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Mar 21, 2017 - •S Supporting Information. ABSTRACT: Multifunctional and multiresponsive hydrogels have presented a promising platform to design and ...
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Facile Access to Multisensitive and Self-Healing Hydrogels with Reversible and Dynamic Boronic Ester and Disulfide Linkages Ruiwei Guo,†,‡ Qian Su,† Jinwei Zhang,‡ Anjie Dong,†,§ Cunguo Lin,‡ and Jianhua Zhang*,†,∥ †

Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, and ∥Tianjin Key Laboratory of Membrane Science and Desalination Technology, Tianjin University, Tianjin 300072, China ‡ State Key Laboratory for Marine Corrosion and Protection, Luoyang Ship Material Research Institute (LSMRI), Qingdao 266101, China § Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China S Supporting Information *

ABSTRACT: Multifunctional and multiresponsive hydrogels have presented a promising platform to design and fabricate smart devices for application in a wide variety of fields. However, their preparations often involve multistep preparation of multiresponsive polymer precursors, tedious reactions to introduce functional groups or sophisticated molecular designs. In this work, a multifunctional boronic acid-based cross-linker bis(phenylboronic acid carbamoyl) cystamine (BPBAC) was readily prepared from inexpensive commercially available 3-carboxylphenylboronic acid (CPBA) and cystamine dihydrochloride, which has the ability to cross-link the cis-diols and catechol-containing hydrophilic polymers to form hydrogels. Due to the presence of the reversible and dynamic boronate ester and disulfide bonds, the obtained hydrogels were demonstrated to not only possess pH, glucose, and redox triresponsive features, but also have autonomic self-healing properties under ambient conditions. Moreover, we can modulate the rheological and mechanical properties by simply adjusting the BPBAC amount. The features, such as commercially available starting materials, easy-to-implement approach, and versatility in controlling cross-linking network and mechanical properties, make the strategy described here a promising platform for fabricating multifunctional and smart hydrogels.

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INTRODUCTION Inspired by the natural intelligent materials, some polymeric hydrogels are designed to be able to exhibit a significant responsivity to a multitude of external chemical/physical/ mechanical stimuli, such as pH value, ionic strength, glucose concentration, enzymatic activity, temperature, light, magnetic field, electric field, pressure, or a combination of them, and thus such smart hydrogels as promising materials have shown tremendous potential in versatile applications, especially in biomedical and pharmaceutical applications.1−4 So far, most responsive hydrogels are responsive to a single or two different stimuli (mainly pH or/and temperature stimuli), whose responsivities are mainly derived from the inherent stimulisensitive properties of build block polymers.5,6 In comparison with the single stimulus-responsive systems, the dual or multiresponsive hydrogels that can respond to two or more environmental stimulus, which have been proven to be able to offer higher flexibility for further applications and more opportunities to achieve higher tunability and realize additional multifunctionality in a synergistic manner.5,7−9 Especially, some specific applications in complex biological environments and natural feedback systems are placing unprecedented demands on multifunctional materials, highlighting the need for the © 2017 American Chemical Society

development of multiresponsive hydrogels with the ability to respond to different stimuli to perform separate functions.3−5,10 For example, because of their specific, distinct, and multiple responses to varied physiological stimuli, the multiresponsive polymer hydrogels with tunable and even biomimetic behavior not only have demonstrated great utility as an innovative drug delivery system for encapsulating and delivering multiple drugs with different properties, but also have shown excellent promise for applications in tissue-engineering systems interacting with the biological environments through various physiological and cellular cues.5,11 However, despite demonstrating great utility and promising potential, the dual or multiresponsive hydrogels, especially the intelligent hydrogels with multiresponsiveness, are still rare, mainly due to the limited availability of polymer precursors with inherent multisensitivities.3−6 Therefore, to meet the rigorous and diverse demands, it is imperative to develop new materials or novel strategies for the fabrication of functional hydrogels with multiresponsive properties. Received: January 19, 2017 Revised: March 20, 2017 Published: March 21, 2017 1356

DOI: 10.1021/acs.biomac.7b00089 Biomacromolecules 2017, 18, 1356−1364

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Scheme 1. Schematic Illustration of Hydrogel Formation from BPBAC and Diols or Catechol-Containing Polymers and the Representative Mechanisms of Its Multiresponsiveness

studies have employed DCB to elaborate multiresponsive materials.32 One of the main reasons can be attributed to the scarcity of available multiresponsive DCBs. Generally, the DCBs only possess mono- or dual-functionality. Therefore, they are not suitable to be used for preparing multiresponsive hydrogels in terms of decreasing synthetic complexity, especially considering the fact that the procedures to create DCB-based materials generally involve tedious modifications to introduce reactive groups on the terminal or side chains of polymers. Therefore, challenges still remain to develop costeffective and efficient methods for the preparation of multiresponsive hydrogels from commercially available and inexpensive components. In this work, a multifunctional boronic acid-based crosslinker bis(phenylboronic acid carbamoyl) cystamine (BPBAC) was readily prepared from inexpensive commercially available 3-carboxylphenylboronic acid (CPBA) and cystamine dihydrochloride. Subsequently, the ability of BPBAC to cross-link the cis-diols and catechol-containing polymers to form dynamic hydrogels with tailorable network and mechanical strengths was demonstrated, as shown in Scheme 1. The reversibility and dynamic nature of the boronate ester and disulfide bonds provided not only pH, glucose, and redox triresponsive features, but also self-healing properties by the autonomic reconstruction without using a healing agent. Considering the commercially available starting materials, ease of fabrication, and versatility in tailoring cross-linking network and regulating the rheological and mechanical properties, the procedure described here offers a promising strategy for the development of multifunctional and smart hydrogels.

A number of approaches have been developed for the preparation of the multiresponsive hydrogels. One of the efficient approaches to produce polymers with complex sensitivity properties is the integration of two or more different single stimulus-responsive polymer units into a single object. Various techniques, such as postmodification strategies,12 highly efficient linking reactions (e.g., click reactions),13,14 conventional radical copolymerization, and controlled radical polymerization (NMP, ATRP, and RAFT),15,16 have been widely used to obtain functional block or graft copolymers and the corresponding hydrogels with multiple responsive properties. Click chemistry and controlled polymerization technologies have greatly boosted the development of polymers with high architectural complexity and functionality. However, these strategies often involve multistep reactions to install clickable reactive groups or require a tedious polymerization process in the presence of a mediating agent, and thus, it is very difficult to combine more than two compatible blocks with different responsive properties into the same polymer.17 Another interesting approach for endowing polymers with multiresponsive properties is the exploitation of host−guest or supramolecular chemistries on the basis of noncovalent interactions, including hydrogen bonding, metal−ligand interactions, donor−acceptor interactions, hydrophobic associations, ionic interactions, and π−π stacking.7,18−21 However, this route is also limited due to the complicated designs and syntheses, the requirement of commercially unavailable reagents, and the poor mechanical properties and low stabilities of the final hydrogels.8,10 Recently, an alternative strategy to the construction of dual or multisensitive hydrogels has emerged by virtue of dynamic covalent bonds (DCB) with the ability to break and reform on exposure to certain environmental stimulus, such as boronate ester linkages (boronic acid-diol reversible reaction),22,23 disulfide bonds (thiol−disulfide interchange reaction),24 carbon−nitrogen bonds (imine or acylhydrazone exchange reactions),25 and cyclohexenes (reversible Diels−Alder cycloaddition reaction).26,27 Due to combining the robustness of classical covalent bonds with the flexibility and reversibility of noncovalent interactions, the dynamic covalent chemistry has offered unique advantages for the creation of function and thus a powerful tool to construct adaptive systems of complex sensitive properties. For example, owing to the capability to bind with cis-diols or catecholcontaining compounds through dynamic covalent bonds, boronic acid-based molecules have gained more and more attention in constructing glucose and pH dual responsive assemblies and hydrogels.22,28−32 Nevertheless, only very few

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MATERIALS AND METHODS

Materials. All reagents were obtained from Jiangtian Chemical Reagents Co., Ltd. (Tianjin, China) unless otherwise stated. 3Carboxylphenylboronic acid (CPBA) and cystamine dihydrochloride were purchased from Kangfu Chemicals Co., Ltd. (Tianjin, China). According to the previous studies,33,34 dopamine methacrylamide (DOPMA) was synthesized via a reaction between dopamine hydrochloride (DOP) and methacrylic anhydride. D-Glucose (Glu), dithiothreitol (DTT), 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC), and N-hydroxysuccinimide (NHS), acrylamide (AM) were used without further purification. The photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) was synthesized according to a previous.35 Poly(vinyl alcohol) (PVA) with a degree of hydrolysis of 99% and an average degree of polymerization of 1750 ± 50, which was used as the diols-containing polymer matrix, was supplied by Shanghai Macklin Biochemical Co., Ltd. Dialysis tubing was purchased from Beijing Huamei Bioscience 1357

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Figure 1. Preparation and characterizations of BPBAC. (A) Schematic of preparation process of BPBAC. (B) 1H NMR spectrum of BPBAC in CH3OD. (C) ESI-MS spectrum of BPBAC. Technology Co., Ltd. (Beijing, China). Deionized water used in the experiments was purified using a UP water purification system (Shanghai Ultrapure Technology, Shanghai, China). All other chemicals were of commercially analytical grade and used as received. Synthesis and Characterization of Bis(phenylboronic acid carbamoyl) Cystamine (BPBAC). The multifunctional cross-linker BPBAC was synthesized by an EDC/NHS coupling reaction. Typically, CPBA (0.165 g, 1 mmol), NHS (0.140 g, 1.22 mmol), and EDC (0.153 g, 0.80 mmol) were dissolved in 10 mL of phosphate buffer solution (PBS, pH 6.86). After dispersing with stirring and incubation for 2 h, cystamine dihydrochloride (0.09 g, 0.40 mmol) was added. The reaction mixture was then stirred at room temperature for 12 h. The product obtained by filtration was washed with deionized water and centrifuged three times. The product was obtained after drying in vacuum oven. BPBAC as a white powder was obtained after purification by recrystallization with methanol. The chemical structure of BPBAC was characterized by 1H NMR and mass spectrometry (MS). Synthesis and Characterization of Catechol-Containing Polymer P(AM-DOPMA). The catechol-containing polymer poly(acrylamide-co-dopamine methacrylamide) (P(AM-DOPMA)) was prepared by copolymerization of DOPMA with AM. A typical polymerization procedure was as follows. The monomer DOPMA (10 mg) was dissolved in 50 μL of dimethyl sulfoxide (DMSO) and then 0.95 mL of deionized aqueous solution containing AM (100 mg) and photoinitiator LAP (3.0 mg) was added into the above DMSO solution. The mixture solution was vigorously stirred until complete dissolution. After thoroughly deoxygenating with nitrogen gas, the solution was UV-irradiated for 10 min with a UV lamp (Thoth Lamp, 365 nm, model UVA-356, Nanjing, China). The copolymer solution was dialyzed in PBS (pH 5.0) for 48 h, followed by dialysis against distilled water for 5 h. After lyophilization, P(AM-DOPMA) was obtained and its structure was determined by 1H NMR, UV, and FTIR. Synthesis and Characterization of Hydrogels. PVA and P(AM-DOPMA) were selected as diol-containing polymer and catechol-containing polymer, respectively. The preparation of PVAbased hydrogel was carried out. A weighed amount of PVA powder was dissolved in distilled water at 90 °C under reflux and stirred for 2 h to prepare a homogeneous PVA solution at a fixed concentration of 5.0 wt %. After adjusting the pH of PVA solution to 10 with 1 M NaOH, 20 μL of BPBAC solution (100 mg/mL in DMSO) was added under gentle stirring to obtain the hydrogel. The hydrogel with different cross-linking density could be simply obtained by adjusting the amount of BPBAC added into the PVA solution. The P(AMDOPMA)-based hydrogel could be obtained by simply mixing the P(AM-DOPMA) solution and BPBAC solution. Typically, 100 mg P(AM-DOPMA) was dissolved in 1 mL of PBS solution (pH 8.0) to prepare a homogeneous P(AM-DOPMA) solution at a fixed

concentration of 10 wt %. And then, a certain amount of BPBAC solution (100 mg/mL in DMSO) was added into the P(AM-DOPMA) solution to obtain P(AM-DOPMA)-based hydrogels with different rheological and mechanical properties. The hydrogel with different cross-linking density could be simply obtained by adjusting the amount of BPBAC added into the P(AM-DOPMA) solution. The obtained hydrogel should be stored under a nitrogen atmosphere to avoid oxidation. The structures and morphologies of hydrogel were characterized by scanning electron microscopy (SEM) after lyophilization and gold coating using a field emission scanning electron microscope (Hitachi S-4800, Tokyo, Japan). The rheological experiments were carried out using an Anton Paar Physica MCR302 rheometer (Gratz, Austria) with a cone−plate system (diameter = 25 mm; cone angle = 2°) in shear fixation. Frequency sweep tests were performed from 1 rad/s to 100 rad/s with constant strain (1%). The storage modulus (G′) and the loss modulus (G″) were plotted against the angular frequency (ω). All rheology studies were done at 25 °C. To investigate the self-healing properties of the P(AM-DOPMA) hydrogel, the rheological experiment was performed by increasing the strain sweep from 1 to 1000% at a constant angular frequency (1 rad/ s), resulting in gel failure. Then, the time sweep test was performed at constant low strain (1%) and angular frequency (1 rad/s) to monitor the mechanical recovery of the storage modulus (G′) and loss modulus (G″) as a function of time. To measure the change of rheologic performance under an environmental stimulus, typically, a piece of the P(AM-DOPMA) hydrogel was putted directly onto the plate of the instrument. After adding a certain amount of DDT solution (20 mg/ mL) on the gel sample, the G′ and G″ was immediately measured as a function of time at 1 rad/s and 1% strain. pH, Glucose, and Redox Responsive Behaviors of Hydrogels. The test tube inverting method was utilized to demonstrate the responsive behaviors of hydrogel. To observe the pH-triggered reversible gel−sol−gel phase transitions of hydrogel, the pH value of P(AM-DOPMA)-based hydrogel was repeatedly adjusted by adding 1 M HCl aqueous solution or 1 M NaOH solution with vigorous shaking. The pH value was monitored by a pH meter (Model PHS-2F, Rex, Shanghai INESA Scientific Instrument Co., Ltd.). The glucose and redox responsiveness was investigated by similar procedures. A total of 0.2 mL of glucose (50 mg/mL) or DTT (20 mg/mL) aqueous solution was added into the hydrogel with vigorous shaking for about 5 min. And then the gel−sol transition was visually observed by inverting the vials. Characterization. The UV−vis spectra were measured by Lambda 850 spectrophotometer (PerkinElmer Inc., Waltham, MA, U.S.A.) using water or DMSO as solvent. 1H NMR spectra of the BPBAC, DOPMA, and P(AM-DOPMA) were recorded on a Varian Inova-500 M instrument (Varian Inc., Palo Alto, U.S.A.) with deuterated methanol (CH3OD), deuterated N,N-dimethylformamide (DCON1358

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Figure 2. Characterization of DOPMA and P(AM-DOPMA). (A) 1H NMR spectrum of DOPMA in DCON(CD3)2. (B) 1H NMR spectrum of P(AM-DOPMA) in D2O. (C) UV curves of DOPMA (0.05 mg/mL in DMSO), PAM, and P(AM-DOPMA) (1 mg/mL in water). (D) FTIR spectrum of DOPMA and P(AM-DOPMA).

4H, −S-CH2-), δ 3.7 ppm (t, 4H, -CH2-NH), δ 7.4 ppm (t, 2H, phenyl proton in position c), δ 7.8 ppm (d, 4H, phenyl proton in position d), and δ 8.2 ppm (s, 2H, phenyl proton in position e), confirming the formation of BPBAC. The ESI-MS was used to further confirm the conjugation reaction and analyze the formation of the BPBAC, as shown in Figure 1C. The mass spectrum of BPBAC was dominated by the protonated ions [M + H]+ at m/z 449.1201 and exhibited negligible fragmentation. In addition, the mass spectrum also showed other ions of lower intensity (the m/z 224.0551 and m/z 471.1008 ions). The fragment ion at m/z 224.0551 could be designated as a compound produced from the decomposition of BPBAC and the ion at m/z 471.1008 was assigned to [M + Na]+ ion. These results indicated that the observed molecular mass was in excellent agreement with the theoretical value of BPBAC, demonstrating the successful synthesis of the cross-linker. Synthesis and Characterization of DOPMA and P(AMDOPMA). Dopamine bearing a unique catechol moiety, a kind of versatile component in mussel adhesive proteins, which are not only able to link with boronic acid groups to produce reversibly boronate esters at weakly alkaline or neutral pH,38,42−45 but also can bind to wet tissue surfaces through either covalent or noncovalent bonds.34,46,47 And, thus, the dopamine and catechol-containing polymers have widely served as robust polymer precursors for the development of multifunctional hydrogels.33,34,46,47 The catechol-containing monomer (DOPMA) was synthesized by an amidation reaction between dopamine and methacrylic anhydride. The molecular structure of DOPMA was confirmed with 1H NMR, as shown in Figure 2A. The characteristic resonance signals of DOPMA in 1H NMR spectrum were assigned as follows: δ 1.9 ppm (s, 3H, -CH3), δ 2.6 ppm (t, 2H, -CH2-), δ 3.4 ppm (t, 2H, -CH2NH), δ 5.3 ppm (s, 1H, CH2C), δ 5.7 ppm (s, 1H, CH2 C), δ 6.5 ppm (s, 1H, phenyl proton in position g), δ 6.7 ppm (m, 2H, phenyl proton in position h and i), δ 8.0 ppm (s, 1H,

(CD3)2), and deuterated water (D2O) as a solvent, respectively. And tetramethylsilane (TMS) was used as the internal standard. The molecular structure of BPBAC was also determined by high performance liquid chromatography−mass spectrometry (HPLCMS) using a reverse-phase HPLC column employing acetonitrile/ methanol as eluent (Waters, Radial Pak, C18 analytical column). The electrospray ionization mass spectrometry (ESI-MS) was a singlequadrupole VG-platform spectrometer with Mass-Lynx version 3.1. Analyses were performed in positive-ion mode. The temperature of drying gas (N2) with a flow of 6 L/min was 180 °C and the skimmer voltage was 40 V. The elution program of HPLC began with a flow of acetonitrile/methanol 50/50 (V/V) at 10 mL/min flow to the ESI-MS source. Sodium formate (0.024 mM) was added to the solvent to enhance the electrospray ion current. Fourier transform infrared (FTIR) spectra were recorded over the region from 4000 to 500 cm−1 using BIO-RAD FT-IR 3000 (BIORAD Company, Hercules, U.S.A.). The exhaustively dehydrated samples were thoroughly ground with KBr powder prior to analysis, and pellets were prepared by compression under vacuum.

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RESULTS AND DISCUSSION Synthesis and Characterization of BPBAC. The reversible and dynamic boronate ester cross-links have recently demonstrated their enormous potential as DCB to prepare responsive and self-healing hydrogels,22,36−38 complex and multifunctional polymers,32,39 and hierarchical and smart nano/ microstructures.40,41 BPBAC as a novel multifunctional boronic acid-appended cross-linker is expected to provide a costeffective and easy-to-implement approach to develop multiresponsive materials with dynamic functionality. BPBAC was first synthesized by conjugating cystamine to the carboxyl group of CPBA using EDC/NHS chemistry, as shown in Figure 1A. Upon purification by recrystallization, 1H NMR was used to verify the molecular structure of BPBAC, as shown in Figure 1B. The 1 H NMR spectrum of BPBAC showed the characteristic resonance signals of CPBA and cystamine. The major peaks of BPBAC were assigned as follows: δ 3.0 ppm (t, 1359

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Biomacromolecules -NH-), δ 8.8 ppm (s, 1H, -OH), which were all consistent with those of DOPMA.34 The obtained DOPMA was used to prepare catechol-containing polymer precursor P(AMDOPMA). The chain structure and chemical composition of P(AM-DOPMA) were characterized by 1HNMR, FTIR, and UV. On inspection of Figure 2B, the 1H NMR spectrum of P(AM-DOPMA) exhibited the characteristic peaks of DOPMA and AM. The peak intensities of the hydrogen protons on the phenyl ring of DOPMA units (f, 6.5−7.0 ppm) and methylidyne protons at 1.9−2.4 ppm (c) of AM block could be used to calculate the content of DOPMA. The DOPMA content in P(AM-DOPMA) was about 7.1% by weight, which was consistent with the result determined by UV−vis spectrophotometry (Figure 2C). Further evidence for the preparation of DOPMA and P(AM-DOPMA) was offered by the FTIR spectra, as shown in Figure 2D. The spectrum of P(AM-DOPMA) exhibited the characteristic peaks of both DOPMA and AM segment, further demonstrating the formation of P(AM-DOPMA). Preparation and Characterization of BPBAC-Prepared Hydrogels. The boronic acid groups of BPBAC could react with cis-diols or catechol group of hydrophilic polymer precursors to form dynamic boronate bonds and corresponding hydrogels.42−45 PVA, one of the important and hydrophilic polymers for preparation of hydrogels, and P(AM-DOPMA) were selected as cis-diols and catechol-containing polymer precursors, respectively. The PVA or P(AM-DOPMA)-based hydrogel could be readily obtained by a solution mixing method based on the diols-boronate or catechol-boronate complexation under an appropriate pH condition. As shown in Figure 3A, the clear and flowing PVA and P(AM-DOPMA) solution changed into hydrogel after adding a certain amount of BPBAC. The rheological properties of the PVA solution and PVA hydrogel was investigated and shown in Figure S1 in Supporting Information and Figure 3B, respectively. The loss moduli (G″) was higher than storage moduli (G′) in the whole oscillation frequency region, showing liquid-like behavior. However, for the BPBAC-treated PVA solution, it could be observed that the G′ dominated over the G″ over the entire range of angular frequencies (1−100 rad/s), indicating predominantly solid-like feature. Similarly, the rheological properties of P(AM-DOPMA) hydrogels with different crosslinking density were shown in Figure 3C. The G′ values were significantly greater than G″ values. Moreover, the G′ and G″ curves were almost frequency independent. These results indicated that P(AM-DOPMA) hydrogels exhibited elastic gellike character. However, careful inspection of the G′ and G″ curves, it could be observed that G′ values gradually approaches to the G″ with decreasing angular frequency. Moreover, especially for the P(AM-DOPMA) hydrogels with relative low cross-linking density, the crossover frequency (where G′ nearly equals G″) could be observed at low angular frequency region (about 1 rad/s), showing a typical behavior of dynamic gel networks.31 More importantly, the results in Figure 3C showed that the amount of BPBAC introduced into the gel matrix had a significant impact on the rheological and mechanical properties. The P(AM-DOPMA) hydrogels obtained by adding higher amount of BPBAC exhibited higher mechanical properties, which could be ascribed to the higher cross-linking density. For example, the G′ curve of the P(AMDOPMA) hydrogel (a, P(AM-DOPMA)/BPBAC = 10/1, wt/ wt) was an almost horizontal straight line, and its G′ values were at least 2 orders of magnitude greater than G″ values.

Figure 3. Preparation and characterization of hydrogels. (A) Photographs of PVA solution, PVA hydrogel prepared by adding BPBAC into the PVA solution (PVA/BPBAC = 25/1, wt/wt; PVA concentration was 5 wt %), P(AM-DOPMA) solution, and P(AMDOPMA) hydrogel prepared by adding BPBAC into the P(AMDOPMA) solution (P(AM-DOPMA)/BPBAC = 10/1, wt/wt; P(AMDOPMA) concentration was 10 wt %). (B) Rheological analysis of PVA hydrogel prepared by adding BPBAC into the PVA solution (PVA/BPBAC = 25/1, wt/wt; PVA concentration was 5 wt %). (C) Rheological analysis of P(AM-DOPMA) hydrogels with different cross-linking density: (a) P(AM-DOPMA)/BPBAC = 10/1, wt/wt; (b) P(AM-DOPMA)/BPBAC = 20/1, wt/wt; (c) P(AM-DOPMA)/ BPBAC = 40/1, wt/wt; P(AM-DOPMA) concentration was 10 wt %. (D) Typical SEM images of the P(AM-DOPMA) hydrogels with different cross-linking density: (a) P(AM-DOPMA)/BPBAC = 10/1, wt/wt; (b) P(AM-DOPMA)/BPBAC = 20/1, wt/wt; (c) P(AMDOPMA)/BPBAC = 40/1, wt/wt; P(AM-DOPMA) concentration was 10 wt %. Scale bar = 100 μm.

These results indicated that the P(AM-DOPMA) hydrogel (a) was a typical strong gel. However, the profiles of G′ and G″ of P(AM-DOPMA) hydrogel (c) showed slight frequency dependence, and the ratio G″/G′ is bigger than 0.1, indicating a weak gel. The difference on gel strength of the P(AMDOPMA) hydrogels should be due to the different crosslinking density, which was further confirmed by the porous microstructures in Figure 3D. The typical SEM images of the lyophilized P(AM-DOPMA) hydrogels showed the heterogeneous porous microstructures, demonstrating the typical polymer-based hydrogel structures. Moreover, the internal morphology and pore sizes illustrated the influence of the amount of the cross-linker BPBAC on the cross-linking density. As shown in Figure 3D, decreasing the amount of cross-linker in the hydrogels led to a significant increase in pore size from 1360

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Figure 4. Photographs of the process of pH-triggered gel−sol−gel phase transitions of P(AM-DOPMA) hydrogel.

about 50 to 100 μm, indicating a decrease in cross-linking density. The typical SEM image of the lyophilized PVA hydrogel was shown in Figure S2, and the typical heterogeneous porous microstructures of polymer-based hydrogel were also observed. These results suggested that the cross-linking density and the rheological and mechanical properties of obtained hydrogels could be readily controlled by adjusting the amount of BPBAC. Multiresponsiveness of BPBAC-Prepared Hydrogels. As demonstrated, the binding between the boronic acid group and cis-diols or catechol is highly pH-dependent and reversible. And, thus, the hydrogels based on the boronate ester bonds possess a pH-responsive property. The process of pH-triggered gel−sol−gel phase transitions of P(AM-DOPMA) hydrogel and PVA hydrogel could be observed also from the digital photos and movie in Figure 4 and Movie S1 and Figure S3 in the Supporting Information. It could be clearly observed that the samples underwent a significant gel−sol transition when the pH condition changed from alkaline to acid by adding HCl. The drastic change of rheology behavior of hydrogels could be ascribed to the dissociation of boronate ester bonds below the pKa of the boronic acid component.22,32,37,38 Moreover, this transition was totally reversible. As demonstrated in Figure 4 and Movie S1, the sample reverted back to a solid-like gel as the pH returns back to alkaline by addition of NaOH, and then the gel could again turn into a viscous liquid under acidic aqueous conditions. It was worth pointing out that, under strong alkaline environment, a red hydrogel was observed. The color change was ascribed that the catechol group in the P(AM-DOPMA) hydrogel was easily oxidized to red benzoquinone under strong alkaline environment. This side reaction, often inevitable but reversible, should have little impact on the hydrogel properties, which was proven by the phenomena of color fading and gel disintegrating upon addition of HCl, as shown in Figure 4 and Movie S1. In addition, the boronic ester bonds are a kind of typical DCBs, which can be reversibly formed and dissociated between the boronic acid group and the diol or catechol group. And, thus, the complexation can be dissociated in the presence of another competitive saccharide molecule, such as glucose. Figure 5 and Figure S3 in the Supporting Information showed the glucose-responsiveness tests of BPBAC-prepared hydrogel. Hydrogel disassembly was observed in the presence of glucose, demonstrating a glucose-responsive property. The presence of disulfide bonds in BPBAC, and the cross-links between PVA and P(AM-DOPMA) chains in the obtained hydrogels will provide an interesting approach for gradual degradation/ disintegration of these hydrogels in the reductive environment. The redox-responsive gel−sol switching due to cleavage of disulfide bonds had demonstrated great potential for biomedical and pharmaceutical applications,5,27,48,49 especially for drug delivery in cancer treatment, considering the specific reductive microenvironment in tumor cells and tissues. It had been demonstrated the large difference in concentration of glutathione (GSH)/glutathione disulfide (GSSG), the most

Figure 5. Glucose and redox responsive behaviors of P(AM-DOPMA) hydrogel.

abundant biological thiol in animal cells, between the tumor and normal milieu. GSH levels in tumor cells were 1000-fold higher than that in the blood plasma, and GSH concentrations of tumor tissues are at least 4-fold higher than that of normal tissues.50−52 We investigated the influence of the redox reagent (DTT) on the phase transition of the BPBAC-prepared hydrogels. As shown in Figure 5 and Figure S3, adding DTT solution into the hydrogels significantly decreased the viscosity, transforming the elastic hydrogel into the flowing solution. In addition, for assessing the time scales for gel−sol transition by an environmental stimulus, typically, a time sweep oscillatory rheology measurement (ω = 1 rad/s and stain = 1%) measuring the change of G′ and G″ of P(AM-DOPMA) hydrogel as a function of time in the presence of 20 mg/mL DTT was carried out and shown in Figure S4. A drastic decrease in both of the G′ and G″ after adding DTT was observed. The result not only further demonstrated the redox responsive property of hydrogel but also reflected its time scale for sol−gel transition. The period of DTT-triggered gel degradation under the experimental condition is about 1 s. Briefly, these results suggested that BPBAC-prepared hydrogels possess pH, glucose, and redox multiresponsive properties. Self-Healing of BPBAC-Prepared Hydrogels. The dynamic equilibrium and bond rearrangement between boronate esters and boronic acids/diols or catechol could endow with the hydrogels not only multiresponsiveness but also self-healing properties.9,22,36,53−55 As expected, the BPBAC-prepared P(AM-DOPMA) hydrogel showed excellent self-healing capacity because of the dynamic boronic acidcatechol bonds. As presented in Figure 6A, two pieces of P(AM-DOPMA) hydrogel could autonomously merge into a single one in about 1 min when they were put together without external treatment. After about 5 min, no obvious cut line could be observed in the region of attachment. Moreover, the jointed interface after healing was strong enough to support its weight without breakage. The self-healing behavior of the BPBACprepared P(AM-DOPMA) hydrogel was further evaluated by 1361

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Figure 6. Self-healing properties of BPBAC-prepared hydrogels. (A) Photographs of evidence of self-healing behavior of two pieces of P(AMDOPMA) hydrogel (P(AM-DOPMA)/BPBAC = 20/1, wt/wt); The red hydrogel was dyed by rhodamine B; The hydrogels are fused together and stretched without fracture after fusion. (B) Strain sweep data for P(AM-DOPMA) hydrogel (P(AM-DOPMA)/BPBAC = 20/1, wt/wt). (C) Selfhealing behavior of P(AM-DOPMA) hydrogel tested by a time sweep analysis.

showed that the cross-linking density and inner structure of BPBAC-prepared hydrogels could be readily tuned by the control of the amount of cross-linker, offering great versatility in fabricating multiresponsive hydrogels with tailorable rheological and mechanical strengths. In addition, the dynamically reversible complexation between boronic acid and cis-diols or catechol groups could endow the obtained hydrogels with fast and autonomic self-healing ability without the use of additional treatment or healing agent. Considering the commercially available starting materials, ease of fabrication, and versatility in tailoring cross-linking network and mechanical properties, the strategy described here offers a promising strategy for the development of multifunctional and smart hydrogels for a variety of potential applications.

rheological measurements. Figure 6B showed the results of rheological analysis in a strain sweep mode from 1 to 1000% at a fixed angular frequency of 1 rad/s. Both G′ and G″ of the P(AM-DOPMA) hydrogel remained nearly independent of strain amplitude for strain up to 700%, indicating that the P(AM-DOPMA) hydrogel behaved like a representative covalently cross-linked hydrogel network.31 However, both G′ and G″ decreased dramatically and the G″ value exceeded the value G′, implying the breakdown of the hydrogel network at large strains due to strain failure and thus exhibiting viscous behavior (loss modulus G″ > storage modulus G′). In addition, time−sweep experiments were immediately performed (ω = 1 rad/s, stain = 1%) after collapsing by a large-amplitude oscillatory (stain = 800%, ω = 1 rad/s) and self-healing of P(AM-DOPMA) hydrogel. The G′ and G″ values of the healed hydrogel was found to recover to almost the same level as that of original hydrogel (Figure 6C), indicating the immediate reorganization of the inner structure of the hydrogel. The selfhealing mechanism could be mainly attributed to the dynamically reversible complexation of boronic acid-catechol.9,22,36,53−55 It was worth pointing out that, the BPBACprepared PVA hydrogel, as shown in Figure S5 in Supporting Information, was proven to possess similar self-healing behavior, due to the reorganizable complexation between boronic acid groups and diols. The fast and automatic healing process without external intervention of BPBAC-prepared P(AM-DOPMA) hydrogel exhibited widely potential applications, such as smart drug delivery system, medical adhesives and sealants.

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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.biomac.7b00089. Rheological analysis of PVA solution, SEM image, and photographs of pH, glucose, and redox-induced responsiveness, as well as self-healing behavior of BPBAC-prepared PVA hydrogel. Rheologic performance after adding DTT of BPBAC-prepared P(AM-DOPMA) hydrogel (PDF). pH-triggered gel-sol-gel phase transitions of BPBACprepared P(AM-DOPMA) hydrogel (AVI).

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CONCLUSIONS In summary, we synthesized a multifunctional boronic acid− based cross-linker (BPBAC) from inexpensive commercially available materials, which could be used to cross-link cis-diols or catechol-containing polymers to prepare pH, redox and glucose trisensitive hydrogels on the basis of the formation of boronate ester bonds. Two different hydrogels were prepared from BPBAC cross-linked PVA and P(AM-DOPMA), a catechol-functionalized copolymer, and then their rheological properties and gel structure were investigated. The results

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +86 22 27890710. ORCID

Jianhua Zhang: 0000-0001-7833-9715 Notes

The authors declare no competing financial interest. 1362

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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (No. 31470925), Tianjin Research Program of Application Foundation and Advanced Technology (No. 15JCQNJC03000), National Basic Research Program of China (No. 2014CB643305), and the Research Fund of State Key Laboratory for Marine Corrosion and Protection of Luoyang Ship Material Research Institute (LSMRI) under the Contract No. KF160401.

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