Molecular Polarizability Regulated Piezoelectricity of Organic Materials from Single-Molecular Level.

Although molecular piezoelectric materials are ideal constituents for next-generation electronic microdevices, their weak piezoelectric coefficients which restrict their practical applications need to be enhanced by some strategies. Herein, a series of d-phenylalanine derivatives are synthesized and an increased molecular piezoelectric coefficient of their assemblies is achieved by acid doping. The acid doping can increase the asymmetric distribution of charges in the molecules and in turn molecular polarizability, leading to the enhanced molecular piezoelectricity of assemblies. The effective piezoelectric coefficients can be promoted up to 38.5 pm V-1 and four times those without doping, which is also higher than those obtained by the reported methods. Moreover, the piezoelectric energy harvesters can generate voltage up to 3.4 V and current up to 80 nA. This practical strategy can enhance piezoelectric coefficients without varying the crystal structures of the assemblies, which may inspire future molecular design of organic functional materials.

Mxene-Based Supramolecular Composite Hydrogels for Antioxidant and Photothermal Antibacterial Activities.

Bacterial infections and oxidative damage caused by various reactive oxygen species (ROS) pose a significant threat to human health. It is highly desirable to find an ideal biomaterial system with broad spectrum antibacterial and antioxidant capabilities. A new supramolecular antibacterial and antioxidant composite hydrogel made of chiral L-phenylalanine-derivative (LPFEG) as matrix and Mxene (Ti3 C2 Tx ) as filler material is presented. The noncovalent interactions (H-bonding and π-π interactions) in between LPFEG and Mxene and the inversion of LPFEG chirality are verified by Fourier transform infrared and circular dichroism spectroscopy. The composite hydrogels show improved mechanical properties revealed by rheological analysis. The composite hydrogel system exhibits photothermal conversion efficiency (40.79%), which enables effective photothermal broad-spectrum antibacterial activities against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria. Furthermore, the Mxene also enables the composite hydrogel to exhibit excellent antioxidant activity by efficiently scavenging free radicals like DPPH•, ABTS•+, and •OH. These results indicate that the Mxene-based chiral supramolecular composite hydrogel, with improved rheological, antibacterial, and antioxidant properties has a great potential for biomedical applications.

Infected Diabetic Wound Regeneration Using Peptide-Modified Chiral Dressing to Target Revascularization.

Revascularization plays a critical role in the healing of diabetic wounds. Accumulation of advanced glycation end products (AGEs) and refractory multidrug resistant bacterial infection are the two major barriers to revascularization, directly leading to impaired healing of diabetic wounds. Here, an artfully designed chiral gel dressing is fabricated (named as HA-LM2-RMR), which consists of l-phenylalanine and cationic hexapeptide coassembled helical nanofibers cross-linked with hyaluronic acid via hydrogen bonding. This chiral gel possesses abundant chiral and cationic sites, not only effectively reducing AGEs via stereoselective interaction but also specifically killing multidrug resistant bacteria rather than host cells since cationic hexapeptides selectively interact with negatively charged microbial membrane. Surprisingly, the HA-LM2-RMR fibers present an attractive ability to activate sprouted angiogenesis of Human Umbilical Vein Endothelial Cells by upregulating VEGF and OPA1 expression. In comparison with clinical Prontosan Wound Gel, the HA-LM2-RMR gel presents superior healing efficiency in the infected diabetic wound with respect to angiogenesis and re-epithelialization, shortening the healing period from 21 days to 14 days. These findings for chiral wound dressing provide insights for the design and construction of diabetic wound dressings that target revascularization, which holds great potential to be utilized in tissue regenerative medicine.

Chirality-influenced antibacterial activity of methylthiazole- and thiadiazole-based supramolecular biocompatible hydrogels.

Chiral stereochemistry is a unique and fundamental strategy that determines the interaction of bacteria cells with chiral biomolecules and stereochemical surfaces. The interaction between bacteria and material surface (molecular chirality or supramolecular chirality) plays a significant role in modulating antibacterial performance. Herein, we developed inherent chiral antibacterial hydrogels by modifying the carboxyl groups of our previously reported supramolecular gelator (LPF-left handed phenylalanine gelator and DPF- right handed phenylalanine gelator) with 2-amino-5-methylthiazole (MTZ) and 5-amino-1,3,4-thiadiazole-2- thiol (TDZ). The new L/D-gelator molecules initiate self-assembly to form hydrogels through non-covalent interactions (Hydrogen bonding and π-π interactions) verified by FTIR and CD spectroscopy. Morphological studies of the xerogels revealed left and right-handed chiral nanofibers for the gelators' L-form and D-form, respectively. The resulting hydrogels exhibited inherent antibacterial activity against Gram-positive (Bacillus subtilis, Staphylococcus aureus) and Gram-negative (Pseudomonas aeruginosa) bacteria, with TDZ hydrogels showing more significant antibacterial activity than MTZ hydrogels. Interestingly, the D-form (having right-handed nanofibers) of both hydrogels (MTZ and TDZ) exhibited higher antibacterial activities compared with the left-handed nanofibrous hydrogels (L-form) attributed to the stereoselective interaction of the chiral helical nanofiber. Moreover, the amplification of chirality moving from a molecular to a supramolecular level essentially improved the antibacterial action. Our results provide deep insight into the development of unique supramolecular chiral antimicrobial agents and hint at the potentiality of right-handed nanofibers (D-form) having enhanced antibacterial activity. STATEMENT OF SIGNIFICANCE: Chiral stereochemistry plays a significant role in many biological processes, which determines the interaction of bacteria cells with chiral biomolecules. The interaction between bacteria and material surface (molecular chirality or supramolecular chirality) plays a significant role in modulating antibacterial performance. Here, we deigned and synthesized unique inherent biocompatible supramolecular chiral hydrogel. From this study we concluded that the D-form (having right-handed nanofibers) of hydrogels exhibited higher antibacterial activities compared with the left-handed nanofibrous hydrogels (L-form) attributed to the stereoselective interaction of the chiral helical nanofiber. Additionally, this study also explored the amplification of chirality moving from a molecular to a supramolecular level essentially improved the antibacterial action.

Antimicrobial Activity with Enhanced Mechanical Properties in Phenylalanine-Based Chiral Coassembled Hydrogels: The Influence of Pyridine Hydrazide Derivatives.

Hydrazide derivatives are known to display a wide range of biological properties including antimicrobial activities, hence making them desirable candidates for soft biomaterials. Herein, we report chiral supramolecular coassembled hydrogels obtained from two phenylalanine gelators (L/DPF and B2L/D) and two dicarbohydrazide molecules (pyridine-2,6-dicarbohydrazide (PDH) and (2,2'-bipyridine)-5,5'-dicarbohydrazide (BDH)) that exhibited enhanced mechanical properties, chirality modulation, and antimicrobial activity. Four lines of coassembled hydrogels were obtained (i.e., L/DPF-PDH, L/DPF-BDH, B2L/D-PDH, and B2L/D-BDH) through hydrogen bonding and π-π stacking with some level of an interpenetrating network, as revealed by the structural characterization analysis. Mechanical properties were significantly improved, especially in the case of hybrid gels involving BDH, with improved average elastic modulus (G') values of 3430 and 3167 Pa for DPF-BDH and B2D-BDH (1:3, molar concentration) over 140 and 1680 Pa for DPF and B2D gelators, respectively. This was attributed to the improved π-π stacking and interpenetrating network due to the bipyridine group and its ease to form fibrous precipitates in the process of heating and cooling to room temperature. PDH, on the other hand, was able to modulate chirality in the L/DPF gelator due to its more planar and less bulky nature and showed antimicrobial activity against Pseudomonas aeruginosa (Gram-negative). Interestingly, when PDH was coassembled with the B2L/D gelator, the hybrid gels exhibited antimicrobial activity against Staphylococcus aureus (Gram-positive) and P. aeruginosa (Gram-negative) by virtue of a synergistic effect of the gelator and the azomethine group of PHD. Hence, by moving from bipyridine (BDH) to pyridine (PDH) as a core structure in the hydrazide molecules, the resulting hybrid hydrogels exhibited desirable properties of antimicrobial activity and improved mechanical attributes.

Mechanically Stable C2-Phenylalanine Hybrid Hydrogels for Manipulating Cell Adhesion.

Tuning of the viscoelastic properties of supramolecular hydrogels to be used as biological material substrates in tissue engineering has become significantly relevant in recent years due to their ability to influence cell fate. In the quest to enhance the stability and mechanical properties of a derived C2-phenylalanine gelator (LPF), derivatives of the polysaccharide dextran were incorporated as additives to promote hydrogen bonding and π-π stacking with the gelator. Dextran was esterified to yield carboxymethyl dextran (CMDH), which was subsequently amidated to furnish amino dextran (AD), the resulting hybrid hydrogels were denoted as LPF-ADx and LPF-CMDHx, where x represents the amount of AD and CMDH (mg). The LPF gelator interacted with the carboxyl and amino functional groups of the CMDH and AD, respectively, through hydrogen bonding and π-π stacking, resulting in mechanically stable hydrogels. Morphological studies revealed that the hybrid hydrogels were formed as a result of dense highly branched thin and broad fibers for LPF-AD and LPF-CMDH, respectively. Rheological studies confirmed the superiority of the hybrid hydrogels over the neat hydrogel, where LPF-CMDH3 exhibited the best mechanical properties with an improved elastic modulus of 11 654 Pa over 1518 and 140 Pa for LPF-AD4.5 and LPF, respectively. The adhesion and spreading behavior of NIH 3T3 fibroblast cells were significantly improved on the LPF-CMDH3 substrate owing to their enhanced mechanical properties. The tuning of the mechanical properties of the therein hydrogels via the facile incorporation of biodegradable and biocompatible functionalized additives opens up avenues for strengthening the supposed weak supramolecular gelators and hence increasing their potential of being employed largely in the field of tissue engineering.

Inversion of Circularly Polarized Luminescence of Nanofibrous Hydrogels through Co-assembly with Achiral Coumarin Derivatives.

Control over the handedness of circularly polarized luminescence (CPL) in supramolecular gels is of special significance in biology and optoelectronics; however, it still remains a great challenge to precisely and efficiently regulate the chirality of CPL. Herein, a chiral phenylalanine-derived hydrogelator and achiral coumarin derivatives can co-assemble into nanofibrous hydrogels with controllable chirality, and the handedness of CPL of these hydrogels can be efficiently inverted by coumarin derivatives through noncovalent interactions, which can be further tuned at will by incorporating metal ions into the co-assembly. The hydrogen bonds, coordination interactions, and steric hindrance are proved to be the crucial factors for the CPL inversion. This study provides feasible strategies to efficiently regulate the handedness of CPL through co-assembly, and these CPL materials may have potential applications in the fields of photoelectric devices, smart chiroptical materials, and biological systems.

Chirality-Enabled Liquid Crystalline Physical Gels with High Modulus but Low Driving Voltage.

Self-supporting liquid crystalline physical gels with facile electro-optic response are highly desirable, but their development is challenging because both the storage modulus and driving voltage increase simultaneously with gelator loading. Herein, we report liquid crystalline physical gels with high modulus but low driving voltage. This behavior is enabled by chirality transfer from the molecular level to three-dimensional fibrous networks during the self-assembly of 1,4-benzenedicarboxamide phenylalanine derivatives. Interestingly, the critical gel concentration is as low as 0.1 wt %. Our findings open doors to understanding and exploiting the role of chirality in organic gels.

Metal-Ion-Mediated Supramolecular Chirality of l-Phenylalanine Based Hydrogels.

For chiral hydrogels and related applications, one of the critical issues is how to control the chirality of supramolecular systems in an efficient way, including easy operation, efficient transfer of chirality, and so on. Herein, supramolecular chirality of l-phenylalanine based hydrogels can be effectively controlled by using a broad range of metal ions. The degree of twisting (twist pitch) and the diameter of the chiral nanostructures can also be efficiently regulated. These are ascribed to the synergic effect of hydrogen bonding and metal ion coordination. This study may develop a method to design a new class of electronically, optically, and biologically active materials.

Stoichiometry-Controlled Inversion of Supramolecular Chirality in Nanostructures Co-assembled with Bipyridines.

To control supramolecular chirality of the co-assembled nanostructures, one of the remaining issues is how stoichiometry of the different molecules involved in co-assembly influence chiral transformation. Through co-assembly of achiral 1,4-bis(pyrid-4-yl)benzene and chiral phenylalanine-glycine derivative hydrogelators, stoichiometry is found to be an effective tool for controlling supramolecular chirality inversion processes. This inversion is mainly mediated by a delicate balance between intermolecular hydrogen bonding interactions and π-π stacking of the two components, which may subtly change the stacking of the molecules, in turn, the self-assembled nanostructures. This study exemplifies a simplistic way to invert the handedness of chiral nanostructures and provide fundamental understanding of the inherent principles of supramolecular chirality.

Amino Acids and Peptide-Based Supramolecular Hydrogels for Three-Dimensional Cell Culture.

Supramolecular hydrogels assembled from amino acids and peptide-derived hydrogelators have shown great potential as biomimetic three-dimensional (3D) extracellular matrices because of their merits over conventional polymeric hydrogels, such as non-covalent or physical interactions, controllable self-assembly, and biocompatibility. These merits enable hydrogels to be made not only by using external stimuli, but also under physiological conditions by rationally designing gelator structures, as well as in situ encapsulation of cells into hydrogels for 3D culture. This review will assess current progress in the preparation of amino acids and peptide-based hydrogels under various kinds of external stimuli, and in situ encapsulation of cells into the hydrogels, with a focus on understanding the associations between their structures, properties, and functions during cell culture, and the remaining challenges in this field. The amino acids and peptide-based hydrogelators with rationally designed structures have promising applications in the fields of regenerative medicine, tissue engineering, and pre-clinical evaluation.

Inversion of the Supramolecular Chirality of Nanofibrous Structures through Co-Assembly with Achiral Molecules.

To understand the behavior of chiral nanostructures, it is of critical importance to study how achiral molecules regulate the chirality of such nanostructures and what the main driving forces for the regulation processes are. In this work, the supramolecular chirality of helical nanofibers consisting of phenylalanine-based enantiomers is inverted by achiral bis(pyridinyl) derivatives through co-assembly. This inversion is mainly mediated by intermolecular hydrogen bonding interactions between the achiral additives and the chiral molecules, which may induce stereoselective interactions and different reorientations for the assembled molecules, as confirmed by calculations. This work not only exemplifies a feasible method to invert the helicity of chiral nanostructures by the addition of achiral molecules, but also provides a method to explore their functions in environments where chiral and achiral molecules are in close proximity.

Installing Logic Gates to Multiresponsive Supramolecular Hydrogel Co-assembled from Phenylalanine Amphiphile and Bis(pyridinyl) Derivative.

Recently, logic gates based on multiresponsive hydrogel systems are attractive because of their potential biological applications. A quite simple supramolecular hydrogel co-assembled from phenylalanine-based amphiphile (LPF2) and bis(pyridinyl) derivative (AP) is constructed. The co-assembled hydrogel exhibited a macroscopic gel-sol transition in response to four distinct input stimuli: temperature, acid, base, and light. A set of techniques including microscopic, spectroscopic, and rheological measurements demonstrate this performance and confirm that the hydrogel is formed through intermolecular hydrogen bonds between amide/pyridine moieties and carbonyl groups. On the basis of its mutiple-stimulus responsiveness, installing gel-based supramolecular logic gates (OR and XOR) is achieved. It may promote the possibility to develop smart soft materials, such as gels, that can be used as tools releasing a drug quantitatively by rational design and fine control of the external stimuli.

Multiresponsive hydrogel coassembled from phenylalanine and azobenzene derivatives as 3D scaffolds for photoguiding cell adhesion and release.

A multiresponsive hydrogel system coassembled from phenylalanine derivative gelator (LPF2) and azobenzene (Azo) derivative (PPI) is constructed, which can respond to temperature, pH, host-guest interaction, and photoirradiation. A set of techniques including circular dichroism, Fourier transform infrared spectroscopy, (1)H NMR, and X-ray powder diffraction confirm that the hydrogel is formed through hydrogen bonds between amide moieties/pyridine and carbonyl groups, enduing the coassembled hydrogel with multiresponsive properties that make it possible to control cell encapsulation and release in three-dimensional environments under multistimulus, for example, UV irradiation. This study brings a novel approach to develop multistimuli-responsive hydrogels by coassembly of various responsive components for biomedical interest, for example, the controlled delivery of various therapeutic biological agents.

Control of three-dimensional cell adhesion by the chirality of nanofibers in hydrogels.

In the three-dimensional (3D) extracellular matrix (ECM), the influence of nanofiber chirality on cell behavior is very important; the helical nanofibrous structure is closely related to the relevant biological events. Herein, we describe the use of the two enantiomers of a 1,4-benzenedicarboxamide phenylalanine derivative as supramolecular gelators to investigate the influence of the chirality of nanofibers on cell adhesion and proliferation in three dimensions. It was found that left-handed helical nanofibers can increase cell adhesion and proliferation, whereas right-handed nanofibers have the opposite effect. These effects are ascribed to the mediation of the stereospecific interaction between chiral nanofibers and fibronectin. The results stress the crucial role of the chirality of nanofibers on cell-adhesion and cell-proliferation behavior in 3D environments.

Convenient three-dimensional cell culture in supermolecular hydrogels.

A convenient three-dimensional cell culture was developed by employing high swelling property of hybrid hydrogels coassembled from C2-phenyl-based supermolecular gelators and sodium hyaluronate. Imaging and spectroscopic analysis by scanning electron microscopy (SEM), atomic force microscopy (AFM), transform infrared (FT-IR) spectra confirm that the hybrid gelators can self-assemble into nanofibrous hydrogel. The high swelling property of dried gel ensures cell migration and proliferation inside bulk of the hydrogels, which provides a facial method to study disease models, the effect of drug dosages, and tissue culture in vitro.

Wettability of supramolecular nanofibers for controlled cell adhesion and proliferation.

By employing smart self-assembly of 1,4-benyldicarbonxamide-phenylalanine (C2) derived supramolecular gelators, a simple way to construct nanofibrous environments with the controllable wettability is developed. The fast cell adhesion and proliferation on the least wettable fibers indicates an efficient control over cells, which is proved to be mainly mediated by the interaction between protein and the fibers. One typical merit superior to other materials is that cell adhesion can be regulated not only on two-dimensional (2D) substrates but also in three-dimensional (3D) microenvironments. This paves a novel way to deeply understand the influence of fiber wettability on cell behaviors in 3D environment.

Dual-specific interaction to detect DNA on gold nanoparticles.

An approach to selectively and efficiently detect single strand DNA is developed by using streptavidin coated gold nanoparticles (StAuNPs) as efficient quenchers. The central concept for the successful detection is the combination the of streptavidin-biotin interaction with specific probe-target DNA hybridization. Biotin labeled probe DNAs act as "bridges" to bring Cy5 labeled targets to the particle surface and the fluorophore dye can be rapidly and efficiently quenched by StAuPNs. By measuring the changes of photoluminescence intensity of Cy5, an efficient, selective, and reversed detection of DNA hybridization is realized. The methodology may pave a new way for simple and rapid detections of biomolecules.

RGD anchored C2-benzene based PEG-like hydrogels as scaffolds for two and three dimensional cell cultures.

Designing new types of cell scaffolds to resist protein adsorption and promote cell adhesion is becoming very important in the field of tissue engineering. Herein, by coupling ethylene glycol (EG) monomers and Arg-Gly-Asp (RGD) onto C2-benzene cores, a family of PEG-like low molecular weight gelators (LMWGs) functionalized with RGD is reported. Imaging and spectroscopic analysis by Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), and Circular Dichroism (CD) spectroscopy confirm that the functionalized LMWGs can self-assemble into nanofibrous hydrogels. The RGD functionalized nano-scaffolds were observed to overcome non-specific protein adsorption and promote adhesion of encapsulated cells through specific RGD-integrin binding. The PEG-like gelators may offer an effective model scaffold for cell cultures that generates specific cell-scaffold interactions with minimal non-specific protein adsorption and addresses some limitations of covalent polymeric scaffolds at the same time.