Letter pubs.acs.org/macroletters
Dynamic Supramolecular Hydrogels: Regulating Hydrogel Properties through Self-Complementary Quadruple Hydrogen Bonds and Thermo-Switch Guangzhao Zhang,† Yunhua Chen,*,‡ Yonghong Deng,§ To Ngai,*,∥ and Chaoyang Wang*,† †
Research Institute of Materials Science, South China University of Technology, Guangzhou 510640, China National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China § Department of Materials Science & Engineering, South University of Science and Technology of China, Shenzhen 518055, China ∥ Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China ‡
S Supporting Information *
ABSTRACT: We report here a supramolecular hydrogel displaying a wide array of dynamic desirable properties. The key is using an ABA triblock copolymer containing a central poly(ethylene oxide) block and terminal poly(N-isopropylacrylamide) (PNIPAm) block with ureido pyrimidinone (UPy) moieties randomly incorporated. Rapid hydrogelation is triggered upon increasing temperature above the lower critical solution temperature (LCST) of the supramolecular copolymer, where PNIPAm segments dehydrate and assemble into micelles, which subsequently provide hydrophobic microenvironments promoting UPy dimerization to grab polymer chains, thus forming hydrogen-bonded cross-linking points. The supramolecular hydrogels demonstrate fascinating shear-thinning, self-healable, thermo-reversible, and injectable properties, which allow withstanding repeated deformations and 3D construction of complex objects. Mesenchymal stem cells mixed with the hydrogel and injected through needles remain highly viable (>90%) during the encapsulation and delivery process. With these attractive dynamic physical properties, the supramolecular hydrogel holds great promise to support cell or drug therapies.
I
cells by avoiding direct contact with enzymes which often cause protein and molecule degradation or inactivation. Much different from the traditional chemically cross-linked hydrogels which are not able to recover to their initial state after damage, injectable hydrogels could exhibit excellent reversibility. Apparently, the cross-linking approach between the hydrophilic polymer chains is the key to preparing injectable hydrogels, which essentially account for the shearthinning and self-healing ability. To date, various cross-linking routes, including π−π stacking,20 host−guest inclusion,21,22 hydrophobic interaction,23 dynamic covalent bonds,3,24 ionic coordination,25−27 and hydrogen bonding interaction,28 have been explored to bridge hydrophilic polymer chains for building 3D hydrogel networks. In this respect, ureido pyrimidinone (UPy) moieties, first reported by Meijer and co-workers, are particularly attractive as they can form self-complementary dimers via quadruple hydrogen bonding interaction and have been used to prepare supramolecular polymers with self-healing
njectable hydrogels, a type of soft material which can be transplanted by simple injection into the human body via syringes due to their excellent shear-thinning properties,1−4 offer new opportunities for larger application of minimally invasive surgery.5,6 Besides the appropriate mechanical properties for easy operation, porous structure,7 good biocompatibility,8 as well as the resemblance to natural extracellular matrices also make the injectable hydrogels one of the most promising candidates for various biomedical applications.9−11 For instance, many bioactive molecules like proteins, drug, DNA, along with antibodies can be easily encapsulated into the hydrogel matrix via simple mixing with the precursor polymer solutions and then placed at target sites on-demand through in situ gelation after injection.12−14 Compared with the direct injection of bioactive molecules into human bodies which often involve substantial molecule diffusion in short time, the release of molecules from a responsive hydrogel carrier could be well controlled, depending on the external stimuli, such as pH,15 temperature,16 light,17 and electric or magnetic fields.18,19 More important, the encapsulated molecules can also be well protected within the hydrogel matrix and keep their therapeutical effect before releasing to the target tissues or © XXXX American Chemical Society
Received: April 12, 2017 Accepted: June 8, 2017
641
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
Letter
ACS Macro Letters ability29−32 and more recently multifunctional hydrogels.15,33 Importantly, Meijer et al. have concluded that the strong affinity of UPy dimers can only be retained in hydrophobic microenvironments, and the dimerization decreases dramatically when the environment becomes hydrophilic.34 Therefore, making hydrogen-bonded hydrogels in water is a challenge although some Hamilton-wedge-like motifs are successful without a specific hydrophobic microenvironment.35 Considering the fact that the whole polymer chain of hydrogel is surrounded by water, the presence of hydrophobic segments around the UPy moieties will be vital to prepare UPy-based injectable hydrogels. Hydrophobic alkyl chains and sodium dodecyl sulfate (SDS) micelles have been utilized to create nonprotic environments for UPy−UPy dimerization enhancement in the preparation of injectable and highly stretchable selfhealing hydrogels, respectively.34,36 The hydrophobic microenvironments contributed from alkyl chain sequences or micelles, however, are settled and unchangeable, which restricted the strong demand for dynamic structures and properties of hydrogels to meet various biological requirements. In this report, we demonstrate a rational design of a supramolecular hydrogel with a dynamic control of the hydrophobic microenvironment for UPy dimerization for the first time, which endows the hydrogel with fascinating tunable properties. The key is using a water-soluble ABA triblock copolymer containing a central poly(ethylene oxide) block (A) and terminal poly(N-isopropylacrylamide) (PNIPAm) block with ureido pyrimidinone (UPy) moieties randomly incorporated (B), which was synthesized by reversible additional fragment transfer (RAFT) polymerization (Scheme 1a, Scheme S4, termed as UNONU). Poly(N-isopropylacrylamide) (PNI-
PAm) can transform from hydrophilic state to hydrophobic state with elevating temperature above the lower critical solution temperature (LCST, about 21 °C, determined by a rheological test) of the copolymer, and dehydrated PNIPAm blocks become hydrophobic and can assemble into micelles/ clusters, subsequently providing a hydrophobic microenvironment promoting UPy dimerization to grab polymer chains, thus forming 3D physical hydrogel networks. More remarkably, this process is totally thermo-reversible (Scheme 1b). The obtained hydrogels exhibit quick self-healing ability after mechanical disruption, and they can withstand repeated deformation and 3D construction of complex objects under temperature switch. These unique properties could be significantly beneficial to minimal invasive operation with convenient handling and injection transplant of hydrogels. A simple vial tilting method was first employed for the gelation investigation of a 10 wt % UNONU (Table S1) at different temperatures. As shown in Figure 1a, the UNONU
Scheme 1. Design of the Thermo-Responsive, Self-Healable, and Injectable Supramolecular Hydrogel: (a) Chemical Structure of the ABA Triblock Copolymer and (b) Schematics of Reversible Sol−Gel Transition of the Prepared Hydrogel under Temperature Switch
Figure 1. Reversible hydrogelation and thermal properties of UNONU and NON polymers. (a) Gelation test of UNONU and NON polymer solutions under cold (4 °C) and warm (37 °C) conditions via simple tilting. (b) DSC characterization curves of UNONU and NON polymers. (c) SEM image of the supramolecular hydrogel (scale bar: 50 μm) and (d) enlarged image showing the internal porous structures (scale bar: 5 μm).
solution transformed from a sol to a gel state with temperature increasing from 4 to 37 °C, suggesting the establishment of a 3D hydrogel network due to the enhanced UPy dimerizations contributed from the protection of dehydrated PNIPAm blocks. The gelation tests of UNONU solution with different polymer concentrations indicate the critical gelation point lies between 4 and 6 wt % (Figure S6). Actually, the 10 wt % UNONU solution can form a gel at even lower temperature 25 °C, reflecting the sufficiently strong association of UPy dimers. While dissolving UNONU into 5 mol/L urea solution (hydrogen bond breaking) with the same polymer concentration, no gel formed at 25 °C (Figure S7), also implying that the quadruple hydrogen bonding interaction of UPy dimers instead of their hydrophobic tag was the key of gel formation. It is well-known that sole hydrophobic interaction can lead to physical gelation;24 therefore, the PNIPAm blocks on their own in the dehydration state are suspected to be the main contribution of gel formation. Thus, a gelation test of 10 wt % of aqueous solution of the NON copolymer without UPy 642
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
Letter
ACS Macro Letters incorporation (Table S1, Scheme S5) was conducted. It can be clearly observed that the NON solution kept in the sol state at both 4 and 37 °C (Figure 1a, right), indicating that the hydrophobic interactions from the dehydration PNIPAm blocks are too weak to build the hydrogel networks, which strongly confirmed the key role of UPy self-complementary dimerization for hydrogel formation. Thermal properties of UNONU and NON copolymers were then investigated by differential scanning calorimetry (DSC) analysis, and the results were shown in Figure 1b. The melting peak temperatures of both UNONU and NON are much lower than that of pure PEO (Figure S8), which could be readily elucidated by the theory that the copolymerization at the dual end of PEO disturbed its crystallization behavior. Additionally, the melting peak temperature of UNONU is higher than that of NON, strongly indicating that the UPy dimers enhance the intermolecular interaction of copolymer chains. SEM images of the freeze-dried UNONU hydrogel show uniform interconnected macroporous structures (ice templating) (Figure 1c and d), which could potentially facilitate the encapsulation and transport of bioactive molecules. To investigate the mechanical properties regarding shearthinning and recovery, we performed rheological tests on a 10 wt % supramolecular hydrogel. From the results of strain sweep measurement of the hydrogel (Figure 2a), it is clear that both the storage modulus (G′) and the loss modulus (G″) remain constant with the increase of strain from 0.1% to 60%, and the value of G′ is much larger than that of G″, suggesting the hydrogel is in a gel state. However, when further increasing the applied strain, the G′ and G″ decrease dramatically. An apparent crossover occurs at the strain of 180%, suggesting that beyond this critical point severe slippage of polymer chains appears and the hydrogel network is disrupted which then converts into a sol state. Meanwhile, repeated dynamic strain amplitude cyclic tests (γ = 0.5% or 200%) of the hydrogel were carried out to investigate its self-healing property. As presented in Figure 2b, when subjected to a 200% strain, the G′ of the hydrogel drops from about 3000 to 50 Pa immediately and becomes smaller than that of G″ in value, indicating that the hydrogel was disrupted and subsequently transformed into a sol state. However, when a small strain (0.5%) was applied after the removal of large strain, both G′ and G″ recovered immediately to their initial values without any loss, suggesting that the broken hydrogel self-healed and rebuilt its 3D networks. After five cycle tests, the hydrogel could still keep its initial mechanical properties, showing excellent recovery ability. This self-healing behavior can be explained appropriately by the inherent reversibility of quadruple hydrogen bonding interaction from UPy dimers. The frequency dependence of G′ and G″ also clearly displays hydrogel-like behavior of the sample as G′ is dominant across the whole frequency range (Figure 2c). In general, the supramolecular hydrogel is soft but highly elastic (tan δ < 0.2). Viscosity measurement on the hydrogel was performed, and an apparent shear-thinning behavior was observed from Figure 2d. This excellent shearthinning property of the prepared hydrogel makes it possible to be injected with a syringe (Figure 2d inset and Figure S9). To intuitively characterize the self-healing ability, optical selfhealing test of the hydrogel was carried out: Two hydrogel pieces could adhere to each other instantly when putting into contact and simultaneously heal into one integral hydrogel (Figure 2e−h). More remarkably, the healed hydrogel was sufficiently strong to withstand stretching (Figure 2i). In
Figure 2. Mechanical properties and self-healing behavior of the supramolecular hydrogel. (a) Strain sweep measurements of the hydrogel at 37 °C (storage modulus G′ and loss modulus G″ as a function of strain γ). (b) Dynamic strain amplitude cyclic test (γ = 0.5% and 200%) of the hydrogel at 37 °C showing rapid self-healing behavior. (c) Frequency-dependent (at a strain of 1%) oscillatory shear rheology of the hydrogel. (d) Viscosity measurement of the hydrogel (inset: injection test of the hydrogel at room temperature). (e) Two disk-shaped supramolecular hydrogels, one stained with rose red and the other stained with methylthionine chloride for clarity. (f) Hydrogels were cut into equal halves by a razor blade. (g) Two hydrogel pieces recontacting. (h) The self-healed hydrogels can carry their own weight. (i) The self-healed hydrogels can also withstand stretching, scale bars: 1 cm. (j and k) Round-shape disruption in the center of hydrogel disappears after 12 h, also displaying the self-healing ability (scale bars: 0.5 cm).
addition, the observation that a 0.5 cm central hole in the hydrogel diminishes and totally disappears after 12 h (Figure 2j and k) also confirms the excellent self-healing property. As we expected in molecular design, the obtained hydrogels exhibit outstanding temperature-responsive property. To characterize the thermo-sensitivity of hydrogel, a temperature ramp test was performed on a 10 wt % hydrogel with a rheometer, in which the G′ and G″ were recorded with increasing temperature from 4 to 37 °C while keeping the heating rate at 1 °C/min. As depicted in Figure 3a, the value of G″ was larger than that of G′ at low temperatures, indicating a sol-like behavior. Upon heating, the storage modulus G′ increases dramatically with a crossover point appearing at 21 °C, which can be defined as the critical sol−gel transition temperature. Beyond this point, the value of G′ continues increasing and becomes greater than that of G″, signifying the gel-like behavior. To further study the reversibility of sol−gel 643
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
Letter
ACS Macro Letters
remained around 18 nm at low temperatures and increased rapidly after the solution was heated over 21 °C (Figure 3c), which is identical with the critical sol−gel transition temperature determined by the rheological measurement. When further increasing temperature over 30 °C, the copolymer chains aggregated into micelles with an average diameter of about 45 nm and did not show further nanoparticle infusion, implying long-term particle/micelle stability is achieved. Note that the phase transition temperature is around 32 °C for the NON copolymer without UPy unit decorating (Figure S10). Different from the reported dopamine-based hydrogel, in which the catechol groups are readily oxidized at atmosphere although protected by PNIPAm,1 the antioxidant activity of our UNONU copolymer is considerably strong in water. To confirm this, a UNONU solution with a polymer concentration of 1 mg/mL was placed in air at 37 °C for 1 week followed by an UV−vis measurement, and no significant absorption change was found between the sample and the original one (Figure S11), revealing the stability of the UNONU copolymer. The excellent thermosensitive sol−gel behavior combining with self-healing property of our supramolecular hydrogel demonstrates great opportunities to build various complex 3D structures by deformation and reconstruction. A “Bagua” pattern was first built by using this dynamic hydrogel. To achieve this, one portion of hydrogel (stained with rose red) at 4 °C was first injected onto the bottom of a round beaker which was separated by an “s”-shaped metal barrier (Figure 3d). Upon warming to room temperature, injection gelling occurred. After removing the barrier, another portion of hydrogel (stained with methylthionine chloride) was injected (Figure 3e and f). The complex 3D pattern was finally obtained after the completed hydrogelation and rapid healing of the two hydrogel portions (Figure 3g). Note that the hydrogels are remarkably reprocessable, as demonstrated in Figure S12, and hydrogel fragments could deform and merge into one integral at low temperature, which then reunited and healed to form a whole hydrogel piece without observable boundaries upon warming to room temperature. Another interesting phenomenon was found in which the hydrogel can display dynamic features when injected onto platforms with different temperatures (Figure 3h−i). It was clear that the injected hydrogels kept in a rod-like performance and could build a two-layered “triangle” monolith when the temperature of the platform was 37 °C (Figure 3h), providing a potential possibility of implementation with 3D printing. However, when the platform temperature was 15 °C (lower than the critical sol−gel transition temperature of UNONU copolymer), the injected hydrogel could not retain its rod shape and collapsed (Figure 3i). In addition, one-dimensional hydrogel fiber can also be instantly formed after the polymer solution was injected into 37 °C water bath, and the formed hydrogel fiber was kept intact long-term at this temperature without fragmentation (Figure 3j). 3D encapsulation and delivery of cells or drugs of hydrogels are highly desirable in biomedical fields. With the remarkable thermo-reversible, self-healable, and injectable properties demonstrated above, our supramolecular hydrogel could serve as a potential promising bioplatform for regenerative medicine. Considering the biocompatibility is of major importance, as the cytotoxicity of the UNONU copolymer was tested at various concentrations ranging from 0.5 wt % to 5 wt % and the cell viability (mouse bone mesenchymal stem cells, mBMSC) was determined by using a CCK-8 assay. In general, the
Figure 3. Thermo-reversible behavior of the supramolecular hydrogel. (a) Temperature-responsive storage (G′) and loss (G″) modulus of a 10 wt % hydrogel. (b) Modulus changes of the hydrogel with four thermal cycles of heating (37 °C) and cooling (13 °C). (c) DLS results showing the alterations of hydrodynamic diameter of UNONU polymers with increased temperature. (d−g) Complex 3D pattern can be formed by injection molding of UNONU polymer solution at low temperature (4 °C) and warming at room temperature (scale bar: 0.5 cm). (h) 3D multilayered triangle-shaped scaffold produced by directinjection printing of the hydrogel onto a 37 °C platform. (i) The injected hydrogel instantly flows and deforms when the temperature of the platform is 15 °C (scale bars: 1 mm). (g) Instant gelation occurs when injecting a 10 wt % UNONU polymer solution into 37 °C deionized water, and the formed hydrogel fiber keeps long-term stability in the 37 °C water (scale bar: 1 cm).
transition between low and high temperature, a cyclic temperature sweep test between 13 and 37 °C was conducted. As presented in Figure 3b, both G′ and G″ remained constant, while the value of G′ was significantly greater than that of G″ at 37 °C. However, when the temperature dropped to 13 °C, the G′ decreased instantly and became smaller than that of G″, indicating the instantaneous gel-to-sol transition. Upon heating to 37 °C again, both G′ and G″ recovered to their initial values, implying the process of sol−gel transition was totally reversible. This excellent reversibility can make the mechanical property of the hydrogel intact even undergoing four cycle tests. A dynamic light-scattering (DLS) measurement was then carried out to monitor the variation of hydrodynamic diameter of UNONU copolymer which is related to the dehydration process of PNIPAm blocks. It is obvious that the hydrodynamic diameter 644
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
Letter
ACS Macro Letters
Figure 4. 3D cell culture and protein release profile of the supramolecular hydrogel. (a) The cell viability of mBMSC versus different polymer concentrations after 24 h culture. Live/Dead assay image of cells encapsulated within hydrogel for (b) 24 h and (c) 48 h (viable cells: green spots, dead cells: red spots). (d) 3D confocal microscopy images of mBMSC cells encapsulated in the hydrogel for 48 h; dimension: 1.0 mm × 1.0 mm × 250 μm. (e) Schematic illustration of protein release from the hydrogel. (f) Protein release profiles of the hydrophilic bovine serum albumin (BSA) from hydrogels (with a polymer concentration of 10 wt %). (g) Release data fitting (Ritger−Peppas equation) indicating BSA was released from the hydrogel by Fickian diffusion within the initial 72 h. All scale bars: 200 μm.
supramolecular triblock copolymer demonstrates extremely good cell viabilities (>90%) for 24 h culturing (Figure 4a). A 3D cell culture was then performed by encapsulating mBMSC cells into the hydrogel. Live/dead cell staining shows dead cells were negligible after culturing for 24 and 48 h, also indicating the excellent cytocompatibility of the hydrogel. The typical round shape morphology of mBMSC in a 3D microenvironment can be clearly observed (Figure 4b and c), which is quite different from that of conventional 2D culturing where cells are more flat and highly spreading (Figure S13). Confocal microscopy images also show the 3D distribution of mBMSC cells within the supramolecular hydrogel (Figure 4d). In addition, protein release test was also carried out on the hydrogel by employing bovine serum albumin (BSA) as a target cargo (Figure 4e). It was clear to see from the release profile (Figure 4f) that the release of BSA was relatively fast during the initial 72 h and slowed down afterward with reaching a final value of 62%. The release profile fitting by the Ritger−Peppas equation37 shows Fickian diffusion mode dominating the initial 72 h of BSA release into the medium, and a non-Fickian sustained release behavior was followed afterward, indicating weak physical interactions between polymer and proteins. Possible on-demand delivery can be realized through facile polymer concentration variation (Figure 4g). Overall, these results demonstrate that the hydrogel could be developed as a promising tissue scaffold or protein carrier. In conclusion, we developed a supramolecular strategy for preparing dynamic hydrogels based on water-soluble ABA triblock copolymer containing a central PEO block and terminal PNIPAm block with ureido pyrimidinone (UPy)
moieties randomly incorporated. The synergistic effect of PNIPAm assembly and UPy dimerization endows the hydrogel with attractive shear-thinning property, quick self-healing ability against external disruption, and also promising thermoreversible and injectable properties which allow hydrogel to withstand repeated deformation and 3D construction of complex objects. The hydrogels demonstrate excellent biocompatibility, and they are very suitable for 3D cell encapsulation and protein delivery. We believe the prepared hydrogel can offer great promises to support cells or drug therapies in biomedical applications.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmacrolett.7b00275. Materials, experimental methods, characterization, and supporting analytical data (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
To Ngai: 0000-0002-7207-6878 Chaoyang Wang: 0000-0002-7270-5451 645
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
Letter
ACS Macro Letters Author Contributions
(24) Li, Z. W.; Lu, W.; Ngai, T.; Le, X. X.; Zheng, J.; Zhao, N.; Huang, Y. J.; Wen, X. F.; Zhang, J. W.; Chen, T. Polym. Chem. 2016, 7, 5343−5346. (25) Hu, Y.; Du, Z. S.; Deng, X. L.; Wang, T.; Yang, Z. H.; Zhou, W. Y.; Wang, C. Y. Macromolecules 2016, 49, 5660−5568. (26) Yang, C. H.; Wang, M. X.; Haider, H.; Yang, J. H.; Sun, J. Y.; Chen, Y. M.; Zhou, J. X.; Suo, Z. G. ACS Appl. Mater. Interfaces 2013, 5, 10418−10422. (27) Meng, H.; Xiao, P.; Gu, J. C.; Wen, X. F.; Xu, J.; Zhao, C. Z.; Zhang, J. W.; Chen, T. Chem. Commun. 2014, 50, 12277−12280. (28) Pawar, G. M.; Koenigs, M.; Fahimi, Z.; Cox, M.; Voets, I. K.; Wyss, H. M.; Sijbesma, R. P. Biomacromolecules 2012, 13, 3966−3976. (29) Kaitz, J. A.; Possanza, C. M.; Song, Y.; Diesendruck, C. E.; Spiering, A. J. H.; Meijer, E. W.; Moore, J. S. Polym. Chem. 2014, 5, 3788−3794. (30) Wang, L.; Gong, Z. L.; Li, S. Y.; Hong, W.; Zhong, Y. W.; Wang, D.; Wan, L. J. Angew. Chem., Int. Ed. 2016, 55, 12393−12397. (31) Chen, Y.; Jones, S. T.; Hancox, I.; Beanland, R.; Tunnah, E. J.; Bon, S. A. F. ACS Macro Lett. 2012, 1, 603−608. (32) Chen, Y.; Ballard, N.; Bon, S. A. F. Chem. Commun. 2013, 49, 1524−1526. (33) Guo, M.; Pitet, L. M.; Wyss, H. M.; Vos, M.; Dankers, P. Y.; Meijer, E. W. J. Am. Chem. Soc. 2014, 136, 6969−6977. (34) Dankers, P. Y.; Hermans, T. M.; Baughman, T. W.; Kamikawa, Y.; Kieltyka, R. E.; Bastings, M. M.; Janssen, H. M.; Sommerdijk, N. A.; Larsen, A.; Luyn, M. J.; Bosman, A. W.; Popa, E. R.; Fytas, G.; Meijer, E. W. Adv. Mater. 2012, 24, 2703−2709. (35) Noack, M.; Merindol, R.; Zhu, B. L.; Benitez, A.; Hackelbusch, S.; Beckert, F.; Seiffert, S.; Mülhaupt, S.; Walther, A. Adv. Funct. Mater. 2017, 1700767. (36) Jeon, I.; Cui, J.; Illeperuma, W. R.; Aizenberg, J.; Vlassak, J. J. Adv. Mater. 2016, 28, 4678−4683. (37) Ritger, P.; Peppas, N. J. Controlled Release 1987, 5, 37−42.
All authors have given approval to the final version of the manuscript. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We gratefully acknowledge funding for this work provided by the National Natural Science Foundation of China (21474032 and 21574110) and Natural Science Foundation of Guangdong Province (2016A030310461).
■
REFERENCES
(1) Li, L.; Yan, B.; Yang, J. Q.; Chen, L. Y.; Zeng, H. B. Adv. Mater. 2015, 27, 1294−1299. (2) Dai, X. Y.; Zhang, Y. Y.; Gao, L. N.; Bai, T.; Wang, W.; Cui, Y. L.; Liu, W. G. Adv. Mater. 2015, 27, 3566−3571. (3) Wei, Z.; Yang, J. H.; Liu, Z. Q.; Xu, F.; Zhou, J. X.; Zrínyi, M.; Osada, Y.; Chen, Y. M. Adv. Funct. Mater. 2015, 25, 1352−1359. (4) Kim, Y. M.; Kim, C. H.; Song, S. C. ACS Macro Lett. 2016, 5, 297−300. (5) Cai, L.; Dewi, R. E.; Heilshorn, S. C. Adv. Funct. Mater. 2015, 25, 1344−1351. (6) Shin, J.; Lee, J.; Lee, C.; Park, H.-J.; Yang, K.; Jin, Y.; Ryu, J. H.; Hong, K. S.; Moon, S.-H.; Chung, H.-M.; Yang, H. S.; Um, S. H.; Oh, J.-W.; Kim, D.-I.; Lee, H.; Cho, S.-W. Adv. Funct. Mater. 2015, 25, 3814−3824. (7) Gilbert, T.; Smeets, N. M. B.; Hoare, T. ACS Macro Lett. 2015, 4, 1104−1109. (8) Yesilyurt, V.; Webber, M. J.; Appel, E. A.; Godwin, C.; Langer, R.; Anderson, D. G. Adv. Mater. 2016, 28, 86−91. (9) Xing, R. R.; Liu, K.; Jiao, T. F.; Zhang, N.; Ma, K.; Zhang, R. Y.; Zou, Q. L.; Ma, G. H.; Yan, X. H. Adv. Mater. 2016, 28, 3669−3676. (10) Griffin, D. R.; Weaver, W. M.; Scumpia, P. O.; Di Carlo, D.; Segura, T. Nat. Mater. 2015, 14, 737−744. (11) Lee, F.; Chung, J. E.; Xu, K.; Kurisawa, M. ACS Macro Lett. 2015, 4, 957−960. (12) Soranno, D. E.; Lu, H. D.; Weber, H. M.; Rai, R.; Burdick, J. A. J. Biomed. Mater. Res., Part A 2014, 102, 2173−2180. (13) Feng, Q.; Wei, K. C.; Lin, S. E.; Xu, Z.; Sun, Y. X.; Shi, P.; Li, G.; Bian, L. M. Biomaterials 2016, 101, 217−228. (14) Li, Y.; Khuu, N.; Gevorkian, A.; Sarjinsky, S.; Therien-Aubin, H.; Wang, Y.; Cho, S.; Kumacheva, E. Angew. Chem., Int. Ed. 2017, 56, 6083. (15) Bastings, M. M.; Koudstaal, S.; Kieltyka, R. E.; Nakano, Y.; Pape, A. C.; Feyen, D.; Slochteren, A.; F. J; Doevendans, P. A.; Sluijter, J. P.; Meijer, E. W.; Chamuleau, S. A.; Dankers, P. Y. Adv. Healthcare Mater. 2014, 3, 70−78. (16) Ding, C.; Zhao, L.; Liu, F.; Cheng, J.; Gu, J.; Dan, S.; Liu, C.; Qu, X.; Yang, Z. Biomacromolecules 2010, 11, 1043−1051. (17) Jia, X. L.; Wang, J. Y.; Wang, K.; Zhu, J. T. Langmuir 2015, 31, 8732−8737. (18) Li, Y. H.; Huang, G. Y.; Zhang, X. H.; Li, B. Q.; Chen, Y. M.; Lu, T. L.; Lu, T. J.; Xu, F. Adv. Funct. Mater. 2013, 23, 660−672. (19) Zhang, Y.; Sun, Y.; Yang, X.; Hilborn, J.; Heerschap, A.; Ossipov, D. A. Macromol. Biosci. 2014, 14, 1249−1259. (20) Latxague, L.; Ramin, M. A.; Appavoo, A.; Berto, P.; Maisani, M.; Ehret, C.; Chassande, O.; Barthelemy, P. Angew. Chem., Int. Ed. 2015, 54, 4517−4521. (21) Rodell, C. B.; MacArthur, J. W.; Dorsey, S. M.; Wade, R. J.; Woo, Y. J.; Burdick, J. A. Adv. Funct. Mater. 2015, 25, 636−644. (22) Wei, K.; Zhu, M.; Sun, Y.; Xu, J.; Feng, Q.; Lin, S.; Wu, T.; Xu, J.; Tian, F.; Xia, J.; Li, G.; Bian, L. M. Macromolecules 2016, 49, 866− 875. (23) Pakulska, M. M.; Vulic, K.; Tam, R. Y.; Shoichet, M. S. Adv. Mater. 2015, 27, 5002−5008. 646
DOI: 10.1021/acsmacrolett.7b00275 ACS Macro Lett. 2017, 6, 641−646
