Infants and children receiving artificial heart-valve replacements face several repeat operations as they grow, since the since the replacements become too small and must be traded for bigger ones. Researchers at Children's Hospital Boston have now developed a solution: living, growing valves created in the lab from a patient's own cells.
In a special issue of Circulation published September 11, they describe making pulmonary valves through tissue engineering. These valves, which provide one-way blood flow from the heart's right ventricle into the pulmonary artery, are often malformed in congenital heart disease, putting an extra burden on the heart.
"The heart valve is a complex organ," says Virna Sales, MD, a researcher in Children's Department of Cardiac Surgery and the study's first author. "It must open and close synchronously, withstand pressure, and be pliable and elastic. We are one of the few labs in the U.S. that's attempting to make heart valves through tissue engineering. We hope these could just be implanted in a child just once, instead of the many heart operations most children have to go through as they get older."
The researchers, led by Sales and senior investigator John Mayer, MD in Children's Department of Cardiac Surgery, first isolated endothelial progenitor cells (precursors of the cells that line blood vessel walls) from the blood of laboratory animals. They then "seeded" the cells onto tiny, valve-shaped biodegradable molds and pre-coated with proteins found in the natural "matrix" that surrounds and supports cells.
Experimenting with different matrix proteins and growth factors, they were able to make pulmonary valve leaflets that had the right mechanical properties - sturdy yet pliable. Tests showed the original cells had differentiated to form both endothelial cells and smooth-muscle-like cells and added to the surrounding matrix to hold them together.
With grants from the American Heart Association and the Cambridge, Mass.-based Center for Integration of Medicine and Innovative Technology (CIMIT), Sales is now refining the lab-grown valves by exposing them to mechanical stress in a bioreactor. She is also using a "cardiac jelly" - a cushiony material rich in matrix components and growth factors - to encourage cells to differentiate and form a heart valve on their own, with only minimal reliance on an artificial scaffold. "I would like to mimic what really happens in the embryo - what Mother Nature does," she says. The next step would be to implant the living valves into animals.
Sales and surgical research fellow Bret Mettler, MD, have already used tiny tissue-engineered patches in sheep to rebuild a portion of the pulmonary artery - an area that often needs augmentation in patients with congenital heart disease. Eventually, Sales hopes to use tissue-engineering techniques to create "living stents" for adults with atherosclerosis.
The current study was funded by the National Institutes of Health, a grant from the U.S. Department of Commerce's National Institute of Standards and Technology program (via Tepha, Inc., Cambridge, Mass.), the Gross Cardiovascular Fund, CIMIT, the National Science Foundation, and an American Heart Association National Scientist Development Grant awarded to Sales.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 11 members of the Institute of Medicine and 10 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 347-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.