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Ultrasound contrast Agents

Introduction of ultrasound contrast agents

Medical ultrasonography
Medical ultrasonography (a.k.a. echography) is the most widely used medical imaging modality. Ultrasound is applied to visualize size and structure of tissue in the human body. Ultrasound waves used for medical applications have frequencies typically in the MHz range. These ultrasound waves travel through the human body and are partially reflected from the layers between different tissues. Specifically, the ultrasound is reflected anywhere there are density or compressibility changes in the tissue in the body. Part of these reflections (i.e. echoes) return to the ultrasound system, which receives and processes them into an image.

Blood is a poor ultrasound reflector and remains dark in an echography. However, the bloodvolume as function of time (i.e. perfusion) in the small capillairies of different organs like liver, kidney and the heart muscle is of high interest, e.g. after an infarction. For these purposes ultrasound contrast agents have been developed. These contrast agents are administered intravenously and are great ultrasound scatterers. Blood vessels filled with contrast agent become bright structures in the echo images.

Composition of the ultrasound contrast agent
An ultrasound contrast agent consists of a liquid with tiny bubbles. These bubbles are typically smaller than 8 micron in diameter, which is smaller than a red blood cell. They consist of air or an inert gas coated with a protein, lipid or polymer layer. Without the coating, the bubbles dissolve in the blood before they can be imaged with the ultrasound system (< seconds). With coating they remain in the body for about 10 minutes. The gas is exhaled by the lungs.

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Physical background
When a gas bubble is hit by an ultrasound wave it is forced into volume pulsation. In the simplest situation, the size of the bubble decreases in the positive cycle of the ultrasound wave, and the bubble expands in the negative cycle. The volume pulsation of the bubble is frequency and amplitude dependent. The dependency on the acoustic pressure amplitude can be divided into three regimes. For small amplitudes of the ultrasound wave, the relative compression and expansion of the bubble are equal, and therefore, the bubble size is linearly related to the applied acoustic pressure. For higher amplitudes, the compression generally retards relative to the expansion of the bubble, which results in a non-linear vibration. Consequently, the backscattered ultrasound signal by the bubble contains in addition to the transmitted ultrasound frequency second and higher harmonics. Because tissue produces in general little harmonic energy, this harmonic energy can be used to discriminate the bubbles from surrounding tissue.

For an optimal exploitation of the echo properties of the contrast agent microbubbles, we study in our lab the interaction between ultrasound and the bubbles. Both acoustic and optical set-ups are applied, which allows us to not only study the ultrasound signals that the bubbles generate, but actually see how the bubbles vibrate in an ultrasound field. Because commercial cameras do not suffice for recording bubble vibrations at MHz frequencies, we have built are own  high-speed camera system, the Brandaris 128 , which is unique in the world. This camera system has already led to a lot of new insight in bubble dynamics and continuously contributes in new studies such as to the interaction between vibrating bubbles and cells .