Abstract
This dissertation describes research into strategies for active delivery and manipulation of ultrasound-controllable agents with the aim at improving the natural targeting regime that simply relies on hemodynamics. This first part of the dissertation investigates the feasibility of transporting phase-change drop-lets using macrophages and for prompt acoustic droplet vaporization (ADV) under ultrasound insonation. The cell-based delivery takes advantage of the homing ability of cellular vesicles toward specific targets in vivo. The droplets vaporized within single DLMs can coalesce into large bubbles upon the onset of vaporization. Inertial cavitation (IC) can be simultaneously induced upon the occurrence of bubbles, presumably in the early stage of bubble coalescence. Since the IC of bubbles has been reported to aid drug extravasation, and bubble coalescence may benefit vascular occlusion, the use of macrophage to transport PFP droplets toward tumors shows great promise for advancing the development of both drug delivery and ADV-based tumor therapies. The use of acoustic radiation forces may further enable the spatial control and acceleration of the cell-based delivery. Acoustic tweezers can exert radiation forces on microscale particles convergent on a specific region or point, and thus have been popularly used for non-invasive and non-contact particle manipulation. With good penetration ability in biological tissue, they show the promising prospective in vivo applications. The second part of the dissertation investigates two different theoretical models of acoustic tweezers valid in the Mie and Rayleigh regimes. The model valid in the Mie regime is the acoustic counterpart of optical tweezers, which may be used as a single-particle manipulator due to the use of a highly focused acoustic beam. It is proposed based on ray acoustics and permits time-course simulation of instantaneous forces exerted by highly focused acoustic pulses of arbitrary lengths. The results have suggested that short acoustic pulses exert negative forces to pull spheres located beyond the focus in the direction opposite to that of wave propagation. Regulating the acoustic pulse length relative to the sphere size can alter the force magnitudes, which may be useful in particle sorting applications. However, the Mie regime means that an ultrasound transducer with a very high acoustic frequency (>100MHz) should be used for microscale particles. The use of such high acoustic frequency may pose several disadvantages for in vivo manipulation including high attenuation and small focal area. Accordingly, the second model is proposed in the Rayleigh regime. A Laguerre-Gaussian beam with phase dislocation around its beam axis (i.e., acoustic vortex) has been theoretically shown to produce a force-potential well that can trap dense and stiff microparticles within the axial null. Inward radiation forces of up to tens of piconewtons are exerted at one-fourth the Rayleigh distance of the transducer. The presence of transverse trapping and the long working distance makes the model useful for two-dimensional manipulation, particularly in in vivo applications. The results support the feasibility of the potential-well model of acoustic tweezers, whose adaptability and flexibility are much superior to those of the first model. It shows great promise in active manipulation of ultrasound controllable vesicles for drug delivery applications. Combining these two strategies for active delivery and manipulation of ultrasound-controllable drug vesicles is expected to facilitate the development of ultrasound theranosis.