Lauren Mancia

Effects of tissue stiffness, ultrasound frequency, and pressure on histotripsy-induced cavitation bubble behavior.

Histotripsy is an ultrasound ablation method that controls cavitation to fractionate soft tissue. In order to effectively fractionate tissue, histotripsy requires cavitation bubbles to rapidly expand from nanometer-sized initial nuclei into bubbles often larger than 50 µm. Using a negative pressure high enough to initiate a bubble cloud and expand bubbles to a sufficient size, histotripsy has been shown capable of completely fractionating soft tissue into acelluar debris resulting in effective tissue removal. Previous work has shown that the histotripsy process is affected by tissue mechanical properties with stiffer tissues showing increased resistance to histotripsy fractionation, which we hypothesize to be caused by impeded bubble expansion in stiffer tissues. In this study, the hypothesis that increases in tissue stiffness cause a reduction in bubble expansion was investigated both theoretically and experimentally. High speed optical imaging was used to capture a series of time delayed images of bubbles produced inside mechanically tunable agarose tissue phantoms using histotripsy pulses produced by 345 kHz, 500 kHz, 1.5 MHz, and 3 MHz histotripsy transducers. The results demonstrated a significant decrease in maximum bubble radius (Rmax) and collapse time (tc) with both increasing Youngs modulus and increasing frequency. Furthermore, results showed that Rmax was not increased by raising the pressure above the intrinsic threshold. Finally, this work demonstrated the potential of using a dual-frequency strategy to modulate the expansion of histotripsy bubbles. Overall, the results of this study improve our understanding of how tissue stiffness and ultrasound parameters affect histotripsy-induced bubble behavior and provide a rational basis to tailor acoustic parameters for treatment of the specific tissues of interest.

Effects of ultrasound frequency and tissue stiffness on the histotripsy intrinsic threshold for cavitation.

Histotripsy is an ultrasound ablation method that depends on the initiation of a cavitation bubble cloud to fractionate soft tissue. Previous work has indicated that a cavitation cloud can be formed by a single pulse with one high-amplitude negative cycle, when the negative pressure amplitude directly exceeds a pressure threshold intrinsic to the medium. We hypothesize that the intrinsic threshold in water-based tissues is determined by the properties of the water inside the tissue, and changes in tissue stiffness or ultrasound frequency will have a minimal impact on the histotripsy intrinsic threshold. To test this hypothesis, the histotripsy intrinsic threshold was investigated both experimentally and theoretically. The probability of cavitation was measured by subjecting tissue phantoms with adjustable mechanical properties and ex vivo tissues to a histotripsy pulse of 1-2 cycles produced by 345-kHz, 500-kHz, 1.5-MHz and 3-MHz histotripsy transducers. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured versus pressure amplitude. The results revealed that the intrinsic threshold (the negative pressure at which probability = 0.5) is independent of stiffness for Youngs moduli (E) <1 MPa, with only a small increase (∼2-3 MPa) in the intrinsic threshold for tendon (E = 380 MPa). Additionally, results for all samples revealed only a small increase of ∼2-3 MPa when the frequency was increased from 345 kHz to 3 MHz. The intrinsic threshold was measured to be between 24.7 and 30.6 MPa for all samples and frequencies tested in this study. Overall, the results of this study indicate that the intrinsic threshold to initiate a histotripsy bubble cloud is not significantly affected by tissue stiffness or ultrasound frequency in the hundreds of kilohertz to megahertz range.

Effects of Temperature on the Histotripsy Intrinsic Threshold for Cavitation

Histotripsy is an ultrasound ablation method that depends on the initiation of a dense cavitation bubble cloud to fractionate soft tissue. Previous work has demonstrated that a cavitation cloud can be formed by a single acoustic pulse with one high-amplitude negative cycle, when the negative pressure amplitude exceeds a threshold intrinsic to the medium. The intrinsic thresholds in soft tissues and tissue phantoms that are water based are similar to the intrinsic threshold of water over an experimentally verified frequency range of 0.3-3 MHz. Previous work studying the histotripsy intrinsic threshold has been limited to experiments performed at room temperature (~20 °C). In this study, we investigate the effects of temperature on the histotripsy intrinsic threshold in water, which is essential to accurately predict the intrinsic thresholds expected over the full range of in vivo therapeutic temperatures. Based on previous work studying the histotripsy intrinsic threshold and classical nucleation theory, we hypothesize that the intrinsic threshold will decrease with increasing temperature. To test this hypothesis, the intrinsic threshold in water was investigated both experimentally and theoretically. The probability of generating cavitation bubbles was measured by applying a single pulse with one high-amplitude negative cycle at 1 MHz to distilled degassed water at temperatures ranging from 10 °C to 90 °C. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured versus pressure amplitude. The results indicate that the intrinsic threshold (the negative pressure at which the cavitation probability = 0.5) significantly decreases with increasing temperature, showing a nearly linear decreasing trend from 29.8 ±0.4 MPa at 10 °C to 14.9 ± 1.4 MPa at 90 °C. Overall, the results of this study support our hypothesis that the intrinsic threshold is highly dependent on the temperature of the medium, which may allow for better predictions of cavitation generation at body temperature in vivo and at the elevated temperatures commonly seen in high-intensity focused ultrasound regimes.

Bubble dynamics in soft materials: Viscoelastic and thermal effects

The oscillations of a single spherical bubble in a soft surrounding medium are investigated numerically. In particular, the combined effects of the viscoelasticity and compressibility of the surroundings, as well as subsequent heating, on the bubble dynamics are quantified for forced and free collapse. In a Keller-Miksis framework, a Kelvin-Voigt viscoelastic model with full thermal effects is considered, in which the elastic term is represented by a Neo-Hookean model to account for the finite strains. The history and spatial distribution of the stresses and temperatures produced in the surroundings are examined and related to potential cavitation damage mechanisms.

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

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 t...

Modeling tissue response to a cavitation bubble in histotripsy

Histotripsy is a noninvasive focused ultrasound procedure that uses cavitation bubbles generated by high-amplitude ultrasound pulses to mechanically homogenize soft tissue. Experimental studies of histotripsy-induced cavitation in tissue phantoms and animal models have shown that tissue mechanical properties such as viscosity and elasticity affect cavitation threshold and bubble behavior. At present, however, the mechanisms responsible for tissue damage observed in histotripsy and other cavitation-inducing ultrasound treatments remain difficult to quantify. In this study, we simulated the dynamics of a single, spherical bubble in a Kelvin-Voigt-based viscoelastic solid, with nonlinear elasticity to better represent nanometer to micron-scale bubble growth. We applied the numerical model to calculate stress, strain, and strain rate distributions produced by a cavitation bubble exposed to forcing representative of a tensile histotripsy cycle. We found that stress and strain in excess of the ultimate tensile ...

Effects of temperature on the histotripsy intrinsic threshold for cavitation

A histotripsy cavitation cloud can be formed by a single acoustic pulse with one high amplitude negative cycle, when the negative pressure exceeds a threshold intrinsic to the medium. The intrinsic threshold in water-based soft tissues, which is similar to the intrinsic threshold of water, has been experimentally verified in the range of 24-30 MPa over a frequency range of 0.3-3 MHz at 20°C. In this study, the effects of temperature on the intrinsic threshold was investigated both experimentally and theoretically. Single pulses with one high amplitude negative cycle at 1 MHz were applied to distilled, degassed water at temperatures ranging from 10°C-90°C. Cavitation was detected and characterized by passive cavitation detection and high-speed photography, from which the probability of cavitation was measured vs. pressure amplitude. The results indicated that the intrinsic threshold significantly decreases with increasing temperature, showing a nearly linear decreasing trend from 29.8±0.4 MPa at 10˚C to 14...

Stress and strain fields produced by violent bubble collapse

Cavitation finds a key application in therapeutic ultrasound. For example, histotripsy relies on the rapid expansion of cavitation bubbles to fractionate soft tissue. To fully understand the mechanisms responsible for tissue fractionation, we numerically model cavitation in a tissuelike medium, focusing on the effect of its viscoelastic properties (viscosity, elasticity, and relaxation). It is hypothesized that ablation is caused by high strain rates and stresses exerted on the surrounding tissue as bubbles rapidly expand from nanometer to micron scales. The present study uses robust numerical techniques to compute the stress fields in the surrounding medium produced by single-bubble expansion. Bubble expansion is driven by a waveform that approximates a histotripsy pulse with relevant parameters, and soft tissue surrounding the bubble is modeled as a viscoelastic medium with Neo-Hookean elasticity. We will examine the stress, strain, and temperature fields produced during this process to explain potential damage mechanisms.