Design Strategies of Stimuli-Responsive Supramolecular HydrogelsRelying on Structural Analyses and Cell-Mimicking ApproachesPublished as part of the Accounts of Chemical Research special issue “Stimuli-Responsive Hydrogels”.

Hajime Shigemitsu† and Itaru Hamachi*,†,‡

†Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura,Kyoto 615-8510, Japan‡Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 5 Sanbancho, Chiyoda-ku,Tokyo 102-0075, Japan

CONSPECTUS: Stimuli-responsive hydrogels are intriguingbiomaterials useful for spatiotemporal controlled release ofdrugs, cells, and biological cues, cell engineering for variousapplications, and medical diagnosis. To date, many physical andchemical stimuli-responsive polymer hydrogels have beendeveloped by chemical modification of polymer chains andcross-linking points. In particular, conjugation with biomole-cules to polymers produced promising biomolecule-responsivehydrogels. These examples clearly indicate high potentialsof stimuli-responsive hydrogels as promising biomaterials.In addition to polymer hydrogels, supramolecular hydrogelsformed by the assembly of small molecules (hydrogelators) vianoncovalent interactions have also been regarded as unique andpromising soft materials due to their flexible programmability in rendering them stimuli-responsive with the larger macroscopicchange (i.e., gel−sol transition).This Account describes our strategies for the rational design of stimuli-responsive supramolecular hydrogels and their biologicalapplications. Following the detailed structural analysis of a lead hydrogelator that clearly indicates the appropriate sites forincorporation of stimuli-responsive modules, we designed supramolecular hydrogels capable of responding to simple physical(thermal and light) and chemical (pH and metal ions) stimuli. More importantly, biomolecule-responsive hydrogels weresuccessfully developed by supramolecularly mimicking the complex yet well-ordered structures and functions of live cellscontaining multiple components (a cell-mimicking approach). Development of biomolecule-responsive supramolecular hydrogelshas been difficult as the conventional strategy relies on the chemical incorporation of stimuli-responsive modules, owing to thelack of modules that can effectively respond to structurally diverse and complicated biomolecules. Inspired by natural systemswhere functional compartments (e.g., cell organelles) sophisticatedly interact with each other, we sought to integrate the twodistinct microenvironments of supramolecular hydrogels (the aqueous cavity surrounded by fibers and the fluidic hydrophobicfiber domain) with other functional materials (e.g., enzymes, peptides or proteins, fluorescent chemosensors, or inorganic porousor layered nanomaterials) for biomolecule responses. In situ fluorescence microscopy imaging clearly demonstrated that chemicalisolation and crosstalk are highly successful between the integrated microenvironments in supramolecular hydrogels, similar toorganelles in living cells, which allow for the construction of unique optical response and sensing systems for biomolecules.Furthermore, programmed hybridization of our chemically reactive hydrogels with appropriate enzymes can provide anunprecedented universal platform for biomolecule-degradable supramolecular hydrogels. Such biomolecule-responsive hydrogelsare a potentially promising tool for user-friendly early diagnostics and on-demand drug-releasing soft materials. We expect thatour rational design strategies for stimuli-responsive supramolecular hydrogels by modification of chemical structures andhybridization with functional materials will inspire scientists in various fields and lead to development of novel soft materials forbiological applications.

1. INTRODUCTIONStimuli-responsive hydrogels have attracted much attention notonly owing to interests in fundamental science but because oftheir potential for a wide range of biological and biomedicalapplications, such as drug delivery systems, regenerativemedicines, cancer therapy, and diagnosis.1−4 Selective and

efficient stimuli response of hydrogels to a particular conditionor molecule is anticipated to allow for the selective release of adrug or biological cue under biological crude conditions (i.e., in

Received: February 3, 2017Published: March 2, 2017

Article

pubs.acs.org/accounts

© 2017 American Chemical Society 740 DOI: 10.1021/acs.accounts.7b00070Acc. Chem. Res. 2017, 50, 740−750

cells, in culture media, in vivo) and the naked-eye detection ofdisease biomarkers without expensive analytical instruments.Additionally, a new strategy for cancer therapy by hydrogelationhas recently emerged.5,6 Many stimuli-responsive polymerhydrogels have been developed for biological applications.7

Chemical modification of polymer chains and cross-linkersproduced various physical and chemical stimuli-responsivepolymer-based hydrogels.8 Also, biomolecule-responsive poly-mer hydrogels have been developed by conjugation withpolymers and biomolecules.9−12 These successful examples ofstimuli-responsive hydrogels clearly indicate their potential aspromising biomaterials.Besides polymer hydrogels, supramolecular hydrogels con-

sisting of small molecules (hydrogelators) have been activelydeveloped and are now recognized as unique and promising softmaterials, owing to their high and flexible programmability inlending them stimuli responsiveness.13−16 It is generally acceptedthat hydrogelators assemble to form nanofibers, which is criticalfor supramolecular hydrogelation. This fiber formation is drivenby a variety of noncovalent interactions such as hydrogen-bonding (H-bonding), hydrophobic, van der Waals, and π/πinteractions. The delicate balance between these noncovalentinteractions can readily modulate the resultant self-assembledstructures, which sensitively affects the hydrogelation. The closeconnection between the gelator structure and macroscopicproperties of the resultant hydrogel should enable one torationally design and tune the properties of stimuli-responsivehydrogels at the small molecule level. In addition, the preparationprotocol of supramolecular hydrogels is largely different fromthat of conventional polymer-based hydrogels that often requirepolymerization in the presence of adducts such as initiators and

cross-linkers. In the case of supramolecular hydrogels, no adductsare required and the operations (e.g., heating and cooling, simpleinjection of hydrogelator to aqueous solution, or ultrasoundtreatment) are quite easy for gelation. This is regarded as animportant advantage of supramolecular hydrogelators forbiological applications.To date, many supramolecular hydrogels have been reported

to exhibit response to stimuli such as heat, pH, metal ions, andlight, and these have been applied to cell cultures, control ofdrug release, and so on. These are usually designed through theinsertion of an appropriate stimuli-responsive group into thehydrogelator scaffold. Given the relationship between the gelatorstructure and the gelation properties, it was reasonably expectedthat a structural perturbation of the gelator given by a stimulusmay cause macroscopic gel−sol or sol−gel changes. However,the employed stimuli have been rather simple so far. The moresophisticated supramolecular hydrogels able to respond tocomplex biomolecules (i.e., bioactive vitamin, saccharides,DNA, RNA, and noncatalytic proteins) are still limited anddifficult to construct,13 while a few enzyme-responsive hydro-gels have been reported by several research groups.17−21

A major obstacle for the development of biomolecule-responsive hydrogels may be the poor molecular recognitioncapability of synthetic molecules as stimuli-responsive groups,and thus it is difficult to find a suitable module capable ofdiscriminating a target molecule among diverse nontargets inthe context of hydrogelator design. Moreover, time-consum-ing efforts are required for incorporating the modules intothe supramolecular hydrogelator, even if stimuli-responsive(molecular recognition) modules with high affinity andselectivity are developed. Therefore, an alternative and more

Figure 1. A combinatorial screening for the development of supramolecular hydrogelators based on solid-phase synthesis.

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general approach is required for the creation of biomolecule-responsive supramolecular hydrogels.Based on our successful examples, we herein describe a few

strategies for the rational design of stimuli-responsive supra-molecular hydrogels composed of lipid mimetic or short peptide-based gelators. One of the strategies substantially relies onthe detailed structural analyses of the supramolecular fibers,a fundamental element of supramolecular hydrogels, and theclear characterization of the two different microenvironmentsinside of the hydrogels. We initially discovered a few supra-molecular hydrogelators comprising lipid-like molecules using acombinatorial screening approach.22−26 The molecular packingresolved by X-ray analysis led to rationally modifying thehydrogelators in order to exhibit stimuli-responsiveness for metalions, pH, and light.27−30 In situ confocal fluorescence microscopyobservation also revealed that two distinct microenvironmentsexist in the supramolecular hydrogels: an aqueous cavity surroundedby self-assembled nanofibers and the hydrophobic domains of theirfiber’s interior.31,32 These proved to be useful for optical response/sensing and chemical (enzymatic) reactions in the hydrogels.Our strategy is also inspired by natural systems such as

living cells, an ultimately complex and sophisticated soft materialcomposed of numerous multiple functional components made ofprotein, lipid, DNA/RNA, etc. Knowledge about living cells hasinspired us to hybridize our supramolecular hydrogels with manysynthetic or biological molecules bearing various structures andfunctions. We expected that controlling and facilitating thecrosstalk between these multiple components could providebiomolecule responses to the hybrid supramolecular hydrogels.A myriad of organic compounds, metal ions, inorganic materials,biological small molecules, and biopolymers were integrated withthe supramolecular hydrogels without loss of function.33

Interestingly, many small molecules are mobile between two(or more) different microenvironments, so that the opticalresponse was effective. Finally, we demonstrated that rational

coupling of enzymatic reactions with chemically reactive hydro-gelators allowed us to design intelligent supramolecular hydro-gels exhibiting unprecedented gel−sol transition in response todisease-related small molecules (biomarkers).34−36

2. RATIONAL MOLECULAR DESIGN FORSTIMULI-RESPONSIVE SUPRAMOLECULARHYDROGELS BASED ON LIPID-LIKE MOLECULES

It has long been known that some molecules with low molecularweights form hydrogels, and the majority of such hydrogelatorswere discovered serendipitously.37 In the last two decades,powerful methods for analyzing nanostructures (e.g., electronand atomic force microscopies) revealed that fibrous self-assembled structures and their entangled 3-D networks play animportant role in hydrogelation.38 Despite structural analysis,rational design of supramolecular hydrogelators ab initio wasdifficult. This is because the delicate balance among pluralnoncovalent intermolecular interactions essential for hydro-gelation is unpredictable in aqueous media. Therefore, we firstdecided to explore a hydrogelator by a combinatorial screeningapproach using a library of synthetic lipid-like molecules.24

We divided the molecular structure into four modules: ahydrophilic (sugar) head, linker, connector, and hydrophobic tail(Figure 1), and constructed a library of the glycolipid mimicsthrough chemical synthesis. Fortunately, a few hydrogelatorswere discovered after screening. Spectroscopic analysis andpowder X-ray diffraction patterns suggested well-developedH-bonding and van-der Waals packing in a supramolecularhydrogel consisting of glycolipid mimics (Figure 2a). Moreover,as shown in Figure 2b, the detailed X-ray crystallographic analysisconfirmed the intermolecular H-bonding networks of the twoamides of the linkers and van der Waals interactions of thehydrophobic cyclohexyl (tail) rings in the packing structure.32

Other H-bonding networks were also revealed between the sugarmoieties via two interfacial water molecules. Such noncovalent

Figure 2. Self-assembly and hydrogelation by GalNAc-suc-methyl-cycC6 molecules. (a) A schematic representation of hierarchical self-assembly ofGalNAc-suc-methyl-cycC6 molecules. (b) Molecular arrangement and noncovalent interactions of GalNAc-suc-methyl-cycC6 molecules in thesupramolecular nanofibers. The structure was revealed by X-ray crystallographic analysis. (c) A CLSM image of GalNAc-suc-methyl-cycC6 nanofibersstained by a NBD derivative.

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interactions are thought to cooperatively operate to maintain thewell-developed fiber structures.During the study on the gelation mechanism, we sought to use

confocal laser scanning microscopy (CLSM) for in situ imagingof the supramolecular fibers without drying processes.31,32 Sincewe noticed from fluorescence spectroscopy that hydrophobicdomains existed in the gelator assemblies, a hydrophobic (andenvironmentally sensitive) fluorophore, such as nitrobenzox-adiazole (NBD) derivatives, was added to the hydrogel to stainthe hydrophobic domains. As shown in Figure 2c, CLSM imagesclearly demonstrate that there are many well-developed fiberswith entanglement and dark spaces surrounded with fibernetworks in the wet hydrogel matrix. Using the two distinctmicroenvironments (i.e., aqueous cavity and the hydrophobicfibers interior) in the hydrogel, these supramolecular hydrogelswere successfully applied as functional materials for the thermallycontrolled release of DNA and for adsorbing bisphenol A, a waterpollutant.31 To the best of our knowledge, this is the first exampleshowing the power of CLSM for in situ imaging of supra-molecular fibers.

This detailed structural elucidation allowed us to rationallydevelop a variety of stimuli-responsive supramolecular hydrogelsby the modulation of their noncovalent interactions (Figure 3).We particularly focused on the β-sheet-like well-developedH-bonding networks in the spacer region, as well as the watermolecule-bridged saccharide modules at the interface (Figure 2b).It was theorized that the stimuli-induced perturbation of theseinteractions could substantially affect the stability of the fibers,resulting in a change in the macroscopic hydrogel state.According to this rationale, the incorporation of a photo-isomerizable C−C double bond into the connector moietyafforded photoresponsive hydrogels (Figure 3a). UV lightirradiation induced a structural change from the trans to cisform at the spacer module, which destabilized the H-bondingnetwork to render the self-assembled fibers to transform intospherical aggregates.28,29 The spherical aggregates were notappropriate for cross-linking each other, relative to the longfibers, so that the gel was destroyed to the sol. Interestingly,the cis form of the spacer region returned back to the trans formby visible light in the presence of Br2, reforming into hydrogel

Figure 3. Rational chemical modifications of a hydrogelator (GalNAc-suc-methyl-cycC6) for development of stimuli-responsive supramolecularhydrogels and the applications of the stimuli-responsive supramolecular hydrogels. (a) A photoresponsive supramolecular hydrogelator (GalNAc-fum-cycC6).GalNAc-fum-cycC6 shows cis to trans photoisomerization upon UV irradiation. Therefore, the supramolecular nanofibers are collapsed by UVirradiation, and microscopic gel−sol transition occurs. (b) A photo- and pH-responsive hydrogelator with lysine group (Lys-fum-cycC6). Lys-fum-cycC6 molecules interact with each other via intermolecular ion paring and form a stiff photo- and pH-responsive supramolecular hydrogel. (c) Amultistimuli responsive hydrogelator with a phosphate group (Phos-fum-cycC6). Phos-fum-cycC6 molecules respond to pH, metal ion, and light in asupramolecular hydrogel in a logic gate fashion.

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state. Utilizing this photoresponsive gel−sol transition, not onlythe light-controlled sol−gel patterning of hydrogels but alsoOFF/ON switching of F1-ATPase rotatory protein motion in alimited small space were carried out.Replacing N-acetylgalactosamine (GalNAc) with lysine in the

hydrophilic head of the fiber−water interface yielded a stiffsupramolecular hydrogel (G′ > 1.0 × 104) (Figure 3b).39,40 Theincreased toughness was optimal at the neutral pH region andmay be derived from the complementary ion pairs (and/orH-bonding) between the ammonium and carboxylate of thelysine moieties. This hydrogel retained the photoresponsiveproperties due to the double bond and thus a photofabricated gelmold was prepared for cell culture, differentiation, and 3-Dspatial pattering. This hydrogel mold is removable as it is slowlydegraded in the culture medium, which offers great promise forbiotechnology and regenerative medicine.We further designed and synthesized a multistimuli responsive

lipid-like hydrogelator Phos-fum-cycC6 equipped with aphosphate group at the interface, which can bind metal ions(e.g., Ca2+) and with the C−C double bond sensitive to UV lightat the spacer (Figure 3c).27 The hydrogel consisting of Phos-fum-cycC6 showed four fundamental logic-gate responsesexhibiting the macroscopic gel−sol transition by four distinctstimuli such as temperature, pH, Ca2+, and light. This hydrogelalso achieved controllable release of bioactive substances inresponse to UV light, presence of a Ca2+ chelator, and pHchanges. We expect that installing logic gate responses to variousstimuli in soft materials could be utilized in a variety of appli-cations, such as environment-sensitive actuator, cell culturematrix, and drug-delivery/controlled-release systems.

3. RATIONAL DESIGN OF STIMULI-DEGRADABLEPEPTIDE-BASED HYDROGELATORS

A variety of peptide-based gelators for supramolecular hydrogelshave been actively developed in recent years. Among them, it has

been shown that very short peptides consisting of only two orthree amino acids form hydrogels by appropriate chemicalmodification.41,42 For example, Xu and Gazit reported a simpleFmoc-Y and Fmoc-FF (Fmoc, fluorenyl-9-methoxycarbonyl; FF,diphenylalanine) as hydrogelators, respectively.17,43 This findinginspired our idea for the rational design of stimuli-responsivehydrogelators comprising short peptides (Figure 4a,b). Xu’sreport suggested that a hydrophobic aromatic group, such asFmoc, at the N-terminus, could play a critical role in stabilizingsupramolecular fibers and their networks. We thus assumed thatthe equipment of a hydrophobic aromatic group removable bystimuli may afford stimuli-responsive supramolecular hydrogels.In design of the H2O2-responsive hydrogel, for instance,dipeptide (FF) was modified at its N-terminus with p-borono-phenylmethoxycarbonyl (BPmoc).34 The BPmoc unit reactswith H2O2 through hydroboration reaction, followed by 1,6-elimination reaction to be cleaved out along with the generationof p-quinonemethide and CO2 (Figure 4b,c). This chemicalreaction-induced structural change diminished the intermolec-ular interactions crucial for hydrogelation, which led to thedestruction of the supramolecular hydrogels. In a similar manner,chemical modification of p-nitro-phenylmethoxycarbonyl(NPmoc) or 6-bromo-7-hydroxycoumarin-4-ylmethoxycarbonyl(Bhcmoc) unit at the N-terminus of FF peptide derivativesafforded reduction-responsive or photoresponsive supramolec-ular hydrogels, respectively (Figure 4c). Using dimethylamino-coumarin-4-yl-methoxycarbonyl (DMACmoc) modified FF,a two-photon-responsive supramolecular hydrogel was success-fully constructed, which was applied to the control of Brownianmotion of nanosized beads and Escherichia coli bacterialmovement in the limited micrometer space of the supra-molecular hydrogel interior.44 A two-photon response is superiorto a one-photon in terms of biological application due to itsreduced toxicity and high biocompatibility. Spatiotemporalcontrol of the fluidity inside a soft hydrogel matrix by external

Figure 4. Rational molecular design for stimuli-responsive supramolecular hydrogels consisting of short peptide derivatives. (a) A simple hydrogelatorreported by Xu’s group (Fmoc-Y). (b) A strategy for development of stimuli-responsive supramolecular hydrogels. Hydrogelators with chemical reactivegroups at the N-terminus are decomposed after addition of a specific stimulus corresponding to each reactive group. (c) Chemical structures of ourstimuli-responsive supramolecular hydrogelators and a schematic representation of the gelation and the stimuli-response mechanisms. (d) A chemicalstructure of a heat-set type hydrogelator.

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stimuli allowed for real-timemanipulation of nano- or microsizedmaterials.This strategy was also extended to the design of stimuli-

responsive hydrogels exhibiting the sol-to-gel transition, insteadof the gel-to-sol transition. We successfully developed a heat-setsupramolecular hydrogel by taking advantage of retro-Diels−Alder (r-DA) reaction by designer bolaamphiphies based onshort peptide-based hydrogelators (Figure 4d).45,46 Beforeheating, the gelator was assembled into spheroidal aggregatesin the sol state. When the solution was heated at 60 °C for 1 han entangled 3D network consisting of 1D nanofibers withlengths of several micrometers was observed by TEM, andhydrogelation occurred. This was derived from molecularconversion of bolaamphiphies into hydrophobic hydrogelatorby r-DA reaction-triggered removal of the hydrophilic moiety atthe N-terminus. Given these results, it is clear that chemicalreaction-based modulation of the N-terminal moiety of shortpeptides is one of the rational design strategies for stimuli-responsive peptide-based hydrogels. Our strategy, that is,tethering a stimuli-responsive (removable) unit, such as aryl-methoxycarbonyl (Armoc) groups, at the N-terminus of shortpeptides, is simple but powerful, which is now followed by manyother reports.47−49

4. OPTICAL RESPONSE AND SENSING FORBIOMOLECULES BY INTEGRATION OFSUPRAMOLECULAR HYDROGEL AND FUNCTIONALMATERIALS

The optical response of supramolecular hydrogels depending onchemical or physical stimuli may provide unique optical sensorscomposed of soft materials. In order to generate clear opticalmodulation in response to stimuli (i.e., analytes), we intendedto utilize distinct microenvironments embedded in the

supramolecular hydrogels, that is, the aqueous cavity andhydrophobic fiber interior. Through the hybridization of avariety of synthetic/biological molecules, we also sought toconstruct other microenvironments orthogonally located withinthe hydrogel (Figure 5a).We initially confirmed that the aqueous cavities in supra-

molecular hydrogels are excellent for the noncovalent immo-bilization of proteins, peptides, chemosensors, and inorganicmaterials without loss of their functions. The function of proteinsimmobilized in the aqueous cavity of supramolecular hydrogelswas evaluated using oxygen-bound myoglobin (oxy-Mb), andshowed that the half-life of oxy-Mb in the hydrogel (8.7 h) wascomparable to or longer than the half-life in water (6.9 h).24 Thisimplies that the supramolecular hydrogels can offer a mediumbetween aqueous fluidic solution and hard dry state, termed“semi-wet environment”, appropriate for the immobilization ofnatural proteins and enzymes with minimal protein denaturation.The hydrophobic environment, on the other hand, can reversiblyentrap hydrophobic molecules in supramolecular hydrogels,which is utilized for a unique fluorescent enzyme (protein/peptide) array (Figure 5b).32,50,51 When lysyl-endopeptidase(LEP), capable of cleaving a peptide bond of Lys at theC-terminal side, was added to the hydrogel containing a substratepeptide ((Ser)4-Lys-DANSen), the fluorescence of the hydrogelincreased and the emission wavelength blue-shifted. Thisindicates that LEP cleaved the peptide and the releasedhydrophobic DANSen molecules changed location from theaqueous cavity to the self-assembled nanofibers. This semiwetenzyme/protein array was readily prepared and was potentiallyapplied to quantitative screening inhibitor. In a similar protocol,we prepared a semiwet lectin array using fluorophore-modifiedlectins (sugar-binding proteins) embedded in supramolecularhydrogels.52 Through the biomolecular fluorescence quenching

Figure 5. A cell mimicking approach for development of biomolecule-responsive supramolecular hydrogels. (a) Integration of two distinctenvironments in supramolecular hydrogels and functional materials for biomolecule sensing. (b) Semiwet enzyme/protein array for optically sensingbiomolecules. The sensing mechanism is shown in a blue square.

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and recovery (BFQR) method, the fluorescent lectin arraycarried out pattern recognition of oligosaccharides or cell type.Hybridization of various artificial chemosensors (for phosphory-lated-peptides, Zn2+, Ca2+, and pH) with supramolecularhydrogels afforded a noncovalently immobilized sensor array,highlighting that host−guest chemistry can be performed underthe supramolecular hydrogel conditions.53−56

Moreover, we constructed more complex sensor systems byincorporation of inorganic nanomaterials and enzymes into thehydrogels (Figure 6a).57,58 Inorganic nanomaterials, such asporous nanoparticles, were expected to provide a third distinctcompartment in a hydrogel that may mimic an organelle of livecells. Organelle communication is ubiquitous in nature andknown to play important roles in cell growth and proliferation,which leads us to expect that the stimuli-responsive communi-cations between supramolecular fiber and other orthogonalcompartments afford a unique sensing capability to the hybridhydrogels (Figure 6b). Mesoporous silica particles bearing well-ordered nanopores, whose surface was functionalized to becationic (NH2-MCM41), were utilized as colorimetric sensorson the basis of ion-exchange phenomena between encapsulatedanionic dyes and polyanions such as carboxylates andphosphates.57 We designed coupling of such anion-exchangeability of NH2-MCM41 to an enzymatic reaction and thehydrophobic supramolecular fiber domain in the semiwethydrogel matrix. The phosphorylated coumarins (P-coum)encapsulated in the nanopores of NH2-MCMs are kicked outby polyanions having a higher affinity via anion-exchange. Thereleased P-coum is dephosphorylated by phosphatase in theaqueous cavity, and the resultant hydrophobic coumarin movedand condensed in the self-assembled nanofibers. Thesesequential events were successfully imaged in situ by CLSMmeasurements. As a result, supramolecular hydrogels changedtheir optical properties depending on the added anions so that

the sensor array can discriminate polysulfates from polyphos-phates (Figure 6c). Montmorillonite (MMT), layered inorganicclay with negative charges, was also embedded in thesupramolecular hydrogel as a host of cationic fluorescent dyes(Figure 6a).58 In this case, polycations caused an ion-exchangereaction to facilitate the release of the cationic fluorophore fromMMT. The released fluorophore moved to the hydrophobic fiberdomain to enhance the fluorescence intensity with a blue-shift ofwavelength. This polycation-triggered fluorescence modulationof the MMT/hydrogel hybrid allowed for optical detection ofbiological polyamines, such as spermidine and spermine, inartificial urine. It is clear that orthogonal domains given by thesematerials and coupling with enzymatic reactions in supra-molecular hydrogels efficiently render the hybrid hydrogelssemiwet sensors with unique optical properties and selectivity.

5. BIOMARKER-DEGRADABLE HYDROGELS BYINTEGRATION OF REDOX-ACTIVESELF-ASSEMBLED NANOFIBERS AND ENZYMES

Hybridizing various enzymes with chemically reactive supra-molecular hydrogels enabled the programmable design ofsophisticated soft materials responsive to structurally andchemically complicated small biomolecules.34,35 There arebiomolecules such as vitamins, lipids, proteins, DNA, andRNA, whose changes in concentration and expression levels areclosely related to their corresponding physiological disorder andpathology. Some biomolecules exhibiting high diversity andcomplexity in structure and functions are called biomarkers. Thedevelopment of biomarker-responsive hydrogels remainschallenging, although it is anticipated to be a promising softmaterial. With the aim of construction of such unprecedentedhydrogels, we sought to employ natural enzymes bearing therigid substrate selectivity together with chemically reactivesupramolecular hydrogels such as H2O2-responsive hydrogel

Figure 6. A cell mimicking approach for biomolecule-responsive supramolecular hydrogels by using inorganic materials as an artificial organelle.(a) Hydrogels encapsulating polyanion or cation sensing systems composed of supramolecular nanofibers and inorganic porous or layered materials.(b) Polyanion sensing mechanism in the hybrid hydrogels consisting of supramolecular nanofibers, enzyme, dyes, and inorganic porous materials.(c) A photograph of MCM−enzyme supramolecular hydrogel hybrid sensory chip containing a BODIPY derivative (FRET acceptor) after addition ofvarious polyanionic biomolecules. The photograph is taken under UV light.

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Figure 7. Biomolecule degradable supramolecular hydrogels consisting of stimuli-responsive hydrogels and enzymes. (a) Biomolecule-responsivesupramolecular hydrogels consisting of H2O2-responsive gel fibers and oxidases. Oxidases generate H2O2 as a byproduct by enzymatic reaction, and thegenerated H2O2 decomposes the gel fibers. Finally, the gel changes to sol. (b) Serial coupling of enzymatic reactions in the BPmoc-FFF hydrogel forexpansion of a chemical-stimuli response.

Figure 8. Supramolecular hydrogels in response to two biomolecules. (a) Lactic acid and NADH responsive supramolecular hydrogels consisting ofreduction-responsive hydrogel (NPmoc-FF), LDH, andNR. An optical photograph in the figure shows the results of gel−sol response test. (b) Booleanlogic gate (AND) response of the supramolecular hydrogel for glucose andNADH. The hydrogels are composed of hybrid supramolecular nanofibers ofBPmoc-FFF and NPmoc-FF, GOx, and NR. G and S indicate gel and sol, respectively.

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(BPmoc-FF).34 It is well-known that many oxidases are able tooxidize the corresponding substrates (biomarkers in some cases)with the concurrent generation of H2O2 as a byproduct. There-fore, we expected that H2O2 produced upon enzymatic reactionwas able to decompose the BPmoc-FF hydrogel matrix to causethe gel−sol transition, when an oxidase is embedded in thehydrogel. Indeed, the addition of glucose to BPmoc-FFF (thehydrogelator superior to BPmoc-FF in terms of critical gelationconcentration (CGC) 0.05 wt %) hydrogels containing glucoseoxidase (GOX) induced the gel−sol transition, as shown inFigure 7a. Owing to the rigid substrate selectivity of GOX, thishybrid gel did not respond to galactose or lactose. In a similarprotocol, we prepared BPmoc-FFF hydrogels encapsulatingvarious oxidases (sarcosine (SOX), choline (COX), urate oxidases(UOX)) and revealed that each hybrid hydrogel selectivelyresponded to substrates of the corresponding oxidases (Figure 7a).It is note-worthy that glucose (diabetes), sarcosine (prostatecancer), and uric acid (gout) are known as biomarkers, and thisbiomarker-responsive gel−sol response is easily visible by thenaked eye. The concurrent encapsulation of two enzymes in thehydrogel allows for increasing the variety of analytes (Figure 7b).When GOX was embedded together with glycosidase inBPmoc-FFF, the addition of lactose to the hybrid hydrogelcaused a gel−sol transition. This indicated that the cascadereaction had occurred; thus, lactose was hydrolyzed by glycosidaseto generate glucose and galactose. The resultant glucose wassubsequently oxidized by GOX to generate H2O2, which destroyedtheBPmoc-FFF hydrogel. The similar cascade reaction took placeby choline esterase andCOX in the hydrogel matrix, which enabledthe detection of acetylcholine by the gel−sol transition.In the case ofNPmoc-FF gel, on the other hand, we are able to

hybridize nitroreductase (NR) andNADH (NAD) as its cofactor(Figure 8a). Combining NR to lactate dehydrogenase (LDH)and NAD in the NPmoc-FF gel matrix afforded lactic acidresponsive supramolecular hydrogels. Lactic acid was oxidized byLDH to generate NADH fromNAD, which reduced nitrophenylgroup ofNPmoc-FF to the gel decomposition. Furthermore, wesucceeded in building Boolean logic gates (OR and AND) in thehybrid hydrogel containing multiple components (Figure 8b).For instance, the mixed hydrogel composed of BPmocFFF andNPmoc-FF containing GOX and NR was able to simultaneouslysense plural biochemicals (glucose and NADH) and execute acontrolled drug release in accordance with the logic operation.Molecular logic-gate is actively explored.59 However, the

employed input signals were somewhat simple, such as pH,cations, or anions, and outputs are largely limited to physicalsignals such as fluorescence or electric signals in most cases. It isconceivable that the present example sidesteps these limitationsby rational coupling of chemically reactive supramolecularhydrogels with natural enzymes.We further revealed that a signal amplification circuit originally

developed by Shabat was useful as a cross-talking componentembedded in the enzyme-hybrid hydrogel, leading to enhancethe detection limit of biomarkers.60,61 Since both the oxidasereaction with the substrates and the subsequent chemicalreactions of H2O2 with BPmoc-FFF are stoichiometric, that is,a 1:1:1 substrate/H2O2/BPmoc-FFF stoichiometry exists,biomarker sensitivity was strictly limited. In case the detectableconcentration of a biomarker is higher than the critical value for aspecific disease, the sensitivity should be improved. Weoptimized an amplification system (a pair of synthetic amplifierand SOX) for the BPmoc-FFF hydrogel, which produced 2 molof H2O2 from 1 mol of substrate (H2O2). In practice, we demon-strated that a multicomponent BPmoc-FFF hydrogel containingthe synthetic amplifier/SOX/UOX successfully created a user-friendly, naked eye detection sensor for the disease level of uricacid in human plasma.

6. CONCLUSION AND FUTURE DIRECTIONSWe briefly present a few promising strategies for the rationaldesign of stimuli-responsive supramolecular hydrogels. Deepunderstanding of both the intermolecular interactions of thegelators and the resultant microenvironment is crucial forachieving the designed gel−sol/sol−gel transition or opticalchanges. In addition, it should be emphasized that integration ofsupramolecular hydrogels with various functional materials suchas fluorescent probes, chemical sensors, natural enzymes/pro-teins, and inorganic materials allowed us to obtain uniqueresponses to complicated biomarkers in supramolecular softmaterials. Very recently, we directly imaged with super-resolutionCLSM a hydrogelator pair (BPmoc-FFF and Phos-fum-cycC6)dynamically self-sorting and orthogonally assembling into twodistinct supramolecular nanofibers in situ (Figure 9).62 Such amulticomponent but well-ordered structure is reminiscent of thecytoskeleton of living cells. Supramolecular chemistry, a fieldoriginating from the strong interest in remarkably well-orderedstructures and intelligent functions of biomolecules, has madegreat efforts for mimicking these biomolecules or systems.

Figure 9. Schematic representation of self-sorting between peptide- and lipid-type hydrogelators and in situCLSM imaging of the self-sorted nanofibers.Scale bar: 5 μm.

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However, there remains a large gap between artificial supra-molecular systems and natural (sophisticated) ones. Naturalsystems consisting of multiple components can effectivelyregulate entropy, fluctuation, and chemicals as energies undervery crude conditions and in far-from-equilibrium states,while most artificial systems are rather simple in the pureand equilibrium state. We believe that by controlling multi-component supramolecular assemblies in their nonequilibrium,orthogonal or cooperative, and spatiotemporal manners we cangenerate novel smart materials. These efforts may also open up“complex (crude) systems chemistry” beyond biomimetics.

■ AUTHOR INFORMATIONCorresponding Author

*Itaru Hamachi. E-mail: ihamachi@sbchem.kyoto-u.ac.jp.

ORCID

Itaru Hamachi: 0000-0002-3327-3916Notes

The authors declare no competing financial interest.

Biographies

Hajime Shigemitsu received his Ph.D. fromOsaka University under thesupervision of Prof. Mikiji Miyata in 2013. He carried out hispostdoctoral research in the group of Prof. Itaru Hamachi at KyotoUniversity. His research interests include supramolecular chemistry andfunctional materials chemistry.

Itaru Hamachi obtained his Ph.D. at the Department of SyntheticChemistry of Kyoto University in 1988 under the supervision of Prof.Iwao Tabushi. He started his carrier in the field of supramolecularchemistry at Kyushu University in 1988 and then shifted his researchfield to protein engineering as an associate professor there. In 2001, hebecame a full professor at Kyushu University and then moved to theDepartment of Synthetic Chemistry and Biological Chemistry of KyotoUniversity in 2005. His interest has now been extended to chemicalbiology and organic chemistry in living systems and supramolecularbiomaterials.

■ ACKNOWLEDGMENTSWe thank all former and current members of the Hamachilaboratory who have contributed to the described work. Thework described herein was supported by generous funding fromJapan Science and Technology Agency (JST), Japan Society forPromotion of Science (JSPS), and the Ministry of Education,Culture, Sports, Science and Technology of Japan (MEXT). H.S.acknowledges a JSPS research fellowship for young scientists.

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