Towards reduced ultrasound localization microscopy acquisition times by uncoupling a bi-disperse microbubble population

Background : Ultrasound Localization Microscopy (ULM) is a milestone in the medical vascular imaging context, enabling the precise characterization of micro-vascular structures using ultrasound imaging. By accurately localizing contrast microbubbles (MBs) flowing in the circulatory system, ULM generates micro-resolved vascular images, overcoming the ultrasonic diffraction limit. However, as ULM relies on precise localization and tracking of individual MBs, high MB concentrations yield to increased localization errors and, ultimately, ULM failure. This constraint limits ULM to low MB concentrations, resulting in long acquisition times that pose challenges in clinical settings.    Methods: Here, we show the feasibility of uncoupling a bi-disperse MB population, composed of two monodisperse MB populations. The uncoupling is performed through a signal processing pipeline that exploits the strong nonlinear response of MBs having resonance frequency tuned with the transmission frequency. After uncoupling, ULM density and velocity flow maps are generated.   Results: Density and velocity maps are generated after uncoupling, when injecting the bi-disperse population individually and simultaneously in a vascular 3D-printed phantom. Furthermore, density maps generated after uncoupling are compared with the one obtained using standard ULM. Results demonstrate the capability of the proposed uncoupling pipeline to separate the bi-disperse population.     Conclusion: This work presents a signal processing pipeline to uncouple a bi-disperse MB population, formed by two monodisperse MB populations. Results are validated in a 3D-printed phantom and demonstrate the feasibility of the uncoupling which, in turn, would enable higher concentrations and reduce acquisition times for micro-vascular imaging.