In Vitro Thrombolytic Efficacy of Single- and Five-Cycle Histotripsy Pulses and rt-PA

Abstract

Although primarily known as an ablative modality, histotripsy can increase the efficacy of lytic therapy in a retracted venous clot model. Bubble cloud oscillations are the primary mechanism of action for histotripsy, and the type of bubble activity is dependent on the pulse duration. A retracted human venous clot model was perfused with and without the thrombolytic recombinant tissue plasminogen activator (rt-PA). The clot was exposed to histotripsy pulses of single-or five-cycle duration and peak negative pressures of 0À30 MPa. Bubble activity within the clot was monitored via passive cavitation imaging. The combination of histotripsy and rt-PA was more efficacious than rt-PA alone for single-and five-cycle pulses with peak negative pressures of 25 and 20 MPa, respectively. For both excitation schemes, the detected acoustic emissions correlated with the degree of thrombolytic efficacy. These results indicate that rt-PA and single-or multicycle histotripsy pulses enhance thrombolytic therapy.

Clot Degradation Under the Action of Histotripsy Bubble Activity and a Lytic Drug

“…Prior to histotripsy exposure, the clot was cut to 1 cm in length and introduced into a venous flow model [24] (Figure 1). The model was composed of a syringe pump (EW-74900-20, Cole-Parmer, Vernon Hills, IL, USA) that drew plasma through 6.35-mm-inner-diameter and 0.79-mm wall thickness latex tubing (McMaster-Carr, Elmhurtst, IL, USA) at a rate of 0.65 mL/min.…”

“…Combing histotripsy with a lytic therapy may therefore provide an effective means to promote clot degradation. Preclinical studies have demonstrated that histotripsy combined with lytic significantly enhances overall treatment efficacy [15], [24]. Two primary mechanisms are hypothesized to contribute to combined histotripsy and lytic therapy: 1.)…”

“…Histotripsy sources generate high tensile pulse amplitudes to activate intrinsic nanoscale nuclei that permeate clots [ 20 ], [ 21 ]. Growth of the nanoscale nuclei into bubbles 10–1000 μ m in diameter imparts strain resulting in hemolysis, disruption of the fibrin network [ 22 ]-[ 24 ], and restoration of flow.…”

Non‐invasive recanalization of deep venous thrombosis by high frequency ultrasound in a swine model with follow‐up

“…This technique applied to a tissue is called histotripsy, and when applied to thrombus is called thrombotripsy. This approach was investigated ex vivo 11‐17 and in vivo in a porcine model 18,19 , and achieved convincing results, but also highlighted important limitations such as potential damage to the vessel walls. Several improvements have been studied to better target the thrombus: microtripsy 12 was based on focusing high‐pressure pulses, and the approach developed by our team, 20 which relied on high frequency to achieve smaller focal zones and obtain better preserved vessel walls.…”

Histotripsy: the first noninvasive, non-ionizing, non-thermal ablation technique based on ultrasound

“…The non-thermal nature also enables histotripsy to overcome many of the limitations associated with thermal devices (e.g., heat sink effect, lack of precise margins, and predictability). Histotripsy has been investigated for many pre-clinical applications, including treatment for tumors in the liver [37][38][39][40][41], kidney [23,40,42,43], and prostate [44,45], neurological diseases [46,47], thrombosis [48][49][50][51], hematoma [52][53][54], neonatal and fetal congenital heart disease [17,55], valvular diseases [56,57], kidney stones [58], abscesses [59], tendons [60], and biofilms [61][62][63]. Phase I human trials have been undertaken for histotripsy treatment of benign prostatic hyperplasia [64], liver cancer, and calcified valve stenosis [65], with early results suggesting safety and feasibility in humans.…”