Making biohybrid lungs implantable

Diseases can affect the lungs in different ways that can be challenging. If the lungs are badly damaged and artificial ventilation (also called artificial respiration) is no longer effective, an ECMO machine comes into play. Right now, artificial lungs reside outside the body and cannot be implanted.

Dr. Bettina Wiegmann studies artificial lungs. In this MEDICA-tradefair.com interview, she explains why ECMO machines cannot be implanted in the body and reveals how research plans to solve this problem.

Dr. Wiegmann, how does extracorporeal membrane oxygenation (ECMO) work?

Dr. Bettina Wiegmann: The name says it all: Extracorporeal means "outside the body" and membrane oxygenation refers to a gas exchange that occurs across cell membranes.

The ECMO machine helps patients breathe when they are unable to breathe on their own. Patients are first treated with mechanical ventilation. An ECMO device is implanted once this process no longer provides enough oxygen to the patient and removes carbon dioxide. This requires vascular access, which means a venous cannula that is about as thick as a thumb is inserted from the groin area. The blood flows from the patient through tubing to an artificial lung in the machine that adds oxygen. You can envision this like a filter system made of hollow fiber membranes. These hollow fiber membranes are like tiny thin straws in a crisscross arrangement. The blood receives oxygen through these straws and the oxygen-enriched blood is pumped back into the body from outside the body. And then the process works like the lungs: Gas exchange occurs through diffusions, meaning the blood is enriched with oxygen and carbon dioxide is removed.

When is ECMO necessary?

Wiegmann: There are various reasons a patient might have lung problems. End-stage lung disease are the most common indication for ECMO. If patients are on a ventilator, their lungs are still working but if the lungs are no longer working properly and can no longer ensure the exchange of gases, you use an ECMO machine, which is a support option that can also help critically ill COVID-19 patients.

What are the current risks of ECMO?

Wiegmann: The biggest problem is that the ECMO systems consist of different plastics which are not considered hemocompatible (referring to the compatibility of blood), thus requiring anticoagulation agents to prevent thrombotic complication since normal hemostasis is disrupted. This treatment is unavoidable because the blood passes by the hollow fiber membranes and tubing and initiates a coagulation and inflammatory response. One response is circuit thrombosis, which has a negative impact on the ECMO and worsens or makes the gas exchange impossible. A potential side effect of rigorous anticoagulant therapy is excessive bleeding, such as cerebral hemorrhage, an uncontrolled bleeding in the brain.

Another problem is that the process involves the insertion of cannulas that are the size of a thumb. This usually occurs via the groin area, which means patients typically must be sedated and ventilated.

What is your approach to solve these issues?

Wiegmann: Our idea is to populate all artificial surfaces that trigger foreign body reactions such as the formation of a thrombus with endothelial cells - that means, we populate the hollow fiber membranes and tubing. Endothelial cells line the interior surface of blood vessels in the human body and are hemocompatible, thus preventing thrombus formation. Since the body's own endothelial cells are not available in sufficient quantities, we use endothelial cells that are not endogenous to the body. We genetically modify them, so the patient’s immune system does not recognize them as foreign and reject them. Another option is to use so-called induced pluripotent stem cells to develop an unlimited source of endothelial cells. To recap, we make the artificial surfaces biological with the endothelial cells to create a so-called biohybrid lung, which lasts a lifetime and eliminates the need for anticoagulation.

The goal is to implant an artificial – biohybrid – lung in patients. What are the next steps to make this a reality?

Wiegmann: One step is to ensure that the endothelial cells adhere firmly enough to the hollow fiber membranes. An implanted biohybrid lung would have to withstand the blood flow of four to six liters each minute. The endothelial cells must be able to withstand the frictional stress caused by this blood flow.

Current ECMO systems measure about 15x15x5 centimeters in size, making implantation in the body impossible. This necessitates miniaturization, which should ideally be tailored to the individual patient as each patient requires a different gas exchange surface area to support the lungs depending on the type and stage of the disease. The membrane size enables us to control the biohybrid lung capacity and performance. Miniaturization should therefore keep individualization in mind. 

What will the future of artificial organs look like?

Wiegmann: That is an interesting and exciting question. There are parallel approaches to this: We try to use so-called tissue engineering to colonize existing surfaces with endothelial cells. Another approach is to grow organs in a lab. And yet another method combines the two approaches: For example, you can take lungs and use decellularization to isolate the extracellular matrix, leaving lung scaffolds for new cell colonization. You could use human or animal lungs, like the lungs of a monkey for this purpose.

Yet regardless of the research approach, you must have sufficient quantities of the different types of cells in the lung. That is because at this point it is not possible to extract these cells from the patient and grow them in the laboratory. You are forced to use exogenous material and ensure that the body does not recognize it as foreign and trigger an immune response. Otherwise, you would be back at the same point where we are today when it comes to organ transplants: The patient must take medication to prevent rejection and ensure the immune system accepts the exogenous cells. Of course, this is something we want to avoid since our goal is to develop an artificial lung that can be permanently implanted as an alternative to a donor organ.

It remains to be seen which of these fields of research will be the most successful in the future – my guess is that it will be a combination of all these approaches.