PhD, University of Cincinnati, 2008, Engineering : Biomedical Engineering

Ultrasound contrast agents (UCAs) stabilized against gas diffusion in the bloodstream yet triggered for destruction by specially designed pulses of ultrasound are desirable for clinical applications in vivo. Echogenic liposomes (ELIP) are nano-sized phospholipid vesicles that contain both gas and fluid. With incorporation of a drug, such as recombinant tissue-Plasminogen Activator (rt-PA), these liposomes may be able to deliver a high local concentration of rt-PA by site-specific delivery of the drug directly to thrombi, with a lower systemic dose overall. Therefore, it is necessary to assess ELIP stability and destruction thresholds in vitro before their application in clinical diagnostic imaging and targeted drug delivery. Several researchers have used optical and acoustic techniques to identify three dominant mechanisms of UCA destruction; static diffusion, acoustically driven diffusion, and fragmentation (Chomas et al, 2001a; Bouakaz et al., 2005; Porter et al., 2006). We have developed new acoustic techniques to assess these three destruction thresholds of an FDA-approved UCA, Optison®, and unmodified ELIP utilizing a clinical diagnostic ultrasound scanner (Porter et al., 2006; Smith et al., 2007a). Recently, in vitro studies were performed with an innovative drug-encapsulated contrast agent, rt-PA-loaded ELIP. Their stability during contrast imaging was assessed using low output B-mode pulses and rt-PA was found to remain associated with the lipid bilayer. They were also fragmented using color Doppler pulses for determination of drug delivery by spectrophotometrically measuring the concentration of rt-PA released (Smith et al., 2007b). The primary objective of this dissertation was to characterize a novel echogenic lipid-based drug-encapsulated UCA using a diagnostic ultrasound scanner for its potential use in both image-guided and ultrasound-triggered drug delivery.

Committee: Christy K. Holland PhD (Committee Chair); William S. Ball MD (Committee Member); George J. Shaw MD, PhD (Committee Member); T. Douglas Mast PhD (Committee Member) Subjects: Acoustics; Biomedical Research; Engineering; Health; Pharmaceuticals; Physics; Radiology; Scientific Imaging

PhD, University of Cincinnati, 2015, Engineering and Applied Science: Biomedical Engineering

Cardiovascular disease (CVD) is the leading cause of death worldwide, and the economic impact of CVD is expected to increase substantially in future decades as disability rates due to ischemic heart disease and stroke rise. More effective diagnostic tools and therapies are necessary to limit the growing burden of CVD, particularly those which manifest in clotting within the arteries of the heart or brain. Echogenic liposomes (ELIP) are nanoparticle theragnostic agents being developed to target and treat cardiovascular disease. ELIP contain a small amount of gas and can function as an injectable ultrasound contrast agent (UCA) to improve visualization of the heart or diseased arteries. Previous investigations have shown that it is possible to load ELIP with bioactive gases, and that pulsed ultrasound exposure can result in the loss of echogenicity from ELIP. The purpose of this study was to determine if pulsed ultrasound exposure can also be used for controlled release of gas from ELIP. Determining the relationship between microbubble activity and acoustically-induced gas release will help to develop a method utilizing ELIP as therapeutic agents for delivery of gas to tissue. In Chapters 2 and 3, acoustic methods were used to characterize a series of novel formulations of ELIP with different shell components and gas content. Estimates of the shell properties of ELIP, as well as two commercially available UCAs, Definity® and MicroMarker®, were obtained using a linearized viscoelastic acoustic scattering model. Overall, ELIP are characterized by higher shell elasticity and shell damping coefficient than the commercially available agents. Replacing air with the high molecular weight gas octafluoropropane and addition of polyethylene glycol into the shell formulation resulted in longer stability and improved high-frequency response, making these ELIP formulations particularly suitable for intravascular ultrasound applications. In addition, ELIP encapsulating octaf (open full item for complete abstract)

Committee: Christy Holland Ph.D. (Committee Chair); Todd Abruzzo Ph.D. (Committee Member); Nico de Jong Ph.D. (Committee Member); Shaoling Huang Ph.D. (Committee Member); T. Douglas Mast Ph.D. (Committee Member) Subjects: Biomedical Research