Mechanistic Models of Anti-HIV Microbicide Drug Delivery

A new modality for preventing HIV transmission is emerging in the form of topical microbicides. Some clinical trials have shown some promising results of these methods of protection while other trials have failed to show efficacy. Due to the relatively novel nature of microbicide drug transport, a rigorous, deterministic analysis of that transport can help improve the design of microbicide vehicles and understand results from clinical trials. This type of analysis can aid microbicide product design by helping understand and organize the determinants of drug transport and the potential efficacies of candidate microbicide products.

Microbicide drug transport is modeled as a diffusion process with convection and reaction effects in appropriate compartments. This is applied here to vaginal gels and rings and a rectal enema, all delivering the microbicide drug Tenofovir. Although the focus here is on Tenofovir, the methods established in this dissertation can readily be adapted to other drugs, given knowledge of their physical and chemical properties, such as the diffusion coefficient, partition coefficient, and reaction kinetics. Other dosage forms such as tablets and fiber meshes can also be modeled using the perspective and methods developed here.

The analyses here include convective details of intravaginal flows by both ambient fluid and spreading gels with different rheological properties and applied volumes. These are input to the overall conservation equations for drug mass transport in different compartments. The results are Tenofovir concentration distributions in time and space for a variety of microbicide products and conditions. The Tenofovir concentrations in the vaginal and rectal mucosal stroma are converted, via a coupled reaction equation, to concentrations of Tenofovir diphosphate, which is the active form of the drug that functions as a reverse transcriptase inhibitor against HIV. Key model outputs are related to concentrations measured in experimental pharmacokinetic (PK) studies, e.g. concentrations in biopsies and blood. A new measure of microbicide prophylactic functionality, the Percent Protected, is calculated. This is the time dependent volume of the entire stroma (and thus fraction of host cells therein) in which Tenofovir diphosphate concentrations equal or exceed a target prophylactic value, e.g. an EC50.

Results show the prophylactic potentials of the studied microbicide vehicles against HIV infections. Key design parameters for each are addressed in application of the models. For a vaginal gel, fast spreading at small volume is more effective than slower spreading at high volume. Vaginal rings are shown to be most effective if inserted and retained as close to the fornix as possible. Because of the long half-life of Tenofovir diphosphate, temporary removal of the vaginal ring (after achieving steady state) for up to 24h does not appreciably diminish Percent Protected. However, full steady state (for the entire stromal volume) is not achieved until several days after ring insertion. Delivery of Tenofovir to the rectal mucosa by an enema is dominated by surface area of coated mucosa and whether the interiors of rectal crypts are filled with the enema fluid. For the enema 100% Percent Protected is achieved much more rapidly than for vaginal products, primarily because of the much thinner epithelial layer of the mucosa. For example, 100% Percent Protected can be achieved with a one minute enema application, and 15 minute wait time.

Results of these models have good agreement with experimental pharmacokinetic data, in animals and clinical trials. They also improve upon traditional, empirical PK modeling, and this is illustrated here. Our deterministic approach can inform design of sampling in clinical trials by indicating time periods during which significant changes in drug concentrations occur in different compartments. More fundamentally, the work here helps delineate the determinants of microbicide drug delivery. This information can be the key to improved, rational design of microbicide products and their dosage regimens.

Variationelle Zeitdiskretisierungen höherer Ordnung der Konvektions-Diffusions-Reaktions-Gleichungen in zeitabhängigen Gebieten

Wir betrachten zeitabhängige Konvektions-Diffusions-Reaktions-Gleichungen in zeitabhängi- gen Gebieten, wobei die Bewegung des Gebietsrandes bekannt ist. Die zeitliche Entwicklung des Gebietes wird durch die ALE-Formulierung behandelt, die die Nachteile der klassischen Euler- und Lagrange-Betrachtungsweisen behebt. Die Position des Randes und seine Geschwindigkeit werden dabei so in das Gebietsinnere fortgesetzt, dass starke Gitterdeformationen verhindert werden. Als Zeitdiskretisierungen höherer Ordnung werden stetige Galerkin-Petrov-Verfahren (cGP) und unstetige Galerkin-Verfahren (dG) auf Probleme in zeitabhängigen Gebieten angewendet. Weiterhin werden das C 1 -stetige Galerkin-Petrov-Verfahren und das C 0 -stetige Galerkin- Verfahren vorgestellt. Deren Lösungen lassen sich auch in zeitabhängigen Gebieten durch ein einfaches einheitliches Postprocessing aus der Lösung des cGP-Problems bzw. dG-Problems erhalten. Für Problemstellungen in festen Gebieten und mit zeitlich konstanten Konvektions- und Reaktionstermen werden Stabilitätsresultate sowie optimale Fehlerabschätzungen für die nachbereiteten Lösungen der cGP-Verfahren und der dG-Verfahren angegeben. Für zeitabhängige Konvektions-Diffusions-Reaktions-Gleichungen in zeitabhängigen Gebieten präsentieren wir konservative und nicht-konservative Formulierungen, wobei eine besondere Aufmerksamkeit der Behandlung der Zeitableitung und der Gittergeschwindigkeit gilt. Stabilität und optimale Fehlerschätzungen für die in der Zeit semi-diskretisierten konservativen und nicht-konservativen Formulierungen werden vorgestellt. Abschließend wird das volldiskretisierte Problem betrachtet, wobei eine Finite-Elemente-Methode zur Ortsdiskretisierung der Konvektions-Diffusions-Reaktions-Gleichungen in zeitabhängigen Gebieten im ALE-Rahmen einbezogen wurde. Darüber hinaus wird eine lokale Projektionsstabilisierung (LPS) eingesetzt, um der Konvektionsdominanz Rechnung zu tragen. Weiterhin wird numerisch untersucht, wie sich die Approximation der Gebietsgeschwindigkeit auf die Genauigkeit der Zeitdiskretisierungsverfahren auswirkt.

Convection-diffusion in MHD: Comparison of primitive variable and vector potential solutions of the magnetic induction equation

Abstract not available

Kinetics and coverage dependent reaction mechanisms of the copper atomic layer deposition from copper dimethylamino-2-propoxide and diethylzinc

Atomic layer deposition (ALD) has been recognized as a promising method to deposit conformal and uniform thin film of copper for future electronic devices. However, many aspects of the reaction mechanism and the surface chemistry of copper ALD remain unclear. In this paper, we employ plane wave density functional theory (DFT) to study the transmetalation ALD reaction of copper dimethylamino-2-propoxide [Cu(dmap)2] and diethylzinc [Et2Zn] that was realized experimentally by Lee et al. [ Angew. Chem., Int. Ed. 2009, 48, 4536−4539]. We find that the Cu(dmap)2 molecule adsorbs and dissociates through the scission of one or two Cu–O bonds into surface-bound dmap and Cu(dmap) fragments during the copper pulse. As Et2Zn adsorbs on the surface covered with Cu(dmap) and dmap fragments, butane formation and desorption was found to be facilitated by the surrounding ligands, which leads to one reaction mechanism, while the migration of ethyl groups to the surface leads to another reaction mechanism. During both reaction mechanisms, ligand diffusion and reordering are generally endothermic processes, which may result in residual ligands blocking the surface sites at the end of the Et2Zn pulse, and in residual Zn being reduced and incorporated as an impurity. We also find that the nearby ligands play a cooperative role in lowering the activation energy for formation and desorption of byproducts, which explains the advantage of using organometallic precursors and reducing agents in Cu ALD. The ALD growth rate estimated for the mechanism is consistent with the experimental value of 0.2 Å/cycle. The proposed reaction mechanisms provide insight into ALD processes for copper and other transition metals.

Understanding the Reaction Mechanism of Nanocomposite Thermites

Nanocomposite energetics are a relatively new class of materials that combine nanoscale fuels and oxidizers to allow for the rapid release of large amounts of energy. In thermite systems (metal fuel with metal oxide oxidizer), the use of nanomaterials has been illustrated to increase reactivity by multiple orders of magnitude as a result of the higher specific surface area and smaller diffusion length scales. However, the highly dynamic and nanoscale processes intrinsic to these materials, as well as heating rate dependencies, have limited our understanding of the underlying processes that control reaction and propagation. For my dissertation, I have employed a variety of experimental approaches that have allowed me to probe these processes at heating rates representative of free combustion with the goal of understanding the fundamental mechanisms. Dynamic transmission electron microscopy (DTEM) was used to study the in situ morphological change that occurs in nanocomposite thermite materials subjected to rapid (10^11 K/s) heating. Aluminum nanoparticle (Al-NP) aggregates were found to lose their nanostructure through coalescence in as little as 10 ns, which is much faster than any other timescale of combustion. Further study of nanoscale reaction with CuO determined that a condensed phase interfacial reaction could occur within 0.5-5 µs in a manner consistent with bulk reaction, which supports that this mechanism plays a dominant role in the overall reaction process. Ta nanocomposites were also studied to determine if a high melting point (3280 K) affects the loss of nanostructure and rate of reaction. The condensed phase reaction pathway was further explored using reactive multilayers sputter deposited onto thin Pt wires to allow for temperature jump (T-Jump) heating at rates of ~5x10^5 K/s. High speed video and a time of flight mass spectrometry (TOFMS) were used to observe ignition temperature and speciation as a function of bilayer thickness. The ignition process was modeled and a low activation energy for effective diffusivity was determined. T-Jump TOFMS along with constant volume combustion cell studies were also used to determine the effect of gas release in nanoparticle systems by comparing the reaction properties of CuO and Cu2O.

Development of computer application for determination of chemical diffusion properties in biological tissues

The main objective of this work was to develop an application capable of determining the diffusion times and diffusion coefficients of optical clearing agents and water inside a known type of muscle. Different types of chemical agents can also be used with the method implemented, such as medications or metabolic products. Since the diffusion times can be calculated, it is possible to describe the dehydration mechanism that occurs in the muscle. The calculation of the diffusion time of an optical clearing agent allows to characterize the refractive index matching mechanism of optical clearing. By using both the diffusion times and diffusion of water and clearing agents not only the optical clearing mechanisms are characterized, but also information about optical clearing effect duration and magnitude is obtained. Such information is crucial to plan a clinical intervention in cooperation with optical clearing. The experimental method and equations implemented in the developed application are described in throughout this document, demonstrating its effectiveness. The application was developed in MATLAB code, but the method was personalized so it better fits the application needs. This process significantly improved the processing efficiency, reduced the time to obtain he results, multiple validations prevents common errors and some extra functionalities were added such as saving application progress or export information in different formats. Tests were made using glucose measurements in muscle. Some of the data, for testing purposes, was also intentionally changed in order to obtain different simulations and results from the application. The entire project was validated by comparing the calculated results with the ones found in literature, which are also described in this document.

Adaptive coatings based on polyaniline for direct 2D observation of diffusion processes in microfluidic systems

[EN] Therefore the understanding and proper evaluation of the flow and mixing behaviour at microscale becomes a very important issue. In this study, the diffusion behaviour of two reacting solutions of HCI and NaOH were directly observed in a glass/polydimethylsiloxane microfluidic device using adaptive coatings based on the conductive polymer polyaniline that are covalently attached to the microchannel walls. The two liquid streams were combined at the junction of a Y-shaped microchannel, and allowed to diffuse into each other and react. The results showed excellent correlation between optical observation of the diffusion process and the numerical results. A numerical model which is based on finite volume method (FVM) discretisation of steady Navier-Stokes (fluid flow) equations and mass transport equations without reactions was used to calculate the flow variables at discrete points in the finite volume mesh element. The high correlation between theory and practical data indicates the potential of such coatings to monitor diffusion processes and mixing behaviour inside microfluidic channels in a dye free environment.

A staggered approach for the coupling of Cahn–Hilliard type diffusion and finite strain elasticity

We develop an algorithm and computational implementation for simulation of problems that combine Cahn–Hilliard type diffusion with finite strain elasticity. We have in mind applications such as the electro-chemo- mechanics of lithium ion (Li-ion) batteries. We concentrate on basic computational aspects. A staggered algorithm is pro- posed for the coupled multi-field model. For the diffusion problem, the fourth order differential equation is replaced by a system of second order equations to deal with the issue of the regularity required for the approximation spaces. Low order finite elements are used for discretization in space of the involved fields (displacement, concentration, nonlocal concentration). Three (both 2D and 3D) extensively worked numerical examples show the capabilities of our approach for the representation of (i) phase separation, (ii) the effect of concentration in deformation and stress, (iii) the effect of Electronic supplementary material The online version of this article (doi:10.1007/s00466-015-1235-1) contains supplementary material, which is available to authorized users. B P. Areias pmaa@uevora.pt 1 Department of Physics, University of Évora, Colégio Luís António Verney, Rua Romão Ramalho, 59, 7002-554 Évora, Portugal 2 ICIST, Lisbon, Portugal 3 School of Engineering, Universidad de Cuenca, Av. 12 de Abril s/n. 01-01-168, Cuenca, Ecuador 4 Institute of Structural Mechanics, Bauhaus-University Weimar, Marienstraße 15, 99423 Weimar, Germany strain in concentration, and (iv) lithiation. We analyze con- vergence with respect to spatial and time discretization and found that very good results are achievable using both a stag- gered scheme and approximated strain interpolation.

Effective Cell-Centred Time-Domain Maxwell's Equations Numerical Solvers

This research work analyses techniques for implementing a cell-centred finite-volume time-domain (ccFV-TD) computational methodology for the purpose of studying microwave heating. Various state-of-the-art spatial and temporal discretisation methods employed to solve Maxwell's equations on multidimensional structured grid networks are investigated, and the dispersive and dissipative errors inherent in those techniques examined. Both staggered and unstaggered grid approaches are considered. Upwind schemes using a Riemann solver and intensity vector splitting are studied and evaluated. Staggered and unstaggered Leapfrog and Runge-Kutta time integration methods are analysed in terms of phase and amplitude error to identify which method is the most accurate and efficient for simulating microwave heating processes. The implementation and migration of typical electromagnetic boundary conditions. from staggered in space to cell-centred approaches also is deliberated. In particular, an existing perfectly matched layer absorbing boundary methodology is adapted to formulate a new cell-centred boundary implementation for the ccFV-TD solvers. Finally for microwave heating purposes, a comparison of analytical and numerical results for standard case studies in rectangular waveguides allows the accuracy of the developed methods to be assessed.

A second order control-volume finite-element least-squares strategy for simulating diffusion in strongly anisotropic media

An unstructured mesh �nite volume discretisation method for simulating di�usion in anisotropic media in two-dimensional space is discussed. This technique is considered as an extension of the fully implicit hybrid control-volume �nite-element method and it retains the local continuity of the ux at the control volume faces. A least squares function recon- struction technique together with a new ux decomposition strategy is used to obtain an accurate ux approximation at the control volume face, ensuring that the overall accuracy of the spatial discretisation maintains second order. This paper highlights that the new technique coincides with the traditional shape function technique when the correction term is neglected and that it signi�cantly increases the accuracy of the previous linear scheme on coarse meshes when applied to media that exhibit very strong to extreme anisotropy ratios. It is concluded that the method can be used on both regular and irregular meshes, and appears independent of the mesh quality.