Ultrasound Technology for Molecular Imaging: From Contrast Agents to Multimodal Imaging.

Ultrasound (US) takes advantage of ultrasound contrast agents (UCAs) to further increase the sensitivity and specificity of monitoring at the cellular level, which has had a considerable effect on the modern molecular imaging field. Gas-filled microbubbles (MBs) as UCAs in the bloodstream generate resonant volumetric oscillations in response to rapid variations in acoustic pressure, which are related to both the acoustic parameters of applied ultrasound and the physicochemical properties of the contrast agents. Nanoscale UCAs have been developed and have attracted much attention due to their utility in detecting extravascular lesions. Ultrasound molecular assessment is achieved by binding disease-specific ligands to the surface of UCAs, which have been designed to target tissue biomarkers in the area of interest, such as blood vessels, inflammation, or thrombosis. Additionally, the development of multimodal imaging technology is conducive for integration of the advantages of various imaging techniques to acquire additional diagnostic information. In this review paper, the present status and the critical issues for developing ultrasound contrast agents and multimodal imaging applications are described. Conventional MB UCAs are first introduced, including their research material, diagnostic applications, and intrinsic limitations. Then, recent progress in developing targeted UCAs and phase-inversion contrast agents for diagnostic purposes is discussed. Finally, we review the present status and the critical issues for developing ultrasound-based multimodal imaging applications and summarize the existing challenges and future prospects.