Sci-Fi Becoming Reality? Brain Regeneration Project Under Way
By Nuala Moran
BOSTON Regenerative medicine pioneer Paolo Macchiarini is now taking the field to its ultimate heights and into the realms of science fiction embarking on a brain regeneration project.
"You'll think I'm crazy," he told delegates at the American Association for the Advancement of Science annual meeting Monday. But there undoubtedly is great unmet medical need, and based on his experience to date in transplanting stem cell-infused donor and bioengineered trachea, Macchiarini said he believes there is a way to replace neurological function lost to road accidents, gunshot wounds and surgery.
Although ambitious, Macchiarini's plan owes less to science fiction than would appear at first glance. His idea is to produce a gel infused with nanofibers and seeded with neuroprotective proteins that would be used to fill the gap left by missing tissue. "It would be a 3D gel that adapts to the defect you find, and includes relevant proteins. It does not regenerate into brain [tissue] but attracts endogenous stem cells and is bridged and filled with connections from healthy tissue," he told delegates. The technique has been tested in rats and mice, with positive results.
Macchiarini described how the lessons learned from transplanting donor trachea that were stripped of donor cells and MHC antigens, and then colonized by epithelial cells and mesenchymal stem cell-derived chondrocytes cultured from cells taken from the recipients have paved the way to the brain regeneration project. The trachea transplants also are informing other programs in acute lung disease, esophagus replacement and the development of a miniature ambulatory bioartificial lung for use by chronic obstructive pulmonary disease patients.
Among positives from the donor trachea transplants are the findings that unlike other allogeneic transplants there is no need for immune suppression, the seeded cells differentiate in situ forming epithelium, and after five years of follow-up, there is no incidence of teratoma, indicating long-term safety. However, the donated scaffolds biodegrade over time, leading the transplanted trachea to became floppy, and there is a problem with restenosis that can occur between the implant and the recipient's own tissue, occluding the trachea.
Macchiarini himself is a surgeon, but he has the backing of a multidisciplinary group at the Karolinska Institutet in Stockholm, Sweden. To investigate the surgical problems, he consulted bench scientists. "That's the beauty of regenerative medicine: You can go back to the lab," Macchiarini said.
Based on the laboratory analyses, Macchiarini and his group are working to reduce the biodegradation process. However, he also decided to test artificial scaffolds and in June 2011 carried out the first transplant of an artificial trachea seeded with the recipient's stem cells. To date, five procedures have been conducted using the technique. Although that gets around the problem of biodegradation, the junction between the natural tissue and the transplant remains a focus for restenosis, and Macchiarini now is looking for more suitable materials from which to fashion trachea.
Data from animal models of artificial trachea implants indicate that three weeks after transplant the seeded cells remain in situ. "This is very important because it allows for a homing effect, and other cells are attracted here to boost regeneration," Macchiarini said.
The evidence that implanted stem cells boost endogenous repair mechanisms has led Macchiarini into cell therapy. He has demonstrated immediate functional improvements in two patients with acute refractory lung failure (though both died of multi-organ failure) and one patient with an ischemic larynx.
Those examples are turning the established dogma of cell therapy of isolating, expanding and injecting specialized cells on its head. "The time has come to start real clinical trials, to provide definitive evidence. Then stem cell therapy would be used not as a last resort, but sooner."
Macchiarini also is switching his attention to the esophagus, an organ that is more complex to transplant than the trachea because it includes muscle. However, once again, Macchiarini said he was driven to take the next step by new laboratory research, with evidence of muscle cells growing on artificial esophagi in bioreactors three days after seeding with mesenchymal stem cells.
For the miniature ambulatory bioartificial lung, the plan is to seed polymers that are capable of basic gas exchange with lung cells. Macchiarini has European Union funding for the project and said it will be in the clinic in two years.
Macchiarini did not say what his future ambitions are for the brain regeneration project, but he concluded, "If you want to do the same as nature you will fail all the time; you need to compromise. So a bioartificial matrix and a human cell matrix is the right approach."
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