Synthetic trachea is a new step in regenerative medicine
Tumors of the trachea or windpipe -- the Y-shaped hollow structure that connects the upper airway to the lungs -- are rare, but have devastating consequences for patients. These tumors are not entirely responsive to chemotherapy and radiation therapy; hence, the only definitive cure is to surgically remove the cancerous trachea. Surgical resection of small tracheal tumors can be achieved with relative ease. Larger tumors, on the other hand, require wider resections, which may involve removal of extensive portions of the trachea, which results in significant irreparable defects. One option for patients requiring larger tumor resections is transplantation of a trachea from a recently deceased donor. The utility of this approach is limited because patients will require immunosuppressant medications after transplant to reduce the risk of immune rejection by the recipient. Also, finding a size match between the donor and recipient poses a challenge.
Researchers and surgeons led by Dr. Pablo Macchinarini, at the Karolinska Institute in Stockholm, Sweden have devised an innovative approach to overcome this problem by using a synthetic trachea to replace the patient’s cancerous trachea. This experimental procedure has only been performed twice. The second patient undergoing this treatment was an American man who had surgery just a few weeks ago for a tracheal malignancy that was not responsive to chemotherapy or radiation. The medical team engineered a scaffold for a synthetic trachea using nanocomposite poylmers. These fibers give the synthetic trachea similar biomechanical properties to a human trachea. In addition, it is designed to be a perfect size for the patient, because its dimensions are calculated based on advanced computed tomography 3-dimensional imaging of the patient. Despite these advantages, several major hurdles remain. If you place a synthetic object made of nanocomposite polymers in a human body, the synthetic material can easily become infected, especially in the case of a trachea that is constantly in contact with outside air. There is also the possibility of an immune-mediated inflammatory reaction against the poylmer, as well as the risk of the artificial tissue eroding into nearby structures like lung tissue or blood vessels. To overcome these hurdles, the researchers coated the synthetic organ with stem cells from the patient’s bone marrow using a bioreactor, a machine that provides the optimal temperature and environment for cell seeding and proliferation on the synthetic organ. Using the right combination of signaling molecules, the bone marrow cells were programmed to differentiate into cell types of the surrounding tracheal tissue, including mononuclear cells, which can ward off infection. This cellular coating will not be rejected by the patient’s immune system because it is derived from his own body. In addition, the coating covers the nanocomposite fibers, preventing an inflammatory reaction, while also serving as a base on which cells from surrounding tissues could expand onto.
It remains to be seen how the two patients receiving synthetic tracheas will do in the long term, but the first patient who underwent this operation several months ago has done well so far. The 12-hour operation is still experimental and costs several hundreds of thousands of dollars. Nevertheless, the implications of this procedure are significant for the field of regenerative medicine and tissue engineering. As I am writing this article, researchers are actively seeking new strategies to synthesize a variety of organs including blood vessels, bladders, kidneys and livers. The Wake Forest University Institute for Regenerative Medicine, led by Dr. Anthony Atala, is one of the centers pioneering such technologies. Using ink-jet machines and 3-dimensional printing techniques, these researchers have developed the capability to print cells in a predetermined order to form 3-dimensional structures that are replicas of organs. Moreover, they are investigating the use of biodegradable scaffolds as skeletons on which various cell types could be coated. These cells will eventually grow on the scaffold and take on the shape of the organ, while the synthetic material in the scaffold will degrade in the body. Dr. Atala’s team has generated and used synthetic bladders on patients with spina bifidia, a spinal cord condition which results in impaired bladder function. In this case, the cells used to coat the different layers of the bladder were not stem cells, but already differentiated muscle cells and epithelial cells, which form the outer and inner layers of the bladder respectively. By coating the inside and outside of the synthetic scaffold with the appropriate cell types, they successfully engineered a synthetic organ comprised of multiple tissues.
Similar technologies are being employed to study whether more complex structures like livers and kidneys could be engineered. Miniature versions of these organs have successfully been generated in the laboratory, but engineering them in their real sizes remains a challenge. There is great promise for future growth of this field and the recent tracheal surgery led by Dr. Macchinarini’s team is proof that this approach, albeit experimental, is achievable. As more operations involving synthetic organs take place, investigators will have more clinical data points to study outcomes in patients and improve technologies. As Dr. Atala recently noted, the goal is to have cost-effective off-the-shelf synthetic organs readily available to patients who need them. A decade ago the idea would have probably made you think science fiction, but today it is no longer far-fetched.
Jungebluth P. et al. “Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.” Lancet, 2011; 378: 1997–2004.
Mironov V. et al. “Organ printing: from bioprinter to organ biofabrication line.” Current Opinion in Biotechnology, 2011, 22:667–673.