The blood-brain-barrier (BBB) is a significant obstacle for treating many neurological disorders. Bubble-assisted focused ultrasound (BAFUS) medicated BBB disruption is a promising technology that enables the delivery of large drug doses at targeted locations across the BBB. However, the current lack of an in vitro model of this process hinders the full understanding of BAFUS BBB disruption for better translation into clinics. In this work, a US-transparent organ-on-chip device has been fabricated that can be critical for the in vitro modeling of the BAFUS BBB disruption. The transparency of the device window to focused ultrasound (FUS) was calculated theoretically and demonstrated by experiments. Nanobubbles were fabricated, characterized by cryogenic transmission electron microscopy (cryo-TEM), and showed bubble cavitation under FUS. Human colorectal adenocarcinoma (Caco-2) cells were used to form a good cellular barrier for BAFUS barrier disruption, as suggested by the measured permeability and transepithelial electrical resistance (TEER). Finally, barrier disruption and recovery were observed in BAFUS disrupted US-transparent organ-on-chips with Caco-2 barriers, showing great promise of the platform for future modeling BAFUS BBB disruption in vitro.

The purpose of this thesis experiment was to design and create an Acoustically Active Cannula (AAC), which is furnished by a piezoelectric crystal placed at its tip that produces an acoustic navigation signal. I tested the functionality of the cannula in vitro and demonstrated its navigational abilities in vivo in anesthetized pigs. This experiment was based upon ultrasound science and technology, and thus some practical experience with conventional (B-mode) and Doppler ultrasound was achieved as well. The results of bench and experimental animal studies indicated proper functionality of the AAC for identification and spatial navigation of its tip with color Doppler ultrasound imaging.

We studied left ventricular flow patterns for a range of rotational orientations of a bileaflet mechanical heart valve (MHV) implanted in the mitral position of an elastic model of a beating left ventricle (LV). The valve was rotated through 3 angular positions (0, 45, and 90 degrees) about the LV long axis. Ultrasound scans of the elastic LV were obtained in four apical 2-dimensional (2D) imaging projections, each with 45 degrees of separation. Particle imaging velocimetry was performed during the diastolic period to quantify the in-plane velocity field obtained by computer tracking of diluted microbubbles in the acquired ultrasound projections. The resulting velocity field, vorticity, and shear stresses were statistically significantly altered by angular positioning of the mechanical valve, although the results did not show any specific trend with the valve angular position and were highly dependent on the orientation of the imaging plane with respect to the valve. We conclude that bileaflet MHV orientation influences hemodynamics of LV filling. However, determination of ‘optimal’ valve orientation cannot be made without measurement techniques that account for the highly 3-dimensional (3D) intraventricular flow.

The application of novel visualization and modeling methods to the study of cardiovascular disease is vital to the development of innovative diagnostic techniques, including those that may aid in the early detection and prevention of cardiovascular disorders. This dissertation focuses on the application of particle image velocimetry (PIV) to the study of intracardiac hemodynamics. This is accomplished primarily though the use of ultrasound based PIV, which allows for in vivo visualization of intracardiac flow without the requirement for optical access, as is required with traditional camera-based PIV methods.

The fundamentals of ultrasound PIV are introduced, including experimental methods for its implementation as well as a discussion on estimating and mitigating measurement error. Ultrasound PIV is then compared to optical PIV; this is a highly developed technique with proven accuracy; through rigorous examination it has become the “gold standard” of two-dimensional flow visualization. Results show good agreement between the two methods.

Using a mechanical left heart model, a multi-plane ultrasound PIV technique is introduced and applied to quantify a complex, three-dimensional flow that is analogous to the left intraventricular flow. Changes in ventricular flow dynamics due to the rotational orientation of mechanical heart valves are studied; the results demonstrate the importance of multi-plane imaging techniques when trying to assess the strongly three-dimensional intraventricular flow.

The potential use of ultrasound PIV as an early diagnosis technique is demonstrated through the development of a novel elasticity estimation technique. A finite element analysis routine is couple with an ensemble Kalman filter to allow for the estimation of material elasticity using forcing and displacement data derived from PIV. Results demonstrate that it is possible to estimate elasticity using forcing data derived from a PIV vector field, provided vector density is sufficient.