title: Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment.
abstract: Histotripsy is a non-invasive ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. With a sufficient number of pulses, histotripsy can completely fractionate tissue into a liquid-appearing homogenate with no cellular structures. The location, shape and size of lesion formation closely match those of the cavitation cloud. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large stress and strain on the tissue structures immediately adjacent to the bubbles. In the work described here, the histotripsy bulk tissue fractionation process is 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 gel phantom to mimic cells inside a 3-D extracellular matrix. To test the hypothesis, the cellular response to single and multiple histotripsy pulses was investigated using high-speed optical imaging. Bubbles were always generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubble during both bubble expansion and collapse. 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 removal. To provide theoretical support to the experimental observations, a numerical simulation was conducted using a single-bubble model, which indicated that histotripsy exerts the largest strains and cell displacements in the regions immediately adjacent to the bubble. The experimental and simulation results support our hypothesis, which helps to explain the formation of the sharp lesions formed in histotripsy therapy localized to the regions directly exposed to the bubbles.
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: evlaisav@umich.edu.
authors.forename: Eli
authors.initials: E
authors.lastname: Vlaisavljevich
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Maxwell
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Mancia
authors.affiliation: Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Johnsen
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Cain
authors.affiliation: Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, USA; Department of Pediatrics and Communicable Diseases, Division of Pediatric Cardiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
mesh_terms: D002450:Cell Communication; D003198:Computer Simulation; D008096:Lithotripsy / Q000379:methods*; D008325:Mammary Neoplasms, Experimental / Q000628:therapy*; D019047:Phantoms, Imaging
keywords: Cancer; Cavitation; Cell–bubble interactions; Histotripsy; Tissue fractionation