Supramolecular Hydrogel System Research Articles

Biochemical Signal-Induced Supramolecular Hydrogelation for Structured Free-Standing Soft Material Formation.

Cells coordinate their activity and regulate biological processes in response to chemical signals. Mimicking natural processes, control over the formation of artificial supramolecular materials is of high interest for their application in biology and medicine. Supramolecular material that can form in response to chemical signals is important for the development of autonomously responsive materials. Herein, a supramolecular hydrogel system is reported enabling in situ generation of hydrogelators in response to a specific chemical signal. Using self-immolative chemistry, spatial control over the formation of supramolecular hydrogel material and structured free-standing hydrogel objects via providing H2O2 locally is demonstrated. In addition, a hybrid system is developed enabling in situ generation of the H2O2 by the action of an enzyme and glucose, providing an extra handle for the development of an intelligent soft material. This generic design should enable the use of various (chemical)stimuli that can be obtained via coupling different stimuli and various chemical and/or biological markers and appears a versatile approach for the design of smart artificial soft materials that can find application in theranostic purposes.

Effects of Nucleophilic Catalysts on the Self‐Assembly of Hydrazone‐Based Supramolecular Hydrogels

AbstractCatalytic control over molecular self‐assembly provides a powerful approach to regulate the structures as well as the functionalities of supramolecular materials. Revealing how the catalysts affect the molecular self‐assembly process is crucial for rational design and control of the supramolecular self‐assembly systems. Herein, relying on a hydrazone‐based dynamic supramolecular hydrogel system, the effects of various nucleophilic catalysts on the self‐assembly of the hydrogels are investigated, demonstrating that the catalyst influences the hydrogelators self‐assembly via facilitating both the reaction and hydrogelators nucleation processes. The catalyst with higher catalytic activity accelerates the formation thereon the self‐assembly of hydrazone‐based hydrogelators, leading to hydrogels with more branched networks and higher stiffness. Importantly, we also verify that the catalysts, depending on the molecular structure, can also accelerate the self‐assembly process by affecting the hydrogelators nucleation process. These findings not only add more details to the effects of nucleophilic catalysts on the hydrazone‐based hydrogelation system, but also suggest that both the catalysis activity and chemical structures should be considered for catalytically controlled molecular self‐assembly.

A natural food-grade supramolecular self-assembly system for creation of hierarchically structured hydrogels.

We develop a novel hierarchically structured hydrogel by the supramolecular self-assembly of all-natural food-grade building blocks, glycyrrhizic acid (GA) and carrageenan (CG). The co-assembled GA-CG hydrogel system displays an unusual structural transition with the appearance from opacity to translucence and then to opacity, as a function of the concentration of metal ions. The unique GA-CG supramolecular hydrogel system can serve as solid, edible, and responsive active cargo delivery platforms for food and biomedical applications.

Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactoryin solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy.

Alginate/polyacrylamide host-guest supramolecular hydrogels with enhanced adhesion

Although injectable hydrogels with minimally invasive delivery have garnered significant interest, their potential applications have been restricted by a singular property. In this study, a supramolecular hydrogel system with improved adhesion was constructed through host-guest interactions between alginate and polyacrylamide. The maximum tensile adhesion strength between the β-cyclodextrin and dopamine-grafted alginate/adamantane-grafted polyacrylamide (Alg-βCD-DA/PAAm-Ad, namely AβCDPA) hydrogels and pigskin reached 19.2 kPa, which was 76 % stronger than the non-catechol-based control hydrogel (β-cyclodextrin-grafted alginate/adamantane-grafted polyacrylamide, Alg-βCD/PAAm-Ad). Moreover, the hydrogels demonstrated excellent self-healing, shear-thinning, and injectable properties. The required pressure to extrude the AβCDPA2 hydrogel from a 16G needle at a rate of 2.0 mL/min was 67.4 N. As the polymer concentration and adamantane substitution degree increased, the hydrogels exhibited higher modulus, stronger network structure, and lower swelling ratio and degradation rate. Encapsulating and culturing cells within these hydrogels demonstrated good cytocompatibility. Therefore, this hydrogel can serve as a viscosity extender or bioadhesive, and as a carrier material to deliver encapsulated therapeutic substances into the body through minimally invasive injection methods.

Bisphosphonate-Modified Functional Supramolecular Hydrogel Promotes Periodontal Bone Regeneration by Osteoclast Inhibition.

Regeneration of periodontal tissue remains a challenge. Under periodontitis, osteoclasts are overactivated and bone loss occurs. We incorporated sodium alendronate (Alen), a medication commonly used to treat osteoporosis, into a supramolecular hydrogel system in order to create a novel biomaterial that would promote periodontal bone regeneration by inhibiting osteoclast overactivation. The Nap-Gly-Phe-Phe (NapGFF) peptide chain was modified to synthesize the functional Nap-Alen gelator. Afterward, the Nap-Alen/HAP supramolecular hydrogel composite with a suitable hydroxyapatite (HAP) ratio was constructed, which has outstanding mechanical properties and 3D structure. In addition to its good biocompatibility, it can inhibit the proliferation of bone marrow-derived macrophages (BMDMs) and differentiation of osteoclasts. Due to the simultaneous introduction of porous HAP, the hydrogel with a nanofiber structure was formed into a 3D mesh-like sparse porous composite hydrogel. While enhancing the mechanical properties of the gel, the porous structure facilitated the attachment and migration of bone regeneration-related cells. Therefore, it can effectively promote the regeneration of periodontal bone. In the future, by modifying the biophysical properties and loading stem cells or cytokines, this supramolecular hydrogel composite constructed in this study may provide a new strategy for tissue regeneration engineering and provide a preliminary experimental basis for relevant clinical translational studies.

Photoregulated supramolecular hydrogels driven by polyradical interactions

Organic radical as a powerful tool has been extensively applied in synthetic chemistry. However, harnessing radical-mediated noncovalent interactions to fabricate soft materials remains elusive. Here we report a new category of supramolecular hydrogel system held by multiple radical-radical (polyradical) interactions, and its photosensitive cross-linking structure. A simple polyacrylamide with triarylamine (TAA) pendants is designed as the precursor. The TAA units in polymer can be converted into active TAA•⁺ radical cations with light and further associate each other via TAA•⁺‒TAA•⁺ stacking interactions to form stable supramolecular network. Temporal control of the light irradiation dictates the degree of radical stacks, thus regulating the mechanical performance of the resulting hydrogel materials on-demand. Moreover, the reversible collapse of this hydrogels can be promoted by adding radical scavenger or exerting reduction voltage.

Host-guest interaction enabled chiroptical property, morphology transition, and phase switch in azobenzene-glutamide amphiphile based hydrogel

To achieve the regulation of both chirality and nanostructure in supramolecular gel is significant and challenging. Here, we prepare a supramolecular hydrogel system by an low-molecule-weight-gelator C4AzoGlu in aqueous solution. C4AzoGlu hydrogel show supramolecular chirality and a structure of nanotwists. When C4AzoGlu complex with α-Cyclodextrin in water, the supramolecular chirality switch, the morphology transition from nanotwists to precipitate and the phase switch from gel to sol could be realized by photoirradiation, which is caused by the trans-cis isomerization of the azobenzene group. This work may provide some insights to the chiroptical property and morphology transition based on host-guest gel formed in aqueous solution.

Polydopamine-doped supramolecular chiral hydrogels for postoperative tumor recurrence inhibition and simultaneously enhanced wound repair

Cancer recurrence remains a major challenge after primary tumor excision, and the inflammation of tumor-caused wounds can hinder wound healing and potentially promote tumor growth. Herein, a chiral L-phenylalanine-based (LPFEG) supramolecular hydrogel system encapsulated with polydopamine nanoparticles (PDA-NPs) has been developed in order to prevent tumor relapse after surgery and promote wound repair. PDA-NPs allow for near-infrared (NIR) light-triggered photothermal therapy, especially, it can scavenge free radicals in the surgical wound. LPFEG can mimic native extracellular matrix (ECM) structure to create a chiral microenvironment that enhances fibroblast adhesion, proliferation, and new tissue regeneration. With anticancer drug doxorubicin (DOX) loaded into the composite hydrogel, the antitumor effect is significantly enhanced by the integration of chemo-photothermal therapy both in vitro and in vivo. The PDA-based chiral supramolecular composite hydrogel as an effective postoperative adjuvant possesses promising applicable prospects in inhibiting tumor recurrence and accelerating wound healing after operation. Statement of SignificanceAfter primary tumor excision, cancer recurrence remains a severe concern, and the inflammation induced by tumor-related wounds can delay wound healing. Herein, we designed a chiral L-phenylalanine-based (LPFEG) supramolecular hydrogel platform that was co-assembled with polydopamine nanoparticles (PDA-NPs). Among them, PDA-NPs can offer photothermal therapy and scavenge free radicals in surgical wounds. LPFEG can create a chiral microenvironment that promotes fibroblast adhesion, proliferation, and new tissue regeneration. Furthermore, with anticancer drug doxorubicin (DOX) loaded into the composite hydrogel, the antitumor effect is considerably boosted. Therefore, the PDA-based chiral supramolecular hydrogel shows high application potential as a postoperative adjuvant in preventing tumor relapse as well as accelerating wound healing after surgery.

Host‐Fueled Transient Supramolecular Hydrogels

AbstractInspired by the dissipative assembly in biological systems, transient hydrogels based on supramolecular interactions have been developed that are under thermodynamic nonequilibrium states. Host–guest interactions possess excellent properties including high selectivity and adjustable association constants, which are beneficial for controlling the properties and behaviors of transient colloidal materials. In this work, a host‐fueled transient supramolecular hydrogel system is reported. The hydrogels based on host–guest interactions are formed by addition of a chemical fuel, α‐cyclodextrin (α‐CD), to the aqueous solutions containing Pluronic F127 and α‐amylase. Meanwhile, as the host molecule of α‐CD consumes, the hydrogel networks start to collapse. The lifetime of the transient supramolecular hydrogels can be precisely controlled by adjusting the temperature and hydrogel composition, and repeated sol‐to‐gel‐to‐sol transitions can be realized by refueling the system with α‐CD. This study provides a new approach to regulate the nonequilibrium host–guest inclusion system by fueling it with host molecules.

Injectable supramolecular hydrogels based on host–guest interactions with cell encapsulation capabilities

Injectable hydrogels, which can deliver cells or drugs directly to tissue sites by minimally invasive injection methods, have attracted considerable attention. In this work, using β-cyclodextrin-grafted alginate as the host polymer and adamantane-grafted polyacrylamide as the guest polymer, an injectable supramolecular hydrogel system was developed based on the host–guest interaction between β-cyclodextrin (βCD) and adamantane (Ad). Simple physical mixing and stirring methods allowed the hydrogels to be prepared in a short time (<1 min). The rheological and mechanical properties and microscopic morphology of the hydrogels were conveniently regulated by changing the grafting degree of βCD and Ad in alginate or polyacrylamide. The shear-thinning and self-healing properties induced by reversible host–guest interactions and a natural, plant-based polysaccharide endow the developed hydrogels with good injectability and biocompatibility, respectively. Experiments showed that the hydrogels effectively adhered to pork tissue. Moreover, human umbilical vein endothelial cells and human ovarian cancer cells encapsulated in the hydrogels showed good viability and three-dimensional distribution after being cultured for three days. Overall, the rapid preparation method and the advantages of injectability, self-healing and cytocompatibility endow the proposed injectable hydrogel system with great potential as a tissue engineering material.

A panther chameleon skin-inspired core@shell supramolecular hydrogel with spatially organized multi-luminogens enables programmable color change

Organization of different iridophores into a [email protected] structure constitutes an evolutionary novelty for panther chameleons that allows their skins to display diverse color change. Inspired by this natural color-changing design, we present a responsive [email protected] multi-luminogen supramolecular hydrogel system that generates a programmable multi-color fluorescent change. Specifically, red Eu3+-amidopicolinate (R) luminogen is incorporated into the core hydrogel, while blue naphthalimide (B) and green perylene-tetracarboxylic acid (G) luminogens are grown into two supramolecular shell hydrogels. The intensities of G/B luminogens could then be controlled independently, which enables its emission color to be programmed easily from red to blue or green, nearly covering the full visible spectrum. Because of the differential excitation energies between these luminogens, a desirable excitation wavelength-dependent fluorescence is also achieved. Colorful materials with a patterned [email protected] structure are also demonstrated for anti-counterfeiting, opening up the possibility of utilizing a bioinspired [email protected] structure to develop an efficient multi-color fluorescent system with versatile uses.

Self-Assembled, Dilution-Responsive Hydrogels for Enhanced Thermal Stability of Insulin Biopharmaceuticals.

Biotherapeutics currently dominate the landscape of new drugs because of their exceptional potency and selectivity. Yet, the intricate molecular structures that give rise to these beneficial qualities also render them unstable in formulation. Hydrogels have shown potential as stabilizing excipients for biotherapeutic drugs, providing protection against harsh thermal conditions experienced during distribution and storage. In this work, we report the utilization of a cellulose-based supramolecular hydrogel formed from polymer–nanoparticle (PNP) interactions to encapsulate and stabilize insulin, an important biotherapeutic used widely to treat diabetes. Encapsulation of insulin in these hydrogels prevents insulin aggregation and maintains insulin bioactivity through stressed aging conditions of elevated temperature and continuous agitation for over 28 days. Further, insulin can be easily recovered by dilution of these hydrogels for administration at the point of care. This supramolecular hydrogel system shows promise as a stabilizing excipient to reduce the cold chain dependence of insulin and other biotherapeutics.

A Reductive Supramolecular Hydrogel: A Platform for Facile Fabrication of Diverse Metal-Nanoparticle-Decorated Conductive Networks with Spatiotemporal Control.

Nanoparticle-hydrogel hybrid composites have a great potential for a broad range of applications, such as antibacterial materials, stimuli-responsive materials and catalysis. A novel supramolecular hydrogel system was developed using an amino acid based amphiphile containing a terminal pyrrole moiety as a gelator. The pyrrole moiety could serve as both reducing agent and monomer, and a variety of metal precursors penetrating into the hydrogel could be reduced in situ into metal nanoparticles while the pyrrole moieties preorganized in hydrogel were oxidized into polyprroles, affording metal-nanoparticle-decorated covalent conductive networks. This strategy allows the facile fabrication of diverse mono- or multimetallic nanoparticle-polymer networks from one hydrogel by a simple reaction-diffusion approach. More importantly, besides homogeneous composites, unique multisegment heterogeneous systems with spatiotemporal control were also easily accessible. Furthermore, based on the same multifunctional molecule, the fabrication of hierarchically pore-structured metal-nanoparticles-polymers as well as metal-nanoparticles-carbon structures was also realized.

Chromophore amphiphile–polyelectrolyte hybrid hydrogels for photocatalytic hydrogen production

Incorporating supramolecular assemblies of chromophore amphiphiles into covalent hydrogels creates a reusable, robust host for photocatalysis.

The aromaticity of the phenyl ring imparts thermal stability to a supramolecular hydrogel obtained from low molecular mass compound

Using Fmoc-phenylalanine and Fmoc-cyclohexylalanine, we show that the aromaticity of the phenyl ring imparts significant thermal stability to a supramolecular hydrogel system and its significance depends on the method of inducing hydrogelation.

Cholesterol Modification of an Anticancer Drug for Efficient Incorporation into a Supramolecular Hydrogel System.

Treatment of cancer in the peritoneal cavity may be improved with macroscale drug delivery systems that offer control over intraperitoneal concentration of chemotherapeutic agents. Currently, suitable drug carriers to facilitate a sustained release of small hydrophilic drugs such as mitomycin C are lacking. For this purpose, a pH-responsive supramolecular hydrogel based on ureido-pyrimidinone (UPy) chemistry is utilized here. In order to provide a sustained release profile, a lipophilicity-increasing cholesterol conjugation strategy is proposed that enhances affinity between the modified drug (mitomycin-PEG24 -cholesterol, MPC) and the hydrophobic compartments in the UPy gel. Additional advantages of cholesterol conjugation include improved chemical stability and potency of mitomycin C. In vitro the tunability of the system to obtain optimal effective concentrations over time is demonstrated with a combinatorial treatment of mitomycin C and MPC in one UPy hydrogel delivery system.

Supramolecular hydrogels based on poly (ethylene glycol)-poly (lactic acid) block copolymer micelles and α-cyclodextrin for potential injectable drug delivery system

A supramolecular hydrogel system was prepared by the host-guest interaction between the α-cyclodextrin (α-CD) and poly (ethylene glycol) (PEG) chains of the poly (ethylene glycol)-block-poly (lactic acid) (PEG-b-PLA) micelles. The formation of inclusion complex (IC) crystals between α-CD and the PEG chains of the micelles was verified by different techniques. Rheological studies indicated that the gelation kinetics and the mechanical strength of the hydrogels could be modulated by the α-CD concentration. Also, the shear-thinning and self-healing properties of the hydrogels were confirmed. Doxorubicin (DOX) could be encapsulated into the hydrogels via the micelles and be released from the hydrogels sustainably, with the release rate dependent on the α-CD concentration. The released DOX showed higher inhibition efficacy against HeLa cells compared with the free drug. These attractive features, together with the superior biocompatibility, make the present hydrogels an potential injectable drug delivery system for tumour treatment.

Physiologically stable F127-GO supramolecular hydrogel with sustained drug release characteristic for chemotherapy and photothermal therapy.

A synthetic method for preparing a Pluronic F127 (F127)-stabilized graphene (GO) supramolecular hydrogel as a safe nanovehicle for combination treatment has been studied. Doxorubicin (DOX) as a model drug is non-covalently bound on the great surface area of GO due to strong π–π interaction, hydrophobic interaction, and the strongest hydrogen bonding. In vitro drug release experiments revealed that this F127-stabilized GO supramolecular hydrogel has a sustained drug release characteristic. Furthermore, the supramolecular hydrogel showed better in vitro antitumor ability under NIR (near infrared) laser irradiation because of the excellent photothermal effect of GO. Moreover, we evaluated its antitumor ability in vivo and the results show that the hydrogel system can also markedly inhibit the growth of a tumor when administered individually, especially under laser irradiation. All these findings make the supramolecular hydrogel system promising for combination therapy with good bioavailability and minimal side effects.

Injectable Supramolecular Hydrogels as Delivery Agents of Bcl-2 Conversion Gene for the Effective Shrinkage of Therapeutic Resistance Tumors.

Injectable hydrogels to deliver therapeutic genes in a minimally invasive manner and to achieve long term sustained release at tumor sites to minimize side effects are attractive for cancer therapy and precision medicine, but its rational design remains a challenge. In this report, an injectable supramolecular hydrogel system is designed based on the polypesudorotaxane formation between α-cyclodextrin (α-CD) and cationic methoxy-poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(ethylene imine) (MPEG-PCL-PEI) copolymer, with the ability to form polyplexes with anionic plasmid DNA for effective sustained gene delivery. To be mentioned, the MPEG-PCL-PEI copolymers show similar pDNA binding ability, better gene transfection efficiency, lower cytotoxicity than nonviral gene transfection gold standard PEI (25 kDa), due to the formation of micelles and more stable polyplexes. More importantly, this MPEG-PCL-PEI/α-CD/pDNA supramolecular hydrogel shows a sustained release of pDNA in form of polyplex for up to 7 d. By taking these advantages, this supramolecular hydrogel system is applied as an injectable carrier for sustained Bcl-2 conversion gene release, in an in vivo rodent model of therapeutic resistant hepatocarcinoma with high expression of antiapoptotic Bcl-2 protein. This work represents the first time that injectable MPEG-PCL-PEI/α-CD supramolecular hydrogels possess good controllable release effect of Bcl-2 conversion genes in the form of polyplex to effectively inhibit in vivo tumor growth and this "enemy to friend" strategy will benefit various applications, including on-demand gene delivery and personalized medicine.