Browsing by Subject "Biomedical Engineering"

Now showing 1 - 20 of 42
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    Applications of the visible heart for cardiac valve repair and replacement devices.
    (2009-05) Quill, Jason Lloren
    The Visible Heart® methodologies utilize an isolated heart apparatus for the investigation of large mammalian hearts, such as human, swine, canine, or sheep. In vitro, the hearts are perfused with a clear buffer, allowing for real-time, intracardiac imaging of a beating heart. These methodologies have been developed, enhanced, and employed at the University of Minnesota for over ten years, with the general methods having been previously described. The primary focus of earlier studies was on lead implantation and assessments of functional anatomy. My work was to investigate how this unique experimental setup could be optimized to better understand valve function. In addition, I designed subsequent experiments as a means to better design products for the repair and/or replacement of pathological cardiac valves. In order to achieve my desired thesis goal, it was paramount to gain a thorough understanding of cardiac anatomy. As such, a review of the four main cardiac valves is provided in Chapter 1. The goal of this chapter is to familiarize the reader with current nomenclature of the cardiac valves as well as the important anatomical features associated with each. In Chapter 2, the capabilities and limitations of the Visible Heart®, in its current state, are discussed in context of the design process for cardiac valve repair and/or replacement products. To this end, the following areas are identified as applications for the Visible Heart® that can aid valve repair and replacement: (1) Functional Anatomy, (2) Device Delivery and Device/Tissue Interactions, (3) Chronic Model Development and Acute Valve Assessment, (4) Acute Assessment of Surgical Repairs, (5) Pre-clinical Human Heart In Vitro Testing, and (6) Early Prototype Testing for Designers. Chapters 3-7 provide detailed examples of employing Visible Heart® methodologies as they relate to each of these areas. The functional anatomy affecting two percutaneous mitral valve repair procedures is discussed in Chapters 3 and 4. Chapter 5 investigates the delivery and device/tissue interactions of a transcatheter pulmonary valve. A chronic animal model of dilated cardiomyopathy was developed in which mitral regurgitation due to ventricular remodeling was observed after several weeks of pacing; this model is now available within the Visible Heart® for acute assessment of devices seeking to treat this valve pathology (Chapter 6). Chapter 7 then looks at the acute assessment of the "edge-to-edge" mitral valve repair technique following induced P2 prolapse and provides control data for any device seeking to mimic this repair procedure percutaneously. Perfusion-fixed human specimens were utilized in Chapters 3 and 4, and a reanimated human heart was utilized for in vitro testing in Chapter 5. Finally, many early prototypes have been studied and tested in our laboratories using the Visible Heart® methods, but it is beyond the scope of this thesis to discuss the details of these studies. This work has advanced our understanding of the capabilities and limitations of a large mammalian, isolated heart preparation as it relates to the design processes for valve replacement and/or repair devices. This work is not an exhaustive list, but rather the beginning of many potential studies that will now be better designed based upon the capabilities and limitations I have identified. Additionally, the Visible Heart® is a dynamic system that will continue to advance and add capabilities, which will only serve to make it more important in the field of valve assessment.
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    Cardiac repair using fibrin patch-based enhanced delivery of stem cells and novel strategies for fast examination of myocaridal energetics in vivo using 31P magnetic resonance spectroscopy.
    (2011-03) Xiong, Qiang
    The dissertation is related to heart disease in both basic scientific and pre-clinic respects. Cardiovascular disease is a leading cause of death in the developed countries even with optimal medical treatment. Recently, the emerging stem cell biology has shown great potentials for cardiac repair. Using both large (swine) and small (rodent) animal models with ischemic heart disease, we examined the functional improvement of enhanced delivery of combined human embryonic stem cell-derived endothelial cells and smooth muscle cells via a fibrin 3D porous scaffold biomatrix. The integration of stem cell biology and tissue engineering has resulted in significant improvement of both regional and global left ventricle function as compared to untreated animals, demonstrating a promising therapeutic strategy of using this cell type and the novel mode of delivery. As a most energy demanding organ, the heart energetic status is tightly associated with the organ's physiological and pathological conditions. Based on the ultra-high-field magnetic resonance imaging/spectroscopy techniques, we developed a noninvasive modality for rapid examination of cardiac energetics in vivo. The new platform will offer unprecedented understanding into the relationship between the cardiac energetic status and the organ's physiological/pathological conditions, and thus it is of great potential in both basic scientific research and clinical diagnosis.
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    Cellular adhesion dynamics: investigation of molecular clutch attachment and force transmission.
    (2008-12) Chan, Clarence Elvin
    As the major structural element of the cell, the cytoskeleton plays a vital role in response and transmission of forces in both extracellular and intracellular environments. For instance, in cell motility, the cell utilizes a host of proteins to physically link F-actin to the extracellular substrate, allowing the cell to exert traction forces as well as probe the mechanics of its local environment. During mitosis, the cell constructs a mitotic spindle, using microtubules and kinetochores to exert forces that segregate sister chromatids. Ultimately, understanding how cells build these robust molecular machines for unique tasks could one day lead to therapeutics that treat disease causing dysfunctions in these vital cellular processes. In order to explore how molecular clutches work in concert with the cytoskeleton to exert forces and maintain attachment under load, we developed a mechano-chemical cellular adhesion dynamics framework to simulate these processes. In the case of cellular motility, we find that a "motor-clutch" mechanism exhibits substrate-stiffness sensitive dynamics. On soft substrates, motor-clutch motility exhibits "load-and-fail" dynamics that lead to higher rates of retrograde flow and lower traction force transmission compared to stiff substrates. We confirm these predictions experimentally using embryonic chick forebrain neurons (ECFNs) plated on compliant polyacrylamide gels (PAGs) demonstrating that a motor clutch system could be the basis of cellular mechanosensing. We also use cellular adhesion dynamics to explore kinetochore-microtubule attachment during mitosis to identify what properties might be important in maintaining attachment during mitosis. We show that molecular clutch microtubule-lattice diffusion is important for relieving clutch stresses, prolonging bond life-times and minimizing detachment forces. Furthermore, molecular clutches that preferentially associate with interdimer interfaces, rather than with intradimer interfaces, promote robust kinetochore attachment by preventing the more distal, attachment-promoting linkers from becoming nonproductive. These findings help further our understanding of the mechanochemical basis of kinetochore attachment and mitosis, a process essential throughout development.
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    Characterizing Uniaxial Mechanics of Single AF Lamella
    (2012-04-18) Golman, Mikhail
    Intervertebral discs (IVD) are shock absorbers made of sheets of collagen fibers that are located between the vertebrae of the spine. They are known to serve as a cushion to absorb impact and protect body structures, as joints that allow the movement of the vertebrae, and as ligaments that hold the adjacent vertebra. Over time, the human aging process causes IVD to degenerate, diminishing its size and reducing its ability to absorb impact. Therefore, investigations of material properties of IVD in physiologically comparable environments provide information to improving modeling and understanding of IVD degeneration. In this study, the mechanical properties of cadaveric single AF lamella were characterized in uniaxial loading conditions, where loads on the single sheet of IVD were applied in one direction. Analyzing the load-displacement curves and strains maps and comparing them for each samples showed the importance of the fiber alignment in on the sample. That is, strains to the samples were directly aligned to the sample fiber rotation, making the tensile behavior vary within the sample. The results also confirmed the tensile nonlinearity by comparing the slope in toe region (Etoe) and in a linear region (Elin). Although the study is limited by a small number of specimens, the result strengthen the importance of uniaxial tests for fiber-reinforced soft tissues and helped towards understanding material properties to consider when engineering a replacement tissue.
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    Computational Modeling of Deep Brain Stimulation in the Globus Pallidus Internus
    (2012-08-27) Malaga, Karlo;
    Neuromodulation is the functional modification of neural structures through the use of electrical stimulation1. Clinical applications include deep brain stimulation (DBS) for the treatment of neurological movement disorders such as Parkinson’s disease and essential tremor. The general procedure involves placing small electrodes in regions of the brain exhibiting pathological activity and then stimulating those regions with continuous pulses of electricity. Treatment outcome is strongly dependent on the precise placement of the electrodes and subsequent adjustment of the stimulation settings to fine-tune the therapy. DBS is now being used for treating dystonic movement disorders, where sustained muscle contractions cause twisting and repetitive movements and/or abnormal postures. One target of DBS for dystonia is the posteroventral globus pallidus internus (GPi). Stimulation of the GPi has yielded promising results for people with dystonia; however, specific stimulation settings providing maximum GPi activation and having minimal side-effects have yet to be determined. Here we use computational models to show how altering parameters such as electrode configuration, DBS lead placement and orientation, and stimulation voltage affects GPi modulation and activation of the cortical spinal tract (CST), the side-effect pathway. In one model, the electrode configuration of the lead was varied. Another model had the DBS lead translated 1 mm medial, lateral, anterior, and posterior from its original position to make predictions of possible motor side-effects in a non-human primate animal model. Such models can provide a framework for neurosurgeons and neurologists to improve current steering techniques that will optimize treatment outcome.
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    Elasticity of the lens capsule as measured by osmotic swelling.
    (2010-06) Powell, Tracy A
    As an alternative to purely mechanical methods, optical tracking of passive osmotic swelling was used to assess mechanical properties of the ocular lens capsule. Although limited by being a single measurement on a heterogeneous tissue, osmotic swelling provides a quantitative assessment of the stiffness of the lens capsule without requiring dissection or manipulation of the lens. A simple model was developed accounting for the permeability of the lens fiber cells and capsule to water, the concentration of fixed charges in the fiber cells, and the capsule’s resistance to the swelling of fiber cells. Fitting the model solution to experimental data provided an estimate of the elastic modulus of the lens capsule under the assumption of linear isotropic elasticity. The model was developed with the porcine lens to provide validity and was extended to a mouse model with X-linked Alport Syndrome, the most common form of the human disease that results in the absence of a collagen IV monomer normally present in the lens capsule. The calculated elastic moduli for the porcine lens is comparable to previously reported moduli of elasticity for the porcine lens capsule at small strains (<10%), and a slight increase with hypotonicity is consistent with the nonlinear mechanical behavior of the lens capsule. The calculated elastic moduli for the mouse lenses were similar between wild type and Alport and are comparable to a reported modulus of elasticity for rat lens capsules at small strains. The mouse lens modulus of elasticity showed a similar response to bath concentrations as the porcine lenses, increasing with hypotonicity. However, the difference in the tendency to rupture of the Alport and wild type lens capsules were statistically significant; for lenses that reached 14% strain in the equatorial direction, the Alport lenses had a greater tendency to rupture. This work will be extended to investigate the temporal effects of Alport syndrome on the elastic modulus and rupture mechanics of lens capsules. Osmotic challenge overcomes the size limitations of previously employed techniques for measuring the elastic modulus of the lens capsule and can provide insight into the properties of basement membranes through its application to other mutant mice.
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    Experimental studies of flow through deformable silicone and tissue engineered valves.
    (2009-12) Amatya, Devesh M.
    Annually, approximately 250,000 repair/replacement heart valve surgeries are performed world-wide. Currently the two options available for valve replacement are mechanical or bioprosthetic valves. Thrombosis (blood clots) and embolic events (movement of the clots through the blood vessels) have been linked with the mechanical valves, so that life-long anticoagulant therapy is required. Deterioration of the structural integrity, in part due to calcification, has been linked with bioprosthetic valves. The current paradigm is to replace a living, but incompetent valve with a non-living valve, be it mechanical or biological prosthetic. A living prosthetic valve grown with patient donor-based tissue engineering paradigm may be a possible solution. The primary objective of this study was to characterize the in vitro performance of the tissue engineered valve equivalents in a cardiovascular pulse duplicator and assess their potential for clinical use as valve replacement prostheses. A second objective was to conduct experiments under different flow conditions with synthetic silicone polymer valves of various geometries and materials similar in mechanical properties to those of the valve equivalents that are more amenable to experimental measurements of velocity and structural deformation using two-dimensional particle image velocimetry of high spatial resolution, three-dimensional velocimetry of volumetric measurements, and hot film anemometry of high temporal resolution. These measurements are needed to validate computational codes incorporating fluid-structure interaction and may be applied towards tissue engineered heart valve design and optimization. All of the silicone materials tested showed a neo-Hookean material response at engineering strains less than 0.5. The silicone linear elastic modulus was similar in order to the values measured in native aortic valve leaflets. The diaphragm valves with an orifice deformed to a concave shape with respect to the upstream flow for both steady and pulsatile flow conditions, along with orifice expansion at increasing flow rates. The orifice expansion (up to 75% increase in area) led to reduced pressure drops as compared with non-expanding or rigid diaphragm valves. A jet with significant inward radial velocity was present immediately downstream of the deformed diaphragm valves for both steady and pulsatile flows. This inward flow was associated with vena contracta. For low Reynolds number, laminar steady upstream flow conditions, the diaphragm valve supported the formation of relatively large scale vortices with passage frequency of St = 0.34. For pulsating flow, a leading vortex ring followed by a trailing jet was present during forward flow acceleration. Phase-averaged velocity measurements show lower fluctuations during the acceleration phase than during the deceleration phase of the flow. The deformation of the transparent bileaflet silicone valve in the pulsating flow showed leaflets deforming in similar concave state with respect to the upstream forward flow of systole and towards the lower pressures during diastole. The bileaflet silicone valve showed asymmetry in root deformation and a slot-like elliptical jet flow profile through the leaflets unlike the circular profile of the diaphragm valve. Downstream flow stagnation and recirculation were present during systole and areas of recirculation were present both upstream and downstream. These flow features were less organized for the latter during diastole. The tissue engineered valve equivalents harvested after development in the bioreactor and placed within a rigid housing were able to withstand pressures of ~50 mmHg, pressure drops of ~40 mmHg, and flow rates of ~25 L/min throughout the loading of the right ventricular cardiac cycle. The temporal pressures and flow signatures replicated right physiological conditions. The flow downstream indicated an elliptical jet during systole similar to the bileaflet silicone valve. The locations of tissue engineered valve equivalent failures were at the leaflet commissure and Dacron cuff-valve root interface.
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    Heart failure and associated structural and functional remodeling: assessment employing various magnetic resonance imaging methodologies.
    (2009-11) Eggen, Michael D.
    Cardiovascular magnetic resonance imaging (MRI), or cardiac MR, is currently considered the "gold" standard for noninvasively characterizing cardiac function and viability, having 3D capabilities and a high spatial and temporal resolution. More recently, the capabilities of MRI have been extended to study tissue microstrucure and fiber orientation in both the brain and the heart through specially designed pulse sequences which are sensitive to diffusion. In this specialized imaging method, known as diffusion tensor magnetic resonance imaging (DTMRI), myofiber orientation can be probed in high resolution and this technique has been successfully utilized to study the helical arrangement of muscle fibers within the myocardium. As such, the counter-wound helical structure of the myocardium is considered to be responsible for the torsional or wringing motion of the left ventricle and serves three main mechanical functions: (1) equalizing myofiber strain and workload; (2) optimizing the volume of blood ejected during systole (stroke volume); and/or (3) storing torsional energy in the intracellular and extracellular matrices and, when released, increasing ventricular filling during diastole. Therefore, cardiac fiber orientation can also be considered as a primary determinant of ventricular pump function, and is of great clinical interest in the study of structure and function within either the normal or diseased heart. To date, the primary focus of cardiac DTMRI has been to characterize myofiber orientation in healthy animal hearts, with little progress in the study of myofiber arrangement in the diseased heart. As such, due to the long scan times required for in vivo DTMRI, and the limited availability of freshly excised human hearts for ex vivo imaging, data are limited in the characterization of fiber orientation in both healthy and diseased human hearts. Therefore, in my thesis research, the primary objective was to investigate myofiber orientation in both healthy and diseased hearts using DTMRI. Specifically, changes in myofiber orientation were investigated in a high rate pacing model of dilated cardiomyopathy in swine, and also in excised healthy and diseased human hearts obtained from the Bequest Anatomy program at the University of Minnesota, and LifeSource (the Upper Midwest, a non-profit organ procurement organization). In addition, the mechanical activation due to cardiac pacing from the right ventricular apex was uniquely characterized in a case study of an isolated human heart using MRI, as cardiac pacing from the right ventricular apex is known to chronically result in deleterious changes in fiber orientation and cardiac function. My thesis was divided into several chapters, in the first it was considered paramount to gain a thorough understanding of cardiac MRI. As such, a review of cardiovascular MRI is provided in Chapter 1. The goal of this chapter was to familiarize the reader with cardiac MR and nomenclature, review current techniques to quantify cardiac function with MRI, and to introduce the reader to cardiac diffusion tensor magnetic resonance imaging (DTMRI), which is used in the present work to quantify fiber orientation in the heart. In Chapter 2, a literature review of cardiac fiber orientation and relevant changes resulting from disease is presented, and the measurement of fiber orientation using DTMRI is further discussed. The intent of this chapter is to familiarize the reader with diffusion imaging and the associated parameters used to characterize fiber orientation and tissue integrity. In addition, the methodologies and computational tools developed to measure fiber orientation using a 3 tesla Siemens MRI clinical scanner are described. Chapters 3-5 describe novel investigations in the assessment of fiber orientation using DTMRI. In chapter 3, the effects of decomposition on the diffusion properties of the myocardium were studied in freshly excised human hearts recovered at varying post mortem intervals. From this study, the time frame for the recovery of a human heart was determined to be 3 days, such that the tissue still remains viable for the measurement of fiber orientation using DTMRI. In Chapter 4, a swine model of dilated cardiomyaphy was used to assess in vivo functional and anatomical changes resulting from severe dilation of both the right and left ventricle. Following in vivo functional imaging, ex vivo DTMRI was used to investigate the resultant fiber orientation. Chapter 5 provides a preliminary comparison of fiber orientation in healthy and diseased human hearts, collected within a post-mortem interval of 3 days. Furthermore, in Chapter 6, the mechanical activation during pacing from the right ventricular apex was studied in an isolated human heart. Since pacing from the right ventricular apex is known to cause deleterious changes in fiber orientation, it was of great interest to characterize myocardial strain and motion during RVA pacing as part of my thesis work. In general, this research project has advanced our overall knowledge as to our understanding of ex vivo DTMRI, and the remodeling of the myocardial architecture in heart failure. This described work is not an exhaustive list of the changes in fiber orientation that occur in every type of cardiomyopathy, but provides novel insights into fiber reorganization which occurs in swine due congestive heart failure, and in human hearts excised from patients with a history of heart failure. Additionally, with the development of methodologies and computational tools presented here, and the study of post mortem intervals on the diffusion properties of the myocardium, the framework has been laid for the future analysis of fiber orientation in other cardiomyopathies presented in human cadaveric hearts.
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    High-field 31P Magnetic Resonance Spectroscopy (MRS) in human brain.
    (2010-01) Qiao, Hongyan
    The pioneer paper of Moon & Richards in 1973 recorded the 31P NMR spectrum of red blood cells. After this breakthrough, the application of 31P NMR to biological systems has become more and more popular. The range of those 31P NMR studies is pretty broad, from the simple observation of anaerobic metabolism to the elegant combination of physiology and spectroscopy. However, the severe overlap of multiplet resonances and relatively low detection sensitivity in the 31P spectra acquired at low fields pose many limitations in in vivo applications. These limitations can be potentially overcome at high fields. The goal of this project is to study the advantages of high-field 31P MRS in human brain through the following specific aims: • To investigate the improvement of sensitivity and spectral resolution of in vivo 31P MRS in human brain at high fields (4T, 7T ) and their field dependence; • To achieve 3D 31P chemical shift imaging covering whole human brain, quantify metabolite concentrations and other physiological parameters provided by in vivo 31P MRS, and study the bioenergetic differentiations among different brain tissues; • To study creatine kinase enzyme activity via 31P magnetization transfer experiments.
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    High-Throughput Method for Microfluidic Placement of Cells in Micropatterned Tissues
    (2013-04-20) Sevcik, Emily
    Recent studies have shown that cell shape and tissue structure can dictate functional behavior in engineered tissues (1). One method for controlling tissue structure in vitro is microcontact printing, where extracellular matrix proteins are patterned on a substrate to construct arrays of single cells or multicellular tissues. This technique is used to create tissues that mimic in vivo architecture which can be used to study tissue properties and disease mechanisms (2). Traditional seeding of cells on the substrate is imprecise, but our group has developed a microfluidic device for spatial control of cell seeding, which creates more replicable high-fidelity tissues. However, the current method is low-throughput and labor intensive. Here, we present a scalable system of multiple microfluidic devices for parallel cell seeding. This high-throughput, precise approach reduces experimental variation, making biochemical assays on single cell arrays possible in future work. We will use this system to create large arrays of single cells of various shapes for phenotypic studies and to create arrays of tissues with varying cellular organization. 1)Alford, P. W., Nesmith, A. P., Seywerd, J. N., Grosberg, A., & Parker, K. K. (2011). Vascular smooth muscle contractility depends on cell shape. Integrative Biology, 3(11), 1063-1070. 2)Ruiz, S. A., & Chen, C. S. (2007). Microcontact printing: A tool to pattern. Soft Matter, 3(2), 168-177.
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    Immersive Anatomical Scenes that Enable Multiple Users to Occupy the Same Virtual Space: A Tool for Surgical Planning and Education
    (2019-01) Deakyne, Alex
    3D modeling is becoming a well-developed field of medicine, but its applicability can be limited due to the lack of software allowing for easy utilizations of generated 3D visualizations. By leveraging recent advances in virtual reality, we can rapidly create immersive anatomical scenes as well as allow multiple users to occupy the same virtual space: i.e., over a local or distributed network. This setup is ideal for pre-surgical planning and education, allowing users to identify and study structures of interest. I demonstrate here such a pipeline on a broad spectrum of anatomical models and discuss its applicability to the medical field and its future prospects.
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    Improving polymer-mediated DNA vaccine delivery.
    (2011-06) Palumbo, Rebecca Noelle
    Vaccination using antigen-encoding plasmid DNA has great potential to generate strong immune response against delivered antigen. In order to effectively generate immune response, antigen must be delivered to antigen presenting cells, primarily dendritic cells (DCs). Using cationic polymers as a delivery vehicle can provide many advantages, including protection of DNA from degradation, ability to add targeting moieties, and easy modification of structure to optimize various properties. We have investigated the use of polyplexes as a DNA delivery vehicle in a variety of settings. We demonstrated the feasibility of using the CD40L as a DC targeting moiety, a protein capable of both binding and stimulating DC maturation, using coated nanoparticles. We have also studied the possibility of delivering antigen through transfection of bystander cells rather than direct expression by DCs using an in vitro model. We confirmed the ability of these DCs to present antigen, become mature, and stimulate T cells. Finally, we studied the interaction of cationic polymer complexes in vivo, both in respect to local tissue dispersion and interaction with specific cell types, using fluorescently labeled DNA. Through these experiments we have illuminated potential pathways for optimizing DNA vaccine efficiency using polymer complexes with slightly different structures.
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    Interview with Stanley Finkelstein
    (University of Minnesota, 2014-11-06) Finkelstein, Stanley; Tobbell, Dominique
    Stanley Finkelstein begins by discussing his educational background and his arrival at the University of Minnesota. He describes at length his research in the field of home monitoring and telehealth, including his research with Jay N. Cohn on the development of a device to measure and monitor arteriovascular compliance in order to diagnose and monitor hypertension and congestive heart failure; his research with Warren Warwick and the development of the first home monitoring system for cystic fibrosis patients; and the subsequent development of home monitoring of lung transplant patients in collaboration with Marshall Hertz. Dr. Finkelstein goes on to discuss the NLM training grant program; the lack of institutional support provided to the Division of Health Computer Sciences; the development of the Institute for Health Informatics; the leadership of Eugene Ackerman and Laël Gatewood; the number of women in the field of biomedical engineering and health informatics; the relationship between the Division of Health Computer Sciences and the Biomedical Library; the collaborative relationship between the University of Minnesota and the Mayo Clinic; and the development of the Masters in Health Informatics.
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    Intrapericardial delivery of anti-arrhythmic agents.
    (2009-05) Richardson, Eric Stephen
    Anti-arrhythmic agents are known for their narrow therapeutic window and common side effects. Delivery of anti-arrhythmic agents into the pericardium has shown to increase their efficacy and minimize their side effects. My work has focused on evaluating the clinical potential of intrapericardial (IP) anti-arrhythmic delivery. This has included working with physicians to identify appropriate clinical applications, developing devices to aid in pericardial drug delivery, and carrying out several large animal studies to test efficacy. In swine models of sinus tachycardia, atrial fibrillation, and ischemia-induced ventricular tachycardias, we have shown the pharmacodynamic benefits of IP-delivered metoprolol, amiodarone, and docosahexaenoic acid. Pharmacokinetic data show that minimal amounts of drug reach the systemic circulation. We propose that IP delivery of anti-arrhythmic agents has potential to maximize therapeutic benefits while minimizing side effects, particularly in the settings of post-operative atrial fibrillation and inappropriate sinus tachycardia.
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    Investigating the use of multipotent adult progenitor cells for treatment of Duchenne muscular dystrophy: a translational approach.
    (2008-07) Frommer, Sarah Anne
    Taking a “translational” approach to developing clinical therapies is a two step process that requires: 1) Basic science research on clinical diseases; and 2) application of knowledge gained or resultant therapeutics from that research to patient care. The collaboration of basic sciences and clinical sciences will result in greater advancement of knowledge within each field. There are many diseases that have no cure, even with the tools that modern medicine has to offer. A good example of this is Duchenne muscular dystrophy (DMD). Unfortunately, there is no cure and no effective long-term treatment to delay the progression of DMD; modern medicine can only ameliorate the symptoms and attempt to give the patient the best quality of life possible. It may one day be possible to cure patients if even one of the many experimental therapies for DMD, aimed at restoring dystrophin in skeletal muscle and shown to improve muscle function in dystrophic animals, could be developed clinically. One such therapy is stem cell therapy. The stem cells used in this work are multipotent adult progenitor cells (MAPC). MAPC were first discovered in the Verfaillie lab here at the University of Minnesota- Twin Cities. It was traditionally believed that adult stem cells like hematopoietic stem cells and mesenchymal stem cells could not differentiate into cells outside the mesodermal lineage; however there are currently numerous reports that challenge this thought. This thesis presents the application of a three-step translational approach toward development of stem cell therapy for treatment of DMD. The three steps are: 1) In vitro study of MAPC myogenic potential; 2) in vivo study of MAPC myogenic potential; and 3) development of a system to measure functional effects of therapies. Chapter 2 describes multifactorial testing of different cytokines in an effort to develop a protocol aimed at directing myogenic induction. Chapter 3 describes methods developed and subsequently tested to enhance MAPC engraftment in the DMD model mouse upon intramuscular injection. Chapter 4 describes the development and testing of a system aimed at detecting functional differences due to therapy.
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    Iris biomechanics in health and disease.
    (2010-05) Amini, Rouzbeh
    Computational models of the eye have been studied by various investigators. The main purpose of developing a computational model is to provide a better understanding of the normal function of the eye as well as the abnormalities causing ocular diseases. For instance, by using computational methods, new insights have been brought to the pathophysiology and anatomical risk factors of angle-closure glaucoma, a mysterious eye disease closely related to the mechanics of the iris. Unlike the clinical research, computational studies are neither hindered by experimental difficulties nor by patient health risks. We developed computational models of the ocular tissues at three different levels to understand the mechanisms by which ocular globe deformation, iris-aqueous-humor interaction, and detailed iris structure affect the iris configuration. These models include: a finite-element model of the whole ocular globe consisting of the iris, cornea, sclera, and limbus, a finite-element model of iris-aqueous-humor interaction in the anterior eye, and a finite element model of the iris with its active and passive constituent tissues. Our whole-globe simulation showed that corneoscleral indentation, a diagnostic and/or treatment method in various glaucoma-related complications, would lead to changes in the anterior chamber angle. Our model showed that the limbus, due to its unique mechanical properties, plays an important role in the deformation of the whole ocular globe. Simulations performed using our anterior-segment model showed that the rapid changes (~sec) in the iris-aqueous-humor system due to corneoscleral indentation may lead to long recovery times (~min). We showed that a similar long recovery mechanism prevents the iris from drifting forward during normal blinking. Finally, simulations based on the detailed iris anatomy showed that the posterior location of the dilator muscle could contribute to the iris anterior bowing following dilation even in the absence of the aqueous humor pressure difference. Clinical studies have emphasized the key role of the iris shape and configuration in physiology and pathophysiology of the eye. In the course of our research, we showed that iris configuration is ultimately affected by many parameters including deformation of the whole ocular globe, interaction with aqueous humor flow, and activation of its constituent muscles.
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    Ligand binding and receptor network formation in the tumor necrosis factor superfamily.
    (2012-07) Valley, Christopher Carlin
    Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a cytokine with anti-tumor potential, binds to transmembrane TRAIL receptors and initiates apoptosis. Although much has been characterized regarding intracellular signaling of TRAIL receptors, early events outside the cell and within the plasma membrane remain poorly understood. The central focus of this thesis is to establish biophysical interactions involved in ligand binding and subsequent receptor structural changes resulting in receptor activation. First, we demonstrate that TRAIL receptor 2 (death receptor 5, or DR5) forms receptor dimers in a ligand-dependent manner, and these receptor dimers exist within high molecular weight networks. We find that receptor dimerization relies upon covalent and non-covalent interactions between membrane-proximal residues, and that the transmembrane structure of two functional isoforms of DR5 are indistinguishable. This is the first evidence using endogenous, full-length receptor to demonstrate that DR5 networks are highly organized. Further, we show that DR5, upon stimulation by ligand, migrates into cholesterol rich membrane regions, and ligand-induced dimerization and network formation rely on cholesterol within the plasma membrane. Depletion of membrane cholesterol prevents structural changes associated with ligand binding as well as function. Therefore, lipid biophysical properties play an active role in determining receptor structure and function. Lastly, we identify and characterize a key, specific interaction between Methionine and aromatic residues that is critical for high affinity ligand-receptor binding and function in the TNF superfamily. Using structural bioinformatics, we demonstrate that this interaction--which occurs at approximately 5Å separation--is present in approximately one-third of known protein structures. Quantum calculations of model compounds and biological molecules demonstrate that this interaction provides additional stabilization over hydrophobic interactions and at distances out to 7Å, suggesting that this interaction may have evolved in proteins where a high degree of stabilization is required at longer distances. This motif may be utilized in the rational design of therapeutics targeting a range of proteins, including TNF members. In summary, our results characterize novel biophysical interactions between ligand-receptor, receptor-receptor, and receptor-membrane that together orchestrate a series of events that ultimately lead to cell death.
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    Magnetoacoustic tomography with magnetic induction for electrical conductivity imaging of biological tissue.
    (2010-09) Li, Xu
    Electrical properties of biological tissue including conductivity and permittivity play important roles in many biomedical and clinical researches such as modeling neural or cardiac electrical activities and management of electromagnetic energy delivery to the body during clinical diagnosis and treatment. More importantly, these electrical properties may serve as an intrinsic contrast for anatomical or functional imaging. It is therefore of great value to noninvasively image the electrical properties of biological tissue with good accuracy and high spatial resolution. This dissertation research aims at developing and evaluating a new modality i.e. magnetoacoustic tomography with magnetic induction (MAT-MI), for imaging electrical conductivity distribution of biological tissue. In MAT-MI, a conductive object is placed in a static magnetic field and a time-varying magnetic stimulation is applied to induce eddy current inside the object volume. Within the static magnetic field, the Lorentz force acting on the induced eddy current causes mechanical movement of those charged particles in the object and leads to detectable ultrasound signals. These ultrasound signals can be acquired by ultrasound probes and used to reconstruct a high spatial resolution image that indicates the object's electrical conductivity contrast. We have proposed and investigated two types of MAT-MI approaches i.e. single-excitation MAT-MI and multi-excitation MAT-MI. The corresponding image reconstruction algorithms, simulation protocols and experiment systems have been developed for feasibility testing and performance evaluation. It is shown in our computer simulation and experiment studies that using the single-excitation MAT-MI we are able to image the conductivity boundaries of the object with several millimeter spatial resolution. In addition, we have also demonstrated that the multi-excitation MAT-MI approach allows us to further extract the internal information and reconstruct more completely the conductivity contrast of the object. For both approaches, two-dimensional (2D) and three-dimensional (3D) images of physical or tissue phantoms have been acquired and showed promising agreement with the target conductivity distribution. All the results we have collected so far from simulations and experiments suggest that the MAT-MI approach is potential to become an important noninvasive modality for electrical conductivity imaging of biological tissue.