Introduction: For venous thrombosis patients, catheter-directed thrombolytic therapy is the standard-of-care to recanalize the occluded vessel. Limitations with thrombolytic drugs make the development of adjuvant treatments an active area of research. One potential adjuvant is histotripsy, a focused ultrasound therapy that lyses red blood cells within thrombus via the spontaneous generation of bubbles. Histotripsy has also been shown to improve the efficacy of thrombolytic drugs, though the precise mechanism of enhancement has not been elucidated. In this study, in silico calculations were performed to determine the contribution of histotripsy-induced changes in thrombus diffusivity to alter catheter-directed therapy.Methods: An established and validated Monte Carlo calculation was used to predict the extent of histotripsy bubble activity. The distribution of thrombolytic drug was computed with a finite-difference time domain (FDTD) solution of the perfusion-diffusion equation. The FDTD calculation included changes in thrombus diffusivity based on outcomes of the Monte Carlo calculation. Fibrin degradation was determined using the known reaction rate of thrombolytic drug.Results: In the absence of histotripsy, thrombolytic delivery was restricted in close proximity to the catheter. Thrombolytic perfused throughout the focal region for calculations that included the effects of histotripsy, resulting in an increased degree of fibrinolysis.Discussion: These results were consistent with the outcomes of in vitro studies, suggesting histotripsy-induced changes in the thrombus diffusivity are a primary mechanism for enhancement of thrombolytic drugs.

Histotripsy is a noninvasive focused ultrasound therapy that utilizes bubble cloud activity for tissue ablation. Real-time ultrasound imaging is used to guide histotripsy, and subharmonic imaging with chirp-coded excitation has been shown to provide effective bubble cloud contrast for targets at depth (>5 cm). Choice of appropriate parameters for the chirped imaging pulse are dependent on a number of factors, including the imaging probe bandwidth. In this study, an analytic method was developed and tested to design chirped imaging pulses for fundamental and subharmonic imaging. In silico studies were conducted to estimate received signal based on the frequency response of a curvilinear imaging probe (C5-2v, Verasonics, Inc., Kirkland, WA). To enable assessment of both bubbles and anatomic information, criteria were set to maximize the probe sensitivity for both fundamental and contrast-specific signals. Based on these analyses, in vitro studies were conducted using a scattering tissue phantom for sequences that highlight fundamental, subharmonic, or equally between the two for bubble cloud visualization. Good qualitative agreement was observed between insilico prediction and in vitro assessment of bubble cloud generation, indicating the formalism developed here is a promising approach for the development of imaging sequences for histotripsy guidance.