A New Vision for Lymphatic Imaging

The University of Alberta has received an Advanced Research Projects Agency for Health (ARPA-H) award to lead a research collaboration aimed at developing high-resolution, 3D ultrasound tools to better image the lymphatic system.

Joining the University of Alberta collaboration is Pengfei Song, associate professor of biomedical engineering at Duke University, and researchers from Thomas Jefferson University. and CliniSonix. The project is part of the ARPA-H Lymphatic Imaging, Genomics, and pHenotyping Technologies (LIGHT) program, which is led by ARPA-H Program Manager Kimberley Steele.

More than 10 million people in the United States are impacted by lymphedema, a disease that occurs when fluid that is normally drained through vessels in the lymphatic system instead builds up and causes uncomfortable and painful swelling in tissues. The disease usually affects the arms and legs, and severe cases can even limit a patient’s ability to move the affected limb and increases the risk of infections and sepsis.

There are two types of lymphedemas: primary lymphedema, which occurs when a genetic condition causes abnormalities in the lymphatic system, or secondary lymphedema, a much more common form of the disease that’s caused by damage to the lymph nodes due to injuries, cancer or chemotherapy. But despite the disease’s prevalence, tools to precisely image and study the affected areas are limited.

“When you’re dealing with lymphedema, you usually need to image a patient’s entire arm or leg, and you’ll need to have a high resolution to adequately see the tiny lymphatic vessels that are involved in the swelling,” said Song. “We can use MRIs or CT scans, but these tools are very expensive and aren’t always easily available. Ultrasound scans are more affordable, but users have to scan and stitch images together to capture the entire area, and their resolution isn’t at the level we need.”

Recognizing the clinical gap, Song partnered with Roger Zemp, a professor of electrical and computer engineering at the University of Alberta, and Priscilla Machado, an assistant professor of radiology at the Thomas Jefferson University, to develop large ultrasound arrays that provide a panoramic, super-resolution ultrasound imaging technique capable of providing 3D images of the lymphatic structure of entire limbs at micrometer spatial resolution.

But developing larger ultrasound arrays is not an easy task. To improve or expand an ultrasound probe’s field of view, researchers need to add individual transducer elements and electrodes to the grid to make it larger and more sensitive. But the larger the array grows, the more wires it requires. “We could make an array that’s 1000 by 1000 elements, but that would require one million wires, which would be both impractical and expensive to use,” said Song.

To overcome this limitation, the team will use a bias-switchable row-column array technology developed by Zemp and his lab and startup company CliniSonix Inc. Rather than create an array made of thousands of individually wired elements, the row-column array relies on transducer elements that are electrically addressed with rows and columns, like a spreadsheet. Zemp’s row-column arrays are unique because they allow researchers to control the specific areas of the probe at the intersections between the rows and columns. This design dramatically reduces the number of required wirings while still allowing precise control over a two-dimensional grid, enabling high-resolution imaging across a large area.

The new array will be combined with an imaging technique from the Song lab called ultrasound localization microscopy (ULM). ULM uses FDA-approved microbubbles—tiny spheres that behave like blood cells as they move through the body. These bubbles contain contrast agents that make them easy to detect with ultrasound. By precisely locating and tracking individual bubbles over time, researchers can reconstruct detailed maps of extremely small blood vessels and lymphatic structures.

“If we’re successful, our project provides researchers with a way to image the lymphatic system at a whole-limb or whole-organ level down to micro-scale resolution for the first time,” said Song. “This will provide vital information for patient care and will revolutionize the way patients with lymphedema are diagnosed and treated.”

The collaboration will receive $5.6 million in funding to support the first phase of the project, which will last two years. If they can fulfill the goals of this first phase, the team will proceed to phase 2, where they’ll receive additional funding for three more years.

“We are grateful for this opportunity from ARPA-H and believe we have a game-changing suite of technologies and a world-class team,” Zemp said. “Together, we aim to bring a paradigm shift in the way vascular and lymphatic diseases are diagnosed and managed.”