Applying Organ-on-a-Chip Tech to the Lymphatic System

Organ-on-a-chip models have garnered increasing attention in recent years, driven by advances in techniques and technologies including cell culture, microfluidics, tissue engineering and bioprinting. While several areas of research ‒ including infectious disease, neuroscience and cancer research ‒ are already benefitting, the field of vascular medicine has fallen behind. However, that could be set to change.

Dr. Abhishek Jain, assistant professor of biomedical engineering at Texas A&M University and colleagues have now developed the first lymphangion-chip to model the functional unit of a lymph vessel. The hope is that the chip will allow researchers to gain a clearer picture of the mechanical forces controlling lymphatic physiology and pathophysiology, which in turn will help to identify new therapeutic targets for conditions such as lymphedema.

To learn more about the research, recently published in Lab on a Chip, Technology Networks spoke with Dr. Jain.

Laura Lansdowne (LL): Why is little research currently focused on understanding the mechanisms of lymphatic vascular diseases?

Abhishek Jain (AJ): This is because lymphatics is a field of vascular medicine that has long remained understudied and under-funded, relative to blood-related vascular medicine. In medical schools, there is rarely a specific specialization and subject-specific education in lymphatics, and there are only a handful of programs that do this rigorously. As a consequence, for decades, this discipline has not seen as much attention as needed in research, even though we now know that millions of people suffer from lymphatic disease, and lymphatic abnormalities contribute to some of the most deadly diseases, including cancer, diabetes, etc.

LL: What are the two main cellular components of a lymphangion and what role do they play in lymphatic function?

AJ: The two main cells are the endothelial cells and the muscle cells. The endothelial cells line the inner surface of the vessel and provide a protective barrier between the cells that are transported through the lymph (for example, immune cells), and the tissue behind the endothelium. The muscle cells, on the other hand, surround the endothelium and are cardinal to the functions of the lymphatic system. Their intrinsic contractile property – the intrinsic lymph pump – represents the principal mechanism by which lymph flow is generated. Lymphatic smooth muscles are sensitive to physical and chemical stimuli, mediating changes in their activity and modulating lymphatic drainage. Because lymphatic endothelial and smooth muscles play such an important role in creating a barrier and fluid transport respectively, their dysfunction may be a component of many inflammatory disease states. 

LL: Can you tell us more about the lymphangion-chip developed by your team, what are its key features?

AJ: Recent advances in organ-on-a-chip technology have permitted the co-culture of human cells in physiologically-relevant microfluidic environments, providing an alternative in vitro approach to model vascular functions. These microsystems, however, still have not modeled lymphatic vessels and are technically limited to being mostly rectangular. To meet these complex challenges, we fabricated a new class of cylindrical microphysiological system that supports the co-culture of the lymphatic endothelial and muscle cells for nearly a week. There are several salient features of our system that make this work novel and an exciting development. First, the cylindrical format of the vascular structure allows a true representation of the vascular architecture. Second, while the co-culture of blood vascular endothelial and muscle cells has been shown in numerous prior studies, it is not obvious and trivial for lymphatics, since it is an underdeveloped field. Third, we demonstrate with rigor how muscle cells over time align and wrap the endothelial cells circumferentially, and create a subendothelial gap as expected in vivo. Simultaneously, the lymphatic endothelial cells align axially and their growth and size are influenced by the presence or absence of the muscle cells in this chip. Finally, we demonstrate the sensitivity of the endothelial-muscle cell crosstalk to flow and inflammatory conditions, thus revealing that this biosystem has a strong potential to serve as a robust preclinical model of lymphatic research.

LL: How can this chip be used to discover new therapeutic targets for lymphatic vascular diseases?

AJ: What we have created is an experimental system that can be used to create disease models of lymphatics. Now that we have a model, it can then be used to identify new druggable targets. But more excitingly, we can even use to test existing drugs that were not imagined to be used to cure lymphatic disease, but perhaps can be tested with the platform and discovered as potential drugs that can immediately benefit patients.

LL: Now that you have bioengineered a platform allowing you to investigate understudied diseases, what are your future plans?

AJ: The field of lymphatic vascular physiology is so vast and there is so much to learn that we feel that we’ve only started. One area where we want to expand is to now include the transport of immune cells and learn how, in health or disease, the immune cells may interact with the endothelial and muscle cells of the transporting lymphangions, and make them respond to stimulatory challenges. Our long-term goal is to deploy this system to find a cure for lymphedema, which doesn’t exist right now.

Dr. Abhishek Jain was speaking to Laura Elizabeth Lansdowne, Managing Editor for Technology Networks.