Expanding a company into a new field of science seems like a daunting challenge. However, Harvard Biosciences (HB) did just that when they aggressively took advantage of an opportunity in regenerative medicine to drive company growth, eventually spinning off Harvard Apparatus Regenerative Technology (HART) in the process. We had a chance to speak with David Green, HART’s current President and CEO and HB’s former President and CEO, about the shift from tissue preservation to tissue regeneration.
Michael Batista, Medgadget: What path did you take that brought you to running a biomedical company?
David Green: I’m British by birth and a scientist by training with a physics degree from Oxford. When I went into business I began in brand management at Unilever, which proved to be a great training ground. I decided to expand my business education by attending Harvard Business School. Afterwards, looking to work in a field related to my degree, I worked at Monitor, a Harvard spin-off started by Michael Porter. At Monitor, we focused on corporate strategy consulting to help big companies grow and become more profitable. An exciting part of that work was ending up in Johannesburg, South Africa for two years consulting on industrial policy during the Mandela elections.
After I returned to the US, I began working with HB. I grew the company and ultimately took it public in 2000. HB focuses on making lab equipment for isolated organ research (a niche within a niche). This allows organs to remain alive outside the body for pharmaceutical companies to test drugs.
Medgadget: What happened at HB that made the company start thinking about regenerative medicine?
Mr. Green: In the summer of 2008, Dr. Harold Ott, now at Massachusetts General Hospital, called HB about our product line. However, he asked for the product to be sterile which was initially confusing for us since this wasn’t the typical use case at the time. What we eventually learned was that he was trying to actually grow organs outside the body for which sterile organ isolation equipment made sense. At the time HB was suffering from low growth and looking for new growth opportunities in the area that eventually became regenerative medicine. We entered into a sponsored research agreement in August 2008 and were on our way to developing bioreactors.
In December of 2008, Professor Paolo Macchiarini published a paper in the Lancet where he described the first clinical transplantation of a tissue-engineered trachea. In the paper he described a bioreactor that he used and built to grow the trachea. We reached out and asked if he was interested in licensing the technology. With this, we were able to then offer a bioreactor product for solid organs (hearts and lungs) and hollow organs (trachea). Of the two, however, only a hollow organ, a trachea, had been implanted in humans.
Keep in mind that HB still did not see itself as a biotechnology company; we were a bioreactor company. At the time scaffolds were also still being reconstituted from dead patients. This was not an ideal approach since natural scaffolds would weaken. Paolo was looking for an alternative solution and began considering synthetic materials.
Medgadget: How were the synthetic scaffolds developed and have they been tried in humans?
Mr. Green: Initially, the first generation synthetic scaffolds still had problems. Those scaffolds were too stiff, hard to suture, and were not porous. Paolo had the idea to use more fibrous materials to make the suturing easier and reduce the stiffness. This characterized the second generation scaffolds and is now used in all our products. To make the fibrous material for the trachea scaffolds we used electrospinning. We worked with an academic lab, which became the spinout, Nanofiber Solutions. While working with the group to make the scaffolds, we realized that we couldn’t sell bioreactors without driving the market for the scaffolds to put in them. There was concern that Nanofiber Solutions could not scale up to meet the need and FDA requirements. In late 2012, we decided to take over production of the scaffolds themselves. In April 2013 we received approval to use the scaffold for the first time in a patient born completely without a trachea. It was a last resort solution for that patient and they, unfortunately, did soon die. It was the first time we manufactured both the bioreactor and the scaffold.
Medgadget: What factors are important when developing a scaffolding material for tissue regeneration and implant?
Mr. Green: There are four important factors that go into a good scaffold. First, for the scaffold to function well we really need the fibers to be down in the 1 micron range, which is possible with electrospinning. Since the cells need to physically make it onto the scaffold, the fibers need to act like a sieve for the cells in media. Second, certain materials improve cell adhesion to the scaffold. We typically use polyethylene terephthalate (PET) for HART’s scaffolds. Third, the cells have to be able to connect with each other so the scaffold needs to be porous to allow optimal interactions between the cells. Fourth, now that you have a well seeded scaffold, it has to get into the patient where vasculature will grow into the scaffold. Part of the trick here is to get the scaffold to vascularize quickly to get the cells to grow. An old technique that is still used is to use omentum, which is separated from the stomach and relocated up to the neck over the trachea scaffold to provide an immediate blood supply. This also helps the new trachea from collapsing since the neck is constantly in motion through swallowing, coughing, sneezing, etc. A lot of mechanical properties have to be met all while providing a safe haven for cell growth.
Medgadget: What about 3D printing organs?
Mr. Green: Our approach is better than 3D printing for a few reasons. There is simply no 3D printer with the resolution we need for the kinds of physical structures the cells are comfortable with. The best resolution you can get is 200 microns. Also, the inks used in 3D printers do not represent the kinds of materials we need our scaffolds made of for optimal cellular interactions. Finally, if you are trying to 3D print biological materials, you are not really making a mechanically robust structure to implant in the body.
Medgadget: At what point did HB and HART become differentiated?
Mr. Green: After this first US surgery with our approved products, we had another discussion with the FDA who told us they did not think HB was a medical device company. Instead, they claimed, we were a biological product company since our solutions used cells. To recap we had now gone from lab equipment, to implantable medical devices, to biotechnology. The final change in thinking occurred when we stopped thinking of the implant material as scaffolding and began thinking about it as a tissue.
We began to invest more and more money into this part of the company. The amount of capital began to increase significantly but was beginning to eat into HB’s profits so we made the decision to split the company in two to give what became the new company, HART, sufficient flexibility to function on its own. This happened on November 1, 2013 and since then HART and HB have functioned as two separate companies.
Medgadget: Why and how did you grow a company from what is still a very new science?
Mr. Green: One of the big motivators was seeing that a trachea has been done and implanted in humans. Many products have been successfully developed in animals that failed in humans. Having proof that we could get a clinically relevant outcome was a huge benefit and a driver of our focusing in on this area of regenerative medicine.
From a business standpoint, when we began looking at regenerative medicine, we were looking at all the companies in the space and seeing that most were failures. The earliest were skin companies like Organogenesis and Advanced Tissue Sciences, which became Advanced Biohealing. Both went bankrupt and continued as smaller companies after massive layoffs. Looking at these, there was not a lot of business success to raise capital and develop a product. Besides skin companies, bladders were being addressed in some ways where clinicians were opening and enlarging their capacities. Tangeon raised and went public but had a tiny cap compared to what was put into the company.
Skin, bladder, blood vessels, knee cartilage, they were all working and could be manufactured at scale but no one was making money. We decided the problem with regenerative science was not the technology but the business. In order to drive sales, the solutions had to have a high value (i.e. be lifesaving) and couldn’t have an easy, cheap alternative. For example, companies are developing blood vessels for heart bypass. However, while this seems like a high medical value, the clinician can get the material to perform this surgery for free from the legs of the patient. We needed to focus on a life threatening indication that could be solved with a tissue engineering or regenerative medicine approach. The trachea was a great option because it is life threatening and had already been shown to be viable in humans.
Medgadget: What is the status of HART’s current clinical studies?
Mr. Green: We have an ongoing clinical trial in Russia and have received a grant to begin a trial in the EU. The Russian clinical trial began over a year ago with five patients implanted. The 6 month follow up was presented at the European Society of Thoracic Surgeons. The patients are doing well but Nanofiber Solutions made the scaffolds, so they are weaker and beginning to narrow in the patients’ necks. This is what partly led
to the impetus to make our own scaffold products. We do expect to have US hospitals as part of a clinical trial. That trial is projected to be completed by 2017.
Medgadget: What other organs can benefit from HART’s approach?
Mr. Green: The next organ to be transplanted in humans will probably be the esophagus due to the technical similarities between it and the trachea. Like the trachea it is a hollow and is transplanted by the same type of surgeons who would perform the trachea operations. A few months ago a paper published by Paolo discussed the regeneration and transplant of an esophagus in a rat.
Medgadget: What are your thoughts on the future of regenerative medicine for more complex organs and tissues?
Mr. Green: Soft tissues and other soft materials are very accessible to printing solutions. It gets a bit more challenging when we think of structures with more variations and multiple different cell types and components: muscle cells, nerves, blood vessels, collagens. It is hard to believe that printing cells will be the right solution for complex organs like the heart. Something incorporating a hybrid of various fabrication technologies seems more plausible at this time.