A. James Clark School of Engineering

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The collections in this community comprise faculty research works, as well as graduate theses and dissertations.

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    INTRACELLULAR REGULATION OF ATRIAL EXCITATION CONTRACTION COUPLING IN NORMAL AND ARRHYTHMOGENIC HEARTS
    (2017) Garber, Libet; Lederer, Jonathan W; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Atrial fibrillation (AF) is the most common arrhythmia with a prevalence of 1-2% of the US population and it is the most important single risk factor for an ischemic stroke. Despite decades of research, successful termination of the arrhythmia remains difficult. The challenge is in part due to our incomplete understanding of atrial myocyte Ca2+ signaling and underlying disease mechanisms. In the atria, like all cardiac tissue, the conducted action potential (AP) underlies triggering of the [Ca2+]i transient, which is responsible for activating contraction. The process that links electrical activity to Ca2+ signaling and contraction is known as excitation-contraction coupling (ECC). The objective of this dissertation is to understand the mechanism of excitation contraction coupling in atrial myocytes. To achieve this goal, we (1) developed tools to specifically study atrial cell biology, (2) we studied the role of altered Ca2+ buffering on ionic membrane currents and Ca2+ signaling, (3) we investigated the role that reactive oxygen species (ROS) plays in altered Ca2+ signaling and the morphology of the AP and (4) we measured intracellular sodium concentration ([Na+]i ) and studied Na+ and Ca2+ signaling in a transgenic murine model of AF. This work includes mathematical modeling of atrial cell electrical and Ca2+ signaling to define our quantitative understanding of the processes involved. Our results indicate that increased Ca2+ buffering plays a major role in speeding the inactivation of the L type Ca2+ current (ICa,L ). This work also shows that low concentrations of H2O2 for a brief period increases atrial Ca2+ spark rate, changes spark characteristics and decreases the duration of the AP. We quantified for the first time the [Na+]i in murine atrial cells both at rest and during field stimulation in control and transgenic mice. Our results indicate that [Na+]i is significantly lower in atrial myocytes in comparison to their ventricular counterparts, which reveal important differences in how [Na+]i is regulated in atrial cells. Moreover, our work demonstrates that [Na+]i and [Ca2+]i homeostasis are profoundly affected during AF. The results further our understanding of mechanisms that modulate excitation-contraction coupling in atrial myocytes in normal and pathophysiological conditions.
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    BILAYER LIPID MEMBRANE (BLM) INTEGRATION INTO MICROFLUIDIC PLATFORMS WITH APPLICATION TOWARD BLM-BASED BIOSENSORS
    (2007-04-27) Hromada, Jr., Louis Paul; DeVoe, Donald L; Mechanical Engineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Bilayer Lipid Membranes (BLMs) have been widely used as an experimental tool to investigate fundamental cellular membrane physics and ion channel formation and transduction. Traditional BLM experimentation is usually performed in a macro-sized electrophysiology rig, which suffers from several well-known issues. First, BLMs have short lifetimes (typically on the order of tens of minutes to a few hours) and the laborious, irreproducible membrane formation process must be repeatedly applied for long-term testing. Second, stray capacitance inherent to traditional test rigs limits the temporal response leading, for example, to poor resolution in determining fast ion channel translocation events. Lastly, BLM testing is done within a single site format thus limiting throughput and increasing data collection time. To mitigate the above drawbacks, BLM technology and microfluidic platforms can be integrated to advance the state-of-the-art of BLM-based biosensor technology. Realization of BLM-based microfluidic biosensors can offer significant improvement towards sensor response characteristics (e.g. lower noise floor, increased time response). In addition, microfluidic biosensing chips can be fabricated with multiple BLM test sites that allow for parallel testing thus increasing data collection efficiency. Other benefits that microfluidics offer are: small reagent sensing volumes, disposable packaging, mass manufacturability, device portability for field studies, and lower device cost. Novel polymer microfluidic platforms capable of both in-situ and ex-situ BLM formation are described in this work. The platforms have been demonstrated for the controlled delivery of trans-membrane proteins to the BLM sites, and monitoring of translocation events through these ion channels using integrated thin film Ag/AgCl electrodes. The detailed design, fabrication, and characterization of various micro-fabricated BLM platforms is presented in this dissertation.