Intrinsic threshold versus shock scattering histotripsy treatment of clots in vitro

Abstract

Catheter-directed thrombolytics are the frontline therapy for iliofemoral deep vein thrombosis. We have demonstrated that histotripsy can enhance the efficacy of the thrombolytic recombinant tissue plasminogen activator (rt-PA) through the mechanical activity of bubble clouds. Depending on the histotripsy pulse duration, bubble activity can be initiated via shock wave scattering or exceeding the peak negative pressure of the intrinsic cavitation threshold. In this study, the thrombolytic efficacy and bubble activity of shock scattering and intrinsic threshold histotripsy were compared. The mass loss was assessed of retracted human whole blood clots exposed to rt-PA (0 or 2.68 μg/mL) and histotripsy pulses of 1 (intrinsic threshold) or 5 (shock scattering) cycles duration. During the histotripsy exposure, bubble cloud emissions were captured on a linear array and processed to form passive acoustic images. The combination of rt-PA and histotripsy was more efficacious than rt-PA alone at 25 MPa peak negative pressure for single-cycle pulses, and 20 MPa peak negative pressure for five-cycle pulses. The degree of thrombolytic efficacy correlated with bubble cloud emissions within the clot. Overall, these results indicate that rt-PA and shock scattering or intrinsic threshold histotripsy is a promising combination thrombolytic therapy.