Date of Award

Spring 6-21-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Mark Borden

Second Advisor

Todd Murray

Third Advisor

Yifu Ding

Fourth Advisor

Franck Vernerey

Fifth Advisor

Andrew Goodwin

Abstract

Ultrasound is already the most widespread clinical imaging modality on the market today, and is set to become even more prevalent as dual-purpose ultrasound contrast and drug delivery agents continue development. Though microbubbles encapsulated with a biocompatible lipid shell show promise as a dual-purpose agent, there is a need to engineer a new robust shell material capable of maintaining its therapeutic properties during rapid temperature and pressure fluctuations.

In this thesis, a biomimicry design approach is taken to further develop a resilient encapsulation material for microbubbles by focusing on the dynamic system of the lung. At the gas-water interface within the lung, a surfactant film lines the many small bubble-like alveoli that stabilizes the highly-curved interconnected surface. The lung surfactant film is adapted here as a shell material for both microbubbles and acoustically activatable nanodroplets.

To start, the elasticities of a lung surfactant and a lipid-only encapsulated microbubble were defined in compression-only experiments. By deriving a model coupling gas dissolution and compression, the stiffness of the lung surfactant material was found to rise with faster compression rates whereas the lipid-only bubble maintained a small constant elasticity. Further, the lung surfactant shell uniquely displayed solid material-like behavior evidenced by repetitive wrinkle-to-fold instabilities, common for thin solid materials in compression.

Next, a photoacoustic technique was used to excite and measure the viscoelastic properties of the same two shell types with temperature. It was found that the lung surfactant microbubble shell was more elastic and less viscous than the single lipid microbubble shell. Rapid heating experiments, using the same photoacoustic technique, revealed that the lung surfactant microbubble quickly recovered its elasticity by rapidly spreading material on the expanding bubble interface. The spreading ability of lung surfactant is promoted by the interactions between the constituent lipids and proteins and is an attractive quality for phase-change nanodroplet encapsulations.

Lastly in this work, the qualities of the lung surfactant encapsulation were exploited for acoustic phase conversion of a liquid droplet to an echogenic bubble. It was demonstrated that lung surfactant droplets activate near the same mechanical index as those coated with a conventional lipid formulation but displayed significantly greater and prolonged ultrasound contrast. The use of such coatings with optimal interfacial transport properties may be essential to the clinical success of ultrasonic dual-purpose phase-change agents.

Available for download on Thursday, January 27, 2022

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