Phase-change contrast agent and its applications in contrast-enhanced ultrasound and photoacoustic imaging

Ultrasound imaging with microbubbles offers substantial benefits and extended diagnostic applications for clinical practice, however the contrast enhancement is mainly limited to the intravascular space due to the size of microbubble. As one of the most actively researched alternative contrast agents, phase-change contrast agent (PCCA), or nanodroplet, has shown great potentials in imaging the extravascular space thanks to its initial sub-micron size. Among a variety of research efforts on driving the PCCA into pre-clinical and translational development, this work focuses on understanding PCCA in contrast-enhanced ultrasound imaging, and extending to photoacoustic imaging. There are three main scientific contributions as follows. Firstly, to improve the understanding for in vivo applications of PCCA, the effect of biologically geometrical confinement on the acoustic vaporisation of PCCAs was investigated. The difference in PCCA-produced ultrasound contrast enhancement after acoustic activation with and without a microvessel confinement was compared on a microchannel phantom. The results indicated more than one-order of magnitude less acoustic power increase in a microchannel than that in a free environment taking into account of the attenuation effect of the vessel on the microbubble scattering. This investigation and quantification provide a new insight of vaporising and imaging PCCAs in a more realistic microenvironment. Secondly, to observe and better understand PCCA behaviour after vaporisation, high-frame-rate ultrasound and optical imaging was employed for capturing the fast phenomenon at a high temporal resolution. It has been revealed that significant difference in the acoustic signals between the vaporised PCCAs and microbubbles. The PCCAs exhibited characteristic acoustic signal features with different amplitude and temporal features compared to that of microbubbles. This work improves the current knowledge for the imaging contrast enhancement from the vaporised PCCAs with high-frame-rate contrast-enhanced ultrasound, which has potential importance for developing PCCA-specific imaging strategies. Finally, the PCCA application was extended to contrast-enhanced photoacoustic imaging, which a novel dual-modality contrast agent, Cy-droplet, has been developed towards low-energy, optical and acoustical triggerability. This sub-micron Cy-droplet was demonstrated to provide three modes of contrast enhancement: 1) photoacoustic imaging contrast, 2) ultrasound contrast with optical activation, and 3) ultrasound contrast with acoustic activation. The phase-transition of Cy-droplets can be optically triggered by pulsed-laser illumination, inducing photoacoustic signal and forming stable gas bubbles that are visible with echo-ultrasound in situ. Alternatively, Cy-droplets can be converted to microbubbles upon acoustic activation with clinical ultrasound. Such versatility of acoustic and optical ‘triggerability’ can potentially benefit for multi-modality and molecular-targeted imaging.Open Acces