the Janus microspheres indicated an excellent “respiratory” function for controlled-release. The results show that the Janus microspheres still have 90% adsorption and 99% release efficiency even after six times reuse, which indicated a high stability. Controlled-Release of PS Nano Beads Janus microspheres with size-controllable single hole and pH stimuli-responsive “respiratory” function can serve as a super container for controlled-release of large size guests or other chemical agents comparing with the conventional hollow spheres with closed shells. Polystyrene (PS) beads with the size of 150 nm were used to examine the drug delivery potential of the hollow Janus microspheres. The PS beads were loaded into the dried PAA-PETPTA Janus microspheres under ultrasonic treatment. The amount of PS beads encapsulated by PETPTA was controlled by the ultrasonic time. The red part was PETPTA shell and the black part was PS beads (see Figure 9a). Figure 9a shows that the black part was deeper with the increase of the ultrasonic time. Figure 9b shows the weight gain of Janus microspheres with the increase of ultrasonic time. When the oscillation time is 1 min, a small amount of PS beads was encapsulated into the shell of PETPTA shell. After ultrasonic for 10 min, the amount of PS beads was greatly increased in PETPTA shell. The maximum PS beads loading amount was 0.127 mg g-1, which corresponded to 1.55×10-3 mg for a single hollow Janus microsphere. Figure 9c shows the SEM images of the hollow-hole part of Janus microspheres with obvious loading of PS beads. Dynamic optical


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images of Figure 9d shows that the PS beads were pushed out from the shell of PETPTA through the breathing out function of the PAA in pure water. The air and the PS beads in the cavity were pushing out slowly at 20s. It was obvious that PAA breathed out continuously from the PETPTA shell with the release of PS beads from 20 to 360 s. The PS beads were completely released at 540 s. It is worth noting that the PS beads cannot be released if no PAA in PETPTA shell. The videos of the controlled-release process for PS beads with and without PAA in PETPTA shell are presented as VS3, VS4 in the supporting information. All of the results indicated that the obtained PAA-PETPTA Janus microspheres have a great potential to be a super container for controlled-release of large guests. In addition, the uniformity of hollow cavities and the controllable cavities size would enable this drug release system to inject a precise dose of drug by controlling the loading amount for every single Janus microsphere, leading to a high reproducibility of drug delivery.37-39 Therefore, the on-demand drug delivery system can be best fulfilled, which may significantly improve the therapeutic effect and effectively reduce systemic toxicity.


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Figure 9. (a) Optical images of PS beads loaded Janus microspheres after different ultrasonic time; (b) PS beads loading amount for a single microsphere as a function of ultrasonic time; (c) SEM images of PS beads loaded PAA-PETPTA Janus microspheres; (d) Dynamic images of PS beads released from Janus microspheres in pure water. Scale bars represent 200 µm. CONCLUSIONS In the present work, pH stimulus-responsive PAA-PETPTA Janus microspheres were successfully prepared by using a simple capillary-based microfluidic device. The structure and morphology of Janus microspheres can be simply adjusted by adjusting the flow rate ratio of AA and ETPTA phases and the concentration of EM90 in the continuous oil phase. The Janus microspheres showed controllable loading and release behavior for different size guests of RhB and PS nano beads (150 nm) in different pH by the breathing function of PAA hydrogels. The regeneration experiment indicated that the obtained Janus microspheres have high stability. Additionally, a rational hypothesis is that the PETPTA shell can be used as host for magnetic nanoparticles, thereby obtaining the magnetic and pH-responsive Janus microspheres, which can be used for point-controlled-release. The obtained Janus microspheres have great potential application in fields like pharmaceuticals, multi-drug chemotherapies, and catalysis.


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ASSOCIATED CONTENT Supporting Information VS1. Video data acquired for contracting behavior of PAA into PETPTA shell in pH of 2.5 water (avi) VS2. Video data acquired for swelling out behavior of PAA from PETPTA shell in pH of 11 water (avi) VS3. Video data acquired from the controlled-release process for PS Nano beads from PAAPETPTA Janus microspheres (avi) VS4. Video data acquired from the controlled-release process for PS Nano beads from opening PETPTA shell (avi) AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected]. *E-mail: [email protected]; [email protected]. ORCID Liang Yu: 0000-0003-2656-857X Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for the financial support from the National Natural Science Foundation of China (No. 21476114) and Priority Academic Program Development of Jiangsu Higher Education Institutions.


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Fabrication of PAA-PETPTA Janus Microspheres with Respiratory

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