In vitroassessment of stiffness-dependent histotripsy bubble cloud activity in gel phantoms and blood clots

Abstract

As a bubble-based ablative therapy, the efficacy of histotripsy has been demonstrated in healthy or acutely diseased models. Chronic conditions associated with stiff tissues may require additional bubble activity prior to histotripsy liquefaction. In this study, histotripsy pulses were generated in agarose phantoms of Young's moduli ranging from 12.3 to 142 kPa, and in vitro clot models with mild and strong platelet-activated retraction. Bubble cloud emissions were tracked with passive cavitation imaging, and the threshold acoustic power associated with phantom liquefaction was extracted with receiver operator characteristic analysis. The power of histotripsy-generated emissions and the degree of liquefaction were tabulated for both clot models. For the agarose phantoms, the acoustic power associated with liquefaction increased with Young's modulus. When grouped based on agarose concentration, only two arms displayed a significant difference in the liquefaction threshold acoustic power (22.1 kPa versus 142 kPa Young's modulus). The bubble cloud dynamics tracked with passive cavitation imaging indicated no strong changes in the bubble dynamics based on the phantom stiffness. For identical histotripsy exposure, the power of acoustic emissions and degree of clot lysis did not vary based on the clot model. Overall, these results indicate that a fixed threshold acoustic power mapped with passive cavitation imaging can be utilized for predicting histotripsy liquefaction over a wide range of tissue stiffness.

In Vitro Thrombolytic Efficacy of Single- and Five-Cycle Histotripsy Pulses and rt-PA

“…The clots were used within 2 wk after the retraction period. A consistent clot stiffness and response to rt-PA have been noted over this period for in vitro studies (Holland et al 2008;Mercado-Shekhar et al 2018b;Hendley et al 2019).…”

Micro-ultrasonic Assessment of Early Stage Clot Formation and Whole Blood Coagulation Using an All-Optical Ultrasound Transducer and Adaptive Signal Processing Algorithm

“…Since the agarose concentration in the gels changes linearly with the gel density, it also depicts the elastic modulus of the gel by the following equation: where B is the elastic modulus, ρ is the density, and C is the sound speed. We note that the 1% (w/v) agarose gel closely depicts the mechanical property of a solid human clot Figure illustrates the prompt increase in the FFT-derived MF with the enhancement in agarose concentration in tissue gels.…”

Enhancing cavitation dynamics and its mechanical effects with dual-frequency ultrasound

“…Previous experimental and numerical studies have established that the cavitation-associated mechanical effects to nearby cells/tissues are highly dependent on the cavitation dynamics and the tissue viscoelasticity (Vlaisavljevich et al 2013, Mancia et al 2017, Bader 2018, Hendley et al 2019, Mancia et al 2019. To reduce the cavitation threshold and enhance the cavitation dynamics, introducing encapsulated microbubbles as cavitation nuclei and utilizing dual-frequency ultrasound excitation have achieved some success.…”

“…Introducing the encapsulated microbubbles is beneficial to reduce the cavitation threshold, but the physical properties of the stabilizing shell would also notably change their acoustic response to ultrasound excitation, and consequently influence the cavitation dynamics and the cavitation-associated effects (Sojahrood et al 2021a). Moreover, the viscoelastic parameters of different biological materials varying within a wide range could also prominently affect the cavitation bubble dynamics and the tissue susceptibility to cavitation-associated mechanical damage (Vlaisavljevich et al 2013, Mancia et al 2017, Bader 2018, Hendley et al 2019, Mancia et al 2019. According to previous studies (Qin et al 2021a, Sojahrood et al 2021a, 2021c, it can be expected that the viscoelasticities of the shell and tissue would restrain the cavitation dynamics, but the advantage of dual-frequency excitation seems to become more evident with the shell and/or tissue viscoelasticity increasing to certain conditions (figures 6 and 7).…”