Tuning Hydrogel Mechanics by Kinetically Dependent Cross-Linking

Article Cite This: Macromolecules XXXX, XXX, XXX−XXX

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Tuning Hydrogel Mechanics by Kinetically Dependent Cross-Linking Xiaofeng Yu,†,‡,§ Zezhao Qin,†,‡ Haiyang Wu,†,‡ Hongying Lv,*,†,‡ and Xiaoniu Yang*,†,‡ †

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, and ‡Polymer Composites Engineering Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China § University of Chinese Academy of Sciences, Beijing 100049, China

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S Supporting Information *

ABSTRACT: Free radical polymerization is an extensively used method to form a hydrogel network, in which the spatial inhomogeneity can be manipulated by kinetic control. However, it is still a challenge to direct mechanical properties by tuning the kinetics of free radical polymerization. Herein, kinetically dependent cross-linking is used to directly connect with the mechanical properties of hydrogels by tuning the reactivity of the macro-crosslinkers. F127 (PEO99−PPO65−PEO99) diallyl ether (F127DE) macro-cross-linker with low reactivity was first synthesized, and it can induce inner-micelles cross-linking due to its kinetic characteristic that its incorporation in the primary chain is slow at an early stage while rapid at a late stage of copolymerization with acrylamide (AAm) monomer. Thus, the highly cross-linked agglomerations can be effectively controlled in the well-dispersed micelle cross-linking, leading to an internally cross-linked micelle that is far stronger than a micelle formed only by weak supramolecular interaction. Compared to the weak and brittle hydrogel based on F127 diacrylate (F127DA) macro-cross-linker with high reactivity, the hydrogel based on F127DE exhibits a homogeneous network and outstanding strength with a fracture stress of 0.8 MPa and a fracture strain of 1600%. This novel and facile strategy can provide new insights into the utilization of cross-linking kinetics to improve the mechanical property of hydrogels.

1. INTRODUCTION Hydrogels based on polymeric networks have great potential for application in tissue engineering, soft sensing, and actuation.1−4 The network of the hydrogel plays a vital role in determining its mechanical performance, which significantly affects its real-world use.5,6 In situ free radical polymerization of vinyl monomers is a common method to prepare the hydrogel.7,8 Special network structure and excellent mechanical properties have been achieved by employing vinyl monomers able to construct different interaction, such as hydrogen bonds, multiple ionic bonds, hydrophobic domain, and so on.9−17 As known, the network formation in free-radical polymerization is a kinetically controlled process, where the spatial inhomogeneity can be tuned by the polymerization technique, crosslinker reactivity, and stoichiometry of cross-linker and initiator.18−27 Previous research has shown that small molecule cross-linkers with higher or lower reactivity than the monomer both tend to build up highly cross-linked agglomerations within the hydrogels, which are ascribed to the uneven distribution of incorporated cross-linkers in the primary chains.28−30 Because of the difficulty of making the crosslinkers have the same reactivity as monomers, the agglomerations are ubiquitous in hydrogel prepared by free radical polymerization. However, the uncontrollable distribution and sizes of these agglomerations are harmful to the mechanical properties. If the distribution and sizes of these highly crosslinked agglomerations could be elaborately controlled in the © XXXX American Chemical Society

network via kinetics, the mechanics of hydrogel prepared by free radical polymerization could be finely tailored. However, to the best of our knowledge, it is still a challenge to direct mechanical properties by taking advantage of these agglomerations directly related to kinetic control in the free radical polymerization. Micelles based on polymeric macro-cross-linkers have been successfully used as cross-linkings in the hydrogels due to their capability of dispersing local stress by the deformation of micelles under stress.31,32 Compared to small molecule crosslinkers, the distribution of incorporated macro-cross-linkers (in the form of micelles) in the primary chains could induce two types of cross-linking: the inter-micelles and inner-micelles cross-linking. The former provides cross-link points in the network and thus contributes to the elasticity of the hydrogel, while the latter forms internally cross-linked micelle, which will significantly improve the strength of micelles but decrease the cross-linking density of the hydrogel network. These two types of cross-linking present synergy effects on the network structure, and thus they can be employed to manipulate the hydrogel network. For the inner-micelles cross-linking in the hydrogel, the highly cross-linked agglomerations ascribed to the uneven distribution of incorporated cross-linkers in the Received: November 13, 2018 Revised: January 15, 2019

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DOI: 10.1021/acs.macromol.8b02410 Macromolecules XXXX, XXX, XXX−XXX

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was further stirred for 1 day at room temperature. Finally, the solid was filtered away, and the solution left was precipitated in diethyl ether to obtain the F127DE, which was dried in vacuo. F127DA was synthesized according to our previous work.37 F127 (20 g) and K2CO3 (2.2 g) were dissolved in dry DCM (250 mL) under N2. Next, the slurry mixture was cooled to 0 °C, and acryloyl chloride (1.5 g) dissolved in anhydrous DCM (10 mL) was added dropwise into the mixture. Then the F127DA was obtained by the method described above. PEG10000 diacrylate (PEG10000DA) and PEG10000 diallyl ether (PEG10000DE) were achieved by the same method. 2.2. Preparation of Hydrogels. The hydrogels were synthesized via a one-pot polymerization. The concentrations of macro-crosslinkers and AAm monomer were 0.006 and 3 mol L−1, respectively. These hydrogels were named as hydrogel-AnEm, where n and m denote the percentage of F127DA and F127DE in macro-cross-linkers for polymerization, respectively. For example, hydrogel-A0.2E0.8 means the hydrogel consisted of 8 g of water, 1.7 g of AAm, 0.12 g of F127DA, and 0.48 g of F127DE. Briefly, potassium persulfate (0.0065 g), macro-cross-linkers (0.6 g), and AAm (1.7 g) were dissolved in water (8 mL). The mixture was frozen in liquid nitrogen. After three freeze/pump/thaw cycles with nitrogen, the solution was injected in a rectangular mold, and the polymerization was performed for 12 h in a water bath at 50 °C. Hydrogels based on mixture of F127DA and F127 were also synthesized by in situ free-radical polymerization, where the total concentration of F127DA and F127 is 0.006 mol L−1. These hydrogels were named as hydrogel-An, where n denotes the percentage of F127DA in the mixture of F127DA and F127. The hydrogels used to monitor the polymerization process at regular time intervals by 1H NMR were synthesized in the nuclear magnetic tube. The sample solutions were prepared by adding macrocross-linker, monomer (AAm), initiator (potassium persulfate), and DSS in D2O and thoroughly mixed prior to use. The concentrations of AAm and macro-cross-linkers were fixed at 0.17 and 0.002 mol L−1, respectively. The reaction mixtures in the nuclear magnetic tube were sealed in an Erlenmeyer flask and then evacuated and backfilled with nitrogen three times before polymerization at 50 °C. To study the conversion of monomer and macro-cross-linker during the reaction, the samples from the reaction system were taken out and exposed to air to quench the polymer reaction at regular intervals. The concentrations of unreacted macro-cross-linkers and monomers remaining in solution were obtained by the integral area ratio of 1H NMR signals which were detected by a 500 MHz NMR system, that is, the vinylic protons of the macro-cross-linkers (5.9 and 6.3 ppm for the acrylate system, 5.2 ppm for the allyl system) versus the vinylic protons of the acrylamide monomer (5.7 and 6.1 ppm). Finally, we obtained the conversion of macro-cross-linkers and monomer against reaction time. 2.3. Characterization. 1H nuclear magnetic resonance (NMR) spectra of F127DA/PEG10000DA and F127DE/PEG10000DE were recorded with a Bruker 400 MHz DRX spectrometer in deuterated chloroform as solvent. The acrylation degree was calculated by the ratio of acryl protons (=CH2, δ = 5.8−6.4) to methyl protons in poly(propylene oxide) groups (−CH3, δ = 1.1). Dynamic light scattering (DLS) curves were measured with a Brookhaven 90Plus size analyzer at 50 °C, and the angle for DLS curves was 173°. The concentration of macro-cross-linkers was 0.006 mol L−1. Small-angle X-ray scattering (SAXS) experiments were performed on a SAXSess mc2 (Anton Paar) apparatus, Austria. The SAXSess used an ID 3003 laboratory X-ray generator (general electric) equipped with a standard sealed tube (PANalytical, λ(Cu Kα) = 0.1542 nm) operating at 40 kV and 50 mA. Each pattern was collected in 300 s in a vacuum environment. The scattering patterns after calibration were averaged over all directions at a constant scattering vector, q, resulting in one-dimensional scattering intensity curves. Scanning electron microscopy (SEM) was performed on a FEI XL-30 at an accelerating voltage of 10 kV. After immersing in water at 37 °C for 24 h, the hydrogel samples were dehydrated by freezedrying, and the cross sections of samples were coated with a thin layer of gold before measuring.

primary chains could be effectively controlled in the micelle cross-linking, which also becomes stronger than the common micelle cross-linking. Therefore, a homogeneous hydrogel network with strong cross-linkings is expected to be achieved by inner-micelles cross-linking. It is known that the types of cross-linking can be significantly influenced by the sequence structure of primary chain, which can be controlled in the copolymerization process by the kinetic factors, such as the reactivity of cross-linker. For example, when the reactivity of macro-cross-linker is lower than that of monomer, the concentrative distribution of incorporated macro-cross-linker on the primary chain can be obtained at high monomer conversion, which will promote the homopolymerization of macro-cross-linkers in one micelle and therefore benefit the inner-micelles cross-linking. However, very limited attention has been paid to the effect of kinetically dependent crosslinking on the network and mechanical properties of the resulted hydrogel. Inspired by the effect of inner-micelles cross-linking on the network and the function of kinetic factors, a new strategy was designed to manipulate kinetically dependent cross-linking via tuning the reactivity of macro-cross-linkers to enhance the mechanical properties of hydrogels. F127 is a well-investigated amphiphilic triblock copolymer, which can self-assemble into micelles with diameter (d) ca. 10 nm in water. F127DA with reactivity close to the AAm monomer has been successfully used as macro-cross-linkers in the hydrogels.33−36 To show the effect of macro-cross-linkers reactivity on the cross-linking type, F127DE with much lower reactivity is first designed, and a series of hydrogels with different cross-linking types were prepared by employing different ratios of F127DA to F127DE. As expected, the reactivity of the macro-cross-linker has a clear correlation with the microstructure and mechanical properties. The concentrative distribution of incorporated F127DE on the primary chain can be obtained at high AAm conversion, which promotes the homopolymerization of F127DE in one micelle and therefore benefits the formation of internally cross-linked micelles. The resultant hydrogels based on F127DE show a homogeneous network and a significantly enhanced tensile performance, while the heterogeneous network and poor mechanical performances are present in the hydrogels based on F127DA. Therefore, a novel and facile strategy for enhancing mechanical properties is developed by tuning cross-linking kinetics to finely control these highly cross-linked agglomerations in the network.

2. EXPERIMENTAL SECTION 2.1. Preparation of F127DE and F127DA. Potassium persulfate (PPs), Pluronic F127, and monomer AAm were purchased from Sigma-Aldrich. Poly(ethylene glycol) (PEG, Mn = 10000 g mol−1), sodium 3-(trimethylsilyl)-1-propanesulfonate (DSS), acryloyl chloride, and allyl bromide were purchased from Energy Chemical Reagent Company (China). Ground potassium carbonate (K2CO3) and flaky potassium hydroxide (KOH) were purchased from Tianjin Guangfu Fine Chemical Research Institute (China). Tetrahydrofuran (THF) and dichloromethane (DCM) were freshly distilled over metallic sodium (Na) and calcium hydride (CaH2), respectively, before use. The pure water was achieved by deionization and filtration (resistivity ≥18.2 MΩ cm). F127DE was synthesized according to the established procedure. First, F127 (20 g) and flaky KOH (0.89 g) were added into 200 mL of anhydrous THF under a nitrogen atmosphere. Next, allyl bromide (1.92 g) dissolved in anhydrous THF (10 mL) was added dropwise into the above slurry mixture under string at 0 °C. Then the mixture B

DOI: 10.1021/acs.macromol.8b02410 Macromolecules XXXX, XXX, XXX−XXX

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Figure 1. (a) Schematic illustration of kinetically dependent micelle cross-linking. (b) Calculated results for macro-cross-linker conversion versus the AAm conversion during the copolymerization of them. r1 and r2 are the reactivity ratios of the AAm monomers and macro-cross-linkers, respectively.

and macro-cross-linker was fixed. The reactivity of reagents can be represented by the reactivity ratios of AAm (r1) and macrocross-linker (r2), which were calculated on the basis of Alfrey− Price equations. The detailed calculation is shown in the Supporting Information, and the corresponding results are listed in Table S1. It can be seen that F127DA (r2 = 0.57) and AAm (r1 = 0.68) have similar reactivity in their free radical copolymerization; therefore, both of them tend to undergo cross-propagation reaction. However, the concentration of F127DA is very low (0.006 M) compared to AAm (3 M), so the incorporated F127DA are sparsely distributed in the primary chain at the very early stage and F127DA is also consumed more quickly than AAm, which make the homopropagation reaction and the formation of internally cross-linked micelle of F127DA difficult. In contrast, F127DE (r2 = 0.06) has much lower reactivity than AAm (r1 = 8.69) in their radical copolymerization, in which F127DE and AAm are prone to experience cross-propagation reaction and homopropagation reaction at an early stage, respectively. Because of the lower reactivity and concentration, the incorporation rate of F127DE in the primary chains is considerably slow, and thus the concentrated distribution of F127DE can be obtained at the late stage (Figure 1a). To better show the effect of macrocross-linker reactivity on their incorporation rate in the primary chain, the conversions of AAm monomer and

2.4. Mechanical Tests of the Hydrogels. Uniaxial tensile tests were measured on dumbbell-shaped gels with the standard size (20 mm (l0) × 4 mm (w) × 2 mm (d)) using a universal tensile tester (Suns MOD UTM 4202) with a 20 N load cell. The deformation was conducted at the rate of 0.167 s−1. The engineering stress (σ) was calculated from σ = F/A0, where F is the applied force to the sample and A0 is the original cross-sectional area of the sample. The engineering strain (ε) was determined by ε = (l − l0)/l0 × 100%, where l and l0 are the length during stretching and initial gauge length of the sample, respectively. The modulus was calculated by fitting the initial linear region of the stress−strain curve.

3. RESULTS AND DISCUSSION 3.1. Effect of Macro-Cross-Linker Reactivity on the Cross-Linking Type. The acrylamide monomer and initiator potassium persulfate both completely dissolved in solution, while the vinyl groups of macro-cross-linkers disperse on the surface of micelles. This polymerization system is a particular solution copolymerization process whose specificity arises from macro-cross-linkers aggregation.38,39 During the free radical copolymerization, the distribution of vinyl species on the primary chain was influenced by several parameters, such as the reactivity of vinyl groups, the concentration of vinyl species, and so on. To exclusively investigate the effect of macro-cross-linker reactivity on the cross-linking type of micelles, herein, the initial concentration of AAm monomer C

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Figure 2. 1H NMR spectra evolution of (a) F127DA/AAm and (b) F127DE/AAm during the formation of the hydrogel.

Figure 3. (a) SAXS profiles of different hydrogel-AnEm. (b) SAXS profiles of the hydrogel-A1E0 and hydrogel-A0E1 at low AAm conversion.

monomer in the early stage, at which a small proportion of AAm monomers still remained. In contrast, only very few F127DE macro-cross-linkers were consumed at the same stage, indicating most of them were incorporated into the polymer chain with a few AAm monomers at late conversion. This result confirms that the incorporation rate of F127DE in primary chain was much slower than that of F127DA in the early stage due to the lower reactivity of allyl ether groups in F127DE than acrylate groups in F127DA. Moreover, to investigate the effect of the aggregation of macro-cross-linkers on the copolymerization process of AAm and macro-cross-linkers, hydrophilic macro-cross-linkers PEG10000DA and PEG10000DE were used in the copolymerization with AAm. Their copolymerization process in D2O was also monitored by 1H NMR at regular time intervals during the formation of hydrogel. As shown in Figure S2, both AAm and F127DA were consumed much faster than the copolymerization using PEGDA as macro-cross-linker, while there was little difference between the copolymerization using F127DE and PEGDE as macro-cross-linker (Figure S3). This result indicates the aggregation of macro-cross-linkers can further increase the difference of polymerization rate between acrylate version and allyl version. On the basis of these results mentioned above, it is anticipated that the microstructures and mechanic properties of hydrogel could be directly connected with kinematical control. 3.2. Preparation and Characterization of Hydrogels. To investigate the impact of macro-cross-linkers reactivity on the microstructure of hydrogel, a series of hydrogels were synthesized by in situ free-radical copolymerization of AAm

macro-cross-linker (F127DA and F127DE) in the radical copolymerization are calculated based on the initial molar ratio of AAm to macro-cross-linker and their reactivity when the aggregation of macro-cross-linker is ignored. The detailed calculation is also shown in the Supporting Information. Figure 1b shows the conversion of F127DE is much lower than that of F127DA at any AAm conversion just due to the lower reactivity of the allyl ether groups than the acrylate groups. Compared to F127DA, the incorporation rate of F127DE in the primary chain is slower at low AAm conversion while becoming significantly higher at high AAm conversion, indicating F127DE is mainly incorporated into the polymer chain at high AAm conversion. For example, when the conversion of AAm is 99.92%, the conversion of F127DE only reached a value 80.22%, and the remaining 20% of F127DE would react with almost equimolar AAm. This indicates F127DE has a high probability of homopropagation and thus forms internally cross-linked micelle at high AAm conversion. Taking only these results into consideration, it is reasonable that F127DA can form cross-linking points for the three-dimensional cross-linked network and contribute to the network elasticity of the hydrogel, while the F127DE should form an internally cross-linked micelle and decrease the crosslinking density of the three-dimensional network. To demonstrate the effect of macro-cross-linker reactivity on their incorporation rate in the primary chain, the copolymerization process of AAm (0.17 M) and macro-cross-linkers (0.002 M) in D2O was monitored by 1H NMR at regular time intervals during the formation of hydrogel. As shown in Figure 2, almost all F127DA macro-cross-linkers reacted with AAm D

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Figure 4. Schematic illustration of the cross-linking types of hydrogel-A1E0 and hydrogel-A0E1.

hydrophobic vinyl groups on the surface of micelles.37 But the difference in characteristic of polymerization process between F127DA and F127DE at low AAm conversion could result in different cross-linking types of micelles. The F127DA and AAm monomers both tend to undergo cross-propagation reaction, indicating the vinyl groups on the surface of large clusters (hundreds of nanometers) are easily connected via the incorporated AAm in the resultant primary chains. As illustrated in Figure 4, the polymerization character of F127DA and AAm can make the aggregation of the F127DA micelles be preserved easily by chemical conjugation at the early stage and then retained in the hydrogel. The SEM images of swollen hydrogel-A1E0 also demonstrated that this aggregation can affect the homogeneity of cross-linked network and deformability of micelles due to its difficulty to be swollen in water. In contrast, F127DE and AAm are prone to experience cross-propagation reaction and homopropagation reaction, respectively. Because of the large initial mole ratio of AAm to F127DE (500/1), lots of AAm monomers were incorporated into the polymer chain at the early stage. It means flexible and long hydrophilic PAAm chain can be formed between F127DE micelles and thus prevent the micelles from aggregating Meanwhile, few F127DE macro-cross-linkers are consumed at the early stage of copolymerization, inducing the low crosslinking density and thus making the aggregation of F127DE micelles difficult to be preserved by chemical conjugation. Accordingly, as shown in the Figure 4, the well-distributed F127DE micelle cross-linkings are obtained, and many allyl groups located on the micelle surface are protected by the surrounding PAAm chain. At the late stage of gelation, the well-distributed F127DE micelle cross-linkings are immobilized in the cross-linked network; thus, the allyl groups mainly react with a radical in the same micelle due to a concentrated distribution of F127DE in the primary chains, leading to the formation of internally cross-linked micelles. Because high cross-linked agglomerates are effectively controlled in the well-

and different ratios of F127DA to F127DE in water. These hydrogels were named as hydrogel-AnEm, where n and m denote the percentage of F127DA and F127DE in macrocross-linkers, respectively. The microstructures of hydrogels were explored by SAXS (Figure 3). For the hydrogel-A1E0, a broad peak was observed, which was assigned to the average distance between hydrophobic domains of micelles. With the proportions of F127DE in the macro-cross-linkers for polymerization increasing, the peak was shifted to lower qvalue and disappeared in the hydrogel-A0E1, indicating the increase of average distance between micelles. Consistent with the SAXS results, the SEM images of swollen hydrogels showed that the heterogeneous network was observed in swollen hydrogel-A1E0, but the heterogeneity in network became less and less with the increase of the F127DE proportion and a uniform network was observed in swollen hydrogel-A0E1 (Figure S4). Interestingly, small molecule cross-linkers with higher or lower reactivity than monomer tend to build up highly crosslinked agglomerations within the hydrogels, which are ascribed to the uneven distribution of incorporated cross-linkers in the primary chains.28−30 However, hydrogel-A0E1 based on macrocross-linkers with low reactivity in this work is subject to yielding homogeneous network. This differences in the microstructure between hydrogels based on small molecule cross-linkers and macro-cross-linkers are attributed to the effect of distribution of micelles self-assembled from macrocross-linkers on the network. For the hydrogels-AnEm, there should be two underlying factors affecting the microstructure. The one is the aggregation of micelles in solution for polymerization, which is harmful to the formation of homogeneous network. The other one is the characteristic of polymerization process at low AAm conversion, which could significantly affect these aggregates during gelation. It can be found that both F127DA and F127DE micelles were easily to aggregate into large clusters in water (Figure S5a), which can be ascribed to the hydrophobic interaction between the E

DOI: 10.1021/acs.macromol.8b02410 Macromolecules XXXX, XXX, XXX−XXX

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Figure 5. (a, d) Tensile stress−strain curves, (b, e) the change of stress and strain at break, (c, f) elastic modulus curves of (a, b, c) hydrogel-AnEm and (d, e, f) hydrogel-An.

by mixing the F127DA and F127, which will greatly influence the mechanical properties of the resultant hydrogels. 3.3. Mechanical Properties of Hydrogels. As mentioned above, the cross-linking type of macro-cross-linkers depending on their reactivity has a great impact on the microstructure of hydrogels, which is a critical factor in determining the mechanical properties. The type of cross-linking can also affect the strength of the micelle, where the inner one could reinforce the strength of the micelle by chemically conjugating the cross-linking points onto the surface of the micelle because of the tetrafunctional character of the employed macro-crosslinker. Thus, it is anticipated that the mechanics of the hydrogels can be tuned by controlling the cross-linking types. Herein, we performed the uniaxial tensile test on the asprepared hydrogels to investigate their mechanical properties. As shown in Figures 5a and 5b, the tensile properties of hydrogel-AnEm were greatly influenced by the proportion of low reactive F127DE in the macro-cross-linkers. The hydrogelA1E0 based on the highly reactive F127DA macro-cross-linker was quite weak and brittle, showing the fracture stress of 0.15 MPa and the fracture strain of 400%. When the percentage of the F127DE micelles increased to 0.8, both the fracture stress and fracture strain of hydrogel-A0.2E0.8 were significantly increased to 0.50 MPa and 1200%, respectively. The fracture strain and fracture stress further increased with increasing the percentage of F127DE, giving a number as high as 1600% and 0.8 MPa in hydrogel-A0E1. Meanwhile, hydrogel-A0E1 could be easily stretched, bended, curled, knotted, and released to its original form. The excellent tensile properties of hydrogel-A0E1 were attributed to the homogeneous network and strong internally cross-linked micelles cross-linkings. To confirm the effect of internally cross-linked micelle on the mechanical properties, hydrogel-An based on F127DA and F127 macro-cross-linkers was measured because the internally cross-linked micelle cannot be formed in them. As shown in Figures 5d and 5e, although the homogeneous network achieved in hydrogel-A0.1 led to a fracture strain of 1600%, the fracture stress was only 0.15 MPa, which is significantly low in comparison with hydrogel-A0E1 (0.8 MPa). This indicates that the internally cross-linked micelle can greatly enhance the fracture strength due to the strong cross-linkings resisting the

dispersed F127DE micelle cross-linkings, the cross-linking density of hydrogel-A0E1 is decreased in comparison with hydrogel-A1E0. It was simply demonstrated by the swelling ratio of hydrogels, which increased with rising the proportion of F127DE in macro-cross-linkers (Figure S6). To prove the effect of the kinetically dependent cross-linking types on the microstructure of hydrogels, we also explored the dispersion state of F127DA and F127DE micelles at low AAm conversion by SAXS. As shown in Figure 3b, the peak representing the aggregation of F127DA micelles is clearly observed after reaction for 1 h. With the reaction proceeding, this peak was shifted to higher q value, which indicates the decrease of average distance between micelles, implying these aggregates were closer. In contrast, the F127DE micelles showed homogeneous distribution once gelation, which became more uniform with increasing polymerization time. The results demonstrate that the macro-cross-linker reactivity has a great influence on the microstructure of hydrogel. F127DA is prone to preserve the aggregation of F127DA micelles, while the F127DE can form well-dispersed internally cross-linked micelles. To further confirm the impact of aggregation of micelles and cross-linking density on the network of hydrogel, hydrogels based on a mixture of F127DA and F127 were also synthesized by in situ free-radical polymerization. These hydrogels were named as hydrogel-An, where n denotes the percentage of F127DA in the mixture of F127DA and F127. The introduction of F127 to F127DA intends to reduce the concentration of hydrophobic vinyl groups on the surface of micelles and the cross-linking density, thus achieving the homogeneous network. The DLS results showed the aggregation of micelle disappeared with the proportion of F127 increasing (Figure S5b). The swelling experiments displayed the swelling ratio of hydrogels increased with the proportion of F127 rising (Figure S6b), indicating the crosslinking density decreased. As expected, a homogeneous network was observed in the hydrogel-A0.1, which contained a low proportion of F127DA (Figure S5c). These results demonstrate that well-dispersed micelles and low cross-linking density benefit the homogeneous network of hydrogels. However, the internally cross-linked micelle cannot be formed F

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Figure 6. (a) Tensile stress−strain curves, (b) the change of stress and strain at break, (c) elastic modulus curves, and (d) swelling ratio of the hydrogels formed at different F127DE concentrations.

cross-linking, where the agglomeration in network can be effectively controlled in the well-dispersed micelle crosslinking, leading to homogeneous network and strong crosslinkings. The hydrogels based on F127DE macro-cross-linker showed significantly enhanced tensile performance with a fracture stress of 0.8 MPa and a fracture strain of 1600%, while hydrogels based on F127DA macro-cross-linker exhibited poor mechanical performances due to the inhomogeneity in network related to the kinematical factor. These provide solid evidence to demonstrate that it is possible to directly manipulate the mechanical properties of hydrogel by taking advantage of the kinetically dependent cross-linking types. Moreover, kinetically dependent cross-linking types are independent of other attributes of network architecture, such as functional groups incorporated to the monomers. This new method provides an excellent platform to tune the microstructure and mechanic properties of the hydrogels in an orthogonal and a ubiquitous way. It can be foreseen that this facile strategy could open up a new route for manipulating mechanics by kinetic control.

applied load. It was noted that elastic modulus decreased with the decrease of F127DA percentage for both hydrogel-AnEm and hydrogel-An (Figures 5c and 5f). This may be ascribed to the decreased cross-linking density in the hydrogel network. The swelling ratio of hydrogel-AnEm and hydrogel-An also decreased with the percentage of F127DA decrease (Figure S6), which is consistent with the decreased cross-linking density. To investigate the influence of cross-linking density on the mechanical properties of hydrogels, we examined hydrogels based on F127DE with different concentrations of F127DE. As showed in Figure 6a, these hydrogels are ultrastretchable upon uniaxial tensile tests, but the fracture strain monotonically decreased with the increase of F127DE due to the increase of cross-linking density. The elastic modulus was increased and swelling ratio decreased with the F127DE increasing, which is also consistent with increase of cross-linking density (Figures 6c and 6d). However, the fracture stress first increased and then decreased with the increase of F127DE, indicating rational cross-linking density is necessary for the excellent mechanical properties of hydrogels. These results demonstrate that the excellent mechanical properties of hydrogel-A0E1 stem from its unique microstructure, which includes the homogeneous cross-linking network and the internally cross-linked micelles. On the one hand, the homogeneous network and appropriate cross-linking density endow the hydrogel with excellent stretchability. On the other hand, the internally crosslinked micelles are strong enough to disperse the local stress and endow the resultant hydrogel with remarkable tensile strength.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.8b02410. Figures S1−S7 and Table S1 (PDF)

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4. CONCLUSION In conclusion, we designed a novel strategy to direct mechanical properties through tuning the reactivity of macro-cross-linkers. F127DE macro-cross-linker with low reactivity was first synthesized, and a series of hydrogels were prepared by employing different ratios of F127DA to F127DE to adjust the cross-linking types of micelles. Compared to F127DA, F127DE could form inner-micelles

AUTHOR INFORMATION

Corresponding Authors

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

Xiaoniu Yang: 0000-0002-7399-5454 Notes

The authors declare no competing financial interest. G

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(19) Sanson, N.; Rieger, J. Synthesis of nanogels/microgels by conventional and controlled radical crosslinking copolymerization. Polym. Chem. 2010, 1 (7), 965−977. (20) Jia, Y.-B.; Ren, W.-M.; Liu, S.-J.; Xu, T.; Wang, Y.-B.; Lu, X.-B. Controlled Divinyl Monomer Polymerization Mediated by Lewis Pairs: A Powerful Synthetic Strategy for Functional Polymers. ACS Macro Lett. 2014, 3 (9), 896−899. (21) Ma, J.; Cheng, C.; Sun, G.; Wooley, K. L. Well-Defined Polymers Bearing Pendent Alkene Functionalities via Selective RAFT Polymerization. Macromolecules 2008, 41 (23), 9080−9089. (22) O’Brien, N.; McKee, A.; Sherrington, D. C.; Slark, A. T.; Titterton, A. Facile, versatile and cost effective route to branched vinyl polymers. Polymer 2000, 41 (15), 6027−6031. (23) Zhao, T.; Zheng, Y.; Poly, J.; Wang, W. Controlled multi-vinyl monomer homopolymerization through vinyl oligomer combination as a universal approach to hyperbranched architectures. Nat. Commun. 2013, 4, 1873. (24) Cerid, H.; Okay, O. Minimization of spatial inhomogeneity in polystyrene gels formed by free-radical mechanism. Eur. Polym. J. 2004, 40 (3), 579−587. (25) Tobita, H.; Hamielec, A. E. Crosslinking kinetics in polyacrylamide networks. Polymer 1990, 31 (8), 1546−1552. (26) Naghash, H. J.; Okay, O. Formation and structure of polyacrylamide gels. J. Appl. Polym. Sci. 1996, 60 (7), 971−979. (27) Orakdogen, N.; Okay, O. Influence of the initiator system on the spatial inhomogeneity in acrylamide-based hydrogels. J. Appl. Polym. Sci. 2007, 103 (5), 3228−3237. (28) Lindemann, B.; Schroder, U. P.; Oppermann, W. Influence of the cross-linker reactivity on the formation of inhomogeneities in hydrogels. Macromolecules 1997, 30 (14), 4073−4077. (29) Gao, H.; Miasnikova, A.; Matyjaszewski, K. Effect of CrossLinker Reactivity on Experimental Gel Points during ATRcP of Monomer and Cross-Linker. Macromolecules 2008, 41 (21), 7843− 7849. (30) Patras, G.; Qiao, G. G.; Solomon, D. H. Controlled formation of microheterogeneous polymer networks: Influence of monomer reactivity on gel structure. Macromolecules 2001, 34 (18), 6396−6401. (31) Xiao, L.; Liu, C.; Zhu, J.; Pochan, D. J.; Jia, X. Hybrid, elastomeric hydrogels crosslinked by multifunctional block copolymer micelles. Soft Matter 2010, 6 (21), 5293. (32) Wiener, C. G.; Wang, C.; Liu, Y.; Weiss, R. A.; Vogt, B. D. Nanostructure Evolution during Relaxation from a Large Step Strain in a Supramolecular Copolymer-Based Hydrogel: A SANS Investigation. Macromolecules 2017, 50 (4), 1672−1680. (33) Wang, P.; Deng, G.; Zhou, L.; Li, Z.; Chen, Y. Ultrastretchable, Self-Healable Hydrogels Based on Dynamic Covalent Bonding and Triblock Copolymer Micellization. ACS Macro Lett. 2017, 6, 881− 886. (34) Sun, Y.-n.; Gao, G.-r.; Du, G.-l.; Cheng, Y.-j.; Fu, J. Super Tough, Ultrastretchable, and Thermoresponsive Hydrogels with Functionalized Triblock Copolymer Micelles as Macro-Cross-Linkers. ACS Macro Lett. 2014, 3 (5), 496−500. (35) Wu, C.-J.; Gaharwar, A. K.; Chan, B. K.; Schmidt, G. Mechanically Tough Pluronic F127/Laponite Nanocomposite Hydrogels from Covalently and Physically Cross-Linked Networks. Macromolecules 2011, 44 (20), 8215−8224. (36) Sun, Y. N.; Liu, S.; Du, G. L.; Gao, G. R.; Fu, J. Multiresponsive and tough hydrogels based on triblock copolymer micelles as multi-functional macro-crosslinkers. Chem. Commun. 2015, 51 (40), 8512−8515. (37) Yu, X.; Qin, Z.; Wu, H.; Lv, H.; Yang, X. pH-driven preparation of small, non-aggregated micelles for ultra-stretchable and tough hydrogels. Chem. Eng. J. 2018, 342, 357−363. (38) Candau, F.; Selb, J. Hydrophobically-modified polyacrylamides prepared by micellar polymerization. Adv. Colloid Interface Sci. 1999, 79 (2−3), 149−172. (39) Hill, A.; Candau, F.; Selb, J. Properties of hydrophobically associating polycrylamides: influence of the method of synthesis. Macromolecules 1993, 26 (17), 4521−4532.

ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant No. 21803069).

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REFERENCES

(1) Lee, K. Y.; Mooney, D. J. Hydrogels for tissue engineering. Chem. Rev. 2001, 101 (7), 1869−1879. (2) Qin, Z.; Qu, B.; Yuan, L.; Yu, X.; Li, J.; Wang, J.; Lv, H.; Yang, X. Injectable shear-thinning hydrogels with enhanced strength and temperature stability based on polyhedral oligomeric silsesquioxane end-group aggregation. Polym. Chem. 2017, 8 (10), 1607−1610. (3) Richter, A.; Paschew, G.; Klatt, S.; Lienig, J.; Arndt, K.-F.; Adler, H.-J. P. Review on hydrogel-based pH sensors and microsensors. Sensors 2008, 8 (1), 561−581. (4) Dong, L.; Agarwal, A. K.; Beebe, D. J.; Jiang, H. R. Adaptive liquid microlenses activated by stimuli-responsive hydrogels. Nature 2006, 442 (7102), 551−554. (5) Zander, Z. K.; Hua, G.; Wiener, C. G.; Vogt, B. D.; Becker, M. L. Control of Mesh Size and Modulus by Kinetically Dependent CrossLinking in Hydrogels. Adv. Mater. 2015, 27 (40), 6283−6288. (6) Yesilyurt, V.; Ayoob, A. M.; Appel, E. A.; Borenstein, J. T.; Langer, R.; Anderson, D. G. Mixed Reversible Covalent Crosslink Kinetics Enable Precise, Hierarchical Mechanical Tuning of Hydrogel Networks. Adv. Mater. 2017, 29 (19), 1605947. (7) Chen, Q.; Zhu, L.; Zhao, C.; Wang, Q. M.; Zheng, J. A Robust, One-Pot Synthesis of Highly Mechanical and Recoverable Double Network Hydrogels Using Thermoreversible Sol-Gel Polysaccharide. Adv. Mater. 2013, 25 (30), 4171−4176. (8) Shi, F.-k.; Zhong, M.; Zhong, L.-q.; Liu, X.-y.; Xie, X.-m. Preparation of Hierachically Crosslinked Poly(acrylamide) Hydrogels by Assistance of Crystallization of Poly(vinyl alcohol). Acta Polym. Sin. 2017, 3, 491−497. (9) Tuncaboylu, D. C.; Sari, M.; Oppermann, W.; Okay, O. Tough and Self-Healing Hydrogels Formed via Hydrophobic Interactions. Macromolecules 2011, 44 (12), 4997−5005. (10) Mihajlovic, M.; Staropoli, M.; Appavou, M. S.; Wyss, H. M.; Pyckhout-Hintzen, W.; Sijbesma, R. P. Tough Supramolecular Hydrogel Based on Strong Hydrophobic Interactions in a Multiblock Segmented Copolymer. Macromolecules 2017, 50 (8), 3333−3346. (11) Jeon, I.; Cui, J. X.; Illeperuma, W. R. K.; Aizenberg, J.; Vlassak, J. J. Extremely Stretchable and Fast Self-Healing Hydrogels. Adv. Mater. 2016, 28 (23), 4678−4683. (12) Dai, X.; Zhang, Y.; Gao, L.; Bai, T.; Wang, W.; Cui, Y.; Liu, W. A Mechanically Strong, Highly Stable, Thermoplastic, and SelfHealable Supramolecular Polymer Hydrogel. Adv. Mater. 2015, 27 (23), 3566−3571. (13) Lin, P.; Ma, S. H.; Wang, X. L.; Zhou, F. Molecularly Engineered Dual-Crosslinked Hydrogel with Ultrahigh Mechanical Strength, Toughness, and Good Self-Recovery. Adv. Mater. 2015, 27 (12), 2054−2059. (14) Sun, T. L.; Kurokawa, T.; Kuroda, S.; Bin Ihsan, A.; Akasaki, T.; Sato, K.; Haque, M. A.; Nakajima, T.; Gong, J. P. Physical hydrogels composed of polyampholytes demonstrate high toughness and viscoelasticity. Nat. Mater. 2013, 12 (10), 932−937. (15) Xiao, L.; Zhu, J.; Londono, D. J.; Pochan, D. J.; Jia, X. Mechano-Responsive Hydrogels Crosslinked by Block Copolymer Micelles. Soft Matter 2012, 8 (40), 10233−10237. (16) Zhao, T. T.; Tan, M.; Cui, Y. L.; Deng, C.; Huang, H.; Guo, M. Y. Reactive macromolecular micelle crosslinked highly elastic hydrogel with water-triggered shape-memory behaviour. Polym. Chem. 2014, 5 (17), 4965−4973. (17) Yang, L. Q.; Lu, L.; Zhang, C. W.; Zhou, C. R. Highly stretchable and self-healing hydrogels based on poly(acrylic acid) and functional POSS. Chin. J. Polym. Sci. 2016, 34 (2), 185−194. (18) Koh, M. L.; Konkolewicz, D.; Perrier, S. A Simple Route to Functional Highly Branched Structures: RAFT Homopolymerization of Divinylbenzene. Macromolecules 2011, 44 (8), 2715−2724. H

DOI: 10.1021/acs.macromol.8b02410 Macromolecules XXXX, XXX, XXX−XXX