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Injectable self-healing hydrogel with antimicrobial and antifouling properties Lin Li, Bin Yan, Jingqi Yang, Weijuan Huang, Lingyun Chen, and Hongbo Zeng ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b16192 • Publication Date (Web): 07 Mar 2017 Downloaded from http://pubs.acs.org on March 8, 2017
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Injectable self-healing hydrogel with antimicrobial and antifouling properties Lin Li1,†, Bin Yan1, 2,†,*, Jingqi Yang3, Weijuan Huang3, Lingyun Chen3, and Hongbo Zeng1,* 1
Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, T6G
1H9, Canada. 2
College of Light Industry, Textile & Food Engineering, Sichuan University, Chengdu, 610065,
China 3
Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, AB,
T6G 2P5, Canada
KEYWORDS: hydrogel, self-healing, antimicrobial, antifouling, catechol
ABSTRACT: Microbial adhesion, biofilm formation and associated microbial infection are common challenges faced by implanted biomaterials (e.g. hydrogels) in bioengineering applications. In this work, an injectable self-healing hydrogel with antimicrobial and antifouling properties was prepared through self-assembly of an ABA tri-block copolymer employing catechol functionalized polyethylene glycol (PEG) as A block and poly{[2-(methacryloyloxy)ethyl] trimethyl ammonium iodide}(PMETA) as B block. This hydrogel exhibits excellent thermo-sensitivity, can effectively inhibit the growth of E. coli (>99.8% killing efficiency) and prevent cell attachment. It can also heal autonomously from repeated damage, through mussel-
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inspired catechol-mediated hydrogen bonding and aromatic interactions, exhibiting great potential in bioengineering applications.
Injectable hydrogels have attracted considerable research interests in biomedical fields such as drug delivery and tissue engineering due to their desirable biocompatibility, ease of operation and minimum tissue invasion.1 Besides the embedding of bioactive molecules such as drugs, proteins and antibodies into precursor solution to achieve target delivery via an in-situ gelation right after injection, the capability of obtaining diverse functionalities by employing various polymers in constructing hydrogel networks have also made this type of material highly competitive in bioengineering applications.2-4 Soaked in complex body fluid environment, the hydrogel materials implanted in vivo are vulnerable to proteins and microorganism accumulation, which would not only block circulation of metabolites and embedded biomolecules, but also lead to possible inflammatory responses.5-6 To address this issue, several approaches have been adopted to endow hydrogel materials with simultaneous antimicrobial and antifouling properties, such as the switching between cationic active hunting state and zwitterionic/mixed charged nonfouling state,7-8 the releasing of antibiotics/silver nanoparticles while maintaining nonfouling nature,9-13 and the inclusion of nonfouling and antimicrobial ingredients into one structure through cross-linking or copolymerization.14-15 However implanted hydrogels are subject to constant mechanical forces from daily body movement which would lead to gel deformation or even damage, not only increasing the risk of infection due to the microorganism intrusion, but also weakening other functional performances due to the rupture of the hydrogel structure. Thus the key point to ensure both the structural and functional integrity is to confer the hydrogel
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materials autonomously self-healing, a property pervasive in biological systems while rare in man-made materials.16 Generally intrinsic self-healable hydrogel networks are constructed through reversible non-covalent bonds such as hydrogen bonding, ionic interactions, π-π stacking and metal-ligand coordination.17-19 Mussel-inspired catecholmetal coordination has been widely employed in preparing self-healing hydrogels.20 However, their bioengineering applications are restrained by the in vivo cytotoxicity of metal ions. Recently using mussel-inspired catechol-mediated hydrogen bonding and aromatic interactions as novel self-healing mechanism to construct reversible hydrogel networks has attracted much attention,
and the prepared materials exhibit great
superiority over those constructed through catechol-metal coordination in bioengineering applications, due to their reduced cytotoxicity and enhanced transparency attributed to the metal-free nature.21-22 To satisfy the different needs in dynamic biomedical processes, a multifunctional hydrogel with features including the in-situ gelation capability and injectability to facilitate operation, the antimicrobial and antifouling property to prevent bacterial growth and biofilm accumulation, and the self-healing property to ensure structural and functional integrity, would be of significant potential for bioengineering applications. However, to the best of our knowledge, combining all the above-mentioned features into one single hydrogel design has not been achieved. In this work, we report a new type of multi-functional hydrogel based on the self-assembly of an ABA tri-block copolymer comprising catechol functionalized polyethylene glycol(PEG)-based A block and quaternized B block, as illustrated in Figure 1a. This tri-block copolymer poly{[2-(2methoxyethoxy)ethyl methacrylate]-co-[oligo(ethylene glycol) methacrylate]-co-(N-3,4-
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dihydroxyphenethyl
acrylamide)}-b-poly{[2-(methacryloyloxy)ethyl]
trimethylammonium [oligo(ethylene
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iodide}-b-poly{[2-(2-methoxyethoxy)ethyl
glycol)
methacrylate]-co-
methacrylate]-co-(N-3,4-dihydroxyphenethyl
acrylamide)},
deviated as P(MEO2MA-co-OEGMA-co-DOPA)-b-PMETA-b-P(MEO2MA-co-OEGMAco-DOPA), was synthesized by reversible additional fragment transfer (RAFT) polymerization, followed successively by the replacement between an active ester and dopamine and the quaternization of the middle B block (see Figure S1 and Polymer Synthesis part in Supporting Information for the detailed synthesis process and characterization). As the PEG-based A blocks are thermo-sensitive and the quaternized B blocks are permanently hydrophilic, the tri-block copolymer can be hydrated and adopt an extended conformation in water at lower temperature, exhibiting a liquid-like behaviour. However, temperature increase can lead to gelation with A blocks dehydrating and associating into micellar core-like crosslinks and middle B blocks acting as network bridges,23-25 as illustrated in Figure 1b.
a
b +
+ +
+
+
+
+ +
+
+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +
Cross-link with catechol groups (red tetragon) trapped in PEO-based A block (blue dot)
+ +
+
+
PMETA B block
Retained water
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Figure 1 (a) Structure of the tri-block copolymer synthesized. (b) Schematic of a proposed structure of the resulting hydrogel and the mussel-inspired self-healing mechanism.
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Figure 2 (a) Storage (G’) and loss (G”) modulus changes of a 20 wt% hydrogel with temperature. (b) Modulus changes of a 20 wt% hydrogel with thermal cycles of heating (37 °C) and cooling (0 °C) for four rounds. (c) Injection of a 4 °C-preserved polymer solution sample into 37 °C DI water. To quantitatively characterize the thermo-sensitivity of the prepared hydrogel, rheological tests were conducted on a 20 wt% sample to measure the changes of its storage modulus (G’) and loss modulus (G”) with temperature. As shown in Figure 2a, at lower temperatures, G” was larger than G’, indicating a liquid-like sol state. While with the heating process, G’ increased significantly faster than G” and surpassed G” at higher temperature, indicating a solid-like gel state. The cross-over point at 18 °C was defined as the gelation temperature. The temperature was then cycled between 0 °C and 37 °C and the tested hydrogel demonstrated a fully reversible sol-gel transition behaviour within the 90 min test duration (Figure 2b), indicating that the hydrogel was constructed mainly through hydrophobic interactions arisen from the PEG-based analogues, rather than
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through irreversible covalent quinone cross-linking arisen from the catechol moieties. The excellent thermo-reversibility endows this novel hydrogel a mouldable property, that a low-temperature preserved precursor solution when transferred to target location can form gel tailored to the specific surface morphology. To facilitate operation, it would be desirable that the transferring process can be achieved through injection using a syringe. As shown in Figure 2c, when a 4 °C-preserved 20 wt% polymer solution was injected to a 37 °C-water bath using a 23G× 3/4” syringe, robust hydrogel formed instantaneously.
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Figure 3 (a) Colony forming units (CFUs) of E. coli in control broth and 1wt% polymer treated broth after 24 h incubation. (b-c) Images of E. coli colonies on agar plates from diluted bacterial suspension without treatment (b) and treated with 1 wt% polymer (c). (de) Representative fluorescence microscopy images of uncoated (d) and hydrogel coated (e) microwell dish after exposure to Caco-2 cells for 48 h. Gram-negative Escherichia coli aw1.7 (E. coli) was used as a model bacterial strain to evaluate the antimicrobial properties of our sample. E. coli suspensions were incubated with control Luria-Bertani (L-B) broth and 1 wt% polymer treated L-B broth respectively, at 37 °C for 24h. The resulting bacterial suspensions were used for agar plating and colony counting to determine the viable bacterial numbers. As shown in Figure 3a-c, 1 wt%
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polymer sample was able to kill E. coli with more than 99.8% reduction in bacterial counts, as compared with the control L-B broth. We attributed this excellent antimicrobial performance to the presence of cationic polymers in the developed hydrogel, which has been verified in a set of control experiments on antibacterial performance of three polymers to E. coli (See Figure S2 for the chemical structures of the polymers and Figure S3 for their antibacterial tests). Compared with antibiotics-releasing materials, the cationic polymers possess antimicrobial function to E. coli via the electrostatic targeting of the negatively-charged microorganism lipid membrane followed by a lysis resulting in cell death26, and are less likely to select and promote the emergence of new resistant strains due to their contact-killing mechanism, which is important for some chronic biomedical processes.27 Human intestinal Caco-2 cell was used as a model cell strain to evaluate the antifouling performance of the prepared hydrogel. Caco-2 cells were cultured in uncoated and hydrogel-coated microwell dishes respectively for 48 h before they were rinsed and stained followed by fluorescence imaging. As shown in Figure 3d, a dense layer of cells attached to the glass bottom of the uncoated microwell dish, with green fluorescence indicating cell membranes and blue fluorescence indicating nuclei. In contrast, the hydrogel-coated microwell dish (Figure 3e) exhibited great resistance against cell attachment, which could be attributed to the presence of PEG-based component and the inherent hydrophilic nature of the prepared hydrogel (see Figure S4 for the antifouling results on pure PEO-based hydrogels and cationic polymer hydrogel).28-29
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Figure 4 (a) Storage (G’) and loss (G”) modulus changes of a 20 wt% hydrogel upon enhanced external strains at 37°C (left) and an instantaneous recovery from the 1000% strain deformation (right). (b) Dynamic strain cyclic tests (γ =1% or 500%) of 20 wt% hydrogel at 37°C showing self-healing behaviour. (c-f) Visual evidence of self-healing: a hydrogel sample (c) was cut in half (d), and the two fragments after brought together to contact for several seconds (e) could heal into one integral piece (f). (g) Viscosity measurement of a 20 wt% hydrogel sample with shear rate. For hydrogels working as bioengineering functions, it’s important that they can spontaneously recover from inflicted damage to maintain both structural and functional integrity. Rheological strain sweep measurements were conducted on a 20 wt% hydrogel to quantitatively investigate its responsive behaviour upon external strains. As shown in Figure 4a, when applied strain was increased from 0.1% to 100%, both G’ and G” values
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maintained unchanged, suggesting the hydrogel could withstand relatively large deformation. However, a further increase of the strain till 1000% resulted in a dramatic drop of both G’ and G” values with a crossover point occurring at around 250%, suggesting that beyond this critical strain limit the hydrogel network got ruptured and turned into a liquid-like sol state due to the severe dislocation of polymer chains. However when a 1% strain was applied immediately after the gel failure (γ=1000%), the mechanical properties of the hydrogel sample got almost fully recovered. Dynamic strain cyclic tests with strain alternating between 1% and 500% were also applied to a 20 wt% hydrogel sample, as illustrated in Figure 4b. G’ dropped from ~550 Pa to ~20 Pa when subjected to the 500% strain, while achieved over 90% recovery within seconds upon the strain returning to 1%. This recovery behaviour was fully reversible and reproducible during the cyclic tests, indicating excellent self-healing performance of our hydrogel. Visual evidence of the self-healing property was demonstrated in Figure 4c-f, where a hydrogel sample was cut into half and the two fragments could automatically heal into one integral piece within seconds when brought into contact. The self-healing mechanism was mainly attributed to catechol-mediated hydrogen bonding and aromatic interactions though other interactions such as cation-π and hydrophobic interactions may also play a role (see Figure 1b and Figure S5 for the effect of hydrogen bonding on gelation and selfhealing), which agrees well with recent discovery of the metal-free self-healing mechanism
of
mussel-inspired
catechol-functionalized
materials.21-22
Viscosity
measurement of a 20wt% hydrogel sample was conducted and a dramatic drop of sample viscosity with increasing shear rate was observed (Figure 4g). This shear-thinning behaviour provides the broken polymer segments (e.g. catechol groups) at the disrupted
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interface with enhanced mobility to interact with each other to reconstruct the physical cross-links, and further to restore the hydrogel network.30 In summary, we have developed a novel injectable thermo-sensitive self-healing hydrogel with antimicrobial and antifouling properties, based on the self-assembly of an ABA tri-block copolymer in metal-free aqueous solution. This hydrogel can effectively inhibit the growth of E. coli due to the presence of cationic quaternary amine, and prevent nonspecific cell attachment due to the presence of a major component PEO. The hydrogel can also heal autonomously from repeated damage, through mussel-inspired catecholmediated hydrogen bonding and aromatic interactions. The combination of features including thermo-sensitivity, injectability, self-healing, antimicrobial and antifouling into one single design endows this hydrogel with great potential in various bioengineering applications.
Supporting Information. Polymer synthesis method and NMR data, experimental procedures for the rheological tests, antifouling assay and antimicrobial assay, additional experimental results on the antifouling and antibacterial performances of the hydrogel, and effects of hydrogen bonding interaction on the gelation and self-healing of the hydrogel. AUTHOR INFORMATION Corresponding Author *Email:
[email protected] (H.Z.) or
[email protected] (B.Y.) Author Contributions
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†
These authors contribute equally to this work.
ACKNOWLEDGMENTS The authors gratefully acknowledge the support from the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (H. Zeng). The authors also gratefully acknowledge the support from the China Opportunity Fund/Joint Research Lab Program at the University of Alberta (H. Zeng). A scholarship from the China Scholarship Council (L. Li) is also acknowledged.
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Table of Contents Graphic Antifouling
Self-healing
Thermo-sensitivity
Antimicrobial
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