Cavitation-Enhanced High-Pressure Pulsed Sonothrombolysis with Perfluorocarbon Nanodroplets versus Microbubbles in Contracted and Uncontracted Clots

Abstract

Microbubbles enhance cavitation effects in sonothrombolysis of acute (uncontracted) blood clots. However, only limited efficacy was demonstrated for the contracted clots due to their dense fibrin structure with less porosity. We hypothesize that nanodroplet-induced cavitation occurs inside of contracted clots due to their submicron size, and the consequent clot dissolution rate is possibly higher than microbubble-mediated treatment. This hypothesis was tested in this work by comparing the efficacy of nanodroplets and microbubbles on both uncontracted and contracted bovine clots with an in-vitro flow model. In-house microbubbles and nanodroplets with decafluorobutane-core and lipid-shell were used. With 8 MPa (peak negative pressure), 0.09%-duty cycle bursts, the percent mass reduction of contracted clots was significantly lower than uncontracted clots for both microbubbles and nanodroplets mediated treatments. For contracted clots, the nanodroplet-infusion case exhibited a 1.6-fold mass reduction of the microbubble-assisted ultrasound, whereas both treatments showed similar mass reduction (~45% on average) for the uncontracted clots. This result correlated with the passive cavitation detection result; nanodroplet cavitation exhibited noticeably higher inertial cavitation level (in arbitrary unit) than microbubble cavitation (530 vs. 300) at contracted clots, whereas uncontracted clot cases showed a relatively smaller difference (546 vs. 500). The cavitation proximity to a target clot will be tested by active cavitation imaging.