Spatio-temporal control of acoustic cavitation during high-intensity focused ultrasound therapy

High-intensity focused ultrasound (HIFU) is rapidly emerging as a viable alterna- tive to conventional therapies in the treatment of deep-seated, solid tumours. In contrast to surgical methods, extracorporeal HIFU transducers non-invasively tar- get pathogenic tissue deep beneath the skin, inducing thermal necrosis of a volume of tissue typically coincident with the ultrasound focus. More recently, cavitation activity has been observed to enhance focal heating, whilst providing a unique op- portunity for real-time treatment monitoring. Unfortunately, the stochastic nature of cavitation makes it difficult to initiate and sustain the level of cavitation activity required for enhanced heating, and to confine the spatial extent of cavitation to the focal volume.
The overall aim of this thesis is to design and implement a real-time, closed- loop controller for sustaining thermally relevant cavitation within the HIFU focal region. This is intended to improve the speed and reproducibility of tissue ablation, whilst providing clinicians with real-time feedback as to the extent and location of the ablated region.
A quantitative relationship between the level of cavitation activity and asso- ciated temperature rise is first sought experimentally, by investigating cavitation- enhanced heating in two different tissue-mimicking materials (TMM) that yield dif- ferent levels of cavitation for the same HIFU exposure conditions. It is found that a minimum level of inertial cavitation activity is required for cavitation-enhanced heating to dominate the heating process, which is achieved in the first material but not the second. However, the introduction of exogenous, artificial nuclei to the second material is seen to augment cavitation levels to the extent that cavitation- enhanced heating becomes dominant.
Subsequently, HIFU experimentation is extended to non-perfused, ex vivo bovine liver, into which a variety of cavitation nuclei are introduced to augment cav- itation levels, and hence heating. Commercially available lipid-shelled microbub- bles are contrasted with custom-made sonosensitive nanoparticles for their ability to seed cavitation events, culminating in an empirical relationship between iner- tial cavitation and heating that is common to both types of exogenous nuclei, and which agrees with the in vitro results. Moreover, the abnormally large lesions pro- duced are found to correlate with a broad spatial distribution of inertial cavitation events, as seen on two-dimensional passive acoustic maps.
Based on these encouraging results, a novel negative-feedback, real-time con- trol system is implemented to sustain inertial cavitation within the focal region for extended periods of time. The controller is designed to be both asymmetric and adaptive, deploying different feedback gains to adjust the peak rarefactional focal pressure (PRFP), depending on whether cavitation activity is above or below the level required for cavitation-enhanced heating. With active cavitation control in vitro, the associated focal temperature elevation is maintained at a cytotoxic level for 20 seconds using less than half the energy input required in the absence of cavi- tation control.
In order to test the applicability of the novel controller to a near-physiological environment, HIFU exposures are eventually performed in a unique normothermic perfused liver model that accounts for both heat advection and nuclei replenish- ment. Following preliminary experimentation, the controller is modified to account for the inherent variability in the cavitation threshold of perfused tissue, whilst the cavitation demand is also increased to account for heat advection. Following these modifications, use of the controller is found to enable greatly improved re- producibility of HIFU-induced lesions compared to those achieved without cavita- tion control, with a lesion size that is directly related to the cavitation demand. A cost-effective method for enabling caviation-enhanced, cavitation-controlled and cavitation-monitored HIFU therapy has thus been developed, which enables suc- cessful tissue ablation at acoustic energies lower than in current clinical use.

Keywords: cavitation
HIFU
Advisor: Coussios, C