Large animal model of chronic venous occlusion: a pilot study to assess composition and sensitivity to histotripsy

Abstract Venous thrombi that transition to chronic occlusions are difficult to address with current interventions. Histotripsy is a focused ultrasound therapy that ablates tissue through bubble cloud activity. Pre-clinical studies indicate acute thrombi are sensitive to histotripsy, but outcomes for aged obstructions require further investigation. In this pilot study, a porcine model was developed to test the hypothesis that histotripsy will disrupt disorganized extracellular matrix within chronic venous occlusions. Thrombi were formed in the femoral vein of female mixed-breed pigs via selective catheterization. The occlusion was monitored for 30 days with ultrasound imaging, after which the femoral bundle was resected for analysis with immunohistochemistry and transcriptomics ( N = 3), or exposed to histotripsy ( N = 3). Changes to the occlusion appearance were noted throughout aging. At 30 days, obstructed venous tissue was composed primarily of collagen (mean: 39.7% by area) with activated macrophages (mean: 22.2% of cells) and fibroblasts (mean: 21.6% of cells). Relative to patient-derived samples of subacute venous thrombi, the occlusions generated in this study exhibited increased coverage by collagen and hematoxylin. Histotripsy resulted in a 59.0% mean reduction in the occlusion area on ultrasound imaging. Tissue components undergoing active remodeling (i.e., disorganized collagen and cells) exhibited increased strong damage. This study demonstrated feasibility for a large animal model of chronic venous thrombosis, and provided proof-of-concept data for targeting the occlusion with histotripsy.