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Ultrasound has long been a staple in medical imaging, predominantly for visualizing larger body structures. However, it has only recently begun to find applications in examining the smallest components of our biology, such as living cells. Baptiste Heiles, the lead author of a groundbreaking study, explains, “While clinical ultrasound techniques exist, like those used for monitoring pregnancies or diagnosing various conditions, they do not reveal what happens at the microscopic level.”
Advancements in 3D Cellular Imaging
A research team comprising scientists from TU Delft, the Netherlands Institute for Neuroscience, and Caltech has made significant strides in utilizing ultrasound to visualize specifically labeled living cells in three dimensions. Their innovative approach enables imaging within entire organs across areas roughly the size of a sugar cube. In stark contrast, traditional light-based microscopy typically necessitates the use of non-living samples, as Heiles points out: “Such methods require the removal and processing of the sample or organ, which eliminates the possibility of tracking dynamic cellular activity.”
The current gold standard for tracking the behavior of live cells in 3D is light sheet microscopy. However, this technique faces limitations, as its effectiveness is largely restricted to translucent or thin specimens due to the inability of light to penetrate more than 1 mm into opaque tissues. As lead researcher David Maresca explains, “Ultrasound can delve centimeters deep into opaque mammalian tissues, providing a non-invasive window into whole organs. This capability reveals how cells operate within their natural context—an aspect that light-based methods struggle to capture in larger, living specimens.”
Innovative Probes for Enhanced Imaging
A pivotal aspect of this advancement in ultrasound imaging is the employment of a technique referred to as Nonlinear sound sheet microscopy. This method was enabled by the development of a sound-reflecting probe from the Shapiro Lab at Caltech. Heiles notes, “This probe functions as a nanoscale gas-filled vesicle that becomes visible in ultrasound images, allowing for cellular observation. The vesicles, encased in a protein shell, can be engineered to adjust their brightness, enabling us to monitor cancer cells effectively.”
Breakthroughs in Brain Imaging
The research team also explored the application of ultrasound coupled with microbubble probes that circulate in the bloodstream to identify brain capillaries. Heiles emphasizes, “To our knowledge, nonlinear sound sheet microscopy is the first method that can visualize capillaries within living brains. This represents a significant advancement with immense potential for diagnosing small vessel diseases.” Since microbubble probes have already received approval for human use, the implementation of this technique in clinical settings could occur within a few years.
Implications for Cancer Research
In addition to its clinical applications, sound-sheet microscopy holds promise for biological research and is poised to revolutionize cancer treatment approaches. Maresca asserts, “Our imaging technique can differentiate between healthy and cancerous tissues. Moreover, it can visualize the necrotic center of a tumor—the area where cells begin to die due to oxygen deprivation. This capability could significantly aid in monitoring cancer progression and response to various treatments.”
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