Article

pubs.acs.org/Biomac

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
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*
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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 prepara-
tion 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.

■ INTRODUCTION
Inspired by the natural intelligent materials, some polymeric
development of multiresponsive hydrogels with the ability to
respond to different stimuli to perform separate functions.3−5,10
hydrogels are designed to be able to exhibit a significant For example, because of their specific, distinct, and multiple
responsivity to a multitude of external chemical/physical/ responses to varied physiological stimuli, the multiresponsive
mechanical stimuli, such as pH value, ionic strength, glucose polymer hydrogels with tunable and even biomimetic behavior
concentration, enzymatic activity, temperature, light, magnetic not only have demonstrated great utility as an innovative drug
field, electric field, pressure, or a combination of them, and thus delivery system for encapsulating and delivering multiple drugs
such smart hydrogels as promising materials have shown with different properties, but also have shown excellent promise
tremendous potential in versatile applications, especially in for applications in tissue-engineering systems interacting with
biomedical and pharmaceutical applications.1−4 So far, most the biological environments through various physiological and
responsive hydrogels are responsive to a single or two different cellular cues.5,11 However, despite demonstrating great utility
stimuli (mainly pH or/and temperature stimuli), whose and promising potential, the dual or multiresponsive hydrogels,
responsivities are mainly derived from the inherent stimuli- especially the intelligent hydrogels with multiresponsiveness,
sensitive properties of build block polymers.5,6 In comparison are still rare, mainly due to the limited availability of polymer
with the single stimulus-responsive systems, the dual or
precursors with inherent multisensitivities.3−6 Therefore, to
multiresponsive hydrogels that can respond to two or more
environmental stimulus, which have been proven to be able to meet the rigorous and diverse demands, it is imperative to
offer higher flexibility for further applications and more develop new materials or novel strategies for the fabrication of
opportunities to achieve higher tunability and realize additional functional hydrogels with multiresponsive properties.
multifunctionality in a synergistic manner.5,7−9 Especially, some
specific applications in complex biological environments and Received: January 19, 2017
natural feedback systems are placing unprecedented demands Revised: March 20, 2017
on multifunctional materials, highlighting the need for the Published: March 21, 2017

© 2017 American Chemical Society 1356 DOI: 10.1021/acs.biomac.7b00089

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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

A number of approaches have been developed for the studies have employed DCB to elaborate multiresponsive
preparation of the multiresponsive hydrogels. One of the materials.32 One of the main reasons can be attributed to the
efficient approaches to produce polymers with complex scarcity of available multiresponsive DCBs. Generally, the
sensitivity properties is the integration of two or more different DCBs only possess mono- or dual-functionality. Therefore,
single stimulus-responsive polymer units into a single object. they are not suitable to be used for preparing multiresponsive
Various techniques, such as postmodification strategies,12 hydrogels in terms of decreasing synthetic complexity,
highly efficient linking reactions (e.g., click reactions),13,14 especially considering the fact that the procedures to create
conventional radical copolymerization, and controlled radical DCB-based materials generally involve tedious modifications to
polymerization (NMP, ATRP, and RAFT),15,16 have been introduce reactive groups on the terminal or side chains of
widely used to obtain functional block or graft copolymers and polymers. Therefore, challenges still remain to develop cost-
the corresponding hydrogels with multiple responsive proper- effective and efficient methods for the preparation of
ties. Click chemistry and controlled polymerization technolo- multiresponsive hydrogels from commercially available and
gies have greatly boosted the development of polymers with inexpensive components.
high architectural complexity and functionality. However, these In this work, a multifunctional boronic acid-based cross-
strategies often involve multistep reactions to install clickable linker bis(phenylboronic acid carbamoyl) cystamine (BPBAC)
reactive groups or require a tedious polymerization process in was readily prepared from inexpensive commercially available
the presence of a mediating agent, and thus, it is very difficult to 3-carboxylphenylboronic acid (CPBA) and cystamine dihydro-
combine more than two compatible blocks with different chloride. Subsequently, the ability of BPBAC to cross-link the
responsive properties into the same polymer.17 Another cis-diols and catechol-containing polymers to form dynamic
interesting approach for endowing polymers with multi- hydrogels with tailorable network and mechanical strengths was
responsive properties is the exploitation of host−guest or demonstrated, as shown in Scheme 1. The reversibility and
supramolecular chemistries on the basis of noncovalent dynamic nature of the boronate ester and disulfide bonds
interactions, including hydrogen bonding, metal−ligand inter- provided not only pH, glucose, and redox triresponsive features,
actions, donor−acceptor interactions, hydrophobic associations, but also self-healing properties by the autonomic reconstruction
ionic interactions, and π−π stacking.7,18−21 However, this route without using a healing agent. Considering the commercially
is also limited due to the complicated designs and syntheses, available starting materials, ease of fabrication, and versatility in
the requirement of commercially unavailable reagents, and the tailoring cross-linking network and regulating the rheological
poor mechanical properties and low stabilities of the final and mechanical properties, the procedure described here offers
hydrogels.8,10 Recently, an alternative strategy to the con- a promising strategy for the development of multifunctional
struction of dual or multisensitive hydrogels has emerged by and smart hydrogels.

■
virtue of dynamic covalent bonds (DCB) with the ability to
break and reform on exposure to certain environmental MATERIALS AND METHODS
stimulus, such as boronate ester linkages (boronic acid-diol
Materials. All reagents were obtained from Jiangtian Chemical
reversible reaction),22,23 disulfide bonds (thiol−disulfide Reagents Co., Ltd. (Tianjin, China) unless otherwise stated. 3-
interchange reaction),24 carbon−nitrogen bonds (imine or Carboxylphenylboronic acid (CPBA) and cystamine dihydrochloride
acylhydrazone exchange reactions),25 and cyclohexenes (rever- were purchased from Kangfu Chemicals Co., Ltd. (Tianjin, China).
sible Diels−Alder cycloaddition reaction).26,27 Due to combin- According to the previous studies,33,34 dopamine methacrylamide
ing the robustness of classical covalent bonds with the flexibility (DOPMA) was synthesized via a reaction between dopamine
and reversibility of noncovalent interactions, the dynamic hydrochloride (DOP) and methacrylic anhydride. D-Glucose (Glu),
covalent chemistry has offered unique advantages for the dithiothreitol (DTT), 1-ethyl-3-(3-(dimethylamino)propyl) carbodii-
creation of function and thus a powerful tool to construct mide hydrochloride (EDC), and N-hydroxysuccinimide (NHS),
adaptive systems of complex sensitive properties. For example, acrylamide (AM) were used without further purification. The
photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate
owing to the capability to bind with cis-diols or catechol- (LAP) was synthesized according to a previous.35 Poly(vinyl alcohol)
containing compounds through dynamic covalent bonds, (PVA) with a degree of hydrolysis of 99% and an average degree of
boronic acid-based molecules have gained more and more polymerization of 1750 ± 50, which was used as the diols-containing
attention in constructing glucose and pH dual responsive polymer matrix, was supplied by Shanghai Macklin Biochemical Co.,
assemblies and hydrogels.22,28−32 Nevertheless, only very few Ltd. Dialysis tubing was purchased from Beijing Huamei Bioscience

1357 DOI: 10.1021/acs.biomac.7b00089

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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 concentration of 10 wt %. And then, a certain amount of BPBAC
experiments was purified using a UP water purification system solution (100 mg/mL in DMSO) was added into the P(AM-DOPMA)
(Shanghai Ultrapure Technology, Shanghai, China). All other solution to obtain P(AM-DOPMA)-based hydrogels with different
chemicals were of commercially analytical grade and used as received. rheological and mechanical properties. The hydrogel with different
Synthesis and Characterization of Bis(phenylboronic acid cross-linking density could be simply obtained by adjusting the
carbamoyl) Cystamine (BPBAC). The multifunctional cross-linker amount of BPBAC added into the P(AM-DOPMA) solution. The
BPBAC was synthesized by an EDC/NHS coupling reaction. obtained hydrogel should be stored under a nitrogen atmosphere to
Typically, CPBA (0.165 g, 1 mmol), NHS (0.140 g, 1.22 mmol), avoid oxidation. The structures and morphologies of hydrogel were
and EDC (0.153 g, 0.80 mmol) were dissolved in 10 mL of phosphate characterized by scanning electron microscopy (SEM) after lyophiliza-
buffer solution (PBS, pH 6.86). After dispersing with stirring and tion and gold coating using a field emission scanning electron
incubation for 2 h, cystamine dihydrochloride (0.09 g, 0.40 mmol) was microscope (Hitachi S-4800, Tokyo, Japan). The rheological experi-
added. The reaction mixture was then stirred at room temperature for ments were carried out using an Anton Paar Physica MCR302
12 h. The product obtained by filtration was washed with deionized rheometer (Gratz, Austria) with a cone−plate system (diameter = 25
water and centrifuged three times. The product was obtained after mm; cone angle = 2°) in shear fixation. Frequency sweep tests were
drying in vacuum oven. BPBAC as a white powder was obtained after performed from 1 rad/s to 100 rad/s with constant strain (1%). The
purification by recrystallization with methanol. The chemical structure storage modulus (G′) and the loss modulus (G″) were plotted against
of BPBAC was characterized by 1H NMR and mass spectrometry the angular frequency (ω). All rheology studies were done at 25 °C.
(MS). To investigate the self-healing properties of the P(AM-DOPMA)
Synthesis and Characterization of Catechol-Containing hydrogel, the rheological experiment was performed by increasing the
Polymer P(AM-DOPMA). The catechol-containing polymer poly-
(acrylamide-co-dopamine methacrylamide) (P(AM-DOPMA)) was strain sweep from 1 to 1000% at a constant angular frequency (1 rad/
prepared by copolymerization of DOPMA with AM. A typical s), resulting in gel failure. Then, the time sweep test was performed at
polymerization procedure was as follows. The monomer DOPMA constant low strain (1%) and angular frequency (1 rad/s) to monitor
(10 mg) was dissolved in 50 μL of dimethyl sulfoxide (DMSO) and the mechanical recovery of the storage modulus (G′) and loss modulus
then 0.95 mL of deionized aqueous solution containing AM (100 mg) (G″) as a function of time. To measure the change of rheologic
and photoinitiator LAP (3.0 mg) was added into the above DMSO performance under an environmental stimulus, typically, a piece of the
solution. The mixture solution was vigorously stirred until complete P(AM-DOPMA) hydrogel was putted directly onto the plate of the
dissolution. After thoroughly deoxygenating with nitrogen gas, the instrument. After adding a certain amount of DDT solution (20 mg/
solution was UV-irradiated for 10 min with a UV lamp (Thoth Lamp, mL) on the gel sample, the G′ and G″ was immediately measured as a
365 nm, model UVA-356, Nanjing, China). The copolymer solution function of time at 1 rad/s and 1% strain.
was dialyzed in PBS (pH 5.0) for 48 h, followed by dialysis against pH, Glucose, and Redox Responsive Behaviors of Hydro-
distilled water for 5 h. After lyophilization, P(AM-DOPMA) was gels. The test tube inverting method was utilized to demonstrate the
obtained and its structure was determined by 1H NMR, UV, and responsive behaviors of hydrogel. To observe the pH-triggered
FTIR. reversible gel−sol−gel phase transitions of hydrogel, the pH value of
Synthesis and Characterization of Hydrogels. PVA and P(AM-DOPMA)-based hydrogel was repeatedly adjusted by adding 1
P(AM-DOPMA) were selected as diol-containing polymer and M HCl aqueous solution or 1 M NaOH solution with vigorous
catechol-containing polymer, respectively. The preparation of PVA- shaking. The pH value was monitored by a pH meter (Model PHS-2F,
based hydrogel was carried out. A weighed amount of PVA powder Rex, Shanghai INESA Scientific Instrument Co., Ltd.). The glucose
was dissolved in distilled water at 90 °C under reflux and stirred for 2 h and redox responsiveness was investigated by similar procedures. A
to prepare a homogeneous PVA solution at a fixed concentration of total of 0.2 mL of glucose (50 mg/mL) or DTT (20 mg/mL) aqueous
5.0 wt %. After adjusting the pH of PVA solution to 10 with 1 M solution was added into the hydrogel with vigorous shaking for about 5
NaOH, 20 μL of BPBAC solution (100 mg/mL in DMSO) was added min. And then the gel−sol transition was visually observed by inverting
under gentle stirring to obtain the hydrogel. The hydrogel with the vials.
different cross-linking density could be simply obtained by adjusting Characterization. The UV−vis spectra were measured by Lambda
the amount of BPBAC added into the PVA solution. The P(AM- 850 spectrophotometer (PerkinElmer Inc., Waltham, MA, U.S.A.)
DOPMA)-based hydrogel could be obtained by simply mixing the using water or DMSO as solvent. 1H NMR spectra of the BPBAC,
P(AM-DOPMA) solution and BPBAC solution. Typically, 100 mg DOPMA, and P(AM-DOPMA) were recorded on a Varian Inova-500
P(AM-DOPMA) was dissolved in 1 mL of PBS solution (pH 8.0) to M instrument (Varian Inc., Palo Alto, U.S.A.) with deuterated
prepare a homogeneous P(AM-DOPMA) solution at a fixed methanol (CH3OD), deuterated N,N-dimethylformamide (DCON-

1358 DOI: 10.1021/acs.biomac.7b00089

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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).

(CD3)2), and deuterated water (D2O) as a solvent, respectively. And 4H, −S-CH2-), δ 3.7 ppm (t, 4H, -CH2-NH), δ 7.4 ppm (t, 2H,
tetramethylsilane (TMS) was used as the internal standard. The phenyl proton in position c), δ 7.8 ppm (d, 4H, phenyl proton
molecular structure of BPBAC was also determined by high in position d), and δ 8.2 ppm (s, 2H, phenyl proton in position
performance liquid chromatography−mass spectrometry (HPLC-
e), confirming the formation of BPBAC. The ESI-MS was used
MS) using a reverse-phase HPLC column employing acetonitrile/
methanol as eluent (Waters, Radial Pak, C18 analytical column). The to further confirm the conjugation reaction and analyze the
electrospray ionization mass spectrometry (ESI-MS) was a single- formation of the BPBAC, as shown in Figure 1C. The mass
quadrupole VG-platform spectrometer with Mass-Lynx version 3.1. spectrum of BPBAC was dominated by the protonated ions [M
Analyses were performed in positive-ion mode. The temperature of + H]+ at m/z 449.1201 and exhibited negligible fragmentation.
drying gas (N2) with a flow of 6 L/min was 180 °C and the skimmer In addition, the mass spectrum also showed other ions of lower
voltage was 40 V. The elution program of HPLC began with a flow of intensity (the m/z 224.0551 and m/z 471.1008 ions). The
acetonitrile/methanol 50/50 (V/V) at 10 mL/min flow to the ESI-MS fragment ion at m/z 224.0551 could be designated as a
source. Sodium formate (0.024 mM) was added to the solvent to
enhance the electrospray ion current. Fourier transform infrared
compound produced from the decomposition of BPBAC and
(FTIR) spectra were recorded over the region from 4000 to 500 cm−1 the ion at m/z 471.1008 was assigned to [M + Na]+ ion. These
using BIO-RAD FT-IR 3000 (BIORAD Company, Hercules, U.S.A.). results indicated that the observed molecular mass was in
The exhaustively dehydrated samples were thoroughly ground with excellent agreement with the theoretical value of BPBAC,
KBr powder prior to analysis, and pellets were prepared by demonstrating the successful synthesis of the cross-linker.
compression under vacuum. Synthesis and Characterization of DOPMA and P(AM-

■ RESULTS AND DISCUSSION

Synthesis and Characterization of BPBAC. The
DOPMA). 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
reversible and dynamic boronate ester cross-links have recently reversibly boronate esters at weakly alkaline or neutral
demonstrated their enormous potential as DCB to prepare pH,38,42−45 but also can bind to wet tissue surfaces through
responsive and self-healing hydrogels,22,36−38 complex and either covalent or noncovalent bonds.34,46,47 And, thus, the
multifunctional polymers,32,39 and hierarchical and smart nano/ dopamine and catechol-containing polymers have widely served
microstructures.40,41 BPBAC as a novel multifunctional boronic as robust polymer precursors for the development of
acid-appended cross-linker is expected to provide a cost- multifunctional hydrogels.33,34,46,47 The catechol-containing
effective and easy-to-implement approach to develop multi- monomer (DOPMA) was synthesized by an amidation reaction
responsive materials with dynamic functionality. BPBAC was between dopamine and methacrylic anhydride. The molecular
first synthesized by conjugating cystamine to the carboxyl structure of DOPMA was confirmed with 1H NMR, as shown
group of CPBA using EDC/NHS chemistry, as shown in Figure in Figure 2A. The characteristic resonance signals of DOPMA
1A. Upon purification by recrystallization, 1H NMR was used to in 1H NMR spectrum were assigned as follows: δ 1.9 ppm (s,
verify the molecular structure of BPBAC, as shown in Figure 3H, -CH3), δ 2.6 ppm (t, 2H, -CH2-), δ 3.4 ppm (t, 2H, -CH2-
1B. The 1 H NMR spectrum of BPBAC showed the NH), δ 5.3 ppm (s, 1H, CH2C), δ 5.7 ppm (s, 1H, CH2
characteristic resonance signals of CPBA and cystamine. The C), δ 6.5 ppm (s, 1H, phenyl proton in position g), δ 6.7 ppm
major peaks of BPBAC were assigned as follows: δ 3.0 ppm (t, (m, 2H, phenyl proton in position h and i), δ 8.0 ppm (s, 1H,
1359 DOI: 10.1021/acs.biomac.7b00089
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-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(AM-
DOPMA). 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) Figure 3. Preparation and characterization of hydrogels. (A)
solution changed into hydrogel after adding a certain amount of Photographs of PVA solution, PVA hydrogel prepared by adding
BPBAC. The rheological properties of the PVA solution and BPBAC into the PVA solution (PVA/BPBAC = 25/1, wt/wt; PVA
PVA hydrogel was investigated and shown in Figure S1 in concentration was 5 wt %), P(AM-DOPMA) solution, and P(AM-
DOPMA) hydrogel prepared by adding BPBAC into the P(AM-
Supporting Information and Figure 3B, respectively. The loss DOPMA) solution (P(AM-DOPMA)/BPBAC = 10/1, wt/wt; P(AM-
moduli (G″) was higher than storage moduli (G′) in the whole DOPMA) concentration was 10 wt %). (B) Rheological analysis of
oscillation frequency region, showing liquid-like behavior. PVA hydrogel prepared by adding BPBAC into the PVA solution
However, for the BPBAC-treated PVA solution, it could be (PVA/BPBAC = 25/1, wt/wt; PVA concentration was 5 wt %). (C)
observed that the G′ dominated over the G″ over the entire Rheological analysis of P(AM-DOPMA) hydrogels with different
range of angular frequencies (1−100 rad/s), indicating cross-linking density: (a) P(AM-DOPMA)/BPBAC = 10/1, wt/wt;
predominantly solid-like feature. Similarly, the rheological (b) P(AM-DOPMA)/BPBAC = 20/1, wt/wt; (c) P(AM-DOPMA)/
properties of P(AM-DOPMA) hydrogels with different cross- BPBAC = 40/1, wt/wt; P(AM-DOPMA) concentration was 10 wt %.
linking density were shown in Figure 3C. The G′ values were (D) Typical SEM images of the P(AM-DOPMA) hydrogels with
different cross-linking density: (a) P(AM-DOPMA)/BPBAC = 10/1,
significantly greater than G″ values. Moreover, the G′ and G″
wt/wt; (b) P(AM-DOPMA)/BPBAC = 20/1, wt/wt; (c) P(AM-
curves were almost frequency independent. These results DOPMA)/BPBAC = 40/1, wt/wt; P(AM-DOPMA) concentration
indicated that P(AM-DOPMA) hydrogels exhibited elastic gel- was 10 wt %. Scale bar = 100 μm.
like 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, These results indicated that the P(AM-DOPMA) hydrogel (a)
especially for the P(AM-DOPMA) hydrogels with relative was a typical strong gel. However, the profiles of G′ and G″ of
low cross-linking density, the crossover frequency (where G′ P(AM-DOPMA) hydrogel (c) showed slight frequency
nearly equals G″) could be observed at low angular frequency dependence, and the ratio G″/G′ is bigger than 0.1, indicating
region (about 1 rad/s), showing a typical behavior of dynamic a weak gel. The difference on gel strength of the P(AM-
gel networks.31 More importantly, the results in Figure 3C DOPMA) hydrogels should be due to the different cross-
showed that the amount of BPBAC introduced into the gel linking density, which was further confirmed by the porous
matrix had a significant impact on the rheological and microstructures in Figure 3D. The typical SEM images of the
mechanical properties. The P(AM-DOPMA) hydrogels ob- lyophilized P(AM-DOPMA) hydrogels showed the heteroge-
tained by adding higher amount of BPBAC exhibited higher neous porous microstructures, demonstrating the typical
mechanical properties, which could be ascribed to the higher polymer-based hydrogel structures. Moreover, the internal
cross-linking density. For example, the G′ curve of the P(AM- morphology and pore sizes illustrated the influence of the
DOPMA) hydrogel (a, P(AM-DOPMA)/BPBAC = 10/1, wt/ amount of the cross-linker BPBAC on the cross-linking density.
wt) was an almost horizontal straight line, and its G′ values As shown in Figure 3D, decreasing the amount of cross-linker
were at least 2 orders of magnitude greater than G″ values. in the hydrogels led to a significant increase in pore size from
1360 DOI: 10.1021/acs.biomac.7b00089
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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 heteroge-
neous 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 Figure 5. Glucose and redox responsive behaviors of P(AM-DOPMA)
Supporting Information. It could be clearly observed that the hydrogel.
samples underwent a significant gel−sol transition when the pH
condition changed from alkaline to acid by adding HCl. The abundant biological thiol in animal cells, between the tumor
drastic change of rheology behavior of hydrogels could be and normal milieu. GSH levels in tumor cells were 1000-fold
ascribed to the dissociation of boronate ester bonds below the higher than that in the blood plasma, and GSH concentrations
pKa of the boronic acid component.22,32,37,38 Moreover, this of tumor tissues are at least 4-fold higher than that of normal
transition was totally reversible. As demonstrated in Figure 4 tissues.50−52 We investigated the influence of the redox reagent
and Movie S1, the sample reverted back to a solid-like gel as the (DTT) on the phase transition of the BPBAC-prepared
pH returns back to alkaline by addition of NaOH, and then the hydrogels. As shown in Figure 5 and Figure S3, adding DTT
gel could again turn into a viscous liquid under acidic aqueous solution into the hydrogels significantly decreased the viscosity,
conditions. It was worth pointing out that, under strong alkaline transforming the elastic hydrogel into the flowing solution. In
environment, a red hydrogel was observed. The color change addition, for assessing the time scales for gel−sol transition by
was ascribed that the catechol group in the P(AM-DOPMA) an environmental stimulus, typically, a time sweep oscillatory
hydrogel was easily oxidized to red benzoquinone under strong rheology measurement (ω = 1 rad/s and stain = 1%) measuring
alkaline environment. This side reaction, often inevitable but the change of G′ and G″ of P(AM-DOPMA) hydrogel as a
reversible, should have little impact on the hydrogel properties, function of time in the presence of 20 mg/mL DTT was carried
which was proven by the phenomena of color fading and gel out and shown in Figure S4. A drastic decrease in both of the
disintegrating upon addition of HCl, as shown in Figure 4 and G′ and G″ after adding DTT was observed. The result not only
Movie S1. further demonstrated the redox responsive property of hydrogel
In addition, the boronic ester bonds are a kind of typical but also reflected its time scale for sol−gel transition. The
DCBs, which can be reversibly formed and dissociated between period of DTT-triggered gel degradation under the exper-
the boronic acid group and the diol or catechol group. And, imental condition is about 1 s. Briefly, these results suggested
thus, the complexation can be dissociated in the presence of that BPBAC-prepared hydrogels possess pH, glucose, and
another competitive saccharide molecule, such as glucose. redox multiresponsive properties.
Figure 5 and Figure S3 in the Supporting Information showed Self-Healing of BPBAC-Prepared Hydrogels. The
the glucose-responsiveness tests of BPBAC-prepared hydrogel. dynamic equilibrium and bond rearrangement between
Hydrogel disassembly was observed in the presence of glucose, boronate esters and boronic acids/diols or catechol could
demonstrating a glucose-responsive property. The presence of endow with the hydrogels not only multiresponsiveness but
disulfide bonds in BPBAC, and the cross-links between PVA also self-healing properties.9,22,36,53−55 As expected, the
and P(AM-DOPMA) chains in the obtained hydrogels will BPBAC-prepared P(AM-DOPMA) hydrogel showed excellent
provide an interesting approach for gradual degradation/ self-healing capacity because of the dynamic boronic acid-
disintegration of these hydrogels in the reductive environment. catechol bonds. As presented in Figure 6A, two pieces of
The redox-responsive gel−sol switching due to cleavage of P(AM-DOPMA) hydrogel could autonomously merge into a
disulfide bonds had demonstrated great potential for single one in about 1 min when they were put together without
biomedical and pharmaceutical applications,5,27,48,49 especially external treatment. After about 5 min, no obvious cut line could
for drug delivery in cancer treatment, considering the specific be observed in the region of attachment. Moreover, the jointed
reductive microenvironment in tumor cells and tissues. It had interface after healing was strong enough to support its weight
been demonstrated the large difference in concentration of without breakage. The self-healing behavior of the BPBAC-
glutathione (GSH)/glutathione disulfide (GSSG), the most prepared P(AM-DOPMA) hydrogel was further evaluated by
1361 DOI: 10.1021/acs.biomac.7b00089
Biomacromolecules 2017, 18, 1356−1364
Biomacromolecules Article

Figure 6. Self-healing properties of BPBAC-prepared hydrogels. (A) Photographs of evidence of self-healing behavior of two pieces of P(AM-
DOPMA) 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) Self-
healing behavior of P(AM-DOPMA) hydrogel tested by a time sweep analysis.

rheological measurements. Figure 6B showed the results of showed that the cross-linking density and inner structure of
rheological analysis in a strain sweep mode from 1 to 1000% at BPBAC-prepared hydrogels could be readily tuned by the
a fixed angular frequency of 1 rad/s. Both G′ and G″ of the control of the amount of cross-linker, offering great versatility
P(AM-DOPMA) hydrogel remained nearly independent of in fabricating multiresponsive hydrogels with tailorable
strain amplitude for strain up to 700%, indicating that the rheological and mechanical strengths. In addition, the
P(AM-DOPMA) hydrogel behaved like a representative dynamically reversible complexation between boronic acid
covalently cross-linked hydrogel network.31 However, both G′ and cis-diols or catechol groups could endow the obtained
and G″ decreased dramatically and the G″ value exceeded the hydrogels with fast and autonomic self-healing ability without
value G′, implying the breakdown of the hydrogel network at the use of additional treatment or healing agent. Considering
large strains due to strain failure and thus exhibiting viscous the commercially available starting materials, ease of fabrication,
behavior (loss modulus G″ > storage modulus G′). In addition, and versatility in tailoring cross-linking network and mechanical
time−sweep experiments were immediately performed (ω = 1
properties, the strategy described here offers a promising
rad/s, stain = 1%) after collapsing by a large-amplitude
strategy for the development of multifunctional and smart
oscillatory (stain = 800%, ω = 1 rad/s) and self-healing of
hydrogels for a variety of potential applications.
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 self-
■
*
ASSOCIATED CONTENT
S Supporting Information
healing mechanism could be mainly attributed to the The Supporting Information is available free of charge on the
dynamically reversible complexation of boronic acid-cate-
ACS Publications website at DOI: 10.1021/acs.bio-
chol.9,22,36,53−55 It was worth pointing out that, the BPBAC-
mac.7b00089.
prepared PVA hydrogel, as shown in Figure S5 in Supporting
Information, was proven to possess similar self-healing Rheological analysis of PVA solution, SEM image, and
behavior, due to the reorganizable complexation between photographs of pH, glucose, and redox-induced
boronic acid groups and diols. The fast and automatic healing responsiveness, as well as self-healing behavior of
process without external intervention of BPBAC-prepared BPBAC-prepared PVA hydrogel. Rheologic performance
P(AM-DOPMA) hydrogel exhibited widely potential applica- after adding DTT of BPBAC-prepared P(AM-DOPMA)
tions, such as smart drug delivery system, medical adhesives and hydrogel (PDF).
sealants. pH-triggered gel-sol-gel phase transitions of BPBAC-

■ CONCLUSIONS
prepared P(AM-DOPMA) hydrogel (AVI).

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
■ AUTHOR INFORMATION
Corresponding Author
or catechol-containing polymers to prepare pH, redox and *E-mail: jhuazhang@tju.edu.cn. Fax: +86 22 27890710.
glucose trisensitive hydrogels on the basis of the formation of ORCID
boronate ester bonds. Two different hydrogels were prepared
from BPBAC cross-linked PVA and P(AM-DOPMA), a
Jianhua Zhang: 0000-0001-7833-9715
catechol-functionalized copolymer, and then their rheological Notes
properties and gel structure were investigated. The results The authors declare no competing financial interest.
1362 DOI: 10.1021/acs.biomac.7b00089
Biomacromolecules 2017, 18, 1356−1364
Biomacromolecules Article

■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science
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■
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1364 DOI: 10.1021/acs.biomac.7b00089

Biomacromolecules 2017, 18, 1356−1364