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Single-Step Fabrication of Computationally Designed Microneedles by Continuous Liquid Interface Production.

ABSTRACT: Microneedles, arrays of micron-sized needles that painlessly puncture the skin, enable transdermal delivery of medications that are difficult to deliver using more traditional routes. Many important design parameters, such as microneedle size, shape, spacing, and composition, are known to influence efficacy, but are notoriously difficult to alter due to the complex nature of microfabrication techniques. Herein, we utilize a novel additive manufacturing ("3D printing") technique called Continuous Liquid Interface Production (CLIP) to rapidly prototype sharp microneedles with tuneable geometries (size, shape, aspect ratio, spacing). This technology allows for mold-independent, one-step manufacturing of microneedle arrays of virtually any design in less than 10 minutes per patch. Square pyramidal CLIP microneedles composed of trimethylolpropane triacrylate, polyacrylic acid and photopolymerizable derivatives of polyethylene glycol and polycaprolactone were fabricated to demonstrate the range of materials that can be utilized within this platform for encapsulating and controlling the release of therapeutics. These CLIP microneedles effectively pierced murine skin ex vivo and released the fluorescent drug surrogate rhodamine.

SUBMITTER: Johnson AR

PROVIDER: S-EPMC5015976 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Engineering a protein-protein interface using a computationally designed library.

Project description:Computational algorithms for protein design can sample large regions of sequence space, but suffer from undersampling of conformational space and energy function inaccuracies. Experimental screening of combinatorial protein libraries avoids the need for accurate energy functions, but has limited access to vast amounts of sequence space. Here, we test if these two traditionally alternative, but potentially complementary approaches can be combined to design a variant of the ubiquitin-ligase E6AP that will bind to a nonnatural partner, the NEDD8-conjugating enzyme Ubc12. Three E6AP libraries were constructed: (i) a naive library in which all 20 amino acids were allowed at every position on the target-binding surface of E6AP (13 positions), (ii) a semidirected library that varied the same residue positions as in the naive library but disallowed mutations computationally predicted to destabilize E6AP, and (iii) a directed library that used docking and sequence optimization simulations to identify mutations predicted to be favorable for binding Ubc12. Both of the directed libraries showed > 30-fold enrichment over the naive library after the first round of screening with a split-dihydrofolate reductase complementation assay and produced multiple tight binders (K(d) < 100 nM) after four rounds of selection. Four rounds of selection with the naive library failed to produce any binders with K(d)'s lower than 50 ?M. These results indicate that protein design simulations can be used to create directed libraries that are enriched in tight binders and that in some cases it is sufficient to computationally screen for well-folded sequences without explicit binding calculations.

| S-EPMC2984139 | biostudies-literature

Single-Step Fabrication of Polymer Nanocomposite Films.

Project description:Polymer nanocomposites are employed in (micro)electronic, biomedical, structural and optical applications. Their fabrication is challenging due to nanoparticle (filler) agglomeration and settling, increased viscosity of blended solutions and multiple tedious processing steps, just to name a few. Often this leads to an upper limit for filler content, requirements for filler?polymer interfacial chemistry and expensive manufacturing. As a result, novel but simple processes for nanocomposite manufacture that overcome such hurdles are needed. Here, a truly single-step procedure for synthesis of polymer nanocomposite films, structures and patterns at high loadings of nanoparticles (for example, >24 vol %) for a variety of compositions is presented. It is highly versatile with respect to rapid preparation of films possessing multiple layers and filler content gradients even on untreated challenging substrates (paper, glass, polymers). Such composites containing homogeneously dispersed nanoparticles even at high loadings can improve the mechanical strength of hydrogels, load-bearing ability of fragile microstructures, gas permeability in thin barriers, performance of dielectrics and device integration in stretchable electronics.

| S-EPMC6073108 | biostudies-literature

A Simplified 2D Numerical Simulation of Photopolymerization Kinetics and Oxygen Diffusion-Reaction for the Continuous Liquid Interface Production (CLIP) System.

Project description:Additive manufacturing is a versatile technology for producing customized 3D products. In 2015, the Continuous Liquid Interface Production (CLIP) system was developed as a part of projection-type, UV-curable resin 3D printers. The CLIP system utilized the dead zone where oxygen inhibition occurs and prevents the UV-cured product from adhering to the UV illumination window. The CLIP system successfully produced complex shapes in a short time. This study investigated how the relationship between the photopolymerization rate, oxygen inhibition rate, and oxygen diffusion rate affects the shape of the product by means of a numerical simulation of the photopolymerization kinetics with oxygen diffusion and reaction. The results indicate that the vertical production speed and transmittance of UV light are crucial to controlling the conversion and shape precision of products.

| S-EPMC7240730 | biostudies-literature

One-Step Fabrication of Bioinspired Lubricant-Regenerable Icephobic Slippery Liquid-Infused Porous Surfaces.

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| S-EPMC6645152 | biostudies-literature

Computationally designed libraries for rapid enzyme stabilization.

Project description:The ability to engineer enzymes and other proteins to any desired stability would have wide-ranging applications. Here, we demonstrate that computational design of a library with chemically diverse stabilizing mutations allows the engineering of drastically stabilized and fully functional variants of the mesostable enzyme limonene epoxide hydrolase. First, point mutations were selected if they significantly improved the predicted free energy of protein folding. Disulfide bonds were designed using sampling of backbone conformational space, which tripled the number of experimentally stabilizing disulfide bridges. Next, orthogonal in silico screening steps were used to remove chemically unreasonable mutations and mutations that are predicted to increase protein flexibility. The resulting library of 64 variants was experimentally screened, which revealed 21 (pairs of) stabilizing mutations located both in relatively rigid and in flexible areas of the enzyme. Finally, combining 10-12 of these confirmed mutations resulted in multi-site mutants with an increase in apparent melting temperature from 50 to 85°C, enhanced catalytic activity, preserved regioselectivity and a >250-fold longer half-life. The developed Framework for Rapid Enzyme Stabilization by Computational libraries (FRESCO) requires far less screening than conventional directed evolution.

| S-EPMC3893934 | biostudies-literature

Room-Temperature Production of Nanocrystalline Molybdenum Disulfide (MoS2) at the Liquid-Liquid Interface.

Project description:Scalable synthesis of 2D materials is a prerequisite for their commercial exploitation. Here, a novel method of producing nanocrystalline molybdenum disulfide (MoS2) at the liquid-liquid interface is demonstrated by decomposing a molecular precursor (tetrakis(N,N-diethyldithiocarbamato) molybdenum(IV)) in an organic solvent. The decomposition occurs over a few hours at room temperature without stirring or the addition of any surfactants, producing MoS2 which can be isolated onto substrates of choice. The formation of MoS2 at the liquid-liquid interface can be accelerated by the inclusion of hydroxide ions in the aqueous phase, which we propose to act as a catalyst. The precursor concentration was varied to minimize MoS2 thickness, and the organic solvent was chosen to optimize the speed and quality of formation. The kinetics of the MoS2 formation has been investigated, and a reaction mechanism has been proposed. The synthesis method is, to the best of our knowledge, the first reported room-temperature synthesis of transition-metal dichalcogenides, offering a potential solution to scalable 2D material production.

| S-EPMC7011726 | biostudies-literature

Modulating non-native aggregation and electrostatic protein-protein interactions with computationally designed single-point mutations.

Project description:Non-native protein aggregation is a ubiquitous challenge in the production, storage and administration of protein-based biotherapeutics. This study focuses on altering electrostatic protein-protein interactions as a strategy to modulate aggregation propensity in terms of temperature-dependent aggregation rates, using single-charge variants of human ?-D crystallin. Molecular models were combined to predict amino acid substitutions that would modulate protein-protein interactions with minimal effects on conformational stability. Experimental protein-protein interactions were quantified by the Kirkwood-Buff integrals (G22) from laser scattering, and G22 showed semi-quantitative agreement with model predictions. Experimental initial-rates for aggregation showed that increased (decreased) repulsive interactions led to significantly increased (decreased) aggregation resistance, even based solely on single-point mutations. However, in the case of a particular amino acid (E17), the aggregation mechanism was altered by substitution with R or K, and this greatly mitigated improvements in aggregation resistance. The results illustrate that predictions based on native protein-protein interactions can provide a useful design target for engineering aggregation resistance; however, this approach needs to be balanced with consideration of how mutations can impact aggregation mechanisms.

| S-EPMC4867096 | biostudies-literature

A Photolithographic Approach to Polymeric Microneedles Array Fabrication.

Project description:In this work, two procedures for fabrication of polymeric microneedles based on direct photolithography, without any etching or molding process, are reported. Polyethylene glycol (average molecular weight 250 Da), casted into a silicone vessel and exposed to ultraviolet light (365 nm) through a mask, cross-links when added by a commercial photocatalyzer. By changing the position of the microneedles support with respect to the vessel, different shapes and lengths can be achieved. Microneedles from a hundred microns up to two millimeters have been obtained just tuning the radiation dose, by changing the exposure time (5-15 s) and/or the power density (9-18 mW/cm²) during photolithography. Different microneedle shapes, such as cylindrical, conic or lancet-like, for specific applications such as micro-indentation or drug delivery, are demonstrated.

| S-EPMC5458808 | biostudies-other

Computationally designed peptides for self-assembly of nanostructured lattices.

Project description:Folded peptides present complex exterior surfaces specified by their amino acid sequences, and the control of these surfaces offers high-precision routes to self-assembling materials. The complexity of peptide structure and the subtlety of noncovalent interactions make the design of predetermined nanostructures difficult. Computational methods can facilitate this design and are used here to determine 29-residue peptides that form tetrahelical bundles that, in turn, serve as building blocks for lattice-forming materials. Four distinct assemblies were engineered. Peptide bundle exterior amino acids were designed in the context of three different interbundle lattices in addition to one design to produce bundles isolated in solution. Solution assembly produced three different types of lattice-forming materials that exhibited varying degrees of agreement with the chosen lattices used in the design of each sequence. Transmission electron microscopy revealed the nanostructure of the sheetlike nanomaterials. In contrast, the peptide sequence designed to form isolated, soluble, tetrameric bundles remained dispersed and did not form any higher-order assembled nanostructure. Small-angle neutron scattering confirmed the formation of soluble bundles with the designed size. In the lattice-forming nanostructures, the solution assembly process is robust with respect to variation of solution conditions (pH and temperature) and covalent modification of the computationally designed peptides. Solution conditions can be used to control micrometer-scale morphology of the assemblies. The findings illustrate that, with careful control of molecular structure and solution conditions, a single peptide motif can be versatile enough to yield a wide range of self-assembled lattice morphologies across many length scales (1 to 1000 nm).

| S-EPMC5017825 | biostudies-other

Characterization of a Biofilm Bioreactor Designed for the Single-Step Production of Aerial Conidia and Oosporein by Beauveria bassiana PQ2.

Project description:Beauveria bassiana is an entomopathogenic fungus that is used for the biological control of different agricultural pest insects. B. bassiana is traditionally cultivated in submerged fermentation and solid-state fermentation systems to obtain secondary metabolites with antifungal activity and infective spores. This work presents the design and characterization of a new laboratory-scale biofilm bioreactor for the simultaneous production of oosporein and aerial conidia by B. bassiana PQ2. The reactor was built with materials available in a conventional laboratory. KLa was determined at different air flows (1.5-2.5 L/min) by two different methods in the liquid phase and in the exhaust gases. The obtained values showed that an air flow of 2.5 L/min is sufficient to ensure adequate aeration to produce aerial conidia and secondary metabolites by B. bassiana. Under the conditions studied, a concentration of 183 mg oosporein per liter and 1.24 × 109 spores per gram of support was obtained at 168 h of culture. These results indicate that the biofilm bioreactor represents a viable alternative for the production of products for biological control from B. bassiana.

| S-EPMC8396940 | biostudies-literature

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