Low Molecular Weight Hydrogelators Research Articles

Low molecular weight hydrogels derived from urea based-bolaamphiphiles as new injectable biomaterials.

There is a critical need for soft materials in the field of regenerative medicine and tissue engineering. However, designing injectable hydrogel scaffolds encompassing both adequate mechanical and biological properties remains a key challenge for invivo applications. Here we use a bottom-up approach for synthesizing supramolecular gels to generate novel biomaterial candidates. We evaluated the low molecular weight gels candidates invivo and identified one urea-containing molecule, compound 16, that avoid foreign body reactions in mice. The self-assembly of bolaamphiphiles creates a unique hydrogel supramolecular structures featuring fast gelation kinetics, high elastic moduli, thixotropic, and thermal reversibility properties. This soft material, which inhibits recognition by macrophages and fibrous deposition, exhibits long-term stability after invivo injection.

Drying Affects the Fiber Network in Low Molecular Weight Hydrogels.

Low molecular weight gels are formed by the self-assembly of a suitable small molecule gelator into a three-dimensional network of fibrous structures. The gel properties are determined by the fiber structures, the number and type of cross-links and the distribution of the fibers and cross-links in space. Probing these structures and cross-links is difficult. Many reports rely on microscopy of dried gels (xerogels), where the solvent is removed prior to imaging. The assumption is made that this has little effect on the structures, but it is not clear that this assumption is always (or ever) valid. Here, we use small angle neutron scattering (SANS) to probe low molecular weight hydrogels formed by the self-assembly of dipeptides. We compare scattering data for wet and dried gels, as well as following the drying process. We show that the assumption that drying does not affect the network is not always correct.

Writing with Fluid: Structuring Hydrogels with Micrometer Precision by AFM in Combination with Nanofluidics.

Hydrogels have many applications in biomedical surface modification and tissue engineering. However, the structuring of hydrogels after their formation represents still a major challenge, in particular due to their softness. Here, a novel approach is presented that is based on the combination of atomic force microscopy (AFM) and nanofluidics, also referred to as FluidFM technology. Its applicability is demonstrated for supramolecular hydrogel films that are prepared from low-molecular weight hydrogelators, such as derivates of 1,3,5-benzene tricarboxamides (BTAs). BTA films can be dissolved selectively by ejecting alkaline solution through the aperture of a hollow AFM-cantilever connected to a nanofluidic controller. The AFM-based force control is essential in preventing mechanical destruction of the hydrogels. The resulting "chemical writing" process is studied in detail and the influence of various parameters, such as applied pressure and time, is validated. It is demonstrated that the achievable structuring precision is primarily limited by diffusion and the aperture dimensions. Recently, various additive techniques have been presented to pattern hydrogels. The here-presented subtractive approach can not only be applied to structure hydrogels from the large class of reversibly formed gels with superior resolution but would also allow for the selective loading of the hydrogels with active substances or nanoparticles.

Preparation of dual responsive low-molecular-weight hydrogel for long-lasting drug delivery

A novel low-molecular-weight hydrogel (LMWG) was fabricated by oligopeptide and phenylboronic acid to obtain a smart molecular hydrogel with dual glucose and pH response for long-term drug delivery in this study. Dual glucose and pH responsiveness of the blank molecular hydrogel was first evaluated by on-line tracking the dynamics curves using UV spectroscopy. Model drugs of phenformin for antidiabetes and doxorubicin for anticancer were selected to evaluate the drug carry and glucose/pH responsive drug release of the molecular hydrogel. The results showed the drug-loaded LMWG had good sustaining and long-lasting drug delivery in physiological or pathological environment.

Investigating the effects of peptoid substitutions in self-assembly of Fmoc-diphenylalanine derivatives.

Low molecular weight agents that undergo self-assembly into fibril networks with hydrogel properties are promising biomaterials. Most low molecular weight hydrogelators are discovered empirically or serendipitously due to imperfect understanding of the mechanisms of self-assembly, the packing structure of self-assembled materials, and how the self-assembly process corresponds to emergent hydrogelation. Herein, the mechanisms of self-assembly and hydrogelation of N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-PhePhe), a well-studied low molecular weight hydrogelator, is probed by systematic comparison with derivatives in which Phe residues are replaced by corresponding N-benzyl glycine peptoid (Nphe) analogs. Peptoids are peptidomimetics that shift display of side chain functionality from the α-carbon to the terminal nitrogen. This alters the hydrogen bonding capacity, the side chain presentation geometry, amide cis/trans isomerization equilibrium, and β-sheet potential of the peptoid relative to the corresponding amino acid in the context of peptidic polymers. It was found that amino acid/peptoid hybrids Fmoc-Phe-Nphe and Fmoc-Nphe-Phe have altered fibril self-assembly propensity and reduced hydrogelation capacity relative to the parent dipeptide, and that fibril self-assembly of the dipeptoid, Fmoc-Nphe-Nphe, is completely curtailed. These findings provide insight into the potential of low molecular weight peptoids and peptide/peptoid hybrids as hydrogelation agents and illuminate the importance of hydrogen bonding and π-π interaction geometry in facilitating self-assembly of Fmoc-Phe-Phe.

Crosslinker-Induced Effects on the Gelation Pathway of a Low Molecular Weight Hydrogel.

The use of polymeric crosslinkers is an attractive method to modify the mechanical properties of supramolecular materials, but their effects on the self-assembly of the underlying supramolecular polymer networks are poorly understood. Modulation of the gelation pathway of a reaction-coupled low molecular weight hydrogelator is demonstrated using (bio)polymeric crosslinkers of disparate physicochemical identities, providing a handle for control over materials properties.

Optimising low molecular weight hydrogels for automated 3D printing.

Hydrogels prepared from low molecular weight gelators (LMWGs) are formed as a result of hierarchical intermolecular interactions between gelators to form fibres, and then further interactions between the self-assembled fibres via physical entanglements, as well as potential branching points. These interactions can allow hydrogels to recover quickly after a high shear rate has been applied. There are currently limited design rules describing which types of morphology or rheological properties are required for a LMWG hydrogel to be used as an effective, printable gel. By preparing hydrogels with different types of fibrous network structures, we have been able to understand in more detail the morphological type which gives rise to a 3D-printable hydrogel using a range of techniques, including rheology, small angle scattering and microscopy.

Hydrogelation Induced by Fmoc-Protected Peptidomimetics.

Four new low molecular weight hydrogelators (LMWGs) have been prepared in multigram scale and their attitude to form hydrogels has been tested. The gelation trigger is pH variation. The resulting gels have been characterized with several techniques: measurement of the melting points (T(gel)), transparency, gelation time, and viscoelastic properties, together with ECD analysis. Among them, Fmoc-L-Tyr-D-Oxd-OH 1 is an excellent gelator that leads to the preparation of strong, transparent, and viscoelastic gels, by pH variation. UV-visible analyses have demonstrated that the gels obtained with the LMWG 1 possess high transparency, with a transmittance up to 25.6% at a wavelength of 600 nm. Results of the amplitude sweep experiments showed that the elastic response component (G') was approximately an order of magnitude larger than the viscous component, indicating an elastic rather than viscous attitude of the gels, confirmed by the frequency independence of G' and G″ values, in the range from 0.1 to 100 rad·s(-1). The thermal behavior of gel obtained from Fmoc-L-Tyr-D-Oxd-OH 1 was characterized performing an "ad hoc" rheological temperature sweep experiment, that indicated that G' remained almost constant from 23 °C up to about 65 °C while G″ increased in the same temperature range. At higher temperatures, both G' and G″ values started to slightly decrease without displaying a crossover point.

Probing gelation ability for a library of dipeptide gelators

Functionalised dipeptides are a class of interesting and useful low molecular weight hydrogelators. Here, we report a significantly expanded library of materials, including dipeptides conjugated to carbazole, phenanthracene, anthracene, pyrene and substituted naphthalenes. We assess the effect of using two different gelation methods; a pH-switch and a solvent switch on the gelation behaviour and properties of the dipeptides. Importantly, we investigate the relationship between the structure of these dipeptides and their ability to form gels. From an analysis of the gelation ability of all these dipeptides, it is clear that those containing a phenylalanine as either of the constituent amino acids are much more likely to lead to a gelator being formed as opposed to using non-aromatic amino acids only.

C2-Symmetric Benzene-based Low Molecular Weight Hydrogel Modified Electrode for Highly Sensitive Detection of Copper Ions

In this paper, a new type of low molecular weight gelators (LMWGs), C2-symmetric benzene-based hydrogel (C2-BHG) with a 1,4-dimine benzene was self-assembled on glassy carbon electrode (GCE) and mica surface based on the hydrogen bond or hydrophobic interaction. Atomic force microscopy (AFM) characterization demonstrated the formation process of the C2-BHG hydrogel layer from particles to clusters, and finally to interconnected fiber network gel. The C2-BHG hydrogel layer resulted in the increase of the hydrophilicity of GCE surface. The C2-BHG modified GCEs (C2-BHG/GCE) with different assembly time were studied by cyclic voltammetry and electrochemical impedance spectroscopy in the presence of Fe(CN)64−/3− redox probe. The rich amide and hydroxyl groups in the gel film make the C2-BHG/GCE suitable as ultrasensitive sensor for the detection of Cu(II) ions by stripping voltammetry with the limit of detection of 5×10−10g/L (S/N>3). Under the optimal conditions, the two linear ranges of Cu(II) ions were found to be 1×10−9∼1×10−7g/L and 1×10−7∼1×10−4g/L. The strong coordination interaction of C2-BHG with Cu(II) ions was confirmed by UV-Visible characterization. This new type of C2-BHG modified electrode was promising for highly sensitive Cu(II) ions sensor application due to high stability and excellent selectivity of the analytical signal.

A low molecular weight hydrogel with unusual gel aging.

We describe a dipeptide hydrogel with unusual aging characteristics. Over time, a transformation from a turbid gel to a transparent gel occurs which is initiated from the air-water interface. Here, we investigate this transition and discuss the implications of this aging on the bulk properties of the gel.

Polymerization of low molecular weight hydrogelators to form electrochromic polymers.

We present a method for the polymerization of low molecular weight hydrogelators to form polymers with unique structures. Carbazole-protected amino acids are shown to form hydrogels by self-assembly into fibrous structures. We show that is possible to directly electropolymerize the hydrogels. This results in the formation of microporous electrochromic polymers with distinctive structure. Polymers formed from the same gelator without the pregelation step show more compact structures. This method opens the possibility of creating polymers templated from pre-assembled gels that have the potential to be used in a wide range of applications.

Hydrogels formed from Fmoc amino acids

A number of Fmoc amino acids can be effective low molecular weight hydrogelators; we compare single crystal structures to fibre X-ray diffraction data.

Synthesis and characterization of pH responsive D-glucosamine based molecular gelators.

Small molecular gelators are a class of compounds with potential applications for soft biomaterials. Low molecular weight hydrogelators are especially useful for exploring biomedical applications. Previously, we found that 4,6-O-benzylidene acetal protected D-glucose and D-glucosamine are well-suited as building blocks for the construction of low molecular weight gelators. To better understand the scope of D-glucosamine derivatives as gelators, we synthesized and screened a novel class of N-acetylglucosamine derivatives with a p-methoxybenzylidene acetal protective group. This modification did not exert a negative influence on the gelation. On the contrary, it actually enhanced the gelation tendency for many derivatives. The introduction of the additional methoxy group on the phenyl ring led to low molecular weight gelators with a higher pH responsiveness. The resulting gels were stable at neutral pH values but degraded in an acidic environment. The release profiles of naproxen from the pH responsive gels were also analyzed under acidic and neutral conditions. Our findings are useful for the design of novel triggered release self-assembling systems and can provide an insight into the influence of the the structure on gelation.

Variable gelation time and stiffness of low-molecular-weight hydrogels through catalytic control over self-assembly

This protocol details the preparation of low-molecular-weight hydrogels (LMWGs) in which the gelation time and mechanical stiffness of the final gel can be tuned with the concentration of the catalyst used in the in situ formation of the hydrogelator. By altering the rate of formation of the hydrazone-based gelator from two water-soluble compounds--an oligoethylene functionalized benzaldehyde and a cyclohexane-derived trishydrazide--in the presence of acid or aniline as catalyst, the kinetics of gelation can be tuned from hours to minutes. The resulting materials display controllable stiffness in the 5-50 kPa range. This protocol works at ambient temperatures in water, at either neutral or moderately acidic pH (phosphate buffer, pH 5) depending on the catalyst used. The hydrazide and aldehyde precursors take a total of 5 d to prepare. The final gel is prepared by mixing aqueous solutions of the two precursors and can take between minutes and hours to set, depending on the catalytic conditions. We also describe analysis of the hydrogels by critical gel concentration (CGC) tests, rheology and confocal laser-scanning microscopy (CLSM).

The effect of self-sorting and co-assembly on the mechanical properties of low molecular weight hydrogels.

Self-sorting in low molecular weight hydrogels can be achieved using a pH triggered approach. We show here that this method can be used to prepare gels with different types of mechanical properties. Cooperative, disruptive or orthogonal assembled systems can be produced. Gels with interesting behaviour can be also prepared, for example self-sorted gels where delayed switch-on of gelation occurs. By careful choice of gelator, co-assembled structures can also be generated, which leads to synergistic strengthening of the mechanical properties.

Electrochemically-triggered spatially and temporally resolved multi-component gels

Composition control in multi-component low molecular weight hydrogels can be achieved, using an electrochemically triggered approach.

The development of low-molecular weight hydrogels for applications in cancer therapy

To improve the anti-cancer efficacy and to counteract the side effects of chemotherapy, a variety of drug delivery systems have been invented in past decades, but few of these systems have succeeded in clinical trials due to their respective inherent shortcomings. Recently, low-molecular weight hydrogels of peptides that self-assemble via non-covalent interactions have attracted considerable attention due to their good biocompatibility, low toxicity, inherent biodegradability as well as their convenience of design. Low-molecular weight hydrogels have already shown promise in biomedical applications as diverse as 3D-cell culture, enzyme immobilization, controllable MSC differentiation, wound healing, drug delivery etc. Here we review the recent development in the use of low-molecular weight hydrogels for cancer therapy, which may be helpful in the design of soft materials for drug delivery.

ChemInform Abstract: The Importance of the Self‐Assembly Process to Control Mechanical Properties of Low Molecular Weight Hydrogels

AbstractReview: 57 refs.

Chiral Packing of Cholesteryl Group as an Effective Strategy To Get Low Molecular Weight Supramolecular Hydrogels in the Absence of Intermolecular Hydrogen Bond

Although the most commonly reported low molecular weight hydrogelators (LMWG) are based on the strong and highly directional hydrogen bond between polar groups, the expansion of novel species of LM...