Effects of Droplet Composition on Nanodroplet-Mediated Histotripsy

Abstract

Nanodroplet-mediated histotripsy (NMH) is a targeted ablation technique combining histotripsy with nanodroplets that can be selectively delivered to tumor cells. In two previous studies, polymer-encapsulated perfluoropentane nanodroplets were used to generate well-defined ablation similar to that obtained with histotripsy, but at significantly lower pressure, when NMH therapy was applied at a pulse repetition frequency (PRF) of 10 Hz. However, cavitation was not maintained over multiple pulses when ultrasound was applied at a lower PRF (i.e., 1-5 Hz). We hypothesized that nanodroplets with a higher-boiling-point perfluorocarbon core would provide sustainable cavitation nuclei, allowing cavitation to be maintained over multiple pulses, even at low PRF, which is needed for efficient and complete tissue fractionation via histotripsy. To test this hypothesis, we investigated the effects of droplet composition on NMH therapy by applying histotripsy at various frequencies (345 kHz, 500 kHz, 1.5 MHz, 3 MHz) to tissue phantoms containing perfluoropentane (PFP, boiling point ∼29°C, surface tension ∼9.5 mN/m) and perfluorohexane (PFH, boiling point ∼56°C, surface tension ∼11.9 mN/m) nanodroplets. First, the effects of droplet composition on the NMH cavitation threshold were investigated, with results revealing a significant decrease (>10 MPa) in the peak negative pressure (p-) cavitation threshold for both types of nanodroplets compared with controls. A slight decrease (∼1-3 MPa) in threshold was observed for PFP phantoms compared with PFH phantoms. Next, the ability of nanodroplets to function as sustainable cavitation nuclei over multiple pulses was investigated, with results revealing that PFH nanodroplets were sustainable cavitation nuclei over 1,000 pulses, whereas PFP nanodroplets were destroyed during the first few pulses (<50 pulses), likely because of the lower boiling point. Finally, tissue phantoms containing a layer of embedded red blood cells were used to compare the damage generated for NMH treatments using PFP and PFH droplets, with results indicating that PFH nanodroplets significantly improved NMH ablation, allowing for well-defined lesions to be generated at all frequencies and PRFs tested. Overall, the results of this study provide significant insight into the role of droplet composition in NMH therapy and provide a rational basis to tailor droplet parameters to improve NMH tissue fractionation.

Effects off-number on the histotripsy intrinsic threshold and cavitation bubble cloud behavior

“…Fractionation of the RBCs turns the color of the embedded cell layer from opaque red to translucent as the RBCs are lysed, which allows direct visualization of the histotripsy-induced fractionation process (Maxwell et al , 2010b; Lin et al , 2014; Vlaisavljevich et al , 2016a; Vlaisavljevich et al , 2013a; Wang et al , 2012). Previous studies have also shown that the lesion visualized in RBC phantoms is similar to the lesion generated in tissue identified by histology (Maxwell et al , 2010b; Lin et al , 2014; Wang et al , 2012).…”

“…In intrinsic threshold histotripsy, a single pulse (≤2 cycles) with a single dominant negative pressure phase at very high pressure is used to form a bubble cloud directly from the negative pressure of the incident wave (Lin et al , 2014; Maxwell et al , 2013; Vlaisavljevich et al , 2015b). Using the short pulses for intrinsic threshold histotripsy, cavitation initiation depends on the amplitude and duration of the applied negative pressure as well as the properties of the media (Vlaisavljevich et al , 2015a; Vlaisavljevich et al , 2016a; Vlaisavljevich et al , 2016b; Vlaisavljevich et al , 2015b; Maxwell et al , 2013; Vlaisavljevich et al , 2013a). Previous work has measured the intrinsic threshold of water-based soft tissues and tissue phantoms to be ~25–30 MPa at ultrasound frequencies ranging from 345 kHz to 3 MHz (Maxwell et al , 2013; Vlaisavljevich et al , 2015b).…”

For Whom the Bubble Grows: Physical Principles of Bubble Nucleation and Dynamics in Histotripsy Ultrasound Therapy

“…Exogenous nuclei reduce the threshold for histotripsy-induced bubble nucleation (Vlaisavljevich et al 2013a), thereby reducing the overall bubble size (Bader 2018). The change in bubble dynamics with exogenous nuclei consequently reduces the efficacy of tissue ablation (Vlaisavljevich et al 2016a).…”

“…A larger number of pulses are required for complete liquefaction of the focal zone for NMH than for insonation without droplets, indicating the smaller size of bubbles nucleated from droplets compared with intrinsic nuclei. Sustainable droplet nucleation is dependent on the boiling temperature of the perfluorocarbon (Vlaisavljevich et al 2016a). At peak negative pressures above the threshold for bubble cloud formation, cavitation is sustained for only 10 pulses for droplets formed with perfluoropentane (boiling point of 29˚C).…”

Transluminal Approach with Bubble-Seeded Histotripsy for Cancer Treatment with Ultrasonic Mechanical Effects

“…Moreover, we aimed to develop a new system for cancer treatment, using direct low-dose antitumor agent administration (Ashida et al 2015;Kawabata et al 2013Kawabata et al , 2014. No other studies on cancer treatments, using tissue fractionation at such a low intensity with the aid of PCNDs seem to have succeeded, although the effects of nanodroplets on histotripsy have been investigated with tissue-mimicking phantoms for drug delivery purposes (Vlaisavljevich et al 2015(Vlaisavljevich et al , 2016.…”