Self-Assembly of the Tetraphenylethylene-Capped Diserine through a Hierarchical Assembly Process.

We report a new peptide-based urchin-shaped structure prepared through two-step self-assembly of tetraphenylethylene-diserine (TPE-SS). Hydrogelation generated nanobelts through the first stage of self-assembly of TPE-SS; these nanobelts further transformed on silicon wafers into urchin-like microstructures featuring nanosized spines. The presence of the TPE moiety in the hydrogelator resulted in aggregation-induced emission characteristics both in the solution and in the gel phases. TPE-SS has the lowest molecular weight of any TPE-capped hydrogelator with ß-sheet-like structures under physiological pH. This new design strategy appears to be useful for generating three-dimensional self-assembled microstructures and multifunctional biomaterials. We found that TPE-SS is biocompatible with human mesenchymal stem cells and breast cancer cells, making them potential applications in tissue engineering and biomedical research.

Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor.

The vasculature of the CNS is structurally and functionally distinct from that of other organ systems and is particularly prone to developmental abnormalities and hemorrhage. Although other embryonic tissues undergo primary vascularization, the developing nervous system is unique in that it is secondarily vascularized by sprouting angiogenesis from a surrounding perineural plexus. This sprouting angiogenesis requires the TGF-ß and Wnt pathways because ablation of these pathways results in aberrant sprouting and hemorrhage. We have genetically deleted Gpr124, a member of the large family of long N-terminal group B G protein-coupled receptors, few members of which have identified ligands or well-defined biologic functions in mammals. We show that, in the developing CNS, Gpr124 is specifically expressed in the vasculature and is absolutely required for proper angiogenic sprouting into the developing neural tube. Embryos lacking Gpr124 exhibit vascular defects characterized by delayed vascular penetration, formation of pathological glomeruloid tufts within the CNS, and hemorrhage. In addition, they display defects in palate and lung development, two processes in which TGF-ß and/or Wnt pathways also play important roles. We also show that TGF-ß stimulates Gpr124 expression, and ablation of Gpr124 results in perturbed TGF-ß pathway activation, suggesting roles for Gpr124 in modulating TGF-ß signaling. These results represent a unique function attributed to a long N-terminal group B-type G protein-coupled receptor in a mammalian system.

Temperature-Induced Nanostructure Transition for Supramolecular Gelation in Water.

Thermogel is an injectable biomaterial that functions at body temperatures due to the ease of the sol-to-gel transition. However, most conventional physically cross-linked thermogels generally have relatively low stiffness, which limits various biomedical applications, particularly for stem-cell-based studies. While chemical cross-linking through double-network (DN) structures can increase the stiffness of the hydrogel, they generally lack injectable and thermoresponsive properties due to strong covalent bonds between molecules. To address this challenge, we have developed a temperature-induced nanostructure transition (TINT) system for preparing physical DN supramolecular hydrogels. These hydrogels possess injectable, thermoreversible characteristics and relatively high storage modulus (G'), which increases ∼14-fold from 20 to 37 °C (body temperature). Our bottom-up strategy is based on the co-assembly of aromatic peptide (Ben-FF) and poly(ethylene glycol) (PEG) to form a thermogel at 37 °C through a nanofiber dissociation pathway that differs from the well-known micelle aggregation or polymer shrinkage mechanisms. Peptide molecules form helical packing and weak, noncovalent interactions with PEG, resulting in co-assembled metastable nanofibers. Thermal perturbation initiates lateral dissociation of nanofibers into extensively cross-linked DN nanostructures and subsequent hydrogelation (ΔG = -13.32 kJ/mol). The TINT hydrogel is nontoxic to human mesenchymal stem cells and supports enhanced cell adhesion, suggesting the potential of this strategy in the applications of tissue engineering and regenerative medicine.

Cell compatible trimethoprim-decorated iron oxide nanoparticles bind dihydrofolate reductase for magnetically modulating focal adhesion of mammalian cells.

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.

Multifunctional, biocompatible supramolecular hydrogelators consist only of nucleobase, amino acid, and glycoside.

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.

The crown ether size and stereochemistry affect the self-assembly, hydrogelation, and cellular interactions of crown ether/peptide conjugates.

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.

ß-Galactosidase-instructed formation of molecular nanofibers and a hydrogel.

Here we report the first example of using ß-galactosidase to trigger the formation of cell compatible, supramolecular nanofibers, which ultimately may lead to a new approach for the development of soft nanotechnology.