Supramolecular Hydrogels Research Articles

Supramolecular hydrogel of mycophenolic acid for treating allergic conjunctivitis

Mycophenolic acid (MPA) is an immunosuppressant less commonly utilized in allergic conjunctivitis. Peptide-based hydrogels improve material performance and are used in different biomedical applications. The current study reported that a cationic peptide Nap-FFKK and MPA were co-assembled into K–M hydrogel for sustained MPA delivery. The study evaluated cytotoxicity in vitro and its effectiveness in alleviating allergic conjunctivitis symptoms with a model. The current study demonstrates a promising strategy for using peptides as vehicles for sustained MPA delivery to the eye for ophthalmic applications.

Tough Supramolecular Hydrogels Crafted via Lignin-Induced Self-Assembly.

Supramolecular hydrogels are typically assembled through weak non-covalent interactions, posing a significant challenge in achieving ultra strength. Developing a higher strength based on molecular/nanoscale engineering concepts is a potential improvement strategy. Herein, a super-tough supramolecular hydrogel is assembled by gradually diffusing lignosulfonate sodium (LS) into a polyvinyl alcohol (PVA) solution. Both simulations and analytical results indicate that the assembly and subsequent enhancement of the crosslinked network are primarily attributed to LS-induced formation and gradual densification of strong crystalline domains within the hydrogel. The optimized hydrogel exhibits impressive mechanical properties with tensile strength of ≈20MPa, Young's modulus of ≈14MPa, and toughness of ≈50MJm⁻3, making it the strongest lignin-PVA/polymer hydrogel known so far. Moreover, LS provides the supramolecular hydrogel with excellent low-temperature stability (<-60°C), antibacterial, and UV-blocking capability (≈100%). Interestingly, the diffusion ability of LS is demonstrated for self-restructuring damaged supramolecular hydrogel, achieving 3D patterning on hydrogel surfaces, and enhancing the local strength of the freeze-thaw PVA hydrogel. The goal is to foster a versatile hydrogel platform by combining eco-friendly LS with biocompatible PVA, paving the way for innovation and interdisciplinarity in biomedicine, engineering materials, and forestry science.

3D printing of lignin-based supramolecular topological shape-morphing architectures with high strength, toughness, resolution, and fatigue resistance

The design and fabrication of customized and sustainable elastomers with supramolecular frameworks remain a central focus of scientific research. 3D printing represents an advanced manufacturing technology that has garnered significant attention. Lignin, a naturally abundant polymer, fits well with 3D printing due to its unique aromatic-rich structures that can provide rigidity and structural support. However, challenges persist in developing UV-curable lignin-based inks and fabricating high-strength lignin-based composite hydrogels with tailored shapes and structures through vat photopolymerization (VPP) printing techniques, largely due to lignin’s inherent heterogeneity, fragility, and poor fluidity. Here, we successfully developed a unique lignin-based photosensitive macromonomer resin tailored for VPP 3D printing. Using an ethanol/water fractionation process, heterogeneous lignosulfonate (LS), a by-product of the pulp and paper industry, was treated to isolate highly reactive lignin fractions rich in phenolic hydroxyl and sulfonic groups. These fractions were then chemically modified to synthesize a lignin-based macromonomer known as urethane acrylated lignosulfonate (UALS). The resulting lignin-based macromonomer (15–35 wt%) exhibits excellent compatibility with photosensitive resin formulations, enabling effective VPP 3D printing. The 3D-printed lignin-based supramolecular composite hydrogels exhibit high strength (tensile strength of ∼2.12 MPa, an elongation at break of ∼220.13 %), high resolution, fatigue resistance (up to 10000 cycles), and moisture-induced responsive behavior. The development of 3D-printed lignin-based supramolecular elastomers with defined shapes and patterned structures significantly advances the discovery of robust and environmentally sustainable soft materials with potential applications in soft robotics and tissue engineering.

Revamping anti-cGAS-STING therapy via an injectable thermo-responsive supramolecular hydrogel for pathological retinal angiogenesis

Retinal neovascularization is a leading cause of blindness. While current anti-VEGF drugs effectively inhibit pathological angiogenesis, some patients develop resistance or reduced responsiveness to treatments over time, leading to diminished effectiveness. In this study, we identified high activation of the cGAS-STING signaling pathway, which exacerbated pathological neovascularization and vessel leakage. We developed an injectable thermo-responsive supramolecular hydrogel loaded with an anti-STING drug. The hydrogel, made of Pluronic F127 (PF·127) consisting of poly(ethylene oxide) and poly(propylene oxide) units, demonstrated excellent transparency and biocompatibility. Importantly, the thermo-sensitive property allowed for precise spatial release of the drug, extending the effective treatment duration of C-176, which suppressed STING activation in the retina, reduced inflammation, and protected retinal tissue. HydroC-176 effectively inhibited microglial cell infiltration and the release of inflammatory angiogenic factors, highlighting its enhanced efficacy. While demonstrating slightly lower effectiveness compared to traditional anti-VEGF therapy, HydroC-176 exhibited more robust capabilities in regulating ocular microenvironmental inflammation. This approach may assist in enhancing the sensitivity and effectiveness of anti-VEGF therapy for reducing ocular inflammation, potentially improving patients’ response to traditional treatment. These results have suggested innovative and comprehensive strategies for the management of retinal neovascularization.

Injectable decellularized extracellular matrix hydrogel with cell-adaptable supramolecular network enhances cartilage regeneration by regulating inflammation and facilitating chondrogenesis

Osteoarthritis, characterized by progressive loss of cartilage, affects millions of people worldwide and clinically lacks effective treatments. Herein, we present an injectable, biodegradable supramolecular decellularized extracellular matrix (dECM) hydrogel, which can be injected into the joints and provide biomimetic microenvironments to drive cartilage regeneration. Benefiting from the cell-adaptable dynamic network and cartilage-specific compositions, the supramolecular dECM hydrogel not only enhances cell proliferation and migration, but also facilitates chondrogenesis. Furthermore, compared with the conventional dECM hydrogels, the supramolecular dECM hydrogel is instrumental in regulating inflammation, which consequently leads to a marked suppression of genes linked to cell death and cartilage degradation. In vivo analysis confirms that stem cells, when delivered via the supramolecular dECM hydrogel, remain viable for up to three months within the restored cartilage. The regenerated tissue exhibits hyaline-cartilage structure, good mechanical properties, and cartilage-specific extracellular matrix deposition that align closely with those of native cartilage. We envision that this supramolecular dECM hydrogel could serve as a valuable platform for cartilage regeneration and could strongly facilitate the clinical translation of dECM-based materials for tissue regeneration.

Self‐healing, adhesive, photothermal responsive, stretchable, and strain‐sensitive supramolecular nanocomposite hydrogels based on host–guest interactions

AbstractThe development of multifunctional supramolecular nanocomposite hydrogels remains challenging. Here, the dynamic host–guest interactions involving the host molecule CB[8] and guest units were utilized to prepare Fe3O4 hybrid supramolecular nanocomposite hydrogels. The results showed that the hydrogels obtained possessed a porous structure. The CB[8]‐modified Fe3O4 (Fe3O4@CB[8]) nanoparticles served as cross‐linkers in forming the network of hydrogels. By adjusting the Fe3O4@CB[8] content, the mechanical properties of the hydrogels could be controlled. The tensile stress was measured at 160 kPa with a fracture strain of 1380%, while the compression stress was 230 kPa at 70% compression strain. The self‐healing efficiency of the hydrogels at room temperature reached 95% after 24 h. The as‐obtained hydrogels show strain sensitivity and have the potential for applications in detecting elbow and finger movements. Our supramolecular nanocomposite hydrogels exhibit multiple functions, including self‐healing, injectability, photothermal responsiveness, and conductivity, making them suitable for integration into flexible electronics.Highlights Fe3O4@CB[8] nanoparticles serve as cross‐linkers for the nanocomposite hydrogels. CB[8] based host–guest interactions enable hydrogels to self‐heal. Fe3O4@CB[8] endow hydrogels with stretchability and photothermal responsiveness. Hydrogels exhibit injectability, NIR responsiveness, and conductive ability.

Engineering Supramolecular Hydrogels via Reversible Photoswitching of Cucurbit[8]uril-Spiropyran Complexation Stoichiometry.

The integration of photoswitchable supramolecular units into hydrogels allows for spatiotemporal control over their nanoscale topological network and macroscale properties using light. Nevertheless, the current availability of photoswitchable supramolecular interactions for the development of such materials remains limited. Here, the molecular design of a novel photoswitchable cucurbit[8]uril-spiropyran host-guest complex exhibiting fast and reversible switching of binding ratios between 1:2 and 1:1 is reported. Photoswitchable complexation stoichiometries are rationally exploited as (de)crosslinking units in multiple polymers for the design of supramolecular hydrogels displaying highly dynamic and switchable features that are spatiotemporally controlled by light. The hydrogels exhibit rapid reversible mechanical softening-hardening upon alternating irradiation with blue and UV light, which is used to significantly accelerate and improve the efficiency of self-healing and shape-remolding of hydrogels. Furthermore, spiropyran endows such materials with unique reversible photochromic properties for reproducible patterning/erasing and information storage. Using a dual-light-assisted extrusion process, meter-scale hydrogel fibers with enhanced structural integrity and photoswitchable ionic conductivity are constructed and woven into various slidable knots and fluorescent shapes. This work represents an innovative molecular design strategy for advancing the development of spatiotemporally engineered supramolecular hydrogels using light and opens avenues for their prospective applications in dynamic materials and adaptive systems.

Achieving Near-Infrared Phosphorescence Supramolecular Hydrogel Based on Amphiphilic Bromonaphthalimide Pyridinium Hierarchical Assembly.

Phosphorescent supramolecular hydrogels are currently a prevalent topic for their great promise in various photonic applications. Herein, an efficient near-infrared (NIR) phosphorescence supramolecular hydrogel is reported via the hierarchical assembly strategy in aqueous solution, which is fabricated from amphiphilic bromonaphthalimide pyridinium derivative (G), exfoliated Laponite (LP) nanosheets, and polymeric polyacrylamide (PAAm). Initially, G spontaneously self-aggregates into spherical nanoparticles covered with positively charged pyridinium units and emits single fluorescence at 410nm. Driven by electrostatic interactions with negatively charged nanosheets, the nanoparticles subsequently function as the cross-linked binders and coassemble with LP into supramolecular hydrogels with an engendered red room-temperature phosphorescence (RTP) up to 620nm. Benefiting from hydrogen-bonding interactions-mediated physical cross-linkage, the further introduction of PAAm not only significantly elevates the mechanical strength of the hydrogels showing fast self-healing capability, but also increases phosphorescence lifetime from 2.49to 4.20ms, especially generating phosphorescence at even higher temperature (τ 363 K = 2.46ms). Additionally, efficient RTP energy transfer occurs after doping a small amount of organic dye heptamethine cyanine (IR780) as an acceptor into hydrogels, resulting in a long-lived NIR emission at 823nm with a high donor/acceptor ratio, which is successfully applied for cell labeling in the NIR window.

A molybdenum sulfide based nitric oxide controlled release oral gel for rapid healing of oral mucosal ulcers

Oral mucosal ulcer is the most prevalent oral mucosal lesion, affecting over 25 % of general population. The current treatment regimens lack efficacy in addressing challenges such as wound bleeding, bacterial infection and inflammation on a continuous basis. Hence, a multi-functional oral gel (termed MPCST) with a long-acting duration is designed. It is based on a tannic acid-thioctic acid (TATA) supramolecular hydrogel which absorbs tissue exudate while exhibiting robust tissue adhesion properties. To form MPCST, TATA is loaded with MPCS, which are composed of polydopamine (PDA)-coated molybdenum disulfide (MoS2) nanoflakes (MoS2@PDA) with high photothermal conversion efficiency, nitric oxide (NO) precursor nitroprusside (SNP) and cerium oxide (CeO2) with high reactive oxygen species (ROS) scavenging rate. Upon exposure to 808 nm near-infrared (NIR) irradiation, MPCS rapidly heats up and releases NO to promote angiogenesis, while exhibiting strong ROS scavenging, antibacterial (including oral common Streptococcus mutans), and anti-inflammatory properties. Animal experiments show that the MPCST oral gel, composed of MPCS and TATA hydrogel, exhibits superior therapeutic efficacy compared to the commonly used dexamethasone patch.

Supramolecular Composite Hydrogel Loaded with CaF2 Nanoparticles Promotes the Recovery of Periodontitis Bone Resorption.

Treatments to reduce periodontal inflammation and rescue periodontitis bone resorption have been of interest to researchers. Bone tissue engineering materials have been gradually used in the treatment of bone defects, but periodontal bone tissue regeneration still faces challenges. Considering the biocompatibility factor, constructing bionic scaffolds with natural extracellular matrix properties is an ideal therapeutic pathway. Based on the pathological mechanism of periodontitis, in this study, short peptide and nanometer inorganic particles were comingled to construct NapKFF-nano CaF2 supramolecular composite hydrogels with different ratios. Material characterization experiments confirmed that the composite hydrogel had suitable mechanical properties and a three-dimensional structure that can function in the resorption region of the alveolar bone and provide spaces for cell proliferation and adhesion. The release of low concentrations of fluoride and calcium ions has been shown to have positive biological effects in both in vivo and in vitro experiments. Vitro experiments confirmed that the composite hydrogel had good biocompatibility and promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Microbiological experiments confirmed that the composite hydrogel inhibited the activity of periodontal pathogenic bacteria. In animal studies, composite hydrogel applied to periodontitis rats in vivo can effectively repair alveolar bone resorption. This composite hydrogel has a simple preparation method and is inexpensive to produce, yet it has antibacterial and osteogenesis-promoting incremental effects, which makes it well suited for the treatment of periodontitis bone resorption, providing a new strategy for periodontal bone tissue engineering.

Multifunctional magneto-plasmonic lipogel based on peptide hydrogel for application in combined cancer therapy.

Supramolecular hydrogels, particularly low-molecular-weight peptide hydrogels, are promising drug delivery systems due to their ability to change the solubility, targeting, metabolism and toxicity of drugs. Magneto-plasmonic liposomes, in addition to being remotely controllable with the application of an external magnetic field, also increase the efficiency of encapsulated drug release through thermal stimulation, for example, with magnetic and optical hyperthermia. Thus, the combination of those two materials-giving magneto-plasmonic lipogels-brings together several functionalities, among which are hyperthermia and spatiotemporally controlled drug delivery. In this work, a novel dehydrodipeptide hydrogelator was synthesised, and the respective hydrogel was functionalized with magneto-plasmonic liposomes. After individually characterising the components with regard to their rheological, spectroscopic and magnetic properties, the magneto-plasmonic lipogel was equally characterised and evaluated concerning its ability to deliver drugs in a controlled fashion. To this end, the response of the 5(6)-carboxyfluorescein-loaded magneto-plasmonic lipogel to near-infrared light was assessed. The results showed that the system is a proper carrier of hydrophilic drugs and allows to envisage photo-responsive drug delivery. These facts, together with the magnetic guidance and hyperthermia capabilities of the developed composite gel, may pave the way to a new era in the treatment of cancer and other diseases.

Photo- and thermo-responsive poly(ionic liquid) hydrogel regulated by hierarchical host–guest interactions

Supramolecular hydrogels constructed through various host–guest interactions have attracted tremendous attention in view of their excellent dynamic and multi-stimuli responsive performances. Herein, benzyl (Bn) and azobenzene (Azo) grafted poly(ionic liquid)s (PILs) were prepared via a one-pot post-synthesis strategy. By virtue of the difference in binding affinity of Azo and Bn groups with the host compound cucurbituril [8] urea (CB[8]), the newly-developed supramolecular hydrogels exhibited distinctive photo- and thermo-responsive behaviors. Under UV light irradiation, PIL-Azo-Bn/CB[8] hydrogel got weaker, while a gel-to-sol transition was observed when treated by heating. Moreover, the above tunable behaviors were highly reversible. Variable-temperature measurements such as proton nuclear magnetic resonance and ultraviolet–visible spectroscopy illustrated that the photo- and thermo-regulated performances of PIL hydrogel were ascribed to the hierarchical host–guest interactions. As a prototype application in smart circuits, PIL hydrogel exhibited a photo- and thermo-tuned conductivity. Thus, our finding presented a novel and versatile platform to fabricate responsive functional hydrogels via host–guest interactions, which has great promising applications in smart materials and flexible sensors.

Fatigue resistant photo-responsive [c2] daisy chain Poly(rotaxane) hydrogel

A photo-responsive poly(rotaxane) hydrogel based on [c2] daisy chain was synthesized. The supramolecular hydrogel was robust with the compression stress of 3136 kPa at the strain of 90 %, the tensile strength of 297 kPa and the elongation at break of 694 %. At the same time, the gel film showed fast photoresponsive behavior even in dry state, showing 15o bending angle under 2 s 365 nm UV irradiation. Besides, the hydrogel exhibited good fatigue resistance. Its recovery ratio remains higher than 80 % during multiple cyclic tensile and compression test, making it an alternative and promising platform for photo-responsive materials with emergent mechanical performances and attractive fatigue resistance.

Oxidation-Responsive Supramolecular Hydrogels Based on Glucosamine Derivatives with an Aryl Sulfide Group.

Supramolecular hydrogels can be obtained via self-assembly of small molecules in aqueous environments. In this study, we describe the development of oxidation-responsive supramolecular hydrogels comprising glucosamine derivatives with an aryl sulfide group. We demonstrate that hydrogen peroxide can induce a gel-sol transition through the oxidation of the sulfide group to the corresponding sulfoxide. Furthermore, we show that this oxidation responsiveness can be extended to photo-responsiveness with the aid of a photosensitizer.

(Invited) Supramolecular Hydrogels for Fabrications of Wearable Sensors and Medical Scaffolds

While hydrogels have enabled a variety of applications in wearable sensors and electronic skins, they are susceptible to fatigue fracture during their cyclic deformations owing to the inefficient fatigue resistance. Design of hydrogels with excellent mechanical properties and highly stable performance during the practical long-term applications of produced wearable sensors and medical scaffolds remains a tremendous challenge. The supramolecular hydrogels with the topological networks consisting of mechanical interlocked units lead to high toughness and robust fracture resistance. In our studies, a type of polymerizable crosslinker is assembled by the precise host-guest recognition, which is then photocured to construct the conductive hydrogel system. This polymerizable crosslinker having the mobile junctions simultaneously endows the resulting conductive hydrogels with three important features in the applications of strain sensors and scaffolds: (1) high stretchability along with superior fatigue resistance, (2) hydrogels applicable for sensors with high conductivity and sensitivity, and (3) suitability for 3D printing fabrication of sensors with altitude complexity. In addition, we have developed a biological metabolism-inspired hydrogel from the dynamic cross-linked natural polymer for reshaping the hostile rheumatoid arthritis microenvironment. The engineered hydrogel exhibits injectable performance and self-healing ability. When the hydrogel is engineered as a 3D stem cell-laden scaffold, the satisfactory reconstruction of large-scale bone defects in rheumatoid arthritis is achieved with effective antioxidant and anti-inflammatory performance simultaneously.

(Invited) Fullerenes for Bio-Applications: The Way of Water

Nano-materials are emerging as important components for a series of bio-applications. In this context, carbon nanostructures such as graphene, carbon nanotubes and fullerenes have unique chemical and physical properties that make them attractive for such applications. Carbon nanomaterials have been used in tissue engineering, biosensing and drug delivery. They have also shown anti-microbial activity. They can be loaded with drugs for controlled local delivery. More importantly, the surface of carbon nanomaterials can be functionalised to enhance their biocompatibility by increasing their water-solubility.In this talk, I will present an update on our work in using fullerenes and their derivatives for developing bio-nanomaterials. I shall focus on the combination of carbon nanostructures and polymeric materials which can result in supramolecular hydrogels with interesting properties. Hydrogels are emerging as important materials in applications such as cellular scaffoldings in regenerative medicine/tissue engineering, tissue replacements, wound dressings, etc.I will present the synthesis of supramolecular hydrogels made from fullerenes of different sizes (C60, C84 and C90–92) that have been hydroxylated and functionalised with hydrophilic oligoethylene glycol chains. To the best of our knowledge, there have been no attempts made at incorporating higher fullerenes and their derivatives into such extended supramolecular structures, before now.I will also show possibilities for extending our approach to endohedral fullerenes such as N@C60. I will show how we can use advanced techniques including AFM to characterise the elasticity of the hydrogels formed. The ability to incorporate endohedral fullerenes in hydrogels may be important in extending the possibility for using these materials as sensors in vitro or even in vivo, exploiting the quantum properties of such molecular systems such as their extended electron and nuclear spin lifetimes.

A supramolecular hydrogel eye-drop alleviates inflammation via clathrin-mediated endocytosis

The modulation of inflammation is effective to treat many ocular surface diseases. Thus the low bioavailability of common anti-inflammatory eye-drops urges the development of ocular drug delivery systems to extend the ocular retention and enhance the cellular uptake for improving anti-inflammatory effect of eye-drops. Here we covalently conjugate two molecules of clinically anti-inflammatory drug (i.e., dexamethasone) with a small peptide (i.e., Tyr–Glu–Asn–Pro–Thr–Tyr) to generate an anti-inflammatory hydrogel eye-drop. With a self-assembled ability, the designed supramolecular hydrogel achieves gel–sol–gel transition by varying shearing forces which increases the pre-corneal retention of drug. The fluorescent imaging reveals the efficient cellular uptake of designed conjugate via clathrin-mediated endocytosis. A rodent model of endotoxin-induced uveitis verifies that the supramolecular hydrogel eye-drop suppresses inflammation responses without ocular irritation. As a rational approach to design anti-inflammatory drugs as eye-drops, this work overcomes the frequent instillation of clinical eye-drops and further improves the bioavailability of anti-inflammatory drugs, which may provide an effective and household way to fight ocular surface inflammation.

From self-Assembly to healing: Engineering ultra-Small peptides into supramolecular hydrogels for controlled drug release

The aim of this study was the evaluation of suitability of novel mucoadhesive hydrogel platforms for the delivery of therapeutics useful for the management of disorders related to the gastrointestinal tract (GI). At this purpose, here we describe the preparation, the physicochemical characterization and drug delivery behaviour of novel hydrogels, based on self-assembling lipopeptides (MPD02-09), obtained by covalently conjugating lauric acid (LA) to SNA’s peptide derivatives gotten by variously combining D- and L- amino acid residues. LA conjugation was aimed at improving the stability of the precursor peptides, obtaining amphiphilic structures, and triggering the hydrogels formation through the self-assembling. Budesonide (BUD), an anti-inflammatory drug, was selected as model because of its use in the treatment in GI disorders. Preliminary studies were performed to correlate the chemical structure of the conjugates with the key physicochemical properties of the materials for drug delivery. Two lipopeptides, MPD03 and MPD08, were found to form hydrogels (MPD03h and MPD08h, respectively) with characteristics suitable for drug delivery. These materials showed mucoadhesiveness of about 60 %. In vitro studies carried out with BUD loaded hydrogels showed about 70 % drug release within 6 h. Wound healing assessed in Caco-2 and HaCaT cells, showed reduction of cell-free area to values lower than 10 %. Taking together these results MPD03h and MPD08h have been shown to be excellent candidates for BUD delivery.

Supramolecular Hydrogels for 3D Biosensors and Bioassays.

Supramolecular hydrogels play a pivotal role in many fields of biomedical research, including emerging applications in designing advanced tools for point-of-care testing, clinical diagnostics, and lab-on-chip analysis. This review outlines the growing relevance of supramolecular hydrogels in biosensing and bioassay devices, highlighting recent advancements that deliver increased sensitivity, real-time monitoring, and multiplexing capabilities through the distinctive properties of these nanomaterials. Furthermore, the exploration extends to additional applications, such as using hydrogels as three-dimensional matrices for cell-based assays.

Exploiting Urea-Carboxylate Synthon for Designing Supramolecular Topical Hydrogel via Simple Organic Salt Formation: Synthesis, Crystal Structures, and Anticancer Behavior against Melanoma B16–F10 Cells

Exploiting Urea-Carboxylate Synthon for Designing Supramolecular Topical Hydrogel via Simple Organic Salt Formation: Synthesis, Crystal Structures, and Anticancer Behavior against Melanoma B16–F10 Cells