The Power of Confocal Laser Scanning Microscopy in Supramolecular Chemistry: In situ Real-time Imaging of Stimuli-Responsive Multicomponent Supramolecular Hydrogels

Multicomponent supramolecular hydrogels are promising scaffolds for applications in biosensors and controlled drug release due to their designer stimulus responsiveness. To achieve rational construction of multicomponent supramolecular hydrogel systems, their in-depth structural analysis is essential but still challenging. Confocal laser scanning microscopy (CLSM) has emerged as a powerful tool for structural analysis of multicomponent supramolecular hydrogels. CLSM imaging enables real-time observation of the hydrogels without the need of drying and/or freezing to elucidate their static and dynamic properties. Through multiple, selective fluorescent staining of materials of interest, multiple domains formed in supramolecular hydrogels (e. g. inorganic materials and self-sorting nanofibers) can also be visualized. CLSM and the related microscopic techniques will be indispensable to investigate complex life-inspired supramolecular chemical systems.     

Microarray-based in vitro evaluation of DNA oligomer libraries designed in silico.

We report on the microarray-based in vitro evaluation of two libraries of DNA oligonucleotide sequences, designed in silico for applications in supramolecular self-assembly, such as DNA computing and DNA-based nanosciences. In this first study which is devoted to the comparison of sequence motif properties theoretically predicted with their performance in real-life, the DNA-directed immobilization (DDI) of proteins was used as an example of DNA-based self-assembly. Since DDI technologies, DNA computing, and DNA nanoconstruction essentially depend on similar prereguisites, in particular, large and uniform hybridization efficiencies combined with low nonspecific cross-reactivity between individual sequences, we anticipate that the microarray approach demonstrated here will enable rapid evaluation of other DNA sequence libraries.     

Supramolecular Polyphenol-DNA Microparticles for In Vivo Adjuvant and Antigen Co-Delivery and Immune Stimulation

DNA-based materials have attracted interest due to the tunable structure and encoded biological functionality of nucleic acids. A simple and general approach to synthesize DNA-based materials with fine control over morphology and bioactivity is important to expand their applications. Here, we report the synthesis of DNA-based particles via the supramolecular assembly of tannic acid (TA) and DNA. Uniform particles with different morphologies are obtained using a variety of DNA building blocks. The particles enable the co-delivery of cytosine-guanine adjuvant sequences and the antigen ovalbumin in model cells. Intramuscular injection of the particles in mice induces antigen-specific antibody production and T cell responses with no apparent toxicity. Protein expression in cells is shown using capsules assembled from TA and plasmid DNA. This work highlights the potential of TA as a universal material for directing the supramolecular assembly of DNA into gene and vaccine delivery platforms.     

Dynamic Hydrogels from Host–Guest Supramolecular Interactions

Hydrogel biomaterials are pervasive in biomedical use. Applications of these soft materials range from contact lenses to drug depots to scaffolds for transplanted cells. A subset of hydrogels is prepared from physical cross‐linking mediated by host–guest interactions. Host macrocycles, the most recognizable supramolecular motif, facilitate complex formation with an array of guests by inclusion in their portal. Commonly, an appended macrocycle forms a complex with appended guests on another polymer chain. The formation of poly(pseudo)rotaxanes is also demonstrated, wherein macrocycles are threaded by a polymer chain to give rise to physical cross‐linking by secondary non‐covalent interactions or polymer jamming. Host–guest supramolecular hydrogels lend themselves to a variety of applications resulting from their dynamic properties that arise from non‐covalent supramolecular interactions, as well as engineered responsiveness to external stimuli. These are thus an exciting new class of materials.     

Supramolecular polymeric hydrogels

The supramolecular crosslinking of polymer chains in water by specific, directional and dynamic non-covalent interactions has led to the development of novel supramolecular polymeric hydrogels. These aqueous polymeric networks constitute an interesting class of soft materials exhibiting attractive properties such as stimuli-responsiveness and self-healing arising from their dynamic behaviour and that are crucial for a wide variety of emerging applications. We present here a critical review summarising the formation of dynamic polymeric networks through specific non-covalent interactions, with a particular emphasis on those systems based on host-guest complex formation, as well as the characterisation of their physical characteristics. Aqueous supramolecular chemistry has unlocked a versatile toolbox for the design and fine-tuning of the material properties of these hydrogels (264 references).     

Developing a Self‐Healing Supramolecular Nucleoside Hydrogel Based on Guanosine and Isoguanosine

Recently, supramolecular hydrogels have attracted increasing interest owing to their tunable stability and inherent biocompatibility. However, only few studies have been reported in the literature on self‐healing supramolecular nucleoside hydrogels, compared to self‐healing polymer hydrogels. In this work, we successfully developed a self‐healing supramolecular nucleoside hydrogel obtained by simply mixing equimolar amounts of guanosine (G) and isoguanosine (isoG) in the presence of K⁺. The gelation properties have been studied systematically by comparing different alkali metal ions as well as mixtures with different ratios of G and isoG. To this end, rheological and phase diagram experiments demonstrated that the co‐gel not only possessed good self‐healing properties and short recovery time (only 20 seconds) but also could be formed at very low concentrations of K⁺. Furthermore, nuclear magnetic resonance (NMR), powder X‐ray diffraction (PXRD), and circular dichroism (CD) spectroscopy suggested that possible G₂isoG₂‐quartet structures occurred in this self‐healing supramolecular nucleoside hydrogel. This co‐gel, to some extent, addressed the problem of isoguanosine gels for the applications in vivo, which showed the potential to be a new type of drug delivery system for biomedical applications in the future.     

Pristine DNA Hydrogels from Biotechnologically Derived Plasmid DNA

DNA hydrogels are of great interest for a variety of biomedical applications owing to their biocompatibility and biodegradability but the advantages of DNA hydrogels have not been exploited yet because of their limited availability. Thus far, DNA hydrogels have been prepared from synthetically derived building blocks, and their production on large scale would be far too expensive. As an alternative, here the generation of DNA hydrogels from plasmid DNA is reported. Plasmid DNA can be prepared on large scale at reasonable costs by a fermentation process. The desired linear DNA building blocks are then obtained from the plasmid DNA by enzymatic digestion. Gel formation is carried out by covalent bond formation between individual building blocks via enzymatic ligation. The generation of pristine DNA hydrogels from plasmid DNA is thus presented for the first time. The viscoelastic properties of the hydrogels were studied by rheology, which confirmed that the gels have storage moduli G′ of >100 Pa.     

Stimuli‐Responsive Biomolecule‐Based Hydrogels and Their Applications

This Review presents polysaccharides, oligosaccharides, nucleic acids, peptides, and proteins as functional stimuli‐responsive polymer scaffolds that yield hydrogels with controlled stiffness. Different physical or chemical triggers can be used to structurally reconfigure the crosslinking units and control the stiffness of the hydrogels. The integration of stimuli‐responsive supramolecular complexes and stimuli‐responsive biomolecular units as crosslinkers leads to hybrid hydrogels undergoing reversible triggered transitions across different stiffness states. Different applications of stimuli‐responsive biomolecule‐based hydrogels are discussed. The assembly of stimuli‐responsive biomolecule‐based hydrogel films on surfaces and their applications are discussed. The coating of drug‐loaded nanoparticles with stimuli‐responsive hydrogels for controlled drug release is also presented.     

Hybrid Hydrogels Assembled from Phenylalanine Derivatives and Agarose with Enhanced Mechanical Strength

A roadblock for supramolecular hydrogels is their poor mechanical properties. Herein, to enhance the mechanical strength of supramolecular hydrogels, agarose(AG) was incorporated into the low molecular weight hydrogelator(G1). The results of scanning electron microscopy(SEM), circular dichroism(CD) and Fourier transform infrared spectroscopy(FTIR) prove that G1 gelators can self-assemble into cross-linked network together with AG. The mechanical properties of the gels are characterized by a rotary rheometer and the mechanical properties of the hybrid hydrogels(Hgel) can be significantly improved and may be further tuned by changing the ratio of the two components. For example, the elastic modulus of Hgel Ⅱ[m(G1):m(AG)=7:3] is about 2 times higher than that of G1 hydrogel. The results demonstrate that the mechanical property of hybrid supramolecular hydrogels can be adjusted through the formation of a cross-linked network.     

Build in seconds: Small-molecule hydrogels of self-assembled tryptophan derivatives

Small-molecule hydrogels based on amino acid derivatives have promising applications in many biological fields, including cell culture, drug delivery, and tissue engineering. Although these hydrogels have been widely reported to have low cytotoxicity, biocompatibility, and tunable bioactivity, problems such as harsh preparation conditions and complex material design hinder their application. Herein, by adjusting pH to induce non-covalent interactions between small-molecule tryptophan derivatives (N-[(phenylmethoxy)carbonyl]-l-tryptophan, Mw: 338.35), we developed a self-assembled three-dimensional network hydrogel that can be rapidly formed in seconds. And the supramolecular self-assembly mechanism of the hydrogels was also investigated in detail through experimental characterizations and density functional theory calculation. As-prepared hydrogels also exhibit reversible pH-stimulated response and self-healing properties. This study details a research process for the simple and rapid preparation of tryptophan derivative-based hydrogels, which provides more reference ideas for the future development of materials based on other amino acid derivatives.     

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.     

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.     

Self-assembly in magnetic supramolecular hydrogels

Most recent advances in the synthesis of supramolecular hydrogels based on low molecular weight gelators (LMWGs) have focused on the development of novel hybrid hydrogels, combining LMWGs and different additives. The dynamic nature of the noncovalent interactions of supramolecular hydrogels, together with the specific properties of the additives included in the formulation, allow these novel hybrid hydrogels to present interesting features, such as stimuli-responsiveness, gel-sol reversibility, self-healing and thixotropy, which make them very appealing for multiple biomedical and biotechnological applications. In particular, the inclusion of magnetic nanoparticles in the hydrogel matrix results in magnetic hydrogels, a particular type of stimuli-responsive materials that respond to applied magnetic fields. This review focuses on the recent advances in the development of magnetic supramolecular hydrogels, with special emphasis in the role of the magnetic nanoparticles in the self-assembly process, as well as in the exciting applications of these materials.     

Self‐Healing Supramolecular Hydrogels for Tissue Engineering Applications

Self‐healing supramolecular hydrogels have emerged as a novel class of biomaterials that combine hydrogels with supramolecular chemistry to develop highly functional biomaterials with advantages including native tissue mimicry, biocompatibility, and injectability. These properties are endowed by the reversibly cross‐linked polymer network of the hydrogel. These hydrogels have great potential for realizing yet to be clinically translated tissue engineering therapies. This review presents methods of self‐healing supramolecular hydrogel formation and their uses in tissue engineering as well as future perspectives.     

A flexible rapid self-assembly scaffold-net DNA hydrogel exhibiting cell mobility control

DNA hydrogels have unique properties, such as specific identifiable molecular structures, programmable self-assembly, and excellent biocompatibility, which have led to increasing researches in the field of nanomaterials and biomedical over the past two decades. However, effective methods to regulate the microstructure of DNA hydrogels still lack, which limits their applications in tissue engineering. By introducing DNA scaffolds into rolling circle amplification (RCA) products and implementing rapid self-assembly strategy, we can produce a regulable new type scaffold-net DNA hydrogel in a short time. Scaffolds concentration and RCA time can regulate the microcharacteristics and physical properties of hydrogels. Scaffold-net DNA hydrogels will be a promising bionic platform for the studies of cancer cell metastatic and microenvironment biophysics.     

Polyoxometalate-Based Photochromic Supramolecular Hydrogels with Highly Ordered Spherical and Cylindrical Micellar Nanostructures

Polyoxometalates (POMs) have attracted much attention in the field of photochromic materials. However, POM-based photochromic supramolecular hydrogels with high transparency and good photochromic properties are seldom reported. In this work, a homogenous, optically transparent, injectable, and photochromic supramolecular hydrogel was fabricated through the coassembly of ammonium heptamolybdate (Mo₇) and an imidazolium-based zwitterionic amphiphile (3-(1-hexadecyl-3-imidazolio)propanesulfonate (C₁₆IPS)). The balance between electrostatic attraction and repulsion of Mo₇ clusters and zwitterionic amphiphiles enables them to coassemble into a homogenous and transparent supramolecular hydrogel. By adjusting the molar ratio of C₁₆IPS/Mo₇, ordered spherical micelle-based hydrogels and aligned wormlike micelle-based hydrogels can be obtained. The incorporation of Mo₇ into hydrogels endows these hydrogels with excellent photochromic properties. Specifically, after coassembly with C₁₆IPS, the photochromic ability of hydrogels is significantly enhanced compared with that of a pure aqueous solution of Mo₇. These hydrogels exhibit great potential applications as photochromic materials for the recording of rewritable information.     

In Situ Synthesis of a Supramolecular Hydrogelator at an Oil/Water Interface for Stabilization and Stimuli‐Induced Fusion of Microdroplets

Supramolecular hydrogels are expected to have applications as novel soft materials in various fields owing to their designable functional properties. Herein, we developed an in situ synthesis of supramolecular hydrogelators, which can trigger gelation of an aqueous solution without the need for temperature change. This was achieved by mixing two precursors, which induced the synthesis of a supramolecular gelator and its instantaneous self‐assembly into nanofibers. We then performed the in situ synthesis of this supramolecular gelator at an oil/water interface to produce nanofibers that covered the surfaces of the oil droplets (nanofiber‐stabilized oil droplets). External stimuli induced fusion of the droplets owing to disassembly of the gelator molecules. Finally, we demonstrated that this stimuli‐induced droplet fusion triggered a synthetic reaction within the droplets. This means that the confined nanofiber‐stabilized droplets can be utilized as stimuli‐responsive microreactors.     

Clamped Hybridization Chain Reactions for the Self‐Assembly of Patterned DNA Hydrogels

DNA hydrogels hold great potential for biological and biomedical applications owing to their programmable nature and macroscopic sizes. However, most previous studies involve spontaneous and homogenous gelation procedures in solution, which often lack precise control. A clamped hybridization chain reaction (C‐HCR)‐based strategy has been developed to guide DNA self‐assembly to form macroscopic hydrogels. Analogous to catalysts in chemical synthesis or seeds in crystal growth, we introduced DNA initiators to induce the gelation process, including crosslinked self‐assembly and clamped hybridization in three dimensions with spatial and temporal control. The formed hydrogels show superior mechanical properties. The use of printed, surface‐confined DNA initiators was also demonstrated for fabricating 2D hydrogel patterns without relying on external confinements. This simple method can be used to construct DNA hydrogels with defined geometry, composition, and order for various bioapplications.     

Metal‐Ion‐Mediated Supramolecular Chirality of l‐Phenylalanine Based Hydrogels

For chiral hydrogels and related applications, one of the critical issues is how to control the chirality of supramolecular systems in an efficient way, including easy operation, efficient transfer of chirality, and so on. Herein, supramolecular chirality of l ‐phenylalanine based hydrogels can be effectively controlled by using a broad range of metal ions. The degree of twisting (twist pitch) and the diameter of the chiral nanostructures can also be efficiently regulated. These are ascribed to the synergic effect of hydrogen bonding and metal ion coordination. This study may develop a method to design a new class of electronically, optically, and biologically active materials.     

Ultrahigh-water-content supramolecular hydrogels exhibiting multistimuli responsiveness

Hydrogels are three-dimensional networked materials that are similar to soft biological tissues and have highly variable mechanical properties, making them increasingly important in a variety of biomedical and industrial applications. Herein we report the preparation of extremely high water content hydrogels (up to 99.7% water by weight) driven by strong host-guest complexation with cucurbit[8]uril (CB[8]). Cellulosic derivatives and commodity polymers such as poly(vinyl alcohol) were modified with strongly binding guests for CB[8] ternary complex formation (K(eq) = 10(12) M(-2)). When these polymers were mixed in the presence of CB[8], whereby the overall solid content was 90% cellulosic, a lightly colored, transparent hydrogel was formed instantaneously. The supramolecular nature of these hydrogels affords them with highly tunable mechanical properties, and the dynamics of the CB[8] ternary complex cross-links allows for rapid self-healing of the materials after damage caused by deformation. Moreover, these hydrogels display responsivity to a multitude of external stimuli, including temperature, chemical potential, and competing guests. These materials are easily processed, and the simplicity of their preparation, their availability from inexpensive renewable resources, and the tunability of their properties are distinguishing features for many important water-based applications.