The development of new imaging paradigms in the field of contrast-enhanced ultrasound (CEUS) is hindered by the difficulty to control complex experimental variables in a laboratory setting, such as vascular geometries, nonlinear ultrasound wave propagation in tissue, or microbubble positions within vessels as a function of time. This development would greatly benefit from the ability to control and reproduce independently these conditions in a simulated environment. Here, we report a physically realistic CEUS simulator, PROTEUS, that generates synthetic contrast-enhanced radio frequency (RF) data. In this article, we show that PROTEUS enables flexible investigations of imaging parameters on CEUS, including innovative transducer architecture, such as row-column addressed arrays, microbubble size distribution, pulse sequences, and vascular geometry. We demonstrate how PROTEUS can emulate various 2-D and 3-D imaging modes, such as pulse inversion (PI) or amplitude modulation (AM), echo particle image velocimetry (PIV), or ultrasound localization microscopy (ULM). Finally, in an investigative simulation case study, we evaluate the impact of microbubble size distribution on ULM on a simulated set of 15000 frames. It is released as an open-source tool for the scientific community.

Ultrasound contrast agents (UCAs) have been used as vascular reporters for the past 40 years. The ability to enhance vascular features in ultrasound images with engineered lipid-shelled microbubbles has enabled breakthroughs such as the detection of tissue perfusion or super-resolution imaging of the microvasculature. However, advances in the field of contrast-enhanced ultrasound are hindered by experimental variables that are difficult to control in a laboratory setting, such as complex vascular geometries, the lack of ground truth, and tissue nonlinearities. In addition, the demand for large datasets to train deep learning-based computational ultrasound imaging methods calls for the development of a simulation tool that can reproduce the physics of ultrasound wave interactions with tissues and microbubbles. Here, we introduce a physically realistic contrast-enhanced ultrasound simulator (PROTEUS) consisting of four interconnected modules that account for blood flow dynamics in segmented vascular geometries, intravascular microbubble trajectories, ultrasound wave propagation, and nonlinear microbubble scattering. The first part of this study describes the numerical methods that enabled this development. We demonstrate that PROTEUS can generate contrast-enhanced radio-frequency (RF) data in various vascular architectures across the range of medical ultrasound frequencies. PROTEUS offers a customizable framework to explore novel ideas in the field of contrast-enhanced ultrasound imaging. It is released as an open-source tool for the scientific community.