nside a North Carolina lab, row upon row of plastic bioreactor bags pulsate gently to the beat of an artificial heart. Within each bag, a lab-forged blood vessel slowly expands, feeding off a primordial cocktail of vitamins and proteins.
The blood vessels start as individual cells, placed inside a sinewy scaffold. Weeks later, they’ve grown into full-fledged arteries and veins that surgeons can use for transplants.
Welcome to the age of tissue engineering.
For decades, scientists and doctors have been seeking a way to manufacture human tissue — including entire organs — in a lab, hoping to make grafts and transplants easier and safer than they are now. The goal has proved elusive, because it’s hard to replicate the complexity of human tissue outside the body. But those in the trenches say the industry could be on the verge of a breakthrough.
“In the past two years, we’ve seen a real evolution in thinking — both in the science and in the practical aspect of tissue engineering,” said Jennifer Elisseef, the director of the Translational Tissue Engineering Center at Johns Hopkins University.
Name a tissue in the body, and you can be sure work’s being done — somewhere — to try and replicate it in the lab, said Robert Langer of the Massachusetts Institute of Technology, a bioengineer who pioneered some of this work in the 1980s.
Jennifer Lewis of Harvard University is using a 3-D bioprinter to layer a mix of cells, as if they were ink, in the form of blood vessels. Australia-based Mesoblast is developing lab-grown tissues, made from stem cells, that could be used for organ repair or new blood vessel formation. In San Diego, a startup called Organovo is trying to using 3-D printing to build livers and kidneys for transplant.
And in North Carolina, a richly funded biotech startup called Humacyte — which has links to the ever-prolific entrepreneur Langer — is moving into late-stage clinical trials on artificial blood vessels.
The work is still fraught with risks, both scientific and commercial.
One cautionary tale: the San Diego startup Advanced BioHealing, which created a promising lab-grown replacement for human skin, to be used in wound care. Anticipating a billion-dollar market, the Irish drug giant Shire bought out Advanced BioHealing in 2011 for $750 million. But insurers such as Medicare were reluctant to cover the skin replacement. Three years later, Shire shed that unit at a loss.
“Tissue engineering has to mature a bit as a market,” said Keith Murphy, the CEO of Organovo. Pharma companies haven’t been rushing to invest in the field, in part because of flops like the skin replacement technology. But Murphy is optimistic: “The science is finally getting to the point where it’s becoming attractive to do these things.”
A ‘barbaric’ procedure
It was a heart bypass surgery that first got Dr. Laura Niklason interested in growing human tissue.
During her anesthesiology residency at Massachusetts General Hospital in the 1990s, Niklason stood by a patient’s bed and watched as surgeons hacked into his legs to find usable veins to replace the clogged arteries in his heart. When that failed, they looked in the patient’s arms, then his abdomen, where they finally found suitable blood vessels for grafting.
“It really was a barbaric thing to watch, to be perfectly honest,” she said.
“At the time, I remember thinking: We know a lot about how blood vessels grow, heal, and develop,” she said. “Why can’t we take that into the lab, and grow them for patients who need them?”
Niklason began working on that problem in Langer’s lab. She founded Humacyte in 2004; Langer sits on the board of directors.
Humacyte, which raised $150 million in venture funding last year, grows each graft individually in its own little plastic sack, which serves as a sort of womb for the vessel as it grows. Each bag’s connected to a central bioreactor tank that pumps out all the nutrients it needs — a carefully crafted “soup” of vitamins, amino acids, and chemicals called cytokines that feed cells directions about how they’re supposed to grow.
“We set up a little miniature, simplified human body where we’ve got a pulse that mimics the beat of a heart,” Niklason said. After all, if these cells aren’t stretched in a way that mimics how arteries expand and contract every time a heart beats, then the resulting tissue will be too weak to function in the body.
The fledgling veins and arteries are delicate in other ways, too: “We need to feed them vitamin C all the time, or they get scurvy,” Niklason said.
The cells grow around a scaffold made of a synthetic polymer that disintegrates over the two-month incubation period. All the while, the cells are producing collagen, a sturdy substance that grows into a new, organic structure in the shape of a blood vessel.
Growing a ‘stealth implant’
At the end of the incubation, technicians wash away the cells, leaving just the lab-grown blood vessel. Niklason describes it as a “stealth implant” because it contains no foreign DNA that might prompt the patient’s body to reject it. Instead, the patient’s own cells wrap around the implant, filling in any gaps and strengthening the new vein or artery.
These lab-grown blood vessels are currently being studied in hemodialysis, a procedure that uses implanted veins as a conduit to remove waste from the blood of patients with kidney failure. Last month, promising results from a 60-patient midstage trial of Humacyte’s product were published in The Lancet.
Humacyte is now kicking off a Phase 3 study of its engineered vessels in 35 sites with 350 patients. It expects to submit data in 2018.
As for the future of tissue engineering, Langer said some applications will be more practical than others.
“Tissues that are more structural in nature will be easier to create than those that are more functional in nature,” Langer said. “I think we’ll see engineered skin, cartilage, and blood vessels on a commercial scale before we see things like the liver, pancreas, heart, or brain.”
As the potential becomes more clear, Elisseef said she’s beginning to see more interest from regulators and doctors, as well as research scientists.
“People are sniffing out that tissue engineering is at a unique stage,” Elisseef said. “You’re seeing a convergence of the science, clinical, regulatory, and manufacturing, all sort of combining and connecting together.”