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Multi-Triggered Supramolecular DNA/Bipyridinium Dithienylethene Hydrogels Driven by Light, Redox and Chemical Stimuli for Shape-Memory and Self-Healing Applications Ziyuan Li, Gilad Davidson-Rozenfeld, Margarita VázquezGonzález, Michael Fadeev, Junji Zhang, He Tian, and Itamar Willner J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b10481 • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 19, 2018

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Journal of the American Chemical Society

Multi-Triggered Supramolecular DNA/Bipyridinium Dithienylethene Hydrogels Driven by Light, Redox and Chemical Stimuli for ShapeMemory and Self-Healing Applications Ziyuan Li,a Gilad Davidson-Rozenfeld,b Margarita Vázquez-González,b Michael Fadeev,b Junji Zhang,a* He Tian a and Itamar Willnerb* aKey

Laboratory for Advanced Materials and Joint International Research Laboratory of Precision Chemistry and Molecular

Engineering, Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry and Molecular Engineering, East China University of Science & Technology, 130 Meilong Road, Shanghai, 200237, China bInstitute

of Chemistry, The Minerva Center for Biohybrid Complex Systems, The Hebrew University of Jerusalem, Jerusalem

91904, Israel

Abstract: Multi-triggered DNA/bipyridinium-dithienylethene (DTE) hybrid carboxymethyl cellulose (CMC) based hydrogels are introduced. DTE exhibits cyclic and reversible photoisomerization properties, switching between the closed state (DTEc), the electron acceptor, and the open isomer (DTEo) that lacks electron acceptor properties. One system includes the synthesis of CMC chains modified with electron donor dopamine sites and self-complementary nucleic acid tethers. In the presence of DTEc and the CMC scaffold, a stiff hydrogel, cooperatively stabilized by dopamine/DTEc donor-acceptor interactions and by the duplex nucleic acids is formed. The cyclic and reversible formation and dissociation of the supramolecular donor-acceptor interactions, through light-induced photoisomerization of DTE, or via the oxidation and subsequent reduction of the dopamine sites, leads to hydrogels of switchable stiffness. Another system introduces a stimuli-responsive hydrogel triggered by one of the three alternative signals. The stiff multi-triggered hydrogel consists of CMC chains crosslinked by the dopamine/DTEc donoracceptor interactions, and by supramolecular K+-stabilized G-quadruplexes. The G-quadruplexes are reversibly separated in the presence of 18-crown-6 ether and reformed upon the addition of K+. The stiff hydrogel undergoes reversible transitions between high-stiffness and low-stiffness states triggered by light, redox agents or K+/crown ether. The hybrid donor-acceptor/G-quadruplex crosslinked hydrogels show shape-memory and self-healing features. By using three different triggers and two alternative memory-codes, e.g. the dopamine/DTEc or the K+-stabilized G-quadruplexes, the guided shape-memory formation of the hydrogel matrices are demonstrated. ACS Paragon Plus Environment

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Introduction Continuous efforts are directed toward the development of hydrogel materials due to their broad applications as separation matrices,1 biomedicines,2 tissue engineering,3 sensors,4 actuators and robotics,5 cell growth6 and prosthetic materials.7 One type of hydrogels is composed of hydrophilic polymer scaffolds crosslinked by different supramolecular bridges such as ligand/receptor units (receptor = cyclodextrin, cucurbituril),8 donor-acceptor supramolecular stuctures,9 biomolecular recognition complexes,10 metal-organic complexes11 and ionic interactions.12 Within this area of hydrogels, stimuliresponsive hydrogels have attracted special interest.13 In these systems, auxiliary or environmental triggers control the stiffness of the hydrogel or stimulate the reversible transitions of the hydrogel matrices into polymer solutions. Different stimuli were applied to switch the stiffness states of the hydrogels, including pH,14 heat,15 chemical agents,16 light17 and magnetic fields.18 The development of nucleic acid (DNA)-based hydrogels have recently become one of the research hotspots.19 The base-sequences comprising nucleic acids introduces substantial structural and functional information into the biopolymer.20 Structural information includes, for example, the switchable K+-stabilization of Gquadruplexes and their separation by crown ethers,21 the pH-induced formation and dissociation of imotif22 or C-G.C+ structures,23 the metal-ion-induced bridging of base mismatches in duplex nucleic acids, and their separation by appropriate ligands,24 e.g., T-Hg2+-T or C-Ag+-C/cysteine, and the light-induced stabilization of duplex nucleic acids by photoisomerizable intercalators,25 e.g., trans-azobenzene units. Functional information encoded in nucleic acids includes the separation of duplex DNAs through the formation of ligand/aptamer complexes,26 or the cleavage of the duplexes by sequence-specific DNAzymes.27 The switchable triggered functions of nucleic acids were widely applied to develop different facets of DNA nanotechnology,28 including the development of DNA-based switches,29 DNA machines,30 nucleic acid-based sensors,31 and nano and micro drug carriers for controlled release.32 Not surprising, stimuli-responsive DNA-based hydrogels attract substantial recent research efforts.33 In these systems, polymer chains, e.g., polyacrylamide or carboxymethyl cellulose, CMC, are functionalized with stimuli-responsive nucleic acids. The presence of appropriate triggers and counter triggers result in the crosslinking of the polymers to form hydrogels and their subsequent separation into the polymer solutions.16, 19a In addition, by the cooperative crosslinking of the polymer chains through permanent duplex nucleic acid bridges and stimuli-responsive crosslinking units, stimuli-responsive hydrogels revealing controlled and switchable stiffness functions were demonstrated. Different applications of DNA-based stimuli-responsive hydrogels were discussed, including their use as shape-memory22, 34 and self-healing materials,35 controlled drug release,36 selective membrane for ion-transport37 and mechanical devices.38 In all of these systems, the stimuli responsive hydrogel matrices included duplex nucleic acids ACS Paragon Plus Environment

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as permanent linkers and co-participating stimuli-responsive switchable nucleic acid or supramolecular complexes bridges. The design of hybrid hydrogels crosslinked by supramolecular complexes and nucleic acid bridges introduces a further dimension to stimuli-responsive “smart” hydrogel materials, providing structural complexity that allows the selective triggered control over the properties and functions of the hydrogels. The successful design of such hybrid hydrogels suggests that by applying appropriate chemical “tools”, one might enhance the complexity of hybrid hydrogels. In the present study, we demonstrated the assembly of a stimuli-responsive hydrogels that selectively response to three triggers consisting of light, redox agents and G-quadruplexes. Specifically, we apply bipyridinium-dithienylethene, DTE,39 as a functional material for the assembly of photo- and redox-responsive hydrogel matrices. Dithienylethene derivatives were broadly used as tunable photochromic materials, as functional building blocks of supramolecular polymers and gels.40 Also, the electron acceptor properties of bipyridinium dithienylethene were applied for the electrochemically dictated uptake and release of bipyridinium dithienylethene from molecular-imprinted matrices, thereby controlling the wettability of electrode surfaces.41 By integrating DTE and stimuli-responsive nucleic acids, multi-triggered hydrogels (threeactivating triggers) that reveal controlled and switchable stiffness are designed. The hybrid hydrogel matrices are used to create shape-memory and self-healing hydrogels. In contrast to previous reports, the present study introduces a unique example where light, redox, and chemical stimuli control the properties and functions of integrated composite hydrogel materials. The systems introduced herein are conceptionally different from the previously reported stimuli-responsive DNA-based hydrogels: (i) The previously reported systems included two interacting polymer chains with complementary tethers for bridging and crosslinking of the hydrogel networks. In the present study, we use single polymer chains modified by dopamine and self-organizing nucleic acid tethers that selfassemble in the presence of DTEc into the hydrogel networks. (ii) The different stimuli-responsive hydrogels reported till now were operated by only one or two triggering stimuli. The present study introduces integrated stimuli-responsive hydrogels of enhanced complexity that can be triggered by three different triggers, e.g. light, redox and ion/crown ether stimuli. (iii) The present study introduces bipyridinium-dithienylethene as a non-leaking, photoisomerizable, diffusional, electron acceptor that guides the complex functions of the different hydrogels. Results and Discussions Synthesis and Manipulation of Hydrogels

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The synthesis of dopamine, self-complementary DNA/dopamine and G-quadruplex/dopamine modified CMC polymer chain as well as bipyridinium dithienylethene is carried out according to our previous works.35, 41, 42 Their structures were fully characterized by UV-Vis spectroscopy, 1H NMR and Diffusion Ordered SpectroscopY (DOSY), see Supporting Information for details. The formation of the hydrogel was based on the heating-cooling gelation process. The triple-stimuli controlled, reversible stiffness conversion of different hydrogel states were carried out with UV (λ = 365 nm, 10 min)/Vis (λ > 570 nm, 2 h), sodium persulfate (SPS, 1 M, 10 μL, 5 min)/ascorbic acid (AA, 1 M, 10 μL, 5 min), K+ (0.2 M, 100 μL, 4h)/18-crown-6 ether (CE, 0.2 M, 100 μL, 4h) cycles, respectively, see Supporting Information for details. Dual responsive CMC-Dopa/DTE Hydrogel DTE exhibits switchable and reversible photoisomerizable properties as outlined in Scheme 1 (see the 1H

NMR of DTE in Figure S1). The open DTE state, DTEo, undergoes photocyclization to the closed

state, DTEc, upon UV irradiation (λ = 365 nm), while the closed state undergoes the reverse ring-opening to DTEo upon Vis irradiation (λ > 570 nm), Figure S2. The closed form, DTEc, exhibits strong electron acceptor properties (due to the quasi-planar structure of the conjugated framework), whereas the open state, DTEo, reveals weak electron acceptor properties (due to steric distortion of the non-conjugated molecular scaffold). In the present study, we examine the formation of donor-acceptor complexes between dopamine (donor) and the DTEc (acceptor) as a functional crosslinker that bridges CMC chains to yield the hydrogel networks. We find that dopamine and DTEc yield in the presence of CMC a 2:1 donoracceptor complex, Ka = 94672 M-1, see Figure S3, Supporting Information.

Scheme 1. Photoisomerization between DTEo and DTEc. The first DTE-based hydrogel matrix, triggered by light or redox stimuli, is depicted in Figure 1(A). The polymer chain, Pa, consists of dopamine-functionalized CMC chains (Figure S4 and S5). The content of dopamine on the CMC chains was calculated by 1H NMR spectroscopy to be 1:15, Figure S4. While the CMC polymer chains in the presence of DTEo exhibit a quasi-liquid state, photoisomerization of DTEo to the electron acceptor DTEc (λ = 365 nm, 10 min) leads to the crosslinking of the chains by donoracceptor interactions, resulting in the formation of a hydrogel in state I.


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Figure 1. (A) Schematic formation and dissociation of a dopamine-functionalized carboxymethyl cellulose hydrogel crosslinked by DTEc using donor-acceptor interactions. (B) Rheometry measurements corresponding to the photoinduced transition of the hydrogel in state I to quasi-liquid state II, and the redox-stimulated transitions of the hydrogel in state I to quasi-liquid state III: Panel I, a and a’ - G’ and G’’ values of the hydrogel in state I. b and b’ - G’ and G’’ values of quasi-liquid state II. c and c’ - G’ and G’’ values of quasi-liquid state III. Panel II – Cyclic G’ and G’’ changes corresponding to the reversible light-induced transitions between states I and II. Panel III – Cyclic G’ and G’’ changes stimulated by the reversible redox triggered transitions between states I and III. The reverse photoisomerization of DTEc to DTEo (λ > 570 nm, 2 h) results in the separation of the hydrogel and the formation of the quasi-liquid state II. The oxidation of the donor-acceptor bridged hydrogel I with sodium persulfate (1 M, 10 μL, 5 min) transforms the hydroquinone electron donor sites into the quinone acceptor sites, leading to the dissociation of the donor-acceptor interactions and the formation of the quasi-liquid hydrogel matrix III. Subsequent reduction of the quinone sites, with ascorbic acid (1 M, 10 μL, 5 min), to the hydroquinone state restores the state I of the hydrogel. Figure 1(B) shows the rheometry properties of the different states. The hydrogel in state I reveals high stiffness (storage moduli G’ = 530 Pa and loss moduli G” = 150 Pa), consistent with its crosslinking by the dopamine/DTEc donor-acceptor interactions, curves a and a’, Panel I. Photoisomerization of DTEc to the DTEo, that lacks electron acceptor properties, yields the quasi-liquid state II (G’ = 70 Pa and G’’ = 30 Pa), curves b and b’, ACS Paragon Plus Environment


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Panel I. The reverse photoisomerization of DTEo to DTEc restores state I. The redox triggered oxidation of the dopamine sites to the quinone sites dissociates the supramolecular donor-acceptor interactions and yields the quasi-liquid state III (G’ = 7 Pa and G” = 3 Pa), curves c and c’, Panel I. Further reduction of the quinone sites to the dopamine sites regenerates state I. The photoinduced stiffness transitions of the hydrogel between states I and II, upon photoisomerization between DTEc and DTEo, are fully reversible, Figure 1(B), Panel II. Similarly, upon the cyclic oxidation and reduction of the supramolecular donoracceptor crosslinked hydrogel, the reversible transitions between the hydrogel in state I and quasi-liquid state III is observed, Panel III. It should be noted that quasi-liquid states II and III should exhibit similar rheometric values. Nonetheless, the state II reveals slightly higher G’ and G’’ values. This might originate from the incomplete photoisomerization of DTEc to DTEo that results in the crosslinking of residual DTEc in state II. In addition, we note that the thickness of the hydrogel is ca. 0.1 to 0.2 cm. Higher thickness will adversely affect the photoisomerization process due to the filtering of the light that prohibits the effective isomerization of internally located DTE units. Dual responsive CMC-duplex DNA-Dopa/DTE Hydrogel In the next step, the dopamine-functionalized CMC chains were further modified with the selfcomplementary nucleic acid stand (1), Figure 2(A). The average loading of the dopamine sites on the CMC was calculated to be 1:15 by 1H NMR spectroscopy (Figure S4). In addition, the loading of the nucleic acid tethers (1) on the CMC was 1:90, Figure S5. In the presence of DTEc, a stiff hydrogel (state IV), is formed, due to the cooperative crosslinking by the donor-acceptor dopamine/DTEc interactions and by the self-complementary (1)/(1) crosslinkers. Photoinduced isomerization of DTEc to DTEo (λ > 570 nm, 2 h) dissociates the donor-acceptor crosslinkers, resulting in a hydrogel of lower stiffness, state V. The reverse photo-induced isomerization of DTEo to DTEc (λ = 365 nm, 10 min) restores the stiff, cooperatively-stabilized hydrogel, state IV. Furthermore, the oxidation of the dopamine residues of the hydrogel in state IV with sodium persulfate (1 M, 10 μL, 5 min) yields the respective quinone sites, and dissociates the donor-acceptor interactions, generating the reduced stiffness state VI of the hydrogel. The reverse reduction of the quinone sites associated with the polymer chains, using ascorbic acid (1 M, 10 μL, 5 min) as reducing agent, regenerates state IV that is cooperatively crosslinked by the donor-acceptor and (1)/(1) crosslinkers. That is, the stiff hydrogel in state IV can be reversibly transformed to hydrogels of lower stiffness in state V or state VI by light or redox stimuli, respectively. Note that although DTE is a diffusional unit in the hydrogel matrix, no leakage of DTE was observed. Presumably, electrostatic interactions between the positively charged DTE and the negatively charged CMC matrix preserve the intact,


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Figure 2. (A) Schematic formation and disassembly of the carboxymethyl cellulose hydrogel, cooperatively crosslinked by the dopamine/DTEc donor-acceptor supramolecular interactions and the duplexes (1)/(1). (B) Rheometry experiments corresponding to the photoinduced transition of the hydrogel between state IV and state V and the redox-stimulated transitions between state IV and state VI: Panel I, a and a’ - G’ and G’’ values of the hydrogel in state IV. b and b’ - G’ and G’’ values of the hydrogel in state V. c and c’ - G’ and G’’ values of the hydrogel in state VI. Panel II – Cyclic G’ and G’’ changes upon the reversible light-induced transitions between the hydrogels in states IV and V. Panel III – Cyclic G’ and G’’ changes stimulated by the reversible redox triggered transitions between the hydrogels in states IV and VI. Panel IV – Cyclic G’ and G’’ changes stimulated by coupled, reversible redox and light triggered transitions between the hydrogels in state IV and V, state IV and VI, respectively. (C) SEM images corresponding to the hydrogels in state IV, V and VI, and the intercoversion between them via light and redox stimuli. integrated structure of the DTE/hydrogel matrix. Figure 2(B), Panel I, depicts the rheometry properties of the photo-/redox-responsive donor-acceptor, (1)/(1) crosslinked hydrogels. The stiff hydrogel crosslinked by the dopamine/DTEc complexes and the (1)/(1) duplexes reveals G’ = 1310 Pa and G” = 190 Pa, curves ACS Paragon Plus Environment


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a and a’, respectively. Photoisomerization of DTEc to DTEo yields the hydrogel in state V that exhibits lower stiffness (G’ = 160 Pa and G” = 30 Pa), curves b and b’. The oxidation of the dopamine to the quinone leads to also a hydrogel of lower stiffness (G’ = 130 Pa and G” = 20 Pa), state VI, consistent with the dissociation of the donor-acceptor interactions, curves c and c’, respectively. The photochemical and redox-triggered transitions between the high-stiffness hydrogel in state IV, and low-stiffness hydrogel in states V and VI are reversible. Figure 2(B), Panel II, shows the cyclic, switchable control of the hydrogel stiffness upon photoisomerization between DTEc and DTEo. Panel III depicts the redox-triggered cyclic stiffness transitions from state IV to state VI. Panel IV shows the switchable stiffness transitions of the hydrogel upon subjecting the stiff hydrogel bridged by the supramolecular donor-acceptor interactions and (1)/(1) crosslinkers to a series of photochemical and redox stimuli. Evidently, the stiffness of the hydrogel can be switched by a programmed sequence of photochemical or redox triggers. Further support for the switchable light-induced or redox-stimulated control over the stiffness of the different hydrogels was obtained by scanning electron microscopy (SEM) imaging of the respective hydrogels, Figure 2(C). The hydrogel in state IV, that is cooperatively crosslinked by bridges (1)/(1) and by dopamine/DTEc interactions reveal a highly porous crosslinked matrix. The light-induced transformation of the DTEc to DTEo leads to the dissociation of the donor-acceptor interactions, resulting in a low-stiffness hydrogel that reveals significantly larger pores, and lower degree of crosslinkings, state V. Similarly, subjecting the stiff hydrogel in state IV to sodium persulfate results in the oxidation of the dopamine sites, the separation of the donor-acceptor interactions, and the generation of lower stiffness hydrogel, state VI. The resulting hydrogel shows the formation of larger pores, as compared to state IV. Since the pore sizes of the hydrogel are controlled by the degree of crosslinking, the pore sizes could relate to the stiffness of the respective hydrogels.43 Shape-memory and Self-healing Properties of the Dual Responsive Hydrogel Recent research activities demonstrated the use of stimuli-responsive nucleic acid-based hydrogels as functional materials for the creation of “shape-memory” hydrogels22, 34 or “self-healing” soft material matrices.35, 42 Shape-memory polymers include “smart” materials with permanent shapes that undergo a transition into a metastable structure, by the addition of appropriate triggers. The metastable structure includes, however, a memory-code to regenerate the original shape by the addition of a counter trigger.44 Stimuli-responsive DNA-based hydrogels that are cooperatively bridged by two different kinds of crosslinkers are excellent materials to tailor “shape-memory” hydrogels. Specifically, the controlled, signal-triggered stiffness of the hydrogels may provide a versatile mechanism to develop the shapememory material, where the triggered dissociation of one of the crosslinking elements leads to a shapeless metastable, quasi-liquid state that includes the second crosslinking bridges as the memory-code (e.g., ACS Paragon Plus Environment

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entanglement of the polymer chains) to regenerate the initial shape, upon the additions of the counter trigger. Nonetheless, the tailoring of “smart” DNA-based hydrogels revealing programmable multitriggered shape-memory properties are unprecedented. In particular, the diffusional mediators that control shape-memory properties of hydrogels is undeveloped. The self-healing of hydrogel matrices is an associated process, where pieces of the hydrogel undergo inter-connection (healing) by the guided bridge of the two soft pieces by cooperative crosslinkers.45 Different bridging self-healing motifs were reported, including supramolecular ligand-receptor interaction, hydrogen bonds and Diels-Alder adducts as bridges.10a, 46 The capability to regulate the stiffness of the hydrogels bridged by the donor-acceptor interactions and (1)/(1) duplexes, with light or redox triggers, were applied to construct the shape-memory and self-healing matrices. Figure 3(A) depicts the method to use the stiff hydrogel (state IV), to assemble photochemicallydriven or redox-triggered shape-memory and self-healing hydrogel matrices. The hydrogel (state IV) was prepared as a triangle-shape. The triangle-shaped hydrogel was then exposed to Vis light, resulting in the quasi-liquid state that included the (1)/(1) duplexes as internal memory-code, state V.

Figure 3. (A) Schematic preparation and shape-memory properties of the hydrogel. (B) Images corresponding to the shape-memory properties of the hydrogel IV. Panel I – Cyclic and reversible lightinduced transitions between the shaped hydrogel, state IV, and the shapeless quasi-liquid hydrogel, state



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V. Panel II – Cyclic redox triggered transitions between state IV and state VI. Panel III – Coupled redoxactivated and photo-stimulated transitions between state IV, states V and VI. The subsequent UV-stimulated photoisomerization of the DTEo to DTEc led to the duplex (memory) guided recovery of the triangle shape. Figure 3(B), Panel I, shows the cyclic and reversible light-induced transitions between the stiff state IV and the quasi-liquid state V. The hydrogel (state IV) was also treated with sodium persulfate to oxidize the dopamine to the quinone sites, lacking electron donor properties. The dissociation of the donor-acceptor crosslinking interactions thus occurred, leading to a quasi-liquid shapeless matrix, state VI. The (1)/(1) duplexes in state VI provided, however, the internal memory that guides the reshaping of the triangle hydrogel. The reduction of the quinone with ascorbic acid reassembled the stiff hydrogel, state IV. Figure 3(B), Panel II, shows the redox-triggered shape transitions. The capability to regulate the shape-memory properties by programmed, consecutive redox and light triggers is demonstrated in Figure 3(B), Panel III. The hydrogel (state IV) was treated with a series of oxidation/reduction and photoisomerization cycles that led to the transformation between state V and VI. The shape-memory functions of the hydrogels at room temperature, could be switched for at least six cycles without noticeable perturbation of the shape features. The self-healing features of the hydrogel triggered by redox-triggers or photochemical stimuli are demonstrated in Figure 4. The stiff hydrogel (state IV) was cut into two pieces that were subjected to the oxidation trigger, sodium persulfate, that yielded the low-stiffness hydrogel, crosslinked only by the (1)/(1) duplexes. The two physically connected pieces were treated with ascorbic acid, Figure 4(A). After 4 h, the two pieces were recombined into a self-healed matrix consisting of the non-separable stiff hydrogel. Similarly, the light-induced self-healing properties of the two hydrogel pieces are demonstrated in Figure 4(B). The two stiff hydrogel pieces bridged by the dopamine/DTEc and (1)/(1) crosslinkers were irradiated with Vis light (λ > 570 nm, 2 h) to transform the DTEc into the DTEo units. This photoisomerization resulted in the separation of the donor-acceptor interactions and the formation of the low-stiffness hydrogel. The physical connection of the soft hydrogel pieces, followed by the light-induced isomerization of the DTEo to the DTEc (λ = 365 nm, 10 min), resulted in a self-healed matrix crosslinked by the two bridging motifs, after a time-interval of 4 h. The tensile force of the undamaged hydrogels corresponded to ca. 20 mN, whereas the self-healed hydrogels revealed tensile forces of 8-10 mN. The values indicate the presence of very soft hydrogels. The control experiments showed that, in the absence of the UV light or reducing agent, no self-healing performances were observed. Gentle shaking of the two pieces adduct resulted in the immediate separation of the pieces (Figure S8). The results reveal that the application of


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respective triggers yields the hydrogel crosslinked by the donor-acceptor interactions and (1)/(1) crosslinkers as self-healed, non-separable matrices.

Figure 4. Self-healing of the dopamine/DTEc and self-complementary nucleic acid crosslinked hydrogel using (A) redox triggers or (B) photochemical triggers. Triple-stimuli Switchable CMC-G-quadruplex-Dopa/DTE Hydrogel In the previous section, the duplex nucleic acid, (1)/(1) acted as a permanent crosslinker of the hydrogel. One may, however, use a stimuli-responsive nucleic acid bridge to cooperatively stabilize the hydrogel with the photoactive/redox-triggered crosslinking units. By this way, the stimuli-responsive nucleic acid might add an additional stiffness-controlling crosslinking element. The three-input guided switchable stiffness features, with the integration of stimuli-responsive G-quadruplexes. and the photo-/redoxresponsive donor-acceptor crosslinkers, is presented in Figure 5(A). The polymer chains, Pc, consists of the CMC scaffold functionalized with the dopamine sites and the nucleic acid tethers (2), half of a Gquadruplex nucleic acid sequence. The loading of the dopamine sites on the CMC was calculated by 1H NMR and it corresponded to 1:15 (Figure S9). The loading of the DNA (2) was 1:110, Figure S10. In the presence of DTEc, the dopamine/DTEc interactions are formed, leading to a crosslinked hydrogel in state VIII. Treating the hydrogel with buffer containing K+ (0.2 M, 100 µL, 4 h) resulted in the formation of the K+-stabilized G-quadruplexes, that cooperatively stabilize the hydrogel by the donor-acceptor and Gquadruplex crosslinkers. This yield a hydrogel of high stiffness, state VII. The subsequent treatment of the hydrogel (state VII) with buffer containing 18-crown-6 ether (0.2 M, 100 µL, 4 h), excludes the K+ from the G-quadruplexes and separates the G-quadruplex crosslinkers, yielding the low-stiffness state VIII. Vis irradiation of the hydrogel in state VII transforms the DTEc to DTEo configuration (λ > 570 nm, 2 h), yielding the hydrogel in state IX, where the dopamine/DTEc donor-acceptor interactions are ACS Paragon Plus Environment


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dissociated. The UV-irradiation (λ = 365 nm, 10 min) of the hydrogel in state IX re-isomerized the DTEo to the DTEc, resulting in the recovery of the stiff hydrogel in state VII, that includes the cooperatively crosslinking of the G-quadruplexes and donor-acceptor interactions. Subjecting the stiff hydrogel in state VII to sodium persulfate (1 M, 10 μL, 5 min) leads to the oxidation of the dopamine to quinone, and yields the low-stiffness hydrogel bridged by the G-quadruplexes, state X. Treating the hydrogel in state X with ascorbic acid (1 M, 10 μL, 5 min) reduces the quinone to dopamine, leading to the regeneration of the stiff hydrogel in state VII, that is bridged by the dopamine/DTEc donor-acceptor interactions and the Gquadruplexes. The scheme outlined in Figure 5(A) suggests unique properties of the stiff hydrogel, state VII, which can

Figure 5. (A) Synthesis of a triple-trigger stimuli-responsive hydrogel responding to light, redox agents or chemical agents. (B) Rheometry results corresponding to the chemically triggered transition of state VII to state VIII, photoinduced transition of state VII to state IX and of the redox-stimulated transition of state VII to state X: Panel I, hydrogel in state VII and state VIII. Panel II, hydrogel in state VII and state IX. Panel III, hydrogel in state VII and state X. Panel I’ – Cyclic G’ and G’’ changes upon the reversible, ACS Paragon Plus Environment

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chemically triggered transitions between the hydrogels in states VII and VIII. Panel II’ – Cyclic G’ and G’’ changes upon the reversible, photoisomerization triggered transitions between the hydrogels in states VII and IX. Panel III’ –Cyclic G’ and G’’ changes upon the reversible, redox triggered transitions between the hydrogels in states VII and X. be transformed by three alternative signals to low-stiffness hydrogel states (18-crown-6 ether; Vis; redox stimuli). Indeed, rheometry experiments, Figure 5(B), confirm the reversible stiffness features of the different states of the hydrogel. Panel I, curves a and a’, show the G’ and G’’ of the hydrogel in state VII (G’ = 1230 Pa and G” = 170 Pa), and curves b and b’ show the G’ and G” values (G’ = 130 Pa and G” = 120 Pa) of the hydrogel in state VIII, low-stiffness hydrogel formed by treating the hydrogel in state VII with 18-crown-6 ether. The results indicate that the hydrogel in state VIII reveals low-stiffness as compared to the hydrogel in state VII, in agreement with the crosslinking of the hydrogel in state VIII only by the donor-acceptor interactions. As expected, the transition between the stiff hydrogel in state VII and in state VIII is cyclic and reversible in the presence of 18-crown-6 ether and K+ as triggers, Panel I’. In addition, Panel II shows the G’ and G” values (G’ = 940 Pa and G” = 110 Pa) of the hydrogel in state VII, curves a and a’, in comparison to the Vis photo-generated hydrogel in state IX, curves b and b’ (G’ = 140 Pa; G” = 10 Pa). Evidently, the hydrogel in state IX generated by the Vis irradiation of the hydrogel in state VII reveals lower stiffness, consistent with the bridging of state IX only by the K+-stabilized Gquadruplexes. Similarly, Figure 5(B), Panel II’ demonstrates that the cyclic irradiation of the hydrogel in state VII with UV/Vis light, transforms reversibly the hydrogel between high-stiffness and low-stiffness states, respectively. Finally, Figure 5(B) Panel III, curves a and a’, show the storage and loss moduli (G’ = 1280 Pa and G” = 140 Pa) of the hydrogel in state VII (high stiffness) in comparison to the G’, G” values (G’ = 260 Pa; G” = 20 Pa) of the hydrogel in state X, curves b and b’. Clearly, the hydrogel in state X, where the hydrogel is crosslinked only by the K+-stabilized G-quadruplex bridges, possesses substantially lower stiffness as compared to the hydrogel in state VII, that is cooperatively crosslinked by the donor-acceptor interactions and G-quadruplexes. As before, the cyclic oxidation of the hydrogel in state VII and the reverse reduction of the hydrogel in state X switch, reversibly, the hydrogel between high and low stiffness, Panel III’. SEM images of the respective hydrogels are presented to further support the triple-stimuli control over the stiffness of the different hydrogel states, Figure 6. The hydrogel in state VII exhibits high stiffness and reveals a highly small-pore crosslinked matrix. Treating the hydrogel in state VII to 18-crown-6 ether dissociates the K+-stabilized G-quadruplexes, resulting in a low-stiffness, quasi-liquid hydrogel that reveals significantly larger pores and a lower degree of crosslinking, state VIII. Illumination of the hydrogel in state VII with Vis light causes the dissociation of the dopamine/DTEc donor-acceptor interactions, resulting in the formation of the low-stiffness hydrogel, state IX. As



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compared to state VII, the hydrogel in state IX reveals larger pores and lower degree of crosslinking. Similarly, the separation of the dopamine/DTEc donor-acceptor interactions was achieved by the oxidation of dopamine to quinone with sodium persulfate, resulting in a low-stiffness hydrogel, state X, that shows larger pores and lower degree of crosslinking as compared to state VII.

Figure 6. SEM images corresponding to the hydrogels shown in Figure 5 (A). The cyclic and reversible interconversion between the high-stiffness hydrogel (state VII) and low-stiffness hydrogels via three different stimuli: K+/CE (state VII – state VIII); UV/Vis (state VII – state IX); Redox (state VII – state X). Shape-memory and Self-healing Properties of the Triple Responsive Hydrogel The control over the reversible stiffness properties of the hydrogels by using three different triggers (K+/crown ether; Vis/UV light; oxidation/reduction stimuli) provides a rich “toolbox” of triggers to design shape-memory hydrogels and self-healing hydrogel matrices. The multi-triggered design of the shapememory matrices is exemplified in Figure 7(A). The high-stiffness hydrogel, crosslinked by the dopamine/DTEc interactions and G-quadruplexes, was configured in a triangle-shaped mold. Subjected the extruded shaped hydrogel, state VII, to 18-crown-6 ether resulted in the dissociation of the Gquadruplexes while preserving the donor-acceptor interactions. This transformed the hydrogel into a lowstiffness, shapeless matrix including the donor-acceptor interactions as the internal memory code, which dictates the entanglement of the polymers and the spatial orientations of the G-quadruplex subunits. Treatment of the resulting low-stiffness, shapeless hydrogel, state VIII, with K+, generated the “memoryguided” bridging of the polymer scaffold by means of the two crosslinking motifs, leading to the


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regeneration of the stiff, triangle-shaped hydrogel (state VII). Similarly, irradiation of the stiff, triangleshaped hydrogel (state VII) with Vis light separates the donor-acceptor interactions and yields the shapeless, low stiffness hydrogel, state IX, that includes the G-quadruplex crosslinkers as the internal memory. The subsequent UV-stimulated irradiation of the shapeless, quasi-liquid hydrogel restores the dopamine/DTEc and the G-quadruplex-guided reformation of the triangle-shaped, stiff hydrogel, state VII.

Figure 7. (A) Shape-memory features of the triple-triggered, stimuli-responsive dopamine/DTEc and K+stabilized G-quadruplex crosslinked hydrogel in state VII. (B) Cyclic shape-memory guided transitions between the stiff, triangle-shaped and shapeless hydrogel systems using different triggering signals: Panel I – The chemically-stimulated cyclic transitions between the triangle shaped hydrogel in state VII and the shapeless hydrogel in state VIII that includes the dopamine/DTEc as the internal memory. Panel II – The light-induced cyclic and reversible transitions between the hydrogel in state VII and the hydrogel in state IX, including the G-quadruplex as the internal memory. Panel III – The redox-triggered cyclic and reversible transitions between the hydrogel in state VII and the hydrogel in state X, including the Gquadruplex as internal memory. In addition, the oxidation of the dopamine sites associated with the triangle-shaped, stiff hydrogel, state VII, resulted in the separation of the donor-acceptor interactions and the generation of a quasi-liquid, shapeless hydrogel matrix, state X, exhibiting low-stiffness, including the G-quadruplexes as the internal memory. The subsequent reduction of the quinone sites regenerates the dopamine/DTEc, G-quadruplex memory-guided formation of the trigangle-shaped stiff hydrogel, state VII. Figure 7(B) demonstrates the ACS Paragon Plus Environment


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shape-memory functions of the hydrogel triggered by the three stimuli. In Panel I, the triangle-shaped hydrogel, crosslinked by the donor-acceptor interactions and G-quadruplexes, is reversibly cycled between shapeless (state VIII) and triangle-shaped matrices (state VII) using crown ether and K+ as triggers. Panel II shows the light-induced reversible transitions of the triangle-shaped stiff hydrogel in state VII into the quasi-liquid shapeless hydrogel in state IX. In Panel III, the redox-triggered shapememory properties of the hydrogel are demonstrated. The multi-triggered hydrogel in state VII was further examined as a potential matrix exhibiting selfhealing properties, Figure 8. In these experiments, the hydrogel in its high-stiffness state (generated by the K+-stabilized G-quadruplexes and the dopamine/DTEc interactions) was cut into two pieces. These pieces were transformed, in the presence of the different stimuli, into the respective low-stiffness hydrogel states. The physical attachment of the low-stiffness hydrogel, followed by the application of the counter signals, resulted in the self-healed, intact, stiff hydrogel matrices. Figure 8(A) depicts the K+-induced selfhealing of the hydrogel. The stiff hydrogel was cut into two pieces that were treated with 18-crown-6 ether to yield the two low-stiffness hydrogel pieces crosslinked only by the dopamine/DTEc interactions. The physically connected pieces were subjected to K+ and this resulted in the integrated, self-healed hydrogel crosslinked by the K+-stabilized G-quadruplexes and the dopamine/DTEc interactions. Figure 8(B) shows the light-triggered self-healing of the hydrogel. In this experiment, the stiff hydrogel was photoisomerized with Vis light to yield the low-stiffness hydrogel, crosslinked only by the K+stabilized G-quadruplexes. The physical interconnection of the two pieces, followed by the UV irradiation, resulted in the self-healed, stiff hydrogel crosslinked by the K+-stabilized G-quadruplexes and the dopamine/DTEc interactions. Similarly, Figure 8(C) displays the redox activated self-healing properties of the hydrogel. The stiff hydrogel was cut into two pieces that were subjected to oxidation, by sodium persulfate, that transformed the dopamine into quinone residues. This process led to two pieces of low stiffness. The resulting two pieces were physically interconnected and treated with ascorbic acid as reducing agent, leading to the reduction of quinone residues to dopamine, resulting in the stiff, healed hydrogel, crosslinked by the dopamine/DTEc interactions and the K+-stabilized G-quadruplexes. The tensile force of the intact hydrogel crosslinked by the K+-stabilized G-quadruplexes and the redox-/photoresponsive dopamine/DTEc interactions, corresponded to 30-32 mN. In turn, the self-healed hydrogels consisting of the K+-induced recovery of the healed hydrogel (cf. Figure 8(a)), revealed a tensile force of 20-22 mN. The photo-induced self-healed hydrogel that involved the dopamine/DTEc crosslinking of the healed hydrogel (cf. Figure 8(b)), exhibited a tensile force of 18-20 mN. The redox-induced self-healing of the hydrogel, through the formation of the dopamine/DTEc interactions (cf. Figure 8(c)), showed a tensile strand that corresponded to 20-22 mN. The undamaged hydrogel and the self-healed hydrogels


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indicate the presence of soft matrices. The control experiments showed that, in the absence of the UV light, K+ or reducing agent, no self-healing performances were observed. Gentle shaking of the two pieces adduct resulted in the immediate separation of the pieces (Figure S11).

Figure 8. The triple-triggered, self-healing of the stiff hydrogel in state VII crosslinked by the Gquadruplexes and dopamine/DTEc interactions using (A) chemical triggers, (B) photochemical triggers or (C) redox triggers. Conclusion The study has introduced bipyridinium-dithienylethene (DTE) as a functional supramolecular unit for designing multi-stimuli responsive hydrogels. The different electron acceptor performances between the open and closed DTE photoisomers enabled the design of photo- and redox-responsive hydrogels exhibiting controlled stiffness properties, using donor-acceptor interactions as the triggering motifs. Carboxymethyl cellulose (CMC) chains modified with electron donating dopamine sites, and with the self-complementary nucleic acid (1) or half G-quadruplex (2) tethers, were used as the functional polymer scaffold for the formation of the stimuli-responsive hydrogels. Cyclic photoisomerization of DTE, redox reaction of dopamine, as well as, treatment with K+/crown ether reversibly switched the hydrogels between its high- and low-stiffness states, respectively.



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These stimuli-responsive hydrogels were applied to develop shape-memory and self-healing hydrogels. For the shape-memory matrices, the shaped, high-stiffness hydrogel was crosslinked by the photo- and redox-responsive donor-acceptor dopamine/DTEc interactions and the self-complementary duplex DNA or K+-stabilized G-quadruplexes. The light or redox-induced separation of the donor-acceptor interactions yielded the quasi-liquid, shapeless hydrogel of low-stiffness, where the self-complementary duplex DNA or the K+-stabilized G-quadruplex bridges provided the memory code for the regeneration of the shaped stiff hydrogel. Similarly, the crown ether-induced separation of the G-quadruplexes in the stiff hydrogel matrix yielded a low stiffness, shapeless hydrogel, where the dopamine/DTEc interactions acted as a memory code to regenerate the shaped, stiff hydrogel crosslinked by the dopamine/DTEc and Gquadruplexes. The multi-triggered suparmolecular DNA/bipyridinium dithienylethene hydrogels driven by light, redox and chemical stimuli introduce functional materials for different further applications. The control over the stiffness of the hydrogel by using any of the triggers could allow the synthesis of bilayer hydrogels that reveal stress-controlled mechanical properties38 or supramolecular machine functions, e.g. walkers.5 Such stimuli-responsive hydrogels could be used as actuators, sensors or robotic devices. In addition, the control over the stiffness of the hydrogel by using three different triggers could be a general model for the multi-triggered release of loads from hydrogels. Finally, by incorporating nanoparticles into the hydrogels, further control of the stiffness of the stimuli-responsive hydrogels could be achieved. Such materials could be of value for the light, redox or chemical stimuli-guided, dictated growth of cells. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT


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