Dynamic Fluctuations of Thermoresponsive Poly(oligo-ethylene glycol

Article Cite This: Macromolecules 2018, 51, 8932−8939

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Dynamic Fluctuations of Thermoresponsive Poly(oligo-ethylene glycol methyl ether methacrylate)-Based Hydrogels Investigated by Dynamic Light Scattering Takuma Kureha, Kyohei Hayashi, Masashi Ohira, Xiang Li, and Mitsuhiro Shibayama* Institute for Solid State Physics, The University of Tokyo, Kashiwa, Japan

Macromolecules 2018.51:8932-8939. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 12/04/18. For personal use only.

S Supporting Information *

ABSTRACT: The dynamics of thermoresponsive and biocompatible gels was investigated using dynamic light scattering. The gels were copolymerized by two types of ethylene glycol methacrylates having short and long hydrophilic side chains consisting of ethylene oxide units. Their dynamics was decomposed to fast and slow modes. The critical temperature was determined from the fast mode (cooperative diffusion) and was controlled lineally by the copolymerization ratio of the two monomers, which is one of the advantages in the gel system. The formation mechanism of hydrophobic domains in the gels was investigated from the slow mode. The hydrophobic domains grew in the gels by rising temperature, and they were copolymerization ratio dependent. The domain formation was suppressed as the copolymerization ratio of the longer side chain was increased. The results of this study should lead to new design strategy for the bioapplications, including drug delivery systems that require a retention of their smart functions.

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gates,18,19 surface coatings,20,21 microspheres for carriers,22−24 and injectable gels.17,25−27 As the cross-linked POEGMA polymers (hydrogels) have been developed such as injectable gels mentioned above, it is important to investigate their thermoresponsive behavior of the gel for further applications including biomolecular separations and sensors. To realize such applications, it is necessary to tune the critical temperature. We hypothesized that the critical temperature (or volume phase transition temperature, VPTT) of the gels could be tuned by the monomer ratio between MeO2MA and OEGMA during the copolymerization without changing the profile of the volume transition. So far, copolymerization of thermosensitive and thermoinsensitive monomers has been applied to tune the critical temperature of the thermoresponsive gels, for example, the most extensively studied LCST-type (N-isopropylacrylamide) (PNIPAM) copolymerized with non-LCST-type acrylic acid, N,N′-dimethylacrylamide, or others.28−31 In those cases, the volume transitions of gels originating from LCSTtype polymers are usually suppressed by incorporating nonLCST-type polymer. Conversely, POEGMA-based gels, which we treat in this work, are made of two LCST-type polymers. Then, the following question arises: does the volume transition undergo by (i) two step transitions at each LCST (two steps) or by (ii) just one step transition? To the best of our knowledge, very few studies have been reported on the physical properties of POEGMA-based gels,

INTRODUCTION Hydrogels have been extensively studied as synthetic matrices for the controlled release of therapeutics and as scaffolds for promoting tissue regeneration because the hydrogels exhibit the excellent properties, including high water content similar to our body, controllable porosity, and mechanical and compositional similarity to native tissues.1−3 For biological applications, the hydrogels should exhibit biocompatibility. Indeed, many synthetic polymers can be used as bioinert materials, including poly(ethylene glycol) (PEG),4−6 sulfobetaine polymers,7 poly(methacryloyloxyethylphosphorylcholine),8,9 and their derivatives. More recently, poly(oligo-ethylene glycol methyl ether methacrylate) (POEGMA)-based polymers have been developed by Lutz et al. as a new type of thermoresponsive polymer.10 They offer a potential alternative to the use of thermoresponsive polymers and PEG for a design of hydrogels for biomedical applications.11 POEGMA-based polymers can be synthesized via facile free radical polymerization, and they display a lower critical solution temperature (LCST) in water that is governed by the ethylene oxide chain length (n) of the OEGMA monomer.12 Through the statistical copolymerization of diethylene glycol methacrylate (MeO2MA, n = 2) and OEGMA (n = 4 or 5), copolymers can be prepared that display the LCST ranging anywhere from ∼20 to ∼63 °C (Figure 1).13−15 They also exhibited all the advantageous nonimmunogenic, noncytotoxic, and protein (and consequently cell)-repellent properties of PEG.16,17 Indeed, many studies related to POEGMA-based materials have been developed to use the advanced biomedical applications, such as bioconju© 2018 American Chemical Society

Received: September 20, 2018 Revised: October 18, 2018 Published: October 31, 2018 8932

DOI: 10.1021/acs.macromol.8b02035 Macromolecules 2018, 51, 8932−8939

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Figure 1. (A) Chemical structure of POEGMA-based hydrogels. (B) Transmittances of the tested gels as a function of temperature. (C) Photographs of the gels in DLS test tubes below and above their LCSTs.

especially for the volume transition during changes in temperature. Furthermore, there have been no reports on volume transition behavior of the LCST−LCST type POEGMA-based gels. Because it may give unexpected changes in their functions and physical properties during the applications, it is very important to reveal the volume transition behavior for these gels to develop adequate strategies that allow the use in vivo, which would be highly attractive for not only the polymer physics field relating to critical phenomena but also advanced biomedical applications. To clarify the above-mentioned conjecture, we investigated the dynamics of LCST−LCST type POEGMA-based gels by dynamic light scattering (DLS) because DLS is a useful tool to investigate the nature of gels which consist of dynamic fluctuations superimposed on the static inhomogeneities inherent in the network.32−38 In this study, we performed a systematic study of polymer chain dynamics in POEGMA gels by DLS as a function of temperature and monomer ratio of MeO2MA and OEGMA.

gE(1)(τ ) ≡

gE(1)(τ ) =

⟨E(t )E(t + τ )⟩T

2

= exp( −Dq τ )

⟨E(t )E*(t + τ )⟩E ⟨E(t )⟩E

2

=

⟨⟨E(t )E*(t + τ )⟩T ⟩E ⟨⟨E(t )⟩T ⟩E 2 (4)

(1)

⟨⟨I ⟩T gT(2)(τ ) − {gT(2)(0) − 1} ⟩E ⟨I ⟩E

(5)

We can obtain the fraction of the static component and 33 (1) dynamic component of g(1) E (τ) from gE (∞) as follows:

Here, ⟨...⟩T denotes time average, E(t) is the scattering electric field, and τ is the lag time. For Brownian particles in a solution, g(1) T (τ) is written with the diffusion coefficient, D, as gT(1)(τ )

(3)

Here, ⟨...⟩E is the ensemble average. g(1) E (τ) can be estimated by taking the ensemble average of the correlation functions for different samples or at many different sample positions of the same sample by using the following relation between g(1) E (τ) 38,39 and g(2) T (τ):

THEORETICAL BACKGROUND For DLS analysis, the time-correlation function of the scattering electric field, g(1) T (τ), is defined by ⟨E(t )⟩T 2

⟨I(t )⟩T 2

The dynamics of polymer gels was first discussed as the cooperative diffusion of polymer networks by Tanaka et al.32 Then, it was recognized that the dynamics of polymer gels is sample-position-dependent due to nonergodic nature of the gel.33−38 Thus, eq 3 cannot be directly applied for gels. For nonergodic materials, such as polymer gels, the ensembleaveraged time-correlation function should be used to capture the dynamics. According to Pusey and Megen,33 the ensembleaverage of the time-correlation function of the scattering electric field, g(1) E (τ), is defined by

■

gT(1)(τ ) ≡

⟨I(t )I(t + τ )⟩T

gT(2)(τ ) ≡

gE(1)(∞) =

(2)

⟨IC⟩E ⟨I ⟩E

1 − gE(1)(∞) =

Here, q is the magnitude of the scattering vector. In most DLS measurements, the time-correlation function of the scattering (1) intensity, g(2) T (τ), is obtained instead of gT (τ).

(static component)

⟨IF ⟩E ⟨I ⟩E

(dynamic component)

(6a)

(6b)

To analyze experimental correlation functions, the following equation is commonly used (Figure 2):40 8933


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(1) Figure 2. Representative τ dependence of (A) g(1) E (τ) and (B) gE,F (τ) for POEGMA-based gels (Me7O3 listed in Table 1) measured at 25 °C. In this study, (A) the dynamic and static components were separated for g(1) E,F (τ), and then (B) the dynamic component in this study was further separated into the fast mode reproduced by a single-exponential function (blue region) and the slow mode decaying in the manner of a power-law (1) function (red region). The solid curves in (A) and (B) show the fitting curves using eq 7a for g(1) E (τ) and eq 7b for gE,F (τ), respectively.

gE(1)(τ ) = [1 − gE(1)(∞)]gE(1) (τ ) + gE(1)(∞) ,F

(7a)

1−A (1 + τ /τ *)Dp

(7b)

gE(1) (τ ) = A exp( −Dq2τ ) + ,F

Table 1. Synthesis Conditions and Critical Temperatures (Tc) of the Resulting Gelsa

Here, A is the fraction of the exponential term (the fast mode) that represents the cooperative diffusion of the semidilute polymer chains, τ* is the lag time at which a power-law type relaxation starts, and Dp is the fractal dimension of scattered light.41 Figure 2 shows a typical result (g(1) E,F (τ)) of the present gels and the fitting curve using eq 7b. The correlation length, that is, a typical length of the cooperative diffusion in a gel, ξ, is evaluated by an analogy of the Stokes−Einstein law.32 ξ=

kBT 6πηD

ratio of MeO2MA and OEGMA

MeO2MA (mol %) (n = 2)

OEGMA (mol %) (m = 4/5)

Tc (VPTT)

Me Me7O3 Me5O5 Me3O7 O

800 800 800 800 800

10:0 7:3 5:5 3:7 0:10

99 69.5 49.5 29.5 0

0 29.5 49.5 69.5 99

22 37 47 54 62

a

The cross-linker (EGDMA), APS, and TEMED were held constant at 1 mol %, 2 mM, and 32 mM, respectively.

stepwise from 10 to 60 °C. We started each DLS measurement at least 60 min after the temperature reached the target temperature for thermal equilibration in the sample. The intensity of the transmitted beam (θ = 0°) was monitored by a laser power meter (FieldMaster GS, Coherent Inc., USA) for the estimation of the transmittance of the sample. Here, the transmittance is defined as fraction of the transmitted light intensities from the sample solution and that from an empty cell.

(8)

Here, kB is the Boltzmann constant, T is absolute temperature, and η is the solvent viscosity.

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code

monomer concn (mM)

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EXPERIMENTAL DETAILS

Materials. Di(ethylene glycol) methyl ether methacrylate (MeO2MA, 95%), poly(ethylene glycol) methyl ether methacrylate (OEGMA, 99%), ethylene glycol dimethacrylate (EGDMA, 98%), and N,N,N′,N′-tetramethylethylenediamine (TEMED, 99%) were purchased from Sigma-Aldrich and used as received. Ammonium peroxodisulfate (APS, 95%) was purchased from Wako Pure Chemical Industries and used as received. Synthesis of POEGMA-Based Hydrogels. Prescribed amounts of MeO2MA and OEGMA were dissolved in deionized water. The total monomer concentration was kept constant (800 mM), while the monomer ratio between MeO2MA and OEGMA was varied from 10:0 to 7:3, 5:5, 3:7, and 0:10. EGDMA (1 mol %) and APS (2 mM) were added to the solutions. These pregel solutions were degassed, and polymerization was initiated in a 10 mm diameter test tube by adding TEMED (32 mM) at 25 °C. To avoid demixing and/or precipitation of PMeO2MA gels (without POEGMA) at the room temperature, we conducted the polymerization in a refrigerator (∼3 °C). Thus, formed gel samples were used for DLS experiments without further treatment. Table 1 shows the sample codes and their compositions. Dynamic Lights Scattering (DLS). Ensemble-average DLS measurements were conducted with a DLS/SLS-5000 (ALV, Langen) with a He−Ne laser (632.8 nm, 22 mW) at a scattering angle 90°. The intensity correlation function, g(2) T (τ), was measured for 120 s per sample position at 30 different positions. The temperature was raised

RESULTS AND DISCUSSION Concentration Fluctuation of POEGMA-Based Gels. To prepare POEGMA-based hydrogels, we used free-radical polymerization, which is the most conventional method for gel synthesis. The synthesis conditions are shown in Table 1. In this study, the monomer ratio of MeO2MA and OEGMA was tuned (denoted as MeXOY, whereby Me and O represent MeO2MA and OEGMA, respectively, while X and Y refer to the molar feed ratios of MeO2MA and OEGMA, respectively, during the polymerization). The obtained gels were transparent comparatively at the prepared temperature (∼3 °C), but their transmittances dramatically decreased by elevating temperature to their critical temperatures of the gels (Figure 1B,C), indicating that the gels have the thermoresponsiveness. Because the transmittances of these gels decreased in narrow temperature ranges, we can judge that each gel has only one critical temperature despite that the gels, Me3O7, Me5O5, and Me7O3, were composed of two LCST-type polymers. The determination of the critical temperature, Tc, listed in Table 1 will be discussed below. Figure 3 shows the ensemble-average time-correlation (1) functions, g(1) E (τ), of the POEGMA gels. In all data, gE (τ) 8934


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Figure 3. Ensemble-average time-correlation functions of the scattering field, g(1) E (τ), of POEGMA-based gels with various monomer ratios measured at different temperatures.

copolymerization system (poly(NIPAM-co-acrylic acid) gels).36 The correlation length, ξ, is estimated from D by eq 8 and shown as Figure 5B. In using eq 8, we corrected the water viscosity for each temperature by using the literature values. Similar to PNIPAM-based gels, ξ diverged with increasing temperature. The critical temperature, Tc, was estimated using the function (ξ = ξ0|T − Tc|−ν), where the value of ν was chosen to be ν = 0.5 (for the mean-field assumption) and ν = 0.625 (for the 3D Ising model) (Figure 5B,C).41,42 The values of Tc obtained from the two models were very close to each other; the maximum difference was only 0.5 °C. The fitting was well done using the same exponent (Figure 5B), suggesting that the LCST−LCST type gels used in this study belong to the same class of critical phenomena. It was also supported by the log−log plots (Figure 5C), where the normalized temperature (= |T − Tc|/Tc) was used to compare the gels with different Tc. It should be noted that ξ of the POEGMA-based gels scaled with the normalized temperature falls on a master curve. Moreover, Tc linearly increased with increasing OEGMA segments because the LCST of POEGMA is higher than that of PMeO2MA (Figure 5C). Tc of the gels can be controlled precisely at any requested temperature in the range 21−61 °C without losing the sharpness of volume transition behavior. This advantage will be great useful for biomedical applications, which requires severe

was relaxed with passage of time, while an unrelaxing (static) component also remained. To focus on the dynamic component of POEGMA gels, we extracted g(1) E,F (τ) from (1) (τ) with eq 7a. g (τ) was able to be separated to the fast g(1) E E,F mode (τ < 0.1 ms) and the slow mode (τ > 0.1 ms) as shown in Figure 4. g(1) E,F (τ) consists of two types decay functions, i.e., a single-exponential decay and a power-law decay functions. The former represents the cooperative diffusion (the fast mode) and the latter the slow mode. The fast modes highly likely represent the cooperative diffusion of polymer chains because the relaxation times of the fast modes are very close to the typical relaxation time of the cooperative diffusion of polymer chains (∼0.1 ms). The cooperative diffusion is a widely observed dynamics in semidilute polymer solutions and in gels as a result of thermal fluctuations of polymer chains. With increasing temperature, the fast mode of g(1) E,F (τ) shifted to longer delay times (Figure 4), suggesting that the cooperative diffusion of the POEGMAbased gel network was suppressed. To characterize cooperative diffusion, the diffusion coefficient, D, was obtained by fitting with eq 7b. The obtained D of these gels drastically decreased as T approaching Tc, as shown in Figure 5A, indicating a critical slowing down of the cooperative diffusion near Tc. Similar phenomena were observed for a homopolymer system (PNIPAM homopolymer gels) and an LCST/non-LCST type 8935


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(1) Figure 4. Dynamic component (g(1) E,F (τ)) in the ensemble-average field correlation function (gE (τ)).

temperature control (e.g., 37 °C (body temperature) and 39− 40 °C (fever temperatures)). Effect of Copolymerization on the Slow Dynamics in the Gels. In Figure 4, not only the fast mode originating from the cooperative diffusion of gels but also the slow mode was observed in g(1) E,F (τ). To confirm the origin of the slow mode in the first place, we focused on the temperature dependence of the fluctuating components of g(1) E,F (τ) originating from the slow mode, that is, (1 − A). Here, we further decomposed ⟨IF⟩E into the portions originating from the slow mode by multiplying ⟨IF⟩E with their portion factor (1 − A) (Figure 6). All the parameters including ⟨I⟩E, ⟨IC⟩E, and A⟨IF⟩E are also shown in Figure S1. Figure 6 shows the scattering intensity variations with temperature responsible for the slow mode, (1 − A)⟨IF⟩E. It can be seen that (1 − A)⟨IF⟩E of these gels was increased with rising temperature, suggesting that the scatterers contributing from the slow mode grew in the gels. In this study, we concluded that the slow mode corresponds to the dynamics of contracted domains composed of polymer aggregates. This is based on the following grounds: Lutz et al. proposed a mechanism that could explain the thermoresponsive behavior of POEGMA-based linear polymers; above their LCSTs, cleavage of hydrogen bonds between the ethylene glycol units and water should be the driving force for the phase

transition.43 The dehydrated oligo(ethylene glycol) chains should fold along the apolar backbone due to hydrophobic interactions, as there are no strong hydrogen-bond donors in POEGMA-based polymers; that is, interactions between the oligo(ethylene glycol) side chains were observed by 1H NMR spectroscopy. In this study, POEGMA-based chains are cross-linked, and thus these gels can be deswollen by the aggregation between the hydrophobic chains, which causes the formation of hydrophobic domains in the gels. Hence, we deduce that the slow mode could be assigned to the dynamics of aggregated domain. According to Martin et al.,40 the fractal dimension of the correlation function is simply obtained as Dp in eq 7b. This is because the intensity correlation function is just a density− density correlation function of the detected photons per unit time, and the time axis can be regarded as one-dimensional space. In our system, for instance, Me7O3 gels, the observed values of Dp seem to be independent of q (Figure S2), suggesting that the slow mode is assumed to be the dynamics due to self-similar clusters.40 Additionally, the rise of (1 − A)⟨IF⟩E is monomer ratio dependent: the values of (1 − A)⟨IF⟩E increases sharply up to each Tc as the ratio of MeO2MA components increases (Figure 6). The normalized plot is also displayed in Figure S3. This means that PMeO2MA segments are easy to aggregate. 8936


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Figure 5. Temperature dependence of the cooperative diffusion of polymer chains in POEGMA gels. (A) The cooperative diffusion coefficient, D, and (B) the correlation length, ξ. (C) The log−log plot of the correlation length vs the normalized critical temperature. The slope of the displayed master curve is 0.5 based on the mean-field assumption. (D) The critical temperature, Tc, for the hydrogels obtained by fitting the experimental data with the function (ξ = ξ0|T − Tc|−ν). The dotted curves shown in (B) represent the fitting curves using this function (black: ν = 0.5; red: ν = 0.625).

Scheme 1. Proposed Mechanism of Thermoresponsive Behavior for POEGMA-Based Gels (e.g., (A) Me7O3 and (B) Me3O7)a

Figure 6. Scattering intensity originating from the slow mode, (1 − A)⟨IF⟩E, as a function of temperature.

Conversely, POEGMA segments interfere with the domain formation. According to these results and discussions, we propose the deswelling behavior and its difference depending on the monomer ratio as shown in Scheme 1. In the case of Me7O3, where the number of PMeO2MA segments with low LCST is larger than that of POEGMA, the void (water-rich domain) is easy to be formed in the gel network (Scheme 1A), allowing the hydrophobic chains in the gel to aggregate with each other. On the other hand, in the case of Me3O7 gels, many POEGMA chains with long side chain suppress the aggregation between the main chains in the gels due to the steric hindrance (Scheme 1B). Furthermore, chemically speaking, random copolymers P(MeO2MA-co-OEGMA)

a

The main chain consisting of methacrylate and the side chain consisting of ethylene glycol are shown in red and blue, respectively. At high temperature, the dehydrated side chains are changed to red.

chains can be considered as homopolymers because their LCST can be changed linearly, and they have the same groups (i.e., ethylene glycol and the methacrylate moiety). However, 8937


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Applications; Matyjaszewski, K., Gnanou, P., Leibler, L., Eds.; WileyVCH: Weinheim, Germany, 2007; Vol. 3, pp 1687−1730. (2) Saalwächter, K.; Seiffert, S. Dynamics-based assessment of nanoscopic polymer-network mesh structures and their defects. Soft Matter 2018, 14, 1976−1991. (3) Shibayama, M.; Li, X.; Sakai, T. Gels: From Soft Matter to BioMatter. Ind. Eng. Chem. Res. 2018, 57, 1121−1128. (4) Poly(ethylene glycol) Chemistry: Biotechnical and Biomedical Applications; Harris, J. M., Ed.; Plenum Press: New York, 1992. (5) Banerjee, I.; Pangule, R. C.; Kane, R. S. Antifouling Coatings: Recent Developments in the Design of Surfaces That Prevent Fouling by Proteins, Bacteria, and Marine Organisms. Adv. Mater. 2011, 23, 690−718. (6) Hayashi, K.; Okamoto, F.; Hoshi, S.; Katashima, T.; Zujur, D. C.; Li, X.; Shibayama, M.; Gilbert, E. P.; Chung, U.; Ohba, S.; Oshika, T.; Sakai, T. Fast-forming hydrogel with ultralow polymeric content as an artificial vitreous body. Nat. Biomed. 2017, 1, 0044. (7) Lowe, A. B.; Vamvakaki, M.; Wassall, M. A.; Wong, L.; Billingham, N. C.; Armes, S. P.; Lloyd, A. W. Well-defined sulfobetaine-based statistical copolymers as potential antibioadherent coatings. J. Biomed. Mater. Res. 2000, 52, 88−94. (8) Ishihara, K.; Ueda, T.; Nakabayashi, N. Preparation of Phospholipid Polylners and Their Properties as Polymer Hydrogel Membranes. Polym. J. 1990, 22, 355−360. (9) Ishihara, K.; Mu, M.; Konno, T.; Inoue, Y.; Fukazawa, K. The unique hydration state of poly(2-methacryloyloxyethyl phosphorylcholine). J. Biomater. Sci., Polym. Ed. 2017, 28, 884−899. (10) Lutz, J.-F.; Hoth, A. Preparation of Ideal PEG Analogues with a Tunable Thermosensitivity by Controlled Radical Copolymerization of 2-(2-Methoxyethoxy)ethyl Methacrylate and Oligo(ethylene glycol) Methacrylate. Macromolecules 2006, 39, 893−896. (11) Lutz, J.-F.; Akdemir, Ö .; Hoth, A. Point by Point Comparison of Two Thermosensitive Polymers Exhibiting a Similar LCST: Is the Age of Poly(NIPAM) Over? J. Am. Chem. Soc. 2006, 128, 13046− 13047. (12) Lutz, J.-F. Polymerization of Oligo(Ethylene Glycol) (Meth)Acrylates: Toward New Generations of Smart Biocompatible Materials. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 3459−3470. (13) Luzon, M.; Boyer, C.; Peinado, C.; Corrales, T.; Whittaker, M.; Tao, L.; Davis, T. P. Water-soluble, thermoresponsive, hyperbranched copolymers based on PEG- methacrylates: synthesis, characterization, and LCST behavior. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 2783−2792. (14) Lei, J.; Mayer, C.; Freger, V.; Ulbricht, M. Synthesis and characterization of poly(ethylene glycol) methacrylate based hydrogel networks for anti- biofouling applications. Macromol. Mater. Eng. 2013, 298, 967−980. (15) Dalgakiran, E.; Tatlipinar, H. The role of hydrophobic hydration in the LCST behaviour of POEGMA300 by all-atom molecular dynamics simulations. Phys. Chem. Chem. Phys. 2018, 20, 15389−15399. (16) Lutz, J.-F.; Andrieu, J.; Ü zgün, S.; Rudolph, C.; Agarwal, S. Biocompatible, Thermoresponsive, and Biodegradable: Simple Preparation of “All-in-One” Biorelevant Polymers. Macromolecules 2007, 40, 8540−8543. (17) Smeets, N. M. B.; Bakaic, E.; Patenaude, M.; Hoare, T. Injectable and tunable poly(ethylene glycol) analogue hydrogels based on poly(oligoethylene glycol methacrylate). Chem. Commun. 2014, 50, 3306−3309. (18) Zarafshani, Z.; Obata, T.; Lutz, J.-F. Smart PEGylation of Trypsin. Biomacromolecules 2010, 11, 2130−2135. (19) Trzebicka, B.; Szweda, R.; Kosowski, D.; Szweda, D.; Otulakowski, Ł.; Haladjova, E.; Dworak, A. Thermoresponsive polymer-peptide/protein conjugates. Prog. Polym. Sci. 2017, 68, 35− 76. (20) Li, D.; Jones, G. L.; Dunlap, J. R.; Hua, F.; Zhao, B. Thermosensitive Hairy Hybrid Nanoparticles Synthesized by SurfaceInitiated Atom Transfer Radical Polymerization. Langmuir 2006, 22, 3344−3351.

in the copolymerized gel system, it is not always the case due to the difference in the domain formation mechanism observed in the slow dynamics.

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CONCLUSION The dynamics of LCST−LCST-type gels with high biocompatibility consisting of Poly(MeO2MA-co-OEGMA) was systematically investigated using DLS, where both MeO2MA with short side chain and OEGMA with long side chain were LCST-type polymers. The cooperative diffusion of the network chains related to the fast mode decreased with elevating temperature, and thus the correlation length diverged up to each Tc, similar to the conventional thermoresponsive gels. The value of Tc for the gels was able to be controlled by tuning the copolymerization ratio between two polymers without changing the profile of the volume transition, allowing us to give a new interpretation for LCST−LCST-type gels. The dynamics of the hydrophobically aggregated domains related to the slow mode was unique; the scattering intensity responsible for the slow mode, (1 − A)⟨IF⟩E, was increased with rising temperature, resulting in the growth of the domain in the gels. Moreover, it was monomer ratio dependent. POEGMA with long side chain and high LCST inhibited the domain formation in the whole gel due to the steric hindrance, which reflected in the small rise of (1 − A)⟨IF⟩E by elevating temperature. We thus demonstrated design guidelines for the thermoresponsive hydrogels with high biocompatibility for biomedical applications.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b02035. Information on the representative time-correlation function of the scattering intensity of the all gels; temperature dependence of the all parameters obtained by DLS measurements; and the scattering intensity originating from the slow mode as a function of the normalized temperature (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Takuma Kureha: 0000-0003-4680-6440 Masashi Ohira: 0000-0001-7425-2946 Xiang Li: 0000-0001-6194-3676 Mitsuhiro Shibayama: 0000-0002-8683-5070 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.S. acknowledges a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 16H02277). T.K. acknowledges a grant-in-aid for JSPS Research Fellows (18J02101).

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REFERENCES

(1) Dusěk, K.; Dusǩová-Smrcǩova, M. In Polymer Networks in Macromolecular Engineering. Precise Synthesis, Materials Properties, 8938


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Dynamic Fluctuations of Thermoresponsive Poly(oligo-ethylene glycol

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