Lymphedema is a poorly understood disease with no cure and little hope for sufferers that 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 at Georgia Tech 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,” Dr. Dixon, an Assistant Professor at the George W. Woodruff School of Mechanical Engineering at Georgia Institute of Technology, explains in a release, “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.”
Also collaborating on the project is Dr. Mariappan (Mari) Muthuchamy, a professor of medical physiology at the Texas A&M Health Science Center in College Station.
Dr. Muthuchamy’s laboratory is interested in understanding the regulatory mechanisms of lymphatic muscle contraction. He notes on his TAMU biographical profile page that the lymphatics normally transport fluids and proteins against net hydrostatic pressure and protein gradients. Lymphatic muscle has strong/phasic contractions, much higher shortening velocities and different intracellular calcium dynamics. The lymphatic muscle contractile characteristics indicate that the lymphatic pump acts similar to the heart in its generation of flow.
Dr. Muthuchamy’s team has shown that lymphatics from different regions of the body exhibited significant functional and contractile differences; in addition lymphatic muscle has a unique combination of smooth and striated muscle components that fit the multi-functional roles of the lymphatic vessels. They are investigating the roles of regulatory proteins in lymphatic muscle contraction by using isolated vessel preparations from rat mesenteric and thoracic duct lymphatics along with pharmacological and siRNA approaches. They also use mouse embryoid body models to address the mechanisms of lymphatic vessel development. Understanding the mechanisms of lymphatic muscle biology is extremely important to ongoing attempts to better understand the lymphatic function and to discover the pathogenesis and the effective treatment of different forms of lymphedema.
“I really think the reason we’re so far behind in lymphatic research compared to vascular research is technology,” says Dr. Dixon. “You can go to the most advanced lymphedema center in the world and its still difficult to say how well your lymphatic system is working.”
Dr. 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 is one of only a handful of engineers in the world that study the mechanical forces at work in lymphedema.
Assistant professor J. Brandon Dixon and graduate student Mike Weiler examine the function of pumping vessels with near-infrared fluorescence imaging at the Parker H. Petit Institute for Bioengineering and Bioscience. (Credit: Rob Felt)
The lymphatic system is difficult to see and access, but Dr. Dixon’s expertise lies in developing engineering technologies such as imaging and recreating the lymphatic environment in his lab, which has pioneered technologies to manipulate the micromechanical environment on cells and in isolated vessels.
For the past 30 years, the release notes that little progress has been made in treating lymphedema. Patients are treated with compression wraps to limit painful swelling. However, by teasing apart the inner workings of the lymphatic system, Dr. 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.
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 difficult to measure the burden that lymphedema places on the healthcare system, and it’s likewise hard to measure the social and economic costs of lymphedema, Dr. Dixon notes, since “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, and scientists don’t yet understand what causes this phenomenon. Dr. 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, and “If the pump doesn’t work, its like a feedback loop,” he says. “You get accumulation of fluid and other remodeling of the tissue, which in turn leads to greater lymphatic failure.”
To test the hypothesis, Dr. Dixon’s lab will mechanically perturb lymphatic vessels in isolated vessels, and cells, stretching them and ramping up fluid flow rates across them, then 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 Dr. 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.
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.