In-vitro Sonothrombolysis Using Thick-shelled Polymer Microbubbles - a Comparison with Thin-shelled Microbubbles

Background: Vascular thrombosis can be treated pharmacologically, however, serious shortcomings such as bleeding may occur. Several studies suggest that sonothrombolysis can induce lysis of the clots using ultrasound. Moreover, intravenously injected thin-shelled microbubbles (MBs) combined with ultrasound can further improve clot lysis. Thick-shelled MBs have been used for drug delivery, targeting and multimodal imaging. However, their capability to enhance sonothrombolysis is unknown. In this study, using an in-vitro set-up, the enhancement of clot lysis using ultrasound and thick-shelled MBs was investigated. Thin-shelled MBs was used for comparison.

Method: The main components in the in-vitro set-up was a vessel mimicking phantom, a pressure mearing system and programmable ultrasound machine. Blood clots were injected and entrapped on a pore mesh in the vessel phantom. Four different protocols for ultrasound transmission and MB exposure (7 blood clots/protocol) were considered together with a control test were no MBs and ultrasound were used. For each protocol, ultrasound exposure of 20 min was used. The upstream pressure of the partially occluded mesh was continuously measured to assess clot burden. At the end of each protocol blood clots were removed from the phantom and the clot mass loss was computed.

Results: For the thick-shelled MBs no difference in clot mass loss compared with the control tests was found. A 10% increase in the clot mass loss compared with the control tests was found when using thin-shelled MBs and low pressure/long pulses ultrasound exposure. Similarly, in terms of upstream pressure over exposure time, no differences were found when using the thick-shelled MBs, whereas thin-shelled MBs showed a 15% decrease achieved within the first 4 min of ultrasound exposure.

Conclusion: No increase in clot lysis was achieved using thick-shelled MBs as demonstrated by no significant change in clot mass or upstream pressure. Although thick-shelled MBs are promising for targeting and drug delivery, they do not enhance clot lysis when considering the ultrasound sequences used in this study. On the other hand, ultrasound in combination with thin-shelled MBs can facilitate thrombolysis when applying long ultrasound pulses with low pressure.