Blinking Phase-Change Nanocapsules Enable Background-Free Ultrasound Imaging

Abstract

Microbubbles are widely used as contrast agents to improve the diagnostic capability of conventional, highly speckled, low-contrast ultrasound imaging. However, while microbubbles can be used for molecular imaging, these agents are limited to the vascular space due to their large size (> 1 μm). Smaller microbubbles are desired but their ultrasound visualization is limited due to lower echogenicity or higher resonant frequencies. Here we present nanometer scale, phase changing, blinking nanocapsules (BLInCs), which can be repeatedly optically triggered to provide transient contrast and enable background-free ultrasound imaging. In response to irradiation by near-infrared laser pulses, the BLInCs undergo cycles of rapid vaporization followed by recondensation into their native liquid state at body temperature. High frame rate ultrasound imaging measures the dynamic echogenicity changes associated with these controllable, periodic phase transitions. Using a newly developed image processing algorithm, the blinking particles are distinguished from tissue, providing a background-free image of the BLInCs while the underlying B-mode ultrasound image is used as an anatomical reference of the tissue. We demonstrate the function of BLInCs and the associated imaging technique in a tissue-mimicking phantom and in vivo for the identification of the sentinel lymph node. Our studies indicate that BLInCs may become a powerful tool to identify biological targets using a conventional ultrasound imaging system.

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

“…The phantom consisted of 21 mL of 40% polyacrylamide (Thermo Fisher Scientific, Walthan, MA, USA), 850 μL of 10% aqueous ammonium persulfate (Sigma‐Aldrich, St. Louis, MO, USA) solution, 106 μL of TEMED (Sigma‐Aldrich, St. Louis, MO, USA), 0.2% w/w silica particles (U.S. Silica, Hurtsboro, AL, USA), 0.01% w/w graphite particles (Dixon Ticonderoga, Lake Mary, FL, USA), and 64 mL of deionized water. Detailed procedures can be found in . Only the inclusion contained 0.1% v/v LANDs.…”

“…More recently, our group and others have developed laser‐activated nanodroplets (LANDs) containing liquid perfluorohexane and optical dye. LANDs repeatedly vaporize and recondense because the boiling point of perfluorohexane (56°C) is higher than physiological temperature (37°C) . This unique, repeatable phase‐changing property of LANDs has enabled or improved many applications, including super‐resolution imaging, background‐free imaging, and photoacoustic imaging .…”

“…Before optical triggering, the LANDs remain liquid nanodroplets, producing very limited ultrasound echoes. However, once activated by pulsed laser irradiation, the LANDs rapidly vaporize into gaseous microbubbles in situ , generating hyperechoic ultrasound signals until the LANDs completely recondense . However, their gaseous period is relatively transient (several to hundreds of milliseconds), which limits human perception of LAND‐based contrast …”

“…LANDs repeatedly vaporize and recondense because the boiling point of perfluorohexane (56°C) is higher than physiological temperature (37°C). [21][22][23] This unique, repeatable phase-changing property of LANDs has enabled or improved many applications, including super-resolution imaging, background-free imaging, and photoacoustic imaging. 22,23 Figure 1 shows the blinking dynamics of the LANDs.…”

“…[21][22][23] This unique, repeatable phase-changing property of LANDs has enabled or improved many applications, including super-resolution imaging, background-free imaging, and photoacoustic imaging. 22,23 Figure 1 shows the blinking dynamics of the LANDs. Before optical triggering, the LANDs remain liquid nanodroplets, producing very limited ultrasound echoes.…”