The National Institutes of Health has awarded Georgia Tech a $2-million research grant to unravel the mechanical forces at play in lymphedema, a poorly understood disease with no cure and little hope for sufferers.
Lymphedema develops when the body fails to circulate lymphatic fluid, a mixture of immune cells, proteins, and lipids. This fluid builds up in the arms, legs and genitals — sometimes causing extreme swelling and permanent remodeling of the tissue. The mechanisms involved in the progression of the disease are unclear, so professor J. Brandon Dixon’s lab will use an engineering approach to studying the disease. This innovative methodology could lead to new technologies to test and treat lymphatic disease.
Solving this biological problem with engineering is an ideal strategy, Dixon said, because the lymphatic system is an engineered system — essentially a very complicated network of pumps. In a healthy person, the lymphatic system pumps the lymphatic fluid around the body, draining excess fluid from tissues and returning it to the circulation. Understanding the details of how the system works, and what goes wrong when it fails during lymphedema, requires engineering expertise.
“I really think the reason we’re so far behind in lymphatic research compared to vascular research is technology,” said Dixon, an assistant professor in the Georgia Tech School of Mechanical Engineering. “You can go to the most advanced lymphedema center in the world and it’s still difficult to say how well your lymphatic system is working.”
Dixon’s lab is located in Georgia Tech’s Parker H. Petit Institute for Bioengineering and Bioscience, a unique collaborative unit of experts from engineering and the life sciences. He’s one of only a handful of engineers in the world that study the mechanical forces at work in lymphedema.
The lymphatic system is difficult to see and access, but Dixon’s expertise lies in developing engineering technologies such as imaging and recreating the lymphatic environment in the lab. His lab has pioneered technologies to manipulate the micromechanical environment on cells and in isolated vessels.
By teasing apart the workings of the lymphatic system, Dixon’s research could lead to diagnostic technologies that measure how well the lymphatic system is functioning, and also to therapies that manipulate the system and stop the painful swelling that occurs during lymphedema.
For the past 30 years, little progress has been made in treating lymphedema. Patients are treated with compression wraps to limit painful swelling.
Limited research on the prevalence of lymphedema suggests that between 20 and 60 percent of post-mastectomy breast cancer patients develop the disease. One in six women will get breast cancer, estimates suggest. Worldwide, lymphedema affects more than 100 million people. In undeveloped countries, parasites can cause a severe form of lymphedema-related swelling known as filariasis.
Scientists cannot yet say what causes lymphedema in post-mastectomy breast cancer patients, nor can they assign a patient-specific risk of developing the disease. And since lymphedema can arise as long as six years after surgery, determining cause and effect is difficult. The later the onset, the more likely patients are to report the swelling to their general practitioner and not their cancer surgeon. This uneven reporting makes it hard to measure the burden that lymphedema places on the healthcare system.
“It’s hard to measure the cost of lymphedema,” Dixon said. “It’s not like a stroke where there’s an obvious event that occurs and a rate of death. People don’t die of lymphedema, per se.”
Long-term lymphedema-related swelling is not from the fluid itself, but from actual growth of the affected limb through fibrosis and the deposition of fats. Scientists don’t yet understand what causes this. Dixon’s hypothesis is that something happens during breast cancer surgery that changes the mechanical forces on lymphatic vessels that impairs their ability to pump this fat-containing fluid.
“If the pump doesn’t work, it’s like a feedback loop,” Dixon said. “You get accumulation of fluid and other remodeling of the tissue, which in turn leads to greater lymphatic failure”
To test the hypothesis, Dixon’s lab will mechanically perturb lymphatic vessels in isolated vessels, and cells. They’ll stretch them and ramp up the fluid flow rates across them and observe changes in vessels function and remodeling. Clues about how the vessels work might be found in genes that are switched on and off, changes in pump rate, buildup of extracellular matrix, and other biological abnormalities.
In another experiment, the lab will use animal models to explore what happens to the lymphatic vessels after breast cancer surgery. The researchers plan to destroy one lymphatic vessel and observe what happens to the system as it tries to compensate for the loss.
Data from the experiments will feed a mathematical model of the growth and remodeling of lymphatic vessels, which is under development by Dixon’s collaborator on the project, Rudolph Gleason, an associate professor in Georgia Tech’s Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.
Also collaborating on the project is Mari Muthuchamy, a professor of medical physiology at the Texas A&M Health Science Center in College Station, Texas.
This research is supported by the National Institutes of Health under award R01HL113061. Any conclusions or opinions are those of the authors and do not necessarily represent the official views of the NIH.
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Writer: Brett Israel