Diagnostic ultrasound is a safe, inexpensive and highly portable real-time imaging modality for viewing the human body. For over two decades, lipid-coated fluorocarbon microbubble contrast agents have been developed to help improve the diagnostic and therapeutic capabilities of ultrasound, but they have certain limitations. Recently, it was found that the microbubbles can be condensed into superheated liquid nanodrops capable of being vaporized by external optical or acoustic triggers. The compact form and vaporization effects of these phase-shift nanodrops may offer advantages over microbubbles for a number of current and future therapeutic and diagnostic applications. The goal of this dissertation work was to study the molecular thermodynamics and interfacial phenomena of these superheated phase-shift nanodrops.
In the first part of this work, a custom microscopy pressure chamber with control over temperature and pressure was used to observe microbubbles during condensation. Compression behaviors of fluorocarbon microbubbles constructed with lipid shells of varying acyl chain lengths were quantified over a broad temperature range. Microbubbles containing lipids of longer acyl chains were found to resist ideal compression and condensation. Dissolution was found to dominate as temperature approached the lipid main phase transition temperature, resulting in incomplete condensation. However, successful condensation of gas-filled microbubbles to liquid-filled nanodrops could be achieved at lower temperatures, and fluorescence microscopy showed that the lipid monolayer shell buckles and folds into surface-attached bilayer strands. The nanodrops were found to be remarkably stable when brought back to standard temperature and pressure. The temperature-pressure data were used to construct condensation phase diagrams to determine the thresholds for successful nanodrop formation.
In the second part of this study, the superheated nanodrops were vaporized back into microbubbles by changes in temperature and pressure. A custom optical chamber with control over temperature and pressure was used to track the kinetics of condensation, vaporization and dissolution of microbubble suspensions with varying fluorocarbon core and lipid shell compositions. A simple model was used to extract kinetic rates from the optical data, and Arrhenius plots were used to determine activation energies. The activation energy for thermal vaporization was found to vary with lipid acyl chain length, and a simple model of lipid intermolecular forces was used to explain this effect. Additionally, thermal vaporization was found to occur near 90% of the critical temperature of the fluorocarbon core, indicating that metastability of the superheated droplets was due to the low probability of homogenous nucleation rather than a Laplace overpressure. The superheated droplets could be reversibly vaporized and condensed to at least ten cycles, showing remarkable stability.
In the final part of this study, the tunability of vaporization was examined through the mixing of fluorocarbon gases in droplet core. A clinical ultrasound imaging system was used to track vaporization as a function of temperature and mechanical index. Discrepancies were found in the vaporization thresholds owing to mass transfer; the high solubility of the lower fluorocarbon caused it to rapidly deplete. However, a successful acoustic temperature probe was demonstrated. The experimental data from all three parts of this study were examined and explained by conventional molecular thermodynamics theory, providing new insights into the behavior and properties of these novel theranostic agents.
|Commitee:||Dayton, Paul, Ding, Yifu, Murray, Todd, Stoykovich, Mark|
|School:||University of Colorado at Boulder|
|School Location:||United States -- Colorado|
|Source:||DAI-B 77/01(E), Dissertation Abstracts International|
|Keywords:||Condensation, Microbubbles, Phase change agents, Sonothermetry, Ultrasound, Vaporization|
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