Passive Acoustic Mapping for vascular permeability assessment

Despite significant research efforts, cancer remains one of the leading causes of death globally, and relative survival rates have not improved significantly over the past 40 years. Larger therapeutic agents rely on a high degree of vascular permeability for delivery and are increasingly being used for treatment, making permeability one of the most important biomarkers in tumour assessment. In this thesis, Passive Acoustic Mapping (PAM) of acoustic cavitation arising from nanoscale cavitation agents is explored in order to assess tumour permeability to molecules of a similar size to the latest therapeutics.
In vitro experiments using a dual High Intensity Focussed Ultrasound (HIFU) and dual linear array setup demonstrate that cavitation nuclei can be extravasated from a flow channel into a tissue mimicking phantom under ultrasound-enhanced delivery, and can then be re-excited using ultrasound and spatially mapped with PAM. In vivo experiments in a bi-lateral murine model following a similar process yield surprising results, namely that when a tumour on one side of the animal is exposed to ultrasound at a 5% duty cycle, the level of cavitation on the contralateral side tumour is increased relative to the treated side tumour and relative to tumours in animals that were treated with different acoustic parameters. It is hypothesised that this is due to a combination of biological and acoustic factors.
Further experiments to assess passive accumulation of nanoscale cavitation nuclei at different developmental stages within a single tumour line, as well as between tumour lines with different stromal composition, demonstrate that passive accumulation occurs to varying degrees depending on developmental stage and tumour type. Micro-CT assessment of tumour vessel structure using radiopaque resin perfusions does not show clear structural differences in tumours with different levels of passive accumulation. This implies that ultrasound and nanoscale cavitation agents could be used to assess passive accumulation of large molecules, even in tumours with similar vessel structures. Finally, it is not always possible to use high resolution dual array PAM in a clinical setting due to geometric constraints. Therefore a new passive acoustic source localisation approach is proposed that relies on Blind Source Separation (BSS) and Acoustic Source Localisation (ASL). Mixed cavitation signals arising from individual sources are first separated using a BSS technique, before the time delays for each separated signal are determined on a linear array and used to estimate individual source position. Simulation results for this approach show good performance, and enable the localisation of multiple sources which, crucially, cannot be identified as separate sources using single array PAM, even with the most advanced algorithms currently available.
Overall, the combination of the proposed source localisation technique, with the assessment of passively accumulated and actively extravasated cavitation nuclei, could eventually be used to provide critical information to clinicians about tumour vasculature permeability.

Keywords: Cavitation
Passive Acoustic Mapping
Vascular Permeability
Acoustic Source Localisation
Blind Source Separation
High Intensity Focussed Ultrasound
Advisor: Coussios, CC