Mammary Epithelial Cell Derived Extracellular Vesicles Influence Tumorigenic Phenotype Suppression In Her2-Positive Breast Cancer Cells, Brenda Okereke

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On a global scale, breast cancer remains the most commonly diagnosed cancer in the world. In 2020 alone, there were over 2.3 million new cases of breast cancer seen and a total of 685,000 deaths globally, this represents 16% or 1 in every 6 cancer deaths seen in women. By 2040 it is projected that the breast cancer burden will rise by over 40% to exceed 3 million new cases a year. Further understanding of the underlying biology and mechanisms behind tumor progression and breast cancers such as HER2+ breast cancer would allow for new therapeutic treatment targets to emerge. …

Development Of Advanced Simulator-Based Metrics For Suturing Skills Assessment And Feedback, Simar Singh

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Vascular surgery demands highly skilled suturing to manipulate and connect delicate vasculature. However, inadequate methods for open suturing skills training necessitate efficient and objective methods to develop skills. To address this need, medical training simulators for objective surgical skills training are gaining popularity for their formative assessment.

This research details the development of a system to classify suturing performance and provide feedback on a suturing skills measurement and feedback platform (called the SutureCoach). The SutureCoach simulator offers a comprehensive assessment of skill through sensors measuring needle driver motions, membrane forces and torques, subcutaneous suture needle movement, and hand motions. We …

Mesenchymal Stromal Cell Response To Degenerated Intervertebral Disc-Like Ph, Kyle Cannon

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Intervertebral disc degeneration (IVDD) has become increasingly prevalent and is a common contributing factor to low back pain. There are currently no clinical treatment options for IVDD that alleviate the symptoms of IVDD while simultaneously promoting repair of IVD tissue. One treatment option being explored is intradiscal administration of mesenchymal stromal cells (MSCs). However, the microenvironment of the degenerating IVD places significant stress on both native IVD cells and implanted cells. There are several questions that need to be addressed which may help further inform the development of efficacious intradiscal MSC therapies for IVDD. These questions include: 1) Do MSCs …

Identifying Temporomandibular Disorder Morphological Risk Factors Via Explainable Deep Learning And Multiscale Biomechanical Modeling, Shuchun Sun

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Clarifying multifactorial musculoskeletal disorder etiologies supports risk analysis and development of targeted prevention and treatment modalities. Deep learning enables comprehensive risk factor identification through systematic analysis of disease datasets but does not provide sufficient context for mechanistic understanding, limiting clinical applicability for etiological investigations. Conversely, multiscale biomechanical modeling can evaluate mechanistic etiology within the relevant biomechanical and physiological context. We propose a hybrid approach combining 3D explainable deep learning and multiscale biomechanical modeling; we applied this approach to investigate temporomandibular joint (TMJ) disorder etiology by systematically identifying risk factors and elucidating mechanistic relationships between risk factors and TMJ biomechanics and …

Novel Nucleus Pulposus Biomaterial Development And Low Field Mri Assessment For Intervertebral Disc Degeneration, Mario Krussig

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Intervertebral disc degeneration (IVDD) is a prominent pathology in the modern world that causes debilitating pain for many patients. The onset of IVDD occurs in the nucleus pulposus (NP). NP biomaterials will play a vital role in mitigating the progression of IVDD. Within this work, we sought to synthesize a solubilized extracellular matrix (ECM)-based NP biomaterial. Utilizing pepsin or urea extraction, bovine NP ECM was successfully solubilized (SBNPs). SBNP formulations were characterized biochemically, evaluated for cytotoxicity, and down-selected for front-running formulations. Leading candidate SBNPs were incorporated into an alginate bead biomaterial model to determine the potential bioactivity with human adipose-derived …

Controlled Manipulation And Transport By Microswimmers In Stokes Flows, Jake Buzhardt

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Remotely actuated microscale swimming robots have the potential to revolutionize many aspects of biomedicine. However, for the longterm goals of this field of research to be achievable, it is necessary to develop modelling, simulation, and control strategies which effectively and efficiently account for not only the motion of individual swimmers, but also the complex interactions of such swimmers with their environment including other nearby swimmers, boundaries, other cargo and passive particles, and the fluid medium itself. The aim of this thesis is to study these problems in simulation from the perspective of controls and dynamical systems, with a particular focus …

Structural Characterization Of Cardiomyocyte Microenvironment In Murine Myocardium By Multimodal Stimulated Emission Depletion Microscopy, Zhao Zhang

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Cardiomyopathy, a disease of the heart muscle, is characterized by structural and functional abnormalities of the myocardium, in the absence of coronary artery disease, hypertension, valvular disease or congenital heart disease. In 2020, there were approximately 6.11 million prevalent cases of cardiomyopathy and myocarditis, and 0.37 million related deaths worldwide. Many affected individuals are asymptomatic, and chronically treated patients are at risk of heart failure. Within the myocardium, cardiomyocytes reside in a complex and dynamic extracellular matrix (ECM), consisting of basement membrane and interstitial matrix. The interactions between cardiomyocytes and myocardial ECM play a critical role in maintaining cardiac geometry …

Ti-6al-4v Β Phase Selective Dissolution: In Vitro Mechanism And Prediction, Michael A Kurtz

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Retrieval studies document Ti-6Al-4V β phase dissolution within total hip replacement systems. A gap persists in our mechanistic understanding and existing standards fail to reproduce this damage. This thesis aims to (1) elucidate the Ti-6Al-4V selective dissolution mechanism as functions of solution chemistry, electrode potential and temperature; (2) investigate the effects of adverse electrochemical conditions on additively manufactured (AM) titanium alloys and (3) apply machine learning to predict the Ti-6Al-4V dissolution state. We hypothesized that (1) cathodic activation and inflammatory species (H₂O₂) would degrade the Ti-6Al-4V oxide, promoting dissolution; (2) AM Ti-6Al-4V selective dissolution would occur …

Engineering Next-Generation Cardiovascular Therapies, Ryan Walker Barrs

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Cardiovascular diseases are the leading cause of death worldwide. Heart disease, in particular, accounted for 1 in every 5 deaths in the United States in 2021, representing a substantial public health burden that will require more effective treatment options to alleviate. Heart transplant surgery is currently the only option to completely restore cardiac function, but many patients die while waiting for a transplant due to a longstanding organ donor shortage. Thus, there is a dire need for accessible treatment options that can repair damaged hearts. Recent advances in tissue engineering and regenerative medicine have accelerated the development of therapies for …

Experimental And Computational Platforms For Studying Systems Mechanobiology, Brendyn Miller

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Mechanical stimulation through physical activity has been shown to play an important role in treating and preventing several non-communicable diseases such as hypertension, lower back pain (LBP), type-2 diabetes mellitus, and several cancers. This is accomplished through the regulation of cellular behavior and tissue remodeling within the body at both the micro- and macro-scale levels. The goal of mechanobiology research is to gain in-depth knowledge and understanding of how cells sense physical forces in conjunction with other biochemical cues and translate those factors into important biological functions that either maintain tissue homeostasis or lead to pathological states. Understanding these processes …

Assessing Chondrocyte Viability Of Articular Cartilage Using Label-Free Imaging Methods, Hongming Fan

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ABSTRACT

Articular cartilage covers the ends of bones, providing a protective layer that can endure forces during movement. Chondrocytes, the only cell type found in articular cartilage, produce collagen fibers and proteoglycans that maintain the extracellular matrix (ECM). Cartilage damage impairs chondrocytes and their ability to maintain tissue stability. There are various factors that can cause cell death, which can be broadly classified into two categories: programmed cell death (apoptosis) and non-programmed cell death (necrosis). The consequences of cell death can have significant impacts on the extracellular matrix (ECM). The ECM is a complex network of proteins and carbohydrates that …

An In Vitro Platform To Characterize Myocardial Wound Remodeling, Jonathan Heywood

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Heart Failure, sometimes called Congestive Heart Failure, is a collection of pathological disruptions in which the heart is unable to pump blood properly. It affects over 6 million people in the United States, with the cost-per-patient at approximately $30,000 and the total cost estimated to be $160 billion by 2030. There is no single cause of heart failure, as it can manifest as a varying array of diseases, disorders, and syndromes. However, many of these underlying diseases result specifically from dysregulation of mechanically active cells called cardiac fibroblasts, which play a critical role in the remodeling of the extracellular matrix …

Prevention And Reversal Of Elastin-Associated And Phosphate-Dependent Arterial Calcification Using Targeted Nanotherapeutics In Pre-Clinical Models, Fatema Tuj Zohora

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Vascular calcification can be life-threatening, involving calcium phosphate crystal deposits in the blood vessels. The calcification in the intimal layer of the arterial wall is usually associated with atherosclerotic plaque build-up that, in the advanced stage, harbors ‘dispersed’ and ‘spotty’ deposits of calcium phosphate crystals in the necrotic core of the plaque. In contrast, medial arterial calcification (MAC) can form independently of atherosclerosis and appears as ‘Railroad-like’ calcific deposits along degraded elastin lamellae in the medial layer of arteries. The mechanisms of such elastin-associated medial arterial calcification and potential therapies are the key concerns of this dissertation. MAC is common …

Development & Validation Of Needle-Based Metrics For Hemodialysis Cannulation Skill Assessment, Ziyang Zhang

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Dialysis is a vital medical treatment for patients with end-stage renal disease. An arteriovenous fistula, a surgically created connection between an artery and a vein, is the preferred vascular access for dialysis due to superior clinical outcomes. However, cannulation complications caused by needle-related errors are common and dangerous, necessitating the need for effective cannulation training. Despite cannulation being a challenging and complex clinical procedure, little is known about the quantitative aspects of needle insertion dynamics necessary for skilled cannulation. The aim of this study was to develop meaningful and instructive needle-based metrics for cannulation skill assessment and training.

Two iterations …

Investigating The Potential Of A Cell-Based Gene Editing Therapy For Inherited Metabolic Liver Disease, Ilayda Ates

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Inherited metabolic diseases (IMDs) affecting the liver are relatively rare but collectively have a prevalence of 1 in 800 live births. These diseases result from autosomal recessive single-gene mutations, leading to organ dysfunction and potentially fatal consequences if left untreated. One potential therapeutic strategy for IMDs of the liver involves using CRISPR-Cas9-induced loss of function mutations. However, translating this approach into the clinic is limited by the need for safe and effective CRISPR delivery methods. Adeno-associated viral vectors (AAVs), commonly used for CRISPR delivery, are associated with significant safety and efficacy concerns, including risks for immunogenicity, off-target mutagenesis, and genotoxicity …

In Vitro And In Vivo Diabetic Models For Assessment Of Tissue Engineered Vascular Grafts, Juan Carlos Carrillo Garcia

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Diabetes has become one of the leading causes of lower-limb loss worldwide. Every 30 seconds, a person loses a limb due to diabetic-related vascular complications. About one-third of patients needing lower-limb bypass surgery have debilitated autologous vessels unsuitable for use, and no other good long-term options are available. These detrimental effects on the vasculature are caused mainly by the hyperglycemic and hyperlipidemic conditions derived from diabetes. Under these conditions, an increase in advanced glycation end products (AGEs) and reactive oxygen species leads to irreversible crosslinks of extracellular matrix proteins, accelerating vascular pathology through vascular stiffening, endothelial dysfunction, inflammation, atherosclerosis, fibrosis, …

Assesment Of Structure, Function, And Microevolutionary Dynamics Of Extrachromosomal Circular Dna In Chinese Hamster Ovary Cells, Dylan Chitwood

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Chinese hamster ovary (CHO) cell lines are among the most popular expression hosts used in biopharmaceutical manufacturing due to relative ease of culture, capacity to perform human-like post-translational modifications, and non-susceptibility to viruses. However, the intrinsic plasticity of the CHO genome can lead to undesired genetic rearrangements, phenotypic shifts, reduced product quality, and early culture termination that prevents continuous biomanufacturing. A characteristic of plastic and unstable genomes that is poorly understood in CHO cells is extrachromosomal circular DNA (eccDNA). EccDNAs are focal amplifications of the genome that reside in the extranuclear space. These plasmid-like entities are structurally complex and are …

3d Printing With Photopolymerizable Polyester Resins For Resorbable Medical Device Applications, Mathew Murphy Stanford

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In the past decade, the healthcare industry has seen a significant increase in the use of additive manufacturing (AM or “3D printing”) with subsequent improvement in clinical outcomes.As an exceptional AM technology, vat-photopolymerization (VP), often called stereolithography, can create complex structures and has thus been adopted for a range of biomedical applications including surgical guides, temporary implants, and resorbable tissue scaffolds.However, limitations remain in the availability of photopolymerizable resin materials with appropriate mechanical performance, biodegradability, and biocompatibility for application to resorbable medical devices.

The objective of this work was to employ novel photopolymerizable polyester-based macromers in the development of resorbable …

Development Of Enzyme-Responsive Polymersomes As A Drug Delivery System For Gm1 Gangliosidosis, Bipin Chakravarthy Paruchuri

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GM1 gangliosidosis is a lysosomal storage disorder caused by deficiency of β-galactosidase (βgal) and subsequent accumulation of GM1 ganglioside in lysosomes. The rare nature of this disorder presents challenges with prognosis and treatment. Enzyme replacement therapy (ERT) can effectively treat systemic deficiencies, but the intravenously administered enzyme cannot cross the blood-brain barrier (BBB) to treat the central nervous system. A delivery system to encapsulate and deliver the enzyme can facilitate enzyme transport across the BBB with suitable surface modifications. One of the pathological aspects of GM1-affected cells is the upregulation of the lysosomal enzyme hexosaminidase A (HexA). In this dissertation, …

In Vitro Bioreactor For Mechanical Control And Characterization Of Tissue Constructs, Samuel Coeyman

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Heart failure (HF) currently affects over 6 million Americans, 50% of whom die within 5 years of their initial diagnosis. A major contributor to the onset of HF is cardiac fibrosis in the myocardium, which arises when fibroblasts (FBs) are activated in response to heightened mechanical stress from overload conditions like hypertension. Activated FBs remodel the extracellular matrix (ECM) and secrete ECM proteins including collagen. FB remodeling has been studied in the past by applying forces and/or deformations to three-dimensional, cell-seeded gels and tissue constructs in vitro. Unfortunately, previous stretching platforms have traditionally not enabled mechanical property assessment to be …

Scalable Data-Driven Predictive Modeling And Analytics For Cho Process Development Optimization, Sarah Mbiki

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In 1982, the FDA approved the first recombinant therapeutic protein, and since then, the biopharmaceutical industry has continued to develop innovative and highly effective biological drugs for various illnesses¹. These drugs are produced using host organisms that are modified to hold the genetic encoding of the targeted protein¹. Of the many host organisms, Chinese hamster ovary (CHO) cells are often used due to capability to perform posttranslational modification (PTM): which allows human-like synthesis of proteins unlikely to invoke immunogenicity in humans ^1,2.

Despite all the positive attributes, many challenges are associated with CHO cell cultures, …

Development Of A Tissue Engineered Cardiac Patch, Howard Herbert

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Cardiovascular Disease(CVD) is the leading cause of mortality in the developed world. CVD is most commonly manifested as atherosclerosis of the coronary arteries leading to Myocardial Infarction(MI). After MI, fibrosis of the ventricular wall leads to heart failure(HF), a pandemic affecting 26 million people globally. While therapies are continuously developed to combat HF, the treatment of choice, whole heart transplant, is limited by the availability of donor hearts. It is clear that there is a need to develop a long-term solution to combat HF and its enormous economic burden. Tissue Engineering and Regenerative Medicine holds promise as a possible solution …

Highly Adherent Antimicrobial Coatings For Orthopedic Implants, Mikhail Bredikhin

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Fracture-related infections (FRIs) are the most devasting sort of complications associated with fracture fixation devices, as they lead to patients’ morbidity, prolonged hospitalization, amputations, and even death.External fixators additionally suffer from pin site infections (PSIs), which initiate at the skin entry points of the skin-metallic pin interface present in the external fixation of the damaged bones, often causing deep tissue infection and osteomyelitis. Small percutaneous pins, commonly known as Kirschner wires (K-wires), are used to treat complex fractures and deformities.They are drilled inside the diseased bone for the healing period and are left protruding outside the skin for fixation adjustments …

Investigating Spatial Heterogeneity In Myocardial Wound Environments To Improve Therapy, Michael Potter

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Heart failure is a broad pathology manifestation categorized by an inability of the heart to successfully pump blood throughout the vast vessel network of the body. Within the United States, heart failure is projected to increase by approximately 46% from 2012 to 2030. Modalities of heart failure are generally related to wall mechanics that are impacted following myocardial infarction events. Interplay exists between the wall mechanics, responding cell populations, and the spatial heterogeneities in the resultant scar. This interplay directs the myocardium towards heart failure modalities governed by overly stiff or compliant states. It is essential to elucidate details underlying …

The Development And Analysis Of Methods Used To Evaluate American Football Facemasks, Alexander Bina

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The motivation for this Ph.D. dissertation is to provide football equipment managers, coaches, parents, athletes, and relevant industry personnel with an understanding of the implication a chosen football facemask design will have on the safety of the athlete. As athletes have increased their capacity for speed, size, and strength, so too has the head injury risk increased in American football. To align with the increase in head impact injury in American football, the protective head impact community must expand its capacity to evaluate protective equipment systems. This dissertation focuses specifically on one helmet system component: the football facemask. This dissertation …

Using In Vitro, In Silico, And In-Classroom Techniques To Address The Gender Data Gap In Health Care, Kelsey Watts

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Cardiovascular diseases (CVDs) are the leading cause of death worldwide in males (XY) and females (XX). Prior to menopause, females have a relative protection against serious cardiac pathologies compared to age-matched males. This phenomenon is widely attributed to the ovarian hormone estrogen. Unfortunately, hormone replacement therapy to maintain estrogen levels in postmenopausal females has overall adverse effects, and it is not recommended for long-term use or as a preventative measure for eCVDs. A major driver of CVDs, specifically heart failure, is cardiac fibrosis: the continued buildup of scar tissue that reduces the heart’s ability to pump. There are currently no …

Multi-Scale Vertebral-Kinematics Based Simulation Pipeline Of The Human Spine With Application To Spine Tissues Analysis, Mohd Jaradat

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This study developed an analytical tool for understanding spine tissues’ behavior in response to vertebral kinematics and spine pathology over a range of body postures. It proposed a novel pipeline of computational models based on predicting individual vertebral kinematics from measurable body-level motions, using musculoskeletal dynamics simulations to drive the vertebrae in corresponding spine FEMs.

A reformulated elastic surface node (ESN) lumbar model was developed for use in MSD simulations. The ESN model modifies the lumbar spine within an existing MSD model by removing non-physiological kinematic constraints and including elastic IVD behavior. The model was scaled using subject-specific anthropometrics and …

Development Of A Reverse Engineered, Parameterized, And Structurally Validated Computational Model To Identify Design Parameters That Influence American Football Faceguard Performance, William Ferriell

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Traumatic brain injury (TBI) continues to have the greatest incidence among athletes participating in American football. The headgear design research community has focused on developing accurate computational and experimental analysis techniques to better assess the ability of headgear technology to attenuate impacts and protect athletes from TBI. Despite efforts to innovate the headgear system, minimal progress has been made to innovate the faceguard. Although the faceguard is not the primary component of the headgear system that contributes to impact attenuation, faceguard performance metrics, such as weight, structural stiffness, and visual field occlusions, have been linked to athlete safety. To improve …

Mitral Valve Tissue Engineering - A Dynamic Model For Investigating The Mechanism Of Valvular Pathology, Collin Owens

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Heart valve disease affects an average of 2.5% of the population in the United States. The mitral valve (MV) is the most complex of the heart’s four valves and is most associated with the disease by exhibiting altered extracellular matrix (ECM) which translates into stenosis or regurgitation. These diseases are typically degenerative in nature and can be accelerated by risk factors such as diabetes and hypertension. With diabetes and hypertension affecting 425 million and 1.39 billion people worldwide, further investigation into these risk factors is warranted. This study aims to develop and test an in vitro model of MV disease. …

Porous Silicon Photonics For Label-Free Interferometric Biosensing And Flat Optics, Tahmid Hassan Talukdar

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This dissertation uses porous silicon as a material platform to explore novel optical effects in three domains: (i) It studies dispersion engineering in integrated waveguides to achieve high performance group index sensing. With proper design parameters, the sensor waveguides can theoretically achieve 6 times larger group index shift compared to the actual bulk effective refractive index shift. We demonstrate the guided mode confinement factor to be a key parameter in design and implementation of these waveguides. (ii) It explores multicolor laser illumination to experimentally demonstrate perceptually enhanced colorimetric sensing, overcoming the limitations faced by many contemporary colorimetric sensors. Our technique …