A groundbreaking study from scientists at TU Delft, the Netherlands Institute for Neuroscience, and Caltech has developed a revolutionary ultrasound-based microscopy technique that allows for the first-ever 3D imaging of living cells within entire organs. This advancement, which is detailed in a recent publication in Science, represents a significant leap forward in the field of medical imaging and offers new possibilities for in vivo observation of cells and capillaries in a living organism.
Ultrasound is widely used in clinical settings, particularly for imaging body parts during pregnancy scans or monitoring various diseases. However, traditional ultrasound technology has been limited in its ability to capture microscopic structures such as cells or capillaries. As Baptiste Heiles, the first author of the study, explains, while ultrasound can create real-time images of body parts, it has struggled to provide insight into what is happening at the microscopic level.
In this new study, the researchers have managed to overcome this challenge by developing a method that allows for the 3D imaging of living cells inside intact organs. This breakthrough is made possible by a unique approach called Nonlinear Sound Sheet Microscopy, which enables ultrasound to reveal cellular behavior within whole organs, a feat that was previously unimaginable. The imaging covers volumes the size of a sugar cube, providing a more comprehensive view than current light-based microscopy methods, which are generally limited to non-living samples or small, thin specimens.
Unlike traditional light sheet microscopy, which requires thin or translucent specimens and can only penetrate about 1 mm into tissues, ultrasound can image several centimeters deep into opaque mammalian tissues. This allows the researchers to monitor living cells in their natural, three-dimensional environment, providing more accurate data about their behavior over time. David Maresca, the lead researcher, explains, “Ultrasound can image centimetres deep in opaque tissue, allowing non-invasive imaging of whole organs. This gives us information about how cells behave in their natural environment, something light-based methods can’t do in larger, living tissues.”
A critical innovation that made this advancement possible is the development of a sound-reflecting probe, which was created in the Shapiro Lab at Caltech. These probes are nanoscale gas-filled vesicles that become visible in ultrasound images, allowing for the visualization of cells. The vesicles have a protein shell and can be engineered to tune their brightness, enabling the team to track specific types of cells, such as cancer cells.
In addition to observing cells, the research team also demonstrated the ability to use ultrasound and microbubbles as probes to detect capillaries in the brain. Heiles states, “To our knowledge, nonlinear sound sheet microscopy is the first technique capable of observing capillaries in living brains.” This breakthrough could have significant implications for diagnosing small vessel diseases, such as those caused by stroke or neurodegenerative conditions. Since microbubbles are already approved for human use, this imaging method could be adopted in hospitals within a few years.
One of the most promising applications of this technique lies in cancer research. The new imaging method allows for the distinction between healthy and cancerous tissue, and can even visualize the necrotic core of a tumor—an area where cells begin to die due to a lack of oxygen. This capability could be crucial for monitoring cancer progression and assessing the response to treatments. Maresca highlights, “Our imaging technique can distinguish healthy versus cancer tissue. Furthermore, it can visualize the necrotic core of a tumor, which could assist in monitoring the progression of cancer and its response to treatment.”
The development of Nonlinear Sound Sheet Microscopy represents a significant leap forward in medical imaging technology. It opens the door to non-invasive, real-time imaging of living cells and organ structures at a depth and scale that was previously unattainable. As the technique continues to evolve, it has the potential to reshape not only cancer research but also broader medical diagnostics, including brain imaging and the study of various diseases.
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