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Dynamic softening or stiffening a supramolecular hydrogel by an ultraviolet or near-infrared light Zhao Zheng, Jingjing Hu, Hui Wang, Junlin Huang, Yihua Yu, Qiang Zhang, and Yiyun Cheng ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.7b07204 • Publication Date (Web): 05 Jul 2017 Downloaded from http://pubs.acs.org on July 5, 2017

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ACS Applied Materials & Interfaces

Dynamic softening or stiffening a supramolecular hydrogel by an ultraviolet or near-infrared light Zhao Zheng1,†, Jingjing Hu1,†, Hui Wang1, Junlin Huang2, Yihua Yu2, Qiang Zhang1, Yiyun Cheng1,2,* 1

Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China

Normal University, Shanghai, 200241, P.R. China. *Email: [email protected] 2

Shanghai Key Laboratory of Magnetic Resonance, Department of Physics, East China

Normal University, Shanghai, 200062, P.R. China. †These authors contributed equally on this manuscript. KEYWORDS: light responsive, smart hydrogel, host-guest interaction, stiffness, selfhealing

ABSTRACT: The development of light-responsive hydrogels that exhibit switchable size and mechanical properties with temporal and spatial resolution is of great importance in many fields. However, it remains challenging to prepare smart hydrogels that dramatically change their properties in response to both ultraviolet and near-infrared lights. Here, we designed a dual-light responsive supramolecular gel by integrating

ACS Paragon Plus Environment


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ultraviolet light-switchable host-guest recognition, temperature responsiveness, and nearinfrared photothermal ability in the gel. The gel could rapidly self-heal and is capable of both softening and stiffening controlled by an ultraviolet and near-infrared light, respectively. Besides stiffness modulation, the bending direction of the gel can be controlled by ultraviolet or near-infrared light irradiation. The smart gel makes it possible to generate dynamic materials that respond to both ultraviolet and near-infrared lights, and represents a useful tool that might be used to modulate cellular microenvironments with spatiotemporal resolution.

1. INTRODUCTION Hydrogels have been widely used in biomedical applications in recent years, and the complexity of biological systems calls for the hydrogels to perform dynamically with precisely tunable mechanical properties.1-6 For example, the microenvironments of biological processes such as embryonic development, stem cell differentiation, wound healing and tumorigenesis are highly dynamic, leading to changes in matrix stiffness over a broad range of timescales.4,

7

As a result, hydrogels that respond to diverse stimuli

including pH,8 redox potential,9,10 enzymes,11,12 temperature change,13,14 light,15 magnetic field,16 electronic field,17 and ultrasound18 are extensively explored. Among these smart hydrogels, light-responsive ones are of great interest because their mechanical properties can be modulated with temporal and spatial resolution.2,19-25 A typical light-responsive gel is formed by cross-linking hydrophilic polymers using a photo-cleavable linker, e.g. ultraviolet (UV) light-responsive chemicals comprised of onitrobenzyl,

coumarin,

quinolone,

xanthene,

or

benzophenone.26

Free-radical

polymerization of monoacrylated poly(ethylene glycol) (PEG) with PEG-di-acrylate


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containing two o-nitrobenzyl groups results in a stiff gel.27 The synthesized gel enables light modulation of gel stiffness with precise control. UV exposure gradually degrades the photocleavable linker and softens the stiff gel to a soft one. In an alternative approach, light-controlled reversible host-guest interactions were used to design light-responsive gels.22,28-29 A light-responsive gel was prepared by mixing a polymer containing αcyclodextrin (α-CD) with another polymer containing azobenzene (Azo). If the polymers in the gel were partly cross-linked using covalent bonds, UV irradiation would induce an expansion-contraction transition in the gel.22 During the transition, properties of the gel such as size and stiffness are gradually changed. Besides photodegradation and photoisomerization induced gel softening, we can stiffen a gel via light-induced secondary crosslinking.30 A soft gel with methacrylate groups can be stiffened by crosslinking the monomers via UV or visible light irradiation. Irradiating the gel through a patterned photomask induces local polymerization and gradient stiffening.30 In a recent study, Suggs et al. reported a near-infrared (NIR) light-responsive alginate hydrogel that is capable of stiffening or softening.4 Stiffness of the alginate gel could be temporally increased by NIR-triggered release of calcium ions from liposomes encapsulated in the gel. Alternatively, the stiffness could be decreased when the liposomes were loaded with calcium chelators. These smart gels show either softening via photo-degradation or stiffening via light-induced polymerization/complexation.2,4,22 Though these smart gels exhibit light-switchable properties and show promising applications in mimicking complicated biological matrices, it remains a great challenge to design a light-responsive gel that is capable of both dynamic stiffening and softening controlled by lights of different wavelengths.



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Herein, we report a supramolecular gel that responds to both UV and NIR lights. The gel with temporally tunable stiffness was prepared by mixing a copolymer consisted of azobenzene acrylamide (Azo-AAm), acrylamide (AAm), N-isopmpylacrylamide (NIPAAm) and PEG-di-acrylate with α-CD-functionalized dendrimer encapsulated with platinum nanoparticles (α-CD-DEPNs). The gel integrates promising properties such as UV light-switchable host-guest inclusion, temperature-responsive property, and NIR photothermal ability. UV light exposure on the gel induces the transition of trans-Azo to cis-Azo which shows dramatically decreased binding affinity to α-CD, thus softening the gel (Fig. 1a). On the contrary, NIR irradiation on the gel undergoes a light-to- heat conversion, and the generated heat further triggers the thermo-responsive polymer (pNIPAAm) to change from a hydrophilic state to a hydrophobic one, thus stiffening the gel (Fig. 1a). Additionally, the Azo moieties in the copolymer were replaced by admantane (ADA), and the α-CD on dendrimer surface by β-cyclodextrin (β-CD) to prepare a control supramolecular hydrogel responded to NIR light only. 2. EXPERIMENTAL SECTION 2.1. Materials. Ethylenediamine-cored generation 5 PAMAM dendrimer was purchased from Dendritech. (Midland, MI). N,N’-Carbonyldiimidazole was purchased from Sigma-Aldrich (St Louis, MO). PEG-di-acrylate was obtained from Sinopeg (Xiamen, China). Acryloyl chloride, 2,2’-azobis(2-methylpropionitrile), acrylamide, admantadine, α-CD, β-CD, dichloromethane, sodium borohydride, and chloroplatinic acid hexahydrate were purchased from Aladdin (Shanghai, China). Tetrahydrofuran, acetonitrile, triethylamine and dimethyl sulphoxide were obtained from Sinopharm Chemical Reagent (Shanghai, China). 4-azobenzene amine and NIPAAm were obtained


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from Energy Chemical (Shanghai, China). G5 PAMAM dendrimer was distilled to remove the methanol before further use. All the other reagents were used without further purification. 2.2. Measurement. 1H and

13

C NMR spectra were recorded on a Bruker NMR

spectrometer at 500 MHz (AscendTM 500, Bruker Corp., Germany) at 298.2 ± 0.1 K. The two-dimensional nuclear Overhauser enhancement spectroscopy (2D-NOESY) were performed with a Bruker 400 MHz NMR spectrometer (AvanceIII 400, Bruker Corp., Germany) with a 1 s relaxation delay, 600 ms acquisition time, 6.5 µs 1H 90o pulse width, and 200 ms mixing time, 16 transients were averaged for 1024 complex t1 points. (AvanceIII 400, Bruker Corp., Germany). The data were processed with NMRpipe software on a Linux workstation with standard Lorents-Gauss window function and zerofilling in both dimensions. TEM image was taken using a transmission electron microscope (HT7700, HITACHI, Japan) operated at an accelerating voltage of 100 kV. Mass spectrum (MS) was recorded using Maxis Impact mass spectrometer (Bruker Corp., USA). UV laser (365 nm, UVSP8V1104, Futansi Electronic Co. Ltd, Shanghai, China) and NIR laser (808 nm, MDL-III-808, New Industries Corp., Changchun, China) were used as the UV and NIR light sources, respectively. Circular dichroism (CD) spectra were measured using a spectropolarimeter (CD/J-815, JASCO Corp., Japan) with 1 mm path length quartz cell. Mechanical properties of the gel were measured on a Discovery Hybrid Rheometer-3 (TA Instruments, USA) under 0.1% strain and 1.0 Hz, using a 25mm diameter crosshatched stainless steel parallel plate. For temperature-dependent rheological measurement, the system temperature was increased from 37 oC to 60 oC at a rate of 2 oC/min, and then decreased from 60 oC to 37 oC at the same rate.



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2.3. Synthesis of Azo-AAm. The monomer Azo-AAm was synthesized according to the method described by Harada et al.22 Generally, 4-azobenzene amine (3.0 g, 15.21 mmol) and triethylamine (3 mL, 21.64 mmol) were dissolved in 110 mL tetrahydrofuran at 4 oC. Acryloyl chloride (1.36 g, 15.03 mmol) dissolved in 10 mL tetrahydrofuran was slowly dropped to the above solution, and the mixture was stirred for 4 h on an ice bath. The precipitate was removed by filtration, and the obtained crude product was purified by recrystallization from dichloromethane for three times. The final product was dried under vacuum (0.9 g, 3.58 mmol, 23.88%) and characterized by 1H NMR, 13C NMR and MS. 2.4. Synthesis of copolymer consisted of AAm, NIPAAm, Azo-AAm and PEG-diacrylate. The copolymer was synthesized by radical polymerization of AAM (5.33 mg, 0.075 mmol), NIPAAm (151.92 mg, 1.34 mmol), Azo-AAm (11.35 mg, 0.045mmol), and PEG-di-acrylate (131.25 mg, 0.0375mmol) in 12 mL dimethyl sulphoxide using 2,2’azobis(2-methylpropionitrile) (10 mg, 0.061 mmol) as the initiator, and the solution was stirred for 10 h at 80 oC. The product was purified by intensive dialysis against doubledistilled water (molecular weight cut off, MWCO, 3500 Da). Finally, the obtained copolymer was lyophilized as yellow powders (201.27 mg, 67.12%) and characterized by 1

H NMR, the low critical solution temperature (LCST) was measured on a variable-

temperature UV spectrometer (SPV-1X0, Agilent, USA). 2.5. Synthesis of α-CD-DEPNs. α-CD (1.29 g, 1.33 mmol) and N,N’carbonyldiimidazole (216 mg, 1.33 mmol) were dissolved in dehydrated dimethyl sulphoxide, and the mixture was stirred for 2 h at 30 oC. Then, generation 5 PAMAM dendrimers (300 mg, 10.41 µmol) dissolved in dehydrated dimethyl sulphoxide were slowly added into the above solution and stirred at room temperature for 48 h. The


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products were purified by intensive dialysis against double-distilled water (MWCO, 3500 Da). The obtained product (α-CD-modified G5 dendrimer) was lyophilized as white powders (183.10 mg, 2.11 µmol) and characterized by 1H NMR. To synthesize α-CDDEPNs, α-CD-modified G5 dendrimer (183.10 mg, 2.11 µmol) was dissolved in 70 mL distilled water (pH 3.0), and chloroplatinic acid hexahydrate (23.82 mg, 45.9 µmol) was added dropwisely into the solution, and the solution was stirred in dark for 48 h. After that, sodium borohydride (17.40 mg, 0.46 mmol) was slowly added to the solution, and the mixture was stirred for 2 h at room temperature. Finally, the obtained α-CD-DEPNs were purified by intensive dialysis against distilled water (MWCO, 3500 Da), lyophilized as black powders (144.20 mg, 75.08%), and characterized by 1H NMR and TEM. 2.6. Gel formation. To prepare the supramolecular gel, α-CD-DEPNs (335 mg) were dissolved in 5 mL distilled water at a concentration of 67 mg/mL, and 201.27 mg copolymer was added to the above solution. The mixture was vortexed and kept overnight to allow gel formation. 3. RESULTS AND DISCUSSION The responsive gel was formed by host-guest interactions between a copolymer containing Azo and NIPAAm moieties with α-CD-DEPNs. The copolymer was synthesized by radical copolymerization of a mixture of AAm, NIPAAm, Azo-AAm, and PEG-di-acrylate in dimethyl sulphoxide (Fig. 1b, characterization data for Azo-AAm and the copolymer are shown in Fig. S1-S4).22 The chains in the synthesized copolymer were cross-linked with PEG-di-acrylate. The mole percentage contents of AAm, NIPAAm, Azo-AAm and PEG-di-acrylate in the copolymer are 5%, 89.5%, 3% and 2.5%, respectively. For pure pNIPAAm, its LCST is about 32


o

C.31 By incorporating


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hydrophilic monomers such as AAm and PEG-di-acrylate into the polymer chain, we obtained a copolymer with an LCST around 45 oC (Fig. 1c, Fig. S5). For the synthesis of α-CD-DEPNs, an amine-terminated generation 5 poly(amino amine) (PAMAM) dendrimer was grafted with a high density of α-CD on its surface, and further used as a template to synthesize platinum nanoparticles (Fig. 1d).23,32 The number of α-CD conjugated on each G5 dendrimer is calculated to be 59 by 1H NMR analysis (Fig. S6). The high-resolution transmission electron microscopy (HRTEM) image reveals that the synthesized platinum nanoparticles have an ultrasmall size around 2 nm (Fig. 1e). The synthesized α-CD-DEPNs show an excellent light-to-heat conversion capability. Temperature of the α-CD-DEPN solution was increased by 30 oC after 2 min irradiation by an 808 nm NIR laser (0.49 W/cm2, Fig. 1f). After mixing the copolymer and α-CDDEPNs, a black-colored gel was obtained. The black color was owing to the homogeneous dispersion of platinum nanoparticles in the gel matrix (Fig. 1g). Within this gel, the azobenzene segment on copolymer and the α-CD segment on dendrimer form host-guest interactions, which contribute to the gel formation as well as UV responsiveness. Additionally, the platinum nanoparticles may transfer NIR light to heat, and when the local temperature increases upon the LCST of the copolymer (45 oC), the phase transition of pNIPAM segment may cause corresponding NIR responsiveness of the gel.


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Figure 1. Preparation of the light-responsive supramolecular hydrogel. (a) Concept of the smart gel that is capable of both softening and stiffening by UV and NIR lights, respectively. (b) Synthesis of copolymer consisted of AAm, NIPAAm, Azo-AAm and PEG-di-acrylate. (c) LCST determination by measurement of copolymer solution optical



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absorption as a function of temperature. (d) Synthesis of α-CD-DEPNs. (e) TEM image of α-CD-DEPNs. (f, g) Photothermal effect of the α-CD-DEPNs solution (f) and supramolecular gel (g) irradiated by an 808 nm NIR laser at a power density of 0.49 W/cm2 for 2 min. 3.1. Characterization of NIR-responsive behavior of the supramolecular gel. The prepared gel was further irradiated by an NIR laser, and the gel thermograph was captured after 10 min light exposure. The gel temperature was significantly increased (Fig. 1g). When the gel temperature is raised above LCST of the copolymer, the thermosensitive polymer undergoes a coil-globule transition (hydrophilic to hydrophobic). As a result, NIR light exposure (0.49 W/cm2, 2 min) induced a significant volume contraction in the gel (~68.3%, Fig. 2a). Once the NIR laser is removed, the gel temperature rapidly fell below LCST of the thermo-sensitive polymer, and the gel volume was almost recovered. A reversible contraction-expansion transition in the gel was observed when the NIR laser is periodically turned on and off (Fig. 2b). We also monitored the mechanical property of the gel by a temperature-dependent rheological measurement. As shown in Fig. 2c, the gel stiffness (storage modulus, G’) is significantly increased when the gel temperature is raised above 45 oC, which equals to the LCST of the thermosensitive polymer, and the storage modulus of the gel is recovered to its initial value when the temperature is below 45 oC (Fig. 2d). The volume and stiffness changes are correlated with phase transitions of the thermo-responsive polymers in the gel (Fig. 2e). These results suggest that the supramolecular gel is capable of dynamic stiffening by NIR light irradiation.


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Figure 2. NIR-responsive behavior of the supramolecular gel. (a) Photographs of the supramolecular gel irradiated by an NIR laser. (b) Volume changes of the gel when an NIR laser is periodically turned on and off. (c, d) Stiffness of the gel at varying temperatures. (e) Mechanism of the NIR-responsive gel. 3.2. Characterization of UV-responsive behavior of the supramolecular gel. We further investigated the volumetric and mechanical behaviors of the gel when it was irradiated by a UV laser. In the supramolecular gel, the host-guest interactions between Azo and α-CD act as additional cross-linking junctions between the polymer chains. UV



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light isomerizes the trans-Azo group into the cis-Azo one, whereas the reverse occurs with visible light exposure.22 The association affinity between α-CD and Azo will be dramatically decreased during UV treatment. As shown in Fig. 3a, an expansion of 179% in volume was observed for the gel when it was irradiated by a 365 nm UV laser for 5 min (1.1 W/cm2), and the gel restored its initial volume when it was treated with visible light for 20 min. The volume changes of the gels are correlated with the host-guest interactions between α-CD and Azo moieties in the gel (Fig. 3b). This can be further confirmed by the 2D-NOESY and CD spectra of copolymer/α-CD complex. As shown in Fig. S7a, NOE signals between the aromatic protons of Azo moiety and the protons (H3 and H5) of α-CD were observed before UV irradiation, suggesting the encapsulation of Azo in the inner cavity of α-CD. The NOE cross-peaks were disappeared when the complex solution was irradiated by a UV laser, indicating the Azo moiety was dissociated from α-CD (Fig. S7b). In addition, the CD spectrum of the complex solution showed a significant positive cotton band at 350 nm assigned to the π-π transition of trans-Azo before UV irradiation, indicating that the trans-Azo moiety inserts in the α-CD cavity and its electronic transition moment parallel to the α-CD axis. Upon UV exposure, the positive cotton band at 350 nm was almost disappeared as the Azo moiety turns to the cis- form and dissociate from the α-CD cavity (Fig. S8). Similarly, a reversible expansion-contraction transition in the gel was observed when the UV laser is periodically turned on and off (Fig. 3c). In addition, the stiffness of the gel was decreased upon UV Irradiation (Fig. 3d), and gradually recovered to its initial value after the removal of UV laser (Fig. 3e). Therefore, the volume and stiffness of the


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gel were tunable upon UV light irradiation. The supramolecular gel is capable of both stiffening and softening controlled by NIR and UV lights, respectively. If the Azo moiety in the copolymer was replaced by admantane (ADA), and the α-CD on dendrimer surface by β-CD (Figure S9-S11), the host-guest interaction between ADA and β-CD also drives the formation of a supramolecular hydrogel. The gel exhibited a significant volume contraction upon NIR irradiation (0.49 W/cm2, 10 min), and the gel stiffness (storage modulus, G’) was significantly increased when the gel temperature is raised above 45 oC. However, the ADA/β-CD gel did not response to a UV laser exposure because the molecular structure of ADA is not changed when irradiated with a UV light. These results suggested that both the Azo/α-CD pair and the pNIPAM segment are essential for the preparation of hydrogels respond to both ultraviolet and near-infrared lights.



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Figure 3. UV-responsive behavior of the supramolecular gel. (a) Photographs of the gel irradiated by a UV laser. (b) Mechanism of the UV-responsive gel. (c) Volume changes of the gel when a UV laser is periodically turned on and off. (d, e) Stiffness of the gel irradiated by a UV laser. 3.4. Light-induced deformation behavior and self-healing property of the gel. Besides gel volume and stiffness, the bending direction of the supramolecular gel can be controlled by NIR or UV irradiation. As shown in Fig. 4a, irradiating the middle region of a ribbon-like gel with an NIR laser (808 nm) from the left side bends the gel to left,


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whereas exposing an UV laser (365 nm) to the gel at the same region triggers the bending of the gel to a reverse direction (Fig. 4b). This light-driven gel bending behavior can be explained by gel volume variation at the irradiated area.22,33 The gel bending behavior upon light exposure can be repeated for several cycles. It is known that supramolecular gels formed by host-guest interactions would exhibit a self-healing property.17,34-36 Two cube-shaped gels were joined together and maintained for 10 min. It is observed that the crack between gels disappeared and the two gels completely healed to form one gel (Fig. 4c). The re-joined gel could be lifted up without breakup. Additionally, the self-healing property was also quantitatively evaluated by the rheological study. It was observed that the gel recovers to 89.8% of its original G’ and G’’ values within 20 min after gel damage, exhibiting a relatively high self-healing efficiency (Fig. S13). The self-healing behavior is attributed to the host-guest recognition between α-CD and Azo groups on the gel surface (Fig. 4d).

Figure 4. Light-induced deformation and self-healing property of the gel. (a, b) Irradiating the middle region of a ribbon-like gel from the left side by a NIR (a) or UV



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(b) laser. (c) Two cube-shaped gels were joined together and a self-healing behavior was observed. (d) Mechanism of the self-healing property.

4. CONCLUSIONS In summary, we developed a supramolecular and self-healing gel based on host-guest inclusions between α-CD and Azo. The gel integrates UV light-switchable host-guest recognition, temperature responsiveness, and near-infrared photothermal ability. It responds to both UV and NIR light irradiations, and exhibits light-switchable volumetric, mechanical, and bending properties with temporal and spatial resolutions. The gel is capable of both dynamic softening and stiffening controlled by UV and NIR light, respectively, and represents a useful tool that might be used as dynamic matrices to regulate cell proliferation, differentiation, and apoptosis.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications via the Internet at http://pubs.acs.org. Characterization of the synthesized Azo-AAm monomer, Azo copolymer, α-CD-DEPNs, ADA-AAm monomer, ADA copolymer, and β-CD-DEPNs. 2D-NOESY and CD spectra of Azo copolymer/αCD complex, self-healing efficiency of Azo/α-CD supramolecular gel, and behaviors of the ADA/β-CD supramolecular gel upon NIR and UV irradiation. AUTHOR INFORMATION Corresponding Author *Email: [email protected]


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Notes The authors declare no competing ﬁnancial interest. ACKNOWLEDGEMENTS. This work was supported by the research programs from Science and Technology Commission of Shanghai Municipality (17XD1401600 and 148014518), the National Natural Science Foundation of China (No. 21404020), and the Fok Ying Tong Education Foundation (No. 151036).

REFERENCES (1) Griffin, D. R.; Weaver, W. M.; Scumpia, P. O.; Di Carlo, D.; Segura, T. Accelerated Wound Healing by Injectable Microporous Gel Scaffolds Assembled from Annealed Building Blocks. Nat. Mater. 2015, 14 (7), 737-744. (2) Khetan, S.; Guvendiren, M.; Legant, W. R.; Cohen, D. M.; Chen, C. S.; Burdick, J. A. Degradation-Mediated Cellular Traction Directs Stem Cell Fate in Covalently Crosslinked Three-Dimensional Hydrogels. Nat. Mater. 2015, 12 (5), 458-465. (3) Annabi, N.; Tamayol, A.; Uquillas, J. A.; Akbari, M.; Bertassoni, L. E.; Cha, C. Camci-Unal, G., Dokmeci, M. R., Peppas, N. A., Khademhosseini, A. 25th Anniversary Article: Rational Design and Applications of Hydrogels in Regenerative Medicine. Adv. Mater. 2015, 26 (1), 85-123. (4) Stowers, R. S.; Allen, S. C.; Suggs, L. J. Dynamic Phototuning of 3D Hydrogel Stiffness. Proc. Natl. Acad. Sci. U.S.A. 2015, 112 (7), 1953-1958. (5) Shastri, A.; McGregor, L. M.; Liu, Y.; Harris, V.; Nan, H.; Mujica, M.; Vasquez, Y.; Bhattacharya, A.; Ma, Y.; Aizenberg, M.; Kuksenok, O.; Balazs, A. C.; Aizenberg, J.; He, X. An Aptamer-Functionalized Chemomechanically Modulated Biomolecule Catch-andRelease System. Nat. Chem. 2015, 7 (5), 447-454.



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(6) Imran, A. B.; Esaki, K.; Gotoh, H.; Seki, T.; Ito, K.; Sakai, Y.; Takeoka, Y. Extremely

Stretchable

Thermosensitive

Hydrogels

by

Introducing

Slide-Ring

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