Search

In this work we study the change on the wettability and solid properties of microcrystalline cellulose (Avicel PH101)after it was wet and dried, through drop penetration experiments in slightly compacted porous beds. We perform these experiments with water and a silicone oil, (Polidimethilsyloxane–PDMS) and we determine a dimensionless parameter that takes into account all the water penetration factors, including wettability and swelling. We consider three different scenarios, original MCC, and after one and two wetting and drying cycles. For each case we study the particle size effects by considering two subset samples SiA)25

This study examines the swelling kinetics of polyacrylamide hydrogel beads in aqueous glycerin solutions of different concentrations. The total absorbed mass of the hydrogel beads remains nearly constant, independent of glycerin concentration, but the swelling process is markedly slower with increasing glycerin concentration in the aqueous solutions. Absorption capacity curves exhibit universal kinetics when time is rescaled using a characteristic time proportional to the viscosity of the solutions. Additionally, a novel visualization technique is employed to observe the core-shell structure of the hydrogel beads at early times in the swelling process. The evolution of the core-shell structure indicates a constant front velocity, which also reveals universal behavior with the same nondimensional time, suggesting a viscous dominated transport of the solution penetrating the beads.

Theoretical analysis based on mean field theory indicates that solvent-induced interactions ( i.e. structural forces due to the rearrangement of wetting solvent molecules) not considered in DLVO theory can induce the kinetic trapping of nanoparticles at finite nanoscale separations from a well-wetted surface, under a range of ubiquitous physicochemical conditions for inorganic nanoparticles of common materials ( e.g. , metal oxides) in water or simple molecular solvents. This work proposes a simple analytical model that is applicable to arbitrary materials and simple solvents to determine the conditions for direct particle-surface contact or kinetic trapping at finite separations, by using experimentally measurable properties ( e.g. , Hamaker constants, interfacial free energies, and nanoparticle size) as input parameters. Analytical predictions of the proposed model are verified by molecular dynamics simulations and numerical solution of the Smoluchowski diffusion equation.

Hypothesis: Identification and quantification of harmful chemicals in e-cigarette aerosol requires collecting the aerosolized e-liquid for chemical analysis. In 2016, Olmedo at al. empirically developed a simple method for aerosol collection by directing the aerosol through a sequence of alternating straight and converging tubing sections, which drain the recovered e-liquid into a collection vial. The tubing system geometry and flow conditions promote inertial impaction of aerosolized e-liquid on tube walls, where it deposits and flows into the collection vial., Experiments: We use high-speed optical imaging to visualize aerosol transport in proxies of the collection system. We also determined collection efficiencies of various configurations of the collection system., Findings: A turbulent jet emerges from converging conical sections and impinges onto the wall of downstream tubing sections, resulting in inertial impaction and deposition of the aerosol. For inertial impaction to occur the tip radius of the converging section must be small enough for a jet to be formed and the sequence of tubing sections must be curved in a polygon-like manner such that the jet emerging from a converging section impinges on the downstream tube wall. The collection efficiency is significantly smaller without such curvature., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. In addition, several podium presentations highlighted opportunities to replace conventional dissolution testing with surrogate test methods to enable robust drug product and process understanding within the context of quality by design (QbD), new manufacturing technologies, and real-time release testing (RTRT). The topics covered on Day 1 laid the foundation for subsequent discussions which focused on the challenges related to establishing an in vitro-in vivo link and approaches for establishing clinically relevant drug product specifications which are becoming an expectation in regulatory submissions. Clarification of dissolution-related terminology used inconsistently among the scientific community, and the purpose of various testing approaches were key discussion topics of the Day 1 breakout sessions. The outcome of these discussions along with creative ways to overcome challenges related to bridging "exploratory dissolution approaches" with methods suitable for end-product control testing are captured within this report.

Accurate assessment of tablet content uniformity is critical for narrow therapeutic index drugs such as phenytoin sodium. This work presents a near-infrared (NIR)-based analytical method for rapid prediction of content uniformity based on a large number of phenytoin sodium formulation tablets. Calibration tablets were generated through an integrated experimental design by varying formulation and process parameters, and scale of manufacturing. A partial least squares model for individual tablet content was developed based on tablet NIR spectra. The tablet content was obtained from a modified United States Pharmacopeia phenytoin sodium high-performance liquid chromatography assay method. The partial least squares model with 4 latent variables explained 92% of the composition variability and yielded a root mean square error of prediction of 0.48% w/w. The resultant NIR model successfully assayed the composition of tablets manufactured at the pilot scale. For one such batch, bootstrapping was applied to calculate the confidence intervals on the mean, acceptance value, and relative SD for different sample sizes, n = 10, 30, and 100. As the bootstrap sample size increased, the confidence interval on the mean, acceptance value, and relative SD became narrower and symmetric. Such a 'large N' NIR-based process analytical technology method can increase reliability of quality assessments in solid dosage manufacturing., (Published by Elsevier Inc.)

Using molecular dynamics simulations, we investigate the fate of a nanoparticle deposited on a solid surface as a liquid-liquid interface moves past it, depending on the wetting of the solid by the two liquids and the magnitude of the driving force. Interfacial pinning is observed below a critical value of the driving force. Above the critical driving force for pinning and for large contact angle values we observe stick-slip motion, with intermittent interfacial pinning and particle sliding at the interface. At low contact angles we observe that particle rolling precedes detachment, which indicates the importance of dynamic effects not present in static models. The findings in this work indicate that particle mobilization, and removal efficiencies, originating in dynamic liquid-liquid interfaces can be significantly underestimated by static models.

Water wettability of pharmaceutical blends affects important quality attributes of final products. We investigate the wetting properties of a pharmaceutical blend lubricated with Magnesium Stearate (MgSt) as a function of the mechanical shear strain applied to the blend. We measure the penetration dynamics of sessile drops deposited on slightly compressed powder beds. We consider a blend composed of 9% Acetaminophen 90% Lactose and 1% MgSt by weight. Comparing the penetration time of water and a reference liquid Polydimethylsiloxane (silicon oil) we obtain an effective cosine of the contact angle with water, based on a recently developed drop penetration method. We repeat the experiments for blends exposed to increasing levels of shear strain and demonstrate a significant decrease in water wettability (decrease in the cosine of the contact angle). The results are consistent with the development of a hydrophobic film coating the powder particles as a result of the increased shear strain. Finally, we show that, as expected dissolution times increase with the level of shear strain. Therefore, the proposed drop penetration method could be used to directly assess the state of lubrication of a pharmaceutical blend and act as a quality control on powder blend attributes before the blend is tableted., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We have investigated the gravity-driven transport of spherical colloids suspended in the nematic liquid crystal 4-cyano-4'-pentylbiphenyl (5CB) within microfluidic arrays of cylindrical obstacles arranged in a square lattice. Homeotropic anchoring at the surfaces of the obstacles created periodic director-field patterns that strongly influenced the motion of the colloids, whose surfaces had planar anchoring. When the gravitational force was oriented parallel to a principal axis of the lattice, the particles moved along channels between columns of obstacles and displayed pronounced modulations in their velocity. Quantitative analysis indicates that this modulation resulted from a combination of a spatially varying effective drag viscosity and elastic interactions engendered by the periodic director field. The interactions differed qualitatively from a sum of pair-wise interactions between the colloids and isolated obstacles, reflecting the distinct nematic environment created by confinement within the array. As the angle α between the gravitational force and principal axis of the lattice was varied, the velocity did not follow the force but instead locked into a discrete set of directions commensurate with the lattice. The transitions between these directions occurred at values of α that were different from those observed when the spheres were in an isotropic liquid, indicating the ability of the liquid crystal forces to tune the lateral displacement behavior in such devices.

Deterministic lateral displacement (DLD) is a promising separation scheme in microfluidic systems. In traditional DLD, a periodic array of solid posts induces the separative migration of suspended particles moving through the system. Here, we present a radical departure from traditional DLD systems and use an array of anchored liquid-bridges as the stationary phase in the DLD device. The liquid-bridges are created between two parallel plates and anchored to the bottom one by cylindrical wells. We show that the non-linear particle dynamics observed in traditional DLD systems is also present in the anchored-liquid case, enabling analogous size-based separation of suspended particles. The use of liquid-bridges as the stationary phase presents additional possibilities in separation technologies, potentially eliminating or significantly reducing clogging, enabling renewable and/or reconfigurable systems, allowing a different set of fabrication methods and providing alternative ways to separate particles based on their interaction with liquid-liquid interfaces. Some of these advantages could also extend to filtration methods based on similar liquid-based stationary phases.

We present a method to characterize the wettability of powders, based on the penetration dynamics of a sessile drop deposited on a slightly compressed powder bed. First, we show that a direct comparison of the wetting properties of different liquids is possible without having to solve the three-dimensional liquid penetration problem, by considering the appropriate dimensionless variables. We show that the contact area between the sessile drop and the powder bed remains constant during most of the penetration process and demonstrate that as a result, the evolution of the dimensionless penetration volume is given by a universal function of the dimensionless time, with no dimensionless parameters. Then, using a reference liquid that completely wets the powder, it is possible to obtain an effective contact angle for a test liquid of interest, independent of other properties of the powder bed, such as permeability and a characteristic pore size. We apply the proposed method to estimate the contact angle of water with different powder blends, by using silicone oil as the reference liquid. Finally, to highlight the potential of the proposed method to characterize pharmaceutical powders, we consider a blend of lactose, acetaminophen, and a small amount of lubricant (magnesium stearate). The proposed method adequately captures a significant decrease in hydrophilicity that results from exposing the blend to excessive mixing, a well-known effect in the pharmaceutical industry.

We present a simple modification to enhance the separation ability of deterministic lateral displacement (DLD) systems by expanding the two-dimensional nature of these devices and driving the particles into size-dependent, fully three-dimensional trajectories. Specifically, we drive the particles through an array of long cylindrical posts, such that they not only move parallel to the basal plane of the posts as in traditional two-dimensional DLD systems (in-plane motion), but also along the axial direction of the solid posts (out-of-plane motion). We show that the (projected) in-plane motion of the particles is completely analogous to that observed in 2D-DLD systems. In fact, a theoretical model originally developed for force-driven, two-dimensional DLD systems accurately describes the experimental results. More importantly, we analyze the particles out-of-plane motion and observe, for certain orientations of the driving force, significant differences in the out-of-plane displacement depending on particle size. Therefore, taking advantage of both the in-plane and out-of-plane motion of the particles, it is possible to achieve the simultaneous fractionation of a polydisperse suspension into multiple streams.

An ultrasound measurement system was employed as a non-destructive method to evaluate its reliability in predicting the tensile strength of tablets and investigate the benefits of incorporating it in a continuous line, manufacturing solid dosage forms. Tablets containing lactose, acetaminophen, and magnesium stearate were manufactured continuously and in batches. The effect of two processing parameters, compaction force and level of shear strain were examined. Young's modulus and tensile strength of tablets were obtained by ultrasound and diametrical mechanical testing, respectively. It was found that as the blend was exposed to increasing levels of shear strain, the speed of sound in the tablets decreased and the tablets became both softer and mechanically weaker. Moreover, the results indicate that two separate tablet material properties (e.g., relative density and Young's modulus) are necessary in order to predict tensile strength. A strategy for hardness prediction is proposed that uses the existing models for Young's modulus and tensile strength of porous materials. Ultrasound testing was found to be very sensitive in differentiating tablets with similar formulation but produced under different processing conditions (e.g., different level of shear strain), thus, providing a fast, and non-destructive method for hardness prediction that could be incorporated to a continuous manufacturing process., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Aminosilanes are routinely employed for charge reversal or to create coupling layers on oxide surfaces. We present a chemical vapor deposition method to pattern mica surfaces with regions of high-quality aminosilane (3-aminopropyltriethoxysilane, APTES) monolayers. The approach relies on the vapor deposition of an aminosilane through a patterned array of through-holes in a PDMS (poly(dimethylsiloxane)) membrane that acts as a mask. In aqueous solutions the surfaces have regular patterns of charge heterogeneities with minimal topographical variations over large areas. This versatile dry lift-off deposition method alleviates issues with multilayer formation and can be used to create charge patterns on curved surfaces. We identify the necessary steps to achieve high quality monolayers and charge reversal of the underlying mica surface: (1) hexane extraction to remove unreacted PDMS oligomers from the membrane that would otherwise deposit on and contaminate the substrate, (2) oxygen plasma treatment of the top of the membrane surfaces to generate a barrier layer that blocks APTES transport through the PDMS, and (3) low of the vapor pressure of APTES during deposition to minimize APTES condensation at the mica-membrane-vapor contact lines and to prevent multilayer formation. Under these conditions, AFM imaging shows that the monolayers have a height of 0.9 ± 0.2 nm with an increase in height up to 3 nm at the mica-membrane-vapor contact lines. Fluorescence imaging demonstrates pattern fidelity on both flat and curved surfaces, for feature sizes that vary between 6.5 and 40 μm. We verify charge reversal by measuring the double layer forces between a homogeneous (unpatterned) APTES monolayers and a mica surface in aqueous solution, and we characterize the surface potential of APTES monolayers by measuring the double-layer forces between identical APTES surfaces. We obtain a surface potential of +110 ± 6 mV at pH 4.0.

We study the transport of Brownian particles under a constant driving force and moving in channels that present a varying centerline but have constant aperture width (serpentine channels). We investigate two types of channels, solid channels, in which the particles are geometrically confined between solid walls and soft channels, in which the particles are confined by the potential energy landscape. We consider the limit of narrow, slowly varying channels, i.e., when the aperture and the variation in the position of the centerline are small compared to the length of a unit cell in the channel (wavelength). We use the method of asymptotic expansions to determine both the average velocity (or mobility) and the effective dispersion coefficient of the particles. We show that both solid and soft-channels have the same effects on the transport properties up to leading order correction. Including the next order correction, we obtain that the mobility in a solid-channel is smaller than that in a soft-channel. However, we discuss an alternative definition of the effective width of a soft channel that leads to equal mobilities up to second order terms. Interestingly, in both cases, the corrections to the mobility of the particles are independent of the Péclet number, and the Einstein-Smoluchowski relation is satisfied.

We perform molecular dynamics simulations to understand the translational and rotational diffusion of Janus nanoparticles at the interface between two immiscible fluids. Considering spherical particles with different affinity to fluid phases, both their dynamics as well as the fluid structure around them are evaluated as a function of particle size, amphiphilicity, fluid density, and interfacial tension. We show that as the particle amphiphilicity increases due to enhanced wetting of each side with its favorite fluid, the rotational thermal motion decreases. Moreover, the in-plane diffusion of nanoparticles at the interface becomes slower for more amphiphilic particles, mainly due to the formation of a denser adsorption layer. The particles induce an ordered structure in the surrounding fluid that becomes more pronounced for highly amphiphilic nanoparticles, leading to increased resistance against nanoparticle motion. A similar phenomenon is observed for homogeneous particles diffusing in bulk upon increasing their wettability. Our findings can provide fundamental insight into the dynamics of drugs and protein molecules with anisotropic surface properties at biological interfaces including cell membranes.

We analyze the trajectory of suspended spherical particles moving through a square array of obstacles, in the deterministic limit and at zero Reynolds number. We show that in the dilute approximation of widely separated obstacles, the average motion of the particles is equivalent to the trajectory followed by a point particle moving through an array of obstacles with an effective radius. The effective radius accounts for the hydrodynamic as well as short-range repulsive nonhydrodynamic interactions between the suspended particles and the obstacles, and is equal to the critical offset at which particle trajectories become irreversible. Using this equivalent system we demonstrate the presence of directional locking in the trajectory of the particles and derive an inequality that accurately describes the "devil's staircase" type of structure observed in the migration angle as a function of the forcing direction. We use these results to determine the optimum resolution in the fractionation of binary mixtures using deterministic lateral-displacement microfluidic separation systems as well as to comment on the collision frequencies when the arrays of posts are utilized as immunocapture devices.

The ability to separate and analyze chemical species with high resolution, sensitivity, and throughput is central to the development of microfluidics systems. Deterministic lateral displacement (DLD) is a continuous separation method based on the transport of species through an array of obstacles. In the case of force-driven DLD (f-DLD), size-based separation can be modelled effectively using a simple particle-obstacle collision model. We use a macroscopic model to study f-DLD and demonstrate, via a simple scaling, that the method is indeed predominantly a size-based phenomenon at low Reynolds numbers. More importantly, we demonstrate that inertia effects provide the additional capability to separate same size particles but of different densities and could enhance separation at high throughput conditions. We also show that a direct conversion of macroscopic results to microfluidic settings is possible with a simple scaling based on the size of the obstacles that results in a universal curve.

We present a microfluidic platform for the continuous separation of suspended particles based on their size and settling velocity. The separation method takes advantage of the flow field in the vicinity and inside slanted open cavities. These cavities induce flow along them, which deflects the suspended particles to a different degree depending on the extent to which they penetrate into the cavities. The cumulative deflection in the periodic array ultimately leads to vector chromatography, with the different species in the sample moving in different directions. We demonstrate density and size based separation over a range of flow rates by separating polystyrene and silica particles and show that purities nearing 100% can be achieved for multicomponent mixtures. We also demonstrate the potential of the platform to separate biological cells by fractionating different blood components. We discuss the presence of two regimes, depending on the ratio between the settling velocity and the velocity of the particles across the open cavities. The proposed platform could also integrate additional separative force fields in the direction normal to the plane of the cavities to fractionate specific mixtures based on the distinguishing properties of the component species.

We investigate the two-dimensional continuous size-based separation of suspended particles in gravity-driven deterministic lateral displacement (g-DLD) devices. The suspended particles are driven through a periodic array of cylindrical obstacles under the action of gravity. We perform experiments covering the entire range of forcing orientations with respect to the array of obstacles and identify specific forcing angles that would lead to vector separation, in which different particles migrate, on an average, in different directions. A simple model, based on the lateral displacement induced on the trajectory of a particle by irreversible particle-obstacle interactions, accurately predicts the dependence of the migration angle on the forcing direction. The results provide design guidance for the development of g-DLD devices. We observe directional locking, which strongly depends on the size of the particle and suggests that relatively small forcing angles are well suited for size-fractionation purposes. We demonstrate excellent separation resolution for a binary mixture of particles at relatively small forcing angles, that is, forcing angles that are close to but smaller than the first transition angle of the larger particles in the mixture.

We investigate the separation of drops in force-driven deterministic lateral displacement (f-DLD), a promising high-throughput continuous separation method in microfluidics. We perform scaled-up macroscopic experiments in which drops settle through a square array of cylindrical obstacles. These experiments demonstrate the separation capabilities-and provide insight for the design-of f-DLD for drops of multiple sizes, including drops that are larger than the gaps between cylinders and exhibit substantial deformation as they move through the array. We show that for any orientation of the driving force relative to the array of obstacles, the trajectories of the drops follow selected locking directions in the lattice. We also found that a simple collision model accurately describes the average migration angles of the drops for the entire range of sizes investigated here, and for all forcing directions. In addition, we found a difference of approximately 20° between the critical angles at which the smallest and largest drops first move across a line of obstacles (column) in the array, a promising result in terms of potential size resolution of this method. Finally, we demonstrate that a single line of cylindrical obstacles rotated with respect to the driving force is capable of performing binary separations. The critical angles obtained in such single line experiments, moreover, agree with those obtained using the full array, thus validating the assumption in which the trajectory (and average migration angle) of the drops is calculated from individual obstacle-drop collisions.

We present a comprehensive description of vector chromatography (VC) that includes deterministic and stochastic transport in one-dimensional periodic free-energy landscapes, with both energetic and entropic contributions, and identifies the parameters governing the deflection angle. We also investigate the dependence of the deflection angle on the shape of the free-energy landscape by varying the width of the linear transitions in an otherwise dichotomous potential. Finally, we present experimental results obtained in a microfluidic system in which gravity drives the suspended particles and, in combination with a bottom surface patterned with shallow rectangular grooves, creates a periodic landscape of (potential) energy barriers. The experiments validate the model and demonstrate that a simple, passive microdevice can lead to VC of colloidal particles based on both size and density. More generally, other fields, e.g., electric, dielectrophoretic, or magnetic, can play or enhance the role of gravity, potentially leading to a versatile technique.

The dynamics of dissolved oxygen (DO) and shear stress in the vasculature microenvironment play a major role in determining the fate of stem cells in adults and during early embryonic development. In this study, we present a microbioreactor (MBR) that provides independent control over oxygen tension and shear stress in cultures of stem and progenitor cell types. We first describe the design principles and use a model-driven approach for the optimization of the MBR geometry and operating conditions prior to its fabrication and assembly. We then demonstrate the utilization of the MBR for culturing adult human endothelial progenitors, human umbilical vein endothelial cells, and human embryonic stem cell-derived smooth muscle cells under different DO and shear stress levels., (Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.)

The ability to control the oxygen level to which cells are exposed in tissue culture experiments is crucial for many applications. Here, we design, develop and test a microbioreactor (MBR) for long-term cell culture studies with the capability to accurately control and continuously monitor the dissolved oxygen (DO) level in the cell microenvironment. In addition, the DO level can be controlled independently from other cues, such as the viscous shear-stress acting on the cells. We first analyze the transport of oxygen in the proposed device and determine the materials and dimensions that are compatible with uniform oxygen tension and low shear-stress at the cell level. The device is also designed to culture a statistically significant number of cells. We use fully transparent materials and the overall design of the device is compatible with live-cell imaging. The proposed system includes real-time read-out of actual DO levels, is simple to fabricate at low cost, and can be easily expanded to control the concentration of other microenvironmental solutes. We performed control experiments in the absence of cells to demonstrate that the MBR can be used to accurately modulate DO levels ranging from atmospheric level to 1%, both under no flow and perfusion conditions. We also demonstrate cancer cell attachment and viability within the MBR. The proposed MBR offers the unprecedented capability to perform on-line measurement and analysis of DO levels in the microenvironment of adherent cultures and to correlate them with various cellular responses.

We investigate by means of macrotransport theory the transport of Brownian particles in a slit geometry in the presence of an arbitrary two-dimensional periodic energy landscape and driven by an external force or convected by a flow field. We obtained analytical expressions for the probability distribution and the average migration angle of the particles under the Fick-Jacobs approximation. The migration angle is shown to differ from the angle of the driving field and to strongly depend on the physical properties of the suspended species, thus providing the basis for vector chromatography, in which different species move in different directions and can be continuously fractionated. The potential of microfluidic devices as a platform for partition-induced vector chromatography is demonstrated by considering the particular case of a piece-wise constant, periodic potential that, in equilibrium, induces the spontaneous partition of different species into high and low concentration stripes, and which can be easily fabricated by patterning physically or chemically one of the surfaces of a channel. We show the feasibility to fractionate a mixture of particles for systems in which partition is induced via 1-g gravity and Van der Waals interactions in physically or chemically patterned channels., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Hypoxia plays an important role in vascular development through hypoxia-inducible factor-1alpha (HIF-1alpha) accumulation and downstream pathway activation. We sought to explore the in vitro response of cultures of human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), human endothelial progenitor cells (hEPCs), and human umbilical cord vein endothelial cells (HUVECs) to normoxic and hypoxic oxygen tensions. We first measured dissolved oxygen (DO) in the media of adherent cultures in atmospheric (21% O(2)), physiological (5% O(2)), and hypoxic oxygen conditions (1% O(2)). In cultures of both hEPCs and HUVECs, lower oxygen consumption was observed when cultured in 1% O(2). At each oxygen tension, feeder-free cultured hESCs and iPSCs were found to consume comparable amounts of oxygen. Transport analysis revealed that the oxygen uptake rate (OUR) of hESCs and iPSCs decreased distinctly as DO availability decreased, whereas the OUR of all cell types was found to be low when cultured in 1% O(2), demonstrating cell adaptation to lower oxygen tensions by limiting oxygen consumption. Next, we examined HIF-1alpha accumulation and the expression of target genes, including VEGF and angiopoietins (ANGPT; angiogenic response), GLUT-1 (glucose transport), BNIP3, and BNIP3L (autophagy and apoptosis). Accumulations of HIF-1alpha were detected in all four cell lines cultured in 1% O(2). Corresponding upregulation of VEGF, ANGPT2, and GLUT-1 was observed in response to HIF-1alpha accumulation, whereas upregulation of ANGPT1 was detected only in hESCs and iPSCs. Upregulation of BNIP3 and BNIP3L was detected in all cells after 24-h culture in hypoxic conditions, whereas apoptosis was not detectable using flow cytometry analysis, suggesting that BNIP3 and BNIP3L can lead to cell autophagy rather than apoptosis. These results demonstrate adaptation of all cell types to hypoxia but different cellular responses, suggesting that continuous measurements and control over oxygen environments will enable us to guide cellular responses.

We performed macroscopic experiments on the motion of a sphere through an array of obstacles that highlight the deterministic nature of the lateral displacements that lead to particle separation in microfluidic systems. The motion of the spheres is irreversible and displays directional locking. The locking directions can be predicted with a single parameter that distinguishes between reversible and irreversible particle-obstacle collisions. These results stress the need to incorporate irreversible interactions to predict the movement of a non-Brownian sphere passing through a periodic array.

We investigate the transport and separation of overdamped particles under the action of a uniform external force in a two-dimensional periodic energy landscape. Exact results are obtained for the deterministic transport in a square lattice of parabolic, repulsive centers that correspond to a piecewise-continuous linear-force model. The trajectories are periodic and commensurate with the obstacle lattice and exhibit phase-locking behavior in that the particle moves at the same average migration angle for a range of orientation of the external force. The migration angle as a function of the orientation of the external force has a Devil's staircase structure. The first transition in the migration angle was analyzed in terms of a Poincare map, showing that it corresponds to a tangent bifurcation. Numerical results show that the limiting behavior for impenetrable obstacles is equivalent to the high Peclet number limit in the case of transport of particles in a periodic pattern of solid obstacles. Finally, we show how separation occurs in these systems depending on the properties of the particles.

The stochastic transport of suspended particles through a periodic pattern of obstacles in microfluidic devices is investigated by means of the Fokker-Planck equation and numerical simulations. Asymmetric arrays of obstacles have been shown to induce the continuous separation of DNA molecules, with particles of different size migrating in different directions within the microdevice (vector separation). We show that the separation of tracer particles only occurs in the presence of a permeating driving force with a nonzero normal component at the surface of the solid obstacles, and arises from differences in the local Peclet number of the particles. On the other hand, finite-size particles also exhibit nonzero, but small, migration angles in the case of nonpermeating fields. Monte Carlo simulations for different driving fields agree with the solutions to the Fokker-Planck equation.

We study an ad hoc extension of the lattice Boltzmann method that allows the simulation of non-Newtonian fluids described by generalized Newtonian models. We extensively test the accuracy of the method for the case of shear-thinning and shear-thickening truncated power-law fluids in the parallel plate geometry, and show that the relative error compared to analytical solutions decays approximately linear with the lattice resolution. Finally, we also tested the method in the reentrant-flow geometry, in which the shear rate is no longer a scalar and the presence of two singular points requires high accuracy in order to obtain satisfactory resolution in the local stress near these points. In this geometry, we also found excellent agreement with the solutions obtained by standard finite-element methods, and the agreement improves with higher lattice resolution.

Equilibrium and nonequilibrium aspects of particle adsorption on the walls of fluid-filled nanochannels are examined via molecular dynamics simulations. The force on the particle and the free energy of the system are found to depend on the particle's history (hysteresis), in addition to its radial position and the wetting properties of the fluid, even when the particle moves quasistatically. The hysteresis is associated with changes in the fluid density in the gap between the particle and the wall, which persist over surprisingly long times. The force and free energy exhibit large oscillations with distance when the lattice of the structured nanoparticle is held in register with that of the tube wall, but not if the particle is allowed to rotate freely. Adsorbed particles are trapped in free-energy minima in equilibrium but can desorb if forced along the channel.

The evolution and spatial structure of displacement fronts in fractures with self-affine rough walls are studied by numerical simulations. The fractures are open and the two faces are identical but shifted along their mean plane, either parallel or perpendicular to the flow. An initially flat front advected by the flow is progressively distorted into a self-affine front with a Hurst exponent equal to that of the fracture walls. The lower cutoff of the self-affine regime depends only on the aperture, while the upper cutoff grows with the lateral shift and linearly with the width of the front.

Using molecular dynamics simulations, we study the motion of a closely fitting nanometer-size solid sphere in a fluid-filled cylindrical nanochannel at low Reynolds numbers. At early times, when the particle is close to the middle of the tube, its velocity is in agreement with continuum calculations, despite large thermal fluctuations. At later times, partially wetting fluids exhibit novel adsorption phenomena: the sphere meanders away from the center of the tube and adsorbs onto the wall, and subsequently either sticks to the wall and remains motionless on average, or separates slightly from the tube wall and then either slips parallel to the mean flow or executes an intermittent stick-slip motion.

Transport properties of three-dimensional self-affine rough fractures are studied by means of an effective-medium analysis and numerical simulations using the Lattice-Boltzmann method. The numerical results show that the effective-medium approximation predicts the right scaling behavior of the permeability and of the velocity fluctuations, in terms of the aperture of the fracture, the roughness exponent, and the characteristic length of the fracture surfaces, in the limit of small separation between surfaces. The permeability of the fractures is also investigated as a function of the normal and lateral relative displacements between surfaces, and it is shown that it can be bounded by the permeability of two-dimensional fractures. The development of channel-like structures in the velocity field is also numerically investigated for different relative displacements between surfaces. Finally, the dispersion of tracer particles in the velocity field of the fractures is investigated by analytic and numerical methods. The asymptotic dominant role of the geometric dispersion, due to velocity fluctuations and their spatial correlations, is shown in the limit of very small separation between fracture surfaces.

Tracer diffusion and hydrodynamic dispersion in two-dimensional fractures with self-affine roughness are studied by analytic and numerical methods. Numerical simulations were performed via the lattice-Boltzmann approach, using a boundary condition for tracer particles that improves the accuracy of the method. The reduction in the diffusive transport, due to the fractal geometry of the fracture surfaces, is analyzed for different fracture apertures. In the limit of small aperture fluctuations we derive the correction to the diffusive coefficient in terms of the tortuosity, which accounts for the irregular geometry of the fractures. Dispersion is studied when the two fracture surfaces are simply displaced normally to the mean fracture plane and when there is a lateral shift as well. Numerical results are analyzed using the Lambda parameter, related to convective transport within the fracture, and simple arguments based on lubrication approximation. At very low Péclet number, in the case where fracture surfaces are laterally shifted, we show using several different methods that convective transport reduces dispersion.

The permeability of two-dimensional fractures with self-affine fractal roughness is studied via analytic arguments and numerical simulations. The limit where the roughness amplitude is small compared with average fracture aperture is analyzed by a perturbation method, while in the opposite case of narrow aperture, we use heuristic arguments based on lubrication theory. Numerical simulations, using the lattice Boltzmann method, are used to examine the complete range of aperture sizes, and confirm the analytic arguments.

Recently, analytical solutions of a nonlinear Fokker-Planck equation describing anomalous diffusion with an external linear force were found using a nonextensive thermostatistical Ansatz. We have extended these solutions to the case when an homogeneous absorption process is also present. Some peculiar aspects of the interrelation between the deterministic force, the nonlinear diffusion, and the absorption process are discussed.

We present experimental results of solute transport in porous samples made of packings of activated carbon porous grains. Exchange experiments, where the tagged solution initially saturating the medium is replaced with the same solution without tracer, are accurately described by macroscopic transport equations. On the other hand, in desorption experiments, where the tagged solution is replaced by water, the solute concentration exhibits a power-law decay for long times, which requires a more detailed, mesoscopic description. We reproduce this behavior within a continuous-time random-walk approach, where the waiting time distribution is related to the desorption isotherm. Results are compatible with a power-law trapping time distribution with divergent first moment, characteristic of anomalous (sub)diffusion.

We have obtained the exact expression of the diffusion propagator in the time-dependent anharmonic potential V(x,t)=1 / 2a(t)x(2)+b ln x. The underlying Euclidean metric of the problem allows us to obtain analytical solutions for a whole family of the elastic parameter a(t), exploiting the relation between the path integral representation of the short time propagator and the modified Bessel functions. We have also analyzed the conditions for the appearance of a nonzero flow of particles through the infinite barrier located at the origin (b<0).