Coupling fluid temperature control and passive cavitation detection during skin sonoporation.
Thesis DisciplineMechanical Engineering
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Skin sonoporation refers to the creation of aqueous pathways in the stratum corneum with ultrasound. The mechanism responsible for the permeability increase that arises from sonoporation is inertial cavitation – the formation and collapse of gaseous cavities in the coupling fluid. In vitro skin sonoporation experiments are usually conducted in Franz diffusion cells – an apparatus designed for passive transdermal transport experiments. During skin sonoporation, the temperature of the coupling fluid often increases to a level which can cause burns. To mitigate temperature increases, previous studies have relied on duty cycles and replacement of the coupling fluid during ultrasound application. Reliance on these two methods has resulted in sonoporation protocols that are not clinically applicable: when using a duty cycle, 12 minutes of ultrasound can take up to 2 hours to administer; while coupling fluid replacement requires constant monitoring and disruptive manual intervention. This thesis introduces a circulation system which enables the coupling fluid to be set and maintained at a specified, safe temperature during continuous ultrasound application. With this new technology, duty cycles and fluid replacement are no longer required during in vitro, in vivo or clinical sonoporation. Using the temperature control system, a series of experiments were conducted to investigate the influence of coupling fluid temperature on post-sonoporation transport. Although the inertial cavitation activity decreased, the post-sonoporation transport increased as the specified coupling fluid temperature increased.
In other therapeutic ultrasound systems, passive cavitation detectors (PCDs) are used to monitor inertial cavitation activity (the main mechanism of permeability increase) to ensure it remains at the desired level during ultrasound application. Passive cavitation detectors cannot be used to effectively monitor inertial cavitation activity in standard Franz diffusion cells as the donor chambers are too small to incorporate a transducer and hydrophone during sonoporation. Researchers have therefore had to assume that, for a given intensity, inertial cavitation activity always remains constant during ultrasound application. A modified diffusion cell setup that incorporates a transducer and PCD hydrophone during sonoporation is introduced. The PCD output was shown to increase with increasing ultrasound intensity (as inertial cavitation does) and decrease with increasing coupling fluid temperature (as inertial cavitation was shown to do). It can be concluded from these results that a PCD positioned in the coupling fluid can be used to monitor the inertial cavitation activity which occurs during skin sonoporation. Applying this system to clinical setups will be of great benefit as it will enable any changes in inertial cavitation activity to be detected and counteracted in real-time.
Acoustic reflections have been shown to significantly influence the ultrasound fields in cell sonoporation setups. The influence of acoustic reflection on the ultrasound field during skin sonoporation has not been investigated. A modified Franz diffusion cell setup was manufactured which allowed for passive measurement of the inertial cavitation at the skin aperture during sonoporation (with and without the suppression of reflections). When acoustic reflection was suppressed, the inertial cavitation dose (ICD) was lower than when the reflection was not supressed. It can be concluded from this result that the acoustic reflections within a low-frequency sonoporation setup can influence the inertial cavitation activity which occurs during ultrasound application. Therefore, for a given set input parameters, the same inertial cavitation activity that was obtained in vitro is not guaranteed in an in vivo or clinical scenario, due to differences in echoic conditions.