Leveraging the Imaging Transmit Pulse to Manipulate Phase-Change Nanodroplets for Contrast-Enhanced Ultrasound

Abstract

Phase-change perfluorohexane nanodroplets (PFHnDs) are a new class of recondensable submicrometer-sized contrast agents that have potential for contrast-enhanced and super-resolution ultrasound imaging with an ability to reach extravascular targets. The PFHnDs can be optically triggered to undergo vaporization, resulting in spatially stationary, temporally transient microbubbles. The vaporized PFHnDs are hyperechoic in ultrasound imaging for several to hundreds of milliseconds before recondensing to their native, hypoechoic, liquid nanodroplet state. The decay of echogenicity, i.e., the dynamic behavior of the ultrasound signal from optically triggered PFHnDs in ultrasound imaging, can be captured using high frame rate ultrasound imaging. We explore the possibility to manipulate the echogenicity dynamics of optically triggered PFHnDs in ultrasound imaging by changing the phase of the ultrasound imaging pulse. Specifically, the ultrasound imaging system was programmed to transmit two imaging pulses with inverse polarities. We show that the imaging pulse phase can affect the amplitude and the temporal behavior of PFHnD echogenicity in ultrasound imaging. The results of this study demonstrate that the ultrasound echogenicity is significantly increased (about 78% improvement) and the hyperechoic timespan of optically triggered PFHnDs is significantly longer (about 4 times) if the nanodroplets are imaged by an ultrasound pulse starting with rarefactional pressure versus a pulse starting with compressional pressure. Our finding has direct and significant implications for contrast-enhanced ultrasound imaging of droplets in applications such as super-resolution imaging and molecular imaging where detection of individual or low-concentration PFHnDs is required.

Nanodroplet-Based Super-Resolution Ultrasound Localization Microscopy

“…When it comes to cancer imaging, nanodroplet-based ULM has the potential to offer enhanced insights into tumor angiogenesis, characterized by the presence of vessels with very slow flows . Nanodroplets are invisible to ultrasound before activation, and when nanodroplets are acoustically or optically activated, they form transient microbubbles that immediately exhibit hyperechogenicity in ultrasound imaging, and as droplets are activated and deactivated at the ultrasound pulse repetition frequency, the signal can accumulate as quickly as sending imaging pulses, enabling fast cumulative localization, resulting in faster super-resolution imaging. − Third, the nanodroplets can extravasate into the cancerous space due to the leaky vasculature of cancerous endothelial walls and the EPR effect, which make them useful in cancer extravasation imaging. ,, Many studies have tried to verify that nanodroplets can extravasate within a range of sizes, usually with an optimum exosmosis size of 100–300 nm. , Rapoport et al performed experiments on mouse thigh subcutaneous muscle and adipose tissue under a microscope, observed the vasculature, and found that the extravasation rate of nanodroplets into the normal tissue was very slow . Song et al have demonstrated that cavitation-facilitated permeability was enhanced across the blood–brain barrier in rats induced by acoustically vaporized nanodroplets .…”

Ultrasound and Photoacoustic Imaging of Laser-Activated Phase-Change Perfluorocarbon Nanodroplets

“…Therefore, PFHnDs can repeatedly vaporize and recondense, providing repeated strong photoacoustic contrast and uniquely enabling novel ultrasound imaging methods. PFHnD's recondensation time is, however, relatively transient, ranging from several to hundreds of milliseconds [16,22,33]. Zhu et al found that the phase of ultrasound imaging pulse impacts the recondensation dynamics [33].…”

“…PFHnD's recondensation time is, however, relatively transient, ranging from several to hundreds of milliseconds [16,22,33]. Zhu et al found that the phase of ultrasound imaging pulse impacts the recondensation dynamics [33]. For example, if the initial part of transmit pulse is rarefactional rather than compressional, it was experimentally shown that the corresponding recondensation time is extended, and the signal-to-noise ratio is improved as well.…”

Repeated Acoustic Vaporization of Perfluorohexane Nanodroplets for Contrast-Enhanced Ultrasound Imaging

“…First, the activation threshold is higher; more energy is needed to vaporize the particles. Second, because the boiling point is above that of the surrounding tissue, the perfluorohexane nanodroplets (HnDs) recondense back to their stable liquid nanodroplet form a short time after each vaporization event [24], [28], [30]- [32]. Thus, the vaporization can be repeated.…”