When a 30-year-old woman from Colombia who had had severe stenosis from airway tuberculosis was referred to the University College London Centre for Stem Cells and Regenerative Medicine, there were more questions than answers.
Explore This IssueNovember 2009
The woman was declining in both function and in clinical evaluations. Her airway could not handle stents. The only traditional approach that would have had any chance of curing her, doctors thought, was to remove her entire lung and a major airway.
Then she spoke with Paolo Macchiarini, MD, PhD, Professor of Thoracic Surgery in Barcelona, about the possibility of having a trachea transplant-not just any transplantation, but one in which the specimen she would be given had been mixed with new cells derived from her own stem cells in a bioreactor-an incubator for cells.
Such a procedure had never been tried in a human being before. But researchers told her, We believe it has potential.
Today, about a year after the transplantation, she has regained her pulmonary function and the new trachea has not been rejected. She’s enjoying a normal life looking after her children, said Martin A. Birchall, MD, Professor of Larygnology at University College London and co-leader of the team, who updated an audience on the case at the annual meeting of the American Broncho-Esophagological Association, conducted as part of the Combined Otolaryngology Spring Meeting.
The case strengthens hopes for using stem cells in this kind of transplantation and for the use of stem cells in general.
The attempt was made out of a great need to try something different, Dr. Birchall said. Stents are variably tolerated, he said. And using the whole prosthetic trachea really hasn’t worked at all.
Researchers, part of a European network, had been experimenting with such scaffolds in pigs. We found that you could use scaffolds, either synthetic or decellularized human scaffolds, and you could support the airway in a pig quite reasonably for up to a month, but after that they universally fail, Dr. Birchall said. However, if you start adding in cells to the mix, you get a different situation altogether.
Adding epithelial cells increased the duration. But using both epithelial cells and cartilage cells together made a huge difference.
This gives almost indefinite survival in our pig model, he said.
The cartilage cells were grown using the patient’s own stem cells, capitalizing on a discovery at Bristol University of how to ensure that they turn into chondrocytes and not into bone-like cells that cause calcification.
Without the transplant, the woman’s hopes were dim. The only solution for this particular woman, who had both tracheal and bronchial compromise, was to take out her entire left lung and lower trachea and sew a stump of the right lung onto the bottom of the larynx, Dr. Birchall said. That has a 50 percent mortality rate, and the people who survive have very little functional capacity for the rest of their lives.
When you try new things, he said, you need a little serendipity. The patient’s mother had once turned down a new treatment for heart disease, but later died. For that reason, she was accepting, possibly, of something that had only previously been tried in pigs and mice, Dr. Birchall said.
Tracheal Transplant Tried
The center received ethical permissions from the Catalan Transplant Organization. And in March 2008, a human donor trachea was retrieved and treated with the detergent-enzymatic method for 25 cycles.
It was placed in the bioreactor with cartilage cells and epithelial cells from the patient, with hopes that the two would mix nicely. Both nasal and bronchial cells were tested for the epithelial cells. But the nasal cells actually grew too quickly, so the bronchial cells were used.
Doctors knew they still had the pneumonectomy as a last-ditch back-up measure if the specimen didn’t turn out well. We didn’t know what we were going to get, Dr. Birchall said. When we took it out of the bioreactor, it was beautiful.
The patient had her operation on June 12, 2008. The diseased bronchus was removed and replaced with the tissue-engineered trachea. The elasticity of the tissue allowed it to be fitted well to the larynx and the bronchi, he said.
While Dr. Birchall called it beautiful, he did admit it was pale because it wasn’t vascularized, but that soon changed. There was not good mucociliary function for two months, but that also improved, he said.
The woman went home after 10 days but was breathing on her own in half that time. She could have gone home after five days, in fact, Dr. Birchall said. In a month, she had normal lung function.
Typically, if a graft is going to be rejected, a person’s system develops antibodies to a graft within two months, but it’s been a year for this patient. She’s been on no immunosuppressant and never has been, he said.
Dr. Birchall is encouraged by the results but is careful not to get carried away. It’s only one patient, he said. It’s only by repeating this experience and incrementally getting it better and better that we will really prove whether this has any long-term prospects.
Small Steps Yield Large Gains
History has shown that little steps can end up yielding big gains.
In Wake Forest, NC, he said, doctors have been making similar attempts, but with bladders, in children since the early 2000s. The first few weren’t perfect, as with our patient, but incrementally, studying each case in depth, he’s getting each one better and better, Dr. Birchall said. And now he’s getting good results in both children and adults.
Still, there are no guarantees, even at this stage. Maybe she’s going to stenose tomorrow, he said. I can’t tell you that’s not going to happen. However, what we mustn’t do is give up.
He said he hopes that eventually transplantations can become effective in children. Some are written off from the time of birth because of no trachea or inadequate trachea, he said. So that’s where we are. It may not be the answer, but we think it’s a start.
The case received rave reviews from experts in the audience. Martin Birchall has really pushed the frontier, said Dana Thompson, MD, Associate Professor of Otolaryngology at the Mayo Clinic. It’s pretty remarkable stuff.
She said it is a breakthrough that could mean new possibilities for patients who have few choices left. Sometimes you run out of options, where you can only resect so much of a person’s trachea and still have someone breathe, she said.
Thomas Gilbert, PhD, Research Assistant Professor of Surgery and Bioengineering at the University of Pittsburgh and a faculty member at the McGowan Institute for Regenerative Medicine, said it was groundbreaking.This was definitely a landmark transformational study, he said. The trachea is really the perfect model system to look at some of the translational aspects of tissue engineering, in large part because of its low-oxygen needs, meaning there is less worry about cell viability.
Dr. Gilbert also commended the collaboration that was involved. They were bridging international boundaries to get this done, he said. The fact that this patient is out a year now, he added, is really a testament to the technology.
©2009 The Triological Society