Molecular Gelators Research Articles

A Very Personal View of Molecular Organogels. Examples Showing the Conceptual Links with Structurally Simple Gelators

Results from studies of some structurally simple molecular gelators developed at Georgetown and the properties of their organogels, formed by cooling their sol phases, in a variety of liquids are presented. Dynamic and structural aspects of the gels at different distance and time scales are discussed. Results from oscillatory rheology have been employed to assess some of the dynamic properties, including their thixotropy.

Protected Amino Acid-Based Hydrogels Incorporating Carbon Nanomaterials for Near-Infrared Irradiation-Triggered Drug Release.

Molecular gels formed by the self-assembly of low-molecular-weight gelators have received increasing interest because of their potential applications in drug delivery. In particular, the ability of peptides and amino acids to spontaneously self-assemble into three-dimensional fibrous network has been exploited in the development of hydrogels. In this context, we have investigated the capacity of binary mixtures of aromatic amino acid derivatives to form hydrogels. Carbon nanomaterials, namely oxidized carbon nanotubes or graphene oxide, were incorporated in the two most stable hydrogels, formed by Fmoc-Tyr-OH/Fmoc-Tyr(Bzl)-OH and Fmoc-Phe-OH/Fmoc-Tyr(Bzl)-OH, respectively. The structural and physical properties of these gels were assessed using microscopic techniques and rheology. Circular dichroism and molecular dynamics simulations demonstrated that the hydrogel formation was mainly driven by aromatic interactions. Finally, a model hydrophilic drug (l-ascorbic acid) was loaded into the hybrid hydrogels at a high concentration. Under near-infrared light irradiation, a high amount of drug was released triggered by the heat generated by the carbon nanomaterials, thus offering interesting perspectives for controlled drug delivery.

Controlled Fabrication of Micropatterned Supramolecular Gels by Directed Self-Assembly of Small Molecular Gelators.

Herein, the micropatterning of supramolecular gels with oriented growth direction and controllable spatial dimensions by directing the self-assembly of small molecular gelators is reported. This process is associated with an acid-catalyzed formation of gelators from two soluble precursor molecules. To control the localized formation and self-assembly of gelators, micropatterned poly(acrylic acid) (PAA) brushes are employed to create a local and controllable acidic environment. The results show that the gel formation can be well confined in the catalytic surface plane with dimensions ranging from micro- to centimeter. Furthermore, the gels show a preferential growth along the normal direction of the catalytic surface, and the thickness of the resultant gel patterns can be easily controlled by tuning the grafting density of PAA brushes. This work shows an effective "bottom-up" strategy toward control over the spatial organization of materials and is expected to find promising applications in, e.g., microelectronics, tissue engineering, and biomedicine.

Low Molecular Weight Hydro-and Organo Gelators Used for Medical Applications

Low Molecular Weight Hydro-and Organo Gelators Used for Medical Applications

Gelled non-toxic microemulsions: phase behavior & rheology.

Bicontinuous microemulsions gelled with a low molecular weight gelator have been shown to be an orthogonally self-assembled system. With the mechanical stability provided by the gel network, gelled non-toxic bicontinuous microemulsions have the potential to be an efficient transdermal drug delivery carrier. However, up to now no suitable system has been formulated for transdermal drug delivery. To fill this gap, we formulated and characterized a gelled non-toxic bicontinuous microemulsion suitable for the mentioned application. Starting from a previously studied scouting system, namely, H2O-n-octane-n-octyl β-d-glucopyranoside (β-C8G1)-1-octanol, the co-surfactant and the oil were replaced by non-toxic components. Subsequently, the expensive pure surfactant was replaced by cheap technical-grade surfactants (Plantacare® series) to make the system economical. Having formulated the non-toxic microemulsion H2O-IPM-Plantacare 1200 UP-1,2-octanediol, three low molecular weight gelators were studied with regard to the gelation of both the scouting system and the non-toxic system. The chosen gelators were 12-hydroxyoctadecanoic acid (12-HOA), 1,3:2,4-dibenzylidene-d-sorbitol (DBS), and N,N'-dibenzoyl-l-cystine (DBC). We found that only DBS gels the non-toxic microemulsion. The gelled non-toxic bicontinuous microemulsion H2O-IPM-Plantacare 1200 UP-1,2-octanediol was characterized with oscillatory shear rheometry and small-angle neutron scattering (SANS) at a DBS concentration of 0.3 wt% to verify that the system is indeed a gel and that the microstructure of the microemulsion is not altered by the gel network.

Molecular motifs encoding self-assembly of peptide fibers into molecular gels.

Peptides are a promising class of gelators, due to their structural simplicity, biocompatibility and versatility. Peptides were synthesized based on four amino acids: leucine, phenylalanine, tyrosine and tryptophan. These peptide gelators, with systematic structural variances in side chain structure and chain length, were investigated using Hansen solubility parameters to clarify molecular features that promote gelation in a wide array of solvents. It is of utmost importance to combine both changes to structural motifs and solvent in simultaneous studies to obtain a global perspective of molecular gelation. It was found that cyclization of symmetric dipeptides, into 2,5-diketopiperazines, drastically altered the gelation ability of the dipeptides. C-l-LL and C-l-YY, which are among the smallest peptide LMOGs reported to date, are robust gelators with a large radius of gelation (13.44 MPa1/2 and 13.90 MPa1/2, respectively), and even outperformed l-FF (5.61 MPa1/2). Interestingly, both linear dipeptides (l-FF and l-LL) gelled similar solvents, yet when cyclized only cyclo-dityrosine was a robust gelator, while cyclo-diphenylalanine was not. Changes in the side chains drastically affected the crystal morphology of the resultant gels. Symmetric cyclo dipeptides of leucine and tyrosine were capable of forming extremely high aspect ratio fibers in numerous solvents, which represent new molecular motifs capable of driving self-assembly.

Using cavitation rheology to understand dipeptide-based low molecular weight gels.

The study of dipeptide-based hydrogels has been the focus of significant effort recently due to their potential for use in a variety of biomedical and biotechnological applications. It is essential to study the mechanical properties in order to fully characterise and understand this type of soft materials. In terms of mechanical properties, the linear elastic modulus is normally measured using traditional shear rheometry. This technique requires millilitre sample volumes, which can be difficult when only small amounts of gel are available, and can present difficulties when loading the sample into the machine. Here, we describe the use of cavitation rheology, an easy and efficient technique, to characterise the linear elastic modulus of a range of hydrogels. Unlike traditional shear rheometry, this technique can be used on hydrogels in their native environment, and small sample volumes are required. We describe our set-up and show how it can be used to probe and understand different types of gels. Gels can be formed by different triggers from the same gelator and this leads to different microstructures. We show that the data from the cavitational rheometer correlates with the underlying microstructure in the gels, which allows a greater degree of understanding of the gels than can be obtained from the bulk measurements.

Hierarchically Compartmentalized Supramolecular Gels through Multilevel Self-Sorting.

Hierarchical compartmentalization through the bottom-up approach is ubiquitous in living cells but remains a formidable task in synthetic systems. Here we report on hierarchically compartmentalized supramolecular gels that are spontaneously formed by multilevel self-sorting. Two types of molecular gelators are formed in situ from nonassembling building blocks and self-assemble into distinct gel fibers through a kinetic self-sorting process; interestingly, these distinct fibers further self-sort into separated microdomains, leading to microscale compartmentalized gel networks. Such spontaneously multilevel self-sorting systems provide a “bottom-up” approach toward hierarchically structured functional materials and may play a role in intracellular organization.

A Biomimetic Supramolecular Approach for Charge Transfer between Donor and Acceptor Chromophores with Aggregation-Induced Emission.

Supramolecular assembly of chromophores with inherent resistance to aggregation-induced self-quenching is significant to applications such as chemical sensing and organic light emitting diodes (OLEDs). In this work, molecular gels with aggregation-induced emission (AIE) are constructed by simply coassembling AIE chromophores (electron donor or acceptor) with a nonfluorescent molecular gelator. The binary gels are fluorescent even at very low concentrations of the AIE chromophores, indicating that the rotation of their aromatic cores is restricted in the gel network. In tertiary gels, the fluorescence of the donor chromophore can be efficiently reduced by the acceptor chromophore through a combination of static and dynamic quenching process, via charge transfer from the donor to the acceptor. This work demonstrates a convenient approach to fabricate a supramolecular charge transfer system using an AIE donor and acceptor.

Unusual Molecular and Supramolecular Structures of Chiral Low Molecular Weight Organogelators with Long Perfluoroalkyl Chains

Gels composed of low molecular weight gelators (LMWGs) are fascinating research targets from the viewpoint of applications because their functionalities are easily modified by designing their molecular structures. Some reliable gelator design approaches have been developed. However, new classes of molecular gelators are sometimes discovered unexpectedly, suggesting that there remain unknown aspects about gelators. To obtain knowledge regarding gelation and crystallization ability, the crystal structure of N,N′-diperfluorooctanoyl-(1R,2R)-1,2-diaminocyclohexane (RR-CF8), which is a derivative of 1,2-diaminocyclohexane, one of the most famous LMWGs, was investigated in addition to the vibrational circular dichroism (VCD) measurements. The crystal structure was solved from powder X-ray diffraction patterns because recrystallization of RR-CF8 afforded no suitable single crystals for single crystal X-ray diffraction measurement. Two unusual structural features were confirmed. One is that the perfluoroalkyl cha...

Using Cholesterol as Low Molecular Mass Gelator for a New Nanogel Preparation

Using Cholesterol as Low Molecular Mass Gelator for a New Nanogel Preparation

Nucleation effects of high molecular weight polymer additives on low molecular weight gels

Polymeric species have been introduced to low molecular weight gelators to tailor their nucleation and rheological behavior. This work combines polymers and molecular gels (MGs) in a different manner by using polymers as the major component in a solution. Additionally, using polymers above their entanglement molecular weight is a step towards building polymer–MG composite materials. Specifically, a cholesterol-pyridine (CP) molecular gel was introduced to poly(ethylene oxide-co-epichlorohydrin) (EO-EPI) and poly(vinyl acetate) (PVAc), which have dissimilar chain conformations in anisole. Dynamic light scattering, scanning electron microscopy, and temperature-dependent small- and wide-angle X-ray studies were utilized to investigate the influence of the solution properties of high molecular weight EO-EPI and PVAc on the CP network structure. The collapsed chain conformation and aggregation of EO-EPI led to isolated, branched CP fiber networks, resulting in unexpectedly high dissociation temperatures. In contrast, PVAc gels displayed transient fiber networks, as evidenced by fiber wrapping and bundling. Cooperative interactions between PVAc and CP resulted in gels with dissociation temperatures higher than those of pure CP gels. These structural characteristics significantly influenced the gel mechanics. The collapsed chain conformation of EO-EPI led to weaker, more viscous gels, and the freely extended PVAc chain conformation led to interconnected, elastic gels independent of the molecular gel concentration. Polymer chain conformation was utilized to control the nucleation of a cholesterol-pyridine molecular gel. Collapsed chain conformations influence gel structure and dissociation behavior by acting as physical barriers that lead to confinement effects and permanent networks. An extended polymer chain conformation allowed for polymer–molecular-gel interactions and increased dissociation temperatures due to its highly ordered structure, resulting in transient networks. Additionally, the high molecular weight polymer solution behavior guided solution mechanics, where collapsed chains lead to viscous solutions and gels and extended chains led to elastic gel networks.

Photochemical liquefaction and softening in molecular materials, polymers, and related compounds

Recent developments in materials showing photo-induced liquefaction and softening, including molecular materials, gels, and polymers, are described. A macrocyclic azobenzene molecule that has long alkoxy chains was first reported to show a photo-induced solid–liquid phase transition at room temperature through trans–cis photoisomerization. The structure–property relationship for understanding the photo-induced phase transition has since been investigated by using model compounds with a simple molecular design. Such azobenzene-based materials also exhibited dynamic motion on glass and water surfaces; these motions are driven by continuous liquefaction/crystallization and dissolution of the liquefied material. Photo-induced liquefaction has been further developed in middle molecular and polymeric materials. The effects of the alkyl chain length, functional groups, and number of azobenzene units on the photo-induced behavior have been extensively investigated. In addition, by using photoresponsive gelators, the photo-induced quasi-solid–liquid (gel–sol) phase transition of gels was accomplished. Moreover, very recently, a photoresponsive plasticizer that can plasticize “photo-inactive” polymers by light irradiation has been proposed. This review focuses on the recent developments on the photo-induced liquefaction and softening of azobenzene-based materials. The trans–cis photoisomerization of azobenzene units incorporated in molecular materials, polymers, and gels induces a variety of state changes such as solid–liquid, gel–sol, and glass–rubber transitions of those materials isothermally. Several novel applications such as reusable and environmentally friendly photoresists, reworkable adhesives, and self-healing materials can be expected using the photochemical liquefaction and softening.

Simple Synthetic Molecular Hydrogels from Self-Assembling Alkylgalactonamides as Scaffold for 3D Neuronal Cell Growth.

In this work, we demonstrated that the hydrogel obtained from a very simple and single synthetic molecule, N-heptyl-galactonamide was a suitable scaffold for the growth of neuronal cells in 3D. We evidenced by confocal microscopy the presence of the cells into the gel up to a depth of around 200 μm, demonstrating that the latter was permissive to cell growth and enabled a true 3D colonization and organization. It also supported successfully the differentiation of adult human neuronal stem cells (hNSCs) into both glial and neuronal cells and the development of a really dense neurofilament network. So the gel appears to be a good candidate for neural tissue regeneration. In contrast with other molecular gels described for cell culture, the molecule can be obtained at the gram scale by a one-step reaction. The resulting gel is very soft, a quality in accordance with the aim of growing neuronal cells, that requires low modulus substrates similar to the brain. But because of its fragility, specific procedures had to be implemented for its preparation and for cell labeling and confocal microscopy observations. Notably, the implementation of a controlled slow cooling of the gel solution was needed to get a very soft but nevertheless cohesive gel. In these conditions, very wide straight and long micrometric fibers were formed, held together by a second network of flexible narrower nanometric fibers. The two kinds of fibers guided the neurite and glial cell growth in a different way. We also underlined the importance of a tiny difference in the molecular structure on the gel performances: parent molecules, differing by a one-carbon increment in the alkyl chain length, N-hexyl-galactonamide and N-octyl-galactonamide, were not as good as N-heptyl-galactonamide. Their differences were analyzed in terms of gel fibers morphology, mechanical properties, solubility, chain parity, and cell growth.

Effective combination therapy of percutaneous ethanol injection and chemotherapy based on injectable low molecular weight gels

Percutaneous ethanol injection (PEI) therapy was used in liver cancer treatment, however, the therapeutic ethanol in PEI easily flew away from injected solid tumours and hinder the treatment effect. In this paper, injectable supramolecular gels formed by self-assembly of low molecular weight gelators (LMWGs) based on glycylglycine modified phenylboronic acid were prepared to localize ethanol and load chemotherapeutic drug for in situ synergistic therapy. The mechanism, morphology and rheological property of supramolecular gels were characterized by NMR, UV, SEM, etc. The rheological study revealed that the gels were formed in situ rapidly and recovered promptly once damaged. The gels were non-toxicity to both normal 3T3 fibroblasts cells and 4T1 breast cancer cells. Doxorubicin (DOX) hydrochloride and ethanol were encapsulated in the gels for the combination of chemotherapy and PEI therapy. The in vivo anticancer activity of the DOX-loaded gels was carried out in tumour bearing mice. The injected gels were coated around tumour tissues to lock ethanol, and DOX was released sustainingly from the gels to maintain effective concentration to induce the apoptosis of tumour cells. DOX-loaded gels and the ethanol exhibited excellent therapeutic efficacy and low side effects in local cancer therapy.

Does Drying Affect Gel Networks?

The properties of low molecular weight gels are determined by the underlying, self-assembled network. To access information on the network, it is common for techniques to be used that require the gel to be dried, such as transmission electron microscopy or scanning electron microscopy. The implicit assumption is that this drying has no bearing on the data collected. Here, we discuss the validity of this assumption.

Controlling Variables in Molecular Gel Science: How Can We Improve the State of the Art?

By design, no references are included in this article. It is intended to be a series of recommendations in which the focus is on lab practices for investigating substances rather than on the substances being investigated. Thus, it discusses some specific areas of concern identified by the author. Other scientists are encouraged to add to or amend the contents. This article should be read as a “living” document, like a blog in which many gel scientists work, over time, to achieve a consensus about reporting everything from acronyms and definitions to procedures and methods. For those entering the field and seeking compendia on the subject, the author suggests “Googling” the words “molecular gels” or “molecular gels books”.

Gelating abilities of metal salts of ricinelaidic acid. Structural and rheological considerations

AbstractThe gelating abilities of metal salts of ricinelaidic acid (D‐REA), the trans isomer of the naturally occurring cis isomer, D‐ricinoleic acid, have been examined in a wide range of liquids. D‐REA is not a good gelator due to its bent shape and low melting temperature. Although upon the formation of metal salts aids aggregation of D‐REA, their gelating ability differs dramatically depending on the nature of the metal cation. The salts with nickel(II), copper(II), and zinc(II) are inefficient gelators, while the calcium salt can gelate various organic liquids and the sodium salt is an ambidextrous gelator. Also, gels of calcium and sodium salts in nitrobenzene and/or in water are among the few known examples with crystalline gelator networks that exhibit thixotropic behavior. Structural insights from FT‐IR and powder X‐ray diffraction indicate that the specific nature of interactions of the salts at their head groups leads to different packing arrangements and changes the strength of the driving forces for 1D growth from secondary interactions. A short comparison between the gelating abilities of the D‐REA and the corresponding salts from 9,10‐dioxooctadecanoic acid, an acid of related structure, is included as well. Insights into the relationships among the interactions at the metal carboxylate centers, their ability to form molecular gels, and the properties of their aggregated structures are provided.

Frontispiece: Low Molecular Weight Supramolecular Gels Under Shear: Rheology as the Tool for Elucidating Structure–Function Correlation

Frontispiece: Low Molecular Weight Supramolecular Gels Under Shear: Rheology as the Tool for Elucidating Structure–Function Correlation

Biocatalytic Self-Assembly on Magnetic Nanoparticles.

Combining (bio)catalysis and molecular self-assembly provides an effective approach for the production and processing of self-assembled materials by exploiting catalysis to direct the assembly kinetics and hence controlling the formation of ordered nanostructures. Applications of (bio)catalytic self-assembly in biologically interfacing systems and in nanofabrication have recently been reported. Inspired by self-assembly in biological cells, efforts to confine catalysts on flat or patterned surfaces to exert spatial control over molecular gelator generation and nanostructure self-assembly have also emerged. Building on our previous work in the area, we demonstrate in this report the use of enzymes immobilized onto magnetic nanoparticles (NPs) to spatially localize the initiation of peptide self-assembly into nanofibers around NPs. The concept is generalized for both an equilibrium biocatalytic system that forms stable hydrogels and a nonequilibrium system that normally has a preset lifetime. Characterization of the hydrogels shows that self-assembly occurs at the site of enzyme immobilization on the NPs to give rise to gels with a "hub-and-spoke" morphology, where the nanofibers are linked through the enzyme-NP conjugates. This NP-controlled arrangement of self-assembled nanofibers enables both remarkable enhancements in the shear strength of hydrogel systems and a dramatic extension of the hydrogel stability in the nonequilibrium system. We are also able to show that the use of magnetic NPs enables the external control of both the formation of the hydrogel and its overall structure by application of an external magnetic field. We anticipate that the enhanced properties and stimuli-responsiveness of our NP-enzyme system will have applications ranging from nanomaterial fabrication to biomaterials and biosensing.