Molecular Hydrogels Research Articles

Microfluidic-Assisted Self-Assembly of Molecular Hydrogelator at Water-Water Interfaces for Continuous Fabrication of Supramolecular Microcapsules.

Control over the self-assembly of small molecules at specific areas is of great interest for many high-tech applications, yet remains a formidable challenge. Here, how the self-assembly of hydrazone-based molecular hydrogelators can be specifically triggered at water-water interfaces for the continuous fabrication of supramolecular microcapsules by virtue of the microfluidic technique is demonstrated. The non-assembling hydrazide- and aldehyde-based hydrogelator precursors are distributed in two immiscible aqueous polymer solutions, respectively, through spontaneous phase separation. In the presence of catalysts, hydrazone-based hydrogelators rapidly form and self-assemble into hydrogel networks at the generated water-water interfaces. Relying on the microfluidic technique, microcapsules bearing a shell of supramolecular hydrogel are continuously produced. The obtained microcapsules can effectively load enzymes, enabling localized enzymatic growth of supramolecular fibrous supramolecular structures, reminiscent of the self-assembly of biological filaments within living cells. This work may contribute to the development of biomimetic supramolecular carriers for applications in biomedicine and fundamental research, for instance, the construction of protocells.

Probing assembly/disassembly of ordered molecular hydrogels.

Supramolecular hydrogels have a wide range of applications in the biomedical field, acting as scaffolds for cell culture, matrices for tissue engineering and vehicles for drug delivery. L-Phenylalanine (Phe) is a natural amino acid that plays a significant role in several physiological and pathophysiological processes (phenylketonuria and assembly of fibrils linked to tissue damage). Since Myerson et al. [Chem. Eng. Commun., 2002, 189(8), 1079-1090] reported that Phe forms a fibrous network in vitro, Phe's self-assembly processes in water have been thoroughly investigated. We have reported structural control over gelation by introduction of a halogen atom in the aromatic ring of Phe, driving changes in the packing motifs, and therefore, dictating gelation functionality. The additional level of control gained over supramolecular gelation via the preparation of multi-component gel systems offers significant advantages in tuning functional properties of such materials. Gaining molecular-level information on the distribution of gelators between the inherent structural and dynamic heterogeneities of these materials remains a considerable challenge. Using multicomponent gels based on Phe and amino-L-phenylalanine (NH2-Phe), we will explore the patterns of ordered/disordered domains in the gel fibres and will attempt to come up with general trends of interactions in the gel fibres and at the fibre/solution interfaces. Phe and NH2-Phe were found to self-assemble in water into crystalline hydrogels. The determined faster dynamics of exchange between the gel and solution states of NH2-Phe in comparison with Phe were correlated with weaker intermolecular interactions, highlighting the role of head groups in dictating the strength of intermolecular interactions. In the mixed Phe/NH2-Phe systems, at a low concentration of NH2-Phe, disruption of the network was promoted by interference of the aliphatics of NH2-Phe with the electrostatic interactions between Phe molecules. At high concentrations of NH2-Phe, multiple-gelator hydrogels were formed with crystal habits different from those of the pure gel fibres. NMR crystallography approaches combining the strengths of solid- and solution-state NMR proved particularly suitable to obtain structural and dynamic insights into the "ordered" fibres, solution phase and fibre/solution interfaces in these gels. These findings are supported by a plethora of experimental (diffraction, rheology, microscopy and thermal analysis) and computational methods.

Application of High Molecular Hydrogel in The Treatment of Myocardial Infarction

Myocardial infarction (MI) is the world's leading disabling and fatal disease. Currently, clinical treatment methods mainly include drug therapy, angioplasty, and coronary artery bypass grafting. These traditional treatment methods are difficult to repair damaged myocardial tissue and cannot restore normal necrotic and fibrotic myocardium. Therefore, it is imperative to improve the efficacy of traditional treatment methods and find new treatment strategies. More and more studies have found that stem cell transplantation can repair damaged myocardium, but stem cells transplanted to the affected site undergo oxidative damage, compression loss, and low cell survival and retention rates. At present, there is an urgent need to seek new methods that can effectively repair damaged myocardium and restore cardiac function. In recent years, with the development of regenerative medicine engineering and the continuous optimization of polymer technology and the development of new biomaterials, it has become a reality to create lost or functionally damaged tissues and organs through theoretical methods of biology and engineering, enabling them to have the structure and function of normal tissues and organs. This article will focus on the latest progress in methods for repairing damaged myocardium in myocardial infarction through polymer hydrogel materials.

Molecular camouflage by a context-specific hydrogel as the key to unlock the potential of viral vector gene therapy

Gene therapy offers hope for currently untreatable diseases; the patient’s own cellular machinery is recruited to create therapeutics. However, unpredictable responses that lead to neutralization by the host immune system and issues in constraining, controlling and sustaining delivery have presented clinical barriers to otherwise promising therapeutic developments. Here, we show that the protective environment provided by advanced biomaterials can function as injectable gene carriers to focus their therapeutic potential. Firstly, we investigated the potential of a tissue-specific molecular hydrogel to package recombinant adeno-associated viruses (rAAVs). Once a delivery pathway was confirmed, a set of rAAV variants were subsequently assessed for their ability to transduce various types of rodent and human neural cells in vitro and in vivo. Based on GFP expression, we identified a relatively new variant, rAAV-DJ, as showing desirable characteristics for constrained delivery and transduction efficiency. For the first time, we demonstrated precise control over the strength and type of interaction between biomaterials and rAAVs enabling the programmed release of viral payloads. This new approach enables specific infection of desired anatomical targets in a programmed fashion.

Creation of Polymer Hydrogelator/Poly(Vinyl Alcohol) Composite Molecular Hydrogel Materials.

Polymer hydrogels, including molecular hydrogels, are expected to become materials for healthcare and medical applications, but there is a need to create new functional molecular gels that can meet the required performance. In this paper, for creating new molecular hydrogel materials, the gel formation behavior and its rheological properties for the molecular gels composed of a polymer hydrogelator, poly(3-sodium sulfo-p-phenylene-terephthalamide) polymer (NaPPDT), and water-soluble polymer with the polar group, poly(vinyl alcohol) (PVA) in various concentrations were examined. Molecular hydrogel composites formed from simple mixtures of NaPPDT aqueous solutions (0.1 wt.%~1.0 wt.%) and PVA aqueous solutions exhibited thixotropic behavior in the relatively low concentration region (0.1 wt.%~1.0 wt.%) and spinnable gel formation in the dense concentration region (4.0 wt.%~8.0 wt.%) with 1.0 wt.% NaPPDT aq., showing a characteristic concentration dependence of mechanical behavior. In contrast, each single-component aqueous solution showed no such gel formation in the concentration range in the present experiments. No gel formation behavior was also observed when mixed with common anionic polymers other than NaPPDT. This improvement in gel-forming ability due to mixing may be due to the increased density of the gel's network structure composed of hydrogelator and PVA and rigidity owing to NaPPDT.

Dilution Driven Self-assembly and Re-entrant Phase Transition in Molecular Hydrogels

TX-100 molecular hydrogels exhibited re-entrant melt-gel-sol phase transition driven solely by dilution, which sequentially altered the self-assembly of the micellar formations and their population was investigated through the monitoring of the physical parameters namely, solution viscosity, particle size histogram, ergodicity, and gel rigidity modulus. This phenomenon was noticed at 20°C in the TX-100 concentration region of 0.2 to 1.2 M much above the critical micellar concentration of 0.22 mM. The particle size histograms revealed the presence of spherical micelles (size »3 nm) in the solution ([TX-100] < 0.5 M) which formed entangled wormlike cylindrical micelles (apparent hydrodynamic radius » 50 nm) when (0.5 M< [TX-100] < 0.9 M) giving rise to a gel-like structure. Further increase in the TX-100 concentration increased the propensity of these wormlike cylindrical micelles that got randomly distributed creating a dense melt phase. Interestingly, we observed transition solely driven by dilution which defined complete re-entrant behavior at room temperature. These molecular gels could be created by dilution of the melt or concentration of the sol unlike in the polymer gels. Remarkably, this hitherto little known unique phenomenon was exhibited by a simple system of non-ionic surfactant solution. Thus, we have a hydration reversible gel at our disposal which has a special place in soft matter arena.

Reconfigurable Touch Panel Based on a Conductive Thixotropic Supramolecular Hydrogel.

Touch panels based on ionic conductive hydrogels perform excellent flexibility and biocompatibility, becoming promising candidates for the next-generation human-machine interface. However, these ionic hydrogels are usually composed of cross-linked polymeric networks that are difficult to be recycled or reconfigured, resulting in environmental issues. Herein, we designed a lithium ion-triggered gelation strategy to provide a conductive molecular hydrogel with thixotropy, which can be mechanically recycled or reconfigured at room temperature. In this hydrogel, lithium ions function as ionic bridges to construct supramolecular nanoassemblies and charge carriers to impart ionic conductivity. With polymer additives, the mechanical accommodability of the hydrogel was improved to meet the requirements of the daily use of touch panels. When this molecular hydrogel was fabricated into a surface capacitive touch panel, real-time sensing and reliable touch locating abilities were achieved. Remarkably, this touch panel can be reconfigured into 1D, 2D, and 3D device structures by a simple stirring-remolding method under ambient conditions. This work brings new insight into enriching the functionalities of hydrogel-based ionotronics with a supramolecular approach.

Correction: Folic acid as a versatile motif to construct molecular hydrogelators through conjugations with hydrophobic therapeutic agents

Correction for ‘Folic acid as a versatile motif to construct molecular hydrogelators through conjugations with hydrophobic therapeutic agents’ by Xingyi Li et al., J. Mater. Chem., 2012, 22, 21838–21840, https://doi.org/10.1039/C2JM35329F.

A thixotropic molecular hydrogel composite composed of polymer hydrogelator and self-doping polyaniline copolymer for electrochromic and glucose sensing applications

An electrochemically active, paintable, thixotropic molecular hydrogel was created by mixing a polymer hydrogelator and polyaniline copolymer, and the gels were used to create electrochromic and glucose-sensing properties.

Dynamic supramolecular hydrogels mediated by chemical reactions.

Supramolecular self-assembly in a biological system is usually dominated by sophisticated metabolic processes (chemical reactions) such as catalysis of enzymes and consumption of high energy chemicals, leading to groups of biomolecules with unique dynamics and functions in an aqueous environment. In recent years, increasing efforts have been made to couple chemical reactions to molecular self-assembly, with the aim of creating supramolecular materials with lifelike properties and functions. In this feature article, after summarising the work of chemical reaction mediated supramolecular hydrogels, we first focus on a typical example where dynamic self-assembly of molecular hydrogels is activated by in situ formation of a hydrazone bond in water. We discuss how the formation of the hydrazone-based supramolecular hydrogels can be controlled in time and space. After that, we describe transient assembly of supramolecular hydrogels powered by out-of-equilibrium chemical reaction networks regulated by chemical fuels, which show unique properties such as finite lifetime, dynamic structures, and regenerative capabilities. Finally, we provide a perspective on the future investigations that need to be done urgently, which range from fundamental research to real-life applications of dynamic supramolecular hydrogels.

Alkaline cations dramatically control molecular hydrogelation by an amino acid-derived anionic amphiphile

Understanding the factors that control the formation of (supra)molecular hydrogels permits a rational tuning of their properties and represents a primary challenge for developing smart biocompatible soft materials. Hydrogel formation by molecular amphiphilic anions at millimolar concentrations is counterintuitive, considering the solubility of these species in water. Here we report hydrogel formation by a simple anionic molecular amphiphile and a rationale for the fibrillisation process observed. The studied molecule, DodValSuc, consists of a 12C alkyl chain, an l-valine unit and a terminal succinic acid moiety. Hydrogelation depends to a large degree on the nature and concentration of the alkaline cations present in the medium (Li+, Na+ or K+). As a result, gelation efficiency and properties like thermal stability or rheology are highly tunable using the alkaline cation present or its concentration as variables.A detailed study is reported, which includes the determination of minimum gelation concentration (MGC) by tabletop rheology, critical micelle concentration (CMC) using pyrene as a fluorescent probe, thermal stability (solubility) by 1H NMR, the morphology of the fibres by transmission electron microscopy (TEM), crystallinity by X-ray diffraction (XRD) and gel strength by oscillatory rheology. Additionally, dynamic light scattering (DLS) was used to evaluate the size of the micelles and permitted monitoring of the fibrillisation process.Altogether, the results are consistent with the formation of micelles that experience head crystallisation and subsequent aggregation into crystalline fibres. The alkaline cations play a crucial role in providing the cement that glues together the gelator molecules, making their concentration a critical parameter for gelation efficiency and properties. Furthermore, the gelation-promoting effects are inversely correlated with the size of the cations so that the highest thermal stability and rheological strength were found for the hydrogels formed in the presence of Li+.

Robust nanostructured POSS-PEG hydrogels. Self-deployment powered by water

Molecular networks of polyethylene glycol (PEG) and polyhedral oligomeric silsesquioxane (POSS) were prepared by UV curing at 90:10 wt% ratio. POSS mechanically reinforced and produced robust molecular hydrogels with shape memory (SM) behavior triggered by water. In solid state POSS induced over an order of magnitude increase of shear modulus and temperature-activated SM behavior [Romo-Uribe, Polymer 250, 124,899, 2022]. Here a hydration-activated SM behavior is reported, at temperature below PEG crystallization temperature; first a temporary shape is imposed by melting and then fixing by the recrystallization of PEG when cooling down the specimen. That is, a temporary shape was locked in by PEG crystallization, and the network “remembered” its permanent shape upon water submersion due to the dissolution of the crystallites. The hydration released the stresses through the crystalline phase and resulted in soft actuation. The viscosity of the hydrogels obeyed the power-law scaling |η*| ∼ ω−1, thus behaving as perfect networks, and POSS induced nearly two orders of magnitude increase of the shear elastic moduli relative to the unreinforced hydrogel. These versatile and mechanically robust hydrogels also exhibited antibacterial behavior towards Candida albicans and Staphylococcus aureus strains therefore enabling applications in actuators, scaffolds, wound healing, and responsive materials.

Polymeric Hydrogelator-Based Molecular Gels Containing Polyaniline/Phosphoric Acid Systems.

To expand the range of applications of hydrogels, researchers are interested in developing novel molecular hydrogel materials that have affinities for the living body and the ability to mediate electrical signals. In this study, a simple mixing method for creating a novel composite molecular gel is employed, which combines a hydrophilic conductive polymer, a polyaniline/phosphoric acid complex, and a polymer hydrogelator as a matrix. The composite hydrogel showed an improved gel-forming ability; more effective mechanical properties, with an increased strain value at the sol–gel transition point compared to the single system, which may be sufficient for paintable gel; and a better electrochemical response, due to the electrically conducting polyaniline component. These findings demonstrate the applicability of the new composite hydrogels to new potential paintable electrode materials.

2D Materials (WS2, MoS2, MoSe2) Enhanced Polyacrylamide Gels for Multifunctional Applications.

Multifunctional polymer composite gels have attracted attention because of their high thermal stability, conductivity, mechanical properties, and fast optical response. To enable the simultaneous incorporation of all these different functions into composite gels, the best doping material alternatives are two-dimensional (2D) materials, especially transition metal dichalcogenides (TMD), which have been used in so many applications recently, such as energy storage units, opto-electronic devices and catalysis. They have the capacity to regulate optical, electronic and mechanical properties of basic molecular hydrogels when incorporated into them. In this study, 2D materials (WS2, MoS2 and MoSe2)-doped polyacrylamide (PAAm) gels were prepared via the free radical crosslinking copolymerization technique at room temperature. The gelation process and amount of the gels were investigated depending on the optical properties and band gap energies. Band gap energies of composite gels containing different amounts of TMD were calculated and found to be in the range of 2.48–2.84 eV, which is the characteristic band gap energy range of promising semiconductors. Our results revealed that the microgel growth mechanism and gel point of PAAm composite incorporated with 2D materials can be significantly tailored by the amount of 2D materials. Furthermore, tunable band gap energies of these composite gels are crucial for many applications such as biosensors, cartilage repair, drug delivery, tissue regeneration, wound dressing. Therefore, our study will contribute to the understanding of the correlation between the optical and electronic properties of such composite gels and will help to increase the usage areas so as to obtain multifunctional composite gels.

Stearoylamido-D-Glucamine Hydrogelators for Thixotropic Molecular Gels with Tunable Softness by Chemical Modification.

Low-molecular-weight hydrogelators containing stearoyl, glycine, and D-glucamine moieties with or without methyl groups were synthesized to prepare chemically tuned molecular hydrogels. To evaluate the role of hydrogen bonding of hydrogelators in molecular hydrogel formation, the author has newly synthesized hydrogelators with or without methyl groups at their N-H in amide groups, contributing to the hydrogen bond formation in fiber in molecular hydrogels. The obtained hydrogels exhibited improved thixotropic performance with tunable softness, exhibiting pseudo-reversible thixotropic cycles that depended on the methyl substitution positions in the hydrogelators. To change the hydrogen bonds' positions by chemical modification has made it possible to tune the mechanical properties of molecular gels.

Supramolecular Glycolipid-Based Hydro-/Organogels with Enzymatic Bioactive Release Ability by Tuning the Chain Length and Headgroup Size.

Designing of supramolecular hydro-/organogels having desired properties, biocompatibility, and stimuli responsiveness is a challenging task. Herein, the gelation ability of amphiphilic glycolipid-based gelators in a wide range of solvents is explored. The structure-function relationship was established by varying the chain length and polar headgroup size of amphiphilic gelators. The prepared hydro-/organogels were characterized by employing several techniques such as differential scanning calorimetry (DSC), rheology, field emission scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM), X-ray diffraction (XRD), etc. The thermal stability of hydro-/organogels increased with an increase in chain length. Rheological analysis depicted that variation in chain length and headgroup size of amphiphilic gelators significantly affected the gel strength and stability. The self-assembled morphology of hydro-/organogel samples revealed the compact entangled fibrillar network structures. After comparing the energy-minimized molecular length with the d-spacing value obtained by XRD, interdigitated bilayer packing in the gel network was established. The bioactive encapsulation and enzymatic release study of hydro-/organogels portrayed their potential application in the biomedical field. To our delight, glycolipid 16M (C16 chain length) formed a molecular hydrogel with injectable and thixotropic behaviors. High critical strain value, thixotropy, injectability, thermoreversibility, and faster bioactive release for the 16M-W hydrogel proved crucial to predict its future applications. Overall, glycolipid amphiphiles designed by upholding proper hydrophilic-lipophilic balance can form multifunctional supramolecular hydrogels with excellent implementation in the drug delivery system.

Гелеобразование в низкоконцентрированных растворах глицирама и аминокислот в присутствии нитрата серебра

Research relevance: low molecular weight supramolecular hydrogels are unique objects that can solve many pressing problems in medicine, food industry and other sectors of the national economy. Research objectives: in recent past, it was discovered that low-concentration solutions of L-cysteine and silver nitrate (CSN) can form, when electrolyte solutions are added to hydrogels. We were faced with the task of obtaining hydrogels from dilute solutions of glycyram (GC) by adding CSN, since GC, due to its poor solubility, has low bioavailability. Materials and research methods: using the method of isomolar series, a comparative study of the formation of hydrogels by dilute GC solutions with the addition of CSN and GCP was carried out. It has been found that most durable hydrogels were obtained using CSN. Thus, GC hydrogels were obtained at a concentration of 10−3 M after adding CSN and GCP, which have a supramolecular character and combine the properties of GC, amino acids, and silver ions. Research results: glycyram hydrogels were obtained at its concentration equal to 10−3 M by mixing it with silver amino acids L-cysteine (CSN) and L-glutamic acid (GCP) solutions in same low concentrations. Conclusions: hydrogels with glycyram form silver solutions of those amino acids that are capable of giving frame structures at a ratio of amino acid: silver nitrate of 1.25.

Triple Enzyme‐Regulated Molecular Hydrogels for Carrier‐Free Delivery of Lonidamine

AbstractCancerous cells exhibit overexpression of multiple enzymes in various cellular compartments. These enzymes are often undruggable, yet display unique advantages in regulating intracellular self‐assembly and dis‐assembly of small molecules for cancer targeting. Herein, a self‐assembling molecule (LND‐1p‐ES) for carrier‐free delivery of lonidamine specifically to cancerous cells is designed, where LND‐1p‐ES executes as both a drug and a carrier with combined benefits thereof. Under the precise regulation of phosphatase (ALP) and esterase (CES), LND‐1p‐ES is capable of self‐assembling intracellularly in a spatiotemporal manner, to confer lonidamine‐borne nanofibers with enhanced cellular uptake. These nanofibers also facilitate controlled drug release with the aid of cellular proteases. Taking advantages of overexpressing ALP and CES as well as proteases in cancerous cells, the LND‐1p‐ES formulation demonstrates enhanced potency and selectivity against melanoma cells A375 in vitro and in vivo. In comparison, none/single enzyme responsive compounds fail to show a similar potency or selectivity, further confirming the indispensable roles of these enzymes in the delivery system. Collectively, the research provides a viable strategy to utilize multiple enzymes in cancerous cells for regulation of intracellular self‐assembly, which can be expanded to design smart soft materials responsive to multiple biologically relevant biomolecules for enhanced therapeutic efficacy.

Cationic self-assembled peptide-based molecular hydrogels for extended ocular drug delivery

The physiological barriers and clearance mechanism of the eye challenge the therapeutic delivery for treating various ocular disorders effectively. Here, we show the use of a cationic peptide (i.e., Nap-FFKK) as the molecular hydrogelator for generating supramolecular hydrogels spontaneously in a pH value of 5-7 which allows it to function as a promising ocular drug vehicle. The cationic peptide-based hydrogel hardly exhibited the cytotoxicity against human corneal epithelial cell (i.e., HCEC) from the in vitro cytotoxicity assay. Moreover, the single topical instillation of the hydrogel resulted in high ocular tolerance and biocompatibility. In vivo corneal distribution of the cationic peptide-based hydrogel showed that it dramatically increased the retention and the adhesion on the surface of cornea, compared to the anionic peptide-based analogue, owing to the ionic interactions with mucin on the ocular surface. In addition, we also synthesized environment-sensitive fluorophore-conjugated analogues (i.e., NBD-FFKK and NBD-FFD) to visualize the uptake of hydrogels in HCEC cells, revealing that the cationic peptide-based hydrogel displayed the better in vitro cellular uptake than the anionic peptide-based hydrogel. More importantly, the resulting cationic Nap-FFKK supramolecular hydrogel displayed a superior ocular bioavailability over that of anionic Nap-FFD supramolecular hydrogel, as indicated by in vivo pharmacokinetics study. This work, as a systematic investigation of ionic peptide-based molecular hydrogels in the ocular application, illustrates a new and powerful supramolecular approach for antagonizing clinically difficult ocular drug delivery. Statement of significanceHere we show the use of a cationic peptide as the molecular hydrogelator for generating supramolecular hydrogels, which allows it to function as a promising ocular drug vehicle for antagonizing the therapeutic delivery difficulties associated with the physiological barriers and clearance mechanism of the eye. The in vitro and in vivo studies of the hydrogel both show high ocular tolerance and biocompatibility. Moreover, the in vivo corneal distribution of the hydrogel exhibits the increased retention and adhesion on the surface of cornea. This work, as an investigation of cationic peptide-based molecular hydrogels in the ocular application, illustrates a powerful supramolecular approach for overcoming clinically difficult ocular drug delivery.

Cationic Self-Assembled Peptide-Based Molecular Hydrogels for Extended Ocular Drug Delivery

Cationic Self-Assembled Peptide-Based Molecular Hydrogels for Extended Ocular Drug Delivery