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Vibrating microbubbles for Imaging and Therapy
Prof Nico Je Jong (Erasmus/TU Delft, NL)

Microbubbles for diagnosis: The mechanism by which the microbubbles enhance the contrast is two- fold. First, acoustic waves are scattered by the bubbles due to the large difference in acoustic impedance between the gas and the surrounding liquid. Second, the large compressibility of the gas bubbles results in radial oscillations of the bubbles in response to the ultrasound pressure waves. The radial oscillations are highly non-linear and produce non-linear sound waves, which are exploited in contrast-enhanced ultrasound imaging. The strong scattering of the microbubbles allows for the visualization and quantification of blood perfusion in organs, e.g. heart, liver, or kidney. The sensitivity of the bubble detection, down to a single bubble in vivo, facilitates targeted molecular imaging applications for the diagnosis of disease at the molecular level. Targeting ligands that bind specifically to selective biomarkers on the blood vessel wall can be labelled to the micro-bubble shell. The approach here is to inject targeted bubbles intravenously, then to wait 5 to 10 minutes for the freely flowing bubbles to be washed out by the lungs and the liver and then to image the adherent bubbles using ultrasound. One other approach is to discriminate acoustically between freely flowing and adherent bubbles through spectral differences through a resonance shift of the adherent bubbles due to the interaction between the bubble and the vessel wall. This approach would require that all bubbles have the same response to the ultrasound driving signal, which is up to now not possible because of the large size distribution of the commercial agents. Recently microbubbles were targeted to stem cells to produce echogenic complexes, which can be directed towards diseased tissue using acoustic radiation forces to up-regulate the therapeutic targeting efficiency Microbubbles for Therapy: Contrast bubbles can themselves serve as therapeutic agents. Several configurations are possible here. First, a drug can be co-administered with the bubbles while ultrasound-induced bubble oscillations close to cells promote local drug uptake through mechanical stress to the adjacent cell membranes, a process called sonoporation. Second, UCAs can be loaded with drugs, e.g. for the local delivery of chemotherapeutic drugs with a narrow therapeutic index, or for the delivery of genes. The payload can be directly incorporated in the bubble coating, or in the core of the bubble, or in liposomes attached to the bubble shell. Drug-loaded microbubbles can be imaged at low acoustic pressures aiding the guidance and real-time monitoring of the therapy, then at higher acoustic pressures rupture of the bubble shell triggers drug release. Ideally, the release of such a payload follows a step response after passing an insonation pressure threshold for the controlled release of the payload in a confined and highly localized region determined by the position of the acoustic focus and the position of the bubbles. The prime focus of such a local delivery is to reduce the systemic exposure to toxic drugs and to increase the delivery efficacy by preventing early capture of the drugs or genes by the systemic system.