Guest-responsive supramolecular hydrogels expressing selective sol–gel transition for sulfated glycosaminoglycans

ABSTRACT This paper describes the stimuli-responsive hydrogels constructed from bola-type amphiphiles composed of two dipeptides containing phenylalanine attached to the ends of a

hydrophobic tetrathiophene. The hydrogel formation ability of the amphiphiles was affected by the _N_-terminal amino acid residue, which is an amphiphile-possessing phenylalanine-lysine

sequence that formed a hydrogel under limited pH conditions. Gel formation occurred because of the phase transition of the gelator assembly from a granular aggregate to a fibrous

architecture, in a process controlled by pH. This stimuli-responsive sol–gel transition was also accomplished by the addition of an anionic polymer, and sulfated glycosaminoglycans were

successfully discriminated using the hydrogel system. You have full access to this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS HOMOPOLYMER SELF-ASSEMBLY

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BEHAVIORS Article 08 April 2022 INTRODUCTION In recent years, the construction of stimuli-responsive supramolecular hydrogels and their application as biomaterials (e.g., drug delivery

systems, biosensors, and tissue engineering) have been widely investigated because of their biocompatibility and low toxicity [1,2,3,4,5,6,7]. Among hydrogels, the development of

peptide-appended supramolecular hydrogelators has been actively conducted as an effective strategy for the construction of intelligent soft materials with remarkable functions [8,9,10]

because the functional properties of peptides can be easily tuned by changing the suitable peptide sequences. From a synthetic viewpoint, minimization of the peptide chain length on the

supramolecular gelator is desirable; thus, examples of a functional supramolecular hydrogelator containing a peptide shorter than three amino acid residues have been reported [11, 12]. More

recently, it has been reported that dipeptides containing phenylalanine can endow functional building blocks with hydrogel formation [13,14,15,16,17,18]. Self-assembled π-conjugated

hydrogels are expected to show phase transitions (e.g., sol–gel or swelling–shrinking interconversion) and spectral and electrochemical changes in response to external stimuli. Because

various readouts can be realized, a π-conjugated supramolecular gel is a promising material for constructing a high-performance sensing system that can accurately identify a target

substance. Therefore, sensing studies using a supramolecular gel composed of a π-conjugated skeleton [19,20,21,22] (e.g., pyrene [23, 24], naphthalene [25,26,27], anthracene [28], and

oligophenylenevinylene [29,30,31]) have been performed. Because oligothiophenes are also effective molecular skeletons for the formation of one-dimensional supramolecular aggregates by

noncovalent π–π stacking [32], molecular recognition studies based on oligothiophene supramolecular gels have been conducted [33, 34]. In this study, we synthesized bola-type amphiphilic

molecules in which dipeptides containing phenylalanine were introduced at both ends of the tetrathiophene skeleton (Fig. 1), and their hydrogel formation ability was evaluated. Furthermore,

the ability to discriminate anionic polysaccharides (Fig. 1) was examined using the cationic bola-type amphiphile Th4-FK. Thus, it was confirmed that Th4-FK underwent a phase transition from

a granular aggregate to a fibrous architecture as a result of not only the pH change but also the addition of chondroitin sulfate C (CS-C) or heparin (Hep). On the basis of this

stimuli-responsive phase transition, guest-induced hydrogel formation was successfully performed. Because hydrogel formation does not progress by the addition of sulfate-free polysaccharides

or an artificial polymer, the supramolecular hydrogel can discriminate sulfated glycosaminoglycans by gel formation behavior. MATERIALS AND METHODS REAGENTS AND INSTRUMENTS Chemical

reagents were purchased from suppliers such as Tokyo Chemical Industry Co., Wako Pure Chemicals Ltd, and Sigma-Aldrich Co. Compound 1 was synthesized according to the literature [33]. 1H-NMR

spectra were acquired on a JEOL JNM-ESC400 spectrometer in DMSO-d6 at 400 MHz. Mass spectra were recorded on a Bruker Autoflex II spectrometer. Circular dichroism (CD) spectra were

collected on a JASCO J-820 spectrometer. Dynamic viscoelasticity measurements were performed using TA instruments Discovery HR-2. SEM observations were carried out on a Keyence VE-9800.

SYNTHESIS OF SUPRAMOLECULAR HYDROGELATOR CANDIDATES TH4-FX The synthetic cascade of the supramolecular hydrogelator candidates is shown in Scheme 1, and the analytical data of the

synthesized molecules are provided in the supplementary information. SYNTHESIS OF 2 HBTU (1.86 g, 4.8 mmol) was added to a DMF (25 mL) solution of 1 (800 mg, 1.6 mmol) with

_N_-(tert-butoxycarbonyl)-1,2-diaminoethane (770 mg, 4.8 mmol) and DIPEA (0.7 mL, 4.8 mmol). The mixture was stirred at room temperature for 1 day. The resulting mixture was evaporated to

dryness under reduced pressure, and the residue was washed with aqueous NaHCO3 and water. After filtration and drying under vacuum, 2 was obtained as an orange solid in 44% yield (560 mg).

SYNTHESIS OF 3 To a solution of 2 (560 mg, 0.71 mmol) in CHCl3 (30 mL) was added trifluoroacetic acid (TFA, 4 mL). The solution was then stirred at room temperature for 4 h. The reaction

mixture was evaporated under reduced pressure to give an orange solid. This residue was mixed with HBTU (678 mg, 1.75 mmol), Fmoc-Phe-OH (665 mg, 1.75 mmol), and DIPEA (1 mL, 7.5 mmol) in

DMF (50 mL), and then this mixture was stirred at room temperature for 1 h. The resulting mixture was evaporated to dryness under reduced pressure, and the residue was washed with aqueous

NaHCO3 and water. After filtration and drying under vacuum, 3 was obtained as an orange solid in 89% yield (836 mg). GENERAL PROCEDURE FOR THE SYNTHESIS OF TH4-FX To a solution of 3 (836 mg,

0.63 mmol) in CH2Cl2 (80 mL) was added piperidine (20 mL). The solution was then stirred at room temperature for 4 h. The reaction mixture was evaporated under reduced pressure, and the

residue was washed with ethyl acetate and CHCl3, filtered, and dried under vacuum to give an orange solid. The resulting residue was mixed with HBTU (348 mg, 0.9 mmol), DIPEA (0.14 mL, 0.9 

mmol), and a corresponding Boc or Fmoc amino acid (0.7 mmol) in DMF (50 mL). This mixture was stirred at room temperature for 10 min and then evaporated to dryness under reduced pressure.

The residue was washed with aqueous NaHCO3 and water, filtered, and dried under vacuum to give an orange solid. As a deprotection reaction, this crude product was treated with TFA (2 mL) in

CHCl3 (20 mL) at room temperature for 2 h. The reaction mixture was evaporated under reduced pressure, and the residue was purified by washing with ethyl acetate or precipitation to give

Th4-FX. HYDROGEL FORMATION STUDY Th4-FX (2 mg) was mixed with 200 μL of water in a vial (the concentration of Th4-XY; 1 wt%, 8.8 mM). The resulting mixture was acidified by the addition of

0.1 M HCl aq. until a transparent solution was formed, and then the pH value of the mixture was gradually changed by the addition of 0.1 M NaOH aq. to promote the formation of a hydrogel. If

hydrogel formation was not observed under any pH conditions, thermal gelation of the mixture was attempted at each pH condition. The gelation state of the materials was evaluated by

assessing whether it was stable to inversion of the vial. RESULTS AND DISCUSSION PH-RESPONSIVE HYDROGEL FORMATION STUDY The gelation behavior of the tetrathiophene derivatives Th4-FX was

evaluated in aqueous media, and the results of the gelation study are summarized in Table 1. It was confirmed that tetraamino-type Th4-FK with a lysine residue at both ends of the molecule

formed a weak opaque hydrogel under a basic pH range of pH 9.5–10.5. However, Th4-FK dissolved in water at pH values lower than 9.5 and strongly aggregated under stronger basic conditions

(pH > 10). Thus, it was revealed that moderate protonation of the four amino groups on Th4-FK was important for hydrogel formation. Th4-FD with amphoteric terminals formed a transparent

solution at pH < 8.0, a viscous aqueous solution in the range of pH 8.0–9.5, and a suspension at pH > 9.5. However, Th4-FS and Th4-FY, which contain moderately hydrophilic dipeptides,

did not dissolve in water under any pH conditions. Although they dissolved when their aqueous mixture was heated, they precipitated after the mixture was cooled to room temperature. Th4-FF

with a phenylalanine dimer showed low water solubility, and neither pH adjustment nor the heating–cooling process resulted in hydrogel formation. This gelation behavior of bola-type

amphiphiles Th4-FX indicates that the dipeptide composed of phenylalanine and a highly hydrophilic amino acid is the effective peptide sequence that endowed the strongly hydrophobic

tetrathiophene unit with hydrogel formation ability. Because a dipeptide is the shortest peptide chain, this finding should be useful for developing a supramolecular hydrogelator containing

a π-conjugated hydrophobic unit owing to its synthetic advantage. DYNAMIC VISCOELASTICITY MEASUREMENT When a hydrogel of Th4-FK was heated, weakening of the physical strength and subsequent

volume shrinkage of the hydrogel were visually observed with an increase in the temperature. Therefore, we next evaluated the strain and temperature dependence of the dynamic viscoelasticity

of the Th4-FK hydrogel (Fig. 2). Because the value of the storage modulus _G_′ is always higher than the value of the loss modulus _G_″ in the tested temperature range, as shown in Fig. 2b,

it is confirmed that the Th4-FK hydrogel maintains its gel state regardless of the temperature. In the temperature region of 20–45 °C, _G_′ and _G_″ gradually decreased, and the value of

the loss factor tan _δ_ (=_G_″/_G_′) increased with increasing temperature. This indicates that the phase transition from the gel to the sol state occurred gradually in this temperature

region. However, when the temperature exceeded 45 °C, both _G_′ and _G_″ increased and tan _δ_ decreased with an increase in the temperature, which indicated that the gel state was

strengthened when the temperature increased in this temperature region. The thermoresponsive macroscopic volume contraction of the hydrogel was observed as mentioned above. Therefore, we

considered that the enhancement of the gel state in the higher temperature region was due to the contraction of the three-dimensional network of the hydrogel. CIRCULAR DICHROISM (CD)

SPECTRAL STUDY AND SCANNING ELECTRON MICROSCOPY (SEM) OBSERVATION To evaluate the mechanism of the pH-dependent formation of the Th4-FK hydrogel, changes in the aggregation state of Th4-FK

upon a pH change from 4 to 12 were evaluated by CD spectroscopy and SEM. Figure 3a shows the pH-dependent CD spectral change of the Th4-FK aqueous solution ([Th4-FK] = 22 μM). No significant

CD signal was observed at pH < 6, whereas a CD signal with a negative maximum at ~370 nm and a positive maximum at ~410 nm was observed in the pH range of 6–8. Because the formation of a

granular aggregate of Th4-FK at pH 6.6 was confirmed by SEM observations, as shown in Fig. 4a, the CD signal is attributed to the granular aggregate of Th4-FK. When the pH value of the

mixture reached the range of 8.5–10, the aqueous Th4-FK solution gave rise to a CD spectrum with a positive absorption band at ~345 nm and a negative absorption band at ~375 nm, and the

gelator formed a fibrous architecture (Fig. 4b). These results imply that the aggregate of Th4-FK underwent a phase transition from granular aggregate to a fibrous architecture in response

to the pH change, and the supramolecular fibers became entangled to form a three-dimensional network that caused hydrogel formation. DISCRIMINATION STUDY OF ANIONIC BIOMACROMOLECULES

Utilizing such an external stimuli-responsive transition of the aggregation state, we next examined the discrimination of anionic polysaccharides using a Th4-FK aqueous solution (8.8 mM).

Th4-FK was dissolved in water, and the pH of the resulting solution was adjusted to induce formation of a granular aggregate of Th4-FK. The anionic polymer [e.g., CS-C, Hep, hyaluronic acid

(HA), polyglutamine acid (p-Glu)] was added to the aqueous solution, and the guest-induced CD spectral change was monitored. As shown in Fig. 5a, when CS-C, a glycosaminoglycan containing

one sulfate group and one carboxyl group on the repeating disaccharide unit, was added to the Th4-FK solution, the CD signal attributed to the granular aggregate gradually changed to that

attributed to the fibrous architecture. This result suggests that CS-C triggers the phase transition of the Th4-FK aggregate, which results in the formation of a fibrous supramolecular

assembly. This spectral change was saturated when the concentration of CS-C reached 6.0 μM (as a repeating disaccharide unit). Then, the CD intensity of the fibrous complex gradually

decreased while maintaining the spectral shape when the concentration of CS-C exceeded 9.0 μM. By adding an excess of CS-C, precipitation of the CS-C/Th4-FK assembly was visually observed.

Thus, the decrease in CD intensity is attributed to the formation of the polyion complex between polyanionic CS-C and the polycationic supramolecular polymer of Th4-FK. A similar

guest-induced CD spectral change was observed when Hep, another glycosaminoglycan possessing three sulfate groups and one carboxyl group on the repeating disaccharide unit, was introduced as

a guest polymer (Fig. SI-1). However, when HA or p-Glu was added to the aqueous Th4-FK solution under the same conditions, the CD spectra of the mixtures were intensified while maintaining

the spectral shape, which is attributed to the granular aggregate (Figs. 5b, SI-2). A similar spectral change was also observed when CS-C or Hep was applied as a guest polymer at pH 5.4

(Fig. SI-3). Thus, these results indicate that the formation of a fibrous aggregate of Th4-FK is promoted by the addition of glycosaminoglycans possessing a sulfate group under suitable pH

conditions. As shown in Fig. 5c, the change of CD intensity at 350 nm by the addition of CS-C or Hep reached a plateau at [CS-C] = 10 mM, [Hep] = 6.0 mM, respectively. This suggests that the

affinity between the Th4-FK aggregate and glycosaminoglycan depends on the number of sulfate groups on the guest polymer. However, because the shapes of the CD spectra for Th4-FK/CS-C and

Th4-FK/Hep are identical (Fig. SI-1), the aggregation state of Th4-FK in the fibrous assembly does not depend on the type of guest polymer. GUEST-INDUCED HYDROGEL FORMATION STUDY As

described above, the phase transition from granular aggregates to a fibrous architecture controlled by pH is a key process of pH-responsive hydrogel formation expressed by Th4-FK.

Furthermore, a similar phase transition was also induced by assembling the Th4-FK aggregate with the anionic polysaccharides. Thus, we next demonstrated the guest-selective sol–gel

transition by utilizing Th4-FK. An aqueous mixture containing 2 wt% (17.6 mM) Th4-FK formed a transparent solution, i.e., sol state, at pH 6.6. Under this condition, the mixture showed a CD

spectrum (Fig. 6a) that had a different shape than that observed for the lower concentration (22 μM). Moreover, the formation of a fibrous aggregate was revealed by SEM (Fig. 7a). After the

addition of CS-C (10 mM), the mixture spontaneously formed a shrunken gel (Fig. 6b). Because the shape of the CD spectrum of the resulting hydrogel (Fig. 6a) was similar to that of the

fibrous architecture constructed under the solution conditions (Fig. 5a), it was suggested that this sol–gel phase transition was caused by the reorganization of fibrous aggregates and the

formation of cross-linked structures by complexation with CS-C. The SEM images of the hydrogel showed a film-like assembly that may be attributed to the bundling of the fibrous architecture

of Th4-FK/CS-C (Fig. 7b). A similar guest-induced sol–gel transition was induced by the addition of Hep. In contrast, hydrogel formation was not observed when HA or p-Glu was added to the

sol, even at concentrations of up to 20 mM, and the mixtures showed the modest CD spectral changes. Therefore, the discrimination of anionic polysaccharides was successfully accomplished by

the guest-selective sol–gel phase transition using the Th4-FK hydrogel. CONCLUSION In conclusion, bola-type amphiphiles containing a π-conjugated tetrathiophene unit were synthesized as

supramolecular hydrogelator candidates, and a dipeptide composed of phenylalanine and lysine residues was determined to be an effective peptide sequence to endow the strongly hydrophobic

tetrathiophene unit with hydrogel formation ability. The hydrogel of Th4-FK underwent a pH- and guest-induced sol–gel transition that is based on the phase transition from the granular

aggregate to the fibrous architecture of the gelator. Using this stimuli-responsiveness, the hydrogel system was successfully applied to the selective discrimination of glycosaminoglycans

composed of a sulfated sugar unit. We believe that these findings will be useful for developing a biosensor system that is based on stimuli-responsive supramolecular hydrogels by minimizing

the synthetic disadvantages. REFERENCES * Aida T, Meijer EW, Stupp SI. Functional supramolecular polymers. Science. 2012;335:813–7. Article  CAS  Google Scholar  * Tovar JD. Supramolecular

construction of optoelectronic biomaterials. Chem Res. 2013;46:1527–37. Article  CAS  Google Scholar  * Shigemitsu H, Hamachi I. Design strategies of stimuli-responsive supramolecular

hydrogels relying on structural analyses and cell-mimicking approaches. Acc Chem Res. 2017;50:740–50. Article  CAS  Google Scholar  * Li J, Mooney DJ. Designing hydrogels for controlled drug

delivery. Nat Rev Mater. 2016;1:16071. Article  CAS  Google Scholar  * Bhattarai N, Gunn J, Zhang M. Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev.

2010;62:83–99. Article  CAS  Google Scholar  * Zhang S. Fabrication of novel biomaterials through molecular self-assembly. Nat Biotechnol. 2003;21:1171–8. Article  CAS  Google Scholar  *

Zhou J, Li J, Du X, Xu B. Supramolecular biofunctional materials. Biomaterials. 2017;129:1–27. Article  CAS  Google Scholar  * Makama P, Gazit E. Minimalistic peptide supramolecular

co-assembly: expanding the conformational space for nanotechnology. Chem Soc Rev. 2018;47:3406–20. Article  Google Scholar  * Fleming S, Ulijn RV. Design of nanostructures based on aromatic

peptide amphiphiles. Chem Soc Rev. 2014;43:8150–77. Article  CAS  Google Scholar  * Ma M, Kuang Y, Gao Y, Zhang Y, Gao P, Xu B. Aromatic-aromatic interactions induce the self-assembly of

pentapeptidic derivatives in water to form nanofibers and supramolecular hydrogels. J Am Chem Soc. 2010;132:2719–28. Article  CAS  Google Scholar  * Zhang Y, Gu H, Yang Z, Xu B.

Supramolecular hydrogels respond to ligand-receptor interaction. J Am Chem Soc. 2003;125:13680–1. Article  CAS  Google Scholar  * Berdugo C, Nalluri SKM, Javid N, Escuder B, Miravet JF,

Ulijn RV. Dynamic peptide library for the discovery of charge transfer hydrogels. ACS Appl Mater Interfaces. 2015;7:25946–54. Article  CAS  Google Scholar  * Ikeda M. Stimuli-responsive

supramolecular systems guided by chemical reactions. Polym J. 2019;51:371–80. Article  CAS  Google Scholar  * Mahler A, Reches M, Rechter M, Cohen S, Gazit E. Rigid, self-assembled hydrogel

composed of a modified aromatic dipeptide. Adv Mater. 2006;18:1365–70. Article  CAS  Google Scholar  * Raeburn J, Mendoza-Cuenca C, Cattoz BN, Little MA, Terry AE, Cardoso AZ, et al. The

effect of solvent choice on the gelation and final hydrogel properties of Fmoc–diphenylalanine. Soft Matter. 2015;11:927–35. Article  CAS  Google Scholar  * Martin AD, Wojciechowski JP,

Warren H, in het Panhuisb M, Thordarson P. Effect of heterocyclic capping groups on the self-assembly of a dipeptide hydrogel. Soft Matter. 2016;12:2700–7. Article  CAS  Google Scholar  *

Ikeda M, Tanida T, Yoshii T, Hamachi I. Rational molecular design of stimulus-responsive supramolecular hydrogel based on dipeptides. Adv Mater. 2011;23:2819–22. Article  CAS  Google Scholar

  * Ikeda M, Tanida T, Yoshii T, Kurotani K, Onogi S, Urayama K, et al. Installing logic-gate response to a variety of biological substances in supramolecular hydrogel-enzyme hybrids. Nat

Chem. 2014;6:511–8. Article  CAS  Google Scholar  * Sukumaran SB, Vakayil KP, Ajayaghosh A. Functional π-gelators and their applications. Chem Rev. 2014;114:1973–2129. Article  Google

Scholar  * Kang S, Lee M, Lee D. Weak links to differentiate weak bonds: size-selective response of π-conjugated macrocycle gels to ammonium ions. J Am Chem Soc. 2019;141:5980–6. Article 

CAS  Google Scholar  * Li Y, Duan P, Liu M. Solvent-regulated self-assembly of an achiral donor-acceptor complex in confined chiral nanotubes: chirality transfer, inversion and

amplification. Chem Eur J. 2017;23:8225–31. Article  CAS  Google Scholar  * Tovar JD. Supramolecular construction of optoelectronic biomaterials. Acc Chem Res. 2013;46:1527–37. Article  CAS

  Google Scholar  * Singha N, Srivastava A, Pramanik B, Ahmed S, Dowari P, Chowdhuri S, et al. Unusual confinement properties of a water insoluble small peptide hydrogel. Chem Sci.

2019;10:5920–8. Article  CAS  Google Scholar  * Pramanik B, Ahmed S, Singha N, Das BK, Dowari P, Das D. Unorthodox combination of cation-π and charge-transfer interactions within a

donor-acceptor pair. Langmuir. 2019;35:478–88. Article  CAS  Google Scholar  * Pati C, Ghosh K. Aryl ethers decorated gallic acid-naphthalimide conjugate: aggregation and sensing towards

amines and F-. Supramol Chem. 2019;31:732–44. Article  CAS  Google Scholar  * Schmuck C, Samanta K, Ehlers M. Two-component self-assembly: hierarchical formation of pH-switchable

supramolecular networks by pi-pi induced aggregation of ion pairs. Chem Eur J. 2016;22:15242–7. Article  CAS  Google Scholar  * Chen Y, Gong G, Fan Y, Zhou Q, Zhang Q, Yao H, et al. A novel

AIE-based supramolecular polymer gel serves as an ultrasensitive detection and efficient separation material for multiple heavy metal ions. Soft Matter. 2019;15:6878–84. Article  CAS  Google

Scholar  * Dawn A, Shiraki T, Ichikawa H, Takada A, Takahashi Y, Tsuchiya Y, et al. Stereochemistry-dependent, mechanoresponsive supramolecular host assemblies for fullerenes: a

guest-induced enhancement of thixotropy. J Am Chem Soc. 2012;134:2161–71. Article  CAS  Google Scholar  * Samanta SK, Dey N, Kumari N, Biswakarma D, Bhattacharya S. Multimodal ion sensing by

structurally simple pyridine-end oligo p-phenylenevinylenes for sustainable detection of toxic industrial waste. ACS Sustain Chem Eng. 2019;7:12304–14. Article  CAS  Google Scholar  * Xue

P, Yao B, Ding J, Shen Y, Wang P, Lu R, et al. Strong fluorescence film of dicyano oligo(p-phenylenevinylene) supramolecular gel for aromatic amine vapors detection. Chem Sel. 2017;2:2841–6.

CAS  Google Scholar  * Bhattacharjee S, Bhattacharya S. Pyridylenevinylene based Cu2+-specific, injectable metallo(hydro)gel: thixotropy and nanoscale metal-organic particles. Chem Commun.

2014;50:11690–3. Article  CAS  Google Scholar  * Liyanage W, Ardona HAM, Mao HQ, Tovar JD. Cross-linking approaches to tuning the mechanical properties of peptide π-electron hydrogels.

Bioconj Chem. 2017;28:751–9. Article  CAS  Google Scholar  * Sobczuk AA, Tsuchiya Y, Shiraki T, Tamaru SI, Shinkai S. Creation of chiral thixotropic gels through a crown-ammonium interaction

and their application to a memory-erasing recycle system. Chem Eur J. 2012;18:2832–8. Article  CAS  Google Scholar  * Sobczuk AA, Tamaru SI, Shinkai S. New strategy for controlling the

oligothiophene aggregation mode utilizing the gel-to-sol phase transition induced by crown-alkali metal interactions. Chem Commun. 2011;47:3093–5. Article  CAS  Google Scholar  * Kyte J,

Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982;157:105–32. Article  CAS  Google Scholar  * Hopp TP, Woods KR. Prediction of protein

antigenic determinants from amino acid sequences. Proc Natl Acad Sci USA. 1981;78:3824–8. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS We sincerely thank Prof. Hirotaka

Ihara, Prof. Makoto Takafuji, and Prof. Yutaka Kuwahara for their kind assistance with the dynamic viscoelasticity measurements. This work was supported by JSPS Grants-in-Aid for Scientific

Research C (18K05067, 17K05848). The authors would like to thank Enago (www.enago.jp) for the English language review. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of

Nanoscience, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto, 860-0082, Japan Naofumi Kuroda, Yukie Tounoue, Kouichiro Noguchi, Yutaro Shimasaki, Hitoshi Inokawa & Shun-ichi Tamaru *

TA Instruments Japan Inc, 5-2-4, Nishigotanda Lexington Plaza Nishigotanda 6f, Shinagawa-ku, 141-0031, Japan Masayoshi Takano * Institute for Advanced Study, Kyushu University, 744 Moto-oka,

Nishi-ku, Fukuoka, 819-0395, Japan Seiji Shinkai Authors * Naofumi Kuroda View author publications You can also search for this author inPubMed Google Scholar * Yukie Tounoue View author

publications You can also search for this author inPubMed Google Scholar * Kouichiro Noguchi View author publications You can also search for this author inPubMed Google Scholar * Yutaro

Shimasaki View author publications You can also search for this author inPubMed Google Scholar * Hitoshi Inokawa View author publications You can also search for this author inPubMed Google

Scholar * Masayoshi Takano View author publications You can also search for this author inPubMed Google Scholar * Seiji Shinkai View author publications You can also search for this author

inPubMed Google Scholar * Shun-ichi Tamaru View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Shun-ichi Tamaru.

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hydrogels expressing selective sol–gel transition for sulfated glycosaminoglycans. _Polym J_ 52, 939–946 (2020). https://doi.org/10.1038/s41428-020-0341-x Download citation * Received: 25

January 2020 * Revised: 16 March 2020 * Accepted: 16 March 2020 * Published: 23 April 2020 * Issue Date: August 2020 * DOI: https://doi.org/10.1038/s41428-020-0341-x SHARE THIS ARTICLE

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