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A Mechanically Strong, Highly Stable, Thermoplastic, and Self-Healable Supramolecular Polymer Hydrogel Xiyang Dai, Yinyu Zhang, Lina Gao, Tao Bai, Wei Wang, Yuanlu Cui, and Wenguang Liu* Over the past decade, high strength hydrogels have received growing interest due to their great potential for extended use in load-bearing applications. Many strategies have been explored to enhance the tensile strength, the compressive strength or toughness of hydrogels, including double network,[1] topological sliding network,[2] composite reinforcement,[3] and covalent/ ionic crosslinking mechanisms.[4] Despite this, development of a hydrogel with high comprehensive mechanical properties that are not weakened by soaking in aqueous media remains challenging.[5] Since chemical crosslinkers are generally essential for the construction of high-strength hydrogels, the resultant gels tend not to be recyclable or reprocessable. Our group recently reported on hydrogels strengthened by diaminotriazine-diaminotriazine (DAT-DAT) hydrogen bonding, which demonstrated both high tensile and compressive strengths and exceptional stability in aqueous solution due to the formation of stable DAT-DAT hydrogen bonding domains.[6] These H-bonding hydrogels were typically synthesized from photoinitated copolymerization of 2-vinyl-4,6-diamino-1,3,5-triazine (VDT) and polyethylene glycol diacrylate in DMSO, which was required to solubilize VDT. These chemically crosslinked PVDT-based organogels were then soaked in water to replace DMSO, converting the organogels into hydrogels and re-establishing cooperative DAT-DAT hydrogen bonding interaction which tremendously increased the mechanical strengths of the resultant fully swollen hydrogel. Nonetheless, the organic solvent needed to make these gels is not environmentally benign. The hydrogen bonding is commonly a weak noncovalent bond, though their cooperative interaction can result in the strength of a covalent bond.[7] However, most hydrogen bonds only exhibit this strength in nonpolar organic solvents, with their strengthening effect severely discounted in polar solvents.[8,9] The remarkable reinforcement effect of DAT-DAT hydrogen bonding originates from the formation of stable hydrogen-bonded microdomain clusters.[6a,10] This principle suggests that the formation of H-bonding microdomains is required for the stable existence of robust H-bonds, as well as X. Dai, Y. Zhang, T. Bai, Dr. W. Wang, Prof. W. Liu School of Materials Science and Engineering Tianjin Key Laboratory of Composite and Functional Materials Tianjin University Tianjin 300072, China E-mail: [email protected] L. Gao, Prof. Y. Cui Research Center of Traditional Chinese Medicine Tianjin University of Traditional Chinese Medicine Tianjin 300193, PR China
DOI: 10.1002/adma.201500534
Adv. Mater. 2015, DOI: 10.1002/adma.201500534
the concomitant strengthening effect shown in condensed matters in polar media.[11] It is known that the secondary structure of proteins is held together by hydrogen bonding between the C O and N H groups, and hydrogen-bonded clusters contribute to their unique native structures.[12,13] As the smallest species of the 20 amino acids found in proteins, glycine is unique since it can fit into hydrophilic or hydrophobic settings. Although O H···N hydrogen bonds can be formed, this interaction is unstable in water and therefore cannot be used to enhance mechanical strength. In the work reported by Tobias et al. on the stability of a model β-sheet in water, the binding free energies of two intermolecular hydrogen bonds and single amide hydrogen bond in the model β-sheet were calculated to be −5.5 and −0.34 kcal mol−1, respectively, suggesting dual hydrogen bonds are quite stable while a simple amide hydrogen bond is only marginally stable.[14] Inspired by this theoretical basis and aiming to amplify the hydrogen bonding interaction of the simplest amino acid, glycine, we proposed to transform glycinamide (amidated glycine), which consists of two amides, into a polymerizable monomer, N-acryloyl glycinamide (NAGA, Scheme 1A), by reacting glycinamide with acryloyl chloride using a reported method.[15,16] N-acryloyl glycinamide can be directly and conveniently initiated in water to form poly(Nacryloyl glycinamide) (PNAGA). From the molecular structure of PNAGA depicted in Scheme 1A, we envisioned that a concentrated aqueous solution of poly(N-acryloyl glycinamide) could form a high-strength supramolecular polymer hydrogel due to the strong physical crosslinking stemming from the highly stable hydrogen bonded interaction domains formed among dual amide motifs in the side chain. To verify our hypothesis, we prepared different concentrations of NAGA aqueous solutions, which were then photoinitiated at room temperature (Table S1). We found that at 1% and 2% NAGA, the polymer solutions were in the sol state, but gelation occurred when concentration was raised to 3%, as verified with the inverted vial method (Figure S5, Supporting Information). The prepared hydrogels were immersed in deionized and distilled water for 7 d, and equilibrium water contents (EWCs) were determined (Figure S6, Supporting Information). Unexpectedly, after reaching swelling equilibrium, the EWCs of the gels initially made with 10–25 wt% NAGA decrease by varied amounts compared with the water contents of the respective original hydrogels. It is possible that the hydrogen bondings among dual amides may reorganize and intensify to result in an increased crosslinking density after the gels are re-immersed in water. PNAGA-30, made with 30% NAGA initially, showed only a slight increase in its EWC. In this case, the hydrogen-bonded supramolecular interactions started to achieve a saturated state. In spite of the increased water content after equilibrium
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Scheme 1. A) Molecular structures of N-acryloyl glycinamide, poly(N-acryloyl glycinamide), acrylamide, and polyacrylamide. B) Instability of single amide hydrogen bonding cannot maintain the integrity of a PAAm hydrogel. C) Mechanisms underlying the reinforcement effect of dual amide hydrogen bonding microdomains and the high stability of the resultant hydrogels in water.
swelling, its volume remained almost unchanged, indicating “nonswellable” properties.[5] The hydrogel microstructures observed by FE-SEM show that with increased NAGA monomer concentration, the pore size of the formed networks is significantly reduced (Figure S7, Supporting Information). This implies an enhanced crosslinking density and more compact network, which restrains water from permeating into the hydrogels with higher NAGA concentrations to an increased extent. To examine whether chemically crosslinking occurred in PNAGA hydrogels, a PNAGA-25 hydrogel was treated with a 5 mol L−1 aqueous NaSCN solution, a hydrogen bond breaking agent. Upon stirring at 90 °C, the PNAGA hydrogel dissolved in NaSCN aqueous solution (Figure S8, Supporting Information). This corroborated that PNAGA hydrogels are crosslinked by reversible H-bonding, and can thus be characterized as supramolecular polymer hydrogels. To further examine the swelling stability of PNAGA hydrogels, fully swollen PNAGA-25 was selected as a representative sample and reimmersed in deionized water. To highlight the pivotal hydrogel-stabilizing role of the dual amides in PNAGA side chains, we also inspected the stability of a poly acrylamide (PAAm) hydrogel as an analogue of PNAGA containing only a single amide motif in its side chains. Herein, PAAm was synthesized via photoinitiated polymerization of 25% acrylamide aqueous solution. While this PAAm solution could form a hydrogel after polymerization, it began to dissolve
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when immersed in water for 3 h and was completely soluble in water at 24 h due to the instability of the single amide H-bonds (Scheme 1B, Figure S9a, Supporting Information). In contrast, the PNAGA hydrogels remained very stable in shape at 24 h (Figure S9b, Supporting Information), and no swelling occurred even after months. It is evident that the hydrogen bonding of a single amide motif was too weak in water to stabilize the hydrogel; while the hydrogen bonding microdomain or cluster formed among dual amide motifs could adequately shield the supramolecular crosslinking from the attack by water molecules, contributing to the remarkable stability of the PNAGA hydrogel network (Scheme 1C). In the Raman spectrum of a PAAm hydrogel (Figure S10, Supporting Information), two peaks are observed at 1612 and 1668 cm−1, assigned to amide I. The lower wavenumber band originates from waterpolymer hydrogen bonding, while the longer wavenumber is from NH···O C hydrogen bonding in the polymer.[17] The large water-polymer H-bonding peak suggests that the PAAm macromolecular chain is highly hydrated, which leads to the instability of intermolecular H-bonds. Comparatively, there is only one main peak in the PNAGA hydrogel at 1648 cm−1, from polymer NH···O C hydrogen bonding, hinting that hydration is significantly suppressed; hence much more stable intermolecular NH···O C hydrogen bonds are formed in water (Scheme 1C). The PANGA hydrogel was placed into a 5 mol L−1 solution urea, a hydrogen bond breaking agent. As expected, the PNAGA hydrogel was dramatically swollen at 24 h at room
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contents reported.[20] In our supramolecular polymer hydrogel, the long macromolecular backbone combined with the intermolecular hydrogen bonding among dual amides both contribute to their extraordinary mechanical performance. The hydrogel also exhibits excellent mechanical strength in PBS and both acidic (pH = 3.0) and alkaline (pH = 10.0) solutions (Figure S11, Supporting Information). All these results verify the high stability of the intermolecular hydrogen bonds formed by dual amide motifs even in harsh conditions. To the best of our knowledge, fully swollen hydrogels, and in particular physically crosslinked hydrogels exhibiting excellent mechanical performance is quite rare in literature.[21] Previously, single-network polyzwitterionic hydrogels crosslinked via electrostatic interactions were reported by Jiang and co-workers.[21a] However, their tensile tensile strength was less than 100 kPa, and the gels disintegrated upon long-term immersion in water. Figure 1E illustrates the compressive Figure 1. Photographs of PNAGA-25 hydrogels showing their ability to withstand A) knotting, B) large stretching, and C) compression. Tensile stress–strain curves of PNAGA hydrogels pre- stress–strain curves of PNAGA hydrogels pared from D) different initial monomer concentrations; E) compressive stress–strain curves with varied NAGA monomer concentraof PNAGA hydrogels with varied initial monomer concentrations. tions. Since the hydrogels did not fracture during the compression in our tests, stresses were determined at 90% strain. Analogous to the extension tests described above, PNAGA hydrogels temperature (Figure S9c, Supporting Information). This further display an increased compressive strength and moduli with proved that PNAGA hydrogels were predominantly reinforced increasing NAGA content (Table S2, Supporting Information), by hydrogen bonding microdomains formed among dual because of the enhanced stiffness stemming from the augamide motifs. mented H-bonded supramolecular interaction density. FurtherConventionally, physically crosslinked hydrogels are more, PNAGA hydrogels with a 25% monomer concentration mechanically weak due to the lack of a strong intermolecular exhibit high toughness with a fracture energy over 1000 J m−2 interaction force.[18] Thus, developing high-strength reversible supramolecular hydrogels is of both theoretical and practical (Figure S13, Supporting Information). This is due to the effisignificance.[19] The above results demonstrate that PNAGA cient energy dissipation provided by dynamic hydrogen bonding crosslinking. It is notable that after unloading, the hydrogel hydrogels were stably crosslinked by hydrogen bonded suprawas able to regain its original shape within 3 h when placed molecular interactions. Next, we examined the mechanical propin deionized water. The loading–unloading curves of PNAGA erties of PNAGA hydrogels. It should be emphasized that all hydrogels show a Wr/W0 (ratio of the work done by second the samples were immersed in deionized water to reach a fully swollen state before testing. We noticed that PNAGA hydrogels loading to that of first loading) approaching 95% when the were able to withstand various forms of deformation including unloaded gels were stored in water for up to 24 h (Figure S14, knotting, large stretching and compression (Figure 1A–C). Supporting Information). This implies perfect recoverability of Figure 1D shows the tensile stress–strain curves of hydrogels the dynamic hydrogen bonding interactions. with varied NAGA monomer concentrations and one can see An important and intriguing feature of PNAGA hydrogels, the PNAGA hydrogels demonstrated high mechanical perforwe observed, is their thermoplasticity. The idea of a thermomances with 160 kPa–1.1 MPa tensile strength, 600–1400% plastic hydrogel has come up previously,[22] but ones with a elongation at break, and 50–150 kPa Young’s modulus (Table S2, high strength have rarely been reported. In our experiment, Supporting Information). We note that the elongation at break PNAGA-10 hydrogels were formed in a plastic syringe and of PNAGA-30 is lower than that of PNAGA-25. An explanaplaced into hot water (90 °C) for about 30 min. At this time, the tion is at 30% NAGA, higher H-bonding crosslinking density hydrogel was softened and but still in a gelled state, and could resulted in increased rigidity of network; thus, its elasticity is be injected into the customized molds. After cooling to room decreased. Overall, the mechanical properties are increased with temperature and demolding, desired gel shapes were achieved higher NAGA monomer concentration, owing to the increased (Figure 2A, Movie S1 and S2, Supporting Information). To conH-bonded crosslinking density. The mechanical performance of firm the repeated processability and remoldability, PNAGA-10 PNAGA hydrogels is even comparable to chemically crosslinked hydrogel fragments were put into a syringe and heated as high strength hydrogels with medium equilibrium water mentioned above. The fully fused hydrogel could be readily
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Figure 2. A) Photographs showing the thermoplastic remoldability of PNAGA-10: (a) Cylindrical, (b) hexangular, and (c) cubic gels. B) Hydrogel fragments were fused at 90 °C and remolded; the cylinder hydrogel was obtained by injection at a temperature of 90 °C and demolding at room temperature. C) Variation in storage moduli and loss moduli of a PNAGA-25 hydrogel and PNAGA-30 hydrogel as a function of temperature.
injected into a cylindrical mold to be reshaped upon cooling (Figure 2B). Additionally, the pure polymer powder was collected and dispersed in water. After heating at 90 °C for 12 h, the powder was completely dissolved to form a 10% polymer solution. This solution could readily be remolded into hydrogels of various shapes upon cooling (Figure S15, Supporting Information), further verifying the supramolecular properties. The tensile strength and elongation at break of the remolded hydrogel were tested, and the results showed that they are slightly increased and decreased, respectively (Figure S16 and Table S2, Supporting Information), possibly due to water lossinduced stiffening of the polymer network. It is necessary to note that thermoreversible gelation of an aqueous PNAGA solution with a monomer concentration of several percent was reported earlier.[23] However, aqueous PNAGA solutions have never been previously developed into high-strength hydrogels. In their work on thermal transitions of a PNAGA solution, Haas and Schuler estimated the heat of crosslink formation to be −5 to −12 kcal mol−1 per crosslink, which was too low to be detected by differential thermal analysis.[23] Here, we also did not observe any transition of PNAGA solution peaks in the DSC curve, in agreement with the recently reported work.[16] Therefore, we conducted the dynamic mechanical analysis (DMA) to inspect the dependence of moduli of PNAGA hydrogel on temperature. Figure 2C shows the variation in storage moduli (K′) and loss moduli (K″) of representative hydrogels PNAGA-25 and PANGA-30 as a function of temperature over a range from 23 to 95 °C. Clearly, both the K′ and K″ values of the hydrogels drop rapidly as temperature is raised from 23 to 76 °C. K′ is dominant over K″ throughout the full 4
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temperature range, suggesting the gelled state can be maintained at a higher temperature. The DMA curves suggest that the hydrogel becomes weak and softened at an elevated temperature due to the dynamic breakage of intermolecular hydrogenbonding crosslinking formed by the dual amide motifs. The thermoplasticity and temperature-sensitive hydrogen bonding encouraged us to test the self-healing ability of PNAGA hydrogels. In this experiment, PNAGA-25 or PNAGA-30 gels were cut into two parts, and one half was stained with Rhodamine B to facilitate discrimination between fused sections (Figure 3A). The surfaces of these two halves were brought into contact within a plastic syringe by slightly pressing the plunger; subsequently, the syringe was transferred to a 90 °C water bath for 3 h. After cooling to room temperature and demolding, we found the gel to heal completely with an indistinguishable interface (Figure 3B). The healed hydrogel can also withstand bending and stretching (Figure 3C,D, and Movie S3, Supporting Information). The underlying healing mechanism is the dynamic dissociation and re-association of hydrogen bonds. During heating, hydrogen bonds dissociate, liberating some donors and acceptors, which can then construct new hydrogen bonds at the interface between two halves brought into contact and cooled. Figure S17, Supporting Information, displays the tensile stress–strain curves of the original gel and repaired hydrogel. Herein, the tensile strength ratio between the healed gel and original gel was used to assay the healing efficiency (HE). Based on force curves shown in Figure S17, Supporting Information, the HEs of PNAGA-25 and PNAGA-30 were able to reach 84% and 80%, respectively. For PNAGA hydrogels, there may be some free hydrogen bonding donors and acceptors left that did not form H-bonding at interface. That will
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versatile approach to fabricate reusable and renewable high performance cytocompatible supramolecular polymer hydrogels (SPHs), lessening environmental burden and expanding the potential applications of SPHs in the biomedical field.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author.
Acknowledgments X.D. and Y.Z. contributed equally to this work. The authors gratefully acknowledge the support for this work from the National Natural Science Foundation of China (Grant Nos. 51173129 and 21274105) and National Natural Science Funds for Distinguished Young Scholar (Grant No. 51325305). The authors are particularly grateful to Andrew Sinclair at Department of Chemical Engineering, University of Washington, Seattle, USA, for his kind help in polishing our English. Figure 3. Photographs portraying the self-reparability of a PNAGA-25 hydrogel. A) A PNAGA-25 hydrogel was cut in the middle and one half was stained with Rhodamine B; B) the two halves healed completely upon heating; the healed hydrogel can withstand C) bending and D) stretching.
influence the ultimate breaking elongation and tensile strength. Nevertheless, the strength of the mended hydrogel was up to 1 MPa, quite encouraging in research on self-healing hydrogels.[24] Note that owing to the slight loss of water, the repaired gels become stiffer, so their strains are sacrificed. Cell viability and calcein/propidium iodide assays indicate that 85%–90% cells remain viable on PNAGA hydrogel surface (Figure S18, Supporting Information). Furthermore, no significant cytotoxicity was found in the calcein/propidium iodide assay (Figure S19, Supporting Information). All results suggest that PNAGA hydrogels have good biocompatibility, portending their potential application as tissue substitutes. In this work, we synthesized NAGA, a glycinamide-conjugated monomer with dual-amide in one side group, to recapitulate and amplify the hydrogen bonding interactions between amino acid residues in a polymer hydrogel and ultimately translate them into the dominant mechanical enhancement mechanism. We demonstrated that photoinitiated aqueous-phase polymerization of a concentrated NAGA solution in the absence of any chemical crosslinker could form a supramolecular polymer hydrogel. The resultant hydrogels prepared from >10 wt% NAGA maintained long-term stability in aqueous media and exhibited excellent mechanical properties—MPa levels of tensile and compressive strength, over 1400% elongation at break, high toughness, and recoverable deformation—which are attributed to the reinforcing effect of self-recognizing H-bonded supramolecular interaction among dual amide motifs. Remarkably, the dynamic hydrogen bonding led the PNAGA gel to be thermoplastic and self-healable, endowing this supramolecular polymer hydrogel with tailorable remoldability, recyclability, and reusability. It is our belief that conjugating sufficient number of amidated amino acid to the starting monomer can dramatically amplify the hydrogen bonding interactions in the resultant polymer. This work demonstrates a simple and
Adv. Mater. 2015, DOI: 10.1002/adma.201500534
Received: February 1, 2015 Revised: April 6, 2015 Published online:
[1] a) J. P. Gong, Y. Katsuyama, T. Kurokawa, Y. Osada, Adv. Mater. 2003, 15, 1155; b) Q. Chen, L. Zhu, C. Zhao, Q. M. Wang, J. Zheng, Adv. Mater. 2013, 25, 4171. [2] Y. Okumura, K. Ito, Adv. Mater. 2001, 13, 485. [3] K. Haraguchi, T. Takehisa, Adv. Mater. 2002, 14, 1120. [4] J. Y. Sun, X. H. Zhao, W. R. K. Illeperuma, O. Chaudhuri, K. H. Oh, D. J. Mooney, J. J. Vlassak, Z. G. Suo, Nature 2012, 489, 133. [5] H. Kamata, Y. Akagi, Y. Kayasuga-Kariya, U. Chung, T. Sakai, Science 2014, 343, 873. [6] a) L. Tang, W. G. Liu, G. P. Liu, Adv. Mater. 2010, 22, 2652; b) H. Gao, N. Wang, X. F. Hu, W. J. Nan, Y. J. Han, W. G. Liu, Macromol. Rapid Commun. 2013, 34, 63. [7] V. L. Deringer, U. Englert, R. Dronskowski, Chem. Commun. 2014, 50, 11547. [8] N. Ben-Tal, D. Sitkoff, I. A. Topol, A. S. Yang, S. K. Burt, B. Honig, J. Phys. Chem. B 1997, 101, 450. [9] E. S. Eberhardt, R. T. Raines, J. Am. Chem. Soc. 1994, 116, 2149. [10] K. E. Maly, C. Dauphin, J. D. Wuest, J. Mater. Chem. 2006, 16, 4695. [11] M. Y. Guo, L. M. Pitet, H. M. Wyss, M. Vos, P. Y. W. Dankers, E. W. Meijer, J. Am. Chem. Soc. 2014, 136, 6969. [12] R. B. Hill, J. K. Hong, W. F. DeGrad, J. Am. Chem. Soc. 2000, 122, 746. [13] A. N. Bondara, S. H. Whiteb, Biochim. Biophys. Acta, Biomembr. 2012, 1818, 942. [14] D. J. Tobias, S. F. Sneddon, C. L. Brooks III, J. Mol. Biol. 1992, 227, 1244. [15] M. Boustta, P. E. Colombo, S. Lenglet, S. Poujol, M. Vert, J. Controlled Release 2014, 174, 1. [16] J. Seuring, S. Agarwal, Macromol. Chem. Phys. 2010, 211, 2109. [17] a) Z. Ahmed, E. A. Gooding, K. V. Pimenov, L. L. Wang, S. A. Asher, J. Phys. Chem. B 2009, 113, 4248; b) L. B. Sagle, Y. Zhang, V. A. Litosh, X. Chen, Y. Cho, P. S. Cremer, J. Am. Chem. Soc. 2009, 131, 9304. [18] H. M. Wang, A. T. Han, Y. B. Cai, Y. Xie, H. Zhou, J. F. Long, Z. M. Yang, Chem. Commun. 2013, 49, 7448.
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www.MaterialsViews.com [19] a) C. Deng, Y. L. Cui, T. T. Zhao, M. Tan, H. Huang, M. Y. Guo, RSC Adv. 2014, 4, 24095; b) Y. L. Cui, M. Tan, A. D. Zhu, M. Y. Guo, J. Mater. Chem. B 2014, 2, 2978. [20] a) X. H. Zhao, Soft Matter 2014, 10, 672; b) L. Tang, Y. Yang, T. Bai, W. G. Liu, Biomaterials 2010, 32,1943; c) T. Bai, P. Zhang, Y. J. Han, Y. Liu, W. G. Liu, X. L. Zhao, W. Lu, Soft Matter 2011, 7, 2825. [21] a) T. Bai, S. J. Liu, F. Sun, A. Sinclair, L. Zhang, Q. Shao, S. Y. Jiang, Biomaterials 2014, 35, 3926; b) F. Zhao, Y. Gao, J. F. Shi,
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H. M. Browdy, B. Xu. Langmuir 2011, 27, 1510; c) Q. G. Wang, J. L. Mynar, M. Yoshida, E. Lee, M. Lee, K. Okuro, K. Kinbara, T. Aida, Nature 2010, 463, 339. [22] E. R. Wright, R. A. McMillan, A. Cooper, R. P. Apkarian, V. P. Conticello, Adv. Funct. Mater. 2002, 12, 149. [23] H. C. Haas, N. W. Schuler, J. Polym. Sci., Part B: Polym. Lett. 1964, 2, 1095. [24] J. Q. Liu, G. S. Song, C. C. He, H. L. Wang, Macromol. Rapid Commun. 2013, 34, 957.
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A Mechanically Strong, Highly Stable, Thermoplastic, and Self-Healable Supramolecular Polymer Hydrogel Xiyang Dai, Yinyu Zhang, Lina Gao, Tao Bai, Wei Wang, Yuanlu Cui, and Wenguang Liu* Over the past decade, high strength hydrogels have received growing interest due to their great potential for extended use in load-bearing applications. Many strategies have been explored to enhance the tensile strength, the compressive strength or toughness of hydrogels, including double network,[1] topological sliding network,[2] composite reinforcement,[3] and covalent/ ionic crosslinking mechanisms.[4] Despite this, development of a hydrogel with high comprehensive mechanical properties that are not weakened by soaking in aqueous media remains challenging.[5] Since chemical crosslinkers are generally essential for the construction of high-strength hydrogels, the resultant gels tend not to be recyclable or reprocessable. Our group recently reported on hydrogels strengthened by diaminotriazine-diaminotriazine (DAT-DAT) hydrogen bonding, which demonstrated both high tensile and compressive strengths and exceptional stability in aqueous solution due to the formation of stable DAT-DAT hydrogen bonding domains.[6] These H-bonding hydrogels were typically synthesized from photoinitated copolymerization of 2-vinyl-4,6-diamino-1,3,5-triazine (VDT) and polyethylene glycol diacrylate in DMSO, which was required to solubilize VDT. These chemically crosslinked PVDT-based organogels were then soaked in water to replace DMSO, converting the organogels into hydrogels and re-establishing cooperative DAT-DAT hydrogen bonding interaction which tremendously increased the mechanical strengths of the resultant fully swollen hydrogel. Nonetheless, the organic solvent needed to make these gels is not environmentally benign. The hydrogen bonding is commonly a weak noncovalent bond, though their cooperative interaction can result in the strength of a covalent bond.[7] However, most hydrogen bonds only exhibit this strength in nonpolar organic solvents, with their strengthening effect severely discounted in polar solvents.[8,9] The remarkable reinforcement effect of DAT-DAT hydrogen bonding originates from the formation of stable hydrogen-bonded microdomain clusters.[6a,10] This principle suggests that the formation of H-bonding microdomains is required for the stable existence of robust H-bonds, as well as X. Dai, Y. Zhang, T. Bai, Dr. W. Wang, Prof. W. Liu School of Materials Science and Engineering Tianjin Key Laboratory of Composite and Functional Materials Tianjin University Tianjin 300072, China E-mail: [email protected] L. Gao, Prof. Y. Cui Research Center of Traditional Chinese Medicine Tianjin University of Traditional Chinese Medicine Tianjin 300193, PR China
DOI: 10.1002/adma.201500534
Adv. Mater. 2015, DOI: 10.1002/adma.201500534
the concomitant strengthening effect shown in condensed matters in polar media.[11] It is known that the secondary structure of proteins is held together by hydrogen bonding between the C O and N H groups, and hydrogen-bonded clusters contribute to their unique native structures.[12,13] As the smallest species of the 20 amino acids found in proteins, glycine is unique since it can fit into hydrophilic or hydrophobic settings. Although O H···N hydrogen bonds can be formed, this interaction is unstable in water and therefore cannot be used to enhance mechanical strength. In the work reported by Tobias et al. on the stability of a model β-sheet in water, the binding free energies of two intermolecular hydrogen bonds and single amide hydrogen bond in the model β-sheet were calculated to be −5.5 and −0.34 kcal mol−1, respectively, suggesting dual hydrogen bonds are quite stable while a simple amide hydrogen bond is only marginally stable.[14] Inspired by this theoretical basis and aiming to amplify the hydrogen bonding interaction of the simplest amino acid, glycine, we proposed to transform glycinamide (amidated glycine), which consists of two amides, into a polymerizable monomer, N-acryloyl glycinamide (NAGA, Scheme 1A), by reacting glycinamide with acryloyl chloride using a reported method.[15,16] N-acryloyl glycinamide can be directly and conveniently initiated in water to form poly(Nacryloyl glycinamide) (PNAGA). From the molecular structure of PNAGA depicted in Scheme 1A, we envisioned that a concentrated aqueous solution of poly(N-acryloyl glycinamide) could form a high-strength supramolecular polymer hydrogel due to the strong physical crosslinking stemming from the highly stable hydrogen bonded interaction domains formed among dual amide motifs in the side chain. To verify our hypothesis, we prepared different concentrations of NAGA aqueous solutions, which were then photoinitiated at room temperature (Table S1). We found that at 1% and 2% NAGA, the polymer solutions were in the sol state, but gelation occurred when concentration was raised to 3%, as verified with the inverted vial method (Figure S5, Supporting Information). The prepared hydrogels were immersed in deionized and distilled water for 7 d, and equilibrium water contents (EWCs) were determined (Figure S6, Supporting Information). Unexpectedly, after reaching swelling equilibrium, the EWCs of the gels initially made with 10–25 wt% NAGA decrease by varied amounts compared with the water contents of the respective original hydrogels. It is possible that the hydrogen bondings among dual amides may reorganize and intensify to result in an increased crosslinking density after the gels are re-immersed in water. PNAGA-30, made with 30% NAGA initially, showed only a slight increase in its EWC. In this case, the hydrogen-bonded supramolecular interactions started to achieve a saturated state. In spite of the increased water content after equilibrium
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Scheme 1. A) Molecular structures of N-acryloyl glycinamide, poly(N-acryloyl glycinamide), acrylamide, and polyacrylamide. B) Instability of single amide hydrogen bonding cannot maintain the integrity of a PAAm hydrogel. C) Mechanisms underlying the reinforcement effect of dual amide hydrogen bonding microdomains and the high stability of the resultant hydrogels in water.
swelling, its volume remained almost unchanged, indicating “nonswellable” properties.[5] The hydrogel microstructures observed by FE-SEM show that with increased NAGA monomer concentration, the pore size of the formed networks is significantly reduced (Figure S7, Supporting Information). This implies an enhanced crosslinking density and more compact network, which restrains water from permeating into the hydrogels with higher NAGA concentrations to an increased extent. To examine whether chemically crosslinking occurred in PNAGA hydrogels, a PNAGA-25 hydrogel was treated with a 5 mol L−1 aqueous NaSCN solution, a hydrogen bond breaking agent. Upon stirring at 90 °C, the PNAGA hydrogel dissolved in NaSCN aqueous solution (Figure S8, Supporting Information). This corroborated that PNAGA hydrogels are crosslinked by reversible H-bonding, and can thus be characterized as supramolecular polymer hydrogels. To further examine the swelling stability of PNAGA hydrogels, fully swollen PNAGA-25 was selected as a representative sample and reimmersed in deionized water. To highlight the pivotal hydrogel-stabilizing role of the dual amides in PNAGA side chains, we also inspected the stability of a poly acrylamide (PAAm) hydrogel as an analogue of PNAGA containing only a single amide motif in its side chains. Herein, PAAm was synthesized via photoinitiated polymerization of 25% acrylamide aqueous solution. While this PAAm solution could form a hydrogel after polymerization, it began to dissolve
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when immersed in water for 3 h and was completely soluble in water at 24 h due to the instability of the single amide H-bonds (Scheme 1B, Figure S9a, Supporting Information). In contrast, the PNAGA hydrogels remained very stable in shape at 24 h (Figure S9b, Supporting Information), and no swelling occurred even after months. It is evident that the hydrogen bonding of a single amide motif was too weak in water to stabilize the hydrogel; while the hydrogen bonding microdomain or cluster formed among dual amide motifs could adequately shield the supramolecular crosslinking from the attack by water molecules, contributing to the remarkable stability of the PNAGA hydrogel network (Scheme 1C). In the Raman spectrum of a PAAm hydrogel (Figure S10, Supporting Information), two peaks are observed at 1612 and 1668 cm−1, assigned to amide I. The lower wavenumber band originates from waterpolymer hydrogen bonding, while the longer wavenumber is from NH···O C hydrogen bonding in the polymer.[17] The large water-polymer H-bonding peak suggests that the PAAm macromolecular chain is highly hydrated, which leads to the instability of intermolecular H-bonds. Comparatively, there is only one main peak in the PNAGA hydrogel at 1648 cm−1, from polymer NH···O C hydrogen bonding, hinting that hydration is significantly suppressed; hence much more stable intermolecular NH···O C hydrogen bonds are formed in water (Scheme 1C). The PANGA hydrogel was placed into a 5 mol L−1 solution urea, a hydrogen bond breaking agent. As expected, the PNAGA hydrogel was dramatically swollen at 24 h at room
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contents reported.[20] In our supramolecular polymer hydrogel, the long macromolecular backbone combined with the intermolecular hydrogen bonding among dual amides both contribute to their extraordinary mechanical performance. The hydrogel also exhibits excellent mechanical strength in PBS and both acidic (pH = 3.0) and alkaline (pH = 10.0) solutions (Figure S11, Supporting Information). All these results verify the high stability of the intermolecular hydrogen bonds formed by dual amide motifs even in harsh conditions. To the best of our knowledge, fully swollen hydrogels, and in particular physically crosslinked hydrogels exhibiting excellent mechanical performance is quite rare in literature.[21] Previously, single-network polyzwitterionic hydrogels crosslinked via electrostatic interactions were reported by Jiang and co-workers.[21a] However, their tensile tensile strength was less than 100 kPa, and the gels disintegrated upon long-term immersion in water. Figure 1E illustrates the compressive Figure 1. Photographs of PNAGA-25 hydrogels showing their ability to withstand A) knotting, B) large stretching, and C) compression. Tensile stress–strain curves of PNAGA hydrogels pre- stress–strain curves of PNAGA hydrogels pared from D) different initial monomer concentrations; E) compressive stress–strain curves with varied NAGA monomer concentraof PNAGA hydrogels with varied initial monomer concentrations. tions. Since the hydrogels did not fracture during the compression in our tests, stresses were determined at 90% strain. Analogous to the extension tests described above, PNAGA hydrogels temperature (Figure S9c, Supporting Information). This further display an increased compressive strength and moduli with proved that PNAGA hydrogels were predominantly reinforced increasing NAGA content (Table S2, Supporting Information), by hydrogen bonding microdomains formed among dual because of the enhanced stiffness stemming from the augamide motifs. mented H-bonded supramolecular interaction density. FurtherConventionally, physically crosslinked hydrogels are more, PNAGA hydrogels with a 25% monomer concentration mechanically weak due to the lack of a strong intermolecular exhibit high toughness with a fracture energy over 1000 J m−2 interaction force.[18] Thus, developing high-strength reversible supramolecular hydrogels is of both theoretical and practical (Figure S13, Supporting Information). This is due to the effisignificance.[19] The above results demonstrate that PNAGA cient energy dissipation provided by dynamic hydrogen bonding crosslinking. It is notable that after unloading, the hydrogel hydrogels were stably crosslinked by hydrogen bonded suprawas able to regain its original shape within 3 h when placed molecular interactions. Next, we examined the mechanical propin deionized water. The loading–unloading curves of PNAGA erties of PNAGA hydrogels. It should be emphasized that all hydrogels show a Wr/W0 (ratio of the work done by second the samples were immersed in deionized water to reach a fully swollen state before testing. We noticed that PNAGA hydrogels loading to that of first loading) approaching 95% when the were able to withstand various forms of deformation including unloaded gels were stored in water for up to 24 h (Figure S14, knotting, large stretching and compression (Figure 1A–C). Supporting Information). This implies perfect recoverability of Figure 1D shows the tensile stress–strain curves of hydrogels the dynamic hydrogen bonding interactions. with varied NAGA monomer concentrations and one can see An important and intriguing feature of PNAGA hydrogels, the PNAGA hydrogels demonstrated high mechanical perforwe observed, is their thermoplasticity. The idea of a thermomances with 160 kPa–1.1 MPa tensile strength, 600–1400% plastic hydrogel has come up previously,[22] but ones with a elongation at break, and 50–150 kPa Young’s modulus (Table S2, high strength have rarely been reported. In our experiment, Supporting Information). We note that the elongation at break PNAGA-10 hydrogels were formed in a plastic syringe and of PNAGA-30 is lower than that of PNAGA-25. An explanaplaced into hot water (90 °C) for about 30 min. At this time, the tion is at 30% NAGA, higher H-bonding crosslinking density hydrogel was softened and but still in a gelled state, and could resulted in increased rigidity of network; thus, its elasticity is be injected into the customized molds. After cooling to room decreased. Overall, the mechanical properties are increased with temperature and demolding, desired gel shapes were achieved higher NAGA monomer concentration, owing to the increased (Figure 2A, Movie S1 and S2, Supporting Information). To conH-bonded crosslinking density. The mechanical performance of firm the repeated processability and remoldability, PNAGA-10 PNAGA hydrogels is even comparable to chemically crosslinked hydrogel fragments were put into a syringe and heated as high strength hydrogels with medium equilibrium water mentioned above. The fully fused hydrogel could be readily
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Figure 2. A) Photographs showing the thermoplastic remoldability of PNAGA-10: (a) Cylindrical, (b) hexangular, and (c) cubic gels. B) Hydrogel fragments were fused at 90 °C and remolded; the cylinder hydrogel was obtained by injection at a temperature of 90 °C and demolding at room temperature. C) Variation in storage moduli and loss moduli of a PNAGA-25 hydrogel and PNAGA-30 hydrogel as a function of temperature.
injected into a cylindrical mold to be reshaped upon cooling (Figure 2B). Additionally, the pure polymer powder was collected and dispersed in water. After heating at 90 °C for 12 h, the powder was completely dissolved to form a 10% polymer solution. This solution could readily be remolded into hydrogels of various shapes upon cooling (Figure S15, Supporting Information), further verifying the supramolecular properties. The tensile strength and elongation at break of the remolded hydrogel were tested, and the results showed that they are slightly increased and decreased, respectively (Figure S16 and Table S2, Supporting Information), possibly due to water lossinduced stiffening of the polymer network. It is necessary to note that thermoreversible gelation of an aqueous PNAGA solution with a monomer concentration of several percent was reported earlier.[23] However, aqueous PNAGA solutions have never been previously developed into high-strength hydrogels. In their work on thermal transitions of a PNAGA solution, Haas and Schuler estimated the heat of crosslink formation to be −5 to −12 kcal mol−1 per crosslink, which was too low to be detected by differential thermal analysis.[23] Here, we also did not observe any transition of PNAGA solution peaks in the DSC curve, in agreement with the recently reported work.[16] Therefore, we conducted the dynamic mechanical analysis (DMA) to inspect the dependence of moduli of PNAGA hydrogel on temperature. Figure 2C shows the variation in storage moduli (K′) and loss moduli (K″) of representative hydrogels PNAGA-25 and PANGA-30 as a function of temperature over a range from 23 to 95 °C. Clearly, both the K′ and K″ values of the hydrogels drop rapidly as temperature is raised from 23 to 76 °C. K′ is dominant over K″ throughout the full 4
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temperature range, suggesting the gelled state can be maintained at a higher temperature. The DMA curves suggest that the hydrogel becomes weak and softened at an elevated temperature due to the dynamic breakage of intermolecular hydrogenbonding crosslinking formed by the dual amide motifs. The thermoplasticity and temperature-sensitive hydrogen bonding encouraged us to test the self-healing ability of PNAGA hydrogels. In this experiment, PNAGA-25 or PNAGA-30 gels were cut into two parts, and one half was stained with Rhodamine B to facilitate discrimination between fused sections (Figure 3A). The surfaces of these two halves were brought into contact within a plastic syringe by slightly pressing the plunger; subsequently, the syringe was transferred to a 90 °C water bath for 3 h. After cooling to room temperature and demolding, we found the gel to heal completely with an indistinguishable interface (Figure 3B). The healed hydrogel can also withstand bending and stretching (Figure 3C,D, and Movie S3, Supporting Information). The underlying healing mechanism is the dynamic dissociation and re-association of hydrogen bonds. During heating, hydrogen bonds dissociate, liberating some donors and acceptors, which can then construct new hydrogen bonds at the interface between two halves brought into contact and cooled. Figure S17, Supporting Information, displays the tensile stress–strain curves of the original gel and repaired hydrogel. Herein, the tensile strength ratio between the healed gel and original gel was used to assay the healing efficiency (HE). Based on force curves shown in Figure S17, Supporting Information, the HEs of PNAGA-25 and PNAGA-30 were able to reach 84% and 80%, respectively. For PNAGA hydrogels, there may be some free hydrogen bonding donors and acceptors left that did not form H-bonding at interface. That will
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versatile approach to fabricate reusable and renewable high performance cytocompatible supramolecular polymer hydrogels (SPHs), lessening environmental burden and expanding the potential applications of SPHs in the biomedical field.
Supporting Information Supporting Information is available from the Wiley Online Library or from the author.
Acknowledgments X.D. and Y.Z. contributed equally to this work. The authors gratefully acknowledge the support for this work from the National Natural Science Foundation of China (Grant Nos. 51173129 and 21274105) and National Natural Science Funds for Distinguished Young Scholar (Grant No. 51325305). The authors are particularly grateful to Andrew Sinclair at Department of Chemical Engineering, University of Washington, Seattle, USA, for his kind help in polishing our English. Figure 3. Photographs portraying the self-reparability of a PNAGA-25 hydrogel. A) A PNAGA-25 hydrogel was cut in the middle and one half was stained with Rhodamine B; B) the two halves healed completely upon heating; the healed hydrogel can withstand C) bending and D) stretching.
influence the ultimate breaking elongation and tensile strength. Nevertheless, the strength of the mended hydrogel was up to 1 MPa, quite encouraging in research on self-healing hydrogels.[24] Note that owing to the slight loss of water, the repaired gels become stiffer, so their strains are sacrificed. Cell viability and calcein/propidium iodide assays indicate that 85%–90% cells remain viable on PNAGA hydrogel surface (Figure S18, Supporting Information). Furthermore, no significant cytotoxicity was found in the calcein/propidium iodide assay (Figure S19, Supporting Information). All results suggest that PNAGA hydrogels have good biocompatibility, portending their potential application as tissue substitutes. In this work, we synthesized NAGA, a glycinamide-conjugated monomer with dual-amide in one side group, to recapitulate and amplify the hydrogen bonding interactions between amino acid residues in a polymer hydrogel and ultimately translate them into the dominant mechanical enhancement mechanism. We demonstrated that photoinitiated aqueous-phase polymerization of a concentrated NAGA solution in the absence of any chemical crosslinker could form a supramolecular polymer hydrogel. The resultant hydrogels prepared from >10 wt% NAGA maintained long-term stability in aqueous media and exhibited excellent mechanical properties—MPa levels of tensile and compressive strength, over 1400% elongation at break, high toughness, and recoverable deformation—which are attributed to the reinforcing effect of self-recognizing H-bonded supramolecular interaction among dual amide motifs. Remarkably, the dynamic hydrogen bonding led the PNAGA gel to be thermoplastic and self-healable, endowing this supramolecular polymer hydrogel with tailorable remoldability, recyclability, and reusability. It is our belief that conjugating sufficient number of amidated amino acid to the starting monomer can dramatically amplify the hydrogen bonding interactions in the resultant polymer. This work demonstrates a simple and
Adv. Mater. 2015, DOI: 10.1002/adma.201500534
Received: February 1, 2015 Revised: April 6, 2015 Published online:
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