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A team from the Langevin Institute (ESPCI,CNRS, Inserm) led by Mickaël Tanter, Inserm research director at ESPCI, has just passed a crucial step towards super high resolution ultrasound medical imaging. Scientists managed to report on the non invasive in vivo rat brain vascular activity, with a much better resolution than any other existing technique. Far from common ultrasound imaging, the technique was rather inspired by ultra high optical resolution (FPALM) which was awarded with the Nobel Prize for Chemistry in 2014. Their work was published in the prestigious journal Nature and constitutes an important breakthrough for biomedical imaging. It is the first microscopic imaging technique allowing to see deep into living tissues. Potential applications are numerous, from the early detection of cancer tumors or other cardiovascular and neurologic pathologies.
Observing microscopic details of living matter still represents a hard challenge to meet. No matter what technique used, scientists face the same obstacle: smaller wavelengths, optimal for high-resolution imaging, lead to higher absorption and scattering in tissues, lowering the depth of penetration of the signal. Scientists thus have to choose between depth penetration and image resolution. Yet, in the last twenty years considerable progress have been made in the ultrasound field particularly suitable for clinical or pre-clinical imaging, where Mickaël Tanter and his team are pioneers. These researchers have developed an ultrafast ultrasound imaging device, already available in many hospitals throughout the world. But this time, they made another important technical step forward, reaching an unprecedented spatial resolution in medical imaging: the micrometer scale (a thousandth of a millimeter).
All began in 2009, when Mickaël Tanter gave a lecture on ultrasound imaging in the United States, and attended a presentation of a new optical fluorescence microscopy technique with a resolution smashing the limit imposed by light diffraction for centuries, a step supposed to be impossible. The inventors of the technique were awarded with the Nobel Prize of Chemistry in 2014. The French scientist understood that the method of these American chemists and optics physicists, still restrained to surface imaging, could be transposed to the world of highly penetrating ultrasound imaging by using the ultrafast ultrasound technique of his laboratory. Once back in France, he and Olivier Couture, CNRS researcher in his team started to develop their own method based on ultrasound.
The scientists decided to use a contrast agent, microbubbles with a diameter of 3 µm, already used in medical diagnostics. As a part of several years of fruitful research collaboration with a team of neurobiologist led by Zsolt Lenkei, Inserm research director (ESPCI/CNRS), they injected the microbubbles in a rat vein and observed the living brain with their ultrasound device. The ultrafast acquisition rate of 5000 pictures per second allowed the very precise extraction of the individual signal emitted from each microbubble, an information usually drown into the noise of all the backscattered signals. Thus, their unique location can be well defined individually with micrometer precision during their travel in the brain vessels.
By tracing the exact location of several millions of bubbles at each imaging plane, researchers managed to rebuild a complete functional map of the cerebrovascular system in the living rat, in a few dozens of seconds. Details even permit to distinguish blood vessels separated by only few micrometers, although the diffraction-limited resolution limit was about a millimeter until now. Moreover, velocity of the blood flow was also measured with a large dynamic range, from several dozens of centimeters per second in the large vessels up to less than a millimeter per second in the smallest vascular systems.
Many direct applications
The excellent gain in resolution - about 20 times as compared to «standard» ultrafast ultrasound -, coupled with the non-invasive and fast properties of the technique may be really valuable for patients. «We think we are entering a new paradigm in medical imaging, says M. Tanter. In a few dozens of seconds, we are already able to collect millions of signatures of our microbubbles and reach microscopic details even at several centimeters depth. We believe that we can still reduce the acquisition time to obtain images in a couple of seconds, paving the way for ultra high resolution functional imaging.»
The technique will soon be used on humans, in particular to visualize the hepatic micro-vascularization of patients suffering from liver tumors or for high-resolution transcranial imaging of the cerebrovascular network in adults. There are many other potential applications, including the early detection of cancers, whose micro-vascularization is impossible to detect right now. In fact it will be possible to obtain a 3D vascular image of any organ, with microscopic resolution, by using a very compact device.
Although most of the current microscopic techniques rely on optical approaches limited to surface imaging, ultrasound came and solve the quest of imaging deep into organs at microscopic scales.
Associated publication:
C.Errico, J. Pierre, S. Pezet, Y. Desailly, Z. Lenkei, O. Couture & Mickael Tanter, Ultrafast ultrasound localization microscopy for deep in vivo super-resolution vascular imaging, Nature, 2015
doi:10.1038/nature16066