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Electrospinning of bioactive dex-PAA hydrogel fibers

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In this work, a novel method is developed for making nano- and micro- fibrous hydrogels capable of preventing the rejection of implanted materials. This is achieved by either (1) mimicking the native cellular environment, to exert fine control over the

In this work, a novel method is developed for making nano- and micro- fibrous hydrogels capable of preventing the rejection of implanted materials. This is achieved by either (1) mimicking the native cellular environment, to exert fine control over the cellular response or (2) acting as a protective barrier, to camouflage the foreign nature of a material and evade recognition by the immune system. Comprehensive characterization and in vitro studies described here provide a foundation for developing substrates for use in clinical applications. Hydrogel dextran and poly(acrylic acid) (PAA) fibers are formed via electrospinning, in sizes ranging from nanometers to microns in diameter. While "as-electrospun" fibers are continuous in length, sonication is used to fragment fibers into short fiber "bristles" and generate nano- and micro- fibrous surface coatings over a wide range of topographies. Dex-PAA fibrous surfaces are chemically modified, and then optimized and characterized for non-fouling and ECM-mimetic properties. The non-fouling nature of fibers is verified, and cell culture studies show differential responses dependent upon chemical, topographical and mechanical properties. Dex-PAA fibers are advantageously unique in that (1) a fine degree of control is possible over three significant parameters critical for modifying cellular response: topography, chemistry and mechanical properties, over a range emulating that of native cellular environments, (2) the innate nature of the material is non-fouling, providing an inert background for adding back specific bioactive functionality, and (3) the fibers can be applied as a surface coating or comprise the scaffold itself. This is the first reported work of dex-PAA hydrogel fibers formed via electrospinning and thermal cross-linking, and unique to this method, no toxic solvents or cross-linking agents are needed to create hydrogels or for surface attachment. This is also the first reported work of using sonication to fragment electrospun hydrogel fibers, and in which surface coatings were made via simple electrostatic interaction and dehydration. These versatile features enable fibrous surface coatings to be applied to virtually any material. Results of this research broadly impact the design of biomaterials which contact cells in the body by directing the consequent cell-material interaction.

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Date Created
2011

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Formation of biomimetic membranes on inorganic supports of different surface morphology and macroscopic geometry

Description

Biological membranes are critical to cell sustainability by selectively permeating polar molecules into the intracellular space and providing protection to the interior organelles. Biomimetic membranes (model cell membranes) are often used to fundamentally study the lipid bilayer backbone structure of

Biological membranes are critical to cell sustainability by selectively permeating polar molecules into the intracellular space and providing protection to the interior organelles. Biomimetic membranes (model cell membranes) are often used to fundamentally study the lipid bilayer backbone structure of the biological membrane. Lipid bilayer membranes are often supported using inorganic materials in an effort to improve membrane stability and for application to novel biosensing platforms. Published literature has shown that a variety of dense inorganic materials with various surface properties have been investigated for the study of biomimetic membranes. However, literature does not adequately address the effect of porous materials or supports with varying macroscopic geometries on lipid bilayer membrane behavior. The objective of this dissertation is to present a fundamental study on the synthesis of lipid bilayer membranes supported by novel inorganic supports in an effort to expand the number of available supports for biosensing technology. There are two fundamental areas covered including: (1) synthesis of lipid bilayer membranes on porous inorganic materials and (2) synthesis and characterization of cylindrically supported lipid bilayer membranes. The lipid bilayer membrane formation behavior on various porous supports was studied via direct mass adsorption using a quartz crystal microbalance. Experimental results demonstrate significantly different membrane formation behaviors on the porous inorganic supports. A lipid bilayer membrane structure was formed only on SiO2 based surfaces (dense SiO2 and silicalite, basic conditions) and gamma-alumina (acidic conditions). Vesicle monolayer adsorption was observed on gamma-alumina (basic conditions), and yttria stabilized zirconia (YSZ) of varying roughness. Parameters such as buffer pH, surface chemistry and surface roughness were found to have a significant impact on the vesicle adsorption kinetics. Experimental and modeling work was conducted to study formation and characterization of cylindrically supported lipid bilayer membranes. A novel sensing technique (long-period fiber grating refractometry) was utilized to measure the formation mechanism of lipid bilayer membranes on an optical fiber. It was found that the membrane formation kinetics on the fiber was similar to its planar SiO2 counterpart. Fluorescence measurements verified membrane transport behavior and found that characterization artifacts affected the measured transport behavior.

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Date Created
2011

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Separating and detecting Escherichia Coli in a microfluidic thannel [i.e., channel] for urinary tract infection (UTI) applications

Description

In this thesis, I present a lab-on-a-chip (LOC) that can separate and detect Escherichia Coli (E. coli) in simulated urine samples for Urinary Tract Infection (UTI) diagnosis. The LOC consists of two (concentration and sensing) chambers connected in series and

In this thesis, I present a lab-on-a-chip (LOC) that can separate and detect Escherichia Coli (E. coli) in simulated urine samples for Urinary Tract Infection (UTI) diagnosis. The LOC consists of two (concentration and sensing) chambers connected in series and an integrated impedance detector. The two-chamber approach is designed to reduce the non-specific absorption of proteins, e.g. albumin, that potentially co-exist with E. coli in urine. I directly separate E. coli K-12 from a urine cocktail in a concentration chamber containing micro-sized magnetic beads (5 µm in diameter) conjugated with anti-E. coli antibodies. The immobilized E. coli are transferred to a sensing chamber for the impedance measurement. The measurement at the concentration chamber suffers from non-specific absorption of albumin on the gold electrode, which may lead to a false positive response. By contrast, the measured impedance at the sensing chamber shows ~60 kÙ impedance change between 6.4x104 and 6.4x105 CFU/mL, covering the threshold of UTI (105 CFU/mL). The sensitivity of the LOC for detecting E. coli is characterized to be at least 3.4x104 CFU/mL. I also characterized the LOC for different age groups and white blood cell spiked samples. These preliminary data show promising potential for application in portable LOC devices for UTI detection.

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Date Created
2011

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Toxicity study in Alzheimer's disease cell model

Description

Alzheimer's disease (AD) is the most common type of dementia, affecting one in nine people age 65 and older. One of the most important neuropathological characteristics of Alzheimer's disease is the aggregation and deposition of the protein beta-amyloid. Beta-amyloid is

Alzheimer's disease (AD) is the most common type of dementia, affecting one in nine people age 65 and older. One of the most important neuropathological characteristics of Alzheimer's disease is the aggregation and deposition of the protein beta-amyloid. Beta-amyloid is produced by proteolytic processing of the Amyloid Precursor Protein (APP). Production of beta-amyloid from APP is increased when cells are subject to stress since both APP and beta-secretase are upregulated by stress. An increased beta-amyloid level promotes aggregation of beta-amyloid into toxic species which cause an increase in reactive oxygen species (ROS) and a decrease in cell viability. Therefore reducing beta-amyloid generation is a promising method to control cell damage following stress. The goal of this thesis was to test the effect of inhibiting beta-amyloid production inside stressed AD cell model. Hydrogen peroxide was used as stressing agent. Two treatments were used to inhibit beta-amyloid production, including iBSec1, an scFv designed to block beta-secretase site of APP, and DIA10D, a bispecific tandem scFv engineered to cleave alpha-secretase site of APP and block beta-secretase site of APP. iBSec1 treatment was added extracellularly while DIA10D was stably expressed inside cell using PSECTAG vector. Increase in reactive oxygen species and decrease in cell viability were observed after addition of hydrogen peroxide to AD cell model. The increase in stress induced toxicity caused by addition of hydrogen peroxide was dramatically decreased by simultaneously treating the cells with iBSec1 or DIA10D to block the increase in beta-amyloid levels resulting from the upregulation of APP and beta-secretase.

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Date Created
2014

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Fast, variable system delay correction for spiral MRI

Description

Magnetic Resonance Imaging using spiral trajectories has many advantages in speed, efficiency in data-acquistion and robustness to motion and flow related artifacts. The increase in sampling speed, however, requires high performance of the gradient system. Hardware inaccuracies from system delays

Magnetic Resonance Imaging using spiral trajectories has many advantages in speed, efficiency in data-acquistion and robustness to motion and flow related artifacts. The increase in sampling speed, however, requires high performance of the gradient system. Hardware inaccuracies from system delays and eddy currents can cause spatial and temporal distortions in the encoding gradient waveforms. This causes sampling discrepancies between the actual and the ideal k-space trajectory. Reconstruction assuming an ideal trajectory can result in shading and blurring artifacts in spiral images. Current methods to estimate such hardware errors require many modifications to the pulse sequence, phantom measurements or specialized hardware. This work presents a new method to estimate time-varying system delays for spiral-based trajectories. It requires a minor modification of a conventional stack-of-spirals sequence and analyzes data collected on three orthogonal cylinders. The method is fast, robust to off-resonance effects, requires no phantom measurements or specialized hardware and estimate variable system delays for the three gradient channels over the data-sampling period. The initial results are presented for acquired phantom and in-vivo data, which show a substantial reduction in the artifacts and improvement in the image quality.

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Date Created
2013

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Coronary artery plaque assessment with fast switched dual energy X-ray computed tomography angiography

Description

Coronary computed tomography angiography (CTA) has a high negative predictive value for ruling out coronary artery disease with non-invasive evaluation of the coronary arteries. My work has attempted to provide metrics that could increase the positive predictive value of coronary

Coronary computed tomography angiography (CTA) has a high negative predictive value for ruling out coronary artery disease with non-invasive evaluation of the coronary arteries. My work has attempted to provide metrics that could increase the positive predictive value of coronary CTA through the use of dual energy CTA imaging. After developing an algorithm for obtaining calcium scores from a CTA exam, a dual energy CTA exam was performed on patients at dose levels equivalent to levels for single energy CTA with a calcium scoring exam. Calcium Agatston scores obtained from the dual energy CTA exam were within ±11% of scores obtained with conventional calcium scoring exams. In the presence of highly attenuating coronary calcium plaques, the virtual non-calcium images obtained with dual energy CTA were able to successfully measure percent coronary stenosis within 5% of known stenosis values, which is not possible with single energy CTA images due to the presence of the calcium blooming artifact. After fabricating an anthropomorphic beating heart phantom with coronary plaques, characterization of soft plaque vulnerability to rupture or erosion was demonstrated with measurements of the distance from soft plaque to aortic ostium, percent stenosis, and percent lipid volume in soft plaque. A classification model was developed, with training data from the beating heart phantom and plaques, which utilized support vector machines to classify coronary soft plaque pixels as lipid or fibrous. Lipid versus fibrous classification with single energy CTA images exhibited a 17% error while dual energy CTA images in the classification model developed here only exhibited a 4% error. Combining the calcium blooming correction and the percent lipid volume methods developed in this work will provide physicians with metrics for increasing the positive predictive value of coronary CTA as well as expanding the use of coronary CTA to patients with highly attenuating calcium plaques.

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Date Created
2013

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Low power, high throughput continuous flow PCR instruments for environmental applications

Description

Continuous monitoring in the adequate temporal and spatial scale is necessary for a better understanding of environmental variations. But field deployments of molecular biological analysis platforms in that scale are currently hindered because of issues with power, throughput and automation.

Continuous monitoring in the adequate temporal and spatial scale is necessary for a better understanding of environmental variations. But field deployments of molecular biological analysis platforms in that scale are currently hindered because of issues with power, throughput and automation. Currently, such analysis is performed by the collection of large sample volumes from over a wide area and transporting them to laboratory testing facilities, which fail to provide any real-time information. This dissertation evaluates the systems currently utilized for in-situ field analyses and the issues hampering the successful deployment of such bioanalytial instruments for environmental applications. The design and development of high throughput, low power, and autonomous Polymerase Chain Reaction (PCR) instruments, amenable for portable field operations capable of providing quantitative results is presented here as part of this dissertation. A number of novel innovations have been reported here as part of this work in microfluidic design, PCR thermocycler design, optical design and systems integration. Emulsion microfluidics in conjunction with fluorinated oils and Teflon tubing have been used for the fluidic module that reduces cross-contamination eliminating the need for disposable components or constant cleaning. A cylindrical heater has been designed with the tubing wrapped around fixed temperature zones enabling continuous operation. Fluorescence excitation and detection have been achieved by using a light emitting diode (LED) as the excitation source and a photomultiplier tube (PMT) as the detector. Real-time quantitative PCR results were obtained by using multi-channel fluorescence excitation and detection using LED, optical fibers and a 64-channel multi-anode PMT for measuring continuous real-time fluorescence. The instrument was evaluated by comparing the results obtained with those obtained from a commercial instrument and found to be comparable. To further improve the design and enhance its field portability, this dissertation also presents a framework for the instrumentation necessary for a portable digital PCR platform to achieve higher throughputs with lower power. Both systems were designed such that it can easily couple with any upstream platform capable of providing nucleic acid for analysis using standard fluidic connections. Consequently, these instruments can be used not only in environmental applications, but portable diagnostics applications as well.

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Date Created
2013

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The effects of deep brain stimulation amplitude on motor performance in Parkinson's disease

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The efficacy of deep brain stimulation (DBS) in Parkinson's disease (PD) has been convincingly demonstrated in studies that compare motor performance with and without stimulation, but characterization of performance at intermediate stimulation amplitudes has been limited. This study investigated the

The efficacy of deep brain stimulation (DBS) in Parkinson's disease (PD) has been convincingly demonstrated in studies that compare motor performance with and without stimulation, but characterization of performance at intermediate stimulation amplitudes has been limited. This study investigated the effects of changing DBS amplitude in order to assess dose-response characteristics, inter-subject variability, consistency of effect across outcome measures, and day-to-day variability. Eight subjects with PD and bilateral DBS systems were evaluated at their clinically determined stimulation (CDS) and at three reduced amplitude conditions: approximately 70%, 30%, and 0% of the CDS (MOD, LOW, and OFF, respectively). Overall symptom severity and performance on a battery of motor tasks - gait, postural control, single-joint flexion-extension, postural tremor, and tapping - were assessed at each condition using the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III) and quantitative measures. Data were analyzed to determine whether subjects demonstrated a threshold response (one decrement in stimulation resulted in ≥ 70% of the maximum change) or a graded response to reduced stimulation. Day-to-day variability was assessed using the CDS data from the three testing sessions. Although the cohort as a whole demonstrated a graded response on several measures, there was high variability across subjects, with subsets exhibiting graded, threshold, or minimal responses. Some subjects experienced greater variability in their CDS performance across the three days than the change induced by reducing stimulation. For several tasks, a subset of subjects exhibited improved performance at one or more of the reduced conditions. Reducing stimulation did not affect all subjects equally, nor did it uniformly affect each subject's performance across tasks. These results indicate that altered recruitment of neural structures can differentially affect motor capabilities and demonstrate the need for clinical consideration of the effects on multiple symptoms across several days when selecting DBS parameters.

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Date Created
2013

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Electrocorticographica analysis of spontaneous conversation to localize receptive and expressive language areas

Description

When surgical resection becomes necessary to alleviate a patient's epileptiform activity, that patient is monitored by video synchronized with electrocorticography (ECoG) to determine the type and location of seizure focus. This provides a unique opportunity for researchers to gather neurophysiological

When surgical resection becomes necessary to alleviate a patient's epileptiform activity, that patient is monitored by video synchronized with electrocorticography (ECoG) to determine the type and location of seizure focus. This provides a unique opportunity for researchers to gather neurophysiological data with high temporal and spatial resolution; these data are assessed prior to surgical resection to ensure the preservation of the patient's quality of life, e.g. avoid the removal of brain tissue required for speech processing. Currently considered the "gold standard" for the mapping of cortex, electrical cortical stimulation (ECS) involves the systematic activation of pairs of electrodes to localize functionally specific brain regions. This method has distinct limitations, which often includes pain experienced by the patient. Even in the best cases, the technique suffers from subjective assessments on the parts of both patients and physicians, and high inter- and intra-observer variability. Recent advances have been made as researchers have reported the localization of language areas through several signal processing methodologies, all necessitating patient participation in a controlled experiment. The development of a quantification tool to localize speech areas in which a patient is engaged in an unconstrained interpersonal conversation would eliminate the dependence of biased patient and reviewer input, as well as unnecessary discomfort to the patient. Post-hoc ECoG data were gathered from five patients with intractable epilepsy while each was engaged in a conversation with family members or clinicians. After the data were separated into different speech conditions, the power of each was compared to baseline to determine statistically significant activated electrodes. The results of several analytical methods are presented here. The algorithms did not yield language-specific areas exclusively, as broad activation of statistically significant electrodes was apparent across cortical areas. For one patient, 15 adjacent contacts along superior temporal gyrus (STG) and posterior part of the temporal lobe were determined language-significant through a controlled experiment. The task involved a patient lying in bed listening to repeated words, and yielded statistically significant activations that aligned with those of clinical evaluation. The results of this study do not support the hypothesis that unconstrained conversation may be used to localize areas required for receptive and productive speech, yet suggests a simple listening task may be an adequate alternative to direct cortical stimulation.

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Date Created
2013

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Mobile health applications of breath analysis: challenges and solutions

Description

The world of healthcare can be seen as dynamic, often an area where technology and science meet to consummate a greater good for humanity. This relationship has been working well for the last century as evident by the average life

The world of healthcare can be seen as dynamic, often an area where technology and science meet to consummate a greater good for humanity. This relationship has been working well for the last century as evident by the average life expectancy change. For the greater of the last five decades the average life expectancy at birth increased globally by almost 20 years. In the United States specifically, life expectancy has grown from 50 years in 1900 to 78 years in 2009. That is a 76% increase in just over a century. As great as this increase sounds for humanity it means there are soon to be real issues in the healthcare world. A larger older population will need more healthcare services but have fewer young professionals to provide those services. Technology and science will need to continue to push the boundaries in order to develop and provide the solutions needed to continue providing the aging world population sufficient healthcare. One solution sure to help provide a brighter future for healthcare is mobile health (m-health). M-health can help provide a means for healthcare professionals to treat more patients with less work expenditure and do so with more personalized healthcare advice which will lead to better treatments. This paper discusses one area of m-health devices specifically; human breath analysis devices. The current laboratory methods of breath analysis and why these methods are not adequate for common healthcare practices will be discussed in more detail. Then more specifically, mobile breath analysis devices are discussed. The topic will encompass the challenges that need to be met in developing such devices, possible solutions to these challenges, two real examples of mobile breath analysis devices and finally possible future directions for m-health technologies.

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Date Created
2012