Contrast-enhanced ultrasound imaging in vivo with laser-activated nanodroplets

Abstract

Purpose This study introduces a real-time contrast-enhanced ultrasound imaging method with recently developed laser-activated nanodroplets (LANDs), a new class of phase-change nanometer-scale contrast agents that provides perceptible, sustained high-contrast with ultrasound. Methods In response to pulsed laser irradiation, the LANDs—, which contain liquid perfluorohexane and optical fuses—blink (vaporize and recondense). That is, they change their state from liquid nanodroplets to gas microbubbles, and then back to liquid nanodroplets. In their gaseous microbubble state, the LANDs provide high-contrast ultrasound, but the microbubbles formed in situ typically recondense in tens of milliseconds. As a result, LAND visualization by standard, real-time ultrasound is limited. However, the periodic optical triggering of LANDs allows us to observe corresponding transient, periodic changes in ultrasound contrast. This study formulates a probability function that measures how ultrasound temporal signals vary in periodicity. Then, the estimated probability is mapped onto a B-scan image to construct a LAND-localized, contrast-enhanced image. We verified our method through phantom and in vivo experiments using an ultrasound system (Vevo 2100, FUJIFILM VisualSonics, Inc., Toronto, ON, Canada) operating with a 40-MHz linear array and interfaced with a 10 Hz Nd:YAG laser (Phocus, Opotek Inc., Carlsbad, CA, USA) operating at the fundamental 1064 nm wavelength. Results From the phantom study, the results showed improvements in the contrast-to-noise ratio of our approach over conventional ultrasound ranging from 129% to 267%, with corresponding execution times of 0.10 s to 0.29 s, meaning that the developed method is computationally efficient while yielding high-contrast ultrasound. Furthermore, in vivo sentinel lymph node (SLN) imaging results demonstrated that our technique could accurately identify the SLN. Conclusions The results indicate that our approach enables efficient and robust LAND localization in real time with substantially improved contrast, which is essential for the successful translation of this contrast agent platform to clinical settings.

Laser-activated perfluorocarbon nanodroplets: a new tool for blood brain barrier opening

“…Consequently, laser-activated droplet adaptability enables a platform for opening of the BBB and delivery of both therapeutics as well as imaging contrast agents to the brain. Furthermore, laser-activated droplets produce localized, temporally modulated ultrasound and photoacoustic contrast and therefore in the future could provide the opportunity for image-guidance of BBB opening as well as image-guidance of delivery of cargo to the tissue [ 18 , 19 , 22 , 34 , 35 ]. Because the process of optimized BBB opening is transient and reversible, localized delivery of cargo to the brain is reproducible, enabling the potential to treat or image longitudinally.…”

Preclinical Ultrasound Imaging—A Review of Techniques and Imaging Applications

“…However, for cancer models it is important to locate the sentinel lymph node i.e., the node to which the primary tumor drains to first. To this end, both novel contrast agents [25] and novel ultrasound imaging techniques are under development to aid the detection of the location of this node [26].…”

Color-coded perfluorocarbon nanodroplets for multiplexed ultrasound and photoacoustic imaging

“…4). PFCnDs have demonstrated utility in wide-ranging applications; but until now, most PFCnD studies have focused on synthesis [22], improving imaging performance or processing algorithms [22,23], and are typically conducted in tissue phantoms, in vitro [24], ex vivo [22], or in preliminary in vivo models [11]. Additionally, most of the in vivo studies focused on shortterm applications, on the order of minutes to few hours and primarily used systemic injections to deliver PFCnDs [14,25,26].…”