Nanobubble Contrast Enhanced Ultrasound Imaging: A Review

Contrast-enhanced ultrasound is currently used worldwide with clinical indications in cardiology and radiology, and it continues to evolve and develop through innovative technological advancements. Clinically utilized contrast agents for ultrasound consist of hydrophobic gas microbubbles stabilized with a biocompatible shell. These agents are used commonly in echocardiography, with emerging applications in cancer diagnosis and therapy. Microbubbles are a blood pool agent with diameters between 1 and 10 μm, which precludes their use in other extravascular applications. To expand the potential use of contrast-enhanced ultrasound beyond intravascular applications, sub-micron agents, often called nanobubbles or ultra-fine bubbles, have recently emerged as a promising tool. Combining the principles of ultrasound imaging with the unique properties of nanobubbles (high concentration and small size), recent work has established their imaging potential. Contrast-enhanced ultrasound imaging using these agents continues to gain traction, with new studies establishing novel imaging applications. We highlight the recent achievements in nonlinear nanobubble contrast imaging, including a discussion on nanobubble formulations and their acoustic characteristics. Ultrasound imaging with nanobubbles is still in its early stages, but it has shown great potential in preclinical research and animal studies. We highlight unexplored areas of research where the capabilities of nanobubbles may offer new advantages. As technology advances, this technique may find applications in various areas of medicine, including cancer detection and treatment, cardiovascular imaging, and drug delivery.