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Histotripsy is the first noninvasive, nonthermal, and nonionizing focused ultrasound ablative therapy that effectively destroys targeted tissue. Histotripsy research began as an early preclinical prototype that eventually underwent small- and large-animal preclinical testing to ensure safe clinical translation to human use. Small-animal studies demonstrated the efficacy of histotripsy in destroying liver tumors and generating immune responses, while large-animal studies in human-sized livers further refined the technology for clinical translation. Preclinical studies revealed that histotripsy is a safe ablative modality that has tissue selectivity, meaning tissues of different structural composition have different thresholds for cavitation-induced destruction, with relative sparing of collagenous structures such as vessels and bile ducts. The noninvasive nature of histotripsy potentially allows for treatment of patients with coagulation abnormalities or those receiving anticoagulation therapy. Additional findings include the creation of well-defined treatment zones that are seen to rapidly resorb over time, a feature allowing for easier treatment response evaluation. This article reviews key observations and results from preclinical and early clinical histotripsy studies leading to U.S. Food and Drug Administration's approval for the treatment of liver cancer. A thorough understanding of the key findings and biologic effects of histotripsy in animal models will facilitate the clinical adoption of histotripsy. Keywords: Ultrasound, Ablation Techniques, Animal Studies, Abdomen/GI, Liver © RSNA, 2025.