Contribution of bubble activity to the efficacy of histotripsy and catheter-directed recombinant tissue plasminogen activator for treatment of porcine thrombi in vitro

Abstract

Histotripsy has been shown to be a promising adjuvant treatment for deep vein thrombosis (DVT), using the mechanical action of bubble clouds to enhance thrombolytic activity and reduce the risk of complications. The objective of this study was to compare the effects of histotripsy with and without recombinant tissue-plasminogen activator, rt-PA in a physiologic, in vitro model mimicking porcine DVT. Highly retracted porcine whole blood clots were treated for 1 h with catheter-directed infusions of either saline or rt-PA [0.04 mg/ml] at 25 ml/h, either with or without histotripsy exposure. Five-cycle, 1.5 MHz histotripsy pulses with a peak negative pressure of 32 MPa and pulse repetition frequency of 40 Hz were applied along the catheter at 0.3 mm/s and repeated 1 mm on either side. This application pattern was repeated 6 times, totaling approximately 120 to 144 K pulses per clot. B-mode and passive cavitation images were acquired every 10pulses. The combination of rt-PA and histotripsy was more efficacious for recanalization than saline with histotripsy, saline, or rt-PA alone. Histotripsy exposure, but not rt-PA, improved mass loss (p < 0.01). These in vitro data support our hypothesis that the mechanical action of histotripsy-induced bubble clouds enhances catheter-directed thrombolytic.