Article

pubs.acs.org/accounts

Design Strategies of Stimuli-Responsive Supramolecular Hydrogels

Relying on Structural Analyses and Cell-Mimicking Approaches
Published 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 intriguing

biomaterials useful for spatiotemporal controlled release of
drugs, cells, and biological cues, cell engineering for various
applications, and medical diagnosis. To date, many physical and
chemical stimuli-responsive polymer hydrogels have been
developed by chemical modification of polymer chains and
cross-linking points. In particular, conjugation with biomole-
cules to polymers produced promising biomolecule-responsive
hydrogels. These examples clearly indicate high potentials
of stimuli-responsive hydrogels as promising biomaterials.
In addition to polymer hydrogels, supramolecular hydrogels
formed by the assembly of small molecules (hydrogelators) via
noncovalent interactions have also been regarded as unique and
promising soft materials due to their flexible programmability in rendering them stimuli-responsive with the larger macroscopic
change (i.e., gel−sol transition).
This Account describes our strategies for the rational design of stimuli-responsive supramolecular hydrogels and their biological
applications. Following the detailed structural analysis of a lead hydrogelator that clearly indicates the appropriate sites for
incorporation 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 were
successfully developed by supramolecularly mimicking the complex yet well-ordered structures and functions of live cells
containing multiple components (a cell-mimicking approach). Development of biomolecule-responsive supramolecular hydrogels
has been difficult as the conventional strategy relies on the chemical incorporation of stimuli-responsive modules, owing to the
lack of modules that can effectively respond to structurally diverse and complicated biomolecules. Inspired by natural systems
where functional compartments (e.g., cell organelles) sophisticatedly interact with each other, we sought to integrate the two
distinct microenvironments of supramolecular hydrogels (the aqueous cavity surrounded by fibers and the fluidic hydrophobic
fiber domain) with other functional materials (e.g., enzymes, peptides or proteins, fluorescent chemosensors, or inorganic porous
or layered nanomaterials) for biomolecule responses. In situ fluorescence microscopy imaging clearly demonstrated that chemical
isolation and crosstalk are highly successful between the integrated microenvironments in supramolecular hydrogels, similar to
organelles 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 an
unprecedented universal platform for biomolecule-degradable supramolecular hydrogels. Such biomolecule-responsive hydrogels
are a potentially promising tool for user-friendly early diagnostics and on-demand drug-releasing soft materials. We expect that
our rational design strategies for stimuli-responsive supramolecular hydrogels by modification of chemical structures and
hybridization with functional materials will inspire scientists in various fields and lead to development of novel soft materials for
biological applications.

1. INTRODUCTION efficient stimuli response of hydrogels to a particular condition

Stimuli-responsive hydrogels have attracted much attention not
only owing to interests in fundamental science but because of
their potential for a wide range of biological and biomedical
applications, such as drug delivery systems, regenerative
medicines, cancer therapy, and diagnosis.1−4 Selective and
or molecule is anticipated to allow for the selective release of a
drug or biological cue under biological crude conditions (i.e., in
Received: February 3, 2017
Published: March 2, 2017

© 2017 American Chemical Society 740 DOI: 10.1021/acs.accounts.7b00070

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Figure 1. A combinatorial screening for the development of supramolecular hydrogelators based on solid-phase synthesis.
cells, in culture media, in vivo) and the naked-eye detection of
disease biomarkers without expensive analytical instruments.
Additionally, a new strategy for cancer therapy by hydrogelation
has recently emerged.5,6 Many stimuli-responsive polymer
hydrogels have been developed for biological applications.7
Chemical modification of polymer chains and cross-linkers
produced various physical and chemical stimuli-responsive
polymer-based hydrogels.8 Also, biomolecule-responsive poly-
mer hydrogels have been developed by conjugation with
polymers and biomolecules.9−12 These successful examples of
stimuli-responsive hydrogels clearly indicate their potential as
promising biomaterials.
Besides polymer hydrogels, supramolecular hydrogels con-
sisting of small molecules (hydrogelators) have been actively
developed and are now recognized as unique and promising soft
materials, owing to their high and flexible programmability in
lending them stimuli responsiveness.13−16 It is generally accepted
that hydrogelators assemble to form nanofibers, which is critical
for supramolecular hydrogelation. This fiber formation is driven
by a variety of noncovalent interactions such as hydrogen-
bonding (H-bonding), hydrophobic, van der Waals, and π/π
interactions. The delicate balance between these noncovalent
interactions can readily modulate the resultant self-assembled
structures, which sensitively affects the hydrogelation. The close
connection between the gelator structure and macroscopic
properties of the resultant hydrogel should enable one to
rationally design and tune the properties of stimuli-responsive
hydrogels at the small molecule level. In addition, the preparation
protocol of supramolecular hydrogels is largely different from
that of conventional polymer-based hydrogels that often require
polymerization in the presence of adducts such as initiators and
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cross-linkers. In the case of supramolecular hydrogels, no adducts
are required and the operations (e.g., heating and cooling, simple
injection of hydrogelator to aqueous solution, or ultrasound
treatment) are quite easy for gelation. This is regarded as an
important advantage of supramolecular hydrogelators for
biological applications.
To date, many supramolecular hydrogels have been reported
to exhibit response to stimuli such as heat, pH, metal ions, and
light, and these have been applied to cell cultures, control of
drug release, and so on. These are usually designed through the
insertion of an appropriate stimuli-responsive group into the
hydrogelator scaffold. Given the relationship between the gelator
structure and the gelation properties, it was reasonably expected
that a structural perturbation of the gelator given by a stimulus
may cause macroscopic gel−sol or sol−gel changes. However,
the employed stimuli have been rather simple so far. The more
sophisticated supramolecular hydrogels able to respond to
complex biomolecules (i.e., bioactive vitamin, saccharides,
DNA, RNA, and noncatalytic proteins) are still limited and
difficult 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 recognition
capability of synthetic molecules as stimuli-responsive groups,
and thus it is difficult to find a suitable module capable of
discriminating a target molecule among diverse nontargets in
the context of hydrogelator design. Moreover, time-consum-
ing efforts are required for incorporating the modules into
the supramolecular hydrogelator, even if stimuli-responsive
(molecular recognition) modules with high affinity and
selectivity are developed. Therefore, an alternative and more
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Figure 2. Self-assembly and hydrogelation by GalNAc-suc-methyl-cycC6 molecules. (a) A schematic representation of hierarchical self-assembly of
GalNAc-suc-methyl-cycC6 molecules. (b) Molecular arrangement and noncovalent interactions of GalNAc-suc-methyl-cycC6 molecules in the
supramolecular nanofibers. The structure was revealed by X-ray crystallographic analysis. (c) A CLSM image of GalNAc-suc-methyl-cycC6 nanofibers
stained by a NBD derivative.
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 on
the detailed structural analyses of the supramolecular fibers,
a fundamental element of supramolecular hydrogels, and the
clear characterization of the two different microenvironments
inside of the hydrogels. We initially discovered a few supra-
molecular hydrogelators comprising lipid-like molecules using a
combinatorial screening approach.22−26 The molecular packing
resolved by X-ray analysis led to rationally modifying the
hydrogelators in order to exhibit stimuli-responsiveness for metal
ions, pH, and light.27−30 In situ confocal fluorescence microscopy
observation also revealed that two distinct microenvironments
exist in the supramolecular hydrogels: an aqueous cavity surrounded
by self-assembled nanofibers and the hydrophobic domains of their
fiber’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 material
composed of numerous multiple functional components made of
protein, lipid, DNA/RNA, etc. Knowledge about living cells has
inspired us to hybridize our supramolecular hydrogels with many
synthetic or biological molecules bearing various structures and
functions. We expected that controlling and facilitating the
crosstalk between these multiple components could provide
biomolecule responses to the hybrid supramolecular hydrogels.
A myriad of organic compounds, metal ions, inorganic materials,
biological small molecules, and biopolymers were integrated with
the supramolecular hydrogels without loss of function.33
Interestingly, many small molecules are mobile between two
(or more) different microenvironments, so that the optical
response was effective. Finally, we demonstrated that rational
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coupling of enzymatic reactions with chemically reactive hydro-
gelators allowed us to design intelligent supramolecular hydro-
gels exhibiting unprecedented gel−sol transition in response to
disease-related small molecules (biomarkers).34−36
2. RATIONAL MOLECULAR DESIGN FOR
STIMULI-RESPONSIVE SUPRAMOLECULAR
HYDROGELS BASED ON LIPID-LIKE MOLECULES
It has long been known that some molecules with low molecular
weights form hydrogels, and the majority of such hydrogelators
were discovered serendipitously.37 In the last two decades,
powerful methods for analyzing nanostructures (e.g., electron
and atomic force microscopies) revealed that fibrous self-
assembled structures and their entangled 3-D networks play an
important role in hydrogelation.38 Despite structural analysis,
rational design of supramolecular hydrogelators ab initio was
difficult. This is because the delicate balance among plural
noncovalent intermolecular interactions essential for hydro-
gelation is unpredictable in aqueous media. Therefore, we first
decided to explore a hydrogelator by a combinatorial screening
approach using a library of synthetic lipid-like molecules.24
We divided the molecular structure into four modules: a
hydrophilic (sugar) head, linker, connector, and hydrophobic tail
(Figure 1), and constructed a library of the glycolipid mimics
through chemical synthesis. Fortunately, a few hydrogelators
were discovered after screening. Spectroscopic analysis and
powder X-ray diffraction patterns suggested well-developed
H-bonding and van-der Waals packing in a supramolecular
hydrogel consisting of glycolipid mimics (Figure 2a). Moreover,
as shown in Figure 2b, the detailed X-ray crystallographic analysis
confirmed the intermolecular H-bonding networks of the two
amides of the linkers and van der Waals interactions of the
hydrophobic cyclohexyl (tail) rings in the packing structure.32
Other H-bonding networks were also revealed between the sugar
moieties via two interfacial water molecules. Such noncovalent
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Figure 3. Rational chemical modifications of a hydrogelator (GalNAc-suc-methyl-cycC6) for development of stimuli-responsive supramolecular
hydrogels 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 UV
irradiation, 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) A
multistimuli responsive hydrogelator with a phosphate group (Phos-fum-cycC6). Phos-fum-cycC6 molecules respond to pH, metal ion, and light in a
supramolecular hydrogel in a logic gate fashion.

interactions are thought to cooperatively operate to maintain the
well-developed fiber structures.
During the study on the gelation mechanism, we sought to use
confocal laser scanning microscopy (CLSM) for in situ imaging
of the supramolecular fibers without drying processes.31,32 Since
we noticed from fluorescence spectroscopy that hydrophobic
domains existed in the gelator assemblies, a hydrophobic (and
environmentally sensitive) fluorophore, such as nitrobenzox-
adiazole (NBD) derivatives, was added to the hydrogel to stain
the hydrophobic domains. As shown in Figure 2c, CLSM images
clearly demonstrate that there are many well-developed fibers
with entanglement and dark spaces surrounded with fiber
networks in the wet hydrogel matrix. Using the two distinct
microenvironments (i.e., aqueous cavity and the hydrophobic
fibers interior) in the hydrogel, these supramolecular hydrogels
were successfully applied as functional materials for the thermally
controlled release of DNA and for adsorbing bisphenol A, a water
pollutant.31 To the best of our knowledge, this is the first example
showing the power of CLSM for in situ imaging of supra-
molecular fibers.
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This detailed structural elucidation allowed us to rationally
develop a variety of stimuli-responsive supramolecular hydrogels
by the modulation of their noncovalent interactions (Figure 3).
We particularly focused on the β-sheet-like well-developed
H-bonding networks in the spacer region, as well as the water
molecule-bridged saccharide modules at the interface (Figure 2b).
It was theorized that the stimuli-induced perturbation of these
interactions 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 moiety
afforded photoresponsive hydrogels (Figure 3a). UV light
irradiation induced a structural change from the trans to cis
form at the spacer module, which destabilized the H-bonding
network to render the self-assembled fibers to transform into
spherical aggregates.28,29 The spherical aggregates were not
appropriate for cross-linking each other, relative to the long
fibers, so that the gel was destroyed to the sol. Interestingly,
the cis form of the spacer region returned back to the trans form
by visible light in the presence of Br2, reforming into hydrogel
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Figure 4. Rational molecular design for stimuli-responsive supramolecular hydrogels consisting of short peptide derivatives. (a) A simple hydrogelator
reported by Xu’s group (Fmoc-Y). (b) A strategy for development of stimuli-responsive supramolecular hydrogels. Hydrogelators with chemical reactive
groups at the N-terminus are decomposed after addition of a specific stimulus corresponding to each reactive group. (c) Chemical structures of our
stimuli-responsive supramolecular hydrogelators and a schematic representation of the gelation and the stimuli-response mechanisms. (d) A chemical
structure of a heat-set type hydrogelator.
state. Utilizing this photoresponsive gel−sol transition, not only
the light-controlled sol−gel patterning of hydrogels but also
OFF/ON switching of F1-ATPase rotatory protein motion in a
limited small space were carried out.
Replacing N-acetylgalactosamine (GalNAc) with lysine in the
hydrophilic head of the fiber−water interface yielded a stiff
supramolecular hydrogel (G′ > 1.0 × 104) (Figure 3b).39,40 The
increased toughness was optimal at the neutral pH region and
may be derived from the complementary ion pairs (and/or
H-bonding) between the ammonium and carboxylate of the
lysine moieties. This hydrogel retained the photoresponsive
properties due to the double bond and thus a photofabricated gel
mold was prepared for cell culture, differentiation, and 3-D
spatial pattering. This hydrogel mold is removable as it is slowly
degraded in the culture medium, which offers great promise for
biotechnology and regenerative medicine.
We further designed and synthesized a multistimuli responsive
lipid-like hydrogelator Phos-fum-cycC6 equipped with a
phosphate group at the interface, which can bind metal ions
(e.g., Ca2+) and with the C−C double bond sensitive to UV light
at the spacer (Figure 3c).27 The hydrogel consisting of Phos-
fum-cycC6 showed four fundamental logic-gate responses
exhibiting the macroscopic gel−sol transition by four distinct
stimuli such as temperature, pH, Ca2+, and light. This hydrogel
also achieved controllable release of bioactive substances in
response to UV light, presence of a Ca2+ chelator, and pH
changes. We expect that installing logic gate responses to various
stimuli in soft materials could be utilized in a variety of appli-
cations, such as environment-sensitive actuator, cell culture
matrix, and drug-delivery/controlled-release systems.
3. RATIONAL DESIGN OF STIMULI-DEGRADABLE
PEPTIDE-BASED HYDROGELATORS
A variety of peptide-based gelators for supramolecular hydrogels
have been actively developed in recent years. Among them, it has
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been shown that very short peptides consisting of only two or
three amino acids form hydrogels by appropriate chemical
modification.41,42 For example, Xu and Gazit reported a simple
Fmoc-Y and Fmoc-FF (Fmoc, fluorenyl-9-methoxycarbonyl; FF,
diphenylalanine) as hydrogelators, respectively.17,43 This finding
inspired our idea for the rational design of stimuli-responsive
hydrogelators comprising short peptides (Figure 4a,b). Xu’s
report suggested that a hydrophobic aromatic group, such as
Fmoc, at the N-terminus, could play a critical role in stabilizing
supramolecular fibers and their networks. We thus assumed that
the equipment of a hydrophobic aromatic group removable by
stimuli 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 reacts
with H2O2 through hydroboration reaction, followed by 1,6-
elimination reaction to be cleaved out along with the generation
of p-quinonemethide and CO2 (Figure 4b,c). This chemical
reaction-induced structural change diminished the intermolec-
ular interactions crucial for hydrogelation, which led to the
destruction 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 derivatives
afforded 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 Brownian
motion of nanosized beads and Escherichia coli bacterial
movement in the limited micrometer space of the supra-
molecular hydrogel interior.44 A two-photon response is superior
to a one-photon in terms of biological application due to its
reduced toxicity and high biocompatibility. Spatiotemporal
control of the fluidity inside a soft hydrogel matrix by external
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Figure 5. A cell mimicking approach for development of biomolecule-responsive supramolecular hydrogels. (a) Integration of two distinct
environments in supramolecular hydrogels and functional materials for biomolecule sensing. (b) Semiwet enzyme/protein array for optically sensing
biomolecules. The sensing mechanism is shown in a blue square.
stimuli allowed for real-time manipulation of nano- or microsized
materials.
This strategy was also extended to the design of stimuli-
responsive hydrogels exhibiting the sol-to-gel transition, instead
of the gel-to-sol transition. We successfully developed a heat-set
supramolecular hydrogel by taking advantage of retro-Diels−
Alder (r-DA) reaction by designer bolaamphiphies based on
short peptide-based hydrogelators (Figure 4d).45,46 Before
heating, the gelator was assembled into spheroidal aggregates
in the sol state. When the solution was heated at 60 °C for 1 h
an entangled 3D network consisting of 1D nanofibers with
lengths of several micrometers was observed by TEM, and
hydrogelation occurred. This was derived from molecular
conversion of bolaamphiphies into hydrophobic hydrogelator
by r-DA reaction-triggered removal of the hydrophilic moiety at
the N-terminus. Given these results, it is clear that chemical
reaction-based modulation of the N-terminal moiety of short
peptides 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 short
peptides, is simple but powerful, which is now followed by many
other reports.47−49
4. OPTICAL RESPONSE AND SENSING FOR
BIOMOLECULES BY INTEGRATION OF
SUPRAMOLECULAR HYDROGEL AND FUNCTIONAL
MATERIALS
The optical response of supramolecular hydrogels depending on
chemical or physical stimuli may provide unique optical sensors
composed of soft materials. In order to generate clear optical
modulation in response to stimuli (i.e., analytes), we intended
to utilize distinct microenvironments embedded in the
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supramolecular hydrogels, that is, the aqueous cavity and
hydrophobic fiber interior. Through the hybridization of a
variety of synthetic/biological molecules, we also sought to
construct other microenvironments orthogonally located within
the 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 inorganic
materials without loss of their functions. The function of proteins
immobilized in the aqueous cavity of supramolecular hydrogels
was evaluated using oxygen-bound myoglobin (oxy-Mb), and
showed that the half-life of oxy-Mb in the hydrogel (8.7 h) was
comparable to or longer than the half-life in water (6.9 h).24 This
implies that the supramolecular hydrogels can offer a medium
between aqueous fluidic solution and hard dry state, termed
“semi-wet environment”, appropriate for the immobilization of
natural proteins and enzymes with minimal protein denaturation.
The hydrophobic environment, on the other hand, can reversibly
entrap 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 the
C-terminal side, was added to the hydrogel containing a substrate
peptide ((Ser)4-Lys-DANSen), the fluorescence of the hydrogel
increased and the emission wavelength blue-shifted. This
indicates that LEP cleaved the peptide and the released
hydrophobic DANSen molecules changed location from the
aqueous cavity to the self-assembled nanofibers. This semiwet
enzyme/protein array was readily prepared and was potentially
applied to quantitative screening inhibitor. In a similar protocol,
we prepared a semiwet lectin array using fluorophore-modified
lectins (sugar-binding proteins) embedded in supramolecular
hydrogels.52 Through the biomolecular fluorescence quenching
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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 of
various polyanionic biomolecules. The photograph is taken under UV light.
and recovery (BFQR) method, the fluorescent lectin array
carried out pattern recognition of oligosaccharides or cell type.
Hybridization of various artificial chemosensors (for phosphory-
lated-peptides, Zn2+, Ca2+, and pH) with supramolecular
hydrogels afforded a noncovalently immobilized sensor array,
highlighting that host−guest chemistry can be performed under
the supramolecular hydrogel conditions.53−56
Moreover, we constructed more complex sensor systems by
incorporation of inorganic nanomaterials and enzymes into the
hydrogels (Figure 6a).57,58 Inorganic nanomaterials, such as
porous nanoparticles, were expected to provide a third distinct
compartment in a hydrogel that may mimic an organelle of live
cells. Organelle communication is ubiquitous in nature and
known 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 orthogonal
compartments afford a unique sensing capability to the hybrid
hydrogels (Figure 6b). Mesoporous silica particles bearing well-
ordered nanopores, whose surface was functionalized to be
cationic (NH2-MCM41), were utilized as colorimetric sensors
on the basis of ion-exchange phenomena between encapsulated
anionic dyes and polyanions such as carboxylates and
phosphates.57 We designed coupling of such anion-exchange
ability of NH2-MCM41 to an enzymatic reaction and the
hydrophobic supramolecular fiber domain in the semiwet
hydrogel matrix. The phosphorylated coumarins (P-coum)
encapsulated in the nanopores of NH2-MCMs are kicked out
by polyanions having a higher affinity via anion-exchange. The
released P-coum is dephosphorylated by phosphatase in the
aqueous cavity, and the resultant hydrophobic coumarin moved
and condensed in the self-assembled nanofibers. These
sequential events were successfully imaged in situ by CLSM
measurements. As a result, supramolecular hydrogels changed
their optical properties depending on the added anions so that
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the sensor array can discriminate polysulfates from polyphos-
phates (Figure 6c). Montmorillonite (MMT), layered inorganic
clay with negative charges, was also embedded in the
supramolecular hydrogel as a host of cationic fluorescent dyes
(Figure 6a).58 In this case, polycations caused an ion-exchange
reaction to facilitate the release of the cationic fluorophore from
MMT. The released fluorophore moved to the hydrophobic fiber
domain to enhance the fluorescence intensity with a blue-shift of
wavelength. This polycation-triggered fluorescence modulation
of the MMT/hydrogel hybrid allowed for optical detection of
biological polyamines, such as spermidine and spermine, in
artificial urine. It is clear that orthogonal domains given by these
materials and coupling with enzymatic reactions in supra-
molecular hydrogels efficiently render the hybrid hydrogels
semiwet sensors with unique optical properties and selectivity.
5. BIOMARKER-DEGRADABLE HYDROGELS BY
INTEGRATION OF REDOX-ACTIVE
SELF-ASSEMBLED NANOFIBERS AND ENZYMES
Hybridizing various enzymes with chemically reactive supra-
molecular hydrogels enabled the programmable design of
sophisticated soft materials responsive to structurally and
chemically complicated small biomolecules.34,35 There are
biomolecules such as vitamins, lipids, proteins, DNA, and
RNA, whose changes in concentration and expression levels are
closely related to their corresponding physiological disorder and
pathology. Some biomolecules exhibiting high diversity and
complexity in structure and functions are called biomarkers. The
development of biomarker-responsive hydrogels remains
challenging, although it is anticipated to be a promising soft
material. With the aim of construction of such unprecedented
hydrogels, we sought to employ natural enzymes bearing the
rigid substrate selectivity together with chemically reactive
supramolecular hydrogels such as H2O2-responsive hydrogel
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Figure 7. Biomolecule degradable supramolecular hydrogels consisting of stimuli-responsive hydrogels and enzymes. (a) Biomolecule-responsive
supramolecular hydrogels consisting of H2O2-responsive gel fibers and oxidases. Oxidases generate H2O2 as a byproduct by enzymatic reaction, and the
generated H2O2 decomposes the gel fibers. Finally, the gel changes to sol. (b) Serial coupling of enzymatic reactions in the BPmoc-FFF hydrogel for
expansion of a chemical-stimuli response.

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

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Figure 9. Schematic representation of self-sorting between peptide- and lipid-type hydrogelators and in situ CLSM imaging of the self-sorted nanofibers.
Scale bar: 5 μm.
(BPmoc-FF).34 It is well-known that many oxidases are able to
oxidize 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 reaction
was able to decompose the BPmoc-FF hydrogel matrix to cause
the gel−sol transition, when an oxidase is embedded in the
hydrogel. Indeed, the addition of glucose to BPmoc-FFF (the
hydrogelator superior to BPmoc-FF in terms of critical gelation
concentration (CGC) 0.05 wt %) hydrogels containing glucose
oxidase (GOX) induced the gel−sol transition, as shown in
Figure 7a. Owing to the rigid substrate selectivity of GOX, this
hybrid gel did not respond to galactose or lactose. In a similar
protocol, we prepared BPmoc-FFF hydrogels encapsulating
various oxidases (sarcosine (SOX), choline (COX), urate oxidases
(UOX)) and revealed that each hybrid hydrogel selectively
responded to substrates of the corresponding oxidases (Figure 7a).
It is note-worthy that glucose (diabetes), sarcosine (prostate
cancer), and uric acid (gout) are known as biomarkers, and this
biomarker-responsive gel−sol response is easily visible by the
naked eye. The concurrent encapsulation of two enzymes in the
hydrogel allows for increasing the variety of analytes (Figure 7b).
When GOX was embedded together with glycosidase in
BPmoc-FFF, the addition of lactose to the hybrid hydrogel
caused a gel−sol transition. This indicated that the cascade
reaction had occurred; thus, lactose was hydrolyzed by glycosidase
to generate glucose and galactose. The resultant glucose was
subsequently oxidized by GOX to generate H2O2, which destroyed
the BPmoc-FFF hydrogel. The similar cascade reaction took place
by choline esterase and COX in the hydrogel matrix, which enabled
the detection of acetylcholine by the gel−sol transition.
In the case of NPmoc-FF gel, on the other hand, we are able to
hybridize nitroreductase (NR) and NADH (NAD) as its cofactor
(Figure 8a). Combining NR to lactate dehydrogenase (LDH)
and NAD in the NPmoc-FF gel matrix afforded lactic acid
responsive supramolecular hydrogels. Lactic acid was oxidized by
LDH to generate NADH from NAD, which reduced nitrophenyl
group of NPmoc-FF to the gel decomposition. Furthermore, we
succeeded in building Boolean logic gates (OR and AND) in the
hybrid hydrogel containing multiple components (Figure 8b).
For instance, the mixed hydrogel composed of BPmocFFF and
NPmoc-FF containing GOX and NR was able to simultaneously
sense plural biochemicals (glucose and NADH) and execute a
controlled drug release in accordance with the logic operation.
Molecular logic-gate is actively explored.59 However, the
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Article
employed input signals were somewhat simple, such as pH,
cations, or anions, and outputs are largely limited to physical
signals such as fluorescence or electric signals in most cases. It is
conceivable that the present example sidesteps these limitations
by rational coupling of chemically reactive supramolecular
hydrogels with natural enzymes.
We further revealed that a signal amplification circuit originally
developed by Shabat was useful as a cross-talking component
embedded in the enzyme-hybrid hydrogel, leading to enhance
the detection limit of biomarkers.60,61 Since both the oxidase
reaction with the substrates and the subsequent chemical
reactions 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 detectable
concentration of a biomarker is higher than the critical value for a
specific disease, the sensitivity should be improved. We
optimized an amplification system (a pair of synthetic amplifier
and SOX) for the BPmoc-FFF hydrogel, which produced 2 mol
of H2O2 from 1 mol of substrate (H2O2). In practice, we demon-
strated that a multicomponent BPmoc-FFF hydrogel containing
the synthetic amplifier/SOX/UOX successfully created a user-
friendly, naked eye detection sensor for the disease level of uric
acid in human plasma.
6. CONCLUSION AND FUTURE DIRECTIONS
We briefly present a few promising strategies for the rational
design of stimuli-responsive supramolecular hydrogels. Deep
understanding of both the intermolecular interactions of the
gelators and the resultant microenvironment is crucial for
achieving the designed gel−sol/sol−gel transition or optical
changes. In addition, it should be emphasized that integration of
supramolecular hydrogels with various functional materials such
as fluorescent probes, chemical sensors, natural enzymes/pro-
teins, and inorganic materials allowed us to obtain unique
responses to complicated biomarkers in supramolecular soft
materials. Very recently, we directly imaged with super-resolution
CLSM a hydrogelator pair (BPmoc-FFF and Phos-fum-cycC6)
dynamically self-sorting and orthogonally assembling into two
distinct supramolecular nanofibers in situ (Figure 9).62 Such a
multicomponent but well-ordered structure is reminiscent of the
cytoskeleton of living cells. Supramolecular chemistry, a field
originating from the strong interest in remarkably well-ordered
structures and intelligent functions of biomolecules, has made
great efforts for mimicking these biomolecules or systems.
DOI: 10.1021/acs.accounts.7b00070
Acc. Chem. Res. 2017, 50, 740−750
Accounts of Chemical Research
However, there remains a large gap between artificial supra-
molecular systems and natural (sophisticated) ones. Natural
systems consisting of multiple components can effectively
regulate entropy, fluctuation, and chemicals as energies under
very crude conditions and in far-from-equilibrium states,
while most artificial systems are rather simple in the pure
and equilibrium state. We believe that by controlling multi-
component supramolecular assemblies in their nonequilibrium,
orthogonal or cooperative, and spatiotemporal manners we can
generate novel smart materials. These efforts may also open up
“complex (crude) systems chemistry” beyond biomimetics.
■ AUTHOR INFORMATION
Corresponding Author
*Itaru Hamachi. E-mail: ihamachi@sbchem.kyoto-u.ac.jp.
ORCID
Itaru Hamachi: 0000-0002-3327-3916
Notes
The authors declare no competing financial interest.
Biographies
Hajime Shigemitsu received his Ph.D. from Osaka University under the
supervision of Prof. Mikiji Miyata in 2013. He carried out his
postdoctoral research in the group of Prof. Itaru Hamachi at Kyoto
University. His research interests include supramolecular chemistry and
functional materials chemistry.
Itaru Hamachi obtained his Ph.D. at the Department of Synthetic
Chemistry of Kyoto University in 1988 under the supervision of Prof.
Iwao Tabushi. He started his carrier in the field of supramolecular
chemistry at Kyushu University in 1988 and then shifted his research
field to protein engineering as an associate professor there. In 2001, he
became a full professor at Kyushu University and then moved to the
Department of Synthetic Chemistry and Biological Chemistry of Kyoto
University in 2005. His interest has now been extended to chemical
biology and organic chemistry in living systems and supramolecular
biomaterials.
■
ACKNOWLEDGMENTS
We thank all former and current members of the Hamachi
laboratory who have contributed to the described work. The
work described herein was supported by generous funding from
Japan Science and Technology Agency (JST), Japan Society for
Promotion 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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