Making pig livers humanlike in quest to ease organ shortage

The ghostly form floating in a large jar was just a few hours ago the strong reddish-brown of a healthy organ. Now it’s a semi-translucent, white tube like the branches you see on a tree. This is a pig liver that is slowly being transformed to look and function like a human’s, part of scientists’ long quest to ease the country’s transplant shortage by bioengineering replacement organs.

The first step for workers in this suburban Minneapolis lab is to shampoo off the pig’s cells, allowing the organ to do its job, slowly fading its color as the cells dissolve and are released. What’s left is a rubbery scaffold, a honeycomb structure of the liver, its blood vessels now empty. Next human liver cells – those unable to be transplanted from donated organs – would return inside that shell.

Those surviving cells move into the nooks and crannies of the scaffold to resume organ function. “We essentially re-grow the limb,” said Jeff Ross, CEO of Mirometrics. “Our bodies won’t see it as pig parts anymore.” This is a bold claim. Sometime in 2023, Miromatrix plans to begin a first-of-its-kind human trial of the bioengineered organ to try to prove it. If the Food and Drug Administration agrees, the initial use will take place outside the patient’s body.

Researchers will place a pig-made human liver next to a hospital bed to temporarily filter the blood of someone whose own liver has suddenly failed. And if that novel “liver assist” works, it would be an important step toward eventually attempting a bioengineered organ transplant—perhaps a kidney. A transplant chief at New York’s Mount Sinai Hospital, one of several hospitals already planning to participate in the liver-assisted study. “It’s probably more than in the near future xenotransplantation,” or transplanting animal parts directly into people.

More than 105,000 people are on the waiting list for organ transplants in the US. Thousands will die before their turn comes. Thousands of people are never included in the list, which is considered a very long shot. “The number of organs we have available will never be able to meet the demand,” said Dr. Amit Tevar, a transplant surgeon at the University of Pittsburgh Medical Center. “It’s our frustration.”

So scientists are looking at animals as another source of organs. A Maryland man lived two months last January after receiving the world’s first heart transplant from a pig — an animal genetically modified so that its organs would not trigger an immediate attack from the human immune system. The FDA is considering whether to allow additional xenotransplantation experiments using kidneys or hearts from gene-edited pigs.

Bioengineering organs are clearly different – no special pigs are needed, just leftover organs from slaughterhouses. “This is something that in the long run could contribute greatly to the development of organs that we can use in humans,” Tevar of Pittsburgh said. He’s not involved with Miromatrix — and cautioned that the planned test outside the body would be only a preliminary first step.

The mirometrics approach stems from research in the early 2000s, when regenerative medicine experts Doris Taylor and Dr. Harald Ott, then at the University of Minnesota, led the way in making a dead rat heart completely decellularized. The team seeded the resulting scaffold with immature heart cells from baby mice, which eventually greenlit the tiny organ, garnering international headlines.

Fast forward, and now the university’s byproduct Miromatrix has rows of large jugs pumping fluids and nutrients into the liver and kidneys at various stages of their metabolism. Ross said that isolating pig cells removes some of the risks of xenotransplantation, such as hiding viruses or hyper-rejection from animals. The FDA already recognizes decellularized pig tissue as safe for another purpose, using it to make a type of surgical mesh. More complex is getting human cells to handle.

“We can’t take billions of cells and push them into the organ all at once,” Ross said. When inserted slowly, “the cells crawl around and when they see the right environment, they stick around.” Source of those human cells: Donated liver and kidneys that will not be transplanted. Nearly a quarter of kidneys donated in the US last year were discarded because hospitals often refuse organ transplants that are less than complete, or because it takes too long to find a matching recipient.

As long as enough cells are still functioning when donation groups offer an organ, Miromatrix biologists isolate the usable cells and multiply them in laboratory dishes. From a salvaged human organ the company says it can grow enough cells to repopulate the scaffolds of several pigs’ livers or kidneys, cells responsible for different functions – for example building blood vessels or filtering waste. Kind. In 2021, researchers from Mirometrics and the Mayo Clinic reported successfully transplanting a version of the bioengineered liver into pigs.

This set the stage for testing “liver-assisted” treatments similar to dialysis, using bioengineered livers to filter the blood of people in acute liver failure, a life-threatening emergency. Doctors no longer have much to offer other than supportive care, unless the person is lucky enough to get a rapid transplant. “If you can just get over the hump, you really can be fine” — because the liver is the only organ that can repair itself and regrow, Mount Sinai’s Florman said. “I’ll be excited when they enroll their first patient and I hope it’s with us.” It is unclear how soon testing could begin.

The FDA recently told Mirometrics that it had questions about the study application. If the liver experiment works outside the body, what happens next? Still more research aims to one day attempt to transplant a bioengineered organ – possibly a kidney, as the patient can survive with dialysis if the operation fails. Dr. Ron Shapiro, a kidney transplant specialist at Mount Sinai, said that while kidney regeneration is not far off, “I was completely stunned by the progress so far.” Years to receive a kidney and likely who would be right on the list for such experiments” – waiting if they come in time.