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Hydrogels are a class of biomaterials used in the field of tissue engineering and drug delivery. Many tissue engineering applications depend on the material properties of hydrogel scaffolds, such as mechanical stiffness, pore size, and interconnectivity. In this work, we describe the synthesis of peptide/polymer hybrid double-network (DN) hydrogels composed of supramolecular and covalent polymers. The DN hydrogels were prepared by combining the self-assembled pentafluorobenzyl diphenylalanyl aspartic acid (PFB-FFD) tripeptide for the first network and the polymeric PNIPAM-PEGDA copolymer for the second network. During this process, self-assembled peptide nanostructures are cross-linked to the polyacrylamide group in the polymer network through non-covalent interactions. The PNIPAM-PEGDA:PFB-FFD hydrogel exhibited higher mechanical stiffness (

N-Cadherin is a transmembrane glycoprotein that plays a crucial role in the condensation of mesenchymal cells by enhancing cell-cell interactions during the process of chondrogenesis. The biophysical and biochemical signals can incite enhanced cell-cell contact which ultimately determines the fate of stem cells. The role of cadherin mimetic peptides on the differentiation of mesenchymal stem cells is obscure and must be explored in greater detail. In this study, we designed and synthesized a series of bioactive peptide sequences that mimic the EC-1 domain of the cadherin peptide sequence His-Ala-Val (HAV) motif. These peptide hydrogelators can self-assemble into stable supramolecular nanofibrous hydrogels at physiological pH in the presence of Fmoc-diphenylalanine (2) with tunable mechanical stiffness. Human mesenchymal stem cells (3A6) were encapsulated in N-cadherin mimetic peptide hydrogels to evaluate their role in stem cell differentiation and chondrogenesis. The results suggested that these peptide hydrogels are nontoxic to 3A6 cells and promoted chondrogenesis. Interestingly, 3A6 cells exposed to Fmoc-GGHAVDI (1d) peptide solution showed an enhanced expression level of chondrogenic specific marker collagen-II (Col-II) in comparison with other peptide sequences. In contrast, when 3A6 cells were encapsulated in the hydrogel blend (2/1c), the peptide sequence with flanking amino acid serine exhibited greater material stiffness with enhanced glycosaminoglycan (GAG) distribution and high expression levels of chondrogenic specific markers for the cartilage-specific matrix. This suggests that substrate stiffness and peptide sequences can influence stem cell differentiation. The hydrogel with the HAV motif with greater substrate stiffness (2/1c) can promote the chondrogenic differentiation of human mesenchymal stem cells which can be a promising candidate for 3D cell culture and stem cell-based cartilage regeneration therapies.

The discovery of crown ethers and their unique interactions with ions make them play a key role in supramolecular chemistry. In this study, we have developed a new type of amphiphilic crown ether (DB18C6, DB24C8)-conjugated phenylalanine dipeptides for the gelation of water at physiological pH. We report here for the first time that the size of the crown ether controlled the morphology of the self-assembled nanostructures of the hydrogels, as well as their interactions with human mesenchymal stem cells (hMSCs; 3A6-RFP) and mouse fibroblasts (L929). For example, relative to its d-form and other crown sizes, DB18C6LFLF exhibited greater cell adhesion and was nontoxic towards hMSCs after culturing for 72 h. We hypothesize that the steric effect of the crown ether moiety in the assemblies has substantial influences on the morphology of the nanostructures and the cell-material response. Such distinct cell responses should be beneficial for the development of supramolecular biomaterials.

A series of FFK tripeptides capped with phenylacetic acid of various fluoro-substitutions at the N-terminus has been synthesized and examined for self-assembly under aqueous conditions. The material properties of the FFK tripeptides dramatically changed from precipitate to hydrogel phase upon increasing the number of fluorine atoms. Peptides linked with benzyl (B-FFK) or monofluoro-benzyl (MFB-FFK) groups rapidly form solid precipitates under physiological pH conditions. The trifluoro-decorated compound (TFB-FFK) self-assembled into a metastable hydrogel which slowly transformed into a solid precipitate upon standing. A stable hydrogel formation was noticed in the case of the pentafluorobenzyl-diphenylalanyllysine (PFB-FFK) compound. TEM analysis indicates that the PFB-FFK peptide assembled into twisted nanofibril structures, which are predominantly stabilized by strong quadrupole π-stacking interactions and electrostatic interactions of amino acid side chains. Furthermore, the combination of PFB-FFK and PFB-FFD peptides was also investigated for hydrogelation and the self-assembly of such systems resulted in the formation of untwisted 1D nanofibril structures. Supramolecular coassembled hydrogels of variable stiffness have also been achieved by modulating the concentration of the peptide components, which was evident from the rheological analysis. Such low molecular weight (LMW) peptide materials with tuneable mechanical properties might be a potential material for a wide range of applications in nanotechnology and biotechnology.

Supramolecular fluorescent materials with aggregation-induced emission (AIE) characteristics have promising applications as fluorescent probes for bio and chemosensors. In this study, a versatile low molecular weight tetraphenylethylene dipeptide hydrogelator (TPE-YY) with efficient AIE characteristics was developed, which was able to form hydrogels in a broad pH range from 3.7 to 10.2. The self-assembly of this hydrogel is completely pH-dependent, with significant structural transitions from high to low pH. At a relatively high pH value (10.2), a weak transparent hydrogel with an entangled network of nanofibers was obtained, while upon neutralization (pH 7.2) with dilute HCl, a stable semi-transparent gel with twisted nanobelts was formed. When the pH of the hydrogel was reduced to below 5.7, a turbid viscous gel and precipitation appeared with the thickening of the nanobelts. Surprisingly, the hydrogel resulting from the glucono-δ-lactone triggered gel showed only nanofibers independent of pH. The nature of the hydrogels and the nanostructures at different pH values were thoroughly examined and discussed via oscillatory rheology, electron microscopy and various spectroscopic techniques {1HNMR, 2D-NMR, Fourier transform infrared (FTIR) and Circular dichroism (CD)}. Interestingly, the self-assembled hydrogel exhibited excellent biocompatibility over 95% using hydrogel leachables on two different cell lines, 3A6 (human MSCs) and L929 (mouse fibroblast cells). Moreover, the self-assembled nanobelts formed at neutral pH showed excellent cell adhesion and proliferation of 3A6 cells, whereas the nanofibers showed poor cell adhesion and proliferation. Overall, we demonstrate the importance of chemical design for the formation of self-assembled nanobelts and supramolecular hydrogels at physiological pH with selective cell adhesion and proliferation, presenting a promising applications in tissue engineering and regenerative medicine.

Understanding the structure-morphology relationships of self-assembled nanostructures is crucial for developing materials with the desired chemical and biological functions. Here, phosphate-based naphthalimide (NI) derivatives have been developed for the first time to study the enzyme-instructed self-assembly process. Self-assembly of simple amino acid derivative NI-Yp resulted in non-specific amorphous aggregates in the presence of alkaline phosphatase enzyme. On the other hand, NI-FYp dipeptide forms spherical nanoparticles under aqueous conditions which slowly transformed into partially unzipped nanotubular structures during the enzymatic catalytic process through multiple stages which subsequently resulted in hydrogelation. The self-assembly is driven by the formation of β-sheet type structures stabilized by offset aromatic stacking of NI core and hydrogen bonding interactions which is confirmed with PXRD, Congo-red staining and molecular mechanical calculations. We propose a mechanism for the self-assembly process based on TEM and spectroscopic data. The nanotubular structures of NI-FYp precursor exhibited higher cytotoxicity to human breast cancer cells and human cervical cancer cells when compared to the nanofiber structures of the similar Fmoc-derivative. Overall this study provides a new understanding of the supramolecular self-assembly of small-molecular-weight hydrogelators.

We report a novel fluorescent bioprobe, tetraphenylethylene-Phe-Asp-Gly-Glu-Ala (TPE-FDGEA), and its self-assembly behavior, photophysical properties, and biocompatibility. The hydrogelator TPE-FDGEA exhibited aggregation-induced emission characteristics, which facilitated imaging of PC-3 human prostate cancer cells, thereby demonstrating the utility of such fluorescent probes for specific labeling of target cells in vitro.

Herein, the influence of an amino acid side chain on the structural and functional properties of hydrogels has been described. In this study, four new hydrogelators based on the conjugates of dipeptides and naphthalimide (NI) have been designed, synthesized, and examined. Homopeptide 1 (NI-FF) of the phenylalanine residue forms a weak hydrogel or a viscous solution of worm-like micelles under basic conditions. On the other hand, dipeptide conjugates of 2 (NI-FY), 3 (NI-YF), and 4 (NI-YY), containing additional hydroxyl groups as tyrosine residues, can self-assemble into supramolecular hydrogels under physiological pH conditions. UV-vis, IR, and rheological studies clearly indicate the formation and stability of these dipeptide hydrogels. The TEM results revealed that the hydrogels (1–4) self-assembled into a nanofibrous morphology. Furthermore, the cell culture results show that NI-YF has better cell compatibility as compared to NI-FY and NI-YY and thus shows potential to be used as a hydrogel biomaterial. Overall, this study highlights the importance of the structure–hydrogelation relationship and provides new insights into the design of self-assembled peptide amphiphiles.

This report describes the two component self-assembly of π-capped amino acid hydrogelators (serine (S), aspartic acid (D), glutamic acid (E) or lysine (K)) prepared from pyrene (Py) based donor and naphthalenediimide (NDI) based acceptor molecules. The co-assembly can be triggered to form hydrogels by varying the pH conditions and the major driving forces behind the hydrogelation were found to be the formation of a strong charge-transfer (CT) complex and hydrogen bonding interactions at suitable pH conditions. The NDI-Py blends with matched donor/acceptor amino acid pairs undergo self-assembly under acidic pH conditions, whereas the blend (NDI-S + Py-K) with a mismatched amino acid pair forms a stable hydrogel under physiological pH conditions. UV-Vis, FTIR and rheological studies clearly indicate the formation and the stability of these CT-induced hydrogels. These hydrogels are of nanofibrous morphology with an average diameter of about 6-9 nm as evidenced by TEM analysis. In addition, this novel NDI-Py mixed component system exhibited good biocompatibility towards PC3 cells. Overall, since hydrogels based on CT-mediated two-component assemblies are very rare, our newly discovered NDI-Py hydrogels provide chemical insights into the design of a CT-induced hydrogelator and might facilitate various applications in biomedical engineering.

Herein, we report the synthesis of simple TPE/single amino acid conjugates, TPE-Ser and TPE-Asp with side-chains featuring functional groups that may provide an additional hydrogen bonding network for hydrogelation in aqueous medium. TPE-Ser, which has the lowest molecular weight, containing hydroxyl groups undergoes self-assembly into supramolecular hydrogels under physiological pH conditions. TPE-Asp with a carboxylic group side chain undergoes the self-assembly and hydrogelation processes under slightly acidic conditions (pH = 6.0). UV-vis, IR, PL and rheological studies clearly indicate the formation, stability and fluorescence properties of TPE-amino acid hydrogels. TEM micrographs of the hydrogels indicate that the compounds are self-assembled into a nanosheet morphology with random size and shape. Further, in vitro analysis of TPE-Ser and TPE-Asp with 3A6 cells shows that the compounds exhibit unique fluorescence signals in microcellular environments thus making them suitable candidates for bioimaging applications. Overall, these findings highlight the importance of the structure-hydrogelation relationship and provide new insights into the design of single amino-acid-based supramolecular hydrogels.

A composite molecule (CM) model is used to investigate the nature of intermolecular interactions in the excited states of π-conjugated oligomers of poly-(p-phenylene) (PPP). The dependence of the charge-transfer (CT) interactions in low-lying excited states as a function of intermolecular distance, conjugation length, and the translation shifts is examined. We demonstrate how the amplitude of CT mixing in two low-lying excited states of PPP dimer is sensitive to various aspects of molecular packing. The largest CT mixing in the two excited states is consistently obtained for cofacial packing. However, from a detailed examination of molecular orbital shapes and interactions, it is seen that specific arrangements promote the CT mixing in two low-lying transitions. With cofacial arrangements, it shows a larger percentage of CT in the first excited states than the corresponding second excited states for phenyl rings on the top of Csp2─Csp2 single bonds. This work illustrates the importance of molecular packing–CT mixing relationship of functional π-conjugated materials.

Herein, we report the synthesis and optimization of an aqueous phase two-component co-assembled nanofibrous hydrogel based on charge-transfer (CT) between pyrenebutyric acid and naphthalene diimide-capped groups. This donor–acceptor CT interaction is a powerful driving force that can induce self-assembly in the aqueous phase even if the molecule contains only a single amino acid. The intermolecular CT interactions for mixed components can also be visualized in the quantum-chemical approach. This two-component supramolecular co-assembly provides a new path for the design of self-assembled nanomaterials.

Gelatin is an important hydrocolloid which has widespread applications in the pharmaceutical industry and biomedical science. However, despite its significance, clinical applications of gelatin are largely limited because of its gel-to-solution transition around human body temperature. In this work, we developed a series of F127–gelatin composite hydrogels with reverse thermo-responsive properties. The stiffness of F127–gelatin hydrogels can be adjusted by varying the types and contents of gelatin (type A, GA and type B, GB). The results of rheological data showed that F127–GA gels have higher gel strengths than those of F127–GB, which might be due to different isoelectric points between GA and GB. In addition, F127–gelatin gels showed significant cell viability and biocompatibility for human mesenchymal stem cells, indicating that these discovered hydrogels can serve as potential biomaterials and implantable scaffolds for applications in tissue engineering and regenerative medicine.

Here we report the generation of a novel gelator from a glycosylated amino acid derivative, which contained three structural units, an aromatic residue, a carbohydrate moiety and a tert-butyl group in a single molecule. These structural units can promote the supramolecular self-assembly of this gelator in both aprotic and protic solvents via coordinated π-π stacking, multiple hydrogen binding and van der Waals interactions. More importantly, due to their non-equilibrium natures, the organogels formed in DCM, chloroform and ethanol can undergo gel to crystal transition in storage, driven by unbalanced gelator-gelator and solvent-gelator interactions. In this process, the gelators were firstly trapped in a kinetically favorable gel state, and then transferred into a more thermodynamically stable crystal state upon ageing, with the generation of microcrystals in different morphologies.

Herein, we report a tetraphenylethylene-diglycine (TPE-GG) hydrogelator from a systematic study of TPE-capped dipeptides with various amphiphilic properties. From a chemical design, we found that the hydrogelation of TPE-GG molecules can be utilized to generate supramolecular nanostructures with a large TPE-based nanobelt width (∼300 nm) and lateral dimension ratio (>30 fold). In addition, TPE-GG has the lowest molecular weight and minimum number of atoms compared to any TPE-capped peptide hydrogelator reported to date. This minimal self-assembled hydrogelator can fundamentally achieve the gel features compared with other TPE-capped peptides. A combined experimental and computational study indicates the π-π interactions, electrostatic interactions and hydrogen-bonding interactions are the major driving forces behind the formation of self-assembled nanobelts. This study demonstrates the importance of structure-property relationships and provides new insights into the design of supramolecular nanomaterials.

Arteriovenous graft (AVG) failure continues to be a life-threatening problem in haemodialysis. Graft failure can occur if the implanted graft is not well-matched to the vasculature of the patient. Likewise, stenosis often develops at the vein-graft anastomosis, contributing to thrombosis and early graft failure. To address this clinical need, a novel ink formulation comprised of ACMO/TMPTA/TMETA for 3D printing a AVG was developed (ACMO-AVG), in which the printed AVG was biocompatible and did not induce cytotoxicity. The ease of customizing the ACMO-AVG according to different requirements was demonstrated. Furthermore, the AVG displayed similar mechanical properties to the commercially available arteriovenous ePTFE graft (ePTFE-AVG). Unlike ePTFE-AVG, the ACMO-AVG displayed excellent anti-fouling characteristics because no plasma protein adsorption and platelet adhesion were detected on the luminal surfaces after 2 h of incubation. Similarly, exposure to human endothelial cells and human vascular smooth muscle cells did not result in any cell detection on the surfaces of the ACMO-AVG. Thus, the present study demonstrates a newly developed 3D printing ink formulation that can be successfully 3D printed into a clinically applicable vascular access used for haemodialysis.

To screen the possibility of forming self-assembled hydrogels under physiological pH, various molar ratios of the hydrogelators based on pentafluorobenzyl-phenylalanine (PFB-F) and pentafluorobenzyl-diphenylalanine (PFB-FF) were studied. The equimolar ratio of PFB-F and PFB-FF formed coassembled nanofibers and a self-supporting hydrogel at the physiological pH of 7.4. The spectroscopic characterization of the blend gel indicates that π–π interactions and hydrogen-bonding interactions are the major driving forces behind the coassembly. In addition, we also prove that the blend hydrogel is biocompatible, thus making it a scaffolding material for biomedical applications. In this work, the utility of two distinct hydrogelators to promote coassembly under physiological condition expands the repertoire of noncovalent interactions that can be used in the development of sophisticated noncovalent biomaterials.

The influence of aliphatic chain lengths on supramolecular hydrogelation of naphthalene diimide-capped dipeptides is described. The dependence of the gelation pH as a function of chain lengths reveals an inverse linear relationship and the gelation pH values cover a broad range from pH 2 to pH 9. In addition, the presence of a n-octyl tail in the hydrogelator could enhance the ability of self-assembly in dilute solution.

The combination of a naphthalene diimide (NDI) group and a single amino-acid of serine (Ser) or lysine (Lys) can be used to promote the formation of a supramolecular hydrogel, which indicates the aromatic amino acid is not necessary to be used in the structural design of NDI-capped small molecule hydrogelators. An equimolar ratio of NDI-Ser and NDI-Lys can form a stable hydrogel under neutral conditions and its gel-to-sol transition temperature is higher than 37 °C. This work, as the first example of NDI-containing hydrogelators without aromatic rings in the side chains of amino acids, illustrates a new approach to design NDI-capped supramolecular hydrogels.

We report a new aromatic-capped peptide amphiphile which is able to form a supramolecular hydrogel under neutral pH. This hydrogel can also be obtained by enzymatic transformation from the hydrogelator precursor. The newly discovered hydrogel has excellent biocompatibility for four different cell lines, thus making it a potentially useful scaffolding material for biomedical applications.

With the replacement of only one hydrogen atom by fluorine, 4-fluorobenzyl-diphenylalanine was able to form a transparent hydrogel, while benzyl-diphenylalanine did not under similar conditions, indicating the remarkable effect of fluorine on supramolecular hydrogelation.

This article describes the self-assembly of π-conjugated building blocks composed of single amino acid and pyrene (Py) moieties. In aqueous conditions, the Py-capped amino acids undergo self-assembly through various non-covalent interactions such as hydrogen-bonding, π–π stacking as well as electrostatic interactions to form supramolecular nanostructures in acidic and basic conditions. Interestingly, we found that the blend of different Py-gelators with oppositely charged amino acids (Py–Glu and Py–Lys) displays unique nano-structural morphologies and gelation properties of the resulting hydrogels at physiological pH when compared with single Py conjugates, which was attributed to additional electrostatic interactions. Overall, this report illustrates the importance of two-component supramolecular co-assembled hydrogels and their structure–morphology relationship, improved mechanical properties, and biocompatibility and thus provides a new insight into the design of self-assembled nanomaterials.

A new system for the incorporation of a phenyl/perfluorophenyl pair in the structure of a peptide hydrogelator was developed. The strategy is based on the idea that the integration of an end-capped perfluorophenyl group and a phenylalanine with a phenyl moiety in the side chain forms an intramolecular phenyl/perfluorophenyl pair, which can be used to promote the formation of the supramolecular nanofibers and hydrogels. This work illustrates the importance of structure-hydrogelation relationship and provides new insights into the design of self-assembly nanobiomaterials.

A novel platinum complex PtC with a tri-armed uracil hydrogen-bonded (H-bonded) unit was synthesized via a modular synthetic approach and characterized by 1H, 13C NMR and MALDI-TOF mass spectroscopies. Two H-bonded tetrads, PtC–(TPAD1)3 and PtC–(TPAD2)3, based on a metal core PtC complexed with two generations of triarylamine dendrimers, TPAD1 and TPAD2 (with electron-donating nature), were successfully constructed with improved organic solubility via a classical H-bonded self-assembly approach. Supramolecular H-bonding in solution and solid state was elucidated by 1H NMR titrations, IR spectral studies and time resolved photoluminescence (TRPL) measurements. The electron/energy transfers, as well as the self-assemblies of supramolecular tetrads, were established by UV-Vis and PL titrations and AFM morphological studies. Furthermore, metal complex core PtC showed selective sensitivity towards Ag+ ions through fluorescence turn-off responses without any interference from other common metal ions. The 1 : 1 binding stoichiometry and complexation mechanism between the probe and Ag+ ion was established by 1H NMR titration. Moreover, PL reversibility of PtC + Ag+ could be achieved on addition of PMDTA.

On the basis of the high affinity binding of trimethoprim (TMP) to Escherichia coli dihydrofolate reductase (eDHFR), TMP-decorated iron oxide nanoparticles bind to eDHFR with high affinity and specificity, which allows magnetic modulation of focal adhesion of mammalian cells adhered to a surface. Besides being the first example of nanoparticles that selectively bind to eDHFR, the biocompatibility of the conjugate of TMP-iron oxide nanoparticles renders a convenient and versatile platform for investigating the cellular responses to specific, mechanical perturbation of proteins via a magnetic force.

By employing the furan annulation protocol, a new series of furan-containing teraryl [n.2]cyclophenes (n= 2-6 and 12) are prepared. These cyclophenes exhibit charge-transfer character in the absorption spectra and unusually large Stokes shifts in the emission spectra. They have neither particularly strong electron-donating moieties nor electron-withdrawing groups, but exhibit unusual second-order nonlinear optical (NLO) properties. The π-systems in teraryl system and in the bridging double bond are highly twisted. Interaction between these twisted π-systems may account for the significant enhancement in hyperpolarizability. Thiophene analog behaved similarly. The five-membered heteroaromatic rings may not only serve as electron donors, but also may accommodate the appropriate geometry to enable the interactions between the oligoaryl systems and the double bond leading to unusual photophysical and NLO properties.

The integration of nucleobase, amino acid, and glycoside into a single molecule results in a novel class of supramolecular hydrogelators, which not only exhibit biocompatibility and biostability, but also facilitate the entry of nucleic acids into cytosol and nuclei of cells. This work illustrates a simple way to generate an unprecedented molecular architecture from the basic biological building blocks for the development of sophisticated soft nanomaterials, including supramolecular hydrogels.

Rh(III) and Ir(III) can be complexed to bipyridine groups attached to the termini of bis(dioxaborine)-capped heptamethines; these chromophores exhibit large third-order polarisabilities at 1.55 μm, while retaining good film-forming properties and linear optical transparency in the near infrared.

Centrosymmetric furan-containing cyclophandienes 3 and 4, synthesized by our furan annulation protocol, have been shown to exhibit extraordinarily large Stokes shifts and second-order nonlinear optical beta values. The beta values for 3 and 4 measured at 1.32 mum are 208 and 530x10(-30) esu, respectively. The beta values of 3 and 4 are similar to those of respective cyclophenes 1 a and 7 in which strong hyperpoarizable interactions between two twisted pi-systems (oligoaryl and bridging double bond) might take place. Symmetry breaking due to the resonance contribution (cf. 2) and the unique structural features of 3 and 4 has been used to account for this unusual photophysical behavior.

Geminal disubstitution on silicon in dialkylsilylene-spaced divinylarene copolymers may dictate the conformation and photophysical properties of the copolymers, bulky (i)Pr substituted copolymers being more folded than Me substituent analogues.

This work reports the first example of the biofunctional magnetic nanoparticles as a “magnetic dock” for directly sorting proteins inside live cells. We decorate the iron oxide nanoparticles with the ligands that bind selectively to fusion proteins consisting of the proteins of interest (POIs) and the ligand receptors. Similar to protein sorting processes on vesicles, the clusters of these functionalized magnetic nanoparticles only bind to the fusion proteins via the interaction with the receptors, but exhibit little interaction to other proteins. This work demonstrates new applications of magnetic nanoparticles and may ultimately contribute to the exploration of the functions of proteins via the selective, spatiotemporal control of the proteins by a magnetic force.

Imparting aromatic-aromatic interactions to the potassium binding epitope affords a supramolecular hydrogelator that responds to the K(+) concentration by self-assembly into nanofibers of different widths and crosslinking patterns, which illustrates a simple approach to generate biomimic materials based on tunable, hierarchical self-assembly of small molecules.