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A multi-drug delivery platform is developed to address current shortcomings of post-operative ocular drug delivery. The sustained biodegradable drug release system is composed of biodegradable polymeric microparticles (MPs) incorporated into a bulk biodegradable hydrogel made from triblock copolymers with poly(ethylene glycol) (PEG) center blocks and hydrophobic biodegradable polyester blocks such as poly(lactide-co-glycolide) (PLGA), Poly(lactic acid) (PLA), or Poly(lactide-co-caprolactone) (PLCL) blocks. This system is engineered to flow as a liquid solution at room temperature for facile injection into the eye and then quickly gel as it warms to physiological body temperatures (approximately 37 °C). The hydrogel acts as an ocular depot that can release three different drug molecules at programmed rates and times to provide optimal release of each species. In this manuscript, the hydrogel is configured to release a broad-spectrum antibiotic, a potent corticosteroid, and an ocular hypotensive, three ophthalmic therapeutic agents that are essential for post-operative management after ocular surgery, each drug released at its own timescale. The delivery platform is designed to mimic current topical application of postoperative ocular formulations, releasing the antibiotic for up to a week, and the corticosteroid and the ocular hypotensive agents for at least a month. Hydrophobic blocks, such as PLCL, were utilized to prolong the release duration of the biomolecules. This system also enables customization by being able to vary the initial drug loading to linearly tune the drug dose released, while maintaining a constant drug release profile over time. This minimally invasive biodegradable multi-drug delivery system is capable of replacing a complex ocular treatment regimen with a simple injection. Such a depot system has the potential to increase patient medication compliance and reduce both the immediate and late term complications following ophthalmic surgery. Statement of Significance After ocular surgery, patients routinely receive multiple medications including antibiotics, steroids and ocular hypotensives to ensure optimal surgical outcomes. The current standard of care for postoperative treatment after ocular surgery involves using eye drops daily, which has limited effectiveness mainly due to poor patient adherence. To improve patient experience and outcomes, this article presents the first thermoresponsive hydrogel able to release multiple drug molecules for the application of post-operative treatment following ocular surgery. By varying the parameters such as hydrogel type and polymer hydrophobicity, the drug release profile, duration and dosage can finely be tuned. The approach presented in this article can readily be applied to other applications by simply changing the drug loaded in the drug delivery system. [ABSTRACT FROM AUTHOR]

We study polymer migration in a periodic pressure-driven sudden contraction-expansion flow with contraction dimension comparable to the polymer radius of gyration, for which several polymer migration mechanisms can be important: (1) sieving by the thin channel of polymers too large to easily enter them; (2) deformation-hydrodynamic coupling, including wall-hydrodynamic interaction, which causes polymers to drift away from the walls towards the center of the channel; (3) streamline-curvature-induced migration, in which polymers traveling along curved streamlines migrate towards the center of curvature; and (4) depletion-convection coupling, in which depletion layers in thin channels are convected across wide side chambers, creating a one-sided diffusion barrier that leads to depletion from the side chamber. We use both Stochastic Rotation Dynamics (SRD), which includes hydrodynamic interaction (HI), and simple Brownian dynamics (BD), with HI omitted and flow field given by finite element analysis. The similarity in results from SRD and BD at Weissenberg number Wi less than 10 (where Wi is based on the shear rate in the narrow region of the contraction channel) shows that HI (Mechanism 2) has only a weak effect on polymer migration in our tight geometry. At Wi > 1, the polymer migrates towards the centerline in the wide region, due mainly to streamline-curvature-induced (SCI) migration (Mechanism 3), but also to depletion-convection-induced migration (Mechanism 4). And we demonstrate these two mechanisms more explicitly in a pressure-driven flow in a grooved channel that is significantly wider than the polymer. SCI migration dominates in the contraction geometry, and produces a migration velocity proportional to Wi². Using the central limit theorem, we accurately predict the position and width of a band of polymer passing through N periodic contractions, thereby demonstrating the potential for SCI migration as a mechanism of size separation in a multi-step planar contraction channel. We find that the best separation is achieved at Wi around 2, where SCI migration has the greatest resolving power between polymers of different size. We also find that sieving (Mechanism 1) is dominant at low Wi less than unity, where the chains with large radius of gyration are delayed in their entry to the thin channel, relative to shorter polymers. This sieving separation mechanism differs from that of size-exclusion chromatography which yields faster migration by the shorter chains. Our strategy of combining simulation methods with the central limit theorem could also be used to predict separation efficiencies of a wide variety of polymers and colloids in microfluidic geometries. [ABSTRACT FROM AUTHOR]

Abstract: To explore the role of lung surfactant proteins SP-B and SP-C in storing and redelivering lipid from lipid monolayers during the compression and re-expansion occurring in lungs during breathing, we simulate the folding of lipid monolayers with and without these proteins. We utilize the MARTINI coarse-grained force field to simulate monolayers containing pure dipalmitoylphosphatidylcholine (DPPC) and DPPC mixed with palmitoyloleoylphosphatidylglycerol (POPG), palmitic acid (PA), and/or peptides. The peptides considered include the 25-residue N-terminal fragment of SP-B (SP-B1 – 25), SP-C, and several SP-B1 – 25 mutants in which charged and hydrophilic residues are replaced by hydrophobic ones, or vice-versa. We observe two folding mechanisms: folding by the amplification of undulations and folding by nucleation about a defect. The first mechanism is observed in monolayers containing either POPG or peptides, while the second mechanism is observed only with peptides present, and involves the lipid-mediated aggregation of the peptides into a defect, from which the fold can nucleate. Fold nucleation from a defect displays a dependence on the hydrophobic character of the peptides; if the number of hydrophobic residues is decreased significantly, monolayer folding does not occur. The addition of POPG or peptides to the DPPC monolayer has a fluidizing effect, which assists monolayer folding. In contrast, the addition of PA has a charge-dependent condensing affect on DPPC monolayers containing SP-C. The peptides appear to play a significant role in the folding process, and provide a larger driving force for folding than POPG. In addition to promoting fold formation, the peptides also display fusogenic behavior, which can lead to surface refining. [ABSTRACT FROM AUTHOR]

Abstract: The effect of salt on the binding of the antimicrobial peptide magainin to POPC lipid bilayers is studied by 40–50 ns molecular dynamics simulations of a POPC bilayer in the presence of different concentrations of Na+ and Cl− ions, corresponding to effective concentrations of 0, 100, 150, 200, 250 and 300 millimolar NaCl, with and without a single molecule of antimicrobial peptide magainin. Simulations without magainin showed that increasing salt concentration leads to the decrease in the area per lipid, a decrease in the head group tilt of the lipids, as well as increased order of lipid tails, in agreement with other recent simulations. Simulations with magainin show that peptide binding to the lipids is stronger at lower concentrations of salt. The peptides disorder the lipids in their immediate vicinity, but this effect is diminished as the salt concentration increases. Our studies indicate that while 50 ns simulations give information on peptide hydrogen bonding and lipid tail ordering that is insensitive to the initial peptide orientation, this run time is not sufficient to equilibrate the peptide position and orientation within the bilayer. [Copyright &y& Elsevier]

We have performed molecular dynamics simulations of the interactions of two α-helical anti-microbial peptides, magainin2 and its synthetic analog of MSI-78, with palmitoyl-oleoyl-phosphatidylcholine (POPC) lipid bilayers. We used various initial positions and orientations of the peptide with respect to the lipid bilayer, including a surface-bound state parallel to the interface, a trans-membrane state, and a partially inserted state. Our 20ns long simulations show that both magainin2 and MSI-78 are most stable in the lipid environment, with the peptide destabilized to different extents in both aqueous and lipid/water interfacial environments. We found that there are strong specific interactions between the lysine residues of the peptides and the lipid head-group regions. MSI-78, owing to its large number of lysines, shows better binding characteristics and overall stability when compared to magainin2. We also find that both peptides destabilize the bilayer environment, as observed by the increase in lipid tail disorder and the induction of local curvature on the lipid head-groups by the peptides. From all the simulations, we conclude that the hydrogen bonding interactions between the lysines of the peptides and the oxygens of the polar lipid head-groups are the strongest and determine the overall peptide binding characteristics to the lipids. [Copyright &y& Elsevier]

We investigate theoretically charge regulation of weakly dissociating polyacids by potentiometric titration of their aqueous solutions. By treating deprotonation and cation binding to the polyacids as reversible reactions in our model, the ionization constant of acid groups along the polyacid chain is adjusted from its intrinsic value by electrostatic correlations. If electrostatic correlations are modeled with a Debye-Hückel electrostatic free energy that ignores the connectivity of acid groups, the theory follows Henderson-Hasselbalch behavior for monoacids at low polyacid concentrations, and does not capture the shift of the ionization constant from its intrinsic value with increasing pH. Using a random phase approximation (RPA) that captures the chain connectivity, the shift of the ionization constant is predicted, which is found to directly originate from the electrostatic repulsions along the polyacid chain. We make predictions for titration of rodlike and Gaussian coil polyacids, and find that the former is followed by hydrophilic poly(acrylic acid), while the latter is followed more closely by hydrophobic poly(acrylamido-2-methyl-1-propanesulfonic acid). The results suggest that development of more advanced free energy models that allow chain configurations to self-adjust with changing pH and chain hydrophobicity could provide accurate a priori modeling of charge regulation of polyacids. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Abstract: The determination of whether two dissimilar polymers are weldable is still largely trial-and-error. Here we suggest a correlation between laser weld strength and the ratio of the equilibrium interpenetration depth (w ∞) of two immiscible polymers to the maximum entanglement tube diameter of the two polymers (a max). Taking the weld strength from a published chart of qualitative weld strength, we find a correlation coefficient between this and the ratio w ∞/a max of 0.67, where w ∞ is based on the simple Hildebrand solubility parameter. This encouraged a quantitative study of the laser weld strength. This was done using a through transmission laser welding process with 0.4% carbon black as an absorber. The laser welds were tensile tested and relative weld strengths obtained. This strength was compared to the w ∞/a max ratio, where w ∞ is based on experimentally determined Hansen solubility parameters. The results suggest weldability between dissimilar polymers is obtainable when w ∞/a max is greater than 0.15. [Copyright &y& Elsevier]

Abstract: To explore the role of individual lung surfactant components in liquid-condensed (LC)/liquid-expanded (LE) phase transitions the MARTINI coarse-grained (CG) model is used to simulate monolayers containing DPPC and additional lipid or peptide components. Our analysis suggests that the LC phase forms from the LE phase via a nucleation and growth mechanism, while the LC–LE transition occurs by melting that originates from defects in the monolayer. On the time scale of our simulations, DPPC monolayers display a substantial hysteresis between the ordering and disordering transitions, which is decreased by the addition of a second component. In binary mixtures of DPPC with lung surfactant peptide fragment SP-B1–25, the ordered side of the hysteresis loop is abolished altogether, suggesting that SP-B1–25 effectively nucleates disorder in the monolayer on heating. SP-B1–25 is observed to perturb the packing of the surrounding lipids leading to local fluidization of the monolayer and to aggregate within the LE phase. In 1:1 DPPC:POPC monolayers, a high concentration of unsaturated phospholipid leads to a substantial decrease in the LC–LE and LE–LC transition temperatures. Adding cholesterol to pure DPPC increases the LC–LE and LE–LC transition temperatures and increases the order on the disordered side of the hysteresis loop leading to a phase of intermediate order, which could be the liquid-disordered (Ld) phase. Cholesterol is also observed to show a preference for LC–LE domain boundaries. The results of our molecular dynamics simulations coincide with many experimental observations and can help provide insight into the physiological roles of individual surfactant components. [Copyright &y& Elsevier]

Abstract: The second transmembrane (TM2) domain of GABAA receptor forms the inner-lining surface of chloride ion-channel and plays important roles in the function of the receptor protein. In this study, we report the first structure of TM2 in lipid bilayers determined using solid-state NMR and MD simulations. The interatomic 13C–15N distances measured from REDOR magic angle spinning experiments on multilamellar vesicles, containing a TM2 peptide site specifically labeled with 13C′ and 15N isotopes, were used to determine the secondary structure of the peptide. The 15N chemical shift and 1H–15N dipolar coupling parameters measured from PISEMA experiments on mechanically aligned phospholipid bilayers, containing a TM2 peptide site specifically labeled with 15N isotopes, under static conditions were used to determine the membrane orientation of the peptide. Our results reveal that the TM2 peptide forms an alpha helical conformation with a tilted transmembrane orientation, which is unstable as a monomer but stable as pentameric oligomers as indicated by MD simulations. Even though the peptide consists of a number of hydrophilic residues, the transmembrane folding of the peptide is stabilized by intermolecular hydrogen bondings between the side chains of Ser and Thr residues as revealed by MD simulations. The results also suggest that peptide–peptide interactions in the tilted transmembrane orientation overcome the hydrophobic mismatch between the peptide and bilayer thickness. [Copyright &y& Elsevier]

Abstract: Transient and steady-state deformations and breakup of viscoelastic polystyrene droplets dispersed in viscoelastic high-density polyethylene matrices were observed in a simple steady shear flow between two transparent parallel disks. By separately varying the elasticities of the individual blend components, the matrix shear viscosity, and the viscosity ratio, their effects on the transient deformation, steady-state droplet size, and the breakup sequence were determined. After the startup of a steady shear flow, the viscoelastic droplet initially exhibits oscillations of its length in the flow direction, but eventually stretches preferentially in the vorticity direction. We find that at fixed capillary number, the oscillation amplitude decreases with increasing droplet elasticity, while the oscillation period depends primarily on, and increases with, the viscosity ratio. At steady-state, the droplet length along the vorticity direction increases with increasing capillary number, viscosity ratio, and droplet elasticity. Remarkably, at a viscosity ratio of unity, the droplets remain in a nearly undeformed state as the capillary number is varied between 2 and 8, apparently because under these conditions a tendency for the droplets to widen in the vorticity direction counteracts their tendency to stretch in the flow direction. When a critical capillary number, Cac, is exceeded, the droplet finally stretches in the vorticity direction and forms a string which becomes thinner and finally breaks up, provided that the droplet elasticity is sufficiently high. For a fixed matrix shear stress and droplet elasticity, the steady-state deformation along the vorticity direction and the critical capillary number for breakup both increase with increasing viscosity ratio. [Copyright &y& Elsevier]

After the start of the flow in a home-built flow-loop, the thickness of a waxy layer deposited on a stainless steel (SS) test section was found to increase immediately, while deposition was delayed for around 4 h on a polyethylene (PE) test section. The radial thermal gradient, wax precipitation rate, radial diffusivity of wax, and shear stresses at the surface of the deposit layer were calculated, eliminating these factors as sources of different deposition behavior. However, the contact angles of oils containing precipitated wax crystals on PE surfaces were found to increase more with increasing wax content than those on SS surfaces. Consistent with this, while the wax contents of deposits were found to be around 18 wt % for both PE and SS pipes, the adhesion of the deposit on the PE surface was found to be much weaker than on the SS surface, as evidenced by the easier of removal of the deposit from PE than from SS pipes when heated in vertical orientation under gravity. These results point to pipe wall wettability as a significant factor in both initial growth of wax deposit, and ease of removal. • The wax deposition is delayed for 4 h in the PE pipe. • Concentration driving force is not dominant during the delayed formation. • Adhesion of deposit on PE surface is weaker than on steel surface. [ABSTRACT FROM AUTHOR]

We describe the design, creation, and usage of a CaO catalyst immobilized onto polymeric mats for environmentally-friendly biodiesel production. The polyacrylonitrile (PAN) fiber mats were prepared by electrohydrodynamic processing (EHD), commonly known as electrospinning or electrospraying, in which immobilized CaO particles were either physically entrapped on the fibers or chemically bound onto the fiber surface by a dopamine linkage. These two catalyst materials were later successfully used in the transesterification of fresh canola oil into biodiesel. Mechanically entrapped CaO particles in the PAN fibers were able to be re-used up to six times in the conversion of triglycerides into biodiesel, while the chemically immobilized catalyst was found impossible to reuse. The use of EHD processing allows us to create an easily separable, reusable catalyst that could be commonly used in transesterification reactions. • Mats made from PAN nanofibers via electrospinning to immobilize heterogenous catalyst • Immobilization of CaO catalyst via both physical and chemical bonding onto the fibers • Successful transesterification of Canola oil using immobilized CaO catalytic mats • Environmentally-friendly biodiesel production—easily separable, reusable catalyst [ABSTRACT FROM AUTHOR]