Multifunctional Supramolecular Hydrogel Research Articles

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.

Gallic acid-doped multifunctional hybrid hydrogel for antioxidant and antibacterial studies

The design and fabrication of multifunctional hybrid hydrogels for various biomedical applications have sparked tremendous scientific interest and still remain a formidable challenge. Here, we report the construction of a multifunctional supramolecular hybrid hydrogel through a facile preparation route by co-assembling the L-phenylalanine-derivative (LPF) gelator with agarose (AG) and gallic acid (GA). The experimental analysis demonstrates that the components of hybrid hydrogel co-assembled to form a cross-linked interpenetrating network that is mainly formed through non-covalent interactions, thereby resulting in remarkable enhancement in rheological properties with an elastic modulus (G′) of 12715 Pa. Due to the inherent antimicrobial property of GA, this hybrid hydrogel exhibited antibacterial activities against both Gram-negative (Pseudomonas aeruginosa, Escherichia coli) and Gram-positive (Staphylococcus aureus) bacterial cells. Furthermore, the presence of GA enabled hybrid hydrogels to offer efficient antioxidant properties by scavenging free radicals such as DPPH· and ABTS·+. The cell adhesion, proliferation, and spreading behavior of L929 cells were significantly improved on the hybrid hydrogel substrate. These experimental findings suggest that this high-performance hybrid hydrogel possessing antibacterial, antioxidant, and biocompatible properties, opens new avenues for extensive applications in the biomedical field.

High Mechanical Strength and Multifunctional Microphase-Separated Supramolecular Hydrogels Fabricated by Liquid-Crystalline Block Copolymer.

The development of multifunctional supramolecular hydrogels with high mechanical strength and multifunction is in high demand. In this work, the diblock copolymer poly(acrylamide-co-1-benzyl-3-vinylimidazolium bromide)-block-polyAzobenzene is synthesized through reversible addition-fragmentation chain transfer polymerization. The dynamic host-guest interactions between the host molecule cucurbit[8] uril and guest units are used to fabricate a 3D network of supramolecular hydrogels. Investigations on the properties of the supramolecular hydrogels show that the tensile stress of the sample is 1.46MPa, eight times higher than that of hydrogel without liquid-crystalline block copolymer, and the self-healing efficiency of the supramolecular hydrogels at room temperature is 88.3% (fracture stress) and 100% (fracture strain) after 24h. Results show that microphase-separated structure plays a key role in the high-strength hydrogel, whereas the host-guest interaction endows the hydrogel with self-healing properties. The supramolecular hydrogels with high mechanical strength, photo-responsivity, injectability, and biocompatibility can be used in various potential applications.

Protocatechuic Acid-Based Supramolecular Hydrogel Targets SerpinB9 to Achieve Local Chemotherapy for OSCC.

Protocatechuic acid (PCA) is a natural phenolic acid present in daily vegetables and fruits. Notably, PCA was demonstrated to inhibit the biological function of SerpinB9 (Sb9) and exhibit an excellent antitumor effect, showing great potential in cancer treatment. However, the short half-life time limits PCA's wide application against cancers. To overcome this shortage of PCA, we integrated PCA and another natural product with strong self-assembling properties, isoguanosine (isoG), to develop a novel multifunctional supramolecular hydrogel with good biocompatibility and injectability, which remarkably lengthens the releasing time of PCA and exerts considerable anticancer effects in vitro and in vivo. Besides, we surprisingly found that PCA could not only target Sb9 but also restrain cancer development through activating the JNK/P38 pathway, decreasing the ROS level, and repairing cancer stemness. In all, our results demonstrate that this PCA-based hydrogel could act as a multifunctional hydrogel system equipped with considerable anticancer effects, providing potential local administration integrating with targeted therapy and chemotherapy in one simple modality.

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.

Transparent Conductive Supramolecular Hydrogels with Stimuli-Responsive Properties for On-Demand Dissolvable Diabetic Foot Wound Dressings.

Diabetic foot ulcers (DFU) remain a very considerable health care burden, and their treatment is difficult. Hydrogel-based wound dressings are appealing to provide an optimal environment for wound repair. However, the currently available hydrogel dressings still need surgical or mechanical debridement from the wound, causing reinjury of the newly formed tissues, wound infection, delayed healing time, and personal suffering. Additionally, to meet people's increasing demand, hydrogel wound dressings with improved performance and multifunctionality are urgently required. Here, a new multifunctional supramolecular hydrogel for on-demand dissolvable diabetic foot wound dressings is designed and constructed. Based on multihydrogen bonds between hydrophilic polymers, the resultant supramolecular hydrogels present controlled and excellent properties, such as good transparency, antibacterial ability, conductive, and self-healing properties. Thus, the supramolecular hydrogels improve the new tissue formation and provide a significant therapeutic effect on DFU by inducing angiogenesis, enhancing collagen deposition, preventing bacterial infection, and controlling wound infection. Remarkably, the resultant hydrogels also exhibit stimuli-responsive ability, which renders its capability to be dissolved on-demand, allowing for a facile DFU dressing removal. This multifunctional supramolecular hydrogel may provide a novel concept in the design of on-demand dissolvable wound dressings.

Multifunctional Supramolecular Hydrogel for Prevention of Epidural Adhesion after Laminectomy.

Postoperative epidural adhesion remains a clinically challenging problem in spine surgery. Currently there are no effective and safe antifibrotic and antiadhesion biomaterials that have been specifically developed for this complication in clinical practice. Herein we designed and engineered an advanced antiadhesion hydrogel with multiple functionalities, including temperature-responsive gelation, self-healing, tissue adhesiveness, antioxidation, anti-inflammation, and antifibrosis. This multifunctional supramolecular hydrogel can be facilely constructed by integrating three functional modules, i.e., a thermosensitive triblock copolymer, poloxamer 407 (PX); a reactive oxygen species-eliminating and anti-inflammatory nanoparticle (TPCD NP); and an adhesion-enhancing compound, tannic acid (TA). The optimal formulation (PXNT) was hierarchically screened based on in vitro properties and in vivo activities. Therapeutically, local treatment with PXNT hydrogel effectively prevented epidural fibrosis and adhesion after laminectomy in both rats and rabbits. Of note, PXNT hydrogel showed more beneficial efficacy than different control thermosensitive hydrogels and a commercially available barrier product, Interceed. Mechanistically, PXNT hydrogel significantly attenuated local oxidative stress, inhibited inflammatory responses, and reduced fibrotic tissue formation. Moreover, treatment with PXNT hydrogel did not cause systemic adverse effects and neurological symptoms. Consequently, PXNT hydrogel is a highly promising biomaterial for preventing postlaminectomy epidural adhesion and adhesions after other surgeries.

Interaction among Worm-like Micelles in Polyoxometalate-Based Supramolecular Hydrogel.

The co-assembly of zwitterionic amphiphile and polyoxometalate is a new and promising technique to construct a hierarchical and multifunctional supramolecular hydrogel. To comprehensively investigate the assemble mechanism, zwitterionic amphiphiles with different cations, namely, 3-(1-hexadecyl-3-imidazolio) propanesulfonate (C16IPS) and 3-(1-hexadecyl-2-methyl-3-imidazolio) propanesulfonate (C16bIPS), were designed to complex with silicotungstic acid (HSiW). Hydrogen bonding between the oxygen atoms of HSiW and the protons on C-2 of the imidazolium rings and the steric effect significantly influence the morphology and rheological property of the hydrogel. Interestingly, cross-linked worm-like micelles in parallel, vertical, and tilted distribution were observed using cryogenic transmission electron microscopy. In addition, these aggregates were further stacked into hexagonal phases on a large scale. Hence, deep insights into the relationship among the structure of zwitterionic amphiphile, self-assembled architecture, and the mechanical property of a polyoxometalate-based hydrogel were disclosed.

Pillar[5]arene-based multifunctional supramolecular hydrogel: multistimuli responsiveness, self-healing, fluorescence sensing, and conductivity

A pillar[5]arene-based multi-stimuli responsive supramolecular hydrogel has been constructed. This hydrogel not only could ultra-sensitively detect Fe3+ by fluorescence, but it is also an excellent self-healing and conductive material.

A photo-degradable supramolecular hydrogel for selective delivery of microRNA into 3D-cultured cells.

Multi-functional supramolecular hydrogels have emerged as smart biomaterials for diverse biomedical applications. Here we report a multi-functional supramolecular hydrogel formed by the conjugate of the bioactive GRGDS peptide with biaryltetrazole that is the substrate of photo-click reaction. The hydrogel was used as a biocompatible matrix to encapsulate live cells for 3D culture. The presence of the RGD epitope in the hydrogelator enhanced the interaction of the nanofiber with integrin over-expressing cells, which resulted in the selective enhancement in the miRNA delivery into the encapsulated U87 cells. The intramolecular photo-click reaction of the biaryltetrazole moiety in the hydrogelator leads to a sensitive photo-response of the hydrogel, which allowed photo-degradation of the hydrogel for release of the encapsulated live cells for further bio-assay of the intracellular species.

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

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

Mussel-inspired multifunctional supramolecular hydrogels with self-healing, shape memory and adhesive properties

A novel multifunctional supramolecular hydrogel with self-healing, shape memory and adhesive properties is successfully developed on the basis of dynamic phenylboronic acid (PBA)–catechol interactions.

PH-Responsive supramolecular hydrogels for codelivery of hydrophobic and hydrophilic anticancer drugs

Codelivery of multiple drugs with one kind of drug carrier provides a promising strategy to suppress the drug resistance and achieve the enhanced therapeutic effect in cancer treatment. In this work, we successfully developed multifunctional supramolecular hydrogels based on in situ host–guest inclusion between polymer-drug conjugates and α-cyclodextrin to codeliver hydrophobic and hydrophilic anticancer drugs with pH-trigged release properties. Taking advantage of the strong hydrophobicity of 4β-aminopodophyllotoxin (NPOD), a derivative of podophyllotoxin (POD), the NPOD molecule was conjugated to low-molecular-weight methoxypoly (ethylene glycol) (mPEG) chain via a pH-responsive imine bond, forming an amphiphilic polymer-drug conjugates (NPOD-PEG). After adding α-cyclodextrin (α-CD) into the NPOD-PEG solutions, the stable supramolecular hydrogels were formed based on a combination of the partial inclusion complexation between one end of the mPEG blocks and α-CD and the hydrophobic aggregation of NPOD groups. The formed hydrogels could further efficiently load another hydrophilic anticancer drug doxorubicin (DOX) for combination therapy purposes. The hydrogel demonstrated unique gel–sol transition properties and pH-dependent dual drug release behavior due to the hydrolysis of imine bond at acidic environments. Furthermore, the cytotoxicity results suggested that the DOX loaded NPOD-PEG/α-CD hydrogels showed an enhanced cytotoxicity in cancer cells in comparison with single modality treatment and the resulting hydrogels are characterized by producing an additive cytotoxicity to cancer cells. In fact, the codelivery of two anticancer drugs with different physicochemical properties and anticancer mechanisms was a key to opening the door to their controlled drug delivery and enhanced anticancer effect. Therefore, DOX loaded NPOD-PEG/α-CD hydrogels as pH-trigged drug codelivery systems might have important potential for combination cancer chemotherapy.

Self-delivery multifunctional anti-HIV hydrogels for sustained release.

None of the clinical trials of anti-HIV gels based on conventional polymers or lipid emulsions has been successful, suggesting the need of new molecular design of the anti-HIV gels. This paper reports the conversion of anti-HIV prodrugs into self-delivery supramolecular hydrogels. By covalently conjugating reverse transcriptase inhibitors to a versatile self-assembly motif, the hydrogelators that self-assemble to form supramolecular nanofibers as the matrices of hydrogels in a weak acidic condition are obtained. Upon the treatment of prostate acid phosphatase (PAP), the hydrogels exhibit drastically enhanced elasticity. The hydrogelators are biocompatible and able to release the inhibitors under physiological condition. The use of the self-assembly motif as a self-delivery agent containing non-steroid anti-inflammatory drug (NSAID) renders this hydrogel to be both anti-inflammatory and anti-HIV. This work illustrates an unprecedented approach for designing multifunctional supramolecular hydrogels that may serve as potential anti-HIV hydrogels for sustained drug release.

Prodrugs forming multifunctional supramolecular hydrogels for dual cancer drug delivery.

Here we report a multifunctional supramolecular hydrogel based on host-guest inclusion for loading two different anticancer drugs with different controlled release profiles. The resulting hydrogels are characterized by possessing dual phase drug release behavior and producing a dose and cell type dependent synergetic cytotoxicity to cancer cells, which can be used for cancer combination therapy.

Self-assembly of small molecules affords multifunctional supramolecular hydrogels for topically treating simulated uranium wounds

Two types of therapeutic agents, which have discrete yet complementary functions, self-assemble into nanofibers in water to formulate a new supramolecular hydrogel as a self-delivery biomaterial to reduce the toxicity of uranyl oxide at the wound sites.