Purpose-This study evaluated histotripsy as a noninvasive, image-guided method of thrombolysis in a porcine model of deep vein thrombosis. Histotripsy therapy uses short, highintensity, focused ultrasound pulses to cause mechanical breakdown of targeted soft tissue by acoustic cavitation, which is guided by real-time ultrasound imaging. This paper is an in-vivo feasibility study of histotripsy thrombolysis.Methods and Materials-Acute thrombi were formed in the femoral vein of juvenile pigs weighing 30-40 kg by balloon occlusion with two catheters and thrombin infusion. A 10-cm diameter 1-MHz focused transducer was used for therapy. An 8 MHz ultrasound imager was used to align the clot with the therapy focus. Therapy consisted of 5 cycle pulses delivered at a rate of 1 kHz and peak negative pressure between 14-19 MPa. The focus was scanned along the long axis of the vessel to treat the entire visible clot during ultrasound exposure. The targeted region identified by a hyperechoic cavitation bubble cloud was visualized via ultrasound during treatment.Results-Thrombus breakdown was apparent as a decrease in echogenicity within the vessel in 10 of 12 cases, and in 7 cases, improved flow through the vein as measured by color Doppler. Vessel histology showed denudation of vascular endothelium and small pockets of hemorrhage in the vessel adventitia and underlying muscle and fatty tissue, but perforation of the vessel wall was never observed. Conclusions-The results indicate histotripsy has potential for development as a noninvasive treatment for deep vein thrombosis.

Hepatocellular carcinoma (HCC) or liver cancer is one of the fastest growing 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. In this study, we demonstrate the feasibility of using histotripsy for non-invasive liver ablation in the treatment of liver cancer. Histotripsy is a non-thermal ablation method that fractionates soft tissue through the control of acoustic cavitation. Twelve histotripsy lesions ~1cm3 were created in the livers of six pigs through an intact abdomen and chest in vivo. Histotripsy pulses of 10 cycles, 500 Hz pulse repetition frequency (PRF), and 14-17 MPa estimated in situ peak negative pressure were applied to the liver using a 1 MHz therapy transducer. Treatments were performed through 4-6 cm of overlying tissue with 30-50% of the ultrasound pathway covered by the ribcage. Complete fractionation of liver parenchyma was observed with sharp boundaries after 16.7 minute treatments. In addition, two larger volumes of 18 cm3 and 60 cm3 were generated within 60 minutes in two additional pigs. As major vessels and gallbladder have higher mechanical strength and are more resistant to histotripsy, the major hepatic vessels and gallbladder remained intact while the liver surrounding these structures was completely fractionated. This work demonstrates that histotripsy is capable of non-invasively fractionating liver tissue while preserving critical anatomical structures within the liver. Results suggest histotripsy has potential for the non-invasive ablation of liver tumors.

Histotripsy is a non-invasive tissue ablation method capable of fractionating tissue by controlling acoustic cavitation. To determine the fractionation susceptibility of various tissues, we investigated histotripsy-induced damage on tissue phantoms and ex vivo tissues with different mechanical strengths. A histotripsy bubble cloud was formed at tissue phantom surfaces using 5-cycle long ultrasound pulses with peak negative pressure of 18 MPa and PRFs of 10, 100, and 1000 Hz. Results showed significantly smaller lesions were generated in tissue phantoms of higher mechanical strength. Histotripsy was also applied to 43 different ex vivo porcine tissues with a wide range of mechanical properties. Gross morphology demonstrated stronger tissues with higher ultimate stress, higher density, and lower water content were more resistant to histotripsy damage in comparison to weaker tissues. Based on these results, a self-limiting vessel-sparing treatment strategy was developed in an attempt to preserve major vessels while fractionating the surrounding target tissue. This strategy was tested in porcine liver in vivo. After treatment, major hepatic blood vessels and bile ducts remained intact within a completely fractionated liver volume. These results identify varying susceptibilities of tissues to histotripsy therapy and provide a rational basis to optimize histotripsy parameters for treatment of specific tissues.

Background-The primary objective of this study was to develop an image-guided, noninvasive procedure to create or enlarge an atrial septal defect for the treatment of neonates with hypoplastic left heart syndrome and an intact or restrictive atrial septum. Histotripsy is an innovative ultrasonic technique that produces nonthermal, mechanical tissue fractionation through the use of high-intensity ultrasound pulses. This article reports the pilot in vivo study to create an atrial septal defect through the use of extracardiac application of histotripsy in an open-chest canine model. Methods and Results-In 10 canines, the atrial septum was exposed to histotripsy by an ultrasound transducer positioned outside the heart. Ultrasound pulses of 6-microsecond duration at a peak negative pressure of 15 MPa and a pulse repetition frequency of 3.3 kHz were generated by a 1-MHz focused transducer. The procedure was guided and monitored by real-time ultrasound imaging. In 9 of 10 canines, an atrial septal defect was produced, and shunting across the atrial septum was visualized. Pathology of the hearts showed atrial septal defects with minimal damage to surrounding tissue. No damage was found on the epicardial surface of the heart or other structures. Conclusions-Under