Enhanced Optical Sensitivity in Thermoresponsive Photonic Crystal

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Enhanced Optical Sensitivity in Thermo-Responsive Photonic Crystal Hydrogels by Operating Near the Phase Transition Sukwon Jung, Kelsey I MacConaghy, Joel L Kaar, and Mark P Stoykovich ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b07179 • Publication Date (Web): 31 Jul 2017 Downloaded from http://pubs.acs.org on August 1, 2017

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ACS Applied Materials & Interfaces

Enhanced Optical Sensitivity in ThermoResponsive Photonic Crystal Hydrogels by Operating Near the Phase Transition Sukwon Jung†, Kelsey I. MacConaghy†, Joel L. Kaar*† and Mark P. Stoykovich*‡

†

Department of Chemical and Biological Engineering, University of Colorado, Boulder,

Colorado 80303, United States ‡

Institute for Molecular Engineering, University of Chicago, Chicago, Illinois 60637, United

States * To whom correspondence should be addressed: [email protected], [email protected]

KEWORDS: thermo-responsive polymers, photonic crystal, crystalline colloidal array, poly(Nisopropylacrylamide), hydrogels, optical sensors

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ABSTRACT Photonic crystal hydrogels composed of analyte responsive hydrogels and crystalline colloidal arrays have immense potential as reagentless chemical and biological sensors. In this work, we investigated a general mechanism to rationally tune the sensitivity of photonic crystal hydrogels consisting of stimuli-responsive polymers to small molecule analytes. This mechanism was based on modulating the demixing temperature of such hydrogels relative to the characterization temperature to, in effect, maximize the extent of phase separation behavior and thus the volume change in response to the target analytes. Using ethanol as a model analyte, we demonstrated that this mechanism led to a dramatic increase in the sensitivity of optically-diffracting poly(Nisopropylacrylamide) (pNIPAM) hydrogel films that exhibit a lower critical solution temperature (LCST) behavior. The demixing temperature of the pNIPAM films was modulated by copolymerization of the films with relatively hydrophobic and hydrophilic co-monomers, as well as by varying the ionic strength of the characterization solution. Our results showed that copolymerization of the films with 2.5 mol% of N-tert-butylacrylamide, which is hydrophobic relative to pNIPAM, enabled the detection limit of the pNIPAM films to ethanol to be lowered ∼2-fold at 30 °C. Additionally, increasing the ionic strength of the characterization solution above 200 mM resulted in a dramatic increase in the extent of contraction of the films in the presence of ethanol. Ultimately it is demonstrated that as little as 16 g/L or 2 vol% of ethanol in water can reliably be detected, and that the sensitivity of the films to ethanol was predictably greatest when operating near the phase transition, such that even small additions of the analyte induced the start of demixing and the hydrogel collapsed. Such a mechanism may be extended to photonic crystal hydrogel sensors prepared from other stimuli-responsive polymers and more broadly exploited to enhance the utility of these sensors for a broad range of analytes. 2 ACS Paragon Plus Environment

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INTRODUCTION Analyte responsive hydrogels in which photonic crystals are embedded (i.e., photonic crystal hydrogels) have gained attention as a simple yet powerful platform for chemical and biological sensing.1-4 As sensors, these materials are highly sensitive to changes in the dimensions of the embedded photonic crystal over nanometer length scales in response to an analyte. The analyte may induce swelling or contraction of the hydrogel, thereby altering the diffraction of light and, when tuned to visible wavelengths, eliciting a change in the structural color of the hydrogel. To date, photonic crystal hydrogels have been used to detect a myriad of analytes, ranging from small molecules and organic solvents to nucleic acids and enzymes.5-11 While much of the emphasis in this area has focused on broadening the spectrum of analytes that can be detected and the specificity of their detection (e.g., using ligands, aptamers, chelating agents, or peptide substrates),8, 12-15 less research has been dedicated to improving the sensitivity of such sensors. Accordingly, the development of approaches to improve the sensitivity of photonic crystal hydrogels would greatly enable the practical utility of such materials for the optical detection of chemical and biological analytes at low concentrations. We have recently demonstrated that the sensitivity of photonic crystals may be significantly improved by rationally tuning the properties of the hydrogel network.13 Specifically, we showed that altering the elastic modulus and the Flory-Huggins interaction parameter () between the polyacrylamide hydrogel and solvent could be used to optimize the swelling response of the hydrogel. The impact of varying and elastic modulus was investigated while developing a photonic crystal hydrogel for the detection of kinase-mediated peptide phosphorylation. In this example, a hydrogel containing a photonic crystal was modified with a peptide substrate for protein kinase A, which induced swelling of the hydrogel by 3 ACS Paragon Plus Environment


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phosphorylating the peptide. The swelling response arose from the modification of the charge of the immobilized peptide and thus the hydrogel upon phosphorylation, which altered the Donnan potential between the hydrogel and solution. By reducing and the elastic modulus, the sensitivity to phosphorylation was increased by ~40-fold, which was consistent with predictions from a theoretical model of the swelling response. In an analogous example, we showed that epigenetic changes in DNA could be readily detected using photonic crystal hydrogels by similarly modulating .8 Methylation of cytosine in a short oligo that corresponded to a sequence from the gene for p53 was detected via immobilizing a complementary sequence in the photonic crystal hydrogel. Although the analyte sequence contained six methylated cytosines, by modulating , as few as two methylation sites would, in theory, be detectable. These prior findings8, 13 provide the framework to rationally engineer photonic crystal hydrogels with enhanced sensitivity, especially for the detection of analytes via non-specific interactions.16-18 Whereas hydrogel swelling in response to specific electrostatic interactions or changes in the hydrogel crosslinking density often dominates the weaker solvent-hydrogel interactions, the ability to design photonic crystal hydrogels to detect these types of non-specific interactions with high sensitivity provides opportunities for the detection of virtually any analyte and operation in high-ionic strength environments (e.g., in media which screens electrostatic interactions). The detection sensitivity (i.e., shift in diffraction wavelength per unit analyte) in systems with non-specific interactions is dominated by the hydrogel-solution interactions and thus ∆/∆ upon exposure to the analyte (e.g., organic solvents in water) where ∆ and ∆ are the changes in the hydrogel volume and Flory-Huggins interaction parameter, respectively. Based on this realization, we hypothesized that the impact of hydrogel properties on the swelling response could be enhanced by using polymers that exhibit stimuli-responsive phase transitions. 4 ACS Paragon Plus Environment

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Phase transitions from a swollen to collapsed hydrogel state yield large (~7-27 fold) volume changes19-23 over a narrow window of as illustrated in Figure 1. Many thermoresponsive polymers in solution are known to undergo phase separation or demixing into polymer-rich and solvent-rich phases, and such behavior may be described by a Gibbs free energy of mixing expression (∆ = ∆ − ∆ ) modeled by Flory-Huggins theory. The entropic term always favors mixing and a swollen hydrogel, and therefore phase separation is driven by the enthalpic term that captures the favorability, strength, and number of polymersolvent interactions. The Flory-Huggins interaction parameter provides a convenient approach to describe these interactions in polymer solutions and may successfully explain exothermic mixing ( < 0) that arises when strong, specific polymer-solvent interactions are present, as well as endothermic mixing ( > 0) when the polymer-solvent interactions are unfavorable. For a given polymer hydrogel, is a function of system temperature, the solvent, and the concentration of the polymer in solution such that = ( , solvent, ). Modulating and the solvent can therefore shift the polymer-solvent and be used to induce phase separation in polymer hydrogels when exceeds a threshold , as illustrated in Figure 1. A well-known thermoresponsive polymer that exhibits a lower critical solution temperature (LCST) phase behavior in water is poly(N-isopropylacrylamide) (pNIPAM),24, 25 which undergoes demixing in response to increases in temperature that raise (Ref. 24 provides an excellent review of the thermodynamics of pNIPAM solution). Alternatively, by using a pNIPAM hydrogel and maintaining the characterization temperature such that is near , the extent of swelling or contraction in response to changes in in the presence of an analyte that changes the solvent quality would be dramatically larger relative to prior photonic crystal hydrogel sensors that have operated far from such transitions. Although photonic crystal sensors based on pNIPAM 5 ACS Paragon Plus Environment


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hydrogels have been developed previously,26-31 the connection between the swelling transition of such hydrogels and the sensitivity in the context of the detection limit to small molecule analytes has yet to be demonstrated.

Figure 1. Schematic plot illustrating the phase transition behavior of stimuli-responsive hydrogels. The sensitivity of photonic crystal hydrogels prepared with pNIPAM is greatest near at which phase separation of the polymer and solvent occurs. To understand how stimuli-responsive materials may exhibit enhanced and tunable sensitivity near a phase transition, pNIPAM hydrogels containing colloidal photonic crystals were prepared and exhaustively characterized. Specifically, pNIPAM-based optically-diffracting hydrogels were prepared as thin films via photopolymerization of the monomer with a crystalline colloidal array (CCA) that consisted of negatively-charged polystyrene (PS) nanoparticles. The films were prepared in wells of 96-well microtiter plates, which permitted optical characterization using a UV/vis spectrophotometric plate reader. For optical characterization, the transmission of light in the visible spectrum was recorded in the presence of ethanol, which was used as a model analyte, while controlling the characterization temperature ( ) relative the temperature at which phase separation occurred ( ). The addition of hydrophobic and


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hydrophilic co-monomers to the pNIPAM films, as well as varying the ionic strength of the solution, provided a means to modulate of the hydrogel and, in turn, enhance the optical response of the photonic crystal hydrogel sensor. The results from this work ultimately establish a novel approach to engineer photonic crystal hydrogels at the nanoscale and molecular-levels to achieve unprecedented control over sensitivity.

EXPERIMENTAL SECTION Materials N-isopropylacrylamide butylacrylamide

(tBA),

(NIPAM),

N-hydroxyethyl

N,N’-methylenebis(acrylamide) acrylamide

(HEAA)

and

(BA),

N-tert-

2-hydroxy-4’-(2-

hydroxyethoxy)-2-methylpropiophenone (Irgacure 2959) for synthesis of hydrogels, and 3(trimethoxysilyl)propyl methacrylate for functionalization of 96-well microplates with UVtransparent bottoms (Corning Inc., Corning, NY) were obtained from Sigma-Aldrich (St. Louis, MO). The NIPAM was purified prior to use via precipitation following dissolution. Other chemicals were used as received. Styrene, divinyl benzene (DVB), sodium 1-allyloxy-2hydroxypropane sulfonate (COPS-1), surfactant Aerosol MA-80-1, and ammonium persulfate for synthesis of charged polystyrene (PS) nanoparticles were also obtained from Sigma-Aldrich. Additionally, ion-exchange mixed bed resin (AG 501-X8) used for the storage of crystalline colloidal arrays (CCAs) consisting of charged PS nanoparticles (~110 nm diameter and a polydispersity of 3.4%, synthesized via emulsion polymerization as described previously9) was obtained from Bio-Rad (Hercules, CA).

Synthesis of photonic crystal-containing hydrogels in 96-well microplates 7 ACS Paragon Plus Environment


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Hydrogel thin films containing the CCA-based photonic crystal were prepared in 96well microplates via photopolymerization of pre-gel solutions containing monomers and the CCA. Specifically, bottoms of the wells of the microplate were first treated with UV/ozone (Novascan UV Ozone Cleaner, Ames, IA) for 15 min and incubated with 3% (v/v) 3(trimethoxysilyl)propyl methacrylate in cyclohexane for 2 h to introduce surface vinyl groups. After treatment, the wells were washed with ethanol and incubated at 40 °C for 1 h to dry the plate. Following drying, 4 µL of pre-gel solution containing 1000 mM NIPAM (or 975 mM NIPAM and 25 mM HEAA or tBA), 10 mM BA, 0.05% (w/v) Irgacure 2959, 7% (w/v) PS nanoparticles, and 15% (v/v) DMSO was added to the wells. Note that the pre-gel solutions were treated with the ion-exchange resin to ensure CCA formation, and utilized upon separation from the resin via centrifugation. Next, acrylic molds were then held in place on the top of the pre-gel solution drops, and the plate bottoms were illuminated with 312 nm UV light for 90 min at 4 °C using an 8 W hand-held UV lamp (Spectronics Corp., Westbury, NY) to polymerize and crosslink the pre-gel solution. The resulting hydrogel thin films of polymerized NIPAM (pNIPAM) containing the CCA photonic crystal were fixed on the bottom of the wells, and were washed and stored with ultrapure deionized water at room temperature.

Differential scanning calorimetry analysis of pNIPAM hydrogel films We conducted differential scanning calorimetry analysis of cross-linked pNIPAM films with or without co-monomers (i.e., HEAA and tBA) using a differential scanning calorimeter (TA DSC Q2000, Dallas, TX). For these measurements, we prepared bulk pNIPAM hydrogel films (i.e., thick free-standing films) without the CCA using pre-gel solutions composed of varying co-monomer compositions (i.e., 0-10 mol% of HEAA or tBA in 1 M of total monomers). 8 ACS Paragon Plus Environment

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The as-prepared bulk hydrogel films were equilibrated in ultrapure deionized water at 15 °C for 10 minutes after which the films were analyzed with differential scanning calorimetry by increasing the temperature from 15 to 60 °C at a rate of 3 °C/min.

Characterization of optical diffraction of CCA-containing hydrogel films The diffraction wavelength of the CCA-containing hydrogel films in 96-well microplates was measured with an Infinite 200 PRO microspectrophotometer (Tecan Systems Inc., San Jose, CA). Specifically, samples were added to wells containing the hydrogel films after which the microplate was equilibrated for 30 min at a constant temperature (24-36 °C). Attenuance ( = −log!" , where represents transmittance)32 of each well was then recorded using the microspectrophotometer while scanning the near UV to near IR range (350-850 nm) with a step size 2 nm, and the diffraction wavelength was determined by measuring the wavelength corresponding to the position of the peak attenuance in the spectrum.

RESULTS AND DISCUSSION Preparation of Optically-diffracting pNIPAM Hydrogel Films Optically-diffracting hydrogels were initially prepared in microplates by embedding a CCA electrostatically self-assembled by PS nanoparticles in poly(N-isopropylacrylamide) (pNIPAM) hydrogel films. The CCA consisted of negatively-charged 110 nm PS nanoparticles arranged in a face-centered cubic lattice structure, with a lattice spacing on the order of a few hundred nanometers (tunable by controlling the precursor concentrations and PS surface charge density) such that the material interacted with light having a wavelength in the visible spectrum. Briefly, small drops of a pre-hydrogel solution containing monomeric and the CCA precursors 9 ACS Paragon Plus Environment


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were added to the bottom of each well in a vinyl functionalized microplate. An acrylic mold was then inserted into the wells of the microplate to press the pre-gel solution drops into uniform thin films that were ~175 µm thick. The entire assembly of the plate and mold was then exposed to 312 nm UV light through the bottom of the plate to polymerize and cross-link the films. During the polymerization process, vinyl groups on the surface of the PS nanoparticles and the microplate reacted with the growing pNIPAM network. Consequently, the CCA was covalently immobilized within the pNIPAM films, which were additionally anchored to the bottom of each well.

Characterization of the Temperature Sensitivity of the Optical Response of pNIPAM Hydrogel Films The mechanism of the optical response of the pNIPAM films as a function of temperature, which can be explained by the Bragg-Snell law,33-35 is shown in Figure 2a. Specifically, the CCA containing pNIPAM hydrogels were initially in a swollen state in water, thereby resulting in a large lattice spacing of the CCA (#! ) that causes diffraction at long wavelengths ($! ). In response to increases in temperature, the swollen hydrogels contract, leading to a decrease in the lattice spacing of the CCA (#% ) and thus peak diffraction at shorter wavelengths ($% ) which is commonly called a “blueshift” in the optical response. A similar response may be elicited by other stimuli, such as the presence of analytes or changes in solution ionic strength, that similarly cause the hydrogel to undergo a decrease in volume. Notably, in this work, the wavelength of peak diffraction by the films was tuned to within the visible range by controlling the size of the PS nanoparticles and thus the lattice spacing of the CCA.36-39


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Figure 2. Characterization of optical diffraction of the CCA containing pNIPAM hydrogel films in a microwell format. (a) Schematic diagram illustrating the optical response of CCAs embedded in hydrogels that shrink or swell due to external stimuli (e.g., temperature or the presence of an analyte). (b) Representative photographs of optically-diffracting pNIPAM hydrogel films in individual microwells in response to increases in temperature. (c) Representative attenuance spectra of the responsive CCA hydrogel films at varying characterization temperatures. The inset shows the temperature dependence of the blueshift in diffraction relative to the diffraction wavelength at 24 °C as a reference, with the error bars representing one standard deviation of the measurements from six independent microwells.

Considering the apparent temperature dependence of the optical response of the films, the impact of temperature on the film response was investigated under tightly controlled conditions. This impact is shown in Figures 2b and c. Whereas many hydrogels exhibit a



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relatively weak swelling response to increases in temperature, which arise through decreases in (i.e., often modeled as ∝ a + b/T where b > 0),40 pNIPAM hydrogels contract as the temperature increases due to the weakening of the favorable hydrogen bonding interactions between the water molecules and pNIPAM chains (i.e., captured roughly by b < 0). Photos of a single microwell with the optically-diffracting pNIPAM film (Figure 2b) show a visible color change from red to blue with increasing temperature, which corresponds to contraction of the pNIPAM hydrogel. Using a microplate reader, the optical diffraction of the CCA hydrogel platform can be readily characterized by measuring the attenuance which represents the loss of incident light intensity as described by the equation, = −log !" where and are attenuance and transmittance, respectively.2, 32 In the attenuance spectra in Figure 2c, the peak diffraction wavelength of the photonic crystal embedded in the hydrogel corresponds to the peak in the attenuance spectrum, and the hydrogel color change shown in Figure 2b can be quantitatively reported as shifts of the peak diffraction wavelength (i.e., blueshifts relative to a reference state). The increased attenuance at low wavelengths in the raw spectra may be attributed to inherent background absorption from the sensor materials, especially the PS nanoparticles of the CCA and the pNIPAM hydrogel. The background spectra was subtracted from the raw attenuance data to extract the diffraction peaks; the resulting diffraction peaks did not exhibit significant changes is diffraction intensity or peak broadening as a function of the extent of hydrogel swelling. The inset graph of Figure 2c shows the extent of diffraction blueshift with increasing temperature, revealing dramatic volumetric changes in the sensors near the LCST of pNIPAM (~32 °C).24,

25

The small error bars for each data point indicate the

uniformity of the CCA hydrogels across multiple distinct microwells, and thus the reliability of this sensing platform for quantifying analyte concentrations. 12 ACS Paragon Plus Environment

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The Optical Response of pNIPAM Hydrogel Films to Ethanol In addition to being sensitive to temperature, the pNIPAM films may be used to detect small molecule analytes that alter solvent quality, including ethanol. The response of the films to ethanol was initially characterized by adding ethanol to the microplate at varying concentrations (0-88 g/L) at a fixed temperature (30 °C) below the of the pNIPAM hydrogel (Figure 3a). Upon addition of ethanol, a blueshift in peak diffraction wavelength from 650 nm (pure water, red squares) to 475 nm (88 g/L ethanol, blue hexagons) was observed. The apparent blueshift may be attributed to the increase in for the polymer-solvent interactions by the addition of ethanol, which causes the hydrogel to contract. The extent of the blueshift, which increased non-linearly with ethanol concentration, was quantified using the peak diffraction wavelength in pure water as a reference (inset of Figure 3a). Due to the non-linear correlation between the extent of blueshift and the ethanol concentration, the pNIPAM films were highly sensitive to changes in ethanol concentration above 40 g/L. Interestingly, while inducing contraction of the pNIPAM films, the presence of ethanol directly lowered the of the pNIPAM hydrogel and shifted it closer to the " characterization temperature. Note that ( =+ , pure solvent, , for pure

solvent) is always constant for our pNIPAM hydrogels and that in the presence of an analyte =+ , solvent + analyte, ,. Stated another way, the addition of the analyte to the water decreased the overall favorability of the polymer-solvent interactions, therefore, " characterization at lower temperatures is able to induce phase separation ( < ). The

impact of ethanol on of the pNIPAM hydrogel was characterized by measuring the blueshift from the diffraction wavelength at 24 °C as a function of the characterization 13 ACS Paragon Plus Environment


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temperature at each ethanol concentration (Figure 3b). Specifically, as the concentration of ethanol was increased, an increase in the curvature and shift of the optical response curves to lower characterization temperatures was observed. As a result, the extent of blueshift was increased at the same characterization temperature as the ethanol concentration increased (see the dashed line as an example). The addition of ethanol at characterization temperatures far below

does increase the Flory-Huggins interaction parameter because the solvent’s ability to solvate the pNIPAM decreases, however, the magnitude of the change in the Flory-Huggins parameter is small and the hydrogel shrinkage falls below the limit provided by the optical detection scheme. This observation highlights the low responsiveness (∆V/∆χ) of photonic crystal hydrogels when not operated close to the phase transition (left side of the curve in Figure 1). Notably, not even 72 g/L of ethanol can be detected using pNIPAM hydrogels at characterization temperatures below 29 °C, which motivates the need to enhance the detection sensitivity. Most importantly, the results presented in Figure 3b suggest that improved sensitivity, which is defined here as the blueshift in the peak diffraction wavelength per unit of ethanol, can be achieved by adjusting closer to the user-selected characterization temperature. In the subsequent sections, we will discuss how modifying leads to predictable changes in optical sensitivity of the hydrogels as sensors for ethanol.


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Figure 3. Characterization of the optically-diffracting pNIPAM hydrogel films in response to ethanol. (a) Representative attenuance spectra of the pNIPAM hydrogel films in the presence of ethanol at 30 °C. The inset summarizes the blueshift in diffraction from that in deionized water by the added ethanol. (b) The optical responses to fixed ethanol contents (0-72 g/L) at varying characterization temperatures (24-33 °C), which are analyzed using the diffraction wavelength measured at 24 °C for each ethanol content as a reference. The error bars represent one standard deviation of the measurements from six microwells characterized at each condition.

Modulating the Phase Transition Behavior of pNIPAM Hydrogel Films via the Addition of Co-Monomers A facile approach to modulating the LCST and phase behavior of CCA-containing pNIPAM films for optical detection entails chemically modifying the composition of the hydrogel film. For example, the composition of the hydrogel film and thus its LCST may be 15 ACS Paragon Plus Environment


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modulated by co-polymerizing the films with low concentrations of co-monomers, which are, hydrophobic or hydrophilic relative to pNIPAM. To demonstrate this approach, pNIPAM hydrogels (in this case without the CCA) were prepared via co-polymerization with the relatively hydrophobic N-tert-butylacrylamide (tBA) or hydrophilic N-hydroxyethyl acrylamide (HEAA) co-monomers, the structures of which are shown in Figure 4a. Upon co-polymerization of the hydrogels, the effect of the co-monomers (5 or 10 mol% of either) on the demixing temperature of pNIPAM hydrogels was determined by differential scanning calorimetry (DSC). In order for the hydrogels to be compatible with the DSC, the hydrogels were prepared as thick free-standing films, rather than in a microwell format. Analysis of the hydrogel phase behavior upon heating by DSC found that addition of tBA and HEAA resulted in a tunable shift in the temperature of the phase transition (Figure 4b). Specifically, the thermogram for the pure pNIPAM hydrogel (black squares) shows endothermic heat flow between 33 and 42 °C, and is attributed to the phase separation transition of the hydrogel as a result of dehydration of the pNIPAM chains.41, 42 Analogously to the endothermic melting of crystals, the peak indicates endothermic heat flow because energy must be added to the system to disrupt the thermally-labile hydrogen bonds between the pNIPAM amide groups and the water solvent that favor polymer-solvent miscibility. The phase transition of the pure pNIPAM hydrogel occurred at 37 °C (based on peak position), which is a few degrees higher than the LCST of 32 °C typically reported for pNIPAM; this deviation, as well as the relatively broad transitions, are suggested to arise because of the different molecular architectures of the pNIPAM in the hydrogels as compared to the linear polymer chains typically characterized in solution43 and the inclusion of 1 mol% of the hydrophilic bifunctionalized acrylamide crosslinker. The phase transition shifted to lower and higher temperatures when the hydrogels 16 ACS Paragon Plus Environment

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were co-polymerized with tBA and HEAA molecules, respectively, suggesting changes in the favorability in the interaction between the hydrogels and water. Notably, the magnitude of the change in favorability in the interaction between the hydrogel and water was a function of the concentration of the co-monomers added to the hydrogel. The addition of tBA, by reducing the favorability of the hydrogel-water interactions (i.e., making the hydrogel more hydrophobic by diminishing the number and strength of the pNIPAM amide-water hydrogen bonding interactions), led to the phase transition of the hydrogel film at lower temperatures. Conversely, the addition of the hydrophilic HEAA monomer, which itself is capable of hydrogen bonding with water, resulted in contraction of the hydrogel film at higher temperatures due to an increase in the favorability of the hydrogel-water interactions.



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Figure 4. Effect of hydrogel composition on the sensitivity of the pNIPAM hydrogel films to ethanol. (a) Chemical structures of the hydrophobic N-tert-butylacrylamide (tBA) and hydrophilic N-hydroxyethyl acrylamide (HEAA) co-monomers used in this study to modulate the LCST and phase behavior of pNIPAM hydrogels. (b) Differential scanning calorimetry thermograms (exo up) upon heating of pNIPAM hydrogels with co-monomer compositions from 10 mol% tBA to 10 mol% HEAA. (c) Optical response to ethanol at 30 °C as reported by the CCA embedded in pNIPAM films tuned by copolymerization with 2.5 mol% tBA or 2.5 mol% HEAA. The blueshift is measured using the diffraction wavelength of each hydrogel in pure water as a reference state.

Given the apparent shift in the transition temperature of the hydrogel films upon the addition of tBA or HEAA co-monomers, it is interesting to consider if such changes in the


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transition behavior altered the sensitivity of the responsive photonic crystal hydrogels to small molecule analytes. To address this question, the sensitivity of hydrogel films containing 2.5 mol% tBA or HEAA to varying ethanol concentrations was characterized at a fixed temperature (30 °C), as shown in Figure 4c. The swelling transition temperatures of the pNIPAM hydrogels copolymerized with 2.5 mol% tBA and HEAA were ~35 and ~38 °C, respectively, as interpolated from the data in Figure 4b. We hypothesized that the addition of tBA would reduce

towards the characterization temperature, resulting in a larger volume change in the presence of ethanol, while the addition of the hydrophilic HEAA co-monomer should have the opposite effect on sensitivity, as more ethanol would be required to shift the solvent quality to reach the phase transition. As expected, the extent of blueshift was significantly greater for pNIPAM films containing tBA (grey bars in Figure 4c) relative to those containing HEAA (white bars) or pure pNIPAM (inset of Figure 3a) at all ethanol concentrations examined here. Notably, the blueshifts from the HEAA-containing films were within the noise of the optical measurements and thus negligible. While it may be anticipated that pNIPAM films containing higher contents of tBA would provide even greater enhancements in the sensitivity, the preparation of such systems as thin films in microwells proved challenging. Specifically, the addition of higher concentrations of tBA resulted in non-uniform photonic crystal structures (i.e., non-uniform colors) in the hydrogel films, which most likely was a result of phase separation between the hydrophilic and hydrophobic components during polymerization.44-47 This challenge may be overcome in the future using co-solvents such as DMSO and/or modified polymerization temperatures where more of the pNIPAM chains are dehydrated and thus more hydrophobic.



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Modulating the Phase Transition Behavior of pNIPAM Hydrogel Films by Altering Ionic Strength The sensitivity of the CCA-containing pNIPAM films to ethanol can also be improved by adjusting the ionic strength of the characterization solution. To understand this impact, the effect of the ionic strength of the characterization solution on the phase transition and of pNIPAM hydrogels was characterized by measuring the blueshift of the pNIPAM films in the presence of different concentrations of NaCl (ranging from 0-250 mM). The of the hydrogels decreased with increasing salt concentration as evidenced by a shift in the optical response curves to lower characterization temperatures (Figure 5a). The apparent shift in the demixing temperature of the pNIPAM films is consistent with previously published results that show the effect of ionic strength on the solvation of pNIPAM and a corresponding decrease in the LCST.48-52 By examining a set of sodium salts, Cremer and coworkers49 showed that the relative extent to which an anion lowered the LCST of pNIPAM generally follows the Hofmeister series. The Cl− anion is intermediate to the strong kosmotropes and chaotropes, which are capable of making or breaking structures with water respectively, and has been found to destabilize the hydration of the hydrophobic portions of pNIPAM (i.e., the polymer backbone and the isopropyl side chains). The increased surface tension of the water/hydrophobic interface therefore yields a moderate salting-out of the polymer and a 1~2 °C reduction in the LCST of pNIPAM, which compares favorably with the magnitude of the response observed here, for salt concentrations up to 250 mM.49 It should be noted that, if desired, greater tunability of the demixing temperature may be achieved at lower salt concentrations by interchanging NaCl with salts that have stronger kosmotropes (e.g., CO32−, SO42−, or H2PO4−), which polarize the water molecules involved in hydrogen bonding with the amide group of pNIPAM.48,49 20 ACS Paragon Plus Environment

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As shown in Figure 5a, the demixing temperature shifts as a function of NaCl concentration and approaches the characterization temperature (as indicated by the dashed vertical line), which leads to an enhanced optical response. Furthermore, reducing the demixing temperature by increasing ionic strength resulted in improvements in the sensitivity of the CCA hydrogel platform to ethanol (Figure 5b) because less of the organic analyte is required to reduce the quality of the polymer solvation and shift the system to exceed that of the phase transition ( ). At a characterization temperature of 30 °C (white bars), the blueshift of the films to 40 g/L ethanol increased in environments with ionic strengths above 200 mM, whereas the optical response was negligible under low ionic strength conditions (≤ 150 mM) as well as in pure water (inset of Figure 3a). The sensitivity was further improved by increasing the characterization temperature nearer to (gray and striped bars) until the CCA hydrogels completely contracted, which occurred at 32 °C, resulting in a blueshift beyond the visible range.



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Figure 5. Effect of the ionic strength of the environment on the optical response of the pNIPAM hydrogel sensors. (a) Optical response of the pNIPAM films to temperature under varying ionic strength conditions (0-250 mM NaCl). (b) Optical response of the pNIPAM films to 40 g/L of ethanol under high ionic strength conditions at varying characterization temperatures (30-32 °C). Error bars represent one standard deviation from six microwells per each condition.

Combined Effect of Ionic Strength and Temperature on the Sensitivity of pNIPAM Hydrogel Films Our prior results suggest varying characterization temperature and ionic strength alters the sensitivity of pNIPAM hydrogels to ethanol. Given this observation, the synergistic effect of varying the characterization temperature and ionic strength on the sensitivity of the responsive CCA-containing pNIPAM hydrogels to ethanol was determined. This effect was specifically 22 ACS Paragon Plus Environment

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determined by measuring the blueshift of the films to various ethanol concentrations at high ionic strength (250 mM) over a range of temperatures (30-33 °C). As shown in Figure 6, characterization of the blueshift at 250 mM salt permitted the detection of as low as 16 g/L ethanol at 33 °C. Differences in the color of the hydrogel films as a function of ethanol concentration at 30 °C was observed visually as evident in photographs of wells in the microplate (Figure 6a). The visual contrast in color at 16 g/L ethanol as well as higher ethanol concentrations was even greater at 32 °C, indicating enhanced sensitivity (Figure 6b). The quantitative relationship between the extent of blueshift and temperature is shown in Figure 6c, which shows a clear increase in blueshift at 250 mM salt with increasing temperature. Notably, at 33 °C, we were able to distinguish as low as 16 g/L (2 vol%) ethanol from background noise, which is remarkably lower than the detection limit at 0 mM salt concentrations. Unlike previously reported photonic crystal hydrogel sensors showing limited ethanol sensing capability (i.e., relatively high detection limits with broad step sizes, 5-10 vol%),53-55 the tunable sensitivity of our sensors allows for the detection of low ethanol concentrations with the ability to distinguish between similar concentrations. Combined with the approach for modulating the sensitivity shown here, the use of composition-tuned pNIPAM hydrogel films with the hydrophobic co-monomer tBA and the hydrophilic co-monomer HEAA may further enhance the sensitivity and expand the dynamic range for detection, respectively. Furthermore, as we have shown previously, the sensitivity of the pNIPAM films may be further improved by reducing the shear modulus of the hydrogels via decreasing crosslinking density of the hydrogel network.13 As such, while the aim of this work was to understand the molecular basis for the enhancement in optical response of photonic crystals using stimuli-responsive polymers, such



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strategies may be combined to engender highly sensitive photonic crystal sensors for a wide range of practical applications.

Figure 6. Sensitivity-tuned pNIPAM hydrogel optical sensors by control of characterization temperature. (a, b) Photos of consecutive microwells with the pNIPAM films upon incubation with 0-80 g/L ethanol in 250 mM ionic strength environments at characterization temperatures of 24 ACS Paragon Plus Environment

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(a) 30 °C and (b) 32 °C. (c) Optical response of the pNIPAM hydrogel films to an ethanol concentration range of 0-40 g/L in 250 mM ionic strength environments at varying characterization temperatures (30-33 °C). Error bars represent one standard deviation from six microwells per each condition.

CONCLUSIONS In summary, we have elucidated a mechanism for modulating the sensitivity of responsive photonic crystal hydrogels for the non-specific detection of analytes via the hydrogelsolvent interactions. Specifically, in this work, we demonstrated that the sensitivity of hydrogelbased photonic crystal sensors can be enhanced by creating such sensors from thermo-responsive polymers that exhibit a lower critical solution behavior. This approach was demonstrated by preparing optically-diffracting pNIPAM hydrogel films which, in the presence of an analyte, exhibited significant reductions in their volume and transduced the response into an easily reported visual signal. Importantly, the sensitivity of such films to changes in hydrogel-solvent interactions was enhanced by shifting the demixing temperature of the films towards the characterization temperature and operating the sensor as close as possible to the sharp phase transition. For example, co-polymerization of the films with 2.5 mol% tBA (LCST of 35 °C) permitted the detection of as little as 24 g/L ethanol at 30 °C, which was below the detection limit of pure pNIPAM films (LCST of 37 °C) at the same characterization temperature. By increasing ionic strength of the characterization solution (thereby decreasing of pNIPAM towards the characterization temperature), as well as increasing the characterization temperature (again towards ), further allows the detection limit of the sensors for ethanol to be decreased considerably. Taken together, our results highlight the potential to enhance the sensitivity of opticallydiffracting pNIPAM hydrogel films via rationally tuning the characterization conditions. In 25 ACS Paragon Plus Environment


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addition, the tunable sensitivities provided by the pNIPAM hydrogels allows a wider dynamic range of analyte concentrations to be quantified than would otherwise be accessible at a fixed sensitivity. The phenomena and operating principles may be generalized such that thermoresponsive polymers other than pNIPAM that exhibit a LCST in water may be used, including those based on poly((oligoethylene glycol) methacrylates) that have tunable LCSTs near room or physiological temperatures.56-59 Moreover, one may anticipate that polymers exhibiting an upper critical solution temperature (UCST) behavior in water60, 61 would also provide opportunities for enhancing the sensitivity of responsive hydrogels to analytes, although in this case the characterization temperatures should be close to, but above the demixing temperature. Ultimately, this understanding of the polymer thermodynamics and phase behavior has widespread implications for rationally designing and improving photonic crystal hydrogel sensors for the detection of a myriad of analytes, while increasing the utility of an already powerful sensing platform.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] * E-mail: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes The authors declare no competing financial interest. 26 ACS Paragon Plus Environment

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ACKNOWLEDGMENTS The authors acknowledge funding from the National Science Foundation (DMR1411320) and the University of Colorado Liquid Crystal Material Research Center (NSF DMR0820579) for this work. Additionally, the authors are also grateful to Prof. Robert Batey for access to the microplate reader.



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Enhanced Optical Sensitivity in Thermoresponsive Photonic Crystal

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