Low Molecular Weight Hydrogelators Research Articles

Recent Advances in Smart Self-Assembled Bioinspired Hydrogels: A Bridging Weapon for Emerging Health Care Applications from Bench to Bedside.

Stimuli-responsive low molecular weight hydrogel interventions for Biomedical challenges are a rapidly evolving paradigm in the bottom-up approach recently. Peptide-based self-assembled nano biomaterials present safer alternatives to their non-degradable counterparts as demanded for today's most urged clinical needs.Although a plethora of work has already been accomplished, programming hydrogelators with appropriate functionalities requires a better understanding as the impact of the macromolecular structure of the peptides and subsequently, their self-assembled nanostructures remain unidentified. Henceforth this review focuses on two aspects: Firstly, the underlying guidelines for building biomimetic strategies to tailor scaffolds leading to hydrogelation along with the role of non-covalent interactions that are the key components of various self-assembly processes. In the second section, it is aimed to bring together the recent achievements with designer assembly concerning their self-aggregation behaviour and applications mainly in the biomedical arena like drug delivery carrier design, antimicrobial, anti-inflammatory as well as wound healing materials. Furthermore, it is anticipated that this article will provide a conceptual demonstration of the different approaches taken towards the construction of these task-specific designer hydrogels. Finally, a collective effort among the material scientists is required to pave the path for the entrance of these intelligent materials into medicine from bench to bedside.

Localized self-assembly of macroscopically structured supramolecular hydrogels through reaction-diffusion.

Localized molecular self-assembly has been developed as an effective approach for the fabrication of spatially resolved supramolecular hydrogels, showing great potential for many high-tech applications. However, the fabrication of macroscopically structured supramolecular hydrogels through molecular self-assembly remains a challenge. Herein, we report on localized self-assembly of low molecular weight hydrogelators through a simple reaction-diffusion approach, giving rise to various macroscopically patterned supramolecular hydrogels. This is achieved on the basis of an acid-catalyzed hydrazone supramolecular hydrogelator system. The acid was pre-loaded in a polydimethylsiloxane (PDMS) substrate, generating a proton gradient in the vicinity of the PDMS surface after immersing the PDMS in the aqueous solution of the hydrogelator precursors. The acid dramatically accelerates the in situ formation and self-assembly of the hydrazone hydrogelators, leading to localized formation of supramolecular hydrogels. The growth rate of the supramolecular hydrogels can be easily tuned through controlling the concentrations of the hydrogelator precursors and HCl. Importantly, differently shaped supramolecular hydrogel objects can be obtained by simply changing the shapes of PDMS. This work suggests that reaction-diffusion-mediated localized hydrogelation can serve as an approach towards macroscopically structuralized supramolecular hydrogels, which may find potential applications ranging from tissue engineering to biosensors.

Synthesis and Characterization of pH Triggered Imine Functional Low Molecular Weight Hydrogel

AbstractA C‐3 symmetric imine functional nonpolymeric low molecular weight gelator is prepared using microwave assisted Schiff base reaction. The synthesized molecule forms a hydrogel at 5 wt% under slightly acidic pH. The material was characterized using an inversion tube test, thermogravimetric analysis (TGA), powder X‐ray diffraction (PXRD) and FT‐IR spectroscopy. Rheological studies show the material forms a strong hydrogel with formation of nanofibrils supported by field‐emission scanning electron microscopy (FE‐SEM). To the best of our knowledge this is the first example of imine based trigonal low molecular weight hydrogelator reported.

Electrogelation: Controlled Fast Formation of Micrometer-Thick Films from Low-Molecular Weight Hydrogelators.

The controlled electrochemical deposition of hydrogels from low-molecular weight hydrogelators (LMWHGs) allows for the defined formation of thin films on electrodes. Here, the deposition of fibrillar networks consisting of N,N',N″-tris(4-carboxyphenylene)-1,3,5-benzenetricarboxamide (BTA) onto ultraflat gold electrodes has been studied. This process, also termed electrogelation, is based on a local change in the pH due to electrolysis of water at the electrode. The protonation of the BTA sodium salt leads to self-assembly into supramolecular fibrillar structures mainly via hydrogen bonding of the uncharged molecules. The resulting hydrogel film was characterized in terms of its thickness by atomic force microscopy (AFM). Two different AFM-based techniques have been used: ex situ imaging of dried films and in situ nanoindentation of the hydrated hydrogel films. The deposition process was studied as a function of gelator concentration, applied potential, and gelation time. These parameters allow control of the film thickness to a high degree of accuracy within a few tenths of nanometers. Film formation takes place in a few seconds at moderate applied potentials, which is beneficial for biomedical applications. The results obtained for the BTA presented here can be transferred to any type of pH-responsive LMWHG and many reversibly formed hydrogel films.

Fabrication of core–shell beads, hollow capsules, and AuNP-embedded catalytic beads from an ultrasmall peptide hydrogel

Hydrogel beads have emerged as a new class of soft materials that infuse the noble properties of macro-dimensional hydrogels in tiny, easily operable, and robust droplets. Usually, polymeric hydrogels are used in the production of hydrogel beads due to their high structural rigidity and durability, and low molecular weight hydrogel beads are relatively uncommon. Herein, we employed an ultra-short peptide (Pyrene-Lys-Cys, PyKC) based low molecular weight injectable hydrogel, that remains insoluble in bulk solvents, to create stable hydrogel beads using a simple extrusion technique. To enhance durability and applicability, the beads are coated with a polymeric shell, resulting in a core–shell configuration. The shell of the core–shell beads can be modified through a variety of organic conjugation reactions. Also, the core (hydrogel) can be sacrificed using DMSO, resulting in the formation of hollow organic capsules. Furthermore, the core–shell beads enabled the in-situ synthesis and stabilization of gold nanoparticles on the bead surface. The gold-loaded beads demonstrated remarkable catalytic efficiency in the reduction of p-nitrophenol and hazardous azo dyes. In a nutshell, the extremely modular and customizable nature of the PyKC-based core–shell hydrogel bead may allow it to function as a unified platform for multifaceted applications.

Differently N-Capped Analogues of Fmoc-FF.

Short and ultra-short peptides have been recently envisioned as excellent building blocks for the formulation of hydrogels with appealing properties. Due to its simplicity and capability to gel under physiological conditions, Fmoc-FF (Nα-fluorenylmethoxycarbonyl-diphenylalanine), remains one of the most studied low molecular-weight hydrogelators. Since its first identification in 2006, a plethora of its analogues were synthetized and investigated for the fabrication of novel supramolecular materials. Here we report a description of the Fmoc-FF analogues in which the aromatic Fmoc group is replaced with other substituents. These analogues are distinguished into five different classes including derivatives: i) customized with solid phase peptide synthesis protecting groups; ii) containing non-aromatic groups, iii) containing aromatic groups, iv) derivatized with metal complexes and v) containing stimuli-responsive groups. The morphological, mechanical, and functional effects caused by this modification on the resulting material are also pointed out.

Low Molecular Weight Hydrogel for Wound Healing.

Octadecylazanediyl dipropionic acid (C18ADPA) is a zwitterionic amphiphile with a dendritic headgroup. C18ADPA self-assembles to lamellar networks, which encompasses water and forms a low-molecular-weight hydrogel (LMWG). In this study, we use the C18ADPA hydrogel as a drug carrier for the in vivo delivery of a copper salt for wound healing in a mouse model. A structural transition was observed based on cryo-scanning electron microscope (cryo-SEM) images after drug loading. The C18ADPA hydrogel, which had a layered structure, transformed into a self-assembled fibrillar network (SAFiN). The mechanical strength of the LMWG has always been an important issue in its applications. However, due to the structural transition, both the storage and loss moduli increased. In vivo tests showed that wound closure was faster after applying the hydrogel formulation compared with the Vaseline formulation. For the first time, we have also provided histological evidence of these effects on skin tissue. The hydrogel formulation exhibited clear advantages in regenerating tissue structure over traditional delivery formulations.

Synthesis and Investigation of Backbone Modified Squaramide Dipeptide Self-Assembly.

Dipeptides are minimalistic peptide building blocks that form well ordered structures through molecular self-assembly. The driving forces involved are cooperative noncovalent interactions such as π-π stacking, hydrogen bonding, and ionic as well as hydrophobic interactions. One of the most intriguing self-assembled motifs that has been extensively explored as a low molecular weight hydrogel for drug delivery, tissue engineering, imaging and techtonics, etc. is Phe-Phe (FF). The backbone of the dipeptide is very crucial for extending secondary structures in self-assembly, and any subtle change in the backbone drastically affect the molecular recognitions. The squaramide (SQ) motif has the unique advantage of hydrogen bonding which can promote the self-assembly process. In this work we have integrated the SQ unit into the dipeptide FF backbone to achieve molecular self-assembly. The resulting carbamate protected backbone modified dipeptide (BocFSAF-OH, 10) has exhibited molecular self-assembly with a fibrilar network. It formed a stable hydrogel (with CAC of 0.024 ± 0.0098 wt %) via the solvent switch method and was found to possess excellent enzymatic stability. The dipeptide and the resulting hydrogel were found to be cytocompatible. When integrated with a polysaccharide based biopolymer, e.g. sodium alginate, the resulting matrix exhibited strong hydrogel character. Therefore, the dipeptide hydrogel of 10 may find its applications in a variety of fields including drug delivery and tissue engineering.

Supramolecular Phenylalanine-Derived Hydrogels for the Sustained Release of Functional Proteins.

Protein-based therapeutics have emerged as next-generation pharmaceutical agents for oncology, bone regeneration, autoimmune disorders, viral infections, and other diseases. The clinical application of protein therapeutics has been impeded by pharmacokinetic and pharmacodynamic challenges including off-target toxicity, rapid clearance, and drug stability. Strategies for the localized and sustained delivery of protein therapeutics have shown promise in addressing these challenges. Hydrogels are critical materials that enable these delivery strategies. Supramolecular hydrogels composed of self-assembled materials have demonstrated biocompatibility advantages over polymer hydrogels, with peptide and protein-based gels showing strong potential. However, cost is a significant drawback of peptide-based supramolecular hydrogels. Supramolecular hydrogels composed of inexpensive low-molecular-weight (LMW) gelators, including modified amino acid derivatives, have been reported as viable alternatives to peptide-based materials. Herein, we report the encapsulation and release of proteins from supramolecular hydrogels composed of perfluorinated fluorenylmethyloxcarbonyl-modified phenylalanine (Fmoc-F5-Phe-DAP). Specifically, we demonstrate release of four model proteins (ribonuclease A (RNase A), trypsin inhibitor (TI), bovine serum albumin (BSA), and human immunoglobulin G (IgG)) from these hydrogels. The emergent viscoelastic properties of these materials are characterized, and the functional and time-dependent release of proteins from the hydrogels is demonstrated. In addition, it is shown that the properties of the aqueous solution used for hydrogel formulation have a significant influence on the in vitro release profiles, as a function of the isoelectric point and molecular weight of the protein payloads. These studies collectively validate that this class of supramolecular LMW hydrogel possesses the requisite properties for the sustained and localized release of protein therapeutics.

Electrofabrication of a low molecular weight hydrogel at high pH

We describe the electrodeposition at high pH of a low molecular weight gelator. Electrodeposition can be used to grow simultaneously two hydrogels at opposing pH extremes on different electrodes.

Aryl-Capped Lysine-Dehydroamino Acid Dipeptide Supergelators as Potential Drug Release Systems.

Employing amino acids and peptides as molecular building blocks provides unique opportunities for generating supramolecular hydrogels, owing to their inherent biological origin, bioactivity, biocompatibility, and biodegradability. However, they can suffer from proteolytic degradation. Short peptides (<8 amino acids) attached to an aromatic capping group are particularly attractive alternatives for minimalistic low molecular weight hydrogelators. Peptides with low critical gelation concentrations (CGCs) are especially desirable, as the low weight percentage required for gelation makes them more cost-effective and reduces toxicity. In this work, three dehydrodipeptides were studied for their self-assembly properties. The results showed that all three dehydrodipeptides can form self-standing hydrogels with very low critical gelation concentrations (0.05–0.20 wt%) using a pH trigger. Hydrogels of all three dehydrodipeptides were characterised by scanning tunnelling emission microscopy (STEM), rheology, fluorescence spectroscopy, and circular dichroism (CD) spectroscopy. Molecular modelling was performed to probe the structural patterns and interactions. The cytotoxicity of the new compounds was tested using human keratinocytes (HaCaT cell line). In general, the results suggest that all three compounds are non-cytotoxic, although one of the peptides shows a small impact on cell viability. In sustained release assays, the effect of the charge of the model drug compounds on the rate of cargo release from the hydrogel network was evaluated. The hydrogels provide a sustained release of methyl orange (anionic) and ciprofloxacin (neutral), while methylene blue (cationic) was retained by the network.

Conformational control of bis-urea self-assembled supramolecular pH switchable low-molecular-weight hydrogelators

We report the synthesis and investigation into the structure-property relationships of eight different low molecular weight hydrogelators based on a bisaromatic urea core unit, all of which form gels as the pH of the solution is lowered. The low molecular weight hydrogelators are functionalized with carboxylic acid moieties on one aromatic ring, and the other aromatic ring features a nitro functional group either in the meta- or para-position relative to the urea linkage. Ortho-methyl substituents were installed on the aromatic rings to enforce a non-coplanar arrangement between the phenyl and urea moieties. Gel formation was triggered by the addition of a mineral acid or the ring-opening hydrolysis of glucono-δ-lactone. The low molecular weight hydrogelators were studied by a variety of analytical techniques, including NMR spectroscopy and rheology. In addition, their ability to uptake a dye, methylene blue, was determined by UV-vis spectroscopy.

Wet spinning of a library of carbohydrate low molecular weight gels

HypothesisRecently, a low molecular weight hydrogel based on a carbohydrate alkyl amide has been successfully used as biomaterial for neuron cell culture and for 3D printing. Varying the molecular structure should make it possible to extend the library of carbohydrate low molecular weight hydrogels available for these applications and to improve their performances. ExperimentsThirteen molecules easy to synthetize and designed to be potentially biocompatible were prepared. They are based on gluconamide, glucoheptonamide, galactonamide, glucamide, aliphatic chains and glycine. Their gelation in water was investigated in thermal conditions and wet spinning conditions, namely by dimethylsulfoxide-water exchange under injection. FindingsNine molecules give hydrogels in thermal conditions. By wet spinning, six molecules self-assemble fast enough, within few seconds, to form continous hydrogel filaments. Therefore, the method enables to shape by injection these mechanically fragile hydrogels, notably in the perspective of 3D printing. Depending on the molecular structure, persistent or soluble gel filaments are obtained. The microstructures are varied, featuring entangled ribbons, platelets or particles. In thermal gelation, molecules with a symmetrical polar head (galacto, glucoheptono) give flat ribbons and molecules with an asymmetrical polar head (gluco) give helical ribbons. The introduction of an extra glycine linker disturbs this trend.

Enzymatic Hydrolysis-Responsive Supramolecular Hydrogels Composed of Maltose-Coupled Amphiphilic Ureas.

Maltose is a ubiquitous disaccharide produced by the hydrolysis of starch. Amphiphilic ureas bearing hydrophilic maltose moiety were synthesized via the following three steps: I) construction of urea derivatives by the condensation of 4-nitrophenyl isocyanate and alkylamines, II) reduction of the nitro group by hydrogenation, and III) an aminoglycosylation reaction of the amino group and the unprotected maltose. These amphiphilic ureas functioned as low molecular weight hydrogelators, and the mixtures of the amphipathic ureas and water formed supramolecular hydrogels. The gelation ability largely depended on the chain length of the alkyl group of the amphiphilic urea; amphipathic urea having a decyl group had the highest gelation ability (minimum gelation concentration=0.4 mM). The physical properties of the supramolecular hydrogels were evaluated by measuring their thermal stability and dynamic viscoelasticity. These supramolecular hydrogels underwent gel-to-sol phase transition upon the addition of α-glucosidase as a result of the α-glucosidase-catalyzed hydrolysis of the maltose moiety of the amphipathic urea.

Advances in engineering of low molecular weight hydrogels for chemotherapeutic applications

Chemotherapy is the primary option for the treatment of cancer, inflammation, and infectious diseases. Conventional drug delivery poses solubility and bioavailability challenges, systemic toxicity, non-specific targeting, and poor accumulation of chemotherapeutic drugs at the desired site. Nanotechnology has led to the development of various nanomaterials that have decreased the toxicity and increased the accumulation of drugs at the target site. Systemic administration of nanomaterials causes burst release and non-specific targeting of chemotherapeutics, leading to off-target organ toxicity. Drug delivery based on low molecular weight hydrogels (LMWHs) provides a suitable alternative for drug delivery due to their ability to entrap chemotherapeutic drugs. Injectable and biodegradable LMWHs allow the administration of chemotherapeutics with minimal invasion, allow the sustained release of chemotherapeutic drugs for long periods, and reduce the challenges of immunogenicity and low drug entrapment efficiency. Herein, we summarize the advances in the engineering of LMWHs for controlled and prolonged delivery of chemotherapeutics for cancer, infectious diseases, and inflammatory disorders.

Forming Low-Molecular-Weight Hydrogels by Electrochemical Methods.

Low-molecular-weight hydrogels (LMWG) can be formed by electrochemical methods. Unique to the electrochemical method, gelation is localized on the electrode surface; therefore, thin hydrogel films can be prepared in seconds while thicker gels can be prepared in minutes. Furthermore, hydrogels are suitable for use in a range of characterization methods. Here, we describe techniques to form hydrogels using cyclic voltammetry and potentiometry.

New injectable self-assembled hydrogels that promote angiogenesis through a bioactive degradation product

Hydrogels used in regenerative medicine are often designed to allow cellular infiltration, degradation, and neovascularization. Low molecular weight hydrogels (LMWHs), formed by self-assembly via non-covalent interactions, are gaining significant interest because they are soft, easy to use and injectable. We propose LMWHs as suitable body implant materials that can stimulate tissue regeneration. We produced four new LMWHs with molecular entities containing nucleic acid and lipid building blocks and analyzed the foreign body response upon subcutaneous implantation into mice. Despite being infiltrated with macrophages, none of the hydrogels triggered detrimental inflammatory responses. Most macrophages present in the hydrogel-surrounding tissue acquired an immuno-modulatory rather than inflammatory phenotype. Concomitantly, no fibrotic capsule was formed after three weeks. Our glyconucleolipid LMWHs exhibited different degradation kinetics in vivo and in vitro. LMWHs with high angiogenic properties in vivo, were found to release glyconucleoside (glucose covalently linked to thymidine via a triazole moiety) as a common by-product of in vitro LMWH degradation. Chemically synthesized glyconucleoside exhibited angiogenic properties in vitro in scratch assays with monolayers of human endothelial cells and in vivo using the chick chorioallantoic membrane assay. Collectively, LMWHs hold promise as efficient scaffolds for various regenerative applications by displaying good biointegration without causing fibrosis, and by promoting angiogenesis through the release of a pro-angiogenic degradation product. Statement of SignificanceThe main limitations of biomaterials developed in the field of tissue engineering remains their biocompatibility and vascularisation properties. In this context, we developed injectable Low Molecular Weight Hydrogels (LMWH) exhibiting thixotropic (reversible gelation) and thermal reversible properties. LMWH having injectability is of great advantage since it allows for their delivery without wounding the surrounding tissues.The resulting gels aim at forming scaffolds that the host cells colonize without major inflammation, and that won't be insulated by a strong fibrosis reaction. Importantly, their molecular degradation releases a product (a glycosyl-nucleoside conjugate) promoting angiogenesis. In this sense, these LMWH represent an important advance in the development of biomaterials promoting tissue regeneration.

Enzyme responsive properties of amphiphilic urea supramolecular hydrogels

Amphiphilic ureas with hydrophilic lactose groups form transparent supramolecular hydrogels. Their gelation abilities are sensitive to the length of the alkyl chain. Amphiphilic ureas bearing hexyl, heptyl, octyl, and nonyl groups form supramolecular hydrogels, but amphiphilic ureas bearing decyl groups or longer alkyl groups do not show gelation ability. The gradual gel-to-sol phase transition of the supramolecular hydrogel is triggered by adding β-galactosidase (β-Gal) as a result of enzymatic hydrolysis of the lactose moiety. Supramolecular hydrogels could stably entrap cationic organic dyes, such as rhodamine 6G (Rh6G), even in water. The entrapped Rh6G could be gradually released in the presence of β-Gal, along with the gel-to-sol phase transition. Lactose-coupled amphiphilic ureas are worked as low-molecular-weight hydrogelators (LMWHGs). Their gelation abilities are sensitive to the length of the hydrophobic alkyl chain. Gradual gel-to-sol phase transition of the supramolecular hydrogel was occurred by adding β-galactosidase (β-Gal) as a result of enzymatic hydrolysis of the lactose moiety. Supramolecular hydrogels could stably entrap cationic organic dyes even in water. The entrapped dye could be gradually released in the presence of β-Gal, along with the gel-to-sol phase transition.

Minimal Coarse-Grained Modeling toward Implicit Solvent Simulation of Generic Bolaamphiphiles.

A dual-site dimer model of bola or bipolar amphiphiles is developed based on an earlier single-site model of monopolar amphiphiles [Dey, S.; Saha, J. Phys. Rev. E 2017, 95, 023315]. This model incorporates both the hydrophobic effect and the hydration force in its anisotropic site-site interactions, thus obviating the need to simulate the water particles explicitly. Such economy of sites and absence of explicit solvents enable molecular dynamics simulations to achieve mesoscopic length and time scales unattainable by any bead-spring model or explicit solvent computations. Our model, however, applies to generic bolas only because the gain in scale can only be obtained by sacrificing the resolution of detailed molecular structures. Thanks to a pivoted dimer architecture, our model can incorporate the essential flexibility of bolas, which leads to their loop or U-shaped conformers. Rigid bolas can also be modeled by the same dimer simply by constraining the rotation about the pivot. Flexible model bolas show fast, spontaneous self-assembly into experimentally observed nanostructures such as micelles and rods. Tightly packed yet fluid monolayers can also be formed from these flexible dimers. Model bolalipids are seen to be less diffusive and produce thicker layers compared to their monopolar counterparts. Bilayers composed of monopolar model lipids show increased stability in the presence of membrane-spanning bolas. Rigid bolas, though achiral themselves, show self-assembly into helical rods. As all these observations agree with well-known characteristics of archaeal lipids and synthetic bolaamphiphiles, our model promises to be useful for mesoscale simulations of bolas in the context of research in lyotropic liquid crystals, biomimetics, drug delivery, and low-molecular-weight hydrogelators.

Supramolecular Hydrogel Induced by Electrostatic Interactions between Polycation and Phosphorylated-Fmoc-Tripeptide

Supramolecular hydrogels formed through noncovalent interactions of low-molecular-weight hydrogelators (LMWHs) show great potential applications in different fields, such as delivery of therapeutic...