The Phoenix Vessel

Deep in one of the labs on Pitt’s campus is a room for electrospinning. Each time the PhD student enters, she steps on sticky paper to get all the dirt off her shoes. There are vents working overtime above her. No dust allowed. Inside the room is a large, clear box with a metal rod the size of a knitting needle. But this rod, charged with 11,000 volts, spins something other than yarn.

 

The graduate student, Chelsea Stowell, pursues research that could improve the health of more than 800,000 people every year. In the electrospinning room, she focuses her attention inside the box, where bits of synthetic filaments fly through the air and collect on the rod, like tiny feathers starting to grow on a wing. The student-bioengineer is working to create something transformative, something entirely new.

At Pitt, Stowell’s research mentor is Yadong Wang, the William Kepler Whiteford Professor of Bioengineering. His work involves regenerative medicine, stimulating the body to regrow damaged parts. His laboratory creates biomaterials that interact with cells, tissues, and organs in particular ways. Wang earned a PhD in chemistry from Stanford University and conducted postdoctoral bioengineering studies at MIT before joining the Pitt faculty in 2008.

A few years later, Stowell met Wang at an annual meeting of the international Biomedical Engineering Society in Atlanta. Then at Vanderbilt University, she was trying to narrow the focus of her future research, looking for a project-compatible professor and lab to establish a viable career, a rite of passage for aspiring graduate students in the sciences and engineering.

As an engineering undergraduate at Vanderbilt, Stowell had conducted research on aortic valve disease in a mechanobiology lab. She was intrigued by the work of Wang’s laboratory, which uses tools from chemistry, biology, materials science, and engineering to advance regenerative medicine.

Now in the graduate bioengineering program at Pitt, Stowell is immersed in the challenge of creating synthetic yet lifelike arteries—with the goal of developing something even more surprising.

Without functioning arteries, the body dies. There’s a tremendous need for vascular grafts, which are used to replace damaged or weak segments of blood-carrying vessels, serving as a connecting bridge to life for hearts and other organs, and as a lifeline for kidney-dialysis patients.

Current models of artificial vessels on the market are made of Teflon and dacron polyester, the same material used in clothing. The material itself feels like a thick drinking straw and remains unchanged in the body.

“It stays the same from the day you put it in until the day you take it out, maybe some 10 years later,” says Wang about existing synthetic-vessel products. “It also acts like a foreign material—it was never alive, and it will never be alive.”

Cells don’t like plastic rigidity. Cells aren’t rigid, and they can sense the difference. They grab onto a new, fake vessel and recognize that something’s not right. The cells start to accumulate at the site where the graft meets the body’s tissue, forming a lump that obstructs blood flow.

This circumstance—called restenosis—is another reason current models on the market aren’t ideal. To fix the lump clogging the fake artery, surgeons have to perform additional procedures to re-open synthetic vessels or to replace them.

During his postdoctoral studies at MIT, Wang used his training as a chemist to design a brand-new type of polymer, one that is also made of polyester but not the type used in clothing. Instead, it’s a form of rubber; it feels like a rubber band and bounces back when squeezed. This flexibility helps the body’s cells to accept the synthetic material.

Wang’s new polymer—an original synthetic compound—is now center stage in Stowell’s PhD research. Significantly, this rubbery material is designed to promote the natural growth of new tissue, and Stowell’s research is advancing these next-generation regenerative properties: Once the graft is surgically inserted, it slowly disappears. As it breaks down over time, regenerated biological tissue grows over the temporary polymer-graft structure.  Eventually, Voila!, a new actual artery forms.

But, to be viable in humans, the research requires extensive development and clinical exploration.

So far, much of the research has occurred on bio-scaffolding in a laboratory and in rat models. Stowell’s PhD work aims to push this advance beyond the laboratory into hospitals and clinics where actual patients will benefit. But that will take scientific grit and a lot of funding support.

Lack of early-stage funding for initial research is a barrier in the quest to improve medical and surgical care. Opportune projects languish or die without start-up funding.

To address this early obstacle, the Pitt Innovation Challenge, or PInCh, financially seeds promising sprouts of research aimed at improving people’s health. Founded by the University’s Clinical and Translational Science Institute, in partnership with the Office of the Provost and the Innovation Institute, PInCh is designed to rev up the engine of innovation at Pitt and in the region.

The program’s motto is “challenging creative minds to tackle difficult health issues,” and the idea is to support emerging science and reward researchers who are willing to take risks in making health-related breakthroughs.

So far, three PInCh competitions have provided $1.15 million in awards, from $25,000 to $100,000 each, to winning teams of researchers whose innovations show exceptional prospects for practical use and potential commercialization, including translating laboratory research into clinical and patient-focused applications.

“We are looking for something that is new, perhaps does not have preliminary data, or is ‘outside the box,’” says PInCh program director John Maier, an assistant professor in the School of Medicine. “A key aspect is that the work is focused on an actual problem as opposed to continuing an existing path of investigation that primarily leads to more knowledge.”

In 2014, Stowell and Wang formed a team including several other bioengineering graduate students to advance the Pitt artificial artery research. The students—who were all interested in learning more about the business of product development—included Piyusha Gade, Daniel Long, and Yen-Lin Wu.

The team’s immediate plan: win the PInCh competition and use the funds to develop Wang’s regenerative polymer graft and move it toward testing in humans. It was time to take things to the next level and prove the graft could work beyond rats in a lab.

But getting the funding wouldn’t be easy: 46 teams entered the 2015 competition, consisting of researchers not only from the Pittsburgh campus but also from other universities, start-ups, incubators, and labs in the region. A requirement is that each team includes at least one Pitt faculty member.

Immediately, Stowell and her research colleagues prepared to compete. They watched videos about how to assess their markets and how to evaluate the regulatory environment. There were plenty of questions to answer:  How were they going to sell this product? What obstacles would they face? What did a regulatory strategy look like? Would medical insurance cover the cost of the end-product, and why?

“It’s a very different mindset,” says Stowell. “When you’re in research, you’re thinking about how something works, why it works, and how you can make it work better. In business, it’s more about how to convince people to use it, how to ensure it’s safe, and how to make a profit. ”

A first step in the business mindset was to name the product, to capture its essence and appeal. The team arrived at Phoenix, to convey the vessel’s ability to transform from a synthetic structure into the body’s own artery.

In the first round of the PInCh competition, the Phoenix team successfully met the challenge of a two-minute video “elevator pitch,” a technique favored by venture capitalists, where a research project and its benefits are described in the span of time equivalent to a quick elevator ride with a potential funder.

The Phoenix team moved on and impressed reviewers in Round 2, making it into the final competition. The challenge: In a six-minute Shark-Tank-like pitch, convince a panel of judges—Pitt faculty and local business and venture experts—about the project’s exceptional benefits, value, and health care impact.

During the final-presentation showcase, six teams vied for three $100,000 prizes; and seven teams for three $25,000 prizes. When the Phoenix team made its pitch to the crowd, Stowell was nervous, but she emphasized a key point about the Phoenix graft: If the technology proved successful, it would be transformative to medicine, and it would save lives.

In November 2015, the winners were announced (www.pinch.pitt.edu), and the Phoenix team was a top prize winner.

“The Phoenix team did a number of things throughout the PInCh process well,” says Maier, who also is Director of Research and Development in the School of Medicine’s Department of Family Medicine. “They took work from their research program and thought carefully about a problem that it could potentially solve. They went on to present the project in a clear, concise way that was accessible to audiences from a number of disciplines.”

With the $100,000 funding released in early 2016, Stowell is now busy with several pressing tasks. First, she’s talking to anyone who could potentially touch the future Phoenix product—surgeons, nurses, patients, dialysis techs—inquiring about existing problems with current products on the market and asking for a description of their ideal graft design.

Stowelll is also making synthetic grafts with Wang’s innovative polymer. She has to scale up the previous model, designed for tiny rat arteries, about one millimeter in diameter. Human arteries are about four times larger in diameter.

It takes her two weeks to make one large graft, which is about six inches long. She makes the grafts on Pitt’s campus, each time stepping into the electrospinning room. There, she focuses on the large, clear box with the metal rod. A pump sends bits of polymer toward the rod, charged with 11,000 volts, where the thin strands gather in layers. Five to six hours later, those tiny polymer feathers have accumulated to become a thin, flexible, hollow structure. The tube is soft and doesn’t hold its shape, so Stowell bakes it in an oven at 120 degrees Celsius for two days, and then washes out any impurities.

Later she’ll make a second, similar layer, but this outer layer disappears more slowly in the body than the inside layer. It’s an intricate design, created to support and stimulate the biologic regeneration of actual blood vessels within the graft in the body.

A second phase of this research involves additional team members offsite, through a bit of global serendipity.

Three years ago, Wang was invited to speak at the First Annual Symposium on Vascular Tissue Engineering in the Netherlands. On a bus in Leiden, he met by chance another invited speaker, Prabir Roy-Chaudhury, a transplant surgeon now at the University of Arizona. The two were sitting next to one another, and began to chat about their work.“Professor Wang was describing a really neat technology, and I was describing a clinical problem,” recalls Roy-Chaudhury, who has expertise in kidney and vascular disease, as well as with dialysis and its complications. The surgeon regularly inserts artificial-vessel grafts in patients for dialysis, and he is frustrated by the narrowing that results when the synthetic grafts contract and restrict blood flow, requiring additional procedures. “Professor Wang wasn’t yet thinking about dialysis access, and we realized we could take his technology and apply it to this niche.”

Now, when Stowell finishes crafting the Phoenix grafts, she sends them to Roy-Chaudhury. His surgical team inserts the grafts in larger-animal models and monitors progress to make sure the grafts are working and blood is flowing properly. They also study the graft surgical sites under a microscope, hoping to find less narrowing of the Phoenix graft compared to traditional synthetic models.

If all goes well, Wang and Stowell estimate that it will take another decade to complete a series of such trials to assess the ultimate future of the Phoenix graft, which could not only eliminate the need for additional surgical procedures for arterial grafts and replacement blood vessels but could also reduce health care costs. Currently, an individual Phoenix graft costs about $300, while competitors’ synthetic grafts can run up to $2,000 each. But the rise of Phoenix biotechnology is just beginning.

Stowell knows that good science takes time and requires sustained funding from multiple sources. Future research and required clinical trials will cost an estimated $200 million before the Phoenix artery might be marketed to surgeons and their patients. “They told us that this would be a long haul,” Stowell says about the PInCh judges’ feedback. “And that it wouldn’t be cheap.”

But the quest for improved health for millions of people keeps the Phoenix team looking up, into the bright unknown.

Written by Jennie Dorris. This story appears in the Winter 2016 issue of Pitt Magazine. View the issue in Zinio Player