Biomedical Engineering and Bioengineering Commons^™

Towards The Discovery Of Prognostic Biomarkers For Glioblastoma Using Resting-State Functional Connectivity, Andy G. S. Daniel

McKelvey School of Engineering Graduate Student Theses & Dissertations

Gliomas are highly diffusive, primary brain tumors. The most malignant form, glioblastoma, has a dismal survival rate: 14-17 months following the current standard of care, which consists of surgery, radiation, and chemotherapy. Insights into the molecular, cellular, and microenvironmental components of glioblastoma have revealed a vast array of factors utilized to support its proliferation, infiltration, and resistance to treatment. Recent advancements have also identified diagnostic and prognostic biomarkers that are now being used to guide treatment planning. However, survival has improved only marginally, thus emphasizing the continued need for novel biomarkers and treatment strategies. Given its delicate location in the …

Quantitative Flow Cytometry-Guided Protein Biomarker Characterization For Translational Proteomics And Precision Medicine, Yingye Fang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Angiogenesis, the growth of blood vessels from pre-existing vasculature, is primarily regulated by vascular endothelial growth factor receptors (VEGFRs). Dysregulated angiogenesis is associated with cancers, obesity, and over 70 vascular diseases. Upregulated VEGFR protein expressions in diseased vasculature are promising biomarkers for predicting clinical outcomes, as indicated by non-quantitative immunohistochemical studies in patients with impaired vascularization or tumor angiogenesis. While the quantitative characterization of VEGFRs is critical in identifying biomarkers for anti-angiogenic therapies, VEGFR biomarker development presents two particular challenges: (1) The invasive tissue biopsy needed limits the amount of VEGFR data that can be collected from both normal and …

Long-Term Neural Activity Recorders Using Energy-Based Sensing, Compressive Computation And Data Logging, Darshit Mehta

McKelvey School of Engineering Graduate Student Theses & Dissertations

Insects are ideal candidates for developing bio-robotic systems owing to their ability to thrive in almost any environment. For example, neurons in their exquisite olfactory sensory systems can be tapped to create a sensing platform for standoff chemical monitoring. However, for enabling such cyborg systems, it is vital that the neural activity of a freely behaving organism can be measured for long periods of time. The current state-of-the-art neural recording techniques are power-intensive and they either need batteries, which make them too bulky for insects, or they have to maintain a continuous telemetry link to an external power source which …

Understanding And Improving Adult Stem Cells For Cartilage Tissue Engineering, Dakota Katz

McKelvey School of Engineering Graduate Student Theses & Dissertations

Articular cartilage allows for near frictionless joint movement; however, when damaged the tissue has very little capacity for self-repair. Tissue engineering can be used to both repair damaged articular cartilage and as an in vitro model for joint disease. Commonly used cell sources for tissue engineering are adipose-derived and bone marrow-derived mesenchymal stem cells (ASCs and MSCs) because they can be patient matched, expand rapidly in culture, and have multipotent differentiation potential. However, donor-to-donor variability of differentiation potential can mask the results of in vitro experiments and ASCs and MSCs only retain their multipotency for a limited number of passages. …

Developing An Induction Protocol And Generating A Selectable Cell Line To Obtain High-Purity V0v Interneuron Cultures From Mouse Embryonic Stem Cells, Jennifer Pardieck

McKelvey School of Engineering Graduate Student Theses & Dissertations

Spinal cord injury (SCI) leads to loss of motor function among other devastating impairments, with patients having a grim outlook on recovery as currently there are no widely efficacious treatment methods. The native regenerative capacity of the neurons in the central nervous system is limited, thus recovery of the axonal connections between the different components of the complex circuitry that enables motor function is minimal after SCI. Investigators aiming to improve motor function post-SCI approach the problem from different angles, including removing inhibitory elements to axonal regeneration and supporting regeneration through implantation of biomaterials, exposure to pro-regenerative factors, and transplantation …

Injectable Ct/Mri Contrast Agent For Gastrointestinal Tumor Tracking, Luna Zhang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Gastrointestinal cancers remain to be of the most common and deadly cancers worldwide. Early detection and treatments are crucial for reducing mortality and improving patient outcome. Radiation therapy is a non-invasive localized tumor treatment method, and utilizes radiation to kill the cancerous cells and shrink tumors at specific sites. Precise localization at the target tumor site is therefore important before radiation therapy, especially for gastrointestinal tumor sites located in the moving bowel. Currently, invasive endoscopies along with ink tattoos are used for identifying tumor location, which often require sedation and bring much discomfort. Imaging tests, including CT and MRI, play …

Magnetic Resonance-Guided High Intensity Focused Ultrasound (Mrghifu) Induced Hyperthermia (Ht) For Treatment Of Cervical Cancer, Lifei Zhu

McKelvey School of Engineering Graduate Student Theses & Dissertations

Hyperthermia (HT), which refers to increasing the temperature of the tumor tissue to 40–45°C for an extended period of time, has been reported to be one of the most effective sensitizers for radiation therapy (RT) and/or chemotherapy. High intensity focused ultrasound (HIFU) has been developed as a non-invasive and non-ionizing tool to induce localized HT. Magnetic resonance thermometry (MR thermometry) is one of the most reliable methods for non-invasively and precisely measuring the in vivo volumetric temperature in real time. The integration of MR thermometry with HIFU has been implemented in commercially available magnetic resonance guided high intensity focused ultrasound …

Laminin-Mimetic Peptide-Functionalized Hydrogel Systems For The Phenotypic Modulation Of Cells Of The Nucleus Pulposus, Marcos Nicolas Barcellona

McKelvey School of Engineering Graduate Student Theses & Dissertations

The intervertebral disc (IVD) has been widely observed to undergo significant structural and biochemical changes with age and maturation. As degeneration progresses, changes in extracellular matrix composition and deposition, tissue cellularity, and metabolic activity have been characterized. Although the epidemiology of disc degeneration remains unclear, it is believed that the nucleus pulposus (NP) region of the IVD may be implicated in early degeneration. Specifically, cells of the nucleus pulposus have been observed to undergo a shift from their notochordal-like juvenile phenotype to a more fibroblast-like state in a manner concomitant to degenerative events. Because the disc has inherently little capacity …

Cortical Organization In Humans And Nonhuman Primates: The Evolution Of Cognitive Areas And Circuits, Chad Joseph Donahue

McKelvey School of Engineering Graduate Student Theses & Dissertations

Similarities in organization of cerebral cortex in humans and nonhuman primates offer the promise of leveraging data from invasive animal studies to better understand the complexities of the human brain, particularly those related to higher cognitive function (e.g. attention, working memory, language). Such comparisons necessitate the identification of convincing cortical homologues (areas or regions presumed to have derived from a common ancestor), requiring an accurate interspecies mapping of cortical areas and features. To this end, I describe (i) a survey of connectivity and its measures across primate species, particularly retrograde tracing and diffusion tractography, (ii) a morphometric analysis of cognitive …

Understanding A Role For Synovium In Intra-Articular Drug Clearance: A Computational And Experimental Approach, Young Guang

McKelvey School of Engineering Graduate Student Theses & Dissertations

The synovium is a membranous tissue that governs molecular transport between the intra-articular (IA) joint space and the systemic circulatory system. Drug delivery to the IA space is an attractive option to treat localized joint diseases such as osteoarthritis. However, short residence times due to rapid clearance from the joint diminishes efficacy of IA injected drugs. While many studies exist on the clearance of drugs from the IA space, these studies lack the ability to isolate and characterize trans-synovial transport.The first aim of this dissertation establishes a computational finite element (FE) model of trans-synovial transport using multiphasic mixture theory. The …

Plasmonically-Enhanced Ultrasensitive Biodetection Technologies, Zheyu Wang

McKelvey School of Engineering Graduate Student Theses & Dissertations

Detection and quantification of biomolecules within biological fluids and tissues is of fundamental importance to biomedical research and clinical diagnostics. It is impossible to fully characterize complex, non-linear, biochemical systems without being able to accurately and quantitatively determine the component molecules. This problem is ubiquitous across all domains of biomedical research, and it is a major barrier to fully understanding health, ageing, and disease. Such bottlenecks are extremely challenging to be solved, especially for proteins and peptides, which do not have amplification schemes such as polymerase chain reaction for nucleic acids, because relevant concentrations of molecules related to diseases such …

Synthetic Gene Circuits For Self-Regulating And Temporal Delivery Of Anti-Inflammatory Biologic Drugs In Engineered Tissues, Lara Pferdehirt

McKelvey School of Engineering Graduate Student Theses & Dissertations

The recent advances in the fields of synthetic biology and genome engineering open up new possibilities for creating cell-based therapies. We combined these tools to target repair of articular cartilage, a tissue that lacks a natural ability to regenerate, in the presence of arthritic diseases. To this end, we developed cell-based therapies that harness disease pathways and the unique properties of articular cartilage for prescribed, localized, and controlled delivery of biologics, creating the next generation of cell therapies and new classes of synthetic circuits. We created tissue engineered cartilage from murine induced pluripotent stem cells that had the ability to …

Assessment And Diagnosis Of Human Colorectal And Ovarian Cancer Using Optical Imaging And Computer-Aided Diagnosis, Yifeng Zeng

McKelvey School of Engineering Graduate Student Theses & Dissertations

Tissue optical scattering has recently emerged as an important diagnosis parameter associated with early tumor development and progression. To characterize the differences between benign and malignant colorectal tissues, we have created an automated optical scattering coefficient mapping algorithm using an optical coherence tomography (OCT) system. A novel feature called the angular spectrum index quantifies the scattering coefficient distribution. In addition to scattering, subsurface morphological changes are also associated with the development of colorectal cancer. We have observed a specific mucosa structure indicating normal human colorectal tissue, and have developed a real-time pattern recognition neural network to localize this specific structure …

Engineering Nucleus Pulposus Cell-Matrix Interactions With Laminin Ligands For Tissue Regeneration, Julie Elizabeth Speer

McKelvey School of Engineering Graduate Student Theses & Dissertations

Low back pain and degenerative conditions of the intervertebral disc (IVD) represent major global socioeconomic and medical burdens. The structures that comprise the IVD including the anulus fibrosis and the nucleus pulposus (NP) work together to stabilize the axial skeleton and distribute mechanical forces. However, the degenerative cascade, which is thought to begin with changes to the NP, results in alterations to the disc that can be seen across length scales including elongated cell shapes, tissue dehydration, and loss of disc height. Patients who present clinically with these changes may also experience altered biomechanics, pain upon motion, impairments to their …

Post-Traumatic Elbow Contracture Characterization And Physical Therapy-Based Treatment Strategies In A Preclinical Model, Alex Reiter

McKelvey School of Engineering Graduate Student Theses & Dissertations

The elbow is the most commonly dislocated joint in the pediatric population and second most common in adults. As one of the most congruous joints in the body, slight changes in biomechanics due to injury can lead to drastic reductions in range of motion causing potential quality of life issues. Post-traumatic joint contracture occurs in 12% of patients following elbow dislocation or fracture, and it is characterized by a loss in ROM, joint stiffness, and pain. Preventing joint contracture and functional deficits from occurring is one of the primary goals when managing these injuries. A rat model of joint contracture …

Computational Modelling Enables Robust Multidimensional Nanoscopy, Matthew D. Lew

Electrical & Systems Engineering Publications and Presentations

The following sections are included:

• Present State of Computational Modelling in Fluorescence Nanoscopy

• Recent Contributions to Computational Modelling in Fluorescence Nanoscopy

• Outlook on Computational Modelling in Fluorescence Nanoscopy

• Acknowledgments

• References

Neural Coding And Organization Principles In The Drosophila Olfactory System, Haoyang Rong

McKelvey School of Engineering Graduate Student Theses & Dissertations

Sensory systems receive and process external stimuli to allow an organism to perceive and react to the environment. How is sensory information subsequently represented, transformed, and interpreted in the neural system? In this dissertation, I have investigated this fundamental question using the fruit fly (Drosophila melanogaster) olfactory system.Chemical cues are transduced into neural signals in the insect antenna by the olfactory receptor neurons (ORNs). The ORNs send their axons to the antennal lobe (AL), with each ORN type innervating a specific neuropil (glomerulus), where they synapse onto excitatory and inhibitory projection neurons (ePNs and iPNs). The ePNs project their axons …

Focused Ultrasound-Mediated Drug Delivery To The Brainstem, Dezhuang Ye

McKelvey School of Engineering Graduate Student Theses & Dissertations

Brainstem gliomas are tumors that occur in the brainstem, the brain region that connects the brain to the spinal cord and controls vital body functions. The critical anatomic location of the brainstem precludes surgical intervention and limits the use of invasive therapeutic techniques. Moreover, the frequently intact blood-brain barrier (BBB) of most brainstem gliomas prevents therapeutic agents from reaching the diseased site. The currently available techniques for brain drug delivery are either invasive (e.g., convection-enhanced delivery) or lack targeting to the diseased site (e.g., intranasal brain drug delivery). Novel techniques that can noninvasively overcome the BBB are critically needed for …

Deep Learning For Task-Based Image Quality Assessment In Medical Imaging, Weimin Zhou

McKelvey School of Engineering Graduate Student Theses & Dissertations

It has been advocated to use objective measures of image quality (IQ) for assessing and optimizing medical imaging systems. Objective measures of IQ quantify the performance of an observer at a specific diagnostic task. Binary signal detection tasks and joint signal detection and localization (detection-localization) tasks are commonly considered in medical imaging. When optimizing imaging systems for binary signal detection tasks, the performance of the Bayesian Ideal Observer (IO) has been advocated for use as a figure-of-merit (FOM). The IO maximizes the observer performance that is summarized by the receiver operating characteristic (ROC) curve. When signal detection-localization tasks are considered, …

Differentiating Human Embryonic Stem Cells In Micropatterns To Study Cell Fate Specification And Morphogenetic Events During Gastrulation, Kyaw Thu Minn

McKelvey School of Engineering Graduate Student Theses & Dissertations

During mammalian embryogenesis, the first major lineage segregation occurs when embryonic epiblast, and extraembryonic trophectoderm and hypoblast arise in the blastocyst. In the next fundamental and conserved phase of animal embryogenesis known as gastrulation, extraembryonic cells provide signals to epiblast to instruct embryonic patterning, and epiblast gives rise to germ layers ectoderm, mesoderm, and endoderm, that will establish all embryonic tissues. Proper specification and morphogenesis of germ layers during gastrulation is vital for correct embryonic development. Due to ethical and legal restrictions limiting human embryo studies, human gastrulation is poorly understood. Our knowledge of human gastrulation has largely been derived …

Uncovering The Roles And Evolved Sequence Grammar Of Hypervariable Intrinsically Disordered Proteins In Bacterial Cell Division, Megan Cohan

McKelvey School of Engineering Graduate Student Theses & Dissertations

Across all domains of life, a defining hallmark of the onset of cell division is the formation of a cytokinetic ring at the center of the cell. Cell division is a tightly controlled process that involves various regulatory factors that modulate the assembly of the cytokinetic ring. In rod-shaped bacteria, the ring is termed the Z-ring after the protein FtsZ, which is foundational to ring formation and is the bacterial homolog of tubulin. Like tubulin, FtsZ is an assembling GTPase, where GTP binding promotes the cooperative assembly into FtsZ polymers that laterally associate to form bundles. While the GTPase domain …

Nanoscale Enhancement Of Photosensitized Radionuclide Stimulated Therapy, Daniel Douglas Lane

McKelvey School of Engineering Graduate Student Theses & Dissertations

Photodynamic therapy (PDT) provides efficient tumor killing through the generation of reactive oxygen species (ROS) from the optical excitation of a photosensitizer (PS). Furthermore, this mechanism is highly immune stimulating, providing systemic tumor immunity with a reduction in metastasis. However, these materials had previously been limited by their dependence upon external light sources, allowing treatment of only laser-accessible malignancy. With the recent development of photosensitized radiation stimulated therapy (PRaST) this depth dependence is broken through co-localization of radionuclides and semiconducting photosensitizers. This dissertation focuses on the enhancement of titanium dioxide (TiO2) based PRaST agents through understanding of TiO2 material parameters …

Evaluating The Structural And Functional Consequences Of Traumatic Joint Injury And Their Relation To Nf-Κb In A Non-Invasive Model Of Post-Traumatic Osteoarthritis, Ian Matthew Berke

McKelvey School of Engineering Graduate Student Theses & Dissertations

Post-traumatic osteoarthritis (PTOA) is a painful and debilitating disease of the synovial joint, characterized by degenerative changes to various joint tissues following traumatic joint injury. While several risk factors have been identified in the symptomatic progression of PTOA following injury, inflammation and NF-κB mediated changes are believed to significantly contribute to symptomatic joint dysfunction and pain. However, the temporal presentation of these pro-inflammatory signals following clinically relevant injury and their relationship to the development of symptomatic disease have not been thoroughly investigated. Therefore, there exists a critical need to better understand how these early inflammatory events following injury may contribute …

Theory, Design And Implementation Of Energy-Efficient Biotelemetry Using Ultrasound Imaging, Sri Harsha Kondapalli

McKelvey School of Engineering Graduate Student Theses & Dissertations

This dissertation investigates the fundamental limits of energy dissipation in establishing a communication link with implantable medical devices using ultrasound imaging-based biotelemetry.

Ultrasound imaging technology has undergone a revolution during the last decade due to two primary innovations: advances in ultrasonic transducers that can operate over a broad range of frequencies and progresses in high-speed, high-resolution analog-to-digital converters and signal processors. Existing clinical and FDA approved bench-top ultrasound systems cangenerate real-time high-resolution images at frame rates as high as 10000 frames per second. On the other end of the spectrum, portable and hand-held ultrasound systems can generate high-speed real-time scans, …

Autologous Stem Cell-Derived Β Cells For Diabetes Cell Replacement Therapy, Kristina G. Maxwell

McKelvey School of Engineering Graduate Student Theses & Dissertations

Autologous stem cell therapy is a promising treatment for patients with diabetes worldwide. Previous stem cell-derived β (SC-β) cell protocols were unable to efficiently differentiate multiple patient induced pluripotent stem cells (iPSCs) into stem cell-derived islets (SC-islets), containing insulin-secreting SC-β cells. Recent updates targeting the actin cytoskeleton have enabled the differentiation of 14 diabetic and nondiabetic stem cell lines into SC-islets. We used genetic engineering, specifically CRISPR/Cas9, to correct the diabetes-causing mutation in stem cells from patients with Wolfram Syndrome. The genetically engineered SC-β cells functioned and had a composition similar to nondiabetic SC-β cells, unlike the unedited SC-β cells …

Liposomal Delivery Of Remdesivir For Localized And Targeted Treatment Of Covid-19, Anupama Melam

McKelvey School of Engineering Graduate Student Theses & Dissertations

Liposomal delivery of Remdesivir for localized and targeted treatment of COVID-19

COVID-19 is a serious, and in many cases lethal, disease that is caused by infection of the upper respiratory tract by the novel betacoronavirus, SARS-Cov-2 virus. This disease has a very high mortality rate and has affected the world in a global pandemic. SARS-Cov-2 binds to the ACE2 receptor via the receptor-binding domain (RBD) in the S protein. After this, the virus fuses with the cell membrane by the formation of a six-helix bundle. Thus, the S protein plays a major role in ensuring that the virus attaches to …

Single‐Molecule 3d Orientation Imaging Reveals Nanoscale Compositional Heterogeneity In Lipid Membranes, Jin Lu, Hesam Mazidi, Tianben Ding, Oumeng Zhang, Matthew D. Lew

Electrical & Systems Engineering Publications and Presentations

In soft matter, thermal energy causes molecules to continuously translate and rotate, even in crowded environments, thereby impacting the spatial organization and function of most molecular assemblies, such as lipid membranes. Directly measuring the orientation and spatial organization of large collections (>3000 molecules μm⁻²) of single molecules with nanoscale resolution remains elusive. In this paper, we utilize SMOLM, single‐molecule orientation localization microscopy, to directly measure the orientation spectra (3D orientation plus “wobble”) of lipophilic probes transiently bound to lipid membranes, revealing that Nile red's (NR) orientation spectra are extremely sensitive to membrane chemical composition. SMOLM images resolve …

The Role Of Gene Transcription And Inflammatory Cytokines In Bone Fracture Repair, Brandon Alan Coates

McKelvey School of Engineering Graduate Student Theses & Dissertations

In most instances, the skeleton has a remarkable capacity for repair following injury. However, in 5 to 10% of patients, fractures fail to properly heal resulting in non-union. A need exists for a more comprehensive understanding of the complex biology of fracture repair, which involves the coordinated work of many cell types including osteoblasts, osteoclasts, and immune cells. Depending on the extent of injury, fractures will heal through either intramembranous bone formation, involving the direct formation of bone callus, or endochondral bone formation, featuring a cartilage intermediary prior to bone callus formation. Both processes begin with inflammation, which sets the …

Quantitative Fluorescence Imaging For Investigation And Treatment Of Disease, Lemoyne Michael Habimana-Griffin

McKelvey School of Engineering Graduate Student Theses & Dissertations

Molecular imaging is a powerful tool that enables interrogation of basic molecular mechanisms, diagnosis of disease, guidance of therapeutic modalities and monitoring of treatment response. Among the various imaging modalities, optical imaging is particularly suited for preclinical molecular imaging owing to its high sensitivity, lack of exposure to ionizing radiation, low cost, portability and scalability of imaging from the microscopic to macroscopic scale. In particular, fluorescence molecular tomography (FMT) provides quantitative 3D reconstructions of fluorescence distributions down to picomole quantities allowing for whole animal molecular imaging. In this work, FMT is applied to detect disease-specific molecular probes, to monitor and …

Application Of Photoacoustic Imaging In Understanding Tissue Remodeling, Yuan Qu

McKelvey School of Engineering Graduate Student Theses & Dissertations

Photoacoustic Imaging (PAI) as an imaging method in biomedical research can provide high spatial resolution, various contrasts, great detection sensitivity, and deep penetration. These advantages are attributed to the combination of optical excitation and acoustic detection, which releases PAI from the ballistic limit faced by other optical imaging technique with high spatial resolution. In this dissertation, we aim to apply this technique to understand the connective tissue remodeling that is a ubiquitous physiological change in various medical complications.Chapter 1 elaborates the mechanism of PAI as well as the motivation of my dissertation.In Chapter 2, I introduce a new contrast mechanism …