Engineering Commons^™

Blood Flow Regulates Atherosclerosis Progression And Regression, Morgan A. Schake

Department of Mechanical and Materials Engineering: Dissertations, Theses, and Student Research

Atherosclerosis is the most prevalent pathology of cardiovascular disease with no known cure. Despite the many systemic risk factors for atherosclerosis, plaques do not form randomly in the vasculature. Instead, they form around bifurcations and the inner curvature of highly curving arterial segments that contain so-called disturbed blood flow that is low in magnitude and multidirectional over the cardiac cycle. Conversely, straight, non-bifurcated arterial segments that contain moderate-to-high and unidirectional (i.e., normal) blood flow are protected from plaque development. Thus, blood flow is a key regulator of atherosclerosis that may be able to be leveraged to develop new therapeutics. Towards …

The Influence Of Myoblast Implantation On Arteriogenesis In Mice With Diet-Induced Obesity, Rayana Gutierrez

Biomedical Engineering

Peripheral arterial occlusive disease (PAOD) is characterized by atherosclerosis, which is the buildup of plaque, consisting largely of cholesterol, in the arterial walls. This plaque accumulation eventually blocks blood flow to the limbs, causing symptoms such as intermittent claudication and tissue death in cases of critical limb ischemia. The body compensates for the reduced perfusion by enlarging pre-existing bypass arteries, known as collaterals, in a process called arteriogenesis. However, in many cases, collateral networks constructed through arteriogenesis fail to enlarge sufficiently or function effectively in patients. Therefore, the development of a therapeutic intervention specifically targeting this process would offer a …

Development And Evaluation Of A Nanomatrix Coated Stent Using A Vascular Sheet With Atherosclerosis Model, Xixi Zhang

All ETDs from UAB

While cardiovascular stent technology has considerable advances, there are hurdles to overcome due to the dysfunctional stented arteries which fail to maintain vascular homeostasis. Current stent designs ignored the significance of promoting functional artery healing (pro-healing). Therefore, we developed a pro-healing nanomatrix coating for stent. Previous studies investigated its effect on individual vascular cell type. In natural artery, there are multiple vascular cell types that strongly affect stent performance. Thus, an in vitro vascular double-layer (VDL) system was used to observe stent effects on different vascular cell types. And the pro-healing ability and mechanism of the nanomatrix coated stent were …

Reactive Oxygen Species (Ros)-Responsive Size-Reducible Nanoassemblies For Deeper Atherosclerotic Plaque Penetration And Enhanced Macrophage-Targeted Drug Delivery, Jianhua He, Wenli Zhang, Xiaoju Zhou, Fengfei Xu, Jiahui Zou, Qiqi Zhang, Yi Zhao, Hongliang He, Hu Yang, Jianping Liu

Chemical and Biochemical Engineering Faculty Research & Creative Works

Nanoparticle-based therapeutics represent potential strategies for treating atherosclerosis; however, the complex plaque microenvironment poses a barrier for nanoparticles to target the dysfunctional cells. Here, we report reactive oxygen species (ROS)-responsive and size-reducible nanoassemblies, formed by multivalent host-guest interactions between β-cyclodextrins (β-CD)-anchored discoidal recombinant high-density lipoprotein (NP³_ST) and hyaluronic acid-ferrocene (HA-Fc) conjugates. The HA-Fc/NP³_ST nanoassemblies have extended blood circulation time, specifically accumulate in atherosclerotic plaque mediated by the HA receptors CD44 highly expressed in injured endothelium, rapidly disassemble in response to excess ROS in the intimal and release smaller NP³_ST, allowing for further …

Nanoanalytical Analysis Of Bisphosphonate-Driven Alterations Of Microcalcifications Using A 3d Hydrogel System And In Vivo Mouse Model, Jessica L. Ruiz, Joshua D. Hutcheson, Luis Cardoso, Amirala Bakhshian Nik, Alexandra Condado De Abreu, Tan Pham, Fabrizio Buffolo, Sara Busatto, Stefania Frederici, Andrea Ridolfi, Masanori Aikawa, Sergio Bertazzo, Paolo Bergese, Sheldon Weinbaum, Elena Aikawa

Publications and Research

Vascular calcification predicts atherosclerotic plaque rupture and cardiovascular events. Retrospective studies of women taking bisphosphonates (BiPs), a proposed therapy for vascular calcification, showed that BiPs paradoxically increased morbidity in patients with prior acute cardiovascular events but decreased mortality in event-free patients. Calcifying extracellular vesicles (EVs), released by cells within atherosclerotic plaques, aggregate and nucleate calcification. We hypothesized that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the risk of plaque rupture. Three-dimensional (3D) collagen hydrogels incubated with calcifying EVs were used to mimic fibrous cap calcification in vitro, while an ApoE−/− mouse was used …

Atherosclerosis: Pathology, Role Of Sd-Ldl, Particle Size Characterization Of Sd-Ldl With Multiangle Light Scattering, Akshay Sudhakar Ukey

Masters Theses

Atherosclerosis is an inflammatory disease due to the accumulation of lipids in the inner wall of arteries. As per the report of Center of Diseases Control and Prevention (CDC), 1 in every 4 deaths is due to heart diseases each year. Atherosclerosis occurs when artery walls harden by the buildup of cholesterol, forming multiple atherosclerotic plaques within the aorta (4). Out of the modern medicines available to control cholesterol, statin is amongst the foremost widely used because it is both safe and effective in lowering high risk patients (9). However, usage of high statins dosage typically leads to some mild …

Oxidized Phospholipid Regulation Of Chronic Inflammation In Endothelial Cells, Cameron Scott Brutsche

Masters Theses

Atherosclerosis, the primary cause of Coronary Heart Disease (CHD), has become one of the top causes of death in the world. As low-density lipoprotein (LDL) particles become trapped and oxidized inside arterial walls, the primary oxidation products of 1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphatidylcholine (PAPC) induce the binding of monocytes which can potentially lead to fatty plaque build ups. A fragment of one of these oxidation products, OxPAPC, has previously been studied and can act as standard for testing new phospholipids and how they affect protein expression levels. The central hypothesis of this study was that three newly studied classes of oxidized fatty …

In Vitro Atherosclerosis Disease Model Via The Ring Stacking Method, Cameron Brandon Pinnock

Wayne State University Dissertations

Creation of an in vitro atherosclerotic disease model using the novel Ring Stacking Method. Singular self-assembling tissue rings made up smooth muscle cells and fibrin hydrogel are stacked on one another to create a tissue engineered vessel. These biologically engineered blood vessels are then seeded with endothelial cells via combined static rotational and dynamic bioreactor in order to create a functional intima layer. Early stage atherosclerosis was induced via the addition of oxidized low-density lipoproteins (ox-LDL) to the fibrin hydrogel that creates the media layer of the engineered vessel. After the creation of the intima layer the engineered vessel was …

Knockdown Of Heparan Sulfate Via Ndst1 Knockout Does Not Inhibit Mouse Aortic Endothelial Cell Alignment In-Vivo, John Diaz De Leon Iii

Dissertations and Theses

Atherosclerotic plaque localizes in predictable areas such as arches and bifurcations which are characterized by disturbed flow patterns and the resulting damage and dysfunction to the endothelium. Endothelial cells (ECs) under sustained laminar flow align in the direction of flow; however, under disturbed flow conditions, ECs sustain damage to their glycocalyx (GCX) which results in unaligned and rounder cells. An investigation into the role of NDST1 sulfation of heparan sulfate (HS), a key component of many proteoglycans which make up the GCX, was conducted. The descending aortas (DAs) of transgenic mice with conditional knockouts (KOs) of NDST1 in vascular ECs …

Pet/Mr Imaging Of Hypoxic Atherosclerotic Plaque Using 64cu-Atsm, Xingyu Nie

McKelvey School of Engineering Theses & Dissertations

ABSTRACT OF THE DISSERTATION

PET/MR Imaging of Hypoxic Atherosclerotic Plaque Using 64Cu-ATSM

by

Xingyu Nie

Doctor of Philosophy in Biomedical Engineering

Washington University in St. Louis, 2017

Professor Pamela K. Woodard, Chair

Professor Suzanne Lapi, Co-Chair

It is important to accurately identify the factors involved in the progression of atherosclerosis because advanced atherosclerotic lesions are prone to rupture, leading to disability or death. Hypoxic areas have been known to be present in human atherosclerotic lesions, and lesion progression is associated with the formation of lipid-loaded macrophages and increased local inflammation which are potential major factors in the formation of vulnerable …

Optical Probing Of Gastrocnemius In Patients With Peripheral Artery Disease Characterizes Myopathic Biochemical Alterations And Correlates With Stage Of Disease, Ryan A. Becker, Kim Cluff, Nithyanandhi Duraisamy, Hootan Mehraein, Hussam Farhoud, Tracie Collins, George P. Casale, Iraklis I. Pipinos, Jeyamkondan Subbiah

Department of Biological Systems Engineering: Papers and Publications

Peripheral artery disease (PAD) is a condition caused by atherosclerotic blockages in the arteries supplying the lower limbs and is characterized by ischemia of the leg, progressive myopathy, and increased risk of limb loss. The affected leg muscles undergo significant changes of their biochemistry and metabolism including variations in the levels of many key proteins, lipids, and nucleotides. The mechanisms behind these changes are poorly understood. The objective of this study was to correlate the severity of the PAD disease stage and associated hemodynamic limitation (determined by the ankle brachial index, ABI) in the legs of the patients with alterations …

Disturbed Cyclical Stretch Of Endothelial Cells Promotes Nuclear Expression Of The Pro-Atherogenic Transcription Factor Nf-Kb, Ryan M. Pedrigi, Konstantinos I. Papadimitriou, Avinash Kondiboyina, Sukhjinder Sidhu, James Chau, Miten B. Patel, Daniel C. Baeriswyl, Emmanuel M. Drakakis, Rob Krams

Department of Mechanical and Materials Engineering: Faculty Publications

Exposure of endothelial cells to low and multidirectional blood flow is known to promote a pro-atherogenic phenotype. The mechanics of the vessel wall is another important mechano-stimulus within the endothelial cell environment, but no study has examined whether changes in the magnitude and direction of cell stretch can be pro-atherogenic. Herein, we developed a custom cell stretching device to replicate the in vivo stretch environment of the endothelial cell and examined whether low and multidirectional stretch promote nuclear translocation of NF-kB. A fluid–structure interaction model of the device demonstrated a nearly uniform strain within the region of cell attachment and …

Lipid Detection In Pig Arteries Using Intravascular Photoacoustic Imaging, Jieying Mai, Yingchun Cao, Ayeeshik Kole, Michael Sturek, Ji-Xin Cheng

The Summer Undergraduate Research Fellowship (SURF) Symposium

Heart disease is the leading cause of death in the United States and worldwide. Each year over 370,000 people died from coronary artery disease in America. As the primary form of coronary artery disease, atherosclerosis behaves as lipid-rich plaque development inside an artery wall. Vulnerable plaques are those prone to rupture, which may result in thrombus or even death. Typical hallmarks of a vulnerable plaque include thin fibrous cap, a large lipid-rich necrotic core and inflammatory infiltrate. The identification and accurate detection of these lipid depositions in the arterial wall is crucial in the diagnosis of atherosclerosis. However, none of …

Temporally And Spatially Resolved Quantification Of Hemodynamic Forces And Endothelial Mechanics, Lori M. Lambert

Department of Mechanical and Materials Engineering: Dissertations, Theses, and Student Research

The endothelium is a thin layer of endothelial cells that line the interior surface of an artery. Due to their direct contact with blood flow, endothelial cells experience varying hemodynamic forces and respond to these forces by altering their morphology. When plaque and other substances accumulate in the walls of arteries, i.e., atherosclerosis, endothelial cells have abnormal responses to blood flow. Studying atherosclerosis progression is, therefore, a two-fold investigation into 1) the hemodynamic forces that cause endothelial responses, and 2) the biological and mechanical responses of endothelial cells. The ultimate goal of this study was to develop an experimental …

Influence Of Shear Stress Magnitude And Direction On Atherosclerotic Plaque Composition, Ryan M. Pedrigi, Vikram V. Mehta, Sandra M. Bovens, Zahra Mohri, Christian Bo Poulsen, Willy Gsell, Jordi L. Tremoleda, Leila Towhidi, Ranil De Silva, Enrico Petretto, Rob Krams

Department of Mechanical and Materials Engineering: Faculty Publications

The precise flow characteristics that promote different atherosclerotic plaque types remain unclear. We previously developed a blood flow-modifying cuff for ApoE^−/− mice that induces the development of advanced plaques with vulnerable and stable features upstream and downstream of the cuff, respectively. Herein, we sought to test the hypothesis that changes in flow magnitude promote formation of the upstream (vulnerable) plaque, whereas altered flow direction is important for development of the downstream (stable) plaque. We instrumented ApoE^−/− mice (n=7) with a cuff around the left carotid artery and imaged them with micro-CT (39.6 μm resolution) eight to nine weeks …

Molecularly Targeted Nanoparticles For Modulation Of Inflammatory Mediators In Atherosclerosis, Rohun Udatta Palekar

McKelvey School of Engineering Theses & Dissertations

The enzyme thrombin has been demonstrated through experimental and clinical studies to play a crucial role in mediating both inflammation and thrombosis in atherosclerosis. The cellular effects of thrombin in promoting atherosclerosis involve the activation of signaling pathways that result in the secretion of a host of various chemokines, cytokines, cell adhesion molecules, etc. that promote vascular inflammation. Due in part to thrombin and other pro-atherogenic molecules, this prolonged inflammatory state in atherosclerosis results in the deterioration of the endothelium, increasing the risk of focal thrombosis. Current treatment strategies to address the role of thrombin in atherosclerosis, despite efficacy of …

Mimicking The Arterial Microenvironment With Peg-Pc To Investigate The Roles Of Physicochemical Stimuli In Smc Phenotype And Behavior, William G. Herrick

Doctoral Dissertations

The goal of this dissertation was to parse the roles of physical, mechanical and chemical cues in the phenotype plasticity of smooth muscle cells (SMCs) in atherosclerosis. We first developed and characterized a novel synthetic hydrogel with desirable traits for studying mechanotransduction in vitro. This hydrogel, PEG-PC, is a co-polymer of poly(ethylene glycol) and phosphorylcholine with an incredible range of Young’s moduli (~1 kPa - 9 MPa) that enables reproduction of nearly any tissue stiffness, exceptional optical and anti-fouling properties, and support for covalent attachment of extracellular matrix (ECM) proteins. To our knowledge, this combination of mechanical range, low …

Oxidized Phospholipids Regulation Of The Monocyte Recruitment Parthway In Human Aortic Endothelial Cells, Piao Jian Tan

Masters Theses

Low-density lipoprotein particles in blood plasma invade the endothelium and become oxidized, creating risk of CHD associated with atherosclerosis, the main underlying condition in coronary heart disease. Oxidation products of the phospholipid 1-palmitoyl- 2-arachidonoyl-sn-glycerol-3-phosphatidylcholine (PAPC) are bioactive components of minimally oxidized LDL that stimulate endothelial cells that line the artery, leading to monocyte binding and atherosclerosis. It is hypothesized that the regulation of the monocyte recruitment pathway by these oxidized phospholipids is mediated by the binding of OxPAPC to one or more mediating proteins. Human recombinant VEGFR2, GRP78, and EP2bind to OxPNB, a biotinylated analog of OxPAPC, demonstrated using Western …

Smooth Muscle Stiffness Sensitivity Is Driven By Soluble And Insoluble Ecm Chemistry, William G. Herrick, Shruti Rattan, Thuy V. Nguyen, Michael S. Grunwald, Christopher W. Barney, Alfred J. Crosby, Shelly Peyton

Chemical Engineering Faculty Publication Series

Smooth muscle cell (SMC) invasion into plaques and subsequent proliferation is a major factor in the progression of atherosclerosis. During disease progression, SMCs experience major changes in their microenvironment, such as what integrin-binding sites are exposed, the portfolio of soluble factors available, and the elasticity and modulus of the surrounding vessel wall. We have developed a hydrogel biomaterial platform to examine the combined effect of these changes on SMC phenotype. We were particularly interested in how the chemical microenvironment affected the ability of SMCs to sense and respond to modulus. To our surprise, we observed that integrin binding and soluble …

Quantification Of Plaque Stiffness By Brillouin Microscopy In Experimental Thin Cap Fibroatheroma, Giuseppe Antonacci, Ryan M. Pedrigi, Avinash Kondiboyina, Vikram V. Mehta, Ranil De Silva, Carl Paterson, Rob Krams, Peter Torok

Department of Mechanical and Materials Engineering: Faculty Publications

Plaques vulnerable to rupture are characterized by a thin and stiff fibrous cap overlaying a soft lipid-rich necrotic core. The ability to measure local plaque stiffness directly to quantify plaque stress and predict rupture potential would be very attractive, but no current technology does so. This study seeks to validate the use of Brillouin microscopy to measure the Brillouin frequency shift, which is related to stiffness, within vulnerable plaques. The left carotid artery of an ApoE^-/- mouse was instrumented with a cuff that induced vulnerable plaque development in nine weeks. Adjacent histological sections from the instrumented and control arteries …

Characterizing Phantom Arteries With Multi-Channel Laser Ultrasonics And Photo-Acoustics, Jami L. Johnson, Kasper Van Wijk, Michelle Sabick

Mechanical and Biomedical Engineering Faculty Publications and Presentations

Multi-channel photo-acoustic and laser ultrasonic waves are used to sense the characteristics of proxies for healthy and diseased vessels. The acquisition system is non-contacting and non-invasive with a pulsed laser source and a laser vibrometer detector. As the wave signatures of our targets are typically low in amplitude, we exploit multi-channel acquisition and processing techniques. These are commonly used in seismology to improve the signal-to-noise ratio of data. We identify vessel proxies with a diameter on the order of 1 mm, at a depth of 18 mm. Variations in scattered and photo-acoustic signatures are related to differences in vessel wall …

Apelin Regulation Of K-Cl Cotransport In Vascular Smooth Muscle Cells., Neelima Sharma

Browse all Theses and Dissertations

Atherosclerosis and high circulating levels of oxidized low density lipoproteins (oxLDL) are considered among the most important risk factors for the occurrence and development of cardiovascular disease (CVD). During the atherosclerotic lesion repair, phenotypic transition of vascular smooth muscle cells (VSMCs) from contractile to synthetic states plays a central role. In this process, enhanced proliferation/migration of VSMCs, from the tunica media to the intima, is required to sustain blood vessel endothelium integrity, and for inducing vessel wall remodeling in response to injury. At the molecular level, the activity of electroneutral potassium-chloride cotransporters or KCCs, is necessary to: a) allow changes …

Piv-Based Investigation Of Hemodynamic Factors In Diseased Carotid Artery Bifurcations With Varying Plaque Geometries, Sarah Kefayati

Electronic Thesis and Dissertation Repository

Ischemic stroke is often a consequence of complications due to clot formation (i.e. thrombosis) at the site of an atherosclerotic plaque developed in the internal carotid artery. Hemodynamic factors, such as shear-stress forces and flow disturbances, can facilitate the key mechanisms of thrombosis. Atherosclerotic plaques can differ in the severity of stenosis (narrowing), in eccentricity (symmetry), as well as inclusion of ulceration (wall roughness). Therefore, in terms of clinical significance, it is important to investigate how the local hemodynamics of the carotid artery is mediated by the geometry of plaque. Knowledge of thrombosis-associated hemodynamics may provide a basis to introduce …

Systems Biology Of The Functional And Dysfunctional Endothelium, Jennifer Frueh, Nataly Maimari, Takayuki Homma, Sandra M. Bovens, Ryan M. Pedrigi, Leila Towhidi, Rob Krams

Department of Mechanical and Materials Engineering: Faculty Publications

This review provides an overview of the effect of blood flow on endothelial cell (EC) signalling pathways, applying microarray technologies to cultured cells, and in vivo studies of normal and atherosclerotic animals. It is found that in cultured ECs, 5–10% of genes are up- or down-regulated in response to fluid flow, whereas only 3–6% of genes are regulated by varying levels of fluid flow. Of all genes, 90%are regulated by the steady part of fluid flow and 10% by pulsatile components. The associated gene profiles show high variability from experiment to experiment depending on experimental conditions, and importantly, the bioinformatical …

Drug Treatment Of Kidney Clip-Induced Hypertension In Rats; Peroxidase Tracer Spot Frequency In Rat Aorta After Chemically Induced Apoptosis, Simon Kleinbart

Dissertations and Theses

No abstract provided.