David Green is the CEO of Harvard Apparatus Regenerative Technology (HART). He holds an undergraduate degree in physics from the University of Oxford in the UK and a business degree from Harvard Business School in the US. However, the journey to his current position as the CEO of a clinical-stage biotechnology company developing regenerative organs for transplant, with an initial focus on the trachea, was an interesting one that really began at Harvard Bioscience, where he first got a taste of organ regeneration.
Harvard Bioscience, where Green was President, focused primarily on making laboratory equipment, but there was also a section devoted to research. “Back in 2008, we started to get interested in the area of stem cells. It was then quite a new field and this whole field of regenerative medicine was sort of science fiction,” said Green.
In the fall of 2008, he signed a sponsored research agreement with Massachusetts General Hospital (MGH) to work on a project for the regeneration of lungs. “What we were doing back then was making laboratory equipment; we made equipment that supported Harald Ott, MD, PhD, at Mass General to do research on regenerated lungs. Our first product line at Harvard Bioscience was a lung bioreactive chamber – which we didn’t even call bioreactive back then. We called it an isolated lung profusion apparatus – not very easy to say,” said Green.
Then in December 2008, Professor Paolo Macchiarini published a paper on tracheal regeneration for transplants in humans. Green read the paper and sent him an email telling him what great work it was. “I also told him I was interested in licensing the technology. He sent an email back saying yes. So that became our second product line. We developed the new equipment with Professor Macchiarini producing hollow organs like the trachea.”
Macchiarini performed the world’s first transplant of a regenerated trachea in 2008. The patient is still alive today, more than five years later. Green explained that all of the other heart and lung regeneration work at that time was being done on animals. He saw this as a very strong incentive to expand into the regeneration of all types of hollow organs using bioreactive technology.
“However, back then, Paolo’s approach was to decellularize donor organs. This was done taking a trachea from a healthy donor after death. It would be cut out and de-cellularized, which means to strip all the cells off of it to avoid immediate rejection by the new host body system. This was then repopulated with bone marrow cells from the patient, creating a viable organ with living cells on it that could begin to grow in the new host body without rejection.”
In 2011, Macchiarini was looking for a way to create a synthetic scaffold to attach the organic cells to, for two reasons. First, there were nowhere near enough donor organs to fill the need. Second, over time, a natural scaffold weakens and often need stents inserted to hold it open until it can re-stiffen on its own. Synthetic scaffolds were the answer.
The first synthetic scaffold that was tried, worked, but was stiff and hard to suture. So Macchiarini worked with Green to develop a new scaffold. “It is totally different,” explained Green. “It is like a fabric or material, so it can be easily sutured. Plus, we can control the physical properties to make it much more like the natural, organic trachea, thus avoiding the issues of the first model. This trachea scaffold is seeded with the patient’s own bone marrow cells, preparing it for implantation. Because the cells used to regenerate the trachea are the patient’s own, there is no rejection of the transplant and no need for anti-rejection drugs.”
These organ scaffolds are made using a technology known as electro spinning, which was developed in the 1930s. “Technically, you fill a syringe with the plastic dissolved in a polymer,” said Green. “You put this thick, sticky liquid in a syringe and you slowly pump it across an electric field. Ten thousand volts are generated between the needle of the syringe and the receiver. Within that electrical field, the droplets coming out of the syringe are pulled into a fine fiber. As the fiber crosses the air gap from the syringe to the mandrel it dries out.”
The material goes from being solubilized to again being a solid fiber. That fiber is wound up on a spool just like thread, and that becomes the fibrous basis for the trachea. “We stiffen this by using rings of plastic material that mimic the rings of any natural trachea. These keep the trachea open so the person can breathe. It is essential. We use PET, which has been used in implants for decades. It is a tried-and-tested polymer that has no toxicity in the human body,” Green added.
All the work culminated in 2013 when Green spun off the regenerative medical business as Harvard Apparatus Regenerative Technology (HART). “I decided to leave my job at Harvard Bioscience and head up this new company solely dedicated to developing regenerative organs for transplant,” he said.
One excellent example of where this new technology could help patients is tracheal cancer. While relatively rare, tracheal cancer is potentially deadly. The prognosis after all the treatments is only about 10 months to live. Green hopes to expand this survival rate, because HART’s technology allows the surgeon to take out as much of the impaired trachea as needed and immediately replace it.
To date, six patients have received the HART trachea. However, since the technology has yet to be approved by the FDA or any other global authority, these patients were all what are termed “compassionate use” patients – they were likely to die without the procedure. The new procedure was allowed in the hope that it would save their lives or at least extend them. Four of the six are alive and well. The two that did not survive did not die because of their tracheal impairment. One was killed in a traffic accident and the other died in a surgical procedure for a secondary affliction not related to the tracheal surgery. “We are beginning the approval process and will be starting clinical trials in 2015 and then work through the FDA in the US and the EMA in Europe,” said Green.
Looking toward the future, Green says that first the tracheal product needs to get a good market established, but then he plans to move to other hollow organs such as the esophagus, the small intestines, and big blood vessels. “We see a lot of opportunities in the hollow organs. But we eventually expect to do whole, solid organs like the lungs and the heart – but that is definitely much further in the future. Right now, I intend to continue to develop the HART technology for the benefit of trachea patients, with the goal of eventually expanding to benefit all patients.”