Letter Cite This: ACS Macro Lett. 2018, 7, 904−908
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Bioinspired Self-Healing Hydrogel Based on BenzoxaboroleCatechol Dynamic Covalent Chemistry for 3D Cell Encapsulation Yangjun Chen,† Diana Diaz-Dussan,† Di Wu,‡ Wenda Wang,† Yi-Yang Peng,† Anika Benozir Asha,† Dennis G. Hall,‡ Kazuhiko Ishihara,§ and Ravin Narain*,† Department of Chemical and Materials Engineering, ‡Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G6, Canada § Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan Downloaded via BOSTON COLG on July 12, 2018 at 20:27:31 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
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S Supporting Information *
ABSTRACT: Boronic ester, one typical example of dynamic covalent bonds, has presented great potential to prepare selfhealing hydrogels. However, most of currently reported hydrogels based on boronic esters are formed at pH > 8, which impeded their further use in physiological conditions. In this study, we designed two kinds of zwitterionic copolymers with benzoxaborole and catechol pendant groups, respectively. Owing to the lower pKa value of benzoxaborole (7.2), gelation can happen easily at pH 7.4 PBS after mixing these two copolymers due to efficient formation of benzoxaborole-catechol complexations. The resulting hydrogels exhibited excellent self-healing property as well as dual pH/sugar responsiveness due to the dynamic nature of boronic ester. Moreover, benefiting from the cell membrane bioinspired 2-methacryloyloxyethyl phosphorylcholine (MPC)based polymeric matrix, the hydrogel was further investigated for 3D cell encapsulation. The combination of biocompatible zwitterionic polymers with dynamic benzoxaborole-catechol complexation makes the hydrogels a promising platform for diverse potential bioapplications like drug delivery and tissue engineering.
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boronic acids and 1,2-/1,3-diols, and the process is favored with solution pH near or higher than the pKa values of boronic acids.27 However, for most of the currently used boronic acids (mainly arylboronic acids), the higher pKa values over physiological pH (7.4) impede their further use in the biomedical areas.13,28 Benzoxaborole is a kind of cyclic analogue of phenylboronic acids (PBAs) with a pKa value (∼7.2) lower than physiological pH27 and has been shown by Hall and co-workers to exhibit high binding affinity with cis1,2-diol of monosaccharides to form stable five-membered boronate rings.29,30 Hydrogels formed by benzoxoborolecontaining polymers and glycopolymers have been explored by our group31−33 and Chen’s lab.34,35 Recently, Narain and Thundat et al.36 further applied the dynamic benzoxaboroleglycopolymer complexation for the detection of dopamine, an important biomolecule with a catechol group. Here it is worth mentioning that there has been numerous research on hydrogels formed by catechol-containing polymers with PBAmodified polymers or borax.37−40 However, almost all of those hydrogels were prepared at pH over 8. In this regard, hydrogel based on pH neutral benzoxaborole-catechol dynamic complexation has never been reported yet.
ydrogels are crosslinked polymeric networks with high water content that mimic physical properties of human tissues.1−3 Though the intrinsic nature of hydrogels offers great potential to serve as platforms for various biomedical applications, hydrogels made from conventional covalent bonds appeared less able to meet the fast-growing demand of modern and future medicine.4 Recently, extensive attention has been paid to self-healing and stimuli-responsive hydrogels.4−6 The self-healing ability can provide longer lifetime and better performance of hydrogels; meanwhile, the responsiveness to internal/external stimuli, such as pH, reduction, and glucose, as well as heat and light, enables hydrogels to spatially and temporally control the release of loaded therapeutic agents.4,7 Generally, non-covalent interactions (e.g., host− guest complexations8 and hydrogen bonding9) and dynamic covalent chemistry (DCC, e.g., Schiff base,10 hydrazone,11 disulfide,12 boronic ester,13 and Diels−Alder reaction14) are the two common ways to obtain self-healing hydrogels,4,5,15 and the latter seems more convenient to achieve the simultaneous stimuli-responsiveness via dissociation of the dynamic covalent bonds. Boronic ester formation is one popular example of dynamic covalent bonds and has been studied in diverse applications ranging from dynamic polymeric assemblies16,17 and hydrogels18−20 and stimuli-responsive drug/gene delivery for cancer therapy21−24 to controlled insulin release for blood glucose regulation.25,26 Boronic esters form readily by condensation of © XXXX American Chemical Society
Received: June 7, 2018 Accepted: July 9, 2018
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DOI: 10.1021/acsmacrolett.8b00434 ACS Macro Lett. 2018, 7, 904−908
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ACS Macro Letters For biomedical hydrogels, biocompatibility is one of the most significant parameters that should be taken into serious consideration.41 Zwitterionic polymers that possess balanced positive and negative charges have proved to have superior antifouling ability and excellent biocompatibility.42−44 2Methacryloyloxyethyl phosphorylcholine (MPC) is a star zwitterionic molecule with cell-membrane mimicking structure and has been enormously investigated for designing functional polymers with a wide range of applications including stealth cancer nanomedicine and nonfouling surface modification.45−47 Therefore, hydrogels made from biocompatible MPC-based polymers can be ideal for biomedical applications such as three-dimensional (3D) cell encapsulation.48,49 Herein, we describe the first report of self-healing and dualresponsive hydrogel crosslinked by benzoxaborole-catechol dynamic covalent chemistry between two MPC-based copolymers (Figure 1). The good biocompatibility of cell membrane inspired zwitterionic polymers enables the hydrogel to serve as an ideal platform for 3D cell encapsulation.
were synthesized via free-radical polymerization of MPC with benzoxaborole-containing monomer 5-methacrylamido-1,2benzoxaborole (MAABO) and catechol-containing monomer dopamine methacrylamide (DMA, purity confirmed by 1H NMR in Figure S1), respectively. 1H NMR and gel permeation chromatography (GPC) were applied to characterize these two copolymers, and detailed information is displayed in Table S1. The benzoxaborole and catechol mol contents in the copolymer chains were calculated by 1H NMR (Figure 2B,D) to be 14.7% and 11.7%, respectively. The molecular weights (Mn) of poly(MPC-st-MAABO) and poly(MPC-stDMA) were determined by aqueous GPC to be 44.2 kg/mol (PDI = 2.54) and 54.7 kg/mol (PDI = 2.58), respectively. Hydrogel formation was confirmed via simple vial tilting method and happened quickly within 30 s after mixing the two polymer solutions (pH 7.4 PBS). The fast gelation should be attributed to the efficient crosslinking by formation of tetrahedral boronates, similar to the hydrogels we previously reported, which formed through benzoxaborole−sugar interactions.33 Three hydrogels, denoted as Gel-7.5%, Gel-10%, and Gel-12.5%, were prepared accordingly with different designed solid contents. Rheological measurements of frequency-sweep were applied to compare the mechanical properties of these three hydrogels. As shown in Figure 3A, all these three
Figure 1. Schematic illustration of the preparation of bioinspired zwitterionic hydrogels (dyed with RhB) based on dynamic benzoxaborole-catechol complexation.
Two kinds of zwitterionic copolymers (Figure 2A,C), namely, poly(MPC-st-MAABO) and poly(MPC-st-DMA),
Figure 3. (A) Dynamic oscillatory frequency sweeps, (B) storage modulus data (G′ at γ = 1%, ω = 1 Hz), and (C) SEM images of hydrogels with different weight ratios (7.5, 10, and 12.5 wt %). (D) Demonstration of self-healing ability. (E) Step-strain sweep at a small strain of 1% and a large strain of 550%.
hydrogels exhibited typical behavior for hydrogels formed by dynamic bonds, that is, both the storage modulus (G′) and loss modulus (G″) exhibited frequency-dependent profile.13,50 At low frequencies, the hydrogels showed liquid-like behavior with G′ < G″. However, G′ exceeded G″ as the elastic component dominates at higher frequencies. The crossover frequencies when G′ equals to G″ for all the three hydrogels were close and located in the range of 2.2−2.6 rad/s. The G′ values of the three hydrogels at a fixed frequency of 1 Hz were collected to study the influence of solid content on mechanical properties. As shown in Figure 3B, the G′ values for Gel-7.5%,
Figure 2. (A) Synthetic route and (B) 1H NMR spectrum of benzoxaborole-containing copolymer poly(MPC-st-MAABO). (C) Synthetic route and (D) 1H NMR spectrum of catechol-containing copolymer poly(MPC-st-DMA). 905
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ACS Macro Letters Gel-10%, and Gel-12.5% were 35.4 ± 11.8, 127.3 ± 49.0, and 319.2 ± 47.7 Pa, respectively, indicating a positive correlation with solid content. The porous morphology of freeze-dried hydrogels was characterized by SEM as shown in Figure 3C. The average pore sizes of Gel-7.5%, Gel-10%, and Gel-12.5% were calculated to be 18.8 ± 5.3, 15.5 ± 4.0, and 12.5 ± 3.3 μm, respectively. The smaller pore size and more compact porous structure observed in hydrogels with higher solid content should be due to the higher crosslinking density, which was consistent with the results of G′ values. The interconnected porous structure of the hydrogels could offer ample space for cell proliferation and facilitate permeation of oxygen and nutrients when applied for 3D cell encapsulation.51 The self-healing ability of the hydrogel was investigated by both visual observation and rheological measurement. As shown in Figure 3D, four separate pieces of dyed hydrogels were joined together and allowed to heal for 1 min to form a complete hydrogel with the jointed interfaces fully healed. The healed joints were strong enough such that the hydrogel can be lifted and stretched to more than two times longer of its original length. From Movie S1, we could also see the fast and efficient self-healing behavior which could happen within ∼20 s. The self-healing ability was further studied by rheological step-strain test at a fixed frequency of 1 Hz. The cyclic tests contained two processes: one is applying a large stain of 550% which is higher than the critical strain required to disrupt the hydrogel network (515%, confirmed by strain-sweep measurement in Figure S2), the other is reducing the strain to 1% for hydrogel network recovery. As displayed in Figure 3E, when the hydrogel was subjected to a large stain of 550%, the G′ value dropped dramatically along with an inversion of G″ exceeding G′, indicating that gel failure occurred. However, when a small strain of 1% was applied, the G′ value recovered immediately to be higher than G″. Though there was a bit loss of the G′ value in the first recovery cycle because of some extent of hydrogel was squeezed out during the high stain test, nearly 100% recovery of the G′ value was observed in the second cyclic test. These results demonstrated that the hydrogel possessed excellent self-healing properties which should be ascribed to the efficient rearrangement of benzoxaborole-catechol complexations. Due to the reversible nature of boronate formation, the benzoxaborole-catechol complexation could be weakened by reducing solution pH or adding competitive diol-containing molecules,20,40 like saccharides. As shown in Figure 4A, the hydrogel completely turned into free-flowing sol state upon the addition of 0.1 M HCl solution. However, hydrogel network could be reconstructed with the addition of 0.1 M NaOH solution to neutralize the acid. Importantly, this process could be well-reproduced even after four cyclic tests due to the reversibility of benzoxaborole-catechol complexations (Figure 4B). The hydrogel could also be decomposed by immersing the hydrogel in PBS solution with 50 mM of fructose (Figure 4C). As shown by Hall and co-workers, the diol groups in fructose exhibit strong binding affinity with benzoxaborole units,29 they can competitively disintegrate the crosslinking sites formed by benzoxaborole-catechol complexation (Figure 4D). By contrast, the hydrogel immersed in PBS solution without saccharides exhibited considerable stability even after 24 h immersion. These results revealed that the hydrogel could potentially be used for controlled drug delivery for certain types of diseases, where the microenvironment has weakly acidic pH of ca. 6.5 such as in tumor tissue (lower than the pKa
Figure 4. (A) Reversible gel−sol−gel transition by changing pH. (B) Schematic illustration for reversible pH responsiveness. (C) Hydrogel stability in PBS (left vial) and PBS with 50 mM of fructose (right vial). (D) Schematic illustration for hydrogel degradation by fructose competition.
of benzoxaborole),52 and where the blood glucose level is over 400 mg/dL such as in diabetic patients.26 MPC-based polymers are widely considered to be nontoxic and safe.42,53 Cell cytotoxicity tests were performed by incubating HeLa cells with culture medium containing the copolymers or hydrogel extracts for 24 h. As shown in Figure S3, poly(MPC-st-DMA) exhibited excellent biocompatibility with over 95% cell viability retained even at the highest tested concentration of 2 mg/mL. For poly(MPC-st-MAABO), a bit lower yet still good viability of around 85% was obtained at the same concentration. The lower cell viability of HeLa cells incubated with poly(MPC-st-MAABO) could be induced by the potential anticancer activity of benzoxaborole derivatives.54 Nevertheless, no significant cytotoxicity was observed for hydrogel extracts obtained from different culture medium/ hydrogel volume ratios with over 90% cells remained viable (Figure S4). Given the good biocompatibility of MPC-based polymeric matrix, the hydrogel was further explored to be used for 3D cell encapsulation. HeLa cells were loaded at a density of 2.5 × 106 cells/mL in the hydrogel and cultured with low glucose DMEM medium for 24 h. The cell viability was evaluated by live/dead assay and imaged by fluorescent confocal microscope as shown in Figure 5. Live cells undergo an enzymatic conversion of cell-permeant calcein AM to the fluorescent calcein, which retains within live cells (green color) and a red color is observed when the cell-impermeant component propidium iodide, enters cells with damaged
Figure 5. Live/dead assay of HeLa cells cultured in Gel-10% hydrogel for 24 h. (A) 2D and (B) 3D images were obtained from fluorescent confocal microscope. Green color represents live cells and red color represents dead cells. 906
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ACS Macro Letters
(4) Wei, Z.; Yang, J. H.; Zhou, J.; Xu, F.; Zrinyi, M.; Dussault, P. H.; Osada, Y.; Chen, Y. M. Self-Healing Hels Based on Constitutional Dynamic Chemistry and Their Potential Applications. Chem. Soc. Rev. 2014, 43, 8114−8131. (5) Wang, Y.; Adokoh, C. K.; Narain, R. Recent Development and Biomedical Applications of Self-Healing Hydrogels. Expert Opin. Drug Delivery 2018, 15, 77−91. (6) Taylor, D. L.; In Het Panhuis, M. Self-Healing Hydrogels. Adv. Mater. 2016, 28, 9060−9093. (7) Li, J.; Mooney, D. J. Designing Hydrogels for Controlled Drug Delivery. Nat. Rev. Mater. 2016, 1, 16071. (8) Nakahata, M.; Takashima, Y.; Yamaguchi, H.; Harada, A. RedoxResponsive Self-Healing Materials Formed from Host-Guest Polymers. Nat. Commun. 2011, 2, 511. (9) Biyani, M. V.; Foster, E. J.; Weder, C. Light-Healable Supramolecular Nanocomposites Based on Modified Cellulose Nanocrystals. ACS Macro Lett. 2013, 2, 236−240. (10) Huang, W.; Wang, Y.; Chen, Y.; Zhao, Y.; Zhang, Q.; Zheng, X.; Chen, L.; Zhang, L. Strong and Rapidly Self-Healing Hydrogels: Potential Hemostatic Materials. Adv. Healthcare Mater. 2016, 5, 2813−2822. (11) Wang, P.; Deng, G.; Zhou, L.; Li, Z.; Chen, Y. Ultrastretchable, Self-Healable Hydrogels Based on Dynamic Covalent Bonding and Triblock Copolymer Micellization. ACS Macro Lett. 2017, 6, 881− 886. (12) Yu, H.; Wang, Y.; Yang, H.; Peng, K.; Zhang, X. Injectable SelfHealing Hydrogels Formed via Thiol/Disulfide Exchange of Thiol Functionalized F127 and Dithiolane Modified PEG. J. Mater. Chem. B 2017, 5, 4121−4127. (13) Yesilyurt, V.; Webber, M. J.; Appel, E. A.; Godwin, C.; Langer, R.; Anderson, D. G. Injectable Self-Healing Glucose-Responsive Hydrogels with pH-Regulated Mechanical Properties. Adv. Mater. 2016, 28, 86−91. (14) Smith, L. J.; Taimoory, S. M.; Tam, R. Y.; Baker, A. E. G.; Binth Mohammad, N.; Trant, J. F.; Shoichet, M. S. Diels-Alder Click-CrossLinked Hydrogels with Increased Reactivity Enable 3D Cell Encapsulation. Biomacromolecules 2018, 19, 926−935. (15) Strandman, S.; Zhu, X. X. Self-Healing Supramolecular Hydrogels Based on Reversible Physical Interactions. Gels 2016, 2, 16. (16) Deng, R.; Derry, M. J.; Mable, C. J.; Ning, Y.; Armes, S. P. Using Dynamic Covalent Chemistry To Drive Morphological Transitions: Controlled Release of Encapsulated Nanoparticles from Block Copolymer Vesicles. J. Am. Chem. Soc. 2017, 139, 7616−7623. (17) Zhang, J.; Tanaka, J.; Gurnani, P.; Wilson, P.; Hartlieb, M.; Perrier, S. Self-Assembly and Disassembly of Stimuli Responsive Tadpole-Like Single Chain Nanoparticles Using a Switchable Hydrophilic/Hydrophobic Boronic Acid Cross-Linker. Polym. Chem. 2017, 8, 4079−4087. (18) Guan, Y.; Zhang, Y. Boronic Acid-Containing Hydrogels: Synthesis and Their Applications. Chem. Soc. Rev. 2013, 42, 8106− 8121. (19) Venkatesh, V.; Mishra, N. K.; Romero-Canelon, I.; Vernooij, R. R.; Shi, H.; Coverdale, J. P. C.; Habtemariam, A.; Verma, S.; Sadler, P. J. Supramolecular Photoactivatable Anticancer Hydrogels. J. Am. Chem. Soc. 2017, 139, 5656−5659. (20) Pettignano, A.; Grijalvo, S.; Haring, M.; Eritja, R.; Tanchoux, N.; Quignard, F.; Diaz Diaz, D. Boronic Acid-Modified Alginate Enables Direct Formation of Injectable, Self-Healing and Multistimuli-Responsive Hydrogels. Chem. Commun. 2017, 53, 3350−3353. (21) Diaz-Dussan, D.; Nakagawa, Y.; Peng, Y.-Y.; C, L. V. S.; Ebara, M.; Kumar, P.; Narain, R. Effective and Specific Gene Silencing of Epidermal Growth Factor Receptors Mediated by Conjugated Oxaborole and Galactose-Based Polymers. ACS Macro Lett. 2017, 6, 768−774. (22) Su, J.; Chen, F.; Cryns, V. L.; Messersmith, P. B. Catechol Polymers for pH-Responsive, Targeted Drug Delivery to Cancer Cells. J. Am. Chem. Soc. 2011, 133, 11850−11853. (23) Wu, X.; Tan, Y. J.; Toh, H. T.; Nguyen, L. H.; Kho, S. H.; Chew, S. Y.; Yoon, H. S.; Liu, X. W. Stimuli-Responsive Multifunc-
membranes in dying and dead cells. The amount of live cells which were colored green took the majority of cells encapsulated and cell viability was calculated to be about 86%, revealing that cells can be kept in good condition inside the hydrogel network. As demonstrated before, both the nontoxic polymeric matrix and the porous network structure which could facilitate nutrition transportation should contribute to provide comfortable microenvironment for cells to achieve normal metabolic functions. In conclusion, hydrogel crosslinked by benzoxaborolecatechol complexation at physiological pH was demonstrated for the first time. The hydrogel exhibited fast self-healing ability and can be dissociated by lowering the pH or adding competitive saccharides. Moreover, the hydrogel with cell membrane bioinspired MPC-based polymeric matrix showed good biocompatibility when used for 3D cell encapsulation. This type of benzoxaborole-catechol complexation can be applied toward the design of smart hydrogels for various potential biomedical applications including drug delivery and tissue engineering.
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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/acsmacrolett.8b00434. Experimental details, chemical composition and molecular weights of poly(MPC-st-DMA) and poly(MPC-stMAABO), 1H NMR spectrum of dopamine methacrylamide (DMA), step-strain sweep of Gel-10%, and MTT results of polymers and gel extracts (PDF). Self-healing property (AVI).
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yangjun Chen: 0000-0002-7449-9348 Dennis G. Hall: 0000-0001-8555-6400 Ravin Narain: 0000-0003-0947-9719 Author Contributions
All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI). Prof. Hongbo Zeng is thanked for the help with the use of rheometer.
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REFERENCES
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