Noninvasive treatment of deep venous thrombosis using pulsed ultrasound cavitation therapy (histotripsy) in a porcine model

Abstract

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, high-intensity, focused ultrasound pulses to cause mechanical breakdown of targeted soft tissue by acoustic cavitation, which is guided by real-time ultrasound imaging. This 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 five cycle pulses delivered at a rate of 1 kHz and peak negative pressure between 14 and 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 found 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.

Figure 1

Experimental treatment apparatus used for histotripsy thrombolysis. A focused therapy transducer is coupled to the legs by a water bath with an acoustic window of polyethylene at the bottom. The transducer is focused on the femoral vein, guided by a phased array ultrasound imager. A motorized positioner is used to scan along the clot during treatment.

Figure 2

(a) Thrombus formed in the femoral vein (FV) of a subject, as visualized by the 8 MHz therapy guidance imager from a distance of approximately 8 cm. (b) A scanning route determined during pretreatment planning, with the approximate focus positions (dashed ellipses) at the start and end of treatment. Each small circle along the path indicates a position of the focus during the treatment.

Figure 3

Example ultrasound images captured with a 10 MHz linear array probe of fully occlusive thrombus in 2D (a) and color Doppler (b). 2D and color Doppler images of a partially occlusive thrombus are shown in (c) and (d).

Figure 4

Progression of a single treatment scan. (a) The echogenic thrombus (white arrow) is differentiated from the darker empty lumen (black arrow) of the vein prior to treatment. During sonication (b,c), the bubble cloud (small arrows) appears as a dynamic hyperechoic zone on or in the thrombus, indicating the focal position of the transducer. After the 300-second treatment (d), the echogenicity of the thrombus is reduced compared with (a), indicating where the clot has been broken down. Treatment time from start of sonication is listed above each image.

Figure 5

Ultrasound images of the femoral vein captured by a linear array imaging probe between treatments of a thrombus. (a) and (b) show the original appearance of the vessel on 2D imaging and with color Doppler. (c) and (d) show the thrombus after 240 seconds of treatment (one scan). (e) and (f) show the final condition of the clot after 720 seconds (three scans). Note the decreased echogenicity in the lumen on (c) and (e) compared with (a). Also, a flow channel is clearly visible on (d) and (f), while none was present before treatment in (b).

Figure 6

Gross images and vessel histology of veins treated by histotripsy. (a) Gross image of femoral bundle showing minimal damage, as seen in 3 of 4 treated vessels. Histology of the vein is shown in (b), with a higher magnification displayed in (c). Minor intramural hemorrhage can be seen within the adventitia. (d) Gross image of femoral bundle shown hemorrhage below the vessel treated by histotripsy. (e) shows histology of the vein, with higher magnification displayed in (f). Greater hemorrhage was present in this specimen and the underlying muscle tissue, although the vessel remained intact.