Clinical uses of microbubbles in diagnosis and treatment

The development of microbubbles as ultrasound contrast agents (USCA) has opened the way for new and extended applications of ultrasound in clinical practise as well as offering rich new research opportunities. Some of the experimentally developed applications have been accepted into clinical practise and the European Federation has published guidelines on their use, particularly in the liver [18]. Many new applications are being explored and the field is unusual in imaging because its proper exploration depends on parallel development by the pharmaceutical and ultrasound equipment manufacturers. Microbubbles are unique amongst contrast agents for imaging in that the imaging process changes the agent and even destroys it. They contain gases that respond to the pressure changes of the ultrasound by changing size and this forms the basis for their selective imaging. In addition, when the volume changes reach a threshold, the oscillations become sufficiently violent that the microbubbles disintegrate (either by fragmentation or dissolution) and thus the contrast effect can be switched off remotely. Their body distribution is different from most contrast agents in that they are too large to diffuse through the endothelium and so behave as pure blood pool agents after intravenous injection. Their main diagnostic uses depend on detecting them in the blood circulation and, in a simple way, this represents an extension of Doppler which is given a boost by the 20? dB additional signal that the microbubbles produce. This is especially useful in situations where Doppler signal are poor. The best example is the cerebral vessels, from which signals are attenuated by the skull: adding microbubbles boosts the signals so that they are more reliably obtained. However, of more general interest is the fact that nonlinear detection techniques do not depend on microbubble movement, instead depending on their presence in the blood vessels regardless of calibre. Thus, not only can the macrovasculature be interrogated but, for the first time, the microvasculature, including the capacious capillary bed, can be imaged. Of course, these ten micron vessels cannot be resolved, as they would be by a microscope, but the signals from microbubbles within them can be displayed, much as in an angiogram. In addition to exploiting the distribution in space of microbubbles, e.g. for tumour diagnosis, the dynamics of their arrival and disappearance, e.g. after bolus injection, can be tracked using the high temporal resolution of ultrasound. This is mostly done in a qualitative way when, for example, the haemodynamics of the blood supply to liver masses is accessed by eye. It can also be measured more formally, using scanner software to quantify the microbubble signal intensity over time and generate time– intensity curves (TICs). This has been shown to be especially promising in evaluating the microvasculature of tumours and of the myocardium.