Tailoring the LCST of Thermosensitive Hydrogel Thin Films Deposited

Article pubs.acs.org/Langmuir

Tailoring the LCST of Thermosensitive Hydrogel Thin Films Deposited by iCVD Abdon Pena-Francesch, Laura Montero, and Salvador Borrós* Grup d’Enginyeria de Materials, Institut Químic de Sarrià-Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain ABSTRACT: Using the iCVD (initiated chemical vapor deposition) polymerization technique, we generated a library of thermosensitive thin film hydrogels in the physiological temperature range. The library shows how a specific hydrogel with a desired temperature response can be synthesized via the copolymerization of three main components: (a) the main thermosensitive monomer, which determines the temperature range of the LCST; (b) the comonomer, which modulates the temperature according to its hydrophilic/hydrophobic behavior; and (c) the cross-linker, which determines the swelling degree and the polymer chain mobility of the resulting hydrogel. The thermosensitive thin films included in the library have been characterized by the water contact angle (WCA), revealing a switchable hydrophobic/ hydrophilic behavior depending on the temperature and a decrease in the WCA with the incorporation of hydrophilic moieties. Moreover, a more accurate characterization by quartz crystal microbalance (QCM) is performed. With temperature and flow control, the switchable swelling properties of the thermosensitive thin films (due to the polymer mixture transition) can be recorded and analyzed in order to study the effects of the comonomer moieties on the lower critical solution temperature (LCST). Thus, the LCST tailoring method has been successfully used in this paper, and thermoresponsive thin films (50 nm in thickness) have been deposited by iCVD, exhibiting LCSTs in the 32−49 °C range. Due to the presented method’s ability to tailor the LCST in the physiological temperature range, the developed thermoresponsive films present potential biosensing and drug delivery applications in the biomedical field.

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INTRODUCTION Stimuli-sensitive polymers shift their physicochemical properties in response to changes in their environmental conditions. When cross-linked, these polymers can absorb or expel water when an external stimulus such as pH,1 temperature,2 light,3 or an electric field4 is applied. These responsive materials have been extensively investigated, and their use as smart surfaces makes them suitable for biological applications such as biosensors and biomedical devices.5 It has been reported6 that temperature-responsive polymers exhibit cell adhesive/ nonadhesive behavior as a function of temperature, presenting potential applications in biofilm formation prevention. Thermosensitive hydrogels change their degree of swelling in water above or below a certain temperature, known as the lower critical solution temperature (LCST).7 Poly(N-isopropylacrylamide) (pNIPAAm) is the most extensively studied of the temperature-responsive polymers,8−10 exhibiting an LCST of 32 °C. Below this temperature, the polymer chains are fully hydrated and the polymer swells (hydrogen bonding predominant), while above this temperature the polymer chains exhibit a change in hydrophobicity and collapse into a globular state, expelling the water (hydrophobic interactions predominant).11 However, it is possible to modify the LCST of a thermosensitive hydrogel by introducing the appropriate monomer moieties. The bulk copolymerization of a main thermosensitive monomer and another comonomer that modulates the LCST of the resulting polymer has been extensively studied,12−18 allowing the thermosensitive polymer to be engineered according to specific needs. © 2014 American Chemical Society

Because of the potential micro- and nanoapplications, interest in the fabrication of pNIPAAm thin films has grown, and many techniques have been described to provide pNIPAAm surface modification,2,19−21 including initiated chemical vapor deposition (iCVD). Initiated chemical vapor deposition (iCVD) is a subset of CVD techniques developed in the Gleason laboratory at MIT22−25 in which the selective thermal decomposition of species is achieved using resistively heated filaments. Similarly to conventional free-radical polymerization, an initiator is used to begin the reaction. The initiator is thermally fragmented to generate radicals that adsorb on the substrate with the monomeric units and start the growth of the polymer. iCVD was previously used to deposit thermosensitive films that were characterized by QCM by other authors.2,26−28 In this work, a series of thermoresponsive thin film hydrogels with a controlled LCST have been deposited by iCVD. Thermoresponsive monomers have been copolymerized with hydrophilic monomers and cross-linkers in order to study their effect on the LCST, generating a library of thermoresponsive thin films by iCVD.

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EXPERIMENTAL SECTION

All reactions were conducted in a custom-built reactor described elsewhere.29 N-Isopropylacrylamide (NIPAAm, Acros Organics, 99%), acrylic acid (AAc, Sigma-Aldrich, 99%), N,N-diethyl acrylamide Received: January 26, 2014 Revised: May 21, 2014 Published: May 29, 2014 7162

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Table 1. Thermosensitive Thin Film Library Composition and LCST thermosensitive monomer A1 A2 A3 B1 B2 B3 C1 C2 C3 D1 D2 D3 D4

NIPAAm 90% NIPAAm 80% NIPAAm 70% NIPAAm 80% NIPAAm 70% NIPAAm 60% NIPAAm 80% NIPAAm 70% NIPAAm 60% DEAAm 90% DEAAm 80% DEAAm 70% DEAAm 60%

hydrophilic comonomer

cross-linker EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA EGDA

DMAAm 10% DMAAm 20% DMAAm 30% AAc 10% AAc 20% AAc 30% DMAAm 10% DMAAm 20% DMAAm 30%

10% 20% 30% 10% 10% 10% 10% 10% 10% 10% 10% 10% 10%

LCST (°C) 32.3 33.5 37.2 36.6 38.5 39.8 35.5 33.7

± ± ± ± ± ± ± ±

0. 0.7 0.6 0.9 0.4 0.3 0.8 to 46.3 ± 0.4 0.9 to 49.5 ± 0.7

38.7 ± 0.7 39.5 ± 1.0 40.1 ± 1.3

Figure 1. Interferometry image of p(DEAAm-co-EGDA) 90/10 with a thickness of 50 nm. calculated without its fraction.25 The deposited film thickness was 50 nm. Thermosensitive Thin Film Hydrogel Library. Four main groups of hydrogels with different compositions (based on a previous bulk thermoresponsive hydrogel combinatorial study)30 were prepared in order to study how the monomers and the cross-linker ratio would affect the LCST:

(DEAAm, Polyscience, 95%), N,N-dimethyl acrylamide (DMAAm, Sigma-Aldrich, 99%), 2-hydroxyethyl methacrylate (HEMA, SigmaAldrich, 99%), ethylene glycol diacrylate (EGDA, Sigma-Aldrich, 90%) as a cross-linker, and tert-butyl peroxide (TBPO, Sigma-Aldrich, 98%) as an initiator were purchased and used without further purification. iCVD Polymerization Parameters. Polymer depositions were performed on Si wafers and QCM gold sensors (QSX-301, Q-sense). Substrates were kept at 36 °C (pNIPAAm depositions), 30 °C (pDEAAm depositions), or 28 °C (pHEMA depositions) by contact with a cooling stage. Monomers were heated, and its vapors were fed into the reactor regulated by needle valves. (NIPAAm was heated to 75 °C, HEMA to 80 °C, EGDA to 65 °C, DMAAm and DEAAm to 85 °C, and AAc to 75 °C, and TBPO was kept at room temperature.) In order to avoid monomer condensation, the monomer feeding pipe and the reactor wall were heated to 95 °C, and the glass window was heated to 70 °C. The filaments were heated to 200 °C. The initial pressure inside the reactor was 2.0 × 10−2 mbar. The main monomer (NIPAAm, DEAAm, or HEMA) was fed into the reactor (at a monomer flow rate of 0.2, 0.2, or 1.0 sccm, respectively) until the pressure increased to 1.5 × 10−1 mbar. The minor comonomer (DMAAm or AAc) and the cross-linker (EGDA) were fed according to the desired feed proportion. Last, TBPO was fed until the pressure increased to 2.0 mbar. The initiator flow was maintained at a constant value for all depositions, and the final flow rate was

- A: p(NIPAAm-co-EGDA) (increasing cross-linker ratio) - B: p(NIPAAm-co-DMAAm-co-EGDA) (increasing DMAAm ratio) - C: p(NIPAAm-co-AAc-co-EGDA) (increasing AAc ratio) - D: p(DEAAm-co-DMAAm-co-EGDA) (increasing DMAAm ratio) Detailed sample names and compositions are listed in Table 1. FTIR Spectroscopy. ATR-FTIR (attenuated total reflectance Fourier transform infrared) spectroscopy data was collected with Thermo Nicolet IR equipment in attenuated total reflection (diamond crystal) mode using Norton−Beer apodization with 4 cm−1 resolution. For each spectrum, 256 scans were coadded. Water Contact Angle Measurements. WCA measurements were performed in a goniometer (DSA 100, Krüss) using 2 μL of MilliQ water droplets. Measurements were made at room temperature and at 55 °C. The corrected standard deviation is calculated from three repetitions per sample (from multiple samples). 7163

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twin sharp band at 1370−1385 cm−1. p(DEAAm-co-EGDA) presents similar spectra. Equivalent spectra for pNIPAAm and pDEAAm polymers have been previously reported in the literature.2,31 The incorporation of cross-linker EGDA can be observed in both spectra as a small band at 1725−1730 cm−1, corresponding to the EGDA carbonyl stretching. The crosslinker ratio in the films has been determined by comparing the intensity of CO stretching bands for NIPAAm and EGDA (considering two carbonyl groups per EGDA molecule). Water Contact Angle. WCA data in Figure 3 confirms the thermosensitivity of the deposited films since the reported

LCST Measurement by QCM. The LCST transition was determined using QCM (model E1, Q-sense). As the deposited substrate, gold-coated sensors (QSX-301, Q-sense) with a fundamental frequency of 5 MHz were used. The seventh harmonic is used for LCST analysis and plotted in the figures. The experiments were carried in a Q-Sense flow module with phosphate buffer solution (PBS) at a flow rate of 50 μL/min. The Peltier heating element was programmed to equilibrate at 25 °C for 5 min and then increase in temperature to 55 °C at a heating rate of 1 °C/min. The criteria for determining the LCST from the QCM data is based on the change in slope in the frequency readings. At temperatures below and above the LCST, the frequency exhibits a linear dependence on temperature. A linear regression is fitted to each linear region, and the LCST is calculated at the intersection point of the resulting fitted lines. For y = a1x + b1 as the linear fit below the LCST and y = a2x + b2 as the linear fit above LCST, the intersection point (and therefore the LCST) is calculated as LCST = (b2 − b1)/(a1 − a2). For samples containing acrylic acid (AAc), a second-order polynomial is fitted to the transition region in addition to the two linear fits, and the two intersection points are calculated separately. The corrected standard deviation is calculated from three repetitions per sample (from multiple samples). Thickness Measurement. The films were cut with a stainless steel scalpel without damaging the Si substrate, and thickness characterization was performed by interferometry (Leica DCM 3D).

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RESULTS AND DISCUSSION Thermoresponsive thin film hydrogels have been deposited by iCVD with a thickness of approximately 50 nm (Figure 1). The films have been characterized by FTIR, WCA, and QCM. The film composition and the reported LCST values are summarized in Table 1. FTIR Spectroscopy. The spectra of p(NIPAAm-co-EGDA) and p(DEAAm-co-EGDA) in a 90/10 ratio are presented in Figure 2. FTIR confirmed the successful polymerization of

Figure 3. Static water contact angles below and above the LCST of iCVD thin films: (a) p(HEMA-co-EGDA) 90/10 nonthermoresponsive control, (b) p(NIPAAm-co-EGDA) 90/10 (sample A1), (c) p(NIPAAm-co-DMAA-co-EGDA) 70/20/10 (sample B2), (d) p(NIPAAm-co-AAc-co-EGDA) 70/20/10 (sample C2), and (e) p(DEAAm-co-EGDA) 90/10 (sample D1).

contact angles below and above the LCST present a difference of 20−30° (versus a nonthermosensitive control with no significantly different contact angles). A decrease in the contact angle compared to that in Figure 3b can be observed both below and above the LCST when hydrophilic moieties are introduced into the hydrogel film, confirming the successful copolymerization of the different comonomers. LCST Determination by QCM. Thermoresponsive NSubstituted Acrylamide. Nonthermosensitive hydrogel p(HEMA-co-EGDA)19,32−34 and thermosensitive hydrogels p(NIPAAm-co-EGDA) and p(DEAAm-co-EGDA) in a 90/10 ratio (A1 and D1 respectively) are analyzed by QCM in Figure 4. As described elsewhere,35 the frequency is linearly correlated with temperature due to the changes in the viscosity of the liquid media. The slope of the frequency is related to the amount of water coupled to the oscillator; therefore, different-

Figure 2. FTIR spectra of iCVD films of (a) p(DEAAm-co-EGDA) in a 90/10 ratio (sample D1) and (b) p(NIPAAm-co-EGDA) in a 90/10 ratio (sample A1).

pNIPAAm and pDEAAm. Bands corresponding to the vinyl group (related to the monomeric form) are not visible in the copolymerized films (bands typically at 1620, 1400, and 3150 cm−1 for NIPAAm). p(NIPAAm-co-EGDA) characteristic bands can be observed at 1645 cm−1 (amide I band, CO stretching), 1544 cm−1 (amide II band, N−H bending and C− N stretching vibrations), and 3200−3300 cm−1 (amide A, N−H stretching vibration). The isopropyl group can be observed as a 7164

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Sample A1 has a minimum cross-linker concentration (10% necessary to prevent polymer dissolution in water). As can be observed in Figure 5, sample A1 shows an LCST of 32.3 ± 0.4

Figure 4. QCM data of the p(HEMA-co-EGDA) 90/10 nonthermoresponsive control and p(NIPAAm-co-EGDA) 90/10 (sample A1) and p(DEAAm-co-EGDA) 90/10 (sample D1) represented by solid lines. Fitting for LCST determination by dashed lines.

Figure 5. QCM data of p(NIPAAm-co-EGDA) with 90/10 (A1), 80/ 20 (A2), and 70/30 (A3) ratios shown by solid lines. The fitting is for the LCST determination shown by dashed lines.

frequency slopes can be associated with different water contents. It can be observed that the p(HEMA-co-EGDA) control sample shows a linear trend (same frequency slope) along the full temperature range, exhibiting a nonthermoresponsive behavior. On the other hand, the transition from hydrophilicity (swollen state) to hydrophobicity (collapsed state) in thermoresponsive thin films generates a loss of water that can be measured by the change in the frequency slope. The LCST of thermoresponsive films is estimated at the intersection point of the linear frequency regions with a stable slope (plotted as dashed lines in Figure 4 for easier LCST identification). Samples A1 and D1 present an LCST calculated at the intersection points of 32.3 ± 0.4 and 38.7 ± 0.7 °C respectively. The LCST has been determined for bulk pNIPAAm in aqueous solution by other authors.9,10 The polymer composition and the LCST values of the complete thermoresponsive thin film library are summarized in Table 1. Due to the fact that pDEAAm has a similar thermosensitivity to pNIPAAm, it has been extensively studied by other researchers.36−39 A set of p(DEAAm-co-DMAAm-co-EGDA) thin film hydrogels (series D) have been polymerized and characterized by QCM, similarly to pNIPAAm hydrogels. p(DEAAm-co-EGDA) with ratio 90/10 (D1) can be observed in Figure 4, presenting an LCST of 38.7 ± 0.7 °C, which is higher than for equivalent pNIPAAm sample A1 (with an LCST of 32.3 ± 0.4 °C). The dehydrated amide groups of pNIPAAm form hydrogen bonds within the chain (CO···H− N) above the LCST, facilitating the dehydration. On the other hand, pDEAAm cannot form the same intramolecular hydrogen bonds due to the lack of NH moieties, resulting in a smaller amount of dehydrated water and a smaller conformational change.36,37 DMAAm moieties are incorporated into p(DEAAm-co-EGDA) in order to increase the hydrophilic content of the polymer. Thin films with increasing DMAAm contents of 10% (D2) and 20% (D3) presented LCST values of 39.5 ± 1.0 and 40.1 ± 1.3 °C, respectively. Sample D4 with 30% DMAAm content did not present any thermosensitivity. (The frequency showed a linear trend with temperature due to the excessive hydrophilic content in the hydrogel.) Cross-Linking Degree. The monomer/cross-linker ratio in p(NIPAAm-co-EGDA) films was modified in order to study the influence of the cross-linking degree in the LCST transition. Three different ratios were compared in p(NIPAAm-co-EGDA) films: A1 (90/10), A2 (80/20), and A3 (70/30).

°C. Samples A2 and A3 exhibit higher LCST values (33.5 ± 0.7 and 37.2 ± 0.6 °C, respectively). This is attributed to the reduction of the swelling capability of the film due to the physical constrains in the polymer network (and eventually resulting in a progressive loss of thermosensitivity for high cross-linker ratios). Moreover, the hydrophobicity of the crosslinker can also modify the LCST, as reported by other authors.2,28 Comonomer Influence. The LCST range is defined by the N-substituted acrylamide thermoresponsive base monomer (in this case, NIPAAm). However, introducing comonomer moieties into the polymer modifies the hydrophobic/hydrophilic behavior of the resulting hydrogel. Figure 6 shows the

Figure 6. QCM data of p(NIPAAm-co-EGDA) 90/10 (A1), p(NIPAAm-co-DMAAm-co-EGDA) 70/20/10 (B2), and p(NIPAAm-co-AAc-co-EGDA) 70/20/10 (C2) shown by solid lines. Fitting for LCST determination shown by dashed lines.

QCM results for the p(NIPAAm-co-DMAAm-co-EGDA) (sample B2) and p(NIPAAm-co-AAc-co-EGDA) (sample C2) hydrogels (maintaining the cross-linking degree at 10%). It can be observed that the incorporation of hydrophilic DMAAm moieties leads to a higher LCST due to a reduction of hydrophobic groups and an increase in the overall hydrophilicity. The reported LCST values for p(NIPAAm-coDMAAm-co-EGDA) thin films are 36.6 ± 0.9 °C for 10% DMAAm content (sample B1), 38.5 ± 0.4 °C for 20% 7165

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DMAAm (B2), and 39.8 ± 0.3 °C for 30% DMAAm (B3). In addition to the increase in the LCST, a progressive decrease in the frequency curvature can be observed. This loss of thermosensitivity can be associated with a great reduction of NIPAAm moieties in the final polymer. Introducing AAc into the polymer structure results in a higher increase (compared to DMAAm) of the overall hydrophilicity (observable as a decrease in WCA and as an increase in the LCST values) due to the incorporation of carboxylic acid groups. However, the transition (associated with the change in the frequency slope) can be observed over a broader temperature range for these polymers, such as sample C2 in Figure 6. LCST values are estimated in temperature ranges of 35.5 ± 0.8 to 46.3.8 ± 0.4 °C for 10% AAc (C1) and 33.7 ± 0.9 to 49.5 ± 0.7 °C for 20% AAc (C2). The effect of the charge in the hydrogel increases the hydrophilicity due to strong interactions between water and charged groups. Additionally, studies have shown a decrease in charge on pNIPAAm copolymers with increasing temperature until a charge limit is achieved at the LCST,13,14 which can explain the different transitions in p(NIPAAm-co-AAc-co-EGDA) films. Sample C3 (30% AAc) does not present thermosensitivity in the studied temperature range (due to the great imbalance of hydrophilic/hydrophobic groups at high AAc ratios).

REFERENCES

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CONCLUSIONS A library of thermosensitive thin film hydrogels with an adjustable LCST have been deposited by iCVD. The tuning of the LCST of the films has been successfully achieved by the copolymerization of three components: (a) the main thermosensitive monomer, which sets the temperature range of the LCST; (b) the comonomer, which shifts the LCST according to the hydrophilic/hydrophobic moieties that are introduced; and (c) the cross-linker, which determines the polymer chain constrains and the swelling degree of the resulting hydrogel. The thermoresponsive thin films have been successfully characterized by the quartz crystal microbalance (QCM) and water contact angle (WCA). The QCM characterization method is able to detect the LCST of the films and the variations induced by the copolymerization. Therefore, the influence of the monomer, comonomer, and cross-linker on the LCST has been measured and analyzed. As the cross-linking degree increases, the polymer chain mobility and the swelling capability are reduced, resulting in a loss of thermosensitivity and an increase in the LCST. If a hydrophilic or charged comonomer is introduced, then the LCST shifts toward higher temperatures due to an increase in the overall hydrophilicity (due to the incorporation of hydrogen bonding moieties and the reduction in hydrophobic groups). The copolymerization method for LCST tailoring has been used to engineer an array of thermoresponsive thin film hydrogels with LCSTs that cover the range of temperatures between 32 and 49 °C. These thermoresponsive thin films present potential applications in the biomedical field as smart surfaces for biosensing devices and drug delivery.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 7166

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