Non-Invasive Ultrasound Liver Ablation Using Histotripsy: Chronic Study in an In Vivo Rodent Model

Abstract

Hepatocellular carcinoma (HCC) or liver cancer has the fastest growing incidence among cancers in the United States. Current liver ablation methods are thermal-based and share limitations due to the heat sink effect from the blood flow through the highly vascular liver. Recently, our group has investigated histotripsy as a non-invasive liver cancer ablation method. Histotripsy is a non-thermal ultrasonic ablation method that fractionates tissue through the control of acoustic cavitation. Previous experiments in an in vivo porcine model show that histotripsy can create well-confined lesions in the liver through ribcage obstruction without damaging the overlying ribs and other tissues. Histotripsy can also completely fractionate liver tissue surrounding major vessels while preserving the vessels. In this study, we investigate the long-term effects of histotripsy liver ablation in a rodent model. We hypothesize that the fractionated histotripsy lesion will be resorbed by the liver, resulting in effective tissue healing. To test this hypothesis, the livers of 20 healthy rats were treated with histotripsy using an 8-element 1 MHz histotripsy transducer. Rats were euthanized after 0, 3, 7, 14, and 28 days (n=4). In vivo and post mortem results showed histotripsy lesions were successfully generated in all 20 rats through the intact abdomen. MRI demonstrated primarily negative contrast on day 0, positive contrast on day 3, and rapid normalization of signal intensity thereafter (i.e. signal amplitude returned to baseline levels seen in healthy liver tissue). Histologically, lesions were completely fractionated into an acellular homogenate. The lesions had a maximum cross-sectional area of 17.2±1.9 mm2 and sharp boundaries between the lesion and the healthy surrounding tissue after treatment. As the animals recovered after treatment, the histotripsy tissue homogenate was almost completely replaced by regenerated liver parenchyma, resulting in a small fibrous lesion (<1 mm2 maximum cross-section) remaining after 28 days. The results of this study suggest that histotripsy has potential as a non-invasive liver ablation method for effective tissue removal.

Robotically Assisted Sonic Therapy as a Noninvasive Nonthermal Ablation Modality: Proof of Concept in a Porcine Liver Model

“…In one of the small body wall injuries, the animal was allowed to survive for 1 month without apparent distress (Fig 6). Follow-up in this animal demonstrated a persistent body wall injury at MR imaging with high T2 signal and a peripheral rim of enhancement (Fig 6), which at histologic analysis demonstrated muscle bisected cells at the lesion boundaries in cases with minimal breathing motion (10,18). Evaluation of the RAST ablation zones in chronic subjects demonstrated or nearby organs was found despite closely placed ablation zones.…”

“…All ablations were performed with a cart-based therapy system (VortxRx; HistoSonics) with a therapeutic ultrasound signal generator and amplifier and embedded diagnostic ultrasound system. Therapeutic ultrasound was 28 days (18). The high peak negative pressure used in histotripsy generates microbubbles in tissue that can be visualized under real-time ultrasonography (US), leading to precise targeting (15).…”

Effects off-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior

“…With sufficiently high pressure and dose, histotripsy can completely fractionate soft tissues into an acellular liquid homogenate by inducing very large strains to the adjacent tissue structures (Parsons et al , 2006a; Vlaisavljevich et al , 2014a; Xu et al , 2005; Vlaisavljevich et al , 2016d). Histotripsy is currently being studied for many clinical applications where noninvasive tissue removal is desired including benign prostatic hyperplasia (Hempel et al , 2011; Roberts et al , 2014), kidney stones (Duryea et al , 2011), deep vein thrombosis (Maxwell et al , 2011a; Zhang et al , 2015), congenital heart disease(Owens et al , 2011; Xu et al , 2010), and cancer (Styn et al , 2010; Vlaisavljevich et al , 2016c; Vlaisavljevich et al , 2013b). …”

Assessment of histotripsy-induced liquefaction with diagnostic ultrasound and magnetic resonance imaging in vitro and ex vivo

“…Physiologic responses due to the therapeutic insonation may obfuscate the ablation extent in post hoc evaluative imaging immediately following treatment (Partanen et al 2013, Zhou 2011. In particular, the use of T 2 W imaging to designate histotripsy ablation may be complicated in vivo by the presence of hemorrhage and lesion evolution (Vlaisavljevich et al 2016). The appearance of post hoc images following histotripsy may therefore be highly dependent on the timing of their acquisition, underscoring the importance of real-time monitoring of bubble cloud activity via PCI for successful histotripsy guidance.…”