Tetra-Sensitive Graft Copolymer Gels as Active Material of

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Tetra-Sensitive Graft Copolymer Gels as Active Material of Chemomechanical Valves David Graf̈ e,†,‡,§ Philipp Frank,§,∥ Tim Erdmann,†,‡,§ Andreas Richter,§,∥ Dietmar Appelhans,*,† and Brigitte Voit*,†,‡,§ †

Leibniz-Institut für Polymerforschung Dresden e. V., Hohe Strasse 6, 01069 Dresden, Germany Chair of Organic Chemistry of Polymers, §Cluster of Excellence “Center for Advancing Electronics Dresden”, and ∥Chair of Polymeric Microsystems, Technische Universität Dresden, 01062 Dresden, Germany

‡

S Supporting Information *

ABSTRACT: Stimuli-responsive hydrogels combine sensor and actuator properties by converting an environmental stimulus into mechanical work. Those materials are highly interesting for applications as a chemomechanical valve in microsystem technologies. However, studies about key characteristics of hydrogels for this application are comparatively rare, and further research is needed to emphasize their real potential. The first part of this study depicts the synthesis of grafted hydrogels based on a poly(N-isopropylacrylamide) backbone and pH-sensitive poly(acrylic acid) graft chains. The chosen approach of grafted hydrogels provides the preparation of multiresponsive hydrogels, which retain temperature sensitivity besides being pH-responsive. A pronounced salt and solvent response is additionally achieved. Key characteristics for an application as a chemomechanical valve of the graft hydrogels are revealed: (1) independently addressable response to all stimuli, (2) significant volume change, (3) sharp transition, (4) reversible swelling−shrinking behavior, and (5) accelerated response time. To prove the concept of multiresponsive hydrogels for flow control, a net-poly(N-acrylamide)-g-poly(acrylic acid) hydrogel containing 0.6 mol % poly(acrylic acid)-vinyl is employed as active material for chemomechanical valves. Remarkably, the chemomechanical valve can be opened and closed in a fluidic platform with four different stimuli. KEYWORDS: graft copolymer gels, multiresponsive gels, hydrogels, hydrogel-based valve, chemofluidic valve, microfluidics

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INTRODUCTION

Hydrogels are water-insoluble, cross-linked polymers that are able to absorb and retain large amounts of water. Stimuliresponsive hydrogels have been developed that change their volume in response to alterations of environmental stimuli like temperature, pH value, ionic strength, and light.7,12−14 These stimuli-responsive hydrogels are highly interesting for an application as a chemomechanical valve for flow control due to the conversion of an environmental stimulus into mechanical work.8,15 Thus, hydrogels combine sensor and actuator properties in one material. Temperature-responsive poly(Nisopropylacrylamide) (PNIPAAm) hydrogels have been found to be suitable for flow control.6,16−18 Here, the regulation function is achieved by the volume change of net-PNIPAAm hydrogels caused by a macroscopic phase separation due to the coil-to-globule transition at the volume phase transition temperature (VPTT).19,20 In addition, charged polyelectrolyte hydrogels have been utilized to regulate the liquid flow in microfluidic devices.21 For a microfluidic application with technological relevance, the use of a multiresponsive net-PNIPAAm hydrogel is highly

Over the past years, microfluidics has been widely studied for analysis, multiplexing, automation, and high-throughput screening.1−3 Due to the miniaturization, it is in terms of application superior to conventional fluidic systems. Transport pathways of heat and mass are shortened leading to reduced operating time, liquid volume, and reagent consumption. Furthermore, various functional units (e.g., sensor, valve, mixer, and heater) can be integrated into one single microfluidic chip.3,4 For this reason, microfluidic devices have been already entered the commercial market and are sold by companies like Fluidigm, Agilent Technologies, Merck KGaA, and MicroFluidic System.5 However, flow control in microfluidics requires mechanical valves, which need an extra power source accompanied by increased costs and weight. Moreover, with increasing complexity of microfluidic platforms additional power is needed for tailoring time-dependent sequential and parallelized liquid flow processes. A useful alternative to control the liquid flow and to reduce the complexity of microfluidic devices is to utilize hydrogels as chemomechanical valves.6−8 Such valves are already occasionally commercialized, e.g., as remote-controlled switching microvalves for life science applications,9 and have potential as chemostats10,11 for automatic control. © XXXX American Chemical Society

Received: November 22, 2016 Accepted: January 26, 2017

A

DOI: 10.1021/acsami.6b14931 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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ACS Applied Materials & Interfaces

the grafting density on the cooperative diffusion coefficient was investigated. As proof of concept, an optimimized tetrasensitive grafted hydrogel was finally used in a fluidic platform for flow control.

promising. The opening and closing function can be accomplished externally (by temperature) as well as internally (by pH value and solvent). However, PNIPAAm shows a significant decrease in temperature response at a comonomer content above 5−10% due to the interruption of the PNIPAAm segments by the comonomer units.22,23 For this reason, random copolymerization of NIPAAm and a second responsive monomer is not a suitable approach to realize a dual-responsive net-PNIPAAm hydrogel with equally strong response toward two stimuli. Alternative approaches to retaining the temperature sensitivity and, simultaneously, to introducing other responses are already reported, such as the formation of semiinterpenetrating networks (semi-IPNs),24 interpenetrating networks (IPNs),25,26 or graft copolymer gels.22,27−30 However, it is very difficult to fabricate patterned IPN particles with photo lithography, which is a key method for integrating miniaturized components into a microfluidic platforms. In addition, semiIPNs can lead to potential leakage of the penetrated polymer chains. For this reason, a constant and reproducible swelling− deswelling behavior, which is needed in high-throughput processes, is not provided. However, the synthetic approach of graft copolymer gels allows for the preparation of multiresponsive networks with a slightly cross-linked gel structure and a few free dangling chains without the drawbacks of IPNs and semi-IPNs. Furthermore, several studies have been reported for enhanced swelling−deswelling rates of grafted hydrogels compared to copolymer gels, indicating great promise for their use in microfluidics.22,29,30 However, only a few studies of multiresponsive grafted hydrogels are known, and further research is needed to emphasize their real potential for applications in microfluidics.30,31 Key material characteristics to establish multiresponsive hydrogels as a chemomechanical valve would be the following: (1) response independently addressable by the various stimuli, (2) significant volume change for all stimuli, (3) sharp transition, (4) reversible swelling−shrinking behavior, (5) accelerated response time, and (6) sufficient mechanical and long-term stability. Furthermore, the most challenging point of multiresponsive hydrogels is to achieve an equal volume change for at least two different stimuli. Overall, our motivation was to develop a new multiresponsive hydrogel material, which fulfills all of the technical material requirements for future applications in microfluidics as chemofluidic transistors18 or chemical oscillators.17 Thus, in this study, we present the synthesis and characterization of multiresponsive hydrogels as active material of chemomechanical valves for microfluidic applications. Temperature- and pH-sensitive grafted hydrogels based on PNIPAAm backbone networks with grafted poly(acrylic acid) (PAA) dangling chains are prepared following a recently by us established approach32 using free radical polymerization of vinyl-functionalized macromonomers, comonomers, and crosslinker for the synthesis of those materials. Remarkably, a pronounced salt and solvent response has been additionally achieved besides the expected temperature and pH response. The grafting density of the PAA macromonomer in netPNIPAAm-g-PAA hydrogels was varied to achieve an optimized material with adequate, fast and reproducible stimuli response toward the different stimuli for a suitable opening and closing function when applied as a chemomechanical valve. The swelling−shrinking behavior was investigated in several cycles to judge the reversibility of switching processes. To evaluate the response time of net-PNIPAAm-g-PAA hydrogels, the effect of

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EXPERIMENTAL SECTION

Characterization Techniques. 1H and 13C nuclear magnetic resonance (NMR) spectra were recorded using Bruker Avanced III 500 spectrometer operating at 500.13 MHz (1H) and 125.77 MHz (13C), with CDCl3, D2O, or DMSO-d6 as solvent at room temperature (rt). Raman spectra were recorded using a RAMAN Imaging System WITec alpha300R equipped with a 532 nm laser. The spectra were recorded in the middle infrared spectroscopic range of 3300−300 cm−1. and IR spectroscopy was performed using a Vertex 80v (Bruker) with a DTGS detector. Samples were dissolved in EtOH. The spectra were recorded in the middle infrared spectroscopic range 4000−400 cm−1 with 2 cm−1 resolution. A total of 32 scans were co-added to every spectrum. Differential scanning calorimetry (DSC) was performed on a DSC Q2000 (TA-Instruments) under N2 in the range 5−50 °C at a heating rate of 1 °C/min as cycles consisting of first heating−cooling-second heating scans. VPTT of the hydrogels was determined by averaging the maximum of the endothermic transition peak in the DSC plot. GPC analysis was performed using a 1 PL aquagel−OH MIXED-H (8 μm, 300 × 7.5 mm ID) column and RI-D K2301 detector (Knauer). Solvent was 0.01 M NaH2PO4*H2O + 0.5 M NaCl. The flow rate was 1 mL/min, and the standard was PAA Materials. All chemicals were obtained from Sigma-Aldrich Chemical Co (Germany). N-Isopropylacrylamide (NIPAAm) was purified by recrystallization from n-hexane and vacuum-dried. Acrylic acid (AA) was distilled under reduced pressure before use. All other chemicals were used as received. Synthesis of 4-Azidomethylstyrene. We adopted a method by O’Shea et al.33 To a 10 mL one-neck round-bottom flask equipped with a magnetic stirrer were added vinyl benzyl chloride (1.5 g, 9.9 mmol), sodium azide (1.3 g, 20 mmol), and 5 mL DMF. The reaction mixture was stirred at rt for 3 days. The solution was washed with brine and extracted with diethyl ether (3 × 50 mL), and the organic phase was dried over magnesium sulfate. After the solvent was removed under reduced pressure, 4-azidomethylstyrene was obtained as yellow oil with a yield of 1.4 g (89%). 1H NMR (300 MHz, D2O, δ): 4.75 (s, 2H, CH2N3), 5.29 (d, 1H, CCH2), 5.85 (d, 1H, C CH2), 6.73 (quart, 1H, CHC), 7.41 (d, 2H, 2CH), 7.47 (d, 2H, 2CH). Synthesis of DTP-alkyne. To a 50 mL one-neck round-bottom flask equipped with a magnetic stirrer 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid (DTP) (1091 mg, 2.99 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (1564 mg, 3.01 mmol), and 3 mL of DCM were added. The solution was stirred at rt for 2 h. In a separate reaction vessel, propargylamine (166 mg, 3.01 mmol) and N,N′-diisopropylethylamine (DIPEA) (929 mg, 7.19 mmol) was added to 2 mL of DCM. The resulting mixture was added to the one-neck round-bottom flask and stirred at rt for 3 days. After the solvent was removed under reduced pressure, the crude product was then eluted through a silica gel column using n-hexane/ethyl acetate (85:15 v/v). DTP-alkyne was obtained as a yellow solid with a yield of 1011 mg (87%). 1 H NMR (500 MHz, CDCl3, δ): 0.89 (t, J = 6.8 Hz, 3H; CH3), 1.27 (m, 16H; C8H16), 1.39 (m, 2H; CH2), 1.6−1.7 (m, 8H; CH2 and C2H6), 2.21 (t, J = 3.0 Hz, 1H; CH), 3.29 (t, J = 7.4 Hz, 2H; CH2), 4.02 (quart, J = 2.6 Hz, 2H; CH2), 6.6 (br. s., 1H; NH). 13C NMR (126 MHz, CDCl3, δ): 14.07 (CH3), 22.65 (CH2), 25.69 (2CH3), 27.70 (CH2), 28.91 (CH2), 29.07 (CH2), 29.30 (CH2), 29.40 (CH2), 29.51 (CH2), 29.59 (2CH2), 30.12 (CH2), 31.88 (CH2), 37.13 (CH2S), 59.84 (C), 71.66 (CH), 79.22 (CCH), 172.42 (CO), 219.65 (CS). Synthesis of PAA-alkyne. To a 10 mL Schlenk-style, long-neck round-bottom flask equipped with a magnetic stirrer, DTP-alkyne (150 mg, 0.38 mmol), acrylic acid (1.74 g, 24.15 mmol), 4,4′-azobis(4B


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ACS Applied Materials & Interfaces Scheme 1. Preparation, Redox Polymerization, and Synthesis of Compoundsa

a

(A) Preparation of the PAA-vinyl macromonomer with RAFT polymerization and CuAAC. (B) Redox polymerization of NIPAAm in the presence of PAA-alkyne as a control experiment to exclude RAFT polymerization during gel formation. (C) Synthesis of net-PNIPAAm-g-PAA hydrogels by free radical polymerization using redox initiation. μL) in 0.2 mL of water were added. The solution was transferred into a glass tube of 3 mm diameter, sealed under argon, and submerged in a water bath maintained at 10 °C. The reaction was carried out for 24 h. The gel was separated from the glass tube and washed several times with water.

cyanovaleric acid) (ACP) (6.9 mg, 0.025 mmol), and 8.2 mL DMF were added. The solution was then subjected to three freeze−pump− thaw cycles, sealed under argon atmosphere, and submerged in an oil bath maintained at 70 °C for 4 h. The reaction was exposed to oxygen and quenched in liquid nitrogen. After the solvent was removed under reduced pressure, the crude product was dissolved in THF/MeOH (50:50 v/v) and precipitated in toluene to yield PAA-alkyne as a yellow solid; Mn = 4200 g/mol (84%), and Đ = 1.6. 1H NMR (500 MHz, DMSO-d6, δ): 0.85 (t, 3H), 1.2−1.9 (m, 2H), 2.0−2.3 (m, 1H), 3.79 (m, 2H) 4.67 (m, 1H). Synthesis of PAA-vinyl. To a 10 mL one-neck round-bottom flask equipped with a magnetic stirrer were added PAA-alkyne (1 g, 0.24 mmol), 1-(azidomethyl)-4-vinylbenzene (100 mg, 0.63 mmol) and 3 mL DMF. In two separate vessels, CuSO4·5H2O (21 mg, 0.13 mmol) and sodium ascorbate (26 mg, 0.13 mmol) were dissolved in 600 μL of water, respectively, and the resulting mixtures were added to the one-neck round-bottom flask. The reaction mixture was stirred at rt for 3 days. After the solvent was removed under reduced pressure, the crude product was dialyzed (MWCO = 1000 Da) in water for 3 days and freeze-dried to yield PAA-vinyl as a yellow solid. 1H NMR (300 MHz, D2O, δ): 0.89 (t, 3H), 1.2−1.9 (m, 1H), 2.1−2.4 (m, 2H), 3.42 (t, 1H, NH), 4.46 (d, 2H, NCH2), 5.37 (d, 1H, CCH2), 5.62 (s, 2H, N3CH2), 5.91 (d, 1H, CCH2), 6.82 (q,1H, CHC), 7.34 (d, 2H, (CH)2), 7.54 (d, 2H, (CH)2), 7.92 (s, 1H, N3CH). Hydrogel Synthesis. To a 5 mL one-neck round-bottom flask equipped with a magnetic stirrer were added NIPAAm (141.5 mg; 1.25 mmol), N,N′-methylenebis(acrylamide) (BIS) (2.89 mg, 0.0188 mmol), and 0.8 mL of water (pH 10). The PAA-vinyl content was varied as follows: (1) 0 mg (0 mmol), (2) 14.7 mg (0.0034 mmol), (3) 29.4 mg (0.0067 mmol), and (4) 58.8 mg (0.0134 mmol). The resulting solution was subjected to three freeze−pump−thaw cycles, and sodium persulfate (SPS) (2.05 mg, 0.0125 mmol) and DIPEA (1

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RESULTS AND DISCUSSION Synthesis. First, a pH-responsive macromonomer based on acrylic acid (AA) with a vinyl end-group was prepared. It has been shown that copper-catalyzed azide−alkyne cycloaddition (CuAAC) in combination with reversible addition−fragmentation chain transfer (RAFT) polymerization is highly effective to synthesis end-group functionalized polymers.34,35 Scheme 1A shows the synthetic pathway to the PAA-vinyl macromonomer using RAFT and CuAAC. In our previous work,32 the functionalization of DTP with 3-azidopropane-1-amine was achieved by an amidation in high yields using PyBOP and DIPEA as coupling agents. The resulting amide bond is an important prerequisite to enhance the long-term stability of the hydrogels toward harsh conditions. The DTP was converted to DTP-alkyne with propargylamine using PyBOP and DIPEA as coupling agents in nearly quantitative conversion (yield of 87%). The high yield implies that no aminolysis of the trithiocarbonate by the primary amine of propargylamine occurred and outlines the high versatility of this approach.34,36 Raman spectroscopy of the product reveals strong absorbance bands at 1069 and 2124 cm−1 for the CS and CC stretch, respectively (Figure S1). The 1H NMR spectrum with peak assignments for the resulting CTA-alkyne is given in Figure S2. C


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to the vinyl proton at 5.89 ppm is about 1 (Figure S5), indicating quantitative conversion of the terminal alkyne functionalization. The successful conjugation is additionally shown by the absence of CC stretch at 2124 cm−1 in the Raman spectrum (Figure S6). Hydrogel Synthesis and Characterization. Our macromonomer PAA-vinyl contains trithiocarbonate units, which are known to undergo RAFT polymerization in water by redox initiation.39−41 For this reason, a control experiment was carried out to evaluate if RAFT polymerization occurs during network formation. This was done by the redox polymerization of NIPAAm in the presence of PAA-alkyne without cross-linker (Scheme 1B). A pair of outcomes were possible: (1) a mixture of PNIPAAm and PAA-alkyne results indicating only FRP of NIPAAm or (2) a block copolymer of PAA-b-PNIPAAm-alkyne is prepared indicating a RAFT polymerization at which PAAalkyne acts as RAFT agent for NIPAAm. Attempts to analyze the control experiment with SEC failed because of the poor solubility of the product in the eluent (i.e., NaH2PO4·H2O + NaCl). Alternatively, we used two-dimensional diffusion ordered spectroscopy (2D-DOSY) NMR spectroscopy, which separates components in a mixture according to their diffusion coefficient.42 Figure 2 shows the 2D-DOSY NMR spectrum of this experiment. Note that the exact investigation of the diffusion coefficients is not the purpose of this study. The values must be considered as relative ones. Two components with different diffusion coefficient representing PAA-alkyne (log D = −10 m2/s) and PNIPAAm (log D = −10.7 m2/s) are clearly visible; thus, two homopolymers are in the mixture as in assumption (1). Therefore, we postulate that PAA-alkyne does not act as a chain transfer agent in a RAFT polymerization at conditions for the hydrogel synthesis; otherwise, an additional blockcopolymer species would have been detected. Furthermore, we assume a network formation by free radical polymerization (FRP) and exclude a controlled radical polymerization (CRP) mechanism. A series of grafted PNIPAAm gels containing 0.25 to 1 mol % PAA-vinyl were synthesized by FRP in water (pH 10) with 1.5 mol % N,N′-methylenebis(acrylamide) (BIS) as the crosslinker (Table 1). To retain the temperature response of the PNIPAAm main network, a low grafting density of PAA-vinyl was chosen. As a useful reference point for the swelling studies, we also synthesized a net-PNIPAAm hydrogel without graft chains. The hydrogel compositions determined by FTIR

A homopolymer of AA was synthesized with DTP-alkyne as the CTA and ACP as the initiator. The polymerization was conducted at 70 °C in DMF under argon atmosphere in a septa-sealed vial. The [ACP]/[CTA-alkyne]/[AA] molar ratio was at 1:17:1088, with an initial monomer concentration of 2.95 M and a target molecular mass of 5000 g/mol. PAA-alkyne was characterized by size-exclusion chromatography (SEC), Fourier transform infrared (FTIR) spectroscopy, and 1H NMR spectroscopy. The absolute molar mass was calculated to be 4200 g/mol by end-group analysis (yield of 80%). Retention of the terminal alkyne functionalization is confirmed by the presence of the CC stretch at 2124 cm−1 in the Raman spectrum (Figure S4). SEC analysis reveals a moderate dispersity (Đ = 1.6, Figure S3), indicating that the polymerization was controlled. High dispersity (Đ ≈ 2) of PAA prepared through RAFT polymerization has been also reported by Claverie and colleagues.37,38 It has been proposed that radical transfer to the solvent at high conversion and [AA]/ [CTA] ratios takes place. This radical transfer results in a lesscontrolled polymerization of AA. Finally, end-group modification of the PAA-alkyne was accomplished with CuSO 4 in conjunction with sodium ascorbate in a DMF−H2O mixture. The 1H NMR spectrum with peak assignments for the resulting PAA-vinyl is given in Figure 1. The integration ratio of the amide proton at 3.42 ppm

Figure 1. 1H NMR spectrum of PAA-vinyl in D2O. The absence of the COOH signal is due to the addition of small amounts of NaOD.

Figure 2. 2D-DOSY NMR spectrum of the control experiment presented in Scheme 1B. A pair of components with different diffusion coefficient representing PAA-alkyne (log D = −10.3 m2/s) and PNIPAAm (log D = −10.7 m2/s) were detected. D


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Table 1. Feed Composition, Molar Composition, and Grafting Efficiency for net-PNIPAAm-g-PAA Samples with Different Grafting Densities sample name 0.00 0.25 0.50 1.00

mol mol mol mol

% % % %

ratioa

feed composition

PAA-vinyl PAA-vinyl PAA-vinyl PAA-vinyl

grafting

NIPAAm (mmol)

PAA-vinyl (μmol)

BIS (μmol)

SPS (μmol)

NIPAAm

AA

efficiencyb(%)

1.25 1.25 1.25 1.25

0.00 3.13 6.25 12.5

18.6 18.6 18.6 18.6

12.5 12.5 12.5 12.5

100 89 79 67

0 11 21 33

− 91 98 94

a

Ratio determined by FTIR; for detailed information, see the Supporting Information. bDetermined based on the results of the molar compositions. BIS: cross-linker. SPS: sodium persulfate.

spectroscopy by the baseline method are in good agreement with the theoretical values (for further information, see the Supporting Information). This implies quantitative incorporation of PAA-vinyl into the hydrogel network, which is mainly based on a good accessibility of the vinyl end-group of the PAA-vinyl macromonomer during the free FRP. Table 1 summarizes feed compositions, molar composition, and grafting efficiency for net-PNIPAAm-g-PAA samples with different grafting densities. All synthesized hydrogels were intensively washed with water to remove unreacted monomer before conducting response studies. Equilibrium swelling degrees of the graft copolymer gels were studied at various temperatures (20−50 °C), pH values (2−10), ethanol−water mixtures (0−100%), and sodium chloride concentrations (0−1 mol·L−1). A hydrogel disk, 5 mm in diameter, was placed in the solution of interest and equilibrated for 1 day. The sample was removed, blotted with filter paper to remove water on the surface and weighed. The swelling degree Qm for the hydrogels was calculated using the following equation: Qm =

Ws − Wd Wd

Figure 3. Equilibrium swelling degree Qm for net-PNIPAAm-g-PAA samples with different grafting densities at rt as a function of the pH value. (Right) pH-response ratio Qm,pH for net-PNIPAAm-g-PAA samples plotted as a function of the PAA-vinyl content (color code in the right part of the figure corresponds to the composition of the curves in the left part).

net-PNIPAAm-g-PAA hydrogels exhibit an increase in swelling from pH 4 to 8. No considerable differences in the swelling degree are observed below pH 3 and above pH 9 for all grafted hydrogels. This is in good agreement with the literature pKa value from 6.4 of AA homopolymers.44 For grafted netPNIPAAm-g-PAA hydrogels, the pH response is provoked by the carboxylic acid groups of the incorporated PAA-vinyl grafts. These side groups get ionized with increasing pH value, which is associated with large osmotic swelling forces and significant swelling of the hydrogel. Naturally, higher amounts of PAAvinyl lead to higher pH response when ionized. For grafted netPNIPAAm-g-PAA hydrogels, sufficient pH response for an adequate volume change (ratio Qm,pH > 3) is achieved above a grafting density of 0.25 mol % (Figure 3). Temperature Response. Figure 4 displays the equilibrium swelling degree Qm for net-PNIPAAm-g-PAA hydrogels with different grafting densities as a function of temperature and the determined ratio Qm,T. Note that the temperature stimulus was quantified in pH 9 buffer solution between 20 and 50 °C. The ratio Qm,T was calculated using start and end temperature of this experiment. All hydrogels, independent of the grafting density, show a decreasing swelling degree with temperature. This decrease is provoked by the coil-to-globule transition of PNIPAAm, which retains in grafted net-PNIPAAm-g-PAA hydrogels because the PNIPAAm segments are only slightly interrupted by the PAA-vinyl grafts. However, the temperature response of ratio Qm,T drops below the required ratio of 3 at a grafting density of 1 mol % PAA-vinyl. For this reason, we assume that the grafting density must be smaller than 1 mol % to retain adequate temperature response, while an additional pH response is introduced. To further investigate the effect of the PAA-vinyl grafts on the temperature response, the VPTT was determined using the

(1)

where Ws is the weight of the swollen hydrogel, and Wd is the weight of the dried gel. An important property of hydrogels for microfluidic applications is an adequate volume change upon a stimulus. To quantify the stimulus response, the ratio of the swelling degree between the swollen and the collapsed state was determined by ratio Q m,i =

Q swollen Q collapsed

(2)

where Qswollen is the swelling degree in the swollen state, and Qcollapsed is the swelling degree in the collapsed state. Note that swollen and collapsed state is highlighted by gray bars in the diagrams. From our own experience and according to the literature, a stimulus response ratio Qm,i from 3 to 5 (volume change of a disk of about 33 to 40%) provides adequate opening and closing functions.4,6 pH Response. Figure 3 shows the equilibrium swelling degree for net-PNIPAAm-g-PAA hydrogels with different grafting densities as a function of the pH value. The pH response was studied in the range of pH values from 2 to 10 at rt and quantified according to eq 2 using pH 3 and pH 9 as the swollen and collapsed states. As expected, the model hydrogel net-PNIPAAm reveals a constant degree of swelling regardless of the pH value (Qm ≈ 8). The slight pH response of ratio Qm,pH = 1.1 may reflect the different salts of the buffer solutions, which leads to slightly different swelling degrees for netPNIPAAm hydrogels.43 On the contrary, the swelling curves of E


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from 32 to 50 °C and, hence, the highest VPTT (43.0 ± 2.2 °C). To summarize, low grafting density is strongly desired to retain suitable temperature response and to provide a sharp temperature transition associated with a low VPTT. Salt and Solvent Response. We also investigated the swelling behavior of net-PNIPAAm-g-PAA samples with different grafting densities regarding their salt and solvent response. The corresponding equilibrium swelling studies can be found in Figure S11 and S12. For the salt response, we used NaCl as a model system because it is inexpensive and readily available. Overall, a good salt response of all grafted netPNIPAAm-g-PAA hydrogels was found with Qm,NaCl values higher than 3. For the solvent response, we used ethanol−water mixtures because they have been already used in microfluidics.18 Importantly, all hydrogels provided a pronounced ethanol response with ratio Qm,EtOH values higher than 3, suitable for an adequate opening and closing when used as a chemomechanical valve. Reproducible Swelling−Shrinking Behavior. For an application of grafted hydrogels as an active material of chemomechanical valves, constant and reproducible swelling− shrinking cycles are highly demanded to ensure multiplexing, automation, and high-throughput screening. Thus, the swelling behavior of net-PNIPAAm-g-PAA hydrogels was tested by repeating cycles between swollen and collapsed state. Exemplarily, Figure 6 shows the swelling degree of net-

Figure 4. (Left) Equilibrium swelling degree Qm for net-PNIPAAm-gPAA samples with different grafting densities in pH 9 buffer solution plotted as a function of the temperature. (Right) Temperatureresponse ratio Qm,T for net-PNIPAAm-g-PAA samples plotted as a function of the PAA-vinyl content (color code in the right part of the figure corresponds to the composition of the curves in the left part).

cloud point method (Figure 5).45 As expected, the netPNIPAAm hydrogel exhibits a sharp volume phase transition

Figure 5. Normalized absorbance for net-PNIPAAm-g-PAA samples with different grafting densities plotted as a function of temperature. The VPTT was determined via the cloud-point method. Samples were measured in distilled water.

from 33 to 36 °C with a VPTT of 34.9 ± 0.1 °C. Differential scanning calorimetry (DSC) additionally revealed the determined VPTT value by an endothermic peak at 36.4 ± 0.0 °C (Figure S10). In contrast, the temperature transition of netPNIPAAm-g-PAA hydrogels is broadened and less-sharp compared to the pure net-PNIPAAm. The VPTT increases with grafting density of PAA-vinyl. DSC measurements illustrate the effect additionally (Table 2). This result is attributed to the hydrophilic character of PAA and is in accordance with the literature.19,46 It has been shown that hydrophilic comonomers increase the lower critical solution temperature and broaden the temperature transition of PNIPAAm. Thus, net-PNIPAAm-g-PAA containing 1 mol % PAA-vinyl shows the broadest temperature transition in a range

Figure 6. Equilibrium swelling degree for net-PNIPAAm-g-PAA samples with different grafting densities at rt when the swelling agent was switched from pH 9 to pH 3 buffer solutions over repeated cycles.

PNIPAAm-g-PAA hydrogels with different grafting densities when the swelling agent was switched from pH 9 to pH 3 buffer solutions. Note that all four stimuli were evaluated and exhibited a similar reproducible response to the presented pH

Table 2. VPTT, Dcoop, Response Time τ, and Diameter Change after Application of Temperature or pH Stimulus for netPNIPAAm-g-PAA Samples with Different Grafting Densities sample name 0.00 0.25 0.50 1.00

mol mol mol mol

% % % %

PAA-vinyl PAA-vinyl PAA-vinyl PAA-vinyl

VPTTa 36.4 ± 0.0 38.3 ± 0.5 40.7 ± 0.3 −

VPTTb (°C) 34.9 36.4 41.3 43.0

± ± ± ±

0.1 0.2 0.2 2.2

Dcoop (cm2/s) 4.26 1.21 2.21 3.17

± ± ± ±

0.25 0.31 0.53 0.08

× × × ×

−7

10 10−6 10−6 10−6

τc (s)

ΔdpH (%)

ΔdT (%)

± ± ± ±

00.7 19.8 23.6 54.1

52.5 38.3 33.5 18.4

23.8 8.4 4.6 3.2

1.4 2.1 1.1 0.8

a Determined in water by DSC, no peak detection for 1 mol % PAA-vinyl. bDetermined in water by UV/vis. cDetermined with eq 2 using a characteristic length l of 100 μm.

F


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information, see the Supporting Information). With the determined Dcoop values, we additionally predicted the response time τ of a spherical hydrogel valve with the smallest dimension l = 100 μm. This nicely illustrates the effect of PAA graft chains within the hydrogel network on the swelling and shrinking rate. A cooperative diffusion coefficient of 4.35(±0.48)·10−7 cm2/s is observed for the net-PNIPAAm hydrogel (Table 2). This value is in good agreement with the literature value of 3.2 × 10−7 cm2/s.49 The predicted response time of 23.8 ± 2.7 (τ = (0.01 cm)2/(π2*4.35(±0.48)*10−7 cm2/s) is in the same range as the closing time of a valve based on net-poly(sodium acrylate) according to literature.51 Overall, net-PNIPAAm-g-PAA hydrogels exhibit higher cooperative diffusion coefficients compared to the pure net-PNIPAAm hydrogel. The Dcoop values increase with the grafting density of PAA-vinyl (Table 2), which is attributed to the repulsive charges within the grafted hydrogels. This also results in a faster response time of 6.5 ± 1.3 s (0.25 mol % PAA-vinyl), 4.4 ± 0.9 s (0.5 mol % PAA-vinyl), and 2.6 ± 0.1 s (1 mol % PAA-vinyl). Remarkably, a low grafting density of 0.25 mol % PAA-vinyl notably increases the response time by a factor of 3.7 compared to pure net-PNIPAAm hydrogel. Consequently, net-PNIPAAm-g-PAA hydrogels are superior to the net-PNIPAAm hydrogel in terms of the swelling and shrinking rate indicating accelerated opening and closing function of these materials as a chemomechanical valve. Application as a Chemomechanical Valve. To proof the concept of multiresponsive grafted hydrogels as an active material in microfluidics, a simple fluidic platform model with a hydrogel-based chemomechanical valve according to an example from literature was developed.16 Our setup consists of a solvent reservoir, an inlet channel, a hydrogel-based valve, and an outlet channel. Figure 8 depicts the fluidic setup and the

stimulus (for detailed information, see the Supporting Information). Naturally, the net-PNIPAAm hydrogel without PAA-vinyl grafts exhibited no considerable differences in swelling upon multiple pH changes, as known from the literature.47 In contrast, all net-PNIPAAm-g-PAA hydrogels, independent of the molar amount of incorporated PAA-vinyl, show a constant pH response between the swollen (pH 9) and collapsed states (pH 3) over four subsequent cycles. This reproducible swelling−deswelling behavior highlights the great potential of grafted net-PNIPAAm-g-PAA hydrogels synthesized by FRP for an application as a chemomechanical valve. Swelling Rate. The swelling−shrinking rate and the response time are important properties for hydrogels as chemomechanical valve in microfluidics. It is known that the response time τ of a hydrogel correlates with the square of its characteristic dimension l (i.e., smallest dimension; the smallest dimension of spherical particles is the radius r) and the cooperative diffusion coefficient Dcoop:48 τ=

l2 π 2Dcoop

(3)

Note that spherical hydrogel particles have the advantage of uniform swelling and shrinking properties, while other hydrogel geometries swell partially nonuniform especially large hydrogel objects. Because spherical hydrogel particles are used in most valves, we are particularly interested in the swelling kinetics of these particles. According to eq 3, faster opening and closing rates in valves based on hydrogel is achieved by down-scaling and enhanced Dcoop values. Because down-scaling is a technical aspect, we are interested in the cooperative diffusion coefficient. There are two ways to determine this value: (1) scattering experiments (e.g., dynamic light scattering) and (2) evaluation of the time dependence of the swelling degree given by the heuristic model of Tanaka.49 We recently presented a modified Tanaka equation to calculate the cooperative diffusion coefficient Dcoop of cylinder-shaped samples with any aspect ratio.50 Figure 7 presents the determined Dcoop values of netPNIPAAm-g-PAA samples with different grafting densities using the improved Tanaka equation and applying it to the temperature response. All of the swelling kinetics investigations were carried out at least three times in pH 9 buffer solution by studying the swelling from 50 °C to rt (for detailed

Figure 8. (Left) Schematic design of the fluidic platform: (1) solvent reservoir, (2) inlet channel, (3) actuator chamber filled with hydrogel particles, and (4) outlet channel. (Right) Working principle of the actuator chamber filled with crushed hydrogel particles; the swelling degree of the enclosed hydrogel directs whether the valve is opened or closed. A small (1 × 10 mm, height × diameter) and a large actuator chamber (4 × 10 mm) were used.

working principle of the hydrogel-based actuator chamber. The hydrogel-based valve is based on a cylinder-shaped actuator chamber filled with crushed hydrogel particles, which are enclosed between two porous membranes. These membranes allow a liquid flow through the chamber, while the hydrogel particles are permanently localized. Thus, the active resistance of the hydrogel particles regulates the flow rate. To open or close the valve, the swelling degree of the enclosed hydrogel

Figure 7. Corrected cooperative diffusion coefficient Dcoop and response time τ for net-PNIPAAm-g-PAA samples plotted as a function of the PAA-vinyl content. The response time was calculated according to eq 3 with a characteristic dimension l = 100 μm for switching from 50 °C to rt at pH = 9. Error bars represent the standard deviation (n = 3). G


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ACS Applied Materials & Interfaces particles have to change by the solution of the inlet flow. We chose the same solvent compositions to swell or collapse the hydrogel as in the response studies (e.g., pH 9 and pH 3 buffer solutions to apply pH stimulus). For the flow rate studies, we fabricated two actuator chambers with different sizes: a small (1 × 10 mm; all sizes quoted are height × diameter) and a large actuator chamber (4 × 10 mm). A requirement for a working chemomechanical valve based on a multiresponsive hydrogel is an equal volume change of the hydrogel independent of the applied stimulus. We predefined in the equilibrium swelling studies that a grafting density between 0.25 and 1 mol % PAA-vinyl provides adequate size change toward all stimuli. To identify the PAA-vinyl content for an equal temperature and pH response, the size change of netPNIPAAm-g-PAA hydrogels was investigated. A total of three optical microscope images of net-PNIPAAm-g-PAA containing 0.25 mol % PAA-vinyl are shown in Figure 9A, whereby the

between the size change and the grafting density is observed. However, whereas the size change by pH stimulus increases from 2% to 54% with increasing grafting density, a decreasing size change by the temperature stimulus from 53% to 19% is observed. The optimal PAA-vinyl content was determined by the intercrossing point of the two slopes. It was found that a PAA-vinyl content of 0.6 mol % results in an equally strong response to pH and temperature. Before the conducting of experiments with the hydrogelbased chemomechanical valve, a control experiment with an empty actuator chamber was carried out to evaluate the flow rate of the different solvents. Surprisingly, all investigated solvents exhibit a different flow rate. The pH 9 buffer solution at 50 °C has the highest flow rate (V50 °C = 0.6 mL/s), while the 40 vol % ethanol solution has the lowest (VEtOH = 0.18 mL/s). This can be contributed to the membrane material of the actuator chamber. This material mainly consists of silicon dioxide (∼80%), known for its interactions with polar and nonpolar solvents.52 To correct the flow rates, we introduced a correction factor ci: V̇ c i = on Vi̇ (5) where Von is the flow rate in the open state (pH 9; hydrogel swollen) and Vi is the uncorrected flow rate. The determined correction factors for each solvent are shown above their bars in Figure 10 (e.g., c50 °C = 0.4 mL·s−1/0.59 mL·s−1 = 0.68). The

Figure 9. (A) Optical microscope images of net-PNIPAAm-g-PAA containing 0.25 mol % PAA-vinyl in the swollen state (rt and pH 9, d = 4.5 mm) and in the collapsed state after applying the pH (rt and pH 3, d = 3.6 mm) or temperature stimulus (50 °C and pH 9, d = 2.8 mm). (B) Size change Δd after applying pH or temperature stimulus as a function of PAA-vinyl content.

Figure 10. Flow rates of different solvents in the fluidic platform with an empty actuator chamber. The correction factors ci are shown above the bar (pH 9 = pH 9 buffer solution at rt, 50 °C = pH 9 buffer solution at 50 °C, pH 3 = pH 3 buffer solution at rt, NaCl = 1 mol/L NaCl solution, EtOH = 40 vol % ethanol solution).

initial hydrogel of this experiment is in the middle (rt and pH 9), and the resulting hydrogels after conducting one of the stimuli are to the left (pH stimulus, rt, and pH 3) and right (temperature stimulus, 50 °C, and pH 9). To ensure an equilibrium swelling degree, all samples were conditioned 24 h at the condition of interest. The size change Δd was calculated using the following equation: ⎛ d ⎞ Δd i = ⎜1 − i ⎟ × 100 d0 ⎠ ⎝

corrected flow rate Vc,i was determined using the following equation (e.g., Vc,50 °C = 0.59 mL·s−1·0.68 = 0.4 mL·s−1): Vc,i̇ = Vi̇ ·c i (6) Note that in the Supporting Information, a diagram is shown with uncorrected and corrected flow rates (Figure S19). For the following flow rate studies, a grafted net-PNIPAAmg-PAA hydrogel containing 0.6 mol % PAA-vinyl was prepared as described above. As a useful reference material, we also prepared a copolymer hydrogel composed of NIPAAm and AA with a similar [NIPAAm]-to-[AA] ratio as our grafted hydrogel. Equilibrium swelling studies of net-P(NIPAAm-co-AA) can be found in the Figure S17 and S18. As expected, net-P(NIPAAmco-AA) shows pronounced pH-response (ratio Qm,pH = 50.1) without retaining the temperature-response of PNIPAAm (ratio Qm,T = 1.1). Table 3 summarizes feed composition, [NIPAAm]-

(4)

where d0 is the initial size and di is the size after applying the stimulus. Exemplarily, for the net-PNIPAAm-g-PAA hydrogel containing 0.25 mol % PAA-vinyl (Figure 9A), we calculated a size change of 19.8% caused by the pH stimulus (d0 = 4.5 mm, dpH = 3.6 mm) and 38.3% by the temperature stimulus (d0 = 4.5 mm, dT = 2.8 mm). We plotted the size change of both stimuli against the molar amount of PAA-vinyl, presented in Figure 9B. In this experiment, an almost linear relationship H


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Table 3. Feed Composition, [NIPAAm]-to-[AA] Ratio, and Comonomer Content for net-PNIPAAm-g-PAA and netP(NIPAAm-co-AA) feed composition

ratio

sample name

NIPAAm (mmol)

PAA-vinyl (μmol)

AA

BIS (μmol)

SPS (μmol)

NIPAAm

AA

comonomer content (μmol %)

net-PNIPAAm-g-PAA net-P(NIPAAm-co-AA)

1.25 1.25

7.5 −

− 2.85

18.6 18.6

12.5 12.5

76 81

24 19

00.6 22.8

to-[AA] ratio, and comonomer content for net-PNIPAAm-gPAA and net-P(NIPAAm-co-AA). Large Actuator Chamber. We equipped our fluidic setup first with a large actuator chamber (size 4 × 10 mm) filled with crushed particles of net-PNIPAAm-g-PAA containing 0.6 mol % PAA-vinyl and investigated the effect of different solvents on the flow rate. Note that crushed particles have the advantage of a minimized response time due to the smaller particle sizes associated with an accelerated opening and closing function of the chemomechanical valve. Figure 11 shows the flow rate

when the temperature of the provided pH 9 buffer was varied between rt and 50 °C. No fluid flow is detected when the temperature of the pH 9 buffer solution was at rt. At these conditions, the hydrogel particles are swollen and shut off the connection between inlet and outlet. In contrast, the valve opens immediately when the solution was changed to a pH 9 buffer solution at 50 °C. Interestingly, it was found that the corrected flow rate increases between first and third cycle followed by a constant flow rate at 0.27 mL/s. As known from the literature, hydrogel valves show poor reproducibility during the first operation known as conditioning effect.16 It is important to note that the large actuator chamber slowly opened (>10 min) when other stimuli (solvent, salt, or pH) were employed. This may be caused by the difference in the transfer coefficient, which is 2 orders of magnitude smaller for mass than for heat transfer.16 Small Actuator Chamber. It was expected that a smaller actuator chamber accelerates the opening rate when the solvent, salt, or pH stimuli are employed. Thus, we equipped our fluidic platform with a small actuator chamber (size 1 × 10 mm). Moreover, to outline the advantageous properties of the grafted net-PNIPAAm-g-PAA hydrogel, we also performed flow rates studies with net-P(NIPAAm-co-AA) of identical NIPAAm−AA composition. As shown in Figure 12, the flow rate was investigated when the inlet solution was varied between pH 3 and pH 9 buffer solution. When the inlet was supplied with a pH 9 buffer solution at rt, the flow rate is reduced at 0.1 mL/s for netPNIPAAm-g-PAA and 0.2 mL/s for net-P(NIPAAm-co-AA). Compared to the large actuator chamber, the small actuator chamber just throttles the flow rate without clogging the channel. On the contrary, when the inlet solution was changed to pH 3 buffer solution, the flow rates immediately increase

Figure 11. Corrected flow rate plotted as a function of the outflow when the temperature of the provided pH 9 buffer solutions was alternated between rt and 50 °C. The fluidic platform was equipped with the large actuator chamber (size 4 × 10 mm, diameter × height). The flow rate was corrected according to eq 6.

Figure 12. Fluidic platform was equipped with a small actuator chamber (size 1 × 10 mm). The actuator chamber was filled with net-PNIPAAm-gPAA (grafted hydrogel) or net-P(NIPAAm-co-AA) (copolymer hydrogel). (Left) Corrected flow rate plotted as a function of the outflow when the inlet solution was switched from pH 3 to pH 9 buffer solution at rt. (Right) Corrected flow rate plotted as a function of the outflow when the temperature of the provided pH 9 buffer solutions was switched between rt and 50 °C. I


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alternating flow rate when the solution was varied between pH 9 buffer solution at rt and a solution at which the hydrogel collapses (pH 9 buffer solution at 50 °C, pH 3 buffer solution, and 1 mol/L NaCl solution). As it could be expected from the previous results, when the hydrogel is swollen at pH 9, the flow rate is reduced to about 0.2 mL/s. It is noteworthy that the slight difference of the flow rate compared to the pH-response experiment presented is attributed to the use of different actuator chambers. When the inlet solution was changed to one of the solutions at which the hydrogel collapses, the flow rate instantly increases about two times. In all cases, the change of flow rate was almost equal and reveals that a PAA-vinyl content of 0.6 mol % leads to an equal temperature, salt, and pH response. Furthermore, the opening and closing of the chemomechanical valve is reproducible over six consecutive cycles even when three different stimuli are applied. This result impressively outlines the high control of the flow rate using a net-PNIPAAm-g-PAA hydrogel containing 0.6 mol % PAAvinyl.

independent of the utilized hydrogel. In addition, it can be seen that the flow rate increases to higher values for net-P(NIPAAmco-AA) than for net-PNIPAAm-g-PAA. This is contributed as well a much more pronounced pH response of net-P(NIPAAmco-AA) compared to net-PNIPAAm-g-PAA. Figure 12 shows also the flow rate studies when the temperature of the pH 9 buffer solution was changed between rt and 50 °C. As expected, the flow rate is more-or-less independent of the temperature of the pH 9 buffer solution for net-P(NIPAAm-co-AA) because of the nonexisting temperature-response. Interestingly, the flow rate is slightly higher when the temperature of the buffer solution was at rt. This is contributed to the different flow rates of the used solvents as shown in Figure 10. In contrast, the flow rate studies with netPNIPAAm-g-PAA showed a reproducible opening and closing of the chemomechanical valve. When the inlet was supplied with a pH 9 buffer solution at rt, the flow rate is throttled at ∼0.2 mL/s, while the flow rate immediately increases by a factor of 2.5 when the inlet was provided with a buffer solution at 50 °C. This behavior is reproducible over five cycles. However, the flow rate slightly shifts to higher values with increasing numbers of cycles. This shift may be caused by conditioning effect as mentioned before. It should be noted that all suitable stimuli of net-PNIPAAm-g-PAA were evaluated and exhibited a similar behavior to the presented stimuli (for further information, see the Supporting Information). Solely for the ethanol response (see the Supporting Information), the flow rate studies showed an irreproducible opening and closing function. We assume that this is provoked by the reaction of the pH 9 buffer solution and ethanol, which results in small air bubbles in the flow channel. However, additional studies are needed for full understanding. To further highlight the great abilities of the grafted netPNIPAAm-g-PAA hydrogel, we conducted a more-challenging experiment, in which we consecutively changed the inlet solution using three different stimuli (e.g., temperature, pH, and salt). Because the hydrogels revealed an irreproducible ethanol response in the single stimulus studies, this stimulus was excluded for the experiment. Figure 13 shows the

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CONCLUSIONS We studied multiresponsive hydrogels as a chemomechanical valve for microsystem technology. First, a series of grafted netPNIPAAm-g-PAA hydrogels composed of a PNIPAAm backbone and PAA grafts were prepared. The chosen approach of grafted hydrogels allowed the preparation of multiresponsive hydrogels, which retain temperature sensitivity besides being pH responsive. Remarkably, ethanol and salt response is additionally achieved. As an important aspect for microfluidics, the stimuli response was quantified using the response ratio Qm,i. Equilibrium swelling studies indicated that a grafting density of PAA-vinyl between 0.25 and 1 mol % is needed to provide adequate stimuli response for all four stimuli. In addition, to ensure function and reproducibility as chemomechanical valve, the swelling and shrinking process was investigated, and it was found to be reproducible over five consecutive cycles for all stimuli. Swelling kinetics studies of the temperature response showed that grafted net-PNIPAAm-g-PAA hydrogels exhibit higher cooperative diffusion coefficients and, therefore, faster response times compared to a pure net-PNIPAAm hydrogel. After the key parameters for an application as chemomechanical valve were successfully illustrated, the concept was proven by using net-PNIPAAm-g-PAA hydrogel containing 0.6 mol % PAA-vinyl as chemomechanical valve within a simple fluidic platform model. Impressively, a reproducible opening and closing function of the actuator chamber filled with hydrogel particles was obtained using pH, temperature, and salt response. To highlight the promising abilities of grafted net-PNIPAAmg-PAA hydrogels, a final experiment was conducted in which we consecutively opened and closed the valve with three different stimuli in one experiment (e.g., temperature, pH, and salt). These results show us the great potential of the designed multisensitive net-PNIPAAm-g-PAA hydrogels as active material of chemomechanical valves due to their specific ability to respond independently and repeatedly to different environmental alterations with a pronounced and accelerated response. Overall, this material concept provides new possibilities for chemostats7,8 as well as chemofluidic transistors.18 Chemical transistors can give access to new functions such as chemical oscillators17 by the bidirectional coupling of the chemical and the fluidic domains through hydrogel-based components.

Figure 13. Corrected flow rate plotted as a function of the outflow when the solution was switched consecutively from pH 9 buffer solution at rt and to one at which the hydrogel collapses (pH 9 buffer solution at 50 °C, pH 3 buffer solution, and 1 mol/L NaCl solution). The fluidic platform was equipped with the small actuator chamber (size: 1 × 10 mm). The flow rate was corrected according to eq 6. J


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(5) Clayton, J. Go with the Microflow. Nat. Methods 2005, 2, 621− 627. (6) Richter, A.; Kuckling, D.; Howitz, S.; Gehring, T.; Arndt, K. F. Electronically Controllable Microvalves Based on Smart Hydrogels: Magnitudes and Potential Applications. J. Microelectromech. Syst. 2003, 12 (5), 748−753. (7) Doring, A.; Birnbaum, W.; Kuckling, D. Responsive Hydrogels Structurally and Dimensionally Optimized Smart Frameworks for Applications in Catalysis, Micro-System Technology and Material Science. Chem. Soc. Rev. 2013, 42 (17), 7391−7420. (8) Eddington, D. T.; Beebe, D. J. Flow Control with Hydrogels. Adv. Drug Delivery Rev. 2004, 56 (2), 199−210. (9) Richter, A. In Hydrogel-Based μTAS. In MEMS/NEMS: Handbook Techniques and Applications; Leondes, C. T., Eds.; Springer: Boston, MA, 2006; pp 473−503. (10) Richter, A.; Türke, A.; Pich, A. Controlled Double-Sensitivity of Microgels Applied to Electronically Adjustable Chemostats. Adv. Mater. 2007, 19 (8), 1109−1112. (11) Richter, A.; Wenzel, J.; Kretschmer, K. Mechanically Adjustable Chemostats Based on Stimuli-Responsive Polymers. Sens. Actuators, B 2007, 125 (2), 569−573. (12) Klouda, L.; Mikos, A. G. Thermoresponsive Hydrogels in Biomedical Applications. Eur. J. Pharm. Biopharm. 2008, 68 (1), 34− 45. (13) Qiu, Y.; Park, K. Environment-Sensitive Hydrogels for Drug Delivery. Adv. Drug Delivery Rev. 2012, 64 (0), 49−60. (14) Zhao, Y.-L.; Stoddart, J. F. Azobenzene-Based Light-Responsive Hydrogel System. Langmuir 2009, 25 (15), 8442−8446. (15) Arndt, K.-F.; Kuckling, D.; Richter, A. Application of Sensitive Hydrogels in Flow Control. Polym. Adv. Technol. 2000, 11 (8−12), 496−505. (16) Richter, A.; Howitz, S.; Kuckling, D.; Arndt, K.-F. Influence of Volume Phase Transition Phenomena on the Behavior of HydrogelBased Valves. Sens. Actuators, B 2004, 99 (2−3), 451−458. (17) Paschew, G.; Schreiter, J.; Voigt, A.; Pini, C.; Chávez, J. P.; Allerdißen, M.; Marschner, U.; Siegmund, S.; Schüffny, R.; Jülicher, F.; Richter, A. Autonomous Chemical Oscillator Circuit Based on Bidirectional Chemical-Microfluidic Coupling. Adv. Mater. Technol. 2016, 1, 1600005. (18) Frank, P.; Schreiter, J.; Haefner, S.; Paschew, G.; Voigt, A.; Richter, A. Integrated Microfluidic Membrane Transistor Utilizing Chemical Information for On-Chip Flow Control. PLoS One 2016, 11 (8), e0161024. (19) Feil, H.; Bae, Y. H.; Feijen, J.; Kim, S. W. Effect of Comonomer Hydrophilicity and Ionization on the Lower Critical Solution Temperature of N-Isopropylacrylamide Copolymers. Macromolecules 1993, 26 (10), 2496−2500. (20) Schild, H. G. Poly(N-isopropylacrylamide): Experiment, Theory and Application. Prog. Polym. Sci. 1992, 17 (2), 163−249. (21) Beebe, D. J.; Moore, J. S.; Bauer, J. M.; Yu, Q.; Liu, R. H.; Devadoss, C.; Jo, B.-H. Functional Hydrogel Structures for Autonomous Flow Control Inside Microfluidic Channels. Nature 2000, 404 (6778), 588−590. (22) Kaneko, Y.; Nakamura, S.; Sakai, K.; Aoyagi, T.; Kikuchi, A.; Sakurai, Y.; Okano, T. Rapid Deswelling Response of Poly(Nisopropylacrylamide) Hydrogels by the Formation of Water Release Channels Using Poly(ethylene oxide) Graft Chains. Macromolecules 1998, 31 (18), 6099−6105. (23) Yoo, M. K.; Sung, Y. K.; Lee, Y. M.; Cho, C. S. Effect of Polyelectrolyte on the Lower Critical Solution Temperature of Poly(N-isopropyl acrylamide) in the Poly(NIPAAm-co-acrylic acid) Hydrogel. Polymer 2000, 41 (15), 5713−5719. (24) Prabaharan, M.; Mano, J. F. Stimuli-Responsive Hydrogels Based on Polysaccharides Incorporated with Thermo-Responsive Polymers as Novel Biomaterials. Macromol. Biosci. 2006, 6 (12), 991−1008. (25) Chen, H.; Hsieh, Y.-L. Dual Temperature- and PH-Sensitive Hydrogels from Interpenetrating Networks and Copolymerization of

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.6b14931. Additional experimental data and spectra, swelling ratios, dynamic scanning calorimetry analysis, swelling−deswelling experiments, swelling kinetic study results; microscope images, flow-rate studies, and equilibrium swelling degree studies. (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Dietmar Appelhans: 0000-0003-4611-8963 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partly supported by the German Research Foundation (DFG) within the Cluster of Excellence “Center for Advancing Electronics Dresden” and was also done within the Research Training Group GRK 1865/1 “Hydrogel-Based Microsystems”. We also thank J. Muche for Raman measurements, Dr. H. Komber for the 2D-DOSY NMR measurements, and L. Häussler for DSC measurements.

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ABBREVIATIONS PNIPAAm, poly(N-isopropylacrylamide) VPTT, volume phase transition temperature semi-IPNs, semi-interpenetrating networks IPNs, interpenetrating networks PAA, poly(acrylic acid) DTP, 2-(dodecylthiocarbonothioylthio)-2-methylpropionic acid PyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate DIPEA, N,N′-diisopropylethylamine ACP, 4,4′-azobis(4-cyanovaleric acid) BIS, N,N′-methylenebis(acrylamide) SPS, sodium persulfate SEC, size-exclusion chromatography DSC, differential scanning calorimetry RAFT, reversible addition−fragmentation chain transfer CRP, controlled-radical polymerization FRP, free-radical polymerization rt, room temperature

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