By Bukre Coskun, Cell Biology, ‘18

Author’s Note:

“The ability to build new organ parts may seem like science fiction, but tissue engineering is a fast-growing field that has already yielded promising results. After reading that congenital heart defects are the most common type of birth defect, I was compelled to do some research on how tissue engineering has sought to improve existing surgical options. After coming across a couple articles about acellular valve conduits, I decided to report on the research of the University of Minnesota, which was recently published in Nature Communications.”

Congenital heart defects are a serious and increasingly prevalent problem, with treatment limited to synthetic valve and vessel replacements. The inability of these replacements to grow and respond to their biological environment calls for repeated open-heart surgeries to resize the prosthetics, especially in children. Scientists, led by the University of Minnesota, have recently developed artificial blood vessels that can grow inside the patient. This advancement could potentially eliminate the need for multiple heart surgeries in children with congenital heart defects.

Cardiac defects, such as pulmonary atresia, sometimes require surgery to create a connection between the arteries and left ventricle. Homografts, tailored pulmonary arteries taken from a person who has died, and bovine jugular vein grafts obtained from cows, are the only two materials currently available to form this connection. However, these materials don’t grow with the child, which means that the graft will eventually be too small. The graft will have to be replaced with a larger one at some point as the child “outgrows” the conduit.  Other complications, such as shrinkage of the conduit due to calcification, add to the probability that the child will have to undergo five to seven procedures during their lifetime. A conduit with the ability to grow would greatly benefit children with heart defects.

Although there are methods being developed that use autologous cell grafts and polymers, researchers at the University of Minnesota have developed an acellular graft with growth potential that does not require cells to be isolated from the patient and cultured before implantation. Instead, the patient’s own cells would be able to colonize and grow on the acellular graft post-implantation. “This might be the first time we have an ‘off-the-shelf’ material that doctors can implant in a patient, and it can grow in the body,” said Robert Tranquillo, who led the research team.

The researchers seeded sheep dermal fibroblast cells into fibrin gel, a biodegradable protein scaffold. The cells secreted extracellular matrix proteins, such as collagen, which are essential for the regular gene expression, migration, proliferation and differentiation of cells. To form the material into vessel-like structures, the cell-populated gel was wrapped into tiny tubes. Then, the material was put in a bioreactor with the necessary nutrients, which also strengthened and stiffened the cells by keeping them in constant motion. The synthetic blood vessels were finally washed with special detergents to remove all the sheep cells, leaving behind a cell-free protein matrix. Because all cells are efficiently removed, there is no risk of rejection and no need for immunosuppression. The resulting tube, composed of mostly collagen, can be stored until needed for an operation.

To test the manufactured blood vessels, the synthetic vessels replaced part of the pulmonary artery in three lambs at five weeks of age. Ultrasound images taken over 50 weeks to monitor the artificial vessels showed that the implanted vessels were successfully populated by the lambs’ own cells, allowing the vessel to grow together with the recipient into adulthood. In fact, the collagen protein increased 465 percent by week 50, confirming that the vessel had not simply expanded but had really grown. “This is the perfect marriage between tissue engineering and regenerative medicine where tissue is grown in the lab and then, after implanting the decellularized tissue, the natural processes of the recipient’s body makes it a living tissue again,” Tranquillo said.

Although Tranquillo’s animal studies are promising, further studies and endeavors are necessary to determine if these artificial vessels can be used in humans. This exciting breakthrough highlights the possibility that vessels grown in labs can grow with the recipient. The benefits of this research are far-reaching, with the potential to eliminate the need for multiple surgeries in children and greatly relieve the health care system of high costs due to the need for periodic replacement of grafts. Most importantly, acellular conduits have the likely power to significantly improve the quality of life of children with congenital heart disease.

Sources

1. Blaszczak-Boxe, Agata. “Artificial Blood Vessels Grow After They’re Implanted.” Live Science. Purch Group, 27 Sept. 2016. Web. 27 Apr. 2017.
2. Cheung, Daniel Y., Bin Duan, and Jonathan T. Butcher. “Current progress in tissue engineering of heart valves: multiscale problems, multiscale solutions.” Expert opinion on biological therapy 15.8 (2015): 1155-1172.
3. Knight, R. L., et al. “The use of acellular matrices for the tissue engineering of cardiac valves.” Proceedings of the Institution of Mechanical Engineers, Part H: Journal of Engineering in Medicine 222.1 (2008): 129-143.
4. Mayo Clinic Staff. “Congenital Heart Defects in Children.” Mayo Clinic. Mayo Foundation for Medical Education and Research, 4 Feb. 2016. Web. 27 Apr. 2017.
5. Sample, Ian. “Synthetic Blood Vessel Breakthrough Could Transform Children’s Heart Surgery.” The Guardian. Guardian News and Media, 27 Sept. 2016. Web. 27 Apr. 2017.
6. Salim, Mubadda A., et al. “The fate of homograft conduits in children with congenital heart disease: an angiographic study.” The Annals of thoracic surgery 59.1 (1995): 67-73.

Syedain, Zeeshan, et al. “Tissue engineering of acellular vascular grafts capable of somatic growth in young lambs.” Nature communications 7 (2016).