Histotripsy fractionation of prostate tissue: local effects and systemic response in a canine model

Abstract

Purpose: Histotripsy is an extracorporeal ultrasound technology that uses cavitational mechanisms to produce nonthermal tissue destruction. Previously we reported the feasibility of histotripsy for prostate tissue fractionation and immediate debulking. In this study we characterized the local effects and systemic response after histotripsy treatment of prostate tissue in an in vivo canine model.

Materials and methods: Histotripsy was applied transabdominally to the prostate in 18 intact male canine subjects under general anesthesia. Acoustic bursts (4 μseconds) were delivered at a 300 Hz pulse repetition rate from a highly focused 750 kHz piezoelectric ultrasound transducer with a 15 cm aperture and 3 × 3 × 8 mm focal volume. Specimens of the prostate and surrounding structures were obtained at prescribed time points (0, 7, 28 or 56 days) after histotripsy. Blood and urine parameters were assessed periodically while clinical evaluation incorporating a validated veterinary pain scale was performed daily.

Results: Conventional transrectal ultrasound facilitated targeting of the focal volume and provided real-time assessment of cavitation activity. Fractionation of the targeted volume and clearance of the resultant debris with urination produced a treatment cavity in each prostate. No acoustic collateral damage was seen and urothelialization of the treatment cavity developed within 28 days of treatment. Only transient laboratory value abnormalities and minimal hematuria were noted after treatment. Pain scores revealed only mild posttreatment discomfort.

Conclusions: Histotripsy produced consistent tissue fractionation and prostate debulking without collateral acoustic injury or clinical side effects and it was well tolerated in the canine model.

Figure 1

Therapeutic US energy is delivered transabdominally from a transducer suspended within a degassed water bath coupled to the shaved abdomen of a canine subject in supine position. A separate 10 MHz transrectal US imaging probe provides high resolution feedback of the cavitation activity during histotripsy treatment.

Figure 2

A sagittal transrectal US image through the left lobe of a canine prostate during in-vivo histotripsy demonstrates cavitation. The hyperechoic (bright) approximately 3×8 mm histotripsy bubble cloud is easily seen within the middle of the prostate tissue and represents the geometric focus of the therapeutic histotripsy transducer which is located above the top of the image and delivers acoustic energy transabdominally. The treated area immediately surrounding the bubble cloud has been fractionated and appears hypoechoic (dark) with respect to untreated tissue.

Figure 3

Transverse US appearance of canine prostate before and 28 days after histotripsy therapy guided manually. The large hypoechoic cavity on the post-treatment image represents a treatment cavity corresponding to the histotripsy targeted volume.

Figure 4

Gross appearance of fixed specimen harvested 28 days after histotripsy therapy with manual guidance. Prostate is same specimen imaged in Figure 3.

Figure 5

Representative histologic prostate cross sections at 0, 7, and 28 days following histotripsy treatment. In each case the cross-sectional area of the targeted volume was 20 × 10 mm and corresponds to the cavities seen on histologic sections. In some cases a portion of the targeted volume on the right side of the prostate was shielded by the os penis and was not fractionated.

Figure 6

By 28 days after histotripsy treatment, urothelialization of the urethra and lining of the treated cavity is apparent. The central prostate and urethra were treated with manual (joystick) control using US feedback to assess adequacy of treatment.