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Bioengineering Program

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Development of virtual mitral valve leaflet models from three-dimensional echocardiography

2012-07-05 , Icenogle, David A.

Mitral valve (MV) disease is responsible for approximately 2,581 deaths and 41,000 hospital discharges each year in the US. Mitral regurgitation (MR), retrograde blood from through the MV, is often an indicator of MV disease. Surgical repair of MVs is preferred over replacement, as it is correlated with better patient quality of life. However, replacement rates are still near 40% because MV surgical repair expertise is not spread across all hospitals. In addition, 15-80% of surgical repair patients have recurrent MR within 10 years. Quantitative patient-specific models could aid these issues by providing less experienced surgeons with additional information before surgery and a quantitative map of patient valve changes after surgery. Real-time 3D echocardiography (RT3DE) can provide high quality 3D images of MVs and has been used to generate quantitative models previously. However, there is not currently an efficient, dynamic, and validated method that is fast enough to use in common practice. To fill this need, a tool to generate quantitative 3D models of mitral valve leaflets from RT3DE in an efficient manner was created. Then an in vitro echocardiography correction scheme was devised and a dynamic, in vitro validation of the tool was performed. The tool demonstrated that it could generate dynamic, complex MV geometry accurately and more efficiently than current methods available. In addition, the ability for mesh interpolation techniques to reduce segmentation time was demonstrated. The tool generated by this study provides a method to quickly and accurately generate MV geometry that could be applied to dynamic patient specific geometry to aid surgical decisions and track patient geometry changes after surgery.

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Incorporation of recombinant fibronectin into genetically engineered elastin-based polymers

2009-11-17 , Balderrama, Fanor Alberto

Cardiovascular disease is the main cause of death in the United States. Many of these conditions require the grafting or bypassing of compromised blood vessels. To this effect, biological vascular grafts (autografts and allografts) are the first line of action. However, when the patient lacks vasculature suitable for grafting use, several synthetic grafting options are available. The search for an inert biomaterial for vascular grafts has proven to be unsuccessful. This makes the interaction taking place on the blood-biomaterial interface critical for the success of the grafts. This thesis introduces a new bio-inspired approach to tackle the mechanical and biological challenges of vascular material design. The hypothesis of this research is that recombinant fibronectin protein can be stably incorporated onto elastin-mimetic polymers to increase endothelialization. Recombinant elastin, designed to recreate the mechanical properties of natural elastin as a candidate material for vascular graft fabrication, was used as a model surface. Recombinant fibronectin-functionalized elastin-mimetic polymer displayed significant improvement in cell adhesion. Quantification of surface bound recombinant fibronectin verified the concentration dependence of this cell adhesive behavior. Modified elastin-mimetic polymer also demonstrated an enhanced ability to support endothelial cell proliferation. Furthermore, the stability of recombinant fibronectin-modified polymers was assessed. These studies provide the foundation for fabricating elastin-mimetic vascular grafts with improved endothelialization and subsequent biological performance.

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Study of early signaling events in T cell activation enabled through a modular and multi-time point microfluidic device

2008-11-19 , Rivet, Catherine Aurelie

Binding of the antigen receptor on T cells initiates a rapid series of signaling events leading to an immune response. To fully understand T cell mediated immunity, underlying regulatory properties of the receptor network must be understood. Monitoring dynamic protein signaling events allows for network analysis. Unfortunately, dynamic data acquisition is often extremely time-consuming and expensive with conventional methods; the number of proteins monitored at the same time on the same sample is limited. Furthermore, with conventional, multi-well plate assays it is difficult to achieve adequate resolution at sub-minute timescales. Microfluidics is a capable alternative, providing uniformity in sample handling to reduce error between experiments and precision in timing, an important factor in monitoring phosphorylation events that occur within minutes of stimulation. We used a two-module microfluidic platform for simultaneous multi-time point stimulation and lysis of T cells to investigate early signaling events with a resolution down to 20 seconds using only small amounts of cells and reagents. The device did not elicit adverse cellular stress in Jurkat cells. The activation of 6 important proteins in the signaling cascade upon stimulation with a soluble form of α-CD3 in the device was quantified and compared under a variety of conditions. First, in comparison to manual pipetting, the microdevice exhibits significantly less error between experiments. Secondly, a comparison between Jurkat cells and primary T cells shows similar dynamic trends across the 6 proteins. Finally, we have used the device to compare properties of long-term vs, short-term cultured primary T cells. As expected, older cells present a much weakened response to antigenic cues, as measured with TCR response markers. This modular microdevice provides a flexible format for investigating cell signaling properties through the use of soluble cue stimuli.

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Analyzing Non-Unique Parameters in a Cat Spinal Cord Motoneuron Model

2006-07-05 , Sowd, Matthew Michael

When modeling a neuron, modelers often focus on the values of parameters that produce a desired output. However, if these parameters are not unique, there could be a number of parameter sets that produce the same output. Thus, even though the values of the various maximum conductances, half activation voltages and so on differ, as a set they can produce the same spike height, firing rates, and so forth. To examine whether or not parameter sets are unique, a 3-compartment motoneuron model was created that has 15 target outputs and 59 parameters. Using parameter searches, over one hundred parameter sets were created for this model that produced the same output (within tolerances). Parameter values vary between parameter sets and indicate that the parameter values are not unique. In addition, some parameters are more tightly constrained than others. Principal component analysis is used to examine the dimensionality of the input and output spaces. However, neurons are more than static output generators. For example, a variety of neuromodulatory influences are known to shift parameter values to alter neuronal output. Thus the question arises as to whether this non-uniqueness extends from model outputs to the models sensitivities to its parameters. In this work, the non-unique parameter sets are further analyzed using sensitivity analyses and output correlations to show that these values vary significantly between these parameter sets. Therefore, each of these models will react to parameter variation differently. This work concludes that parameter sets are non-unique but have varying sensitivity analyses and output correlations. The ramifications of this are discussed for both modelers and neuroscientists.

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Mechanisms of platelet capture at very high shear

2011-04-05 , Wellings, Peter John

Arterial thrombus forms from the capture and accumulation of circulating platelets on a stenosis. As the thrombus grows, the lumen becomes further stenotic producing very high shear rates as the blood velocities increase through the narrowed cross-section. This study explores the molecular binding conditions that may occur under these pathologic shear conditions where circulating platelets must adhere quickly and with strong bonds. Platelets binding in an arterial stenosis of >75% are subject to drag forces exceeding 10,000 pN. This force can be balanced by 100 simultaneous GPIb-vWFA1 bonds of 100 pN each. The number and density of GPIb on platelets is sufficiently high; however, platelet capture under high shear would require the density of A1 receptors to be increased to over 416 per square micron. A computational model is used to determine platelet capture as a function of shear rate, surface receptor density, surface contact and kinetic binding rate. A1 density could be increased by a combination of vWF events of: i) plasma vWF attach to the thrombus surface and elongate under shear; ii) the elongated vWF strands create a net with 3-D pockets; and iii) additional vWF is released from mural platelets by activation under shear. With all three events, A1 density matches the existing high GPIbα densities to provide sufficient multivalency for capture at 100,000 s-1 with greater than 170 bonds per platelet. If the on-rate is greater than 108 M-1s-1, then a platelet could be captured within 15 microseconds, the amount of time available to form bonds before the platelet is swept away. This mechanism of platelet capture allows for the rapid platelet accumulation in atherothombosis seen clinically and in high shear experiments.

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Long-term patency of a polymer vein valve

2009-07-08 , Midha, Prem Anand

Chronic Venous Insufficiency (CVI) is a condition in present in almost 27% of adults in which an insufficient amount of blood is pumped back to the heart due to damaged or poorly apposed one-way valves in the leg veins. During forward flow, vein valves allow blood to return to the heart while posing very little resistance to the flow. During gravity-driven reverse flow, normal valves close and prevent blood from flowing backward through the valve. Incompetent, or damaged, vein valves cannot prevent this reverse flow and lead to a pooling of blood at the feet. CVI is a painful disease presents itself in various ways, including varicose veins, ulcerations of the lower extremities, and severe swelling. Current therapies and treatments include compressive stockings, destruction or removal of affected veins, valve repair, and valve transplants. The implantation of prosthetic vein valves is a future treatment option that does not require an invasive surgery, human donor, or lengthy hospital stay. While no prosthetic vein valves are currently commercially available, this thesis describes the design, verification, and validation of a novel prosthetic vein valve. Verification tests include CFD simulations, functional tests, mechanical tests, and in vitro thromogenicity tests. The validation of the device was done through an animal study in sheep external jugular veins. CFD analysis verified that shear rates within the valve support its lower thrombogenicity as compared to a previous vein valve. Benchtop tests demonstrate superiority in short-term patency over a previous polymer valve. In a sheep study, patency was shown at 6 weeks, surpassing many autograft valves and showing great potential to meet the goal of 3 month patency in sheep.

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Three-dimensional Extracellular Matrix Hydrogel Environments for Embryonic Stem Cell Growth

2007-05-09 , Ebong, Ima Mbodie

Embryonic stem cells (ESCs) are pluripotent cells derived from the inner cell mass of the blastocyst that can give rise to cells of the ectoderm, endoderm and mesoderm lineages. Once isolated from the blastocyst, ESCs can be cultured indefinitely in vitro in an undifferentiated state or can be induced to differentiate. In the case of mouse ESCs (mESCs), the cytokine leukemia inhibitory factor (LIF) is added to culture media to maintain pluripotency and is removed to induce differentiation. Although it is known that extracellular matrix (ECM) components influence stem cell maintenance, proliferation and differentiation, the precise effects of ECM environments on embryonic stem cell behavior have not been systematically studied. The main purpose of this thesis project was to investigate the behavior of undifferentiated mESCs cultured in different 3D hydrogel matrices and to determine whether viscoelastic and biochemical variations in the matrices differentially affect the ability of stem cells to self-renew; that is, retain their pluripotency or undifferentiated phenotype. Their behavior in 3D environments was compared to mESC behavior in traditional 2D culture. In addition, a new method of casting hydrogels in polydimethylsiloxane (PDMS) molds was developed in order to efficiently cast multiple hydrogels of varying sizes and shapes. The findings of this thesis project will benefit both the scientific and engineering community as it encourages researchers to re-evaluate the quality of standard 2D embryonic stem cell culture methods versus potentially novel and advantageous 3D hydrogel culture methods.

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Non-ionic highly permeable polymer shells for the encapsulation of living cells

2011-04-05 , Carter, Jessica L.

In this study, we introduce novel, truly non-ionic hydrogen-bonded layer-by-layer (LbL) coatings for cell surface engineering capable of long-term support of cell function. Utilizing the LbL technique imparts the ability to tailor membrane permeability, which is of particular importance for encapsulation of living cells as cell viability critically depends on the diffusion of nutrients through the artificial polymer membrane. Ultrathin, permeable polymer membranes are constructed on living cells without a cationic pre-layer, which is usually employed to increase the stability of LbL coatings. In the absence of the cytotoxic PEI pre-layer, viability of encapsulated cells drastically increases to 94%, as compared to 20-50% in electrostatically-bonded shells. Engineering surfaces of living cells with natural or synthetic compounds can mediate intercellular communication, render the cells less sensitive to environmental changes, and provide a protective barrier from hostile agents. Surface engineered cells show great potential for biomedical applications, including biomimetics, biosensing, enhancing biocompatibility of implantable materials, and may represent an important step toward construction of an artificial cell.

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Stucture and thermomechanical behavior of nitipt shape memory alloy wires

2009-04-10 , Lin, Brian E.

The objective of this work is to understand the structure-property relationships in a pseudoelastic composition of polycrystalline NiTiPt (Ti-42.7 at% Ni-7.5 at% Pt). Structural characterization of the alloy includes grain size determination and texture analysis while the thermo-mechanical properties are explored using tensile testing. Variation in heat treatment is used as a vehicle to modify microstructure. The results are compared to experiments on Ni-rich NiTi alloy wires (Ti-51.0 at% Ni), which are in commercial use in various biomedical applications. With regards to microstructure, both alloys exhibit a <111> fiber texture along the wire drawing axis, however the NiTiPt alloy's grain size is smaller than that of the Ni-rich NiTi wires, while the latter materials contain second phase precipitates. Given the nanometer scale grain size in NiTiPt and the dispersed, nanometer scale precipitate size in NiTi, the overall strength and ductility of the alloys are essentially identical when given appropriate heat treatments. Property differences include a much smaller stress hysteresis and smaller temperature dependence of the transformation stress for NiTiPt alloys compared to NiTi alloys. Potential benefits and implications for use in vascular stent applications are discussed.

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Thick brain slice cultures and a custom-fabricated multiphoton imaging system: progress towards development of a 3D hybrot model

2007-01-11 , Rambani, Komal

Development of a three dimensional (3D) HYBROT model with targeted in vivo like intact cellular circuitry in thick brain slices for multi-site stimulation and recording will provide a useful in vitro model to study neuronal dynamics at network level. In order to make this in vitro model feasible, we need to develop several associated technologies. These technologies include development of a thick organotypic brain slice culturing method, a three dimensional (3D) micro-fluidic multielectrode Neural Interface system (µNIS) and the associated electronic interfaces for stimulation and recording of/from tissue, development of targeted stimulation patterns for closed-loop interaction with a robotic body, and a deep-tissue non-invasive imaging system. To make progress towards this goal, I undertook two projects: (i) to develop a method to culture thick organotypic brain slices, and (ii) construct a multiphoton imaging system that allows long-term and deep-tissue imaging of two dimensional and three dimensional cultures. Organotypic brain slices preserve cytoarchitecture of the brain. Therefore, they make more a realistic reduced model for various network level investigations. However, current culturing methods are not successful for culturing thick brain slices due to limited supply of nutrients and oxygen to inner layers of the culture. We developed a forced-convection based perfusion method to culture viable 700µm thick brain slices. Multiphoton microscopy is ideal for imaging living 2D or 3D cultures at submicron resolution. We successfully fabricated a custom-designed high efficiency multiphoton microscope that has the desired flexibility to perform experiments using multiple technologies simultaneously. This microscope was used successfully for 3D and time-lapse imaging. Together these projects have contributed towards the progress of development of a 3D HYBROT. ----- 3D Hybrot: A hybrid system of a brain slice culture embodied with a robotic body.

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