Self-Healing and Multistimuli-Responsive Hydrogels Formed via a

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Self-Healing and Multi-Stimuli Responsive Hydrogels Formed via a Cooperation Strategy and Their Application in Detecting Biogenic Amines Liuyan Tang, Shanshan Liao, and Jinqing Qu ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b09534 • Publication Date (Web): 23 Jul 2018 Downloaded from http://pubs.acs.org on July 24, 2018

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ACS Applied Materials & Interfaces

Self-Healing and Multi-Stimuli Responsive Hydrogels Formed via a Cooperation Strategy and Their Application in Detecting Biogenic Amines Liuyan Tang, Shanshan Liao, Jinqing Qu* School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, China KEYWORDS: hydrogels, metal-ligand coordination, hydrophobic interaction, self-healing, multi stimuli responsive, biogenic amines, food spoilage

ABSTRACT: We reported here a new platform of supramolecular hydrogels crosslinked by the cooperation of metal-ligand coordination and hydrophobic interaction. An arylhydrazone-base ligand-terminal poly(ethylene glycol) (2SBH-PEG) was synthesized and formed small micelles in an aqueous environment. Addition of Ni2+ connected the low molecular weight 2SBH-PEG into a metallopolymer via metal-ligand coordination and led to micelle aggregation, resulting in gelation due to the enhancement of hydrophobic interaction. The forming hydrogel, Ni-PEGel, exhibited rapid self-healing ability and reversible pH-responsive property. Because of the containing metal coordination bond, it was also sensitive to the strong competing ligands, like EDTA and pyridine. In addition, Ni-PEGel showed colorimetric changes when exposed to biogenic amines (BAs) vapor. The color development of Ni-PEGel towards BAs making it a good candidate in monitoring food spoilage.

■ INTRODUCTION

ACS Paragon Plus Environment

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Stimuli-responsive hydrogels have attracted considerable attention over the past decade.1, 2 These hydrogels can undergo gel-sol or gel-solid transitions upon exposure to different triggers. They have a wide range of applications, including their use as “smart” materials for actuators, reaction switches and logic-gate operations,3 and as biological materials for drug delivery, regenerative medicines and tissue engineering.4 Their stimuli-responsive properties are attributed to the environmental sensitive units in their bulk matrix. Metal coordination bond is one of the good candidates to be the sensitive unit. On the one hand, bond rupture and transfer will occur after the presence of stronger competing ligand.5–7 On the other hand, many metal coordination bonds will weaken or disappear in the environment existing triggers that will change their metal ionic valent, such as oxidant/reductant or UV-light.8–10 Except for serving as the sensitive unit, these coordination structures also provide additional features for the hydrogels system due to their metal centers: sensitization,11,12 conductivity,13 optics,14 catalysis,15 or molecular magnetism.16 However, previous reports on ligands introduced to hydrogel fabrication are limited in several structures: carboxyl group,17,18 amine group,10 terpyridine,19,20 iminodiacetate14 or some bioinspired ligands, like phosphate,21,22 catechol,23,24 and histidine.25,26 The main obstacle to extend available ligand structures into hydrogel network is the hydrophobicity of most ligands that hinder the dispersion of ligands in aqueous media. Excitingly, our previous studies solved this issue by linking the hydrophobic ligand to an amphiphilic polymer and obtained good dispersion of the ligand in water by forming micelles.27 In addition, it is well known that the increase of the micelle concentration promotes gelation caused by hydrophobic interaction.28 Hydrogels crosslinked by hydrophobic interaction exhibit intrinsic self-healing properties owing


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to the dynamic nature of the micelles.29 This dynamic nature also improves the mechanical strength of the hydrogel by offering additional dissipation of the crack energy.30,31 Hence, inspired by our previous study and the advantage of hydrophobic interaction in hydrogel fabrication, herein, we develop a cooperation strategy to form hydrogels with metal coordination moieties (metallo-hydrogel, MH): utilizing metal-ligand coordination to synthesize amphiphilic metallopolymers with hydrophobic metal coordination units, promoting gelation by the enhancement of hydrophobic interaction after polymerization (Scheme 1). MH was successfully obtained using this strategy (Ni-PEGel). Low molecular weight poly(ethylene glycol) (Mw = 2000 g/mol) was functionalized by a hydrophobic ligand, salicylaldehyde benzoyl hydrazone (SBH). SBH was a hydrazone-base ligand that will hydrolyze in acidic condition and reform after neutralizing. Its pH sensitization endows Ni-PEGel with a pH-responsive gel-sol transition. The SBH functionalized poly(ethylene glycol) (2SBH-PEG) dispersed well in water. The addition of Ni2+ led to the metal coordination between Ni2+ and 2SBH-PEG, which enhanced the hydrophobic interaction of the whole system. At the same time, the enhancement of hydrophobic interaction caused the formation of Ni-PEGel. As crosslinking by the cooperation of two non-covalent bonds (metal coordination and hydrophobic interaction), Ni-PEGel displayed rapid self-healing property and triggered degradation abilities towards EDTA and pyridine. Moreover, the color change of Ni-PEGel was observed while exposed to biogenic amine (BAs) vapors. BAs are produced during the food spoilage process via the thermal or microbial enzymatic decarboxylation of amino acids.32,33 They often serve as an indicator for food spoilage because s their concentrations are normally lower in fresh food, but higher in fermented food.34 Eating fermented food can lead to serious damage to people’s health, including diseases like diarrhea and cancer.35,36 Therefore, the detection of food spoilage is significant for


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our society. Our study showed that Ni-PEGel was a colorimetric sensor for BAs and enables to use to detect the freshness of real meat sample, exhibiting high potential in monitoring food spoilage. ■ EXPERIMENTAL SECTION

Materials. All the starting materials and solvents were purchased from Sigma-Aldrich and used as received unless otherwise noted. α,ω- dihydroxy-poly(ethylene glycol) (PEG, Mw = 2000 g/mol, or PEG8k, Mw = 8000 g/mol) was dried by placing into an oven under vacuum at 60 °C for 24 h before use. Histamine (97%) was purchased from Acros Organics. Mesylate-terminated poly(ethylene

glycol),

methyl

benzoate-terminated

poly(ethylene

glycol)

and

benzaacylhydrazide-terminated poly(ethylene glycol) were synthesized as reported.37 Scheme 1. Illustration of Gelation Strategy Utilizing the Cooperation of Metal Coordination and Hydrophobic Interaction.


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Synthesis of salicylaldehyde benzoyl hydrazine-terminated poly(ethylene glycol) (2SBHPEG). To a solution of acylhydrazine-terminated poly(ethylene glycol) (5.0 g, 2.2 mmol) in 12 mL methanol, salicylaldehyde (1.84 mL, 17.6 mmol) was added dropwise for 10 min. The reaction mixture was then stirred at room temperature for 24 h and precipitated in cold ethyl ether twice. The precipitate was dried under vacuum overnight to give a yellowish powder (4.89 g, 2.0 mmol, 90% yield). The synthesis of 2SHB-PEG8k followed the same method and its 1H NMR spectrum is showed in Figure S1. Preparation of Ni-PEGel. 0.3 M Ni(OAc)2 solution was first prepared as a stock solution. In a typical hydrogel formation experiment, 25 mg 2SBH-PEG was dissolved completely in 133 µL deionized water (Millipore Milli-Q Gradient A10), and then 34 µL 0.3 M Ni(OAc)2 solution (0.5 equiv. of Ni2+ with respect to the ligand concentration) was added to the above solution. After vigorously stirred for 20 seconds, the formation of hydrogel was observed and confirmed by glass vial inversion method. Measurements and Characterization. Nuclear Magnetic Resonance (NMR) Spectroscopy. The NMR spectra were recorded using a Bruker 500 MHz spectrometer with broad-band CryoProbe and automation. Chemical shifts were reported in δ (ppm) relative to the residual solvent peak DMSO-d6 (2.50 ppm), CD3Cl-d (7.26 ppm) or D2O (4.80 ppm). Matrix-assisted Laser Desorption/Ionization Time-of-flight (MALDI-TOF) Mass Spectrometry. The MALDI-TOF mass spectrum was done on an Autoflex III smartbeam MALDI TOF/TOF MS (Bruker Daltonics, Germany). The data were acquired at 355 nm nitrogen laser in positive reflector mode. The matrix in use was 2,5-Dihydroxybenzoic acid (DHB).


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Attenuated Total Internal Reflection Fourier transform infrared (ATR-FTIR) spectroscopy. The ATR-FTIR spectra were obtained on a Nexus 670 Thermo-Nicolet Fourier Transform Infrared Spectrometer. Gel sample was freeze-dried before tested. UV-vis Spectroscopy. UV-vis absorption spectra were measured on a Shimadzu UV-2450 spectropolarimeter at room temperature. The concentration of 2SBH-PEG aqueous solution for these experiments was 0.05 mg/mL. Dynamic Light Scattering (DLS). The size and size distribution measurements were carried out by a Zetasizer Nano ZS instrument (Malvern, U.K.) at 25 °C using a 90° detection angle equipped with a Peltier temperature control unit. The hydrodynamic radius of nanoparticles was determined by a Laplace inversion program (CONTIN). The concentration of 2SBH-PEG aqueous solution for these experiments was 0.1 mg/mL, and 0.3 M Ni2+ aqueous solution was added based on the stoichiometric ratio. Morphology. The morphological observation of Ni-PEGel was conducted by Scanning electron microscopy (SEM, Quanta 450 FEG, FEI) and Transmission Electron Microscopy (TEM, Philips CM200, FEI). Gel samples for SEM were either freeze-dried or dried under vacuum at 60 °C for 24 h before coated with gold using a Denton Desk II TSC turbo-pumped sputter coater for 60 s. Samples for TEM were prepared by dropping the prepared solution (dilute 2SBH-PEG solution or 2SBH-PEG-Ni2+ solution) onto the carbon-coated copper grids and airdrying for 24 h. Rheological Measurements. The rheological properties of Ni-PEGel were measured by a G2ARES stress control rheometer (TA Instruments, USA) with a parallel plate geometry of 25 mm diameter at 21 °C. Oscillatory strain sweep experiments were carried out with strain ranging


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from 0.1 to 100% at a frequency of 1 rad/s. Oscillatory frequency sweep experiments were conducted with frequency ranging from 0.1 to 100 rad/s at 2% strain amplitude. X-ray Diffraction (XRD). X-ray patterns of 2SBH-PEG and Ni-PEGel were collected by Xray diffractometer (X'Pert3 Powder, PANalytical B.V., Holland). Working voltage and current were 40 kV and 40 mA, respectively. Cu Kα radiation with a wavenumber of 0.15418 nm was used. The scanning rate was 12°/ min in the range from 3° to 55° (2θ). Stimuli-responsive Test. To test the pH-responsive properties, 5 µL 5 M HCl aqueous solution was added onto the Ni-PEGel surface. After 10 min, the hydrogel was completely liquefied. 5 µL 5 M NaOH aqueous solution was subsequently added to neutralize the acid and the Ni-PEGel was regenerated immediately. This process was repeated for 2 cycles. For the competing ligand-triggered degradation of Ni-PEGel, 30 µL 0.3 M EDTA aqueous solution was added onto the Ni-PEGel surface and degradation occurred after 1 h. For the pyridine triggered degradation experiment, 10 µL pyridine was added onto the Ni-PEGel surface and degradation occurred after 8 min. Testing of Meat Sample. The meat sample (pork) was cut into pieces and weighted to about 15 g. A sterile Petri dish with Ni-PEGel (contain 100 mg 2SBH-PEG) inside the dish was served as the container for the meat sample. The dish was then sealed and stored at 25 °C or 4 °C (control). Optical photos were taken every 24 h and the experiment was last for four days. ■ RESULTS AND DISCUSSION

Preparation of Ni-PEGel. Scheme 2 illustrates the synthesis of 2SBH-PEG started from the benzaacylhydrazide-terminated poly(ethylene glycol) (2BH-PEG). The preparations of the other


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intermediate PEG derivatives are reported elsewhere37.

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2SBH-PEG was obtained by the

condensation between 2BH-PEG and salicylaldehyde. The 1H NMR spectra of 2BH-PEG and 2SBH-PEG are showed in Figure 1. The degree of SBH-functionalization was close to 100% as determined by the integral 1H NMR spectrum of 2SBH-PEG (Figure S2). Mass spectrometry of 2SBH-PEG (Figure S3) confirmed its double functionalization with masses corresponding to PEG chains containing repeat units. Scheme

2.

Synthetic

Route

of

Salicylaldehyde

Benzoyl

Hydrazine-Terminated

Poly(Ethylene Glycol) (2SBH-PEG)


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Figure 1. 1H NMR spectra of (I) 2BH-PEG and (Ⅱ) 2SBH-PEG in DMSO-d6.


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Figure 2. (a) FTIR spectra of the 2SBH-PEG (red) and freeze-dried Ni-PEGel (blue). (b) UV-vis spectral titration of 2SBH-PEG (0.05 mg/mL) upon different 2SBH-PEG: Ni2+ ratios from 1: 0 to 1: 4. (c) the Job’s plot for 2SBH-PEG and Ni2+, with the total concentration of 2.0 x 10-5 M. (d) the proposed chelate structure of 2SBH-PEG and Ni2+. 2SBH-PEG dispersed well in water due to the hydrophilic PEG chain. The combination of 2SBH-PEG aqueous solution and Ni2+ (molar ratio = 1: 1) led to gel formation in 20 seconds (Video 1), while the transparent and stable hydrogel was achieved after 3 hours. 2SBH-PEG exhibited good selectivity in gel formation towards different divalent metal ions. As shown in


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Figure S4, after adding different divalent metal acetate salts (Ni2+, Zn2+, Co2+, Mn2+, Cu2+, Ca2+), only Ni-PEGel was obtained. The discussion of the specific selectivity in 2SBH-PEG crosslinking was showed in Supporting Information (Figure S5). The FTIR spectrum of freezedried Ni-PEGel (Figure 2a, blue) did not show the amide C=O (1672 cm-1) stretch and the peak for NH at 3266 cm-1 that observed in the FTIR spectrum of 2SBH-PEG (Figure 2a, red). Instead, a new peak at 1381 cm-1 belongs to the C-Ophenolic bond appears. These results indicated the two SBH ligands of 2SBH-PEG were deprotonated and in their enolate form when coordinating with Ni2+. Also, a UV-vis absorption titration of 2SBH-PEG dilute solution with increasing Ni2+ concentration (Figure 2b) was performed. The intensity increase at 390 nm and the intensity decrease at 330 nm in the UV-vis spectra stopped when the molar ratio between 2SBH-PEG and Ni2+ reached 1:1. This revealed the SBH ligand and Ni2+ form 2:1 complex in aqueous media. The corresponding Job’s plots for 2SBH-PEG and Ni2+ also verified this conclusion (Figure 2c). Base on the FTIR and UV-vis results, the illustration of 2SBH-PEG-Ni2+ coordination is displayed in Figure 2d, correlating with the previous report on Ni2+-SBH complex in solid state38–40. This coordination structure convinced us of the formation of metallopolymers, as Ni2+ was able to connect different 2SBH-PEG chain. Unfortunately, we could not test the molecular weight of the metallopolymers because freeze-dried Ni-PEGel was insoluble in organic solvents and would depolymerize after suspending in the organic solvents for 24 hours. TEM (Figure 3a) and SEM (Figure 3b) analysis confirmed the formation of Ni-PEGel was induced by micelle aggregation. Especially, the aggregation showed clearly in the TEM spectrum of the 2SBH-PEG-Ni2+ mixture solution, whereas homogenously dispersive micelles were showed in the TEM spectrum of the 2SBH-PEG dilute solution. In addition, an obvious size increase of the micelles appeared (from 72 nm to 287 nm) after 2SBH-PEG coordinated with


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Ni2+ as determined by DLS measurement (Figure 3c). In contrast, the size change of 2SBHPEG8k before and after adding Ni2+ was mild (from 124 nm to 164 nm) (Figure S6). Moreover, the attempt to crosslink 2SBH-PEG8k was not successful: even increasing the content of 2SBHPEG8k up to 30%, only a viscous liquid was gained after adding Ni2+. Compare to 2SBH-PEG, 2SBH-PEG8k has longer PEG chain. As PEG chain is hydrophilic, the longer PEG chain will result in the lower hydrophobic association between polymer chain, reducing the micelle aggregation. The unsuccessful gelation of 2SBH-PEG8k evidenced the important of hydrophobic interaction as a driving force in fabricating Ni-PEGel. We also compared the XRD spectra of 2SBH-PEG and Ni-PEGel (Figure S7), and the decrease in crystallinity of Ni-PEGel was observed, verifying the amorphous nature of the metallopolymer network. Taking the above data into account, we believe the formation of Ni-PEGel was forced by the hydrophobic interaction of the metallopolymer synthesizing by the coordination between 2SBH-PEG and Ni2+. The NiPEGel was still stable after stored for 6 months. The high stability of Ni-PEGel was owing to the good stability of the 2SBH-PEG-Ni2+ micelles: by checking the size of the micelles in 2SBHPEG solution with Ni2+ (0.1 mg/mL) for two week, we found that the size change of the micelles was limited (Figure S8).


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Figure 3. Structure analysis of Ni-gel. (a) TEM images of dilute 2SBH-PEG solution with (right) and without (left) the presence of Ni2+. (b) SEM images of freeze-dried (left) or vacuum-dried (right) Ni-PEGel. (c) DLS result of the hydrodynamic size change for the micelles in 2SBH-PEG solution (0.1 mg/mL) before and after adding Ni2+. Rheological and self-healing properties of Ni-PEGel. To investigate the mechanical strength and elasticity of Ni-PEGel, a strain sweep and a frequency sweep on this hydrogel were carried out. The strain sweep study disclosed the linear viscoelastic region of Ni-PEGel was up


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to 12% (Figure 4a). Over this region, G’ decreased rapidly and crossed over with G” at 88% strain. The 88% strain was the critical strain of Ni-PEGel. It indicated the rupture of Ni-PEGel network and at the strain higher than this critical point, Ni-PEGel transformed to a liquid state. Figure 4b revealed that Ni-PEGel had frequency dependent G′ and G″ moduli. With increasing frequency, its G’ and G” gradually increased and exhibited a crossover point (β) at 1.3 rad/s. At lower frequency (longer time scale, ≤ β), the Ni-PEGel system was flow and viscous as G” > G’, whereas this system was rubbery as the elastic component dominated (G’

Self-Healing and Multistimuli-Responsive Hydrogels Formed via a

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