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    Effects of droplet composition on nanodroplet-mediated histotripsy
    (Elsevier Science Inc, 2016) Vlaisavljevich, Eli; Aydın, Ömer; Durmaz Yüksel, Yasemin; Lin, Kuang-Wei; Fowlkes, Brian; Xu, Zhen; ElSayed, Mohamed E. H.
    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, whenNMHtherapy 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 similar to 29 degrees C, surface tension similar to 9.5 mN/m) and perfluorohexane (PFH, boiling point similar to 56 degrees C, surface tension similar to 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 (similar to 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.
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    Effects of ultrasound frequency on nanodroplet-mediated histotripsy
    (Elsevier Science, 2015) Vlaisavljevich, Eli; Aydın, Ömer; Yüksel Durmaz, Yasemin; Lin, Kuangwei; Fowlkes, Brian; Elsayed, Mohamed; Xu, Zhen
    Nanodroplet-mediated histotripsy (NMH) is a targeted ultrasound ablation technique combining histotripsy with nanodroplets that can be selectively delivered to tumor cells for targeted tumor ablation. In a previous study, it was reported that by use of extremely short, high-pressure pulses, histotripsy cavitation bubbles were generated in regions containing nanodroplets at significantly lower pressure (similar to 10.8 MPa) than without nanodroplets (similar to 28 MPa) at 500 kHz. Furthermore, it was hypothesized that lower frequency would improve the effectiveness of NMH by increasing the size of the focal region, increasing bubble expansion, and decreasing the cavitation threshold. In this study, we investigated the effects of ultrasound frequency (345 kHz, 500 kHz, 1.5 MHz, and 3 MHz) on NMH. First, the NMH cavitation threshold was measured in tissue phantoms with and without nanodroplets, with results indicating that the NMH threshold was significantly below the histotripsy intrinsic threshold at all frequencies. Results also indicated that the NMH threshold decreased at lower frequency, ranging from 7.4 MPa at 345 kHz to 13.2 MPa at 3 MHz. In the second part of this study, the effects of frequency on NMH bubble expansion were investigated, with results indicating larger expansion at lower frequency, even at a lower pressure. In the final part of this study, the ability of perfluoropentane-encapsulated nanodroplets to act as sustainable cavitation nuclei over multiple pulses was investigated, with results indicating that the nanodroplets are destroyed by the cavitation process and only function as cavitation nuclei for the first few pulses, with this effect being most pronounced at higher frequencies. Overall, the results of this study support our hypothesis that using a lower frequency will improve the effectiveness of NMH by increasing the size of the focal region, increasing bubble expansion and decreasing the cavitation threshold.
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    Noninvasive ablation of prostate cancer spheroids using acoustically-activated nanodroplets
    (Amer Chemical Soc, 2016) Aydın, Ömer; Vlaisavljevich, Eli; Yüksel Durmaz, Yasemin; Xu, Zhen; ElSayed, Mohamed E. H.
    We have developed acoustically activated nanodroplets (NDs) using an amphiphilic triblock copolymer, which self-assembles and encapsulates different perfluorocarbons including perfluoropentane (PFP) and perfluorohexane (PFH). Applying histotripsy pulses (i.e., short, high pressure, ultrasound pulses) to solutions of PFP- and PFH-NDs generated bubble clouds at a significantly reduced acoustic pressure compared to the cavitation pressure observed for histotripsy treatment alone. In this report, we summarize the results of combining histotripsy at low frequency (345 and 500 kHz) with PFP-NDs and PFH-NDs on the ablation of PC-3 and C4-2B prostate cancer cells. Using custom built histotripsy transducers coupled to a microscope and a high speed recording camera, we imaged the generation of a cavitation bubble cloud in response to different ultrasound regimes in solution and in tissue-mimicking gel phantoms. We quantified the associated ablation of individual cancer cells and 3D spheroids suspended in solution and embedded in tissue phantoms to compare the ablative capacity of PFP-NDs and PFH-NDs. Results show that histotripsy pulses at high acoustic pressure (26.2 MPa) ablated 80% of prostate cancer spheroids embedded in tissue-mimicking gel phantoms. In comparison, combining histotripsy pulses at a dramatically lower acoustic pressure (12.8 MPa) with PFP-NDs and PFH-NDs caused an ablation of 40% and 80% of the tumor spheroid volumes, respectively. These results show the potential of acoustically activated NDs as an image-guided ablative therapy for solid tumors and highlight the higher ablative capacity of PFH-NDs, which correlates with the boiling point of the encapsulated PFH and the stability of the formed bubble cloud.
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    The role of positive and negative pressure on cavitation nucleation in nanodroplet-mediated histotripsy
    (Iop Publishing Ltd, 2016) Vlaisavljevich, Eli; Aydın, Ömer; Lin, Kuang-Wei; Durmaz Yüksel, Yasemin; Fowlkes, Brian; ElSayed, Mohamed; Xu, Zhen
    Nanodroplet-mediated histotripsy (NMH) is an ultrasound ablation technique combining histotripsy with acoustically sensitive perfluorocarbon (PFC) nanodroplets that can be selectively delivered to tumor cells for targeted tumor ablation. NMH takes advantage of the significantly reduced cavitation threshold of the nanodroplets, allowing for cavitation to be selectively generated only in regions containing nanodroplets. Understanding the physical mechanisms underlying the nanodroplet cavitation process is essential to the development of NMH. In this study, we hypothesize that cavitation nucleation is caused by the negative pressure (p-) exposed to the PFC, and the NMH cavitation threshold is therefore determined by the incident p- of the single-cycle pulses commonly used in NMH. This paper reports the first study that separately investigates the effects of negative and positive pressure on the NMH cavitation threshold using near half-cycle ultrasound pulses with dominant negative (negative-polarity pulses) or positive (positive-polarity pulses) pressure phases. Tissue phantoms containing perfluorohexane (PFH) nanodroplets were exposed to negative-polarity and positive-polarity pulses generated by a frequency compounding transducer recently developed in our lab, and the probability of generating cavitation was measured as a function of peak negative (p-) and peak positive (p+) pressure. The results showed close agreement in the p-cavitation threshold for PFH phantoms exposed to negative-polarity (11.4 +/- 0.1 MPa) and positive-polarity (11.7 +/- 0.2 MPa) pulses. The p+ at the cavitation threshold, in contrast, was measured to be significantly different for the negative-polarity (4.0 +/- 0.1 MPa) and positive-polarity (42.6 +/- 0.2 MPa) pulses. In the final part of this study, the experimental results were compared to the cavitation threshold predicted by classical nucleation theory (CNT), with results showing close agreement between simulations and experiments. Overall, the results support our hypothesis and provide significant insight into the physical mechanisms underlying NMH.