Abstract. Stem cells are known to differentiate in response toHowever, identification of these stem cell inducing molecules is non-trivial and rational approaches to discover drugs for achieving reproducible, targeted stem cell control remain elusive. Here, we demonstrate the design of supramolecular hydrogels that allow targeting of a range of stem cell phenotypes, providing a useful platform for discovery of differentiation inducing metabolites. These gels are simple in composition, containing a fibre forming aromatic peptide amphiphile, which is coassembled with a surfactant-like amphiphile that provides hydrophilic surface functionality to the fibres. The stiffness of the gels can be precisely tuned over the entire range that is typically associated with stem cell differentiation (0.1-40 kPa). 3We demonstrate that the gels can be used to direct stem cell differentiation without the need for induction media and they are therefore ideally suited to study stem cell behaviour -including as drug discovery platforms. To achieve this, we study the cell's usage of biological small molecules, metabolites, during differentiation and select bioactive metabolites that can target bone and cartilage formation specifically. This new use of designed supramolecular biomaterials can be envisaged to remove serendipity from discovery of metabolites associated with biological processes as drug candidates. Introduction.
Silk has a robust clinical track record and is emerging as a promising biopolymer for drug delivery, including its use as nanomedicine. However, silk-based nanomedicines still require further refinements for full exploitation of their potential; the application of "stealth" design principals is especially necessary to support their evolution. The aim of this study was to develop and examine the potential of PEGylated silk nanoparticles as an anticancer drug delivery system. We first generated B. mori derived silk nanoparticles by driving β-sheet assembly (size 104 ± 1.7 nm, zeta potential -56 ± 5.6 mV) using nanoprecipitation. We then surface grafted polyethylene glycol (PEG) to the fabricated silk nanoparticles and verified the aqueous stability and morphology of the resulting PEGylated silk nanoparticles. We assessed the drug loading and release behavior of these nanoparticles using clinically established and emerging anticancer drugs. Overall, PEGylated silk nanoparticles showed high encapsulation efficiency (>93%) and a pH-dependent release over 14 days. Finally, we demonstrated significant cytotoxicity of drug loaded silk nanoparticles applied as single and combination nanomedicines to human breast cancer cells. In conclusion, these results, taken together with prior silk nanoparticle data, support a viable future for silk-based nanomedicines.
We report on a pronounced specific-ion effect on the intermolecular and chiral organization, supramolecular structure formation, and resulting materials properties for a series of low molecular weight peptide-based hydrogelators, observed in the presence of simple inorganic salts. This effect was demonstrated using aromatic short peptide amphiphiles, based on fluorenylmethoxycarbonyl (Fmoc). Gel-phase materials were formed due to molecular self-assembly, driven by a combination of hydrogen bonding and π-stacking interactions. Pronounced morphological changes were observed by atomic force microscopy (AFM) for Fmoc-YL peptide, ranging from dense fibrous networks to spherical aggregates, depending on the type of anions present. The gels formed had variable mechanical properties, with G' values between 0.8 kPa and 2.4 kPa as determined by rheometry. Spectroscopic analysis provided insights into the differential mode of self-assembly, which was found to be dictated by the hydrophobic interactions of the fluorenyl component, with comparable H-bonding patterns observed in each case. The efficiency of the anions in promoting the hydrophobic interactions and thereby self-assembly was found to be consistent with the Hofmeister anion sequence. Similar effects were observed with other hydrophobic peptides, Fmoc-VL and Fmoc-LL. The effect was found to be less pronounced for a less hydrophobic peptide, Fmoc-AA. To get more insights into the molecular mechanism, the effect of anions on sol-gel equilibrium was investigated, which indicates the observed changes result from the specific-ion effects on gels structure, rather than on the sol-gel equilibrium. Thus, we demonstrate that, by simply changing the ionic environment, structurally diverse materials can be accessed providing an important design consideration in nanofabrication via molecular self-assembly.
Alleles at 12 Short Tandem Repeat loci have been sequenced to investigate candidate loci for a multiplex Short Tandem Repeat system for forensic identification, and for single-locus amplification of Short Tandem Repeat loci. Variation from the consensus sequence was found at 6 loci, while one locus, D21S11, was found to be complex in sequence. The presence of non-consensus alleles does not rule out loci for inclusion as forensic identification markers, but size differences between alleles of 1 base pair require very precise sizing. We suggest criteria for the suitability of Short Tandem Repeat loci as forensic identification markers, and propose a universal allele nomenclature for simple and compound Short Tandem Repeats. The effect of the repeat unit sequence of the evolution of Short Tandem Repeats is discussed.
High throughput materials discovery using combinatorial polymer microarrays to screen for new biomaterials with new and improved function is established as a powerful strategy. Here we combine this screening approach with high throughput surface characterisation (HT-SC) to identify surface structure-function relationships. We explore how this combination can help to identify surface chemical moieties that control protein adsorption and subsequent cellular response. The adhesion of human embryoid body (hEB) cells to a large number (496) of different acrylate polymers synthesized in a microarray format is screened using a high throughput procedure. To determine the role of the polymer surface properties on hEB cell adhesion, detailed HT-SC of these acrylate polymers is carried out using time of flight secondary ion mass spectrometry (ToF SIMS), x-ray photoelectron spectroscopy (XPS), pico litre drop sessile water contact angle (WCA) measurement and atomic force microscopy (AFM). A structure-function relationship is identified between the ToF SIMS analysis of the surface chemistry after a fibronectin (Fn) pre-conditioning step and the cell adhesion to each spot using the multivariate analysis technique partial least squares (PLS) regression. Secondary ions indicative of the adsorbed Fn correlate with increased cell adhesion whereas glycol and other functionalities from the polymers are identified that reduce cell adhesion. Furthermore, a strong relationship between the ToF SIMS spectra of bare polymers and the cell adhesion to each spot is identified using PLS regression. This identifies a role for both the surface chemistry of the bare polymer and the preadsorbed Fn, as-represented in the ToF SIMS spectra, in controlling cellular adhesion. In contrast, no relationship is found between cell adhesion and wettability, surface roughness, elemental or functional surface composition. The correlation between ToF SIMS data of the surfaces and the cell adhesion demonstrates the ability of identifying surface moieties that control protein adsorption and subsequent cell adhesion using ToF SIMS and multivariate analysis.
Amphiphilic self-assembling peptides are functional materials, which, depending on the amino acid sequence, the peptide length, and the physicochemical conditions, form a variety of nanostructures including nanovesicles, nanotubes, and nanovalves. We designed lipid-like peptides with an aspartic acid or lysine hydrophilic head and a hydrophobic tail composed of six alanines (i.e., ac-A6K-CONH2, KA6-CONH2, ac-A6D-COOH, and DA6-COOH). The resulting novel peptides have a length similar to biological lipids and form nanovesicles at physiological conditions. AFM microscopy and light scattering analyses of the positively charged lipid-like ac-A6K-CONH2, KA6-CONH2 peptide formulations showed individual nanovesicles. The negatively charged ac-A6D-COOH and DA6-COOH peptides self-assembled into nanovesicles that formed clusters that upon drying were organized into necklace-like formations of nanovesicles. Encapsulation of probe molecules and release studies through the peptide bilayer suggest that peptide nanovesicles may be good candidates for sustained release of pharmaceutically active hydrophilic and hydrophobic compounds. Lipid-like peptide nanovesicles represent a paradigm shifting system that may complement liposomes for the delivery of diagnostic and therapeutic agents.
Water contact angle measurement is the most common method for determining a material's wettability, and the sessile drop approach is the most frequently used. However, the method is generally limited to macroscopic measurements because the base diameter of the droplet is usually greater than 1 mm. Here we report for the first time on a dosing system to dispense smaller individual droplets with control of the position and investigate whether water contact angles determined from picoliter volume water droplets are comparable with those obtained from the conventional microliter volume water droplets. This investigation was conducted on a group of commonly used polymers. To demonstrate the higher spatial resolution of wettability that can be achieved using picoliter volume water droplets, the wettability of a radial plasma polymer gradient was mapped using a 250 microm interval grid.
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