Supramolecular hydrogels containing inorganic salts and acids

l-Lysine-based hydrogelators can form supramolecular hydrogels over a wide pH range and contain inorganic salts and acids, especially, 3 forms hydrogels containing 1 M HCl and H₂SO₄ at 1 g/L.     

Co‐assembly of Polyoxometalates and Zwitterionic Amphiphiles into Supramolecular Hydrogels: From Crystalline Fibrillar to Amorphous Micellar Networks

Gelation mechanism is of utmost importance to the rational design of supramolecular hydrogelators. Although both kinetic and thermodynamic controlled self‐assembly processes have been widely studied in hydrogels, the formation relationship between crystalline and amorphous gel networks still remains ambiguous. Herein, a gelation transformation from a kinetic to a thermodynamic process was achieved by balancing the rigidity and flexibility of the inorganic–organic co‐assemblies. By using polyoxometalates and zwitterionic amphiphiles, the transition morphologies between crystalline and amorphous hydrogel networks were evidenced for the first time, as ordered wormlike micelles. Given the versatile applications of hydrogels in biological systems and materials science, these findings may highlight the potential of inorganic–organic binary supramolecular hydrogelators and fill in the blank between kinetic and thermodynamic controlled gelation processes.     

Supramolecular hydrogel formed by glucoheptonamide of l-lysine: simple preparation and excellent hydrogelation ability

We describe the simple preparation of new l-lysine derivatives with a gluconic or glucoheptonic group, their hydrogelation properties, and the thermal and mechanical properties of the supramolecular hydrogels. The l-lysine derivatives with a gluconic group have no hydrogelation ability, while the l-lysine-glucoheptonamide derivatives functioned as hydrogelators. Their hydrogelation abilities increased with the decreasing length of the spacer between the l-lysine segment and the glucoheptonic group. The compound, which has no spacer, formed a supramolecular hydrogel at 0.05 wt % in pure water. The thermal stability and high mechanical strength of the supramolecular hydrogels based on this compound significantly depended on the aqueous solutions. Electron microscopy and FTIR studies demonstrated that the hydrogelators created a three-dimensional network through hydrogen bonding and hydrophobic interactions in the supramolecular hydrogel. In addition, it was found that hydrophobic interactions played an important role in the thermal stability of the supramolecular hydrogel.     

Converting drugs into gelators: supramolecular hydrogels from N-acetyl-L-cysteine and coinage-metal salts

Here we present the concept of metallophilic hydrogels, supramolecular systems in which the gelator species are metal-thiolates that self-assemble through metallophilic attractions. The principle is applied for a small drug, the mucolytic agent N-acetyl-l-cysteine (NAC), which readily forms hydrogels in the presence of Au(iii), Ag(i) and Cu(ii) salts. The resulting transparent hydrogels present pH induced sol/gel transition. Scanning electron microscopy (SEM) measurements reveal a microporous structure in form of flakes for the three of them. The low pH at which these hydrogels are formed (pH < 4) limits their direct use as drug-delivery systems, but still this system constitutes a novel method for easy and fast conversion of small drugs into potent hydrogelators. Future developments will help to fully develop the idea in order to create a new class of supramolecular drug-delivery systems.     

Hydrogelators of cyclotriveratrylene derivatives

Developing cavity-based supramolecular hydrogels is in its infancy because not many such hydrogelators are available. Reported herein is our creation of rigid cavitand cyclotriveratrylene (CTV) based hydrogelators from the molecular backbones of CTVs that were in limited cases shown to form organogels. For doing so deprotonable -COOH or protonable -NH(2) was introduced as terminal group into the rigid and hydrophobic CTV backbones. We thus successfully obtained optically anisotropic supramolecular hydrogels from these new CTVs hydrogelators with excellent thermostability and high tolerance towards strong electrolytes. The obtained CTV-1 and CTV-2 hydrogels are luminescent and exhibit reversible gel-to-sol and sol-to-gel transitions upon pH variations. The success in creating CTV-1 and CTV-2 hydrogelators on the basis of the skeleton of a CTV-organogelator suggests that balancing the hydrophilic and hydrophobic characters of the ionic and hydrophobic moieties well in the gelator molecule is important for designing a promising hydrogelator.     

Stimuli‐Responsive Supramolecular Hydrogels and Their Applications in Regenerative Medicine

Supramolecular hydrogels are a class of self‐assembled network structures formed via non‐covalent interactions of the hydrogelators. These hydrogels capable of responding to external stimuli are considered to be smart materials due to their ability to undergo sol–gel and/or gel–sol transition upon subtle changes in their surroundings. Such stimuli‐responsive hydrogels are intriguing biomaterials with applications in tissue engineering, delivery of cells and drugs, modulating tissue environment to promote innate tissue repair, and imaging for medical diagnostics among others. This review summarizes the recent developments in stimuli‐responsive supramolecular hydrogels and their potential applications in regenerative medicine. Specifically, various structural aspects of supramolecular hydrogelators involved in self‐assembly, the role of external stimuli in tuning/controlling their phase transitions, and how these functions could be harnessed to advance applications in regenerative medicine are focused on. Finally, the key challenges and future prospects for these versatile materials are briefly described.     

New l-valine-based hydrogelators: formation of supramolecular hydrogels

New l-valine derivatives, which have a positively charged group, function as excellent hydrogelators that can gel pure water, saline, and aqueous solutions containing inorganic acids and salts at 0.2 wt %.     

Supramolecular Nanofibers/Hydrogels of the Conjugates of Nucleobase,Saccharide, and Amino Acids

Three new hydrogelators based on the conjugates of three naturally occurring biological building blocks: nucleobase, saccharide, and amino acids, were explored. Being synthesized via a facile solid phase peptide synthesis route, the hydrogelators self‐assemble in water to afford supramolecular nanofibers and hydrogels. Transmission electron microscopy, oscillation rheometry, and circular dichroism reveal that the hydrogels consist of largely helix‐based nanofibers of the widths of 5–12 nm and exhibit storage moduli up to 1 kPa. These hydrogelators also exhibit excellent cell‐compatibility. This work illustrates a new platform for constructing molecular soft materials for nanobiotechnology.     

Supramolecular Hydrogels Made of Basic Biological Building Blocks

As a consequence of the self‐assembly of small organic molecules in water, supramolecular hydrogels are evolving from serendipitous events during organic synthesis to become a new type of materials that hold promise for applications in biomedicine. In this Focus Review, we describe recent advances in the use of basic biological building blocks for creating molecules that act as hydrogelators and the potential applications of the corresponding hydrogels. After introducing the concept of supramolecular hydrogels and defining the scope of this review, we briefly describe the methods for making and characterizing supramolecular hydrogels. We then discuss representative hydrogelators according to the categories of their building blocks, such as amino acids, nucleobases, and saccharides, and highlight the applications of the hydrogels when necessary. Finally, we offer our perspective and outlook on this fast‐growing field at the interface of organic chemistry, materials, biology, and medicine. By providing a snapshot for chemists, engineers, and medical scientists, we hope that this Focus Review will contribute to the development of multidisciplinary research on supramolecular hydrogels for a wide range of applications in different fields.     

Multifunctional, biocompatible supramolecular hydrogelators consist only of nucleobase, amino acid, and glycoside

The integration of nucleobase, amino acid, and glycoside into a single molecule results in a novel class of supramolecular hydrogelators, which not only exhibit biocompatibility and biostability but also facilitate the entry of nucleic acids into cytosol and nuclei of cells. This work illustrates a simple way to generate an unprecedented molecular architecture from the basic biological building blocks for the development of sophisticated soft nanomaterials, including supramolecular hydrogels.     

Utilizing the Hofmeister Effect to Induce Hydrogelation of Nonionic Supramolecular Polymers into a Therapeutic Depot

Nonionic hydrogels are of particular interest for long-term therapeutic implantation due to their minimal immunogenicity relative to their charged counterparts. However, in situ formation of nonionic supramolecular hydrogels under physiological conditions has been a challenging task. In this context, we report on our discovery of salt-triggered hydrogelation of nonionic supramolecular polymers (SPs) formed by self-assembling prodrug hydrogelators (SAPHs) through the Hofmeister effect. The designed SAPHs consist of two SN-38 units, which is an active metabolite of the anticancer drug irinotecan, and a short peptide grafted with two or four oligoethylene glycol (OEG) segments. Upon self-assembly in water, the resultant nonionic SPs can be triggered to gel upon addition of phosphate salts. Our ¹H NMR studies revealed that the added phosphates led to a change in the chemical shift of the methylene protons, suggestive of a disruption of the water-ether hydrogen bonds and consequent reorganization of the hydration shell surrounding the SPs. This deshielding effect, commensurate with the amount of salt added, likely promoted associative interactions among the SAPH filaments to percolate into a 3D network. The formed hydrogels exhibited a sustained release profile of SN-38 hydrogelator that acted potently against cancer cells.     

Supramolecular hydrogels based on short peptides linked with conformational switch

Short peptides appropriately linked with an azobenzene conformational switch were found to be motif and pH dependant supramolecular hydrogelators. The hydrogelation properties of the short peptides linked with the conformational switch were studied in detail with respect to dependence on amino acid residue, pH and salt effect. The presence of amino acids with aromatic side chains such as Phe and Tyr was found to be favorable for the short peptides to gel water at an appropriate pH range. Cationic amino acid residues such as Arg and Lys in the short peptides were found to be unfavorable for hydrogelation. pH and salt effect were also found to be important factors for the hydrogelation properties of the short peptides. A series of short peptides with bioactive sequences were linked with the conformational switch and their hydrogelation properties were investigated. Photoresponsive supramolecular hydrogels were realized based on the E-/Z- transition of the conformational switch upon light irradiation. Proper combination of amino acid residues in the short peptides resulted in smart supramolecular hydrogels with responses to multiple stimuli.     

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.     

Supramolecular Self-organization of Potential Hydrogelators on Attracting Surfaces

This article highlights the aggregation behaviour of potential low molecular weight hydrogelators on attracting surfaces. Our goal was the development of a method, which enables the finding of new hydrogelators that are not easily recognizable as such because they only form instable or no hydrogels in aqueous solution. To this end, a series of negatively charges azo-dyes was synthesized and positive charged glass slides were immersed into their aqueous solutions. All dyes showed supramolecular organization and significant concentration on the attracting glass surface. Microscopic investigations mostly revealed the formation of crystals. However, one compound, (1-(2-n-octylphenylazo)-2-hydroxy-6-naphthalenesulphonate, selectively formed a hydrogel on the surface whereas it does not gel in aqueous solution. This reveals the hydrogel as the stable form of this compound under equilibrium conditions. This method of surface-induced hydrogelation might facilitate the identification of new hydrogelators. Further more, it might also allow the mimicking of surface gelation as a process of biological relevance.     

Facile Construction of Bio-Based Supramolecular Hydrogels from Dehydroabietic Acid with a Tricyclic Hydrophenanthrene Skeleton and Stabilized Gel Emulsions

Supramolecular hydrogels have attracted great attention due to their special properties. In this research, bio-based supramolecular hydrogels were conveniently constructed by heating and ultrasounding two components of dehydroabietic acid with a rigid tricyclic hydrophenanthrene skeleton and morpholine. The microstructures and properties of hydrogels were investigated by DSC, rheology, SAXS, CD spectroscopy, and cryo-TEM, respectively. The critical gel concentration (CGC) of the hydrogel was 0.3 mol·L⁻¹ and the gel temperature was 115 °C. In addition, the hydrogel showed good stability and mechanical properties according to rheology results. Cryo-TEM images reveal that the microstructure of hydrogel is fibrous meshes; its corresponding mechanism has been studied using FT-IR spectra. Additionally, oil-in-water gel emulsions were prepared by the hydrogel at a concentration above its CGC, and the oil mass fraction of the oil-in-water gel emulsions could be freely adjusted between 5% and 70%. This work provides a convenient way to prepare bio-based supramolecular hydrogels and provides a new method for the application of rosin.     

Supramolecular hydrogelators of N-terminated dipeptides selectively inhibit cancer cells

Consisting of N-terminated diphenylalanine, a new type of supramolecular hydrogelators forms hydrogels within a narrow pH window (pH 5.0 to 6.0) and selectively inhibits growth of HeLa cells, which provides important and useful insights for designing molecular nanofibers as potential nanomedicines.     

An Easy Access to Organic Salt‐Based Stimuli‐Responsive and Multifunctional Supramolecular Hydrogels

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β‐alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table‐top rheology and dynamic rheology. FTIR, variable‐temperature ¹H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π–π stacking in hydrogelation. Single‐crystal X‐ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide–amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli‐responsive and were capable of sensing ammonia and adsorbing water‐soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.     

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.     

Cyclohexane bis-urea compounds for the gelation of water and aqueous solutions

A new class of efficient hydrogelators has been developed by a simple modification of the peripheral substituents of cyclohexane bis-urea organogelators with hydrophilic hydroxy or amino functionalities. These bis-urea hydrogelators were synthesised in two or three steps using an alternative procedure to the common isocyanate method. Gelation was obtained with organic solvents, water and strongly basic aqueous solutions like 25% ammonia. Hydrogelation was found to depend on a delicate balance between the hydrophobicity of the alkyl chains, hydrophilicity of the terminal substituents and the enantiomeric purity of the compound. The hydrogels consisted of a network of fibers, in which all urea groups are involved in intermolecular hydrogen bonding. Most likely, gelation is driven by hydrophobic interactions of the methylene units, whereas hydrogen bond formation between the urea groups provides the necessary anisotropy of the aggregation and the high thermal stability of the gels.     

Head group modulated pH-responsive hydrogel of amino acid-based amphiphiles: entrapment and release of cytochrome c and vitamin B12

The present study describes the rational design and synthesis of amino acid-based amphiphilic hydrogelators, which were systemically fine-tuned at the head group to develop pH-responsive hydrogels. To understand the basic structural requirements of a low molecular weight amphiphilic hydrogelator, 10 analogous amphiphiles based on L-phenylalanine and L-tyrosine with structurally related head group were synthesized. Among them, three with quaternary ammonium substitution at the head group formed transparent hydrogels at room temperature while others were unable to gelate water. To establish correlations between the head group architecture of the gelators and their supramolecular arrangements, a variety of spectroscopic and microscopic techniques were investigated that showed that a balance between hydrophilicity and hydrophobicity is required to achieve hydrogelation. Interestingly, the gelator with tyrosinate in its head group showed remarkable response toward external pH. All hydrogels including the pH-responsive one were used in the controlled and/or pH-triggered release of entrapped (with in hydrogels) vitamin B12 and cytochrome c at different pHs. Since the hydrogels were formed at room temperature without heating, this could be very important during the entrapment of biomolecules such as proteins because of their heat sensitivity. At biological pH (7.4), the release of entrapped biomolecules from all three hydrogels was caused by diffusion through the gel structure, but at endosomal pH (approximately 5.5) and further lower pH, the release rate of biomolecules from the pH-responsive hydrogel with tyrosinate head group (pKa approximately equal to 7.2) increased by 9-10-fold compared to that observed at physiological pH, because of gel dissolution. Retention of the structure and activity of released biomolecule has established the prospect of the hydrogel as an efficient drug delivery vehicle.