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Super-resolution ultrasound imaging techniques have shown promising potential in non-invasive imaging of deep-lying tissue. However, these methods utilize microbubbles, limiting its utility to visualization of vasculature with moving bubbles. To resolve extravascular targets, our group previously introduced a method for super-resolution ultrasound imaging based on laser-activated nanodroplets (LANDs) that repeatedly vaporize and recondense in response to optical irradiation. The method resolves the location of LANDs from the difference between two imaging frames capturing vaporization and recondensation of individual LANDs. However, since only two neighboring frames are used to produce a difference frame, this method is sensitive to noise-related errors limiting the improvement in spatial resolution. In this study, we introduce a new approach to super-resolution imaging. In our approach, ultrafast imaging, which typically captures images at over several thousand frames per second, was used for spatio-temporal compounding. Specifically, multiple successive ultrasound frames were used to obtain the difference frame with improved reliability and repeatability thus enhanced spatial resolution. To evaluate our approach, we imaged a phantom containing uniformly-distributed LANDs using an ultrasound system equipped with a linear array transducer and interfaced with pulsed laser. An ultrafast plane-wave compounding approach was used to capture ultrasound images at 6 kHz frame rate. We achieved a four-fold improvement in spatial resolution over the previous approach. In addition, three-dimensional super-resolution imaging of a phantom with microcapillaries containing LANDs was performed illustrating the robustness of our method. These results suggest that our approach has the potential for high-resolution molecular imaging of intravascular and extravascular targets.
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