For the last 23 years, Christopher Breuer, MD, and Toshiharu Shinoka, MD, PhD, co-directors of the Tissue Engineering Program at Nationwide Children’s Hospital, have been working together to use tissue engineering in congenital heart surgery. Shortly after they met at Harvard in 1994, they developed one of the first tissue engineered blood vessels and the first tissue engineered valve.
At Yale in 2012, they implanted the first tissue engineered vascular graft in a patient in the United States just before moving to Nationwide Children’s. Since then, they have implanted three additional tissue engineered vascular grafts (TEVGs) in children with congenital heart anomalies.
“Tissue engineered vascular grafts are superior to other options for pediatric congenital heart patients for several reasons, the most important of which is the graft’s growth capacity,” Dr. Shinoka says. “Our grafts don’t require immunosuppression or anti-rejection medications because they are made up of the patient’s own cells. And they grow with the child, decreasing the number of follow-up surgeries needed with conventional grafts.”
The doctors have discovered important aspects about how TEVGs respond in the human body, most notably the leading complication: stenosis.
After the Fontan procedure — the surgery in which the TEVG is placed — the blood flows from the heart to the body and then back to the lungs. It is oxygenated passively, not pumped through the lungs as in normal circulation.
“If narrowing of the graft occurs, less blood will flow to the lungs to be oxygenated, resulting in patients who do poorly and have worse exercise tolerance. Having a widely open blood vessel is critical to these patients,” says Dr. Shinoka. “It’s the difference between children playing outside at recess or sitting on the sidelines, or worse yet, waiting for another surgery.”
Briefly, the process of creating and implanting a TEVG involves: placing the scaffold in a vacuum, seeding it with cells obtained from the patient’s bone marrow at the beginning of surgery and then placing the graft. Over the next six months, the body acts as a bioreactor to grow a new vessel. The scaffold disintegrates. When they started, they assumed that the cells that were seeded onto the scaffold made the resulting vessel, but surprisingly, they found the host cells actually were the ones that made the vessel.
In fact, Dr. Breuer explains, “We discovered that you could make the vessels without seeding the scaffolds, but they didn’t work as well and were more prone to stenosis. Our later work shows a correlation between stenosis and the number of cells seeded on the scaffold.”
The scaffold is essential, but once it is in place, the body takes over and runs the show. According to Drs. Breuer and Shinoka, the cells that are the most important to the whole process are the immune cells, particularly macrophages.
“Macrophages orchestrate the whole process,” says Dr. Breuer. “If you can control them, you can control vascular graft formation.
“Our efforts to discover interventions against stenosis and optimize the scaffold design are rapidly approaching clinical translation. This is the essence of translational medicine and the hope for curing congenital heart disease.”