Application of supramolecular hydrogel in supercapacitors: Opportunities and challenges

Supercapacitors(SCs)are studied and used in variousfields due to their high power density,fast charging/discharging rate,as well as long cycle life.Compared to other traditional electrode and electrolyte materials,supramolecular hydrogels have great advantages in the application of SCs due to their excellent properties.Unlike covalent bonds,supramolecular systems are assembled through dynamic reversible bonds,including host–guest interactions,ion interactions,electrostatic interactions,hydrogen bonding,coordination interactions,etc.The resulting supramolecular hydrogels show some special functions,such as stretching,compression,adhesion,self-healing,stimulus responsiveness,etc.,making them strong candidates for the next generation of energy storage devices.This paper reviews the representative progress of electrodes,electrolytes,and SCs based on supramolecular hydrogels.Besides,the properties of supramolecular hydrogels,such as conductivity,exten-sibility,compressibility and elasticity,self-healing,frost resistance,adhesion,andflexibility,are also reviewed to highlight the key role of excellent properties of hydro-gel materials in SCs.In addition,this article also discusses the challenges faced by current technologies,hoping to continue promoting future research in thisfield.

Construction and Properties of the Me_(10)Q[5]/2,7-diaminofluorenedihydrochloride Supramolecular Hydrogel

Compared to traditional polymer hydrogels,supramolecular hydrogels exhibits superior reversibility and stimulus response due to the instantaneous and reversible nature of non-covalent bonds.In this paper,we utilized the host-guest exclusion interaction between Decamethylcucurbit[5]uril(Me_(10)Q[5])and the 2,7-diaminofluorenedihydrochloride(DAF·HCl)to construct a Q[n]-based hydrogel system.The composition,structure,and properties of the hydrogel were compre-hensively characterized using rheometer,nuclear magnetic resonance,scanning electron microscope.This cost-effective and straightforward hydrogel synthesis method paves the way for the scalable production of practical and commercially viable Q[n]-based hydrogels.

Highly stable supramolecular hydrogels formed from 1,3,5-benzenetricarboxylic acid and hydroxyl pyridines

New supramolecular hydrogels with the maximal sol-gel transition temperature （Tgel） of 95 ℃ were obtained by using gelators formed from 1,3,5-benzenetricarboxylic acid （BTA） and para-hydroxyl pyridine （PHP） or meta-hydroxyl pyridine （MHP）. The single crystal structure of the complex formed from BTA and ortho-hydroxyl pyridine （OHP） indicated that the molecules assembled into superstructure via both hydrogen bonds and π--π stacking interaction.

Assembling and releasing performance of supramolecular hydrogels formed from simple drug molecule as the hydrogelator

A simple drug compound, 4-oxo-4-（2-pyridinylamino） butanoic acid （defined as AP）, was able to gel water at 4 wt% concentration under various conditions. In the superstructure, AP molecules assembled into fibrous aggregates driving by hydrogen bonds and π-π stacking interaction. The gels with different backbone structures released drug molecules in different speeds.

Influence of gelator structures on formation and stability of supramolecular hydrogels

A supramolecular hydrogel （defined as G1） formed from 1,2,4,5-benzene tetracarboxylic acid （BTCA） and 2-amino-3- hydroxypyridine possessed higher Tgel than that of another hydrogel （defined as G2） formed from BTCA and 3-hydroxypyridine. Based on the analysis of their xerogels by 1H NMR, IR and XRD, the higher stability of G1 was attributed to the formation of stronger hydrogen binding enhanced by the ortho amino group of 2-amino-3-hydroxypyridine.

New Hydrogen Bonded Supramolecular Hydrogels Formed through Gelating Two Isomeric Building Units Simultaneously

New hydrogen bonded supramolecular hydrogels were formed through simultaneously gelating two isomeric building units, 4-oxo-4-（2-pyridinylamino）butanoic acid （G1） and 4-oxo-4-（3-pyridinylamino）butanoic acid （G2） at various molar ratios in water.

Effect of hydrogen bonding and hydrophobic interaction on the formation of supramolecular hydrogels formed by L-phenylalanine derivative hydrogelator

A new hydrogelator, pyridinium bromide salt of N-6-bromohexanoyl-L-phenylamino octadecane, was synthesized. Supramolecular hydrogels can be formed through the self-assembly of this hydrogelator in water. In this work, D2O was used instead of H2O as solvent for FT-IR measurement due to the fact that it is impossible to obtain useful Fr-IR information on the hydrogen bonding in water. The investigation of PT-IR and steady-state fluorescence indicated that the driving forces for the self-assembly were mainly hydrogen bonding and hydrophobic interaction. Based on the data of XRD and molecular modeling, the possible mechanism of the formation of hydrogelator aggregates was proposed.

Penetrating efficiency of supramolecular hydrogel eye drops:Electrostatic interaction surpasses ligand-receptor interaction

The low drug bioavailability of eye drops challenges the therapy of ocular disorders with high efficacy.One of solutions is to extend the corneal retention and enhance the penetration of drug into cornea.Here we synthesize two fluorophore-conjugated peptide based analogs rich in positive charges(i.e.,NBDFFKK)and with a specific ligand(i.e.,NBD-FFRGD),respectively,to visualize their performances in vitro and in vivo.The peptides both can self-assemble into supramolecular hydrogels with the microstructure of nanofibers.The in vitro experiments exhibit that two peptides are both uniformly distributed in cytoplasm,and the intracellular amount of peptide rich in positive charges is significantly larger than that of peptide with a specific ligand.The living corneal fluorescence shows that two peptides enter the corneal stroma within 15 min,and the peptide rich in positive charges is accumulated more extensively throughout the entire cornea,revealing that the supramolecular hydrogel eye drops penetrate the cornea more efficiently via electrostatic interaction than that via ligand-receptor interaction.This work,as a comparative study of supramolecular hydrogel eye drops on penetrating efficiency,indicates a possible direction for the design of eye drops with efficient corneal penetration.

Enhancing cartilage repair with optimized supramolecular hydrogel-based scaffold and pulsed electromagnetic field

Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage.Hydrogel is widely used because it could provide rapid defect filling and proper structure support,and is biocompatible for cell aggregation and matrix deposition.Efforts have been made to seek suitable scaffolds for cartilage tissue engineering.Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties.Gelation time,swelling ratio,biodegradability and biocompatibility of the hydrogels were systematically characterized,and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair.Furthermore,the new hydrogel design introduces a pre-gel state before photo-crosslinking,where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition.This granted multiple administration routes to the hydrogels,which brings hydrogels the ability to adapt to complex clinical situations.Pulsed electromagnetic fields(PEMF)have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials.PEMF treatment offers a better clinical outcome with fewer,if any,side effects,and wildly used in musculoskeletal tissue repair.Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering.In this study,the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model,and the potential application of PEMF in cartilage tissue engineering were investigated.PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro,and facilitate chondrogenesis and cartilage repair in vivo.All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment,this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.

DNA-based supramolecular hydrogels:From construction strategies to biomedical applications

DNA-based supramolecular hydrogels are important and promising biomaterials for various applications due to their inherent biocompatibility and tunable physicochemical properties.The three-dimensional supramolecular matrix of DNA formed by non-covalently dynamic cross-linking provides exceptional adaptability,self-healing,injectable and responsive properties for hydrogels.In addition,DNA hydrogels are also ideal bio-scaffold materials owing to their tissue-like mechanics and intrinsic biological functions.Technically,DNA can assemble into supramolecular networks by pure complementary base pairing;it can also be combined with other building blocks to construct hybrid hydrogels.This review focuses on the development and construction strategies of DNA hydrogels.Assembly and synthesis methods,diverse responsiveness and biomedical applications are summarized.Finally,the challenges and prospects of DNA-based supramolecular hydrogels are discussed.

Reinforcing DNA Supramolecular Hydrogel with Polymeric Multiple-Unit Linker

While supramolecular hydrogels have received growing interest due to their unique dynamic features,their relatively weak mechanical properties have largely limited their biomedical applications.In this study,we propose and demonstrate a strategy to reinforce the mechanical properties of supramolecular hydrogel by introducing polymeric multiple-unit linker(PMUL),which incorporates multiple supramolecular units into a polymeric backbone to crosslink supramolecular hydrogel.We demonstrated that PMUL can effectively improve the kinetic stability of supramolecular crosslinkers through multiple-unit interaction in a DNA supramolecular hydrogel model system,thus leading to higher mechanical strength.Meanwhile,the dynamic features of the supramolecular hydrogels have been well preserved,including shear-thinning,self-healing properties,and reversible thermal responsiveness.This strategy offers a simple but effective way for mechanical reinforcement of supramolecular hydrogels to construct novel biomaterials.

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.

Autocatalytic strategy for tuning drug release from peptide-drug supramolecular hydrogel

Peptide-drug conjugates(PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However,the achievement of controllable and rapid drug release at targeted site by PDCs is still a great challenge for pharmaceutist. Herein, we introduced the histidine residue into PDCs to generate a supramolecular hydrogel via a p H-trigger strategy, which exhibited an autocatalytic effect to precisely tune drug release from PDCs hydrogel. Using indomethacin(Idm) as model drug, various PDCs(Y(Idm)EEH, Y(Idm)EEK and Y(Idm)EER) were synthesized and their self-assembling properties were investigated in terms of critical aggregation concentration(CAC), transmission electron microscopy(TEM) and rheometer. Introduction of histidine residue into PDCs presented a robust catalytic activity on the ester hydrolysis of p-nitrophenyl acetate in aqueous solution, as well conferred the autocatalytic capacity to hydrolyze the PDCs into active parent drug(Idm). Overall, we reported an autocatalytic activity of histidine residue to precisely tune drug release from PDCs hydrogels.

Enzyme-instructed self-assembly of peptides containing phosphoserine to form supramolecular hydrogels as potential soft biomaterials

Enzyme-instructed self-assembly （EISA） offers a facile approach to explore the supramolecular assemblies of small molecules in cellular milieu for a variety of biomedical applications. One of the commonly used enzymes is phosphatase, but the study of the substrates of phosphatases mainly focuses on the phos- photyrosine containing peptides. In this work, we examine the EISA of phosphoserine containing small peptides for the first time by designing and synthesizing a series of precursors containing only phosphoserine or both phos- phoserine and phosphotyrosine. Conjugating a phospho- serine to the C-terminal of a well-established self- assembling peptide backbone, （naphthalene-2-1y）-acetyl- diphenylalanine （NapFF）, affords a novel hydrogelation precursor for EISA. The incorporation ofphosphotyrosine, another substrate of phosphatase, into the resulting precursor, provides one more enzymatic trigger on a single molecule, and meanwhile increases the precursors＇ propensity to aggregate after being fully dephosphorylated. Exchanging the positions of phosphorylated serine and tyrosine in the peptide backbone provides insights on how the specific molecular structures influence self-assembling behaviors of small peptides and the subsequent cellular responses. Moreover, the utilization of D-amino acids largely enhances the biostability of the peptides, thus providing a unique soft material for potential biomedical applications.

Near-infrared light-controllable bufalin delivery from a black phosphorus-hybrid supramolecular hydrogel for synergistic photothermal-chemo tumor therapy

Bufalin is efficacious in treating various tumors, however, the clinical application of which is restricted by the myocardial toxicity. Developing a smart synergetic delivery system is widely considered as a promising therapeutic strategy. To address this issue, a black phosphorus hybrid polypeptides hydrogel was designed to highly load bufalin, and achieved near-infrared (NIR)-controllable drug release with synergistic photothermal-chemo therapeutic effect. Black phosphorus nanosheets (BPNSs) and bufalin were co-loaded in temperature-sensitive supramolecular hydrogel to receive smart hybridization (BP-bufalin@SH). With NIR irradiation (1 W·cm−2), BP-bufalin@SH exhibited a rapid and large temperature increase and released bufalin via light-controllable manner, with which the side effects of bufalin were greatly decreased. Combined with photothermal-chemo therapeutic effect, BP-bufalin@SH could collapse the mitochondrial transmembrane potential resulting in the irreversible apoptosis of tumor cells, and realize a highly efficient in vivo tumor elimination with good biosafety and biocompatibility. This work provides a new hydrogel platform for controlling bufalin release, and thus further promotes the practical application on antitumor therapy.

Injectable Supramolecular Hydrogels via Inclusion Complexation of m PEG-grafted Copolyglutamate with α-Cyclodextrin

A series of monomethoxy poly（ethylene glycol） （mPEG） grafted copolyglutamates （PmPEGs） were synthesized through ring-opening polymerization （ROP） followed by click chemistry. Supramolecular hydrogels based on polymer inclusion complexes （ICs） between PmPEG and α-cyclodextriri （α-CD） were prepared in aqueous solution. The rheological measurements indicated their gelation properties were affected by several factors including the mPEG length, graft density and the sample concentration. These hydrogels displayed thermo-sensitive gel-sol transition under appropriate conditions due to the reversible mPEG and α-CD inclusion complexation. These hydrogels also showed pH-sensitive behavior due to the deprotonate of carboxylic acid side groups. The ICs formation of a channel-type crystalline structure induced gelation mechanism was verified by various techniques. In vitro cytotoxicity assays demonstrated that the supramolecular hydrogels are nontoxic and cytocompatible.

3D-printable supramolecular hydrogels with shear-thinning property: fabricating strength tunable bioink via dual crosslinking

3-dimensional(3D)bioprinting technology provides promising strategy in the fabrication of artificial tissues and organs.As the fundamental element in bioprinting process,preparation of bioink with ideal mechanical properties without sacrifice of biocompatibility is a great challenge.In this study,a supramolecular hydrogel-based bioink is prepared by polyethylene glycol(PEG)grafted chitosan,α-cyclodextrin(α-CD)and gelatin.It has a primary crosslinking structure through the aggregation of the pseudo-polyrotaxane-like side chains,which are formed from the host-guest interactions betweenα-CD and PEG side chain.Apparent viscosity measurement shows the shear-shinning property of this bioink,which might be due to the reversibility of the physical crosslinking.Moreover,withβ-glycerophosphate at different concentrations as the secondary crosslinking agent,the printed constructs demonstrate different Young's modulus(p<0.001).They could also maintain the Young's modulus in cell culture condition for at least 21 days(p<0.05).By co-culturing each component with fibroblasts,CCK-8 assay demonstrate cellular viability is higher than 80%.After bioprinting and culturing,immunofluorescence staining with quantification indicate the expression of Ki-67,Paxillin,and N-cadherin is higher in day 14 than those in day 3(p<0.05).Oil red O and Nissl body specific staining reflect strength tunable bioink may have impact on the cell fate of mesenchymal stem cells(p<0.05).This work might provide new idea for advanced bioink in the application of re-establishing complicated tissues and organs.

Antibacterial conductive self-healable supramolecular hydrogel dressing for infected motional wound healing

Wounds on stretchable parts of the human body cause prolonged suffering and involve more severe healing processes than wounds on stationary parts. However, they have received insufficient attention compared with other types of chronic wounds. In this study, a novel supramolecular gelatin(GT) hydrogel composed of GT-graft-aniline tetramer and quaternized chitosan was presented. The hydrogel was crosslinked by monoaldehyde β-cyclodextrin via host-guest interaction and dynamic Schiff base and was free from permanent covalent bonds, heavy metals, and oxidants. Given its dynamic feature, the hydrogel exhibited flexibility, self-healing, and tissue adhesiveness and well adapted to motion wounds. Moreover, the hydrogel was bioactive with conductivity, antioxidant property, hemostatic effect, antibacterial, and photothermal effect(the killing ratio for methicillinresistant Staphylococcus aureus(MRSA) was higher than 99.8% after 5 min of near-infrared irradiation) and exhibited ondemand removability. In the full-thickness MRSA-infected motional wound healing experiment, this novel hydrogel exhibited a significantly enhanced wound healing efficacy with a fast wound closure ratio(about 99.0% for 14 days), mild inflammatory response, high level of collagen deposition, and enhanced re-epithelialization by downregulating interleukin-6 and CD68 and upregulating vascular endothelial growth factor. The results indicated that this hydrogel has great potential in wound healing and skin tissue engineering and serves as an inspiration for the design of supramolecular biomaterials.

Bioinspired self-assembly supramolecular hydrogel for ocular drug delivery

Based on a recent report concerning endogenous agents(i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein(ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide(Nap FFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate(Dexp) to generate a Nap FFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery.The Nap FFKKFKLKL/Dexp hydrogel formed instantly after the complexation of Nap FFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy(TEM), fluorescent spectrum, circular dichroism(CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release.Following a single intravitreal injection, the proposed Nap FFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis(EAU) rat model,we demonstrated that the resulting Nap FFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting Nap FFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders(i.e., uveitis).

A conductive supramolecular hydrogel creates ideal endogenous niches to promote spinal cord injury repair

The current effective method for treatment of spinal cord injury(SCI)is to reconstruct the biological microenvironment by filling the injured cavity area and increasing neuronal differentiation of neural stem cells(NSCs)to repair SCI.However,the method is characterized by several challenges including irregular wounds,and mechanical and electrical mismatch of the material-tissue interface.In the current study,a unique and facile agarose/gelatin/polypyrrole(Aga/Gel/PPy,AGP3)hydrogel with similar conductivity and modulus as the spinal cord was developed by altering the concentration of Aga and PPy.The gelation occurred through non-covalent interactions,and the physically crosslinked features made the AGP3 hydrogels injectable.In vitro cultures showed that AGP3 hydrogel exhibited excellent biocompatibility,and promoted differentiation of NSCs toward neurons whereas it inhibited over-proliferation of astrocytes.The in vivo implanted AGP3 hydrogel completely covered the tissue defects and reduced injured cavity areas.In vivo studies further showed that the AGP3 hydrogel provided a biocompatible microenvironment for promoting endogenous neurogenesis rather than glial fibrosis formation,resulting in significant functional recovery.RNA sequencing analysis further indicated that AGP3 hydrogel significantly modulated expression of neurogenesis-related genes through intracellular Ca2+signaling cascades.Overall,this supramolecular strategy produces AGP3 hydrogel that can be used as favorable biomaterials for SCI repair by filling the cavity and imitating the physiological properties of the spinal cord.