Convection-Enhanced Delivery of Macromolecules to the Brain Using Electrokinetic Transport

Electrokinetic transport in brain tissue represents the movement of molecules due to an applied electric field and the interplay between the electrophoretic and electroosmotic velocities that are developed. This dissertation provides a framework for understanding electrokinetic transport and how it may be utilized for short-distance ejections, relevant to capillary iontophoresis, and long-distance infusions, for the clinical management of malignant brain tumors as a novel convection-enhanced drug delivery system.In particular, electrokinetic transport was first analyzed in a series of poly(acrylamide-co-acrylic acid) hydrogels that demonstrated varying electroosmotic velocities. Moreover, a hydrogel was synthesized to mimic the electrokinetic properties of organotypic hippocampal slice cultures (OHSC), as a surrogate for brain tissue. Short- and long-distance capillary infusions of molecules into the hydrogels and OHSC provided a framework to understand the relevant phenomena, such as the effect of varying the capillary tip size, applied electrical current, ζ-potential of the capillary or the outside matrix, infusion time, tortuosity, and properties of the solute (including molecular weight and electrophoretic mobility). Control of the directional transport of molecules was also demonstrated over a distance of several hundred micrometers to millimeters. Finally, electrokinetic infusions were conducted in vivo in the adult rat brain, with results compared to those of pressure-driven infusions.The experiments and results described in this dissertation provide a foundation for further development, by presenting a methodical means to increase the ejection profile and attain clinically relevant penetration distances while minimizing adverse effects to the brain tissue, including from the electric field itself. The rate of electrokinetic transport is greater than the rate of diffusion, and therefore it represents a novel form of convection-enhanced drug delivery system

Doctor of Philosophy

dissertationMonitoring and remediation of environmental contaminants (biological and chemical) form the crux of global water resource management. There is an extant need to develop point-of-use, low-power, low-cost tools that can address this problem effectively with min­ imal environmental impact. Nanotechnology and microfluidics have made enormous ad­ vances during the past decade in the area of biosensing and environmental remediation. The "marriage" of these two technologies can effectively address some of the above-mentioned needs [1]. In this dissertation, nanomaterials were used in conjunction with microfluidic techniques to detect and degrade biological and chemical pollutants. In the first project, a point-of-use sensor was developed for detection of trichloroethylene (TCE) from water. A self-organizing nanotubular titanium dioxide (TNA) synthesized by electrochemical anodization and functionalized with photocatalytically deposited platinum (Pt/TNA) was applied to the detection. The morphology and crystallinity of the Pt/TNA sensor was characterized using field emission scanning electron microscope, energy dis­ persive x-ray spectroscopy, and X-ray diffraction. The sensor could detect TCE in the concentrations ranging from 10 to 1000 ppm. The room-temperature operation capability of the sensor makes it less power intensive and can potentially be incorporated into a field-based sensor. In the second part, TNA synthesized on a foil was incorporated into a flow-based microfluidic format and applied to degradation of a model pollutant, methylene blue. The system was demonstrated to have enhanced photocatalytic performance at higher flow rates (50-200 ^L/min) over the same microfluidic format with TiO2 nanoparticulate (commercial P25) catalyst. The microfluidic format with TNA catalyst was able to achieve 82% fractional conversion of 18 mM methylene blue in comparison to 55% in the case of the TiO2 nanoparticulate layer at a flow rate of 200 L/min. The microfluidic device was fabricated using non-cleanroom-based methods, making it suitable for economical large-scale manufacture. A computational model of the microfluidic format was developed in COMSOL Multiphysics® finite element software to evaluate the effect of diffusion coefficient and rate constant on the photocatalytic performance. To further enhance the photocatalytic performance of the microfluidic device, TNA synthesized on a mesh was used as the catalyst. The new system was shown to have enhanced photocatalytic performance in comparison to TNA on a foil. The device was then employed in the inactivation of E. coli O157:H7 at different flow rates and light intensities (100, 50, 20, 10 mW/cm2). In the second project, a protocol for ultra-sensitive indirect electrochemical detection of E. coli O157:H7 was reported. The protocol uses antibody functionalized primary (magnetic) beads for capture and polyguanine (polyG) oligonucleotide functionalized sec­ ondary (polystyrene) beads as an electrochemical tag. The method was able to detect concentrations of E. coli O157:H7 down to 3 CFU/100 mL (S/N=3). We also demonstrate the use of the protocol for detection of E. coli O157:H7 seeded in wastewater effluent samples

Microfluidics and Nanofluidics Handbook

The Microfluidics and Nanofluidics Handbook: Two-Volume Set comprehensively captures the cross-disciplinary breadth of the fields of micro- and nanofluidics, which encompass the biological sciences, chemistry, physics and engineering applications. To fill the knowledge gap between engineering and the basic sciences, the editors pulled together key individuals, well known in their respective areas, to author chapters that help graduate students, scientists, and practicing engineers understand the overall area of microfluidics and nanofluidics. Topics covered include Finite Volume Method for Numerical Simulation Lattice Boltzmann Method and Its Applications in Microfluidics Microparticle and Nanoparticle Manipulation Methane Solubility Enhancement in Water Confined to Nanoscale Pores Volume Two: Fabrication, Implementation, and Applications focuses on topics related to experimental and numerical methods. It also covers fabrication and applications in a variety of areas, from aerospace to biological systems. Reflecting the inherent nature of microfluidics and nanofluidics, the book includes as much interdisciplinary knowledge as possible. It provides the fundamental science background for newcomers and advanced techniques and concepts for experienced researchers and professionals

Transport processes and instabilities induced by electric fields acting on fluidic interfaces

Electrohydrodynamics (EHD) describes the area of research, which studies the interactions of fluid motion and electric fields. In liquids with non-negligible conductivity, charged regions are confined to thin layers closest to boundaries, where EHD effects are most pronounced. In the present work, different phenomena that involve the actuation of fluidic interfaces by electric fields are studied. Electro-osmosis describes the fluid flow due to electric fields acting on charged regions close to the interface of a fluidic domain. When a liquid is deposited above a microstructured superhydrophobic surface, additional charges can be brought to the enclosed gas-liquid interface by placing a gate electrode below the surface. In this work, the production of a superhydrophobic surface with both micro- and nano-scales is described. In addition to inducing charges, a gate electrode exerts a force on the gas-liquid interface, pulling it in between the structures. Experimentally, the wetting state stability is characterized using reflection microscopy, revealing a continuous range of wetting states at dual-scale surfaces. By using non-constant electro-osmotic flow, complex height-averaged flow fields can be induced in a Hele-Shaw cell, which is characterized by a small distance between the parallel bounding walls compared to a characteristic lateral length scale. The governing equations for of the flow field are derived, accounting both for stationary and oscillatory electric fields. The electro-osmotic flow field is characterized above a single disc-shaped gate electrode in a microfluidic channel, using particle tracking velocimetry. In addition, using proof-of-principle experiments, the ability to create complex flow patterns is demonstrated. In order to use flow shaping in biochemical applications, a height-averaged transport model for a passive species is derived using a perturbation method, accounting for advection, diffusion and sample dispersion. The effects of sample dispersion are represented by a non-isotropic dispersion tensor. The reduced-order model shows good agreement to three-dimensional simulations, and potential applications are discussed. Electric fields lead to forces on fluidic interfaces, and in this work, two different EHD instabilities at an interface between a dielectric and a conducting liquid are investigated. Upon application of a spatially homogeneous, harmonically oscillating electric field, a resonant response of the interface can be observed above a critical amplitude. An experimental setup with a circular domain is used to observe the spatial structure of the instability, which is extracted from light-refraction at the liquid-liquid interface. The resulting dominant wavelengths and instability modes show good agreement to an analytical model. Furthermore, the role of the domain boundary is investigated. Upon applying a spatially inhomogeneous, but time-constant electric field, the interface exhibits EHD tip streaming above a critical voltage, emitting droplets into the dielectric phase. The presence of conducting droplets alters the spatial structure from a Taylor cone located centric below the pin electrode to a surface depression, where the interface moves away from the electrode and cones emerge from the rim. By experimentally characterizing a submerged electrospray and using additional numerical modeling, it is shown that the droplets induce a flow in the dielectric liquid, which is responsible for the change of the spatial structure of the instability

Electrohydrodynamic focusing and light propagation in 2-dimensional microfluidic devices for preconcentration of low abundance bioanalytes

This thesis presents work on electrohydrodynamic focusing (EHDF) and photon transmission to aid the development of species preconcentration and identification. EHDF is an equilibrium focusing method, where a target ion becomes stationary under the influence of a hydrodynamic force opposed by an electromigration force. To achieve this one force must have a non-zero gradient. In this research a novel approach of using a 2-dimensional planar microfluidic device is presented with an open 2D-plane space instead of conventional microchannel system. Such devices can allow pre-concentration of large volume of species and are relatively simple to fabricate. Fluid flow in these systems is often very complex making computer modelling a very useful tool. In this research, results of newly developed simulations using COMSOL Multiphysics® 3.5a are presented. Results from these models were compared to experimental results to validate the determined flow geometries and regions of increased concentration. The developed numerical microfluidic models were compared with previously published experiments and presented high correspondence of the results. Based on these simulations a novel chip shapes were investigated to provide optimal conditions for EHDF. The experimental results using fabricated chip exceeded performance of the model. A novel mode, named lateral EHDF, when test substance was focused perpendicularly to the applied voltage was observed in the fabricated microfluidic chip. As detection and visualisation is a critical aspect of such species preconcentration and identification systems. Numerical models and experimental validation of light propagation and light intensity distribution in 2D microfluidic systems was examined. The developed numerical mode of light propagation was used to calculate the actual light path through the system and the light intensity distribution. The model was successfully verified experimentally in both aspects, giving results that are interesting for the optimisation of photopolymerisation as well as for the optical detection systems employing capillaries

Heat Transfer

Over the past few decades there has been a prolific increase in research and development in area of heat transfer, heat exchangers and their associated technologies. This book is a collection of current research in the above mentioned areas and describes modelling, numerical methods, simulation and information technology with modern ideas and methods to analyse and enhance heat transfer for single and multiphase systems. The topics considered include various basic concepts of heat transfer, the fundamental modes of heat transfer (namely conduction, convection and radiation), thermophysical properties, computational methodologies, control, stabilization and optimization problems, condensation, boiling and freezing, with many real-world problems and important modern applications. The book is divided in four sections : "Inverse, Stabilization and Optimization Problems", "Numerical Methods and Calculations", "Heat Transfer in Mini/Micro Systems", "Energy Transfer and Solid Materials", and each section discusses various issues, methods and applications in accordance with the subjects. The combination of fundamental approach with many important practical applications of current interest will make this book of interest to researchers, scientists, engineers and graduate students in many disciplines, who make use of mathematical modelling, inverse problems, implementation of recently developed numerical methods in this multidisciplinary field as well as to experimental and theoretical researchers in the field of heat and mass transfer

Lattice Boltzmann methods for multiphase flow and phase-change heat transfer

Over the past few decades, tremendous progress has been made in the development of particle-based discrete simulation methods versus the conventional continuum-based methods. In particular, the lattice Boltzmann (LB) method has evolved from a theoretical novelty to a ubiquitous, versatile and powerful computational methodology for both fundamental research and engineering applications. It is a kinetic-based mesoscopic approach that bridges the microscales and macroscales, which offers distinctive advantages in simulation fidelity and computational efficiency. Applications of the LB method are now found in a wide range of disciplines including physics, chemistry, materials, biomedicine and various branches of engineering. The present work provides a comprehensive review of the LB method for thermofluids and energy applications, focusing on multiphase flows, thermal flows and thermal multiphase flows with phase change. The review first covers the theoretical framework of the LB method, revealing certain inconsistencies and defects as well as common features of multiphase and thermal LB models. Recent developments in improving the thermodynamic and hydrodynamic consistency, reducing spurious currents, enhancing the numerical stability, etc., are highlighted. These efforts have put the LB method on a firmer theoretical foundation with enhanced LB models that can achieve larger liquid-gas density ratio, higher Reynolds number and flexible surface tension. Examples of applications are provided in fuel cells and batteries, droplet collision, boiling heat transfer and evaporation, and energy storage. Finally, further developments and future prospect of the LB method are outlined for thermofluids and energy applications

A model for sample stacking in microcapillary DNA electrophoresis

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2002.Includes bibliographical references (leaves 129-135).Sanger's method of chain termination is the method of choice in DNA sequencing, where electrophoresis is used to separate the different sized DNA. In the past decade, microfabricated capillary devices have been developed and are increasingly used to perform DNA electrophoresis. While tremendous progress has been made in the process, sample injection has not been well understood. In an earlier study, images of sample injection obtained using video microscopy showed sharp sample stacking peak at the trailing edge of the sample plug. This thesis examines the underlying physics that explain the behavior of DNA in microcapillary electrophoresis. A developed model captures the dynamics of the major electrolytes in the system. The applied voltage and the conductivity profile determine the local electric field. The electric field drives the analyte transport. The analyte consists of DNA molecules of various fragment sizes. Since the DNA concentration is smaller than the electrolyte concentration by a few orders of magnitude, its concentration does not affect the conductivity. The major components of the sample are identified, and role during injection is investigated. Analytical studies of the electrolyte boundary dynamics and evolution and the transport of DNA are presented. The effect of the buffer, applied voltage during injection, and sample mobility on stacking are shown.(cont.) A numerical model is implemented to quantitatively predict the stacking of DNA in microcapillary electrophoresis. The numerical model has been developed for the 1-dimensional case. The model is verified using analytical results. Results of numerical models that predict the behavior of DNA under experimental conditions are presented. The numerical model is compared with real experimental data to evaluate its predictive power. Preliminary numerical simulations have also been done for 2-dimensional geometries. A procedure has been developed for design of injector lengths to obtain a given resolution of separation in a microcapillary channel of specified length. Strategies for optimization are presented for improving the performance of the devices.by Alok Srivastava.Ph.D

Análise e desenvolvimento de modelo de transporte de massa visando a aplicação em células a combustível tipo PEM

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Mecânica, Florianópolis, 2012O atual cenário mundial na área de energia demanda o desenvolvimento tecnológico de alternativas sustentáveis, e de menor impacto ambiental. O uso eficiente de fontes de energia renováveis para a produção de energia elétrica em sistemas descentralizados e isolados, bem como para o setor de mobilidade, destaca-se como um ingrediente capaz de mitigar a agressão ambiental dos sistemas de energia. A célula a combustível é um dispositivo eletroquímico que converte diretamente a energia interna de ligação química de combustíveis em energia elétrica e calor com alta eficiência global, ausência de ruído e emissões. O elevado custo de desenvolvimento destes sistemas sugere que estratégias que combinem medições e previsões teóricas apresentem a maior chance de atingir os desenvolvimentos necessários. O principal objetivo da presente tese é desenvolver uma teoria para o transporte de massa em uma célula a combustível tipo PEM a partir de uma análise fenomenológica com base nos fundamentos do transporte de massa multicomponente, multifásico em meios porosos. O modelo tem por objetivo prever o comportamento do transporte elétrico e de massa com uma formulação adequada. Para este fim, foram revisadas as escalas de comprimento característicos dos diferentes componentes e fenómenos dentro da célula a combustível visando determinar as relações entre os processos termodinâmicos, eléctricos e eletroquímicos em uma célula de combustível tipo PEM. Foi revisada a grande quantidade de informações sobre teoria, modelagem e simulação da célula a combustível tipo PEM, a fim de classificar os diferentes modelos, ressaltar sua aplicabilidade e definir as necessidades de melhoria. A curva de polarização de um sistema de célula de combustível foi medida com o objetivo de identificar os fenómenos que controlam o transporte e a fenomenologia química, avaliar a aplicabilidade dos modelos globais disponíveis e determinar a ordem de grandeza dos parâmetros característicos globais da operação da célula de combustível. Então, foram revisadas as teorias fundamentais de transporte de massa e carga em duas fases, em fluxo multicomponente em meios porosos, focando na base do continuo e da termodinâmica para o tratamento de Maxwell-Stefan do transporte de massa. Finalmente, foi proposto um modelo fenomenológico geral para transferência de massa e carga aplicável às células a combustível tipo PEM. O modelo foi comparado com outros modelos da literatura e alguns problemas mais simples fundamentais foram resolvidos.Abstract : The present world energy scenario requires the development of alternative and sustainable energy sources and conversion systems that also result in an overall smaller impact in the environment. The efficient use of renewable energy sources for the production of electrical power in decentralized and isolated systems, as well as for the mobility sector, stands out as a possible ingredient to mitigate the environmental aggression from energy systems. Fuel cells are electrochemical devices that convert internal energy of chemical bond in electricity and heat power in an efficient, noiseless and lower emissions form. The relative high cost of system development suggests that a combined measurement, theoretical and simulation effort is the way to achieve the required breakthroughs. The main objective of the present thesis is to develop a theory for mass transport in a PEM fuel cell from a phenomenological analysis based on the fundamentals of the multicomponent, multiphase mass transport in porous media. The model aims at predicting the electric and mass transport behaviors with a formulation suitable for solution with current computational resources. To this end, the characteristic length scales of the different components and phenomena within the fuel cell were revised aiming at determining the relations between thermodynamic, electric and electrochemical processes in a PEM fuel cell. The vast amount of information on PEM fuel cell theory, modeling and simulation was reviewed with a view to classify the different models, point out their applicability and define the needs for further improvements. The polarization curve for a fuel cell system was measured with the purpose of identifying the controlling transport and chemical phenomena, assess the applicability of the available lumped models and to determine the orders of magnitude of global parameters characteristic of the fuel cell operation. Then, the fundamental theories of mass and charge transport in two-phase, multicomponent flow in porous media were reviewed, focusing on the continuum and thermodynamic basis for the Maxwell-Stefan treatment of mass transport. Finally, a general phenomenological model for mass and charge transfer applicable to PEM fuel cells was proposed, compared to other models from the literature and a few simpler fundamental problems were solved