What is contrast enhanced ultrasound and how does it work?

Solstice Pharma believes that everybody should have access to high-quality and effective healthcare. Most healthcare applications start with an imaging procedure. Which can be expensive when an CT or MRI is necessary. An ultrasound procedure is an alternative imaging modality which when used in combination with contrast agents can be very (cost) effective.

What is ultrasound and how does it work

Ultrasound are sound waves with frequencies higher than those which are audible to humans (>20 kHz). Ultrasonic images are made by sending short high-frequency pulses (1-7 MHz) into the body using a transducer, which is placed directly on the skin with an ultrasonic gel to improve this contact, to conduct the sound waves. The pulses are reflected by the different organs or tissues, and the recorded echoes are displayed as images (figure 1).

Figure 1: Artist impression of an ultrasound examination of the abdomen. A transducer, held against the skin of the abdomen, is connected to an ultrasound system and transmits ultrasound waves into the patient’s body. The ultrasound waves are reflected by internal organs and tissues, and the recorded echoes are recorded and displayed as images.

Compared to other medical imaging modalities, such as Magnetic Resonance Imaging (MRI) and Computed Tomography (CT), ultrasound has several advantages. It provides images in real-time and can be brought to the bedside of the patient. Due to its real-time character, tissue motion or blood flow in big vessels can be displayed using ultrasound, even in a three-dimensional format. Moreover, it is substantially lower in cost and safer since it does not use harmful ionising radiation.

What is contrast enhanced ultrasound (CEUS)?

Ultrasound imaging is a versatile diagnostic imaging modality and its application has expanded enormously during the last few decades. This increased use is supported by the introduction of microbubbles as ultrasound contrast agents, allowing new meaningful physiological and pathological information to be created. The contrast-agent microbubbles are smaller than red blood cells, and they remain for a short period in the blood pool after an intravenous injection into the human body. Consequently, they circulate through the (micro)vascular system enabling perfusion imaging of organs during ultrasound procedures.

Contrast-enhanced ultrasound (CEUS) permits real-time visualisation of contrast enhancement patterns in various organs. Moreover, thanks to the capacity to image both macro- and microvasculature, CEUS has expanded to new applications, in which a perfusion abnormality can be an indicator of a defined pathologic condition. Due to this, and in combination with its sensitive, safe, inexpensive, and portable nature, CEUS has become a modality considered equivalent or superior to other modalities such as CT, MRI and nuclear medicine.

Microbubble contrast agent

Figure 2: A schematic drawing of a contrast-agent microbubble comprised of a gas core stabilised by a phospholipid shell.

Ultrasound contrast agent microbubbles comprise of a gas core stabilised by a thin monolayer phospholipid shell. The shell reduces surface tension and stabilises the gas core against rapid dissolution. Persistence during circulation is further improved by using perfluorinated gases with a low solubility in water, such as sulphur hexafluoride or perfluorocarbon, resulting in a persistence in the blood circulation sufficient for clinical use after intravenous injection. An illustrative example of such a microbubble can be seen in the figure 2.

When a gas bubble is insonified by ultrasound, it responds to the frequency emitted by the ultrasound transducer and enhances the reflected echo. The key to contrast enhancement is a peak in natural resonance of the microbubbles at the diagnostic frequencies used by the ultrasound equipment (typically 1-7 MHz). The difference in acoustic response of a resonating microbubble and echoes from surrounding tissue ensures a high contrast-to-tissue ratio and thus improved contrast enhancement. This allows clinicians to obtain functional information related to perfusion of the organs and tissues.

Figure 3: Ultrasound image of polydisperse microbubbles (left) vs uniform microbubbles (right) acquired under the same conditions.

Microbubble size plays a crucial role in the quality of information which can be acquired, since peak resonance is only achieved when the resonance size of the microbubble precisely matches the operating frequency emitted by the ultrasound transducer. In fact, uniform microbubbles, as compared to polydisperse microbubbles, can maximise efficiency for obtaining useful diagnostic information. This enables further development of ultrasound towards new applications such as focused ultrasound therapy in combination with microbubbles and targeted drug delivery. The difference in ultrasound signal between uniform and polydisperse microbubbles acquired under the same conditions can be seen in figure 3.

Summary and future of CEUS?

During the last decades, CEUS has gained broad clinical acceptance as a diagnostic modality with a clinical performance equivalent or even superior compared to other contrast-enhanced modalities such as MRI and CT1). Furthermore, CEUS is an extremely valuable tool for the diagnostic imaging sector since:

  1. -it is a real-time imaging modality performed at the bedside of the patient;

  1. -it has an increasing use and widespread adoption worldwide due to its added diagnostic value combined with the lack of using ionizing radiation and without the risk of nephrotoxicity;

  1. -ultrasound contrast agents have a proven safety record for over 20 years of usage in Europe and in the United States.

These key safety and quality points are why we at Solstice Pharma believe everybody should have access to high-quality and effective healthcare, and CEUS can play a major part in achieving that.

  1. 1)Lu MD, Yu XL, Li AH, Jiang TA, Chen MH, Zhao BZ, Zhou XD, Wang JR. Comparison of contrast enhanced ultrasound and contrast enhanced CT or MRI in monitoring percutaneous thermal ablation procedure in patients with hepatocellular carcinoma: a multi-center study in China. Ultrasound Med Biol. 2007 Nov;33(11):1736-49.


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