Optimized ultrasound imaging of phase-change nanodroplets

Phase-change nanodroplets (PCNDs) continue to generate significant research interest due to their potential to extravasate into tissue, to be targeted for molecular imaging and drug delivery, and to undergo an induced phase-change to "activated" microbubbles (MBs) for ultrasound (US) imaging. To accurately quantify molecular markers, however, one assumes a consistent proportion of PCNDs in a region of interest (ROI) are stably activated and imaged. Herein we present a framework for developing a diagnostic sequence that is optimized for PCND activation uniformity, contrast, and acquisition time. To develop this framework, activation was examined at three scales of increasing complexity: single, adjacent, and full ROI activation(s). First, transmit parameters for a single activation were optimized using PCNDs across concentrations (1.0 × 10⁷-10⁹ PCND/mL) in controlled phantom experiments, considering contrast-to-noise ratio (CNR), area, and offset (e.g., centroid axial distance from transmit focus) of the activation region along with acquisition time. Activation regions were also compared to prospective estimates based on US-beam imaging. Next, overlap and order of adjacent activation regions was optimized by maximizing spacing while preserving uniformity and minimizing signal loss from adjacent transmit interactions. Finally, an optimized raster-scanning scheme was applied to a mock tumor ROI, yielding 1.4-7.0 dB greater contrast enhancement over unoptimized schemes while reducing acquisition time. Further, PCND concentration was found to share a nonlinear relationship with US signal enhancement that differed significantly between linear and harmonic imaging modes. In conclusion, our framework's optimization of contrast, uniformity, acquisition time, and cavitation mitigation for PCND US imaging should help facilitate its eventual clinical translation.