Biomedical Engineering and Bioengineering Commons^™

Kcnq1/Kcne1 Interaction In The Cardiac Iks Channel And Its Physiological Consequences, Jiajing Xu

McKelvey School of Engineering Graduate Student Theses & Dissertations

Dynamic conformational changes of ion channel proteins during activation gating determine their function as carriers of current. The relationship between these molecular movements and channel function over the physiological timescale of the action potential (AP) has not been fully established due to limitations of existing techniques. We constructed a library of possible cardiac IKs protein conformations and applied a combination of protein segmentation and energy linearization to study this relationship computationally. Simulations reproduced the effects of the beta-subunit (KCNE1) on the alpha-subunit (KCNQ1) dynamics and function, observed in experiments. Mechanistically, KCNE1 increased the probability of “visiting” conducting pore conformations on …

Investigating Cyanobacteria Metabolism And Channeling-Based Regulations Via Isotopic Nonstationary Labeling And Metabolomic Analyses, Mary Helen Abernathy

McKelvey School of Engineering Graduate Student Theses & Dissertations

Cyanobacteria have the potential to be low-cost and sustainable cell factories for bio-products; however, many challenges face cyanobacteria as biorefineries. This dissertation seeks to advance non-model photosynthetic organisms for biotechnology applications by characterizing central carbon metabolism and its regulations. Cyanobacteria phenotypes for bio-production are examined and their intracellular metabolism is quantified. Using isotopic labeling experiments, phenotypic relationships between biomass composition, central carbon fluxes, and metabolite pool sizes are investigated. Metabolic analyses of cyanobacteria led to new investigations of flux regulation mechanisms via protein spatial organizations or metabolite channeling. Metabolite channeling is further explored as a hypothesis to explain enigmatic labeling …

Molecular Basis Of Class Ib Drug Interactions With The Nav Channel Macromolecular Complex: A Route To Personalized Medicine For Cardiac Arrhythmia, Wandi Zhu

McKelvey School of Engineering Graduate Student Theses & Dissertations

The heart rhythm is precisely controlled by the electrical impulse that propagate in the cardiac tissue. In single cardiomyocytes, the electrical activity generated by action potentials (AP). Cardiac NaV channels (NaV1.5) carry a large influx of Na+ that mediates the initiation and propagation of the AP in both atria and ventricles. Disruption of NaV1.5 function by genetic variants or external factors can result in deadly arrhythmias, such as long QT syndrome and Brugada syndrome. Thus, NaV channels are import therapeutic targets. The class I antiarrhythmics are the modulators of the NaV channels. Although they have been used clinically for over …

Basis Vector Model Method For Proton Stopping Power Estimation Using Dual-Energy Computed Tomography, Shuangyue Zhang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Accurate estimation of the proton stopping power ratio (SPR) is important for treatment planning and dose prediction for proton beam therapy. The state-of-the-art clinical practice for estimating patient-specific SPR distributions is the stoichiometric calibration method using single-energy computed tomography (SECT) images, which in principle may introduce large intrinsic uncertainties into estimation results. One major factor that limits the performance of SECT-based methods is the Hounsfield unit (HU) degeneracy in the presence of tissue composition variations. Dual-energy computed tomography (DECT) has shown the potential of reducing uncertainties in proton SPR prediction via scanning the patient with two different source energy spectra. …

Acetylation Profiles Of Histone And Non-Histone Proteins In Breast Cancer, Alla Karpova

McKelvey School of Engineering Graduate Student Theses & Dissertations

This study evaluates the impact of protein acetylation on breast cancer gene expression and the regulation of metabolism. Acetylation is the second abundant post-translational modification after phosphorylation, regulating protein activity and function. The alterations in acetylation of both histone and non-histone proteins is known to be related to many human diseases, including cancer. Acetylation and deacetylation of histones is closely associated with the regulation of gene expression, while acetylation of non-histone proteins may have a broad effect on major cellular processes, such as proliferation, metabolism, cell cycle and apoptosis, imbalanced regulation of which is essential for cancer development. Therefore, it’s …

Numerical Simulation And Optimization Of Blalock-Taussig Shunt, Thomas Hess, Ramesh K. Agarwal

McKelvey School of Engineering Graduate Student Theses & Dissertations

The goal of this study is to create an optimized Blalock-Taussig shunt used to temporarily repair pulmonary vascular blockages allowing a child time to grow so a more permanent surgical repair of the heart and vasculature can be performed. Blalock-Taussig or BT shunts are a surgical procedure performed on infants suffering from cyanosis or “Blue Baby Syndrome.” A BT shunt is an artificial vessel placed between the right ventricle and the pulmonary artery to increase blood flow in the lung and blood oxygen saturation levels. In a study of 96 patients with currently in use modified BT shunts, 32 patients …

Controlling The Oxygen Microenvironment: The Role Of Hif-1Α In Early Tumor Progression, Sandra Lam

McKelvey School of Engineering Graduate Student Theses & Dissertations

Cancer drug efficacy has remained a critical obstacle for researchers as it has one of the lowest probabilities of success compared to other diseases. One method to help improve this success rate is to create better tumor models on which to perform the drug testing. With growing interesting in microphysiological systems, scientists can create more advanced in vitro models of human organ systems as well as diseased states. These “organ-on-a-chip” platforms aim to improve drug response prediction for both efficacy and toxicity. One underappreciated characteristic of many disease states is that they are often at a lower oxygen tension that …

Assessment And Diagnosis Of Human Ovarian And Colorectal Cancer Using Optical And Photoacoustic Imaging, Sreyankar Nandy

McKelvey School of Engineering Graduate Student Theses & Dissertations

Optical imaging modalities have the advantage of high resolution, label free, rapid, low cost imaging for both in vivo and ex vivo diagnosis of biological tissues. Optical scattering, which is the main contrast of optical coherence tomography (OCT), is related to elastic scattering components, mainly stromal collagen. Tissue elasticity has recently emerged as an important diagnostic parameter associated with tumor development and progression and is also related to the distribution of structural components such as tissue collagen. We have used an optical coherence tomography elastography (OCTE) system for characterizing the differences in the micro-mechanical properties of benign and malignant human …

Engineering Robust And Programmable Biological Systems, Tatenda Shopera

McKelvey School of Engineering Graduate Student Theses & Dissertations

The ability to engineer programmable biological systems using complex artificial gene networks has great potential to unlock important innovative solutions to many biotechnological challenges. While cells have been engineered to implement complex information processing algorithms and to produce food, materials, and pharmaceuticals, many innovative applications are yet to be realized due to our poor understanding of how robust, reliable, and predictable artificial gene circuits are built. In this work, we demonstrate that robust complex cellular behaviors (e.g., bistability and gene expression dynamics) can be achieved by engineering gene regulatory architecture and increasing the complexity of genetic networks. We further demonstrate …

Mathematical Models Of Innate Immune Cell Signaling Networks Using Protein Phosphorylation Patterns, Allison Anne Throm

McKelvey School of Engineering Graduate Student Theses & Dissertations

Immune dysregulation has been implicated in pediatric autoimmune disease

pathogenesis, but the underlying mechanisms still remain poorly understood. We explored

immune cell signaling dysregulation in two different pediatric autoimmune diseases:

polyarticular juvenile idiopathic arthritis (JIA), a disease characterized by pain, swelling, and

limited range of motion in five or more joints and juvenile dermatomyositis (JDM), a disease

characterized by pathognomonic skin rashes and proximal muscle weakness. Both polyarticular

JIA and JDM can be controlled with newer biologic medications, but a substantial fraction of

patients still experiences refractory disease courses. To explore potential immune cell signaling

dysregulation, mass cytometry was performed …

Noninvasive Multi-Modality Studies Of Cardiac Electrophysiology, Mechanics, And Anatomical Substrate In Healthy Adults, Arrhythmogenic Cardiomyopathy, And Heart Failure, Christopher Andrews

McKelvey School of Engineering Graduate Student Theses & Dissertations

Heart disease is a leading cause of death and disability and is a major contributor to healthcare costs. Many forms of heart disease are caused by abnormalities in the electrical function of heart muscle cells or the cardiac conduction system. Electrocardiographic Imaging (ECGI) is a noninvasive modality for imaging cardiac electrophysiology. By combining recordings of the voltage distribution on the torso surface with anatomical images of the heart-torso geometry, ECGI reconstructs voltages on the epicardium. This thesis applies ECGI to novel studies of human heart function and disease and explores new combinations of ECGI with additional imaging modalities.

ECGI was …

Brain-Computer Interfaces Using Electrocorticography And Surface Stimulation, Jesse Wheeler

McKelvey School of Engineering Graduate Student Theses & Dissertations

The brain connects to, modulates, and receives information from every organ in the body. As such, brain-computer interfaces (BCIs) have vast potential for diagnostics, medical therapies, and even augmentation or enhancement of normal functions. BCIs provide a means to explore the furthest corners of what it means to think, to feel, and to act—to experience the world and to be who you are. This work focuses on the development of a chronic bi-directional BCI for sensorimotor restoration through the use of separable frequency bands for recording motor intent and providing sensory feedback via electrocortical stimulation. Epidural cortical surface electrodes are …

Radiological Pathological Correlations In Chronic Traumatic Encephalopathy, Mihika Gangolli

McKelvey School of Engineering Graduate Student Theses & Dissertations

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that has been increasingly linked to traumatic brain injury. The neuropathology that distinguishes CTE from other tauopathies includes hyperphosphorylated tau (pTau) tangles and tau positive astrocytes irregularly distributed in cortical sulcal depths and clustered around perivascular foci. These features are clearly identified using immunohistochemistry, but are undetectable to current clinical imaging methods. Diffusion imaging has been proposed as a noninvasive method to detect the pathognomonic lesion of CTE in vivo because of its high sensitivity to microstructural alterations in tissue structure. While several diffusion imaging approaches, ranging from diffusion tensor imaging …

Development And Evaluation Of Biocompatible Engineered Nanoparticles For Use In Ophthalmology, Bedia Begum Karakocak

McKelvey School of Engineering Graduate Student Theses & Dissertations

The synthesis and design of biocompatible nanoparticles for targeted drug delivery and bioimaging requires knowledge of both their potential toxicity and their transport. For both practical and ethical reasons, evaluating exposure via cell studies is a logical precursor to in vivo tests. As a step towards clinical trials, this work extensively investigated the toxicity of gold nanoparticles (Au NPs) and carbon dot (CD) nanoparticles as a prelude to their in vivo application, focusing specifically on ocular cells. As a further step, it also evaluated their whole-body transport in mice. The research pursued two approaches in assessing the toxicity of engineered …

Hemodynamic Effects On Embryonic Arterial Growth And Matrix Remodeling, Maria Gabriela Espinosa

McKelvey School of Engineering Graduate Student Theses & Dissertations

Hemodynamic forces drive cardiovascular morphogenesis and remodeling in the developing embryo. Changes to the embryonic hemodynamic environment have been shown to induce a variety of congenital heart defects, but little attention has been given to vasculature-specific defects. Although vascular development has been widely studied in the context of genetics and molecular biology, this work investigates the impact of hemodynamic forces on arterial development and mechanics.

The dorsal aorta (DA) is the first intraembryonic vessel to form. Its passive mechanical properties are determined by the deposition of extracellular matrix (ECM) proteins, a hallmark of arterial maturation. We hypothesized that hemodynamic changes …

Forward Electrophysiological Modeling And Inverse Problem For Uterine Contractions During Pregnancy, Mengxue Zhang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Uterine contractile dysfunction during pregnancy is a significant healthcare challenge that imposes heavy medical and financial burdens on both human beings and society. In the U.S., about 12% of babies are born prematurely each year, which is a leading cause of neonatal mortality and increases the possibility of having subsequent health problems. Post-term birth, in which a baby is born after 42 weeks of gestation, can cause risks for both the newborn and the mother. Currently, there is a limited understanding of how the uterus transitions from quiescence to excitation, which hampers our ability to detect labor and treat major …

In Vivo Vascular Imaging With Photoacoustic Microscopy, Hsun-Chia Hsu

McKelvey School of Engineering Graduate Student Theses & Dissertations

Photoacoustic (PA) tomography (PAT) has received extensive attention in the last decade for its capability to provide label-free structural and functional imaging in biological tissue with highly scalable spatial resolution and penetration depth. Compared to modern optical modalities, PAT offers speckle-free images and is more sensitive to optical absorption contrast (with 100% relative sensitivity). By implementing different regimes of optical wavelength, PAT can be used to image diverse light-absorbing biomolecules. For example, hemoglobin is of particular interest in the visible wavelength regime owing to its dominant absorption, and lipids and water are more commonly studied in the near-infrared regime.

In …

Super‐Resolution Imaging Of Amyloid Structures Over Extended Times By Using Transient Binding Of Single Thioflavin T Molecules, Kevin Spehar, Tianben Ding, Yuanzi Sun, Niraja Kedia, Jin Lu, George R. Nahass, Matthew D. Lew, Jan Bieschke

Electrical & Systems Engineering Publications and Presentations

Oligomeric amyloid structures are crucial therapeutic targets in Alzheimer's and other amyloid diseases. However, these oligomers are too small to be resolved by standard light microscopy. We have developed a simple and versatile tool to image amyloid structures by using thioflavin T without the need for covalent labeling or immunostaining. The dynamic binding of single dye molecules generates photon bursts that are used for fluorophore localization on a nanometer scale. Thus, photobleaching cannot degrade image quality, allowing for extended observation times. Super‐resolution transient amyloid binding microscopy promises to directly image native amyloid by using standard probes and record amyloid dynamics …

Chronic Nerve Interfacing Utilizing Graft-Embedded Regenerative Macro-Sieve Electrodes, Amrita Nishtala

McKelvey School of Engineering Graduate Student Theses & Dissertations

Custom-designed macro-sieve electrodes represent a novel means of facilitating chronic high specificity nerve stimulation needed to control distal nerve musculature and restore sensorimotor function. Implantation of these electrodes requires the transection of the nerve, which has shown to disrupt muscle fiber distribution. This present study assesses the feasibility of implementing these electrodes in an end-to-side nerve graft. The macro-sieve electrodes were fabricated and micro-surgically implanted into 3.2 cm nerve autografts harvested from the sciatic nerve of 12 male Lewis rats. Electrode-enabled nerve grafts were micro-surgically implanted in an end-to-side manner into donor rat sciatic nerves without the need for a …

Developing Wavefront Shaping Techniques For Focusing Through Highly Dynamic Scattering Media, Ashton Hemphill

McKelvey School of Engineering Graduate Student Theses & Dissertations

One of the prime limiting factors of optical imaging in biological applications is the diffusion of light by tissue, which prevents focusing at depths greater than the optical diffusion limit of ~1 mm in soft tissue. This greatly restricts the utility of optical diagnostic and therapeutic techniques, such as optogenetics, microsurgery, optical tweezing, and phototherapy of deep tissue, which require focused light in order to function. Wavefront shaping extends the depth at which optical focusing may be achieved by compensating for phase distortions induced by scattering, allowing for focusing through constructive interference.

However, due to physiological motion, scattering of light …

Fluorescence Guided Tumor Imaging: Foundations For Translational Applications, Jessica P. Miller

McKelvey School of Engineering Graduate Student Theses & Dissertations

Optical imaging for medical applications is a growing field, and it has the potential to improve medical outcomes through its increased sensitivity and specificity, lower cost, and small instrumentation footprint as compared to other imaging modalities. The method holds great promise, ranging from direct clinical use as a diagnostic or therapeutic tool, to pre-clinical applications for increased understanding of pathology. Additionally, optical imaging uses non-ionizing radiation which is safe for patients, so it can be used for repeated imaging procedures to monitor therapy, guide treatment, and provide real-time feedback. The versatile features of fluorescence-based optical imaging make it suited for …

Functional Electrical Stimulation Of Peripheral Nerve Tissue Via Regenerative Sieve Microelectrodes, Matthew Reagan Macewan

McKelvey School of Engineering Graduate Student Theses & Dissertations

Functional electrical stimulation (FES) of peripheral nervous tissue offers a promising method for restoring motor function in patients suffering from complex neurological injuries. However, existing microelectrodes designed to stimulate peripheral nerve are unable to provide the type of stable, selective interface required to achieve near-physiologic control of peripheral motor axons and distal musculature. Regenerative sieve electrodes offer a unique alternative to such devices, achieving a highly stable, selective electrical interface with independent groups of regenerated nerve fibers integrated into the electrode. Yet, the capability of sieve electrodes to functionally recruit regenerated motor axons for the purpose of muscle activation remains …

Photoacoustic Elastography And Next-Generation Photoacoustic Tomography Techniques Towards Clinical Translation, Pengfei Hai

McKelvey School of Engineering Graduate Student Theses & Dissertations

Ultrasonically probing optical absorption, photoacoustic tomography (PAT) combines rich optical contrast with high ultrasonic resolution at depths beyond the optical diffusion limit. With consistent optical absorption contrast at different scales and highly scalable spatial resolution and penetration depth, PAT holds great promise as an important tool for both fundamental research and clinical application. Despite tremendous progress, PAT still encounters certain limitations that prevent it from becoming readily adopted in the clinical settings. This dissertation aims to advance both the technical development and application of PAT towards its clinical translation.

The first part of this dissertation describes the development of photoacoustic …

Developing Photoacoustic Tomography Devices For Translational Medicine And Basic Science Research, Tsz Wai Wong

McKelvey School of Engineering Graduate Student Theses & Dissertations

Photoacoustic (PA) tomography (PAT) provides volumetric images of biological tissue with scalable spatial resolutions and imaging depths, while preserving the same imaging contrast—optical absorption. Taking the advantage of its 100% sensitivity to optical absorption, PAT has been widely applied in structural, functional, and molecular imaging, with both endogenous and exogenous contrasts, at superior depths than pure optical methods. Intuitively, hemoglobin has been the most commonly studied biomolecule in PAT due to its strong absorption in the visible wavelength regime.

One of the main focuses of this dissertation is to investigate an underexplored wavelength regime—ultraviolet (UV), which allows us to image …

Transcriptional Regulation Of Arrhythmia: From Mouse To Human, Yun Qiao

McKelvey School of Engineering Graduate Student Theses & Dissertations

In the last two decades, our understanding of cardiac arrhythmias has been accelerated immensely by the development of genetically engineered animals. Transgenic and knockout mice have been the “gold standard” platforms for delineating disease mechanisms. Much of our understanding of the pathogenesis of atrial and ventricular arrhythmias is gained from mouse models that alter the expression of specific ion channels or other proteins. However, cardiac arrhythmias such as atrial fibrillation are heterogeneous diseases with numerous distinct conditions that could not be explained exclusively by the disruption of ionic currents. Increasing evidence suggests disruption of signaling pathways in the pathogenesis of …

The Role Of Obesity And Dietary Fatty Acid Content In Regulating Humeral Bone And Cartilage Homeostasis, Lauren Votava

McKelvey School of Engineering Graduate Student Theses & Dissertations

Objective: The goal of this study was to investigate the effects of different dietary fatty acids in the context of diet-induced obesity on bone and cartilage in the humerus. It is known that obesity increases the severity of injury-induced osteoarthritis in the knee, however it is not fully understood what pathological changes have occurred due to diet alone¹. Additionally, while it is known that shoulder osteoarthritis has a link to obesity, the alterations in this joint are incompletely described.

Methods: In order to examine diet-induced changes in both bone and cartilage, this research utilized mice that had been …

Ls301 Fluorescence-Guided Photodynamic Therapy Of Brain Cancer Using Ppix Photosensitizer, Haini Zhang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Incomplete brain tumor removal always causes neurologic deficit, disease recurrence and high mortality. Protoporphyrin IX (PpIX) accumulated in glioma cells with exogenous 5-aminolevulinic acid (5-ALA) serves as contrast agent for fluorescence-guided surgery and as well as acts as a photosensitizer for photodynamic therapy (PDT). However, the accurate tumor delineation using PpIX is limited by autofluorescence and superficial penetration depth. LS301 is a tumor-targeted near-infrared (NIR) contrast agent developed in our lab which allows deeper tumor imaging and avoids autofluorescence. My project aims to investigate whether LS301 can improve PpIX mediated PDT and tumor removal surgery. We have demonstrated co-localization of …

System Characterizations And Optimized Reconstruction Methods For Novel X-Ray Imaging, Huifeng Guan

McKelvey School of Engineering Graduate Student Theses & Dissertations

In the past decade there have been many new emerging X-ray based imaging technologies developed for different diagnostic purposes or imaging tasks. However, there exist one or more specific problems that prevent them from being effectively or efficiently employed. In this dissertation, four different novel X-ray based imaging technologies are discussed, including propagation-based phase-contrast (PB-XPC) tomosynthesis, differential X-ray phase-contrast tomography (D-XPCT), projection-based dual-energy computed radiography (DECR), and tetrahedron beam computed tomography (TBCT). System characteristics are analyzed or optimized reconstruction methods are proposed for these imaging modalities. In the first part, we investigated the unique properties of propagation-based phase-contrast imaging technique …

Binding Affinity And Specificity Of Sh2 Domain Interactions In Receptor Tyrosine Kinase Signaling Networks, Tom Ronan

McKelvey School of Engineering Graduate Student Theses & Dissertations

Receptor tyrosine kinase (RTK) signaling mechanisms play a central role in intracellular signaling and control development of multicellular organisms, cell growth, cell migration, and programmed cell death. Dysregulation of these signaling mechanisms results in defects of development and diseases such as cancer. Control of this network relies on the specificity and selectivity of Src Homology 2 (SH2) domain interactions with phosphorylated target peptides. In this work, we review and identify the limitations of current quantitative understanding of SH2 domain interactions, and identify severe limitations in accuracy and availability of SH2 domain interaction data. We propose a framework to address some …

Identification Of Prognostic Cancer Biomarkers Through The Application Of Rna-Seq Technologies And Bioinformatics, Nathan Wong

McKelvey School of Engineering Graduate Student Theses & Dissertations

MicroRNAs (miRNAs) are short single-stranded RNAs that function as the guide sequence of the post-transcriptional regulatory process known as the RNA-induced silencing complex (RISC), which targets mRNA sequences for degradation through complementary binding to the guide miRNA. Changes in miRNA expression have been reported as correlated with numerous biological processes, including embryonic development, cellular differentiation, and disease manifestation. In the latter case, dysregulation has been observed in response to infection by human papillomavirus (HPV), which has also been established as both oncogenic in cervical cancers and oropharyngeal cancers and favorable for overall patient survival after tumor formation. The identification of …