Visualizing the histotripsy process: Bubble cloud-cancer cell interactions in a tissue-mimicking environment

Abstract

Histotripsy is an ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large strain on the tissue structures immediately adjacent to the bubbles. In this work, the histotripsy fractionation process was visualized at the cellular level for the first time using a custom-built 2 MHz transducer incorporated into a microscope stage. A layer of breast cancer cells were cultured within an optically transparent fibrin-based phantom to mimic cells inside an extracellular matrix environment. The response to single and multiple histotripsy pulses was investigated using high speed optical imaging. Bubbles were generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubbles. The largest displacements were observed during collapse for cells immediately adjacent to the bubble, with cells moving more than 150-300 μm in less than 100 μs. Cells often underwent multiple large deformations (>150% strain) over multiple pulses, resulting in the bisection of cells multiple times before complete rupture. These results support our hypothesis and help to explain the formation of the sharp lesions formed in histotripsy therapy.