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Quality control for translational biomedical informatics

2009-07-02 , Moffitt, Richard Austin

Translational biomedical informatics is the application of computational methods to facilitate the translation of basic biomedical science to clinical relevance. An example of this is the multi-step process in which large-scale microarray-based discovery experiments are refined into reliable clinical tests. Unfortunately, the quality of microarray data is a major issue that must be addressed before microarrays can reach their full potential as a clinical molecular profiling tool for personalized and predictive medicine. A new methodology, titled caCORRECT, has been developed to replace or augment existing microarray processing technologies, in order to improve the translation of microarray data to clinical relevance. Results of validation studies show that caCORRECT is able to improve the mean accuracy of microarray gene expression by as much as 60%, depending on the magnitude and size of artifacts on the array surface. As part of a case study to demonstrate the widespread usefulness of caCORRECT, the entire pipeline of biomarker discovery has been executed for the clinical problem of classifying Renal Cell Carcinoma (RCC) specimens into appropriate subtypes. As a result, we have discovered and validated a novel two-gene RT-PCR assay, which has the ability to diagnose between the Clear Cell and Oncocytoma RCC subtypes with near perfect accuracy. As an extension to this work, progress has been made towards a quantitative quantum dot immunohistochemical assay, which is expected to be more clinically viable than a PCR-based test.

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Development of a small animal model to study tissue engineering strategies for growth plate defects

2007-07-10 , Coleman, Rhima M.

The growth plate is a cartilaginous tissue responsible for the longitudinal growth of long bones. It is a complex tissue composed of chondrocytes whose maturation and proliferation is tightly regulated by a biochemical feedback loop. Injury to this tissue can result in a limb length discrepancy or angular deformity that may lead to life long disability. Given the recent rise in the number of growth plate injuries and the variability in success of current therapies, there is a significant need for a greater understanding of growth plate injury pathology and the development of improved treatment strategies. Cartilage tissue engineering strategies offer an attractive alternative to regenerating growth plate tissue and restoring growth function. Bone marrow-derived stem cells (BMSCs) have been shown to be able to undergo chondrogenic differentiation and in vitro and in vivo and therefore offers an appealing and abundant cell resource for developing tissue engineering strategies for the treatment of growth plate defects. However, the dependence of chondrogenic differentiation and matrix accumulation on monolayer expansion protocols and three-dimensional (3D) culture environment has received little attention. Prior to developing treatment strategies for growth plate injury repair, it is essential to first understand the interconnection between alterations in growth plate morphology and subsequent limb deformities. To that end, we have established a surgical defect model of growth plate injury in Sprague Dawley rats and developed a novel technique to quantitatively monitor growth plate morphology in health and disease using microcomputed tomography (micro-CT) imaging. In an effort to develop a tissue engineering treatment strategy for growth plate injury, the role of monolayer expansion, 3D scaffold, and growth factor regimen in the chondrogenic differentiation of rat BMSCs was also examined. This research study has demonstrated the utility of micro-CT as a non-invasive imaging modality for assessing growth plate injury and repair. This work has also provided an improved understanding of the interrelationship of monolayer expansion, 3D culture environment, and growth factor regimen in BMSC chondrogenic differentiation. Finally, this work suggests that an injectable in situ gelling hydrogel is a feasible method for decreasing limb length discrepancies, however, neither implantation of agarose alone into the defect nor the inclusion of BMSCs fully corrects growth disruption.

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Techniques for FPGA neural modeling

2006-11-21 , Weinstein, Randall Kenneth

Neural simulations and general dynamical system modeling consistently push the limits of available computational horsepower. This is occurring for a number of reasons: 1) models are progressing in complexity as our biological understanding increases, 2) high-level analysis tools including parameter searches and sensitivity analyses are becoming more prevalent, and 3) computational models are increasingly utilized alongside with biological preparations in a dynamic clamp configuration. General-purpose computers, as the primary target for modeling problems, are the simplest platform to implement models due to the rich variety of available tools. However, computers, limited by their generality, perform sub-optimally relative to custom hardware solutions. The goal of this thesis is to develop a new cost-effective and easy-to-use platform delivering orders of magnitude improvement in throughput over personal computers. We suggest that FPGAs, or field programmable gate arrays, provide an outlet for dramatically enhanced performance. FPGAs are high-speed, reconfigurable devices that can implement any digital logic operation using an array of parallel computing elements. Already common in fields such as signal processing, radar, medical imaging, and consumer electronics, FPGAs have yet to gain traction in neural modeling due to their steep learning curve and lack of sufficient tools despite their high-performance capability. The overall objective of this work has been to overcome the shortfalls of FPGAs to enable adoption of FPGAs within the neural modeling community. We embarked on an incremental process to develop an FPGA-based modeling environment. We first developed a prototype multi-compartment motoneuron model using a standard digital-design methodology. FPGAs at this point were shown to exceed software simulations by 10x to 100x. Next, we developed canonical modeling methodologies for manual generation of typical neural model topologies. We then developed a series of tools and techniques for analog interfacing, digital protocol processing, and real-time model tuning. This thesis culminates with the development of Dynamo, a fully-automated model compiler for the direct conversion of a model description into an FPGA implementation.

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Mechanoregulation of chondrocytes and chondroprogenitors: the role of TGF-BETA and SMAD signaling

2005-11-28 , Mouw, Janna Kay

In pathological states such as osteoarthritis, the complex metabolic balance of cartilage is disrupted, leading to a loss in the integrity and biomechanical function of cartilage. Osteoarthritis affects more than 20 million Americans, costing the United States economy over $60 billion yearly. Risk factors for osteoarthritis include age, excessive joint loading, and joint injury. Tissue engineering offers a potential solution for the replacement of diseased and/or damaged cartilage. Unfortunately, plentiful donor cell populations are difficult to assemble, as chondrocytes have a well characterized lack of expansion potential. Mesenchymal progenitor cells offer an alternative with a high expansion potential capable of supplying large quantities of cells. Using an immature bovine model, the chondrogenic differentiation of articular chondrocytes and bone marrow stromal cells was found to be scaffold, media and mechanical stimulation dependent. TGF-beta signaling participated in the response of articular chondrocytes to dynamic compressive loading, as well as enhanced the chondrogenesis of bovine BMSCs, through interactions between loading and TGF-beta/Smad signaling. Also, dynamic loading altered gene expression, matrix synthesis rates and intracellular phosphorylation for bovine BMSCs. However the response of the cells to dynamic loading depends on both media supplementation and the duration of unloaded culture. These studies establish signaling through the TGF-beta pathway as a mechanotransduction pathway for chondrocytes and chondroprogenitors in 3D culture.

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Development of a visualization and information management platform in translational biomedical informatics

2009-04-06 , Stokes, Todd Hamilton

Translational Biomedical Informatics (TBMI) is an emerging discipline expanding beyond traditional bioinformatics, with a focus on developing computational technologies for real-world biomedical practice. The goal of my Ph.D. research is to address a few key challenges in TBI, including: (1) the high quality and reproducibility required by medical applications when processing high throughput data, (2) the need for knowledge management solutions that allow molecular data to be handled and evaluated by researchers, regulators, and doctors collectively, (3) the need for near real-time, efficient access to decision-oriented visualizations of integrated data and data processing results, and (4) the need for an integrated solution that can evolve as medical consensus evolves, without requiring retraining, overhaul or replacement. This dissertation resulted in the development and adoption of concrete web-based application deliverables in regular use by bioinformaticians, clinicians, biologists and nanotechnologists. These include: the Chip Artifact Correction (caCORRECT) web site and grid services, the ArrayWiki community microarray repository, and the SimpleVisGrid visualization grid services (including eGOMiner, nanoDRIVE, PathwayVis and SphingoVisGrid).

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Coated microneedles and microdermabrasion for transdermal delivery

2007-07-09 , Gill, Harvinder Singh

The major hurdle in the development of transdermal route as a versatile drug delivery method is the formidable transport barrier provided by the stratum corneum. Despite decades of research to overcome the stratum corneum barrier, limited success has been achieved. The objectives of this research were to develop and characterize two different strategies to overcome the stratum corneum barrier for transdermal delivery of biopharmaceuticals and vaccines. In the first strategy, coated microneedles (sharp-tipped, micron-sized structures) were developed to enable delivery of drugs directly into the skin by bypassing the stratum corneum barrier. In the second strategy, instead of bypassing the barrier, microdermabrasion was used to selectively abrade stratum corneum with sharp microparticles for topical drug application. Coated microneedles For developing painless microneedles, the first detailed study was performed to characterize the effect of microneedle geometry on pain caused by microneedle insertions in human volunteers. This study demonstrated that microneedles are significantly less painful than a 26-gage hypodermic needle and that decreasing microneedle length and numbers reduces pain. Next, the first in-depth study of microneedle coating methods and formulations was performed to (i) develop a novel micron-scale dip-coating process, (ii) test the breadth of compounds that can be coated onto microneedles, and (iii) develop a rational basis to design novel coating formulations based on the physics of dip-coating. Finally, a plasmid DNA-vaccine was coated onto microneedles to immunize mice, to provide the first evidence that microneedle-based skin immunization can generate a robust in vivo antigen-specific cytotoxic-T-lymphocyte response using similar, or lower, DNA doses on microneedles as when using the gene gun or intramuscular injection. Microdermabrasion We demonstrated for the first time that microdermabrasion in monkeys and humans can selectively, yet completely remove the stratum corneum layer. Using a mobile mode of microdermabrasion, an increase in the number of treatment passes led to greater tissue removal. Furthermore, topical application of Modified Vaccinia Ankara virus after microdermabrasion induced virus-specific antibodies in monkeys. In conclusion, both coated microneedles and microdermabrasion were developed to enable delivery of biomolecules into the skin, indicating their potential for transdermal delivery of a wide range of biopharmaceuticals and vaccines.

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FAK Modulates Cell Adhesion Strengthening Via Two Distinct Mechanisms: Integrin Binding and Vinculin Localization

2006-11-16 , Michael, Kristin E.

Cell adhesion to the extracellular matrix (ECM) provides tissue structure and integrity as well as triggers signals that regulate complex biological processes such as cell cycle progression and tissue-specific cell differentiation. Hence, cell adhesion is critical to numerous physiological and pathological processes, including embryonic development, cancer metastasis, and wound healing, as well as biotechnological applications, such as host responses to implanted devices and integration of tissue-engineered constructs. During the adhesion process, integrin surface receptors bind ECM proteins, cluster, and associate with the actin cytoskeleton. Subsequent strengthening of the integrin/actin cytoskeleton interaction occurs via complexes of proteins known as focal adhesions. Due to the close association between biochemical and biophysical processes within adhesion complexes, mechanical analyses can provide important new insights into structure/function relationships involved in regulating the adhesion process. The objective of this project was to investigate the role of the protein tyrosine kinase FAK in cell adhesion strengthening. Our central hypothesis was that FAK regulates adhesion strengthening by modulating interactions between integrins and FA structural components. Using a novel combination of genetically engineered cells to control the interactions of FAK, a spinning disk adhesion assay with micropatterned substrates to obtain reproducible and sensitive measurements of adhesion strength, and quantitative biochemical assays for analyzing changes in adhesive complexes, we demonstrate that FAK modulates adhesion strengthening via two distinct mechanisms: (1) FAK expression results in elevated integrin activation leading to regulation of strengthening rate and (2) FAK regulates steady-state adhesion strength via vinculin recruitment to focal adhesions. We also show that the autophosphorylation and catalytic sites of FAK are critical to this regulation of adhesion strengthening. This work is significant because it both identifies functional mechanisms of FAK and provides the first evidence that focal adhesion signaling regulates the adhesion strengthening process. Furthermore, this research demonstrates that the dependency of migration on adhesion strength is highly complex and establishes a need for adhesion strengthening metrics in analyzing the functional mechanisms of molecules within adhesion complexes.

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Microstimulation and multicellular analysis: A neural interfacing system for spatiotemporal stimulation

2008-05-19 , Ross, James

Willfully controlling the focus of an extracellular stimulus remains a significant challenge in the development of neural prosthetics and therapeutic devices. In part, this challenge is due to the vast set of complex interactions between the electric fields induced by the microelectrodes and the complex morphologies and dynamics of the neural tissue. Overcoming such issues to produce methodologies for targeted neural stimulation requires a system that is capable of (1) delivering precise, localized stimuli a function of the stimulating electrodes and (2) recording the locations and magnitudes of the resulting evoked responses a function of the cell geometry and membrane dynamics. In order to improve stimulus delivery, we developed microfabrication technologies that could specify the electrode geometry and electrical properties. Specifically, we developed a closed-loop electroplating strategy to monitor and control the morphology of surface coatings during deposition, and we implemented pulse-plating techniques as a means to produce robust, resilient microelectrodes that could withstand rigorous handling and harsh environments. In order to evaluate the responses evoked by these stimulating electrodes, we developed microscopy techniques and signal processing algorithms that could automatically identify and evaluate the electrical response of each individual neuron. Finally, by applying this simultaneous stimulation and optical recording system to the study of dissociated cortical cultures in multielectode arrays, we could evaluate the efficacy of excitatory and inhibitory waveforms. Although we found that the proximity of the electrode is a poor predictor of individual neural excitation thresholds, we have shown that it is possible to use inhibitory waveforms to globally reduce excitability in the vicinity of the electrode. Thus, the developed system was able to provide very high resolution insight into the complex set of interactions between the stimulating electrodes and populations of individual neurons.

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Bayesian based risk stratification of atrial fibrillation in coronary artery bypass graft patients

2007-05-22 , Wiggins, Matthew Corbin

Roughly thirty percent of coronary artery bypass graft (CABG) patients develop atrial fibrillation (AF) in the five days following surgery, increasing the risk of stroke, prolonging hospital stay three to four days, and increasing the overall cost of the procedure. Current pharmacologic and nonpharmacologic means of AF prevention are suboptimal, and their side effects, expense, and inconvenience limit their widespread application. An accurate method for identifying patients at high risk for postoperative AF would allow these methods to be focused on the patients on which its utility would be highest. The main objective of this research was to develop a Bayesian network (BN) which could model/predict/assign risk of the occurrence of atrial fibrillation in CABG patients using retrospective data. A secondary objective was to develop an integrated framework for more advanced methods of feature selection and fusion for medical classification/prediction. We determined that the naïve Bayesian network classifier used with features selected by a genetic algorithm is a better classifier to use, given our cohort. The naïve BN allows for reasonable prediction despite being presented with patients with missing data points as might occur in the hospital. This classifier achieves a sensitivity of 0.63 and a specificity of 0.73 with an AUC of 0.74. Furthermore, this system is based on probabilities that are well understood and easily incorporated into a clinical environment. These probabilities can be altered based on the cardiologists prior knowledge through Bayesian statistics, allowing for online sensitivity analysis by doctors, to perceive the best treatment options. Contributions of this research include: - An accurate, physician-friendly, postoperative AF risk stratification system that performs even under missing data conditions, while outperforming the state of the art system, - A thorough analysis of previously examined and novel pre- and postoperative clinical and ECG features for postoperative AF risk stratification, - A new methodology for genetic algorithm-built traditional Bayesian network classifiers allowing dynamic structure through novel chromosome, operator, and fitness definitions, and - An integrated methodology for inclusion of doctor s expert knowledge into a probabilistic diagnosis support system.

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Apoferritin Crystallization in relation to Eye Cataract

2006-08-22 , Bartling, Karsten

Protein crystallization is significant in both biotechnology and biomedical applications. In biotechnology, crystallization is essential for determining the structure of both native and synthesized therapeutically important proteins. It can also be used as a final purification step and as a stable form for protein storage. With regard to biomedical systems, protein crystallization appears to be involved in the development and manifestation of certain human diseases. In particular, there exists evidence that L-rich ferritin crystals are involved in Hereditary Hyperferritinemia Cataract Syndrome (HHCS). In the current research a microbatch crystallization apparatus has been introduced that enables (1) multiple batch crystallization experiments at various temperatures and solution conditions in parallel and (2) quantitative monitoring of crystal growth without disturbing the progress of an experiment for observation. The primary application of the apparatus is, but not limited to, screening of protein crystallization conditions, although the system can also be used for other macromolecular and small-molecule crystallization experiments. Multiwell microbatch experiments demonstrated the dependence of apoferritin crystal growth kinetics and final crystal size on temperature and cadmium concentration. Although the solubility of apoferritin might be independent of temperature, the results of this study show that the crystal growth kinetics are affected by temperature, profoundly under some conditions. For apoferritin under near physiological conditions the solution thermodynamics in the form of the second virial coefficient have proofed to be a valuable predictor for the crystallization outcome. Furthermore, the significance of the elevated level of some divalent cations in cataractous lenses has been studied both in dilute solutions and under crystallization conditions and cadmium seems to be sole menace in apoferritin condensation.

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