Histotripsy Ablation in Preclinical Animal Models of Cancer and Spontaneous Tumors in Veterinary Patients: A Review

Abstract

New therapeutic strategies are direly needed in the fight against cancer. Over the last decade, several tumor ablation strategies have emerged as stand-alone or combination therapies. Histotripsy is the first completely non-invasive, non-thermal, and non-ionizing tumor ablation method. Histotripsy can produce consistent and rapid ablations, even near critical structures. Additional benefits include real-time image-guidance, high precision, and the ability to treat tumors of any predetermined size and shape. Unfortunately, the lack of clinically and physiologically relevant pre-clinical cancer models is often a significant limitation with all focal tumor ablation strategies. The majority of studies testing histotripsy for cancer treatment have focused on small animal models, which have been critical in moving this field forward and will continue to be essential for providing mechanistic insight. While these small animal models have notable translational value, there are significant limitations in terms of scale and anatomical relevance. To address these limitations, a diverse range of large animal models and spontaneous tumor studies in veterinary patients have emerged to complement existing rodent models. These models and veterinary patients are excellent at providing realistic avenues for developing and testing histotripsy devices and techniques designed for future use in human patients. Here, we provide a review of animal models used in preclinical histotripsy studies and compare histotripsy ablation in these models using a series of original case reports across a broad spectrum of preclinical animal models and spontaneous tumors in veterinary patients.

Ultrasound-guided in vivo histotripsy in rabbit kidneys using millisecond-length two-stage ultrasound pulses combined with fundamental and second harmonic superposition

“…The accumulation of red blood cells at the boundary of lesions may be due to the rupture of some capillaries across the treated-untreated area under the action of microbubbles. Figure 10(f) shows that there was no apparent damage found to several renal arteriole tubes and fat layer near the lesions in the collecting system, indicating that the major blood vessels and connective tissue were resistant to histotripsy, which is similar to other studies (Vlaisavljevich et al 2013, Hendricks-Wenger et al 2022a. The sensitivity of histotripsy is related to collagen content, Young's modulus, and the mechanical properties of different tissues (Vlaisavljevich et al 2014, Vlaisavljevich et al 2015.…”

“…The tissue selectivity of histotripsy allows safe ablation of target tissue while preserving adjacent critical structures (Khokhlova et al 2019). Ultrasound imaging can be used for treatment guidance and real-time monitoring, and it can assess treatment outcomes (Schade et al 2019, Hendricks-Wenger et al 2022a, 2022b.…”

Development of an ultrasound guided focused ultrasound system for 3D volumetric low energy nanodroplet-mediated histotripsy

“…Histotripsy is a widely investigated method for noninvasive US surgery which has taken great strides forward in recent years [39][40][41][42] . The combination of NDs and histotripsy has been proposed for targeted tumor treatment since these NDs with their small diameters can extravasate from blood vessels into the tumor tissue 5,16,18,43,44 .…”

Mechanical High-Intensity Focused Ultrasound (Histotripsy) in Dogs with Spontaneously Occurring Soft Tissue Sarcomas

“…Similarly, a case of an abscopal effect was identified in the human clinical trial investigating histotripsy for liver tumor ablation [21]. These findings, combined with prior work showing that thermal HIFU can target and treat STS tumors in both dogs [22,23] and humans [24][25][26], have led our team to initiate this study to investigate histotripsy's ablative and immunological effects for treating STS in pet dogs as a clinical model [10,27].…”