Photo gel-sol/sol-gel transition and its patterning of a supramolecular hydrogel as stimuli-responsive biomaterials

In a focused library of glycolipid-based hydrogelators bearing fumaric amide as a trans-cis photoswitching module, several new photoresponsive supramolecular hydrogelators were discovered, the gel-sol/sol-gel transition of which was pseudo-reversibly induced by light. Studying the optimal hydrogel by NMR spectroscopy and various microscopy techniques showed that the trans-cis photoisomerization of the double bond of the fumaric amide unit effectively caused assembly or disassembly of the self-assembled supramolecular fibers to yield the macroscopic hydrogel or the corresponding sol, respectively. The entanglement of the supramolecular fibers produced nanomeshes, the void space of which was roughly evaluated to be 250 nm based on confocal laser scanning microscopy observations of the size-dependent Brownian motion of nanobeads embedded in the supramolecular hydrogel. It was clearly shown that such nanomeshes become a physical obstacle that captures submicro- to micrometer-sized substrates such as beads or bacteria. By exploiting the photoresponsive property of the supramolecular nanomeshes, we succeeded in off/on switching of bacterial movement and rotary motion of bead-tethered F(1)-ATPase, a biomolecular motor protein, in the supramolecular hydrogel. Furthermore, by using the photolithographic technique, gel-sol photopatterning was successfully conducted to produce sol spots within the gel matrix. The fabricated gel-sol pattern not only allowed regulation of bacterial motility in a limited area, but also off/on switching of F1-ATPase rotary motion at the single-molecule level. These results demonstrated that the photoresponsive supramolecular hydrogel and the resulting nanomeshes may provide unique biomaterials for the spatiotemporal manipulation of various biomolecules and live bacteria.     

Mechanical reinforcement of a supramolecular hydrogel comprising an artificial glyco-lipid through supramolecular copolymerization

Supramolecular copolymer hydrogels were prepared by mixing 1 and the additives 2-8, and their rheological properties were evaluated. It was found that additive 3 reinforced the mechanical strength of the resultant hydrogel most efficiently, increasing the yield stress of SCH 1+3 about fourfold. The optimal mixing between the glyco-lipid hydrogelator 1 and the additive 3 sufficiently enhanced the mechanical strength of the resultant SCH, which improved the handling of the SH on the large scale. These results indicate that supramolecular copolymerization can provide the supramolecular hydrogel with desired properties and/or functions.     

Lanthanide-containing photoluminescent materials: from hybrid hydrogel to inorganic nanotubes

Functional photoluminescent materials are emerging as a fascinating subject with versatile applicability. In this work, luminescent organic-inorganic hybrid hydrogels are facilely designed through supramolecular self-assembly of sodium cholate, and lanthanide ions such as Eu(3+), Tb(3+), and Eu(3+)/Tb(3+). Fluorescence microscopy and TEM visualization demonstrates the existence of spontaneously self-assembled nanofibers and 3D networks in hybrid hydrogel. Photoluminescence enhancement of lanthanide ions is realized through coordination with cholate and co-assembly into 1D nanofibers, which can successfully shield the Eu(3+) from being quenched by water. The photoluminescence emission intensity of a hybrid hydrogel exhibits strong dependence on europium/cholate molar ratio, with maximum emission appearing at a stoichiometry of 1:3. Furthermore, the emission color of a lanthanide-cholate hydrogel can be tuned by utilizing different lanthanide ions or co-doping ions. Moreover, photoluminescent lanthanide oxysulfide inorganic nanotubes are synthesized by means of a self-templating approach based on lanthanide-cholate supramolecular hydrogels. To the best of our knowledge, this is the first time that the lanthanide oxysulfide inorganic nanotubes are prepared in solution under mild conditions.     

Graphene oxide-based supramolecular hydrogels for making nanohybrid systems with Au nanoparticles

In the presence of a small amount of a proteinous amino acid (arginine/tryptophan/histidine) or a nucleoside (adenosine/guanosine/cytidine), graphene oxide (GO) forms supramolecular stable hydrogels. These hydrogels have been characterized by field-emission scanning electron microscopy (FE-SEM), atomic force microscopy (AFM), X-ray diffraction (XRD) analysis, Raman spectroscopy, and rheology. The morphology of the hydrogel reveals the presence of nanofibers and nanosheets. This suggests the supramolecular aggregation of GO in the presence of an amino acid/nucleoside. Rheological studies of arginine containing a GO-based hydrogel show a very high G' value (6.058 × 10(4) Pa), indicating the rigid, solid-like behavior of this gel. One of these hydrogels (GO-tryptophan) has been successfully utilized for the in situ synthesis and stabilization of Au nanoparticles (Au NPs) within the hydrogel matrix without the presence of any other external reducing and stabilizing agents to make Au NPs containing the GO-based nanohybrid material. The Au NPs containing the hybrid hydrogel has been characterized by using UV/vis spectroscopy, X-ray diffraction (XRD), and transmission electron microscopy (TEM). In this study, gold salt (Au(3+)) has been bioreduced by the tryptophan within the hydrogel. This is a facile "green chemical" method of preparing the GO-based nanohybrid material within the hydrogel matrix. The significance of this method is the in situ reduction of gold salt within the gel phase, and this helps to decorate the nascently formed Au NPs almost homogeneously and uniformly on the surface of the GO nanosheets within the gel matrix.     

Self-assembled hybrid nanofibers confer a magnetorheological supramolecular hydrogel

Most magnetorheological materials, composed of magnetic microparticles in a liquid, require significant amounts of magnetic particles and a large magnetic field to achieve the desired effects. Here, we report on a new type of magnetorheological materials consisting of small amounts of magnetic nanoparticles (0.8 wt %) but exhibiting large rheological change (i.e., a gel-sol transition) upon the application of a small magnetic field. We use self-assembly to create hybrid nanofibers, which consist of supramolecular hydrogelators and magnetic nanoparticles, as the matrices of the hydrogel. Localized in the nanofibers at a distance of 1-2 nm, the magnetic nanoparticles occupy a small volume fraction of the hydrogel, significantly enhancing the magnetic dipole interactions between them, which results in the large magnetoresponse. This strategy generates a hierarchical nanostructure and eliminates several drawbacks of the simple mixture of polymers with nanoparticles, and thus provides a new methodology that uses magnetic force to control the nanostructures and properties of soft materials.     

Using a kinase/phosphatase switch to regulate a supramolecular hydrogel and forming the supramolecular hydrogel in vivo

We have designed and synthesized a new hydrogelator Nap-FFGEY (1), which forms a supramolecular hydrogel. A kinase/phosphatase switch is used to control the phosphorylation and dephosphorylation of the hydrogelator and to regulate the formation of supramolecular hydrogels. Adding a kinase to the hydrogel induces a gel-sol phase transition in the presence of adenosine triphosphates (ATP) because the tyrosine residue is converted into tyrosine phosphate by the kinase to give a more hydrophilic molecule of Nap-FFGEY-P(O)(OH)(2) (2); treating the resulting solution with a phosphatase transforms 2 back to 1 and restores the hydrogel. Electron micrographs of the hydrogels indicate that 1 self-assembles into nanofibers. Subcutaneous injection of 2 in mice shows that 80.5 +/- 1.2% of 2 turns into 1 and results in the formation of the supramolecular hydrogel of 1 in vivo. This simple biomimetic approach for regulating the states of supramolecular hydrogels promises a new way to design and construct biomaterials.     

Viscoelastic and fractal characteristics of a supramolecular hydrogel hybridized with clay nanoparticles

The supramolecular hydrogels derived from low-molecular-mass gelators represent a unique class of soft matters and have important potential applications in biomedical fields, separation technology and cosmetic science. However, they suffer usually from weak mechanical and viscoelastic properties. In this work, we carry out the in situ hybridization of clay nanoparticles (Laponite RD) into the supramolecular hydrogel formed from a low-molecular-mass hydrogelator, 2,6-di[N-(carboxyethyl carbonyl)amino]pyridine (DAP), and investigate the viscoelastic and structural characteristics of resultant hybrid hydrogel. It was found that a small concentration of Laponite RD could lead to a significant increase in the storage modulus, loss modulus or complex viscosity. Compared with neat DAP hydrogel, the hybrid hydrogel has a greater hydrogel strength and a lower relaxation exponent. In particular, the enhancement of the clay nanoparticles to the viscoelastic properties of the DAP hydrogel is more effective in the case of higher DAP concentration. By relating its macroscopic elastic properties to a scaling fractal model, such a hybrid hydrogel was confirmed to be in the strong-link regime and to have a more complex network structure with a higher fractal dimension when compared with neat DAP hydrogel.     

Diffusion and birefringence of bioactive dyes in a supramolecular guanosine hydrogel

Transparent self-standing supramolecular hydrogels were readily prepared by the potassium-ion-mediated self-organization of guanosine and 8-bromoguanosine whilst the individual components precipitated within a few hours. VT-NMR spectroscopy showed that bromoguanosine was a superior gelator compared to guanosine. XRD analysis showed that gel formation was caused by stacked G-quartets. AFM analysis revealed dendritic architectures of the nanofibers in the two-component hydrogel network. DSC profiles showed that the hybrid hydrogels underwent sol-gel transition at lower temperature than the pure guanosine and bromoguanosine hydrogels. Interestingly, bioactive dyes, such as rose bengal, rhodamine-6-G, and fluorescein, could be diffused and released in a controlled manner. UV/Vis absorption and fluorescence spectroscopy and CLSM were used to investigate the diffusion behavior of dyes in the hydrogel network. These dyes exhibited strong birefringence in the gel network (0.07-0.1) as a result of the anisotropic organization.     

Novel supramolecular gelation route to in situ entrapment and sustained delivery of plasmid DNA

In this work, cationic block copolymer (F-68-PLL) composed of Pluronic F-68 and poly(L-lysine) segments was first prepared for the binding with plasmid DNA due to the electrostatic interaction between poly(L-lysine) segments and plasmid DNA, and subsequently used to interact with α-cyclodextrin (α-CD) in aqueous system for the supramolecular gelation by the inclusion complexation between Pluronic F-68 segments and α-CD. It was found that such a fabrication process could lead to the in situ entrapment of plasmid DNA into the supramolecular hydrogel matrix under mild conditions. Depending on the amounts of F-68-PLL and α-CD, the resultant hybrid hydrogel was found to have adjustable gelation time and mechanical strength. For the plasmid DNA complexes released from the supramolecular hydrogel, controlled release and sustained gene transfection were confirmed.     

Enzymatic Dissolution of Biocomposite Solids Consisting of Phosphopeptides to Form Supramolecular Hydrogels

Enzyme‐catalyzed dephosphorylation is essential for biomineralization and bone metabolism. Here we report the exploration of using enzymatic reaction to transform biocomposites of phosphopeptides and calcium (or strontium) ions to supramolecular hydrogels as a mimic of enzymatic dissolution of biominerals. ³¹P NMR shows that strong affinity between the phosphopeptides and alkaline metal ions (e.g., Ca²⁺ or Sr²⁺) induces the formation of biocomposites as precipitates. Electron microscopy reveals that the enzymatic reaction regulates the morphological transition from particles to nanofibers. Rheology confirms the formation of a rigid hydrogel. As the first example of enzyme‐instructed dissolution of a solid to form supramolecular nanofibers/hydrogels, this work provides an approach to generate soft materials with desired properties, expands the application of supramolecular hydrogelators, and offers insights to control the demineralization of calcified soft tissues.     

Preparation of single-handed helical phenolic resin nanoflbers using a supramolecular templating method

Single-handed helical phenolic resin nanofibers were synthesized through a supramolecular templating approach using the supramolecular self-assemblies of a pair of chiral low-molecular-weight amphiphiles as the templates and 2,4-dihydroxybenzoic acid and formaldehyde as the precursors.The phenolic resin nanofibers were characterized using field-emission scanning electron microscopy,transmission electron microscopy and diffused reflection circular dichroism.The results indicated that the chirality of the supramolecular self-assemblies was successfully transferred to the phenolic resin nanofibers.The left- and right-handed helical phenolic resin nanofibers exhibited opposite optical activity.     

Anions bonded on the supramolecular hydrogel surface as the growth center of biominerals

In this work, a supramolecular hydrogel formed from N,N',N'-tris(3-pyridyl)-trimesic amide was reported to serve as the matrix for the growth of biominerals. The organic hydrogel scaffold contains nitrogen heterocyclic ring and amide groups that can bind anions of the mineral (specially here, carbonate ions and phosphate ions) through hydrogen bonding interactions and act as the biomineralization active sites for growing biominerals. Calcium carbonate nucleated on the site of the hydrogel fiber where carbonate ions bonded and left obvious hydrogel fiber prints on the obtained product. Calcium phosphate grew into curved platelike nanostructures along the hydrogel fibrous network. XRD pattern and FT-IR spectra confirmed the formation of minerals on the hydrogel. The results indicate that the hydrogen bonding interaction can provide strong enough binding force for the growth of the minerals on organic scaffolds. Our finding extends the organic scaffolds into biodegradable small molecule hydrogels and also extends the growth centers of the minerals from conventional carboxylate groups binding Ca(2+) to amide and pyridyl groups binding PO(4)(3-).     

A novel route to in‐situ incorporation of silver nanoparticles into supramolecular hydrogel networks

A novel strategy was developed for the in situ incorporation of silver nanoparticles into the supramolecular hydrogel networks, in which colloidally stable silver hydrosols were firstly prepared in the presence of an amphiphilic block copolymer of poly(oxyethylene)‐poly(oxypropylene)‐poly(oxyethylene) and then mixed with aqueous solution of α‐cyclodextrin. The analyses from rheology, X‐ray diffraction, and scanning electron microscopy confirmed the formation of the supramolecular‐structured hydrogels hybridized with silver nanoparticles. In particular, the colloidal stability of the resultant silver hydrosol and its gelation kinetics in the presence of α‐cyclodextrin as well as the viscoelastic properties of the resultant hybrid hydrogel were investigated under various concentrations of the used block copolymer. It was found that the used block copolymer could act not only as the effective reducing and stabilizing agents for the preparation of the silver hydrosol but also as the effective guest molecule for the supramolecular self‐assembly with α‐cyclodextrin. In addition, the effects of silver nanoparticles on the gelation process and the hydrogel strength were also studied. Such a hybrid hydrogel material could show a good catalytic activity for the reduction of methylene blue dye by sodium borohydride. © 2009 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 47: 740–749, 2009     

pH-Responsive shrinkage/swelling of a supramolecular hydrogel composed of two small amphiphilic molecules

A pH-responsive volume-change function was successfully introduced into a supramolecular hydrogel that contained GalNAc-appended (GalNAc=N-acetylgalactosamine) glutamate ester 1 by the simple mixing of it with an appropriate amount of 2 a or 2 b amphiphilic carboxylic acid. In the 1:1 mixture (1:2), the hydrogel swelled under neutral pH conditions, but shrank to almost half of its original volume under acidic pH conditions. The structure and pH response of the mixed hydrogel were characterized by using X-ray diffraction (XRD), confocal laser scanning microscopy (CLSM), transmission or scanning electron microscopy (TEM, SEM), and Fourier transform IR (FTIR) spectroscopy. Well-developed fibers formed a stable hydrogel by self-assembly, and under acidic conditions the charge of the carboxylic acid terminal (from the carboxylate anion) was neutralized and then these fibers became densely packed. This macroscopic pH response was also applied to the pH-triggered release of bioactive substances. In this mixed supramolecular hydrogel, the hydrogelator 1 provides a stable hydrogel structure and the additive 2 acts as a commander that is sensitive to an environmental pH signal. The present supramolecular copolymerization strategy should be useful for the construction of novel, stimuli-responsive, soft materials.     

Heat‐Induced Morphological Transformation of Supramolecular Nanostructures by Retro‐Diels–Alder Reaction

Controlling the morphology of supramolecular nanostructures in response to external stimuli is an important challenge in the development of functional soft materials. Here we show that a morphological transformation from 2D nanosheets to a network of 1D nanofibers is triggered by heating, which induces molecular conversion of a bolaamphiphile to a hydrogelator by means of a retro‐Diels–Alder reaction, thereby producing a new heat‐set supramolecular hydrogel. We anticipate that our design will be a starting point for more sophisticated supramolecular systems that integrate the thermodynamics of molecular assembly and the kinetics of chemical reactions to create complex supramolecular nanostructures.     

Three distinct read-out modes for enzyme activity can operate in a semi-wet supramolecular hydrogel

Assays of hydrolytic enzyme activity, such as of glycosidases and phosphatase, as well as several proteases, using a semi-wet supramolecular hydrogel array composed of a glycosylated amino acetate are described. It has been demonstrated that the microcavity formed by gel fibrils is suitable to immobilize native enzymes without denaturation under semi-wet conditions, and thus the nanofiber has been rationally used as a sensing domain to monitor enzymatic reactions. By using a fluorogenic substrate, reducing the size of the hydrogel can significantly improve the problem of suppressed diffusion within the gel matrix thus making the hydrogel a promising semi-wet matrix for evaluating enzyme activity. Confocal laser scanning microscopy observations have shown that an environmentally sensitive fluorescent probe accumulates in the hydrophobic domain of the gel fiber and emits fluorescence more strongly upon hydrolytic cleavage of the substrate peptides. Not only a simple environmentally sensitive probe but also a FRET (fluorescence resonance energy transfer)-type read-out mode can be devised to analyze the enzymatic hydrolysis-triggered redistribution of the probe between the nanospace and the nanofiber to accomplish a more clearly distinguished enzyme assay. Thus, it is clear that three distinct read-out modes, that is, 1) fluorogenic substrates, 2) substrates bearing an environmentally sensitive probe, or 3) a substrate exhibiting FRET, can operate under the semi-wet hydrogel conditions used in these investigations. In addition, owing to the unique properties of the present supramolecular hydrogel in semi-wet conditions, that is, its phase-segregation properties and dynamics, the supramolecular substrate/enzyme array has successfully been used for high-throughput screening of single and multiple enzymes based on their activity, lysate analysis, and quantitative evaluation of inhibitor potency and selectivity.     

Self-assembly of amphiphiles with terthiophene and tripeptide segments into helical nanostructures

We previously reported a class of tripeptide amphiphiles known as peptide lipids that self-assemble into one-dimensional nanostructures with superhelical twisting. The pitch of this supramolecular twisting is controlled directly through sterics in the molecular structure of hydrophobic segments. In this work we study the supramolecular behavior of these nanoscale helices by substituting with a terthiophene conjugated segment of potential electronic interest and also through variations in the stereochemistry of the tripeptide. This terthiophene peptide lipid was shown to self-assemble into one-dimensional helical nanofibers with a regular diameter of 9±1 nm and helical pitch of 65±6 nm, and also found to form hierarchical double- and triple-stranded helices, which could be associated with terthiophene J-aggregate interactions among fibers. For stereochemical effects, we compared four diastereomers in the tripeptide sequence using l-glutamic acid and l- and d-alanine residues to probe their ability to control supramolecular organization. Interestingly, we found by atomic force microscopy that the LLD diastereomers formed cylindrical nanofibers without any twisting, whereas LDD diastereomeric segments self-assembled into helical nanofibers with a pitch of 40±6 nm. LDL diastereomeric segments formed, on the other hand, aggregates without any regular shape. We propose that these profound effects of chirality with amino acid sequence are related to changes in the β-sheet sub-structure within the nanofibers.     

Water gelation of an amino acid-based amphiphile

The water immobilization by a simple amino acid-containing cationic surfactant was investigated. A variety of techniques, such as (1)H NMR spectroscopy, circular dichroism (CD), steady-state fluorescence spectroscopy, and field-emission scanning electron microscopy (FESEM) were applied to determine the formation and architecture of the hydrogel. The new gelator with a minimum gelation concentration (MGC) of 0.3 % w/v shows prolonged stability and a low melting temperature (39 degrees C). (1)H NMR experiments revealed that intermolecular hydrogen bonding between the amide groups and pi-pi stacking of the indole rings are the two regulating parameters for gelation. Furthermore, fluorescence studies with 8-anilino-1-naphthalenesulfonic acid (ANS) as the probe indicate the participation of hydrophobicity during gelation. The luminescence study using both ANS and pyrene, along with FESEM results, indicate a critical concentration, well below the MGC, at which fibres begin to form. These cross-link further to give thicker fibers, leading to the formation of a hydrogel (0.3 % w/v). This new hydrogelator expresses high supramolecular chirality, as evidenced by the CD spectra. In addition, the gelator molecule was found to be nontoxic up to a concentration of 4 mM (0.2 % w/v). The high supramolecular chirality, prolonged stability, low melting point, and biocompatibility of the molecule make it a focus of chemical and biological interest.     

The Power of Confocal Laser Scanning Microscopy in Supramolecular Chemistry: In situ Real-time Imaging of Stimuli-Responsive Multicomponent Supramolecular Hydrogels

Multicomponent supramolecular hydrogels are promising scaffolds for applications in biosensors and controlled drug release due to their designer stimulus responsiveness. To achieve rational construction of multicomponent supramolecular hydrogel systems, their in-depth structural analysis is essential but still challenging. Confocal laser scanning microscopy (CLSM) has emerged as a powerful tool for structural analysis of multicomponent supramolecular hydrogels. CLSM imaging enables real-time observation of the hydrogels without the need of drying and/or freezing to elucidate their static and dynamic properties. Through multiple, selective fluorescent staining of materials of interest, multiple domains formed in supramolecular hydrogels (e. g. inorganic materials and self-sorting nanofibers) can also be visualized. CLSM and the related microscopic techniques will be indispensable to investigate complex life-inspired supramolecular chemical systems.     

Stiff,Multistimuli‐Responsive Supramolecular Hydrogels as Unique Molds for 2D/3D Microarchitectures of Live Cells

Supramolecular hydrogels constructed through molecular self‐assembly of small molecules have unique stimuli‐responsive properties; however, they are mechanically weak in general, relative to conventional polymer gels. Very recently, we developed a zwitterionic amino acid tethered amphiphilic molecule 1 , which gave rise to a remarkably stiff hydrogel comparable with polymer‐based agarose gel, retaining reversible thermal‐responsive properties. In this study, we describe that rational accumulation of multiple and orthogonal noncovalent interactions in the supramolecular nanofibers of 1 played crucial roles not only in the mechanical reinforcement but also in the multistimuli responsiveness. That is, the zwitterionic amino acid moiety and the C C double bond unit of the hydrogelator 1 can function as a pH‐responsive unit and a light‐responsive unit, respectively. We also demonstrated that this stiff and multistimuli‐responsive supramolecular hydrogel 1 is applied as a unique mold for 2D and 3D‐patterning of various substances. More significantly, we succeeded in the fabrication of a collagen gel for spatial patterning, culturing, and differentiation of live cells by using hydrogel 1 molds equipped with 2D/3D microspace channels (100–200 μm in diameter).