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It weighs 3 to 4 pounds, includes seven different cell types and features an intricate web of blood vessels that help it filter toxins, guard against pathogens, metabolize nutrients and carry out hundreds of other biological functions.

The human liver, experts say, is an architectural wonder. But its complexity has also made it immensely difficult to replicate in the lab.

Now, a multi-institution team, including scientists at the ������ý����, MIT, Harvard and Columbia universities, is taking on the challenge. Supported by a new five-year, up to $25 million award from the Advanced Research Projects Agency for Health (ARPA-H) Personalized Regenerative Immunocompetent Nanotechnology Tissue () program,��they’re working to develop 3D-printed liver tissue made of human cells and able to be transplanted into anyone without their body rejecting it.����

An AI generated illustration of a liver. Adobe Stock photo

“There are many patients out there that either never get a transplant or are stuck on the waiting list for years,” said Jason Burdick, a professor of chemical and biological engineering whose lab at CU’s BioFrontiers Institute will lead the 3D printing part of the project.��

“If there were an off-the-shelf alternative, once a patient needs a liver they could get a transplant almost immediately,” he said. “That’s our goal.”

Organs on demand

About have been diagnosed with liver disease, and about 52,000 die annually of liver failure. At any given time, roughly 15,000 people in the U.S. are on the transplant list, with waits ranging from .

Patients who do get a transplant from a cadaver or living donor must take drugs to keep their immune system from rejecting it. Those medications come with their own health challenges, and sometimes the body rejects their new liver anyway.

Above, research associate Matt Davidson looks at a liver organoid under the microscope. Below, Left to Right: Makhoul, research associate Megan Cooke, Professor Jason Burdick and Davidson in the lab.

In 2024, ARPA-H launched the Personalized Regenerative Immunocompetent Nanotechnology Tissue (PRINT) program, an ambitious, fast-track endeavor driven by a single question:�� “ any organ on demand?” The PRINT program is led by ARPA-H Program Manager Ryan Spitler, Ph.D.

In January, the agency announced the ImPLANT project team (short for Immunoshielded Printed Liver Assist NeoOrgan for Transplant). Led by Harvard University’s Wyss Institute, the project brings together a dream team of the world’s leading experts in synthetic biology, transplant immunology, vascular engineering and 3D bioprinting to develop life-like replacements for the body’s largest organ.

“We all recognize the moonshot nature of the program and are thankful that ARPA-H is making it possible,” said Chris Chen, M.D., PhD, the ImPLANT project’s principal investigator (PI) at the Wyss Institute.

How to make an organ

Standing at a microscope in the Burdick Biomaterials and Biofabrication lab, research associate Matt Davidson zooms in on a tray of spherical cell clusters known as�� ‘liver organoids.’

In the room next door, research assistant Jonathan Makhoul switches on a glistening white 3D printer which uses a sharp tool, akin to a sewing machine needle, to print delicate channels deep within a vat of gelatin-like liquid known as a hydrogel.

While these are early days, the effort to manufacture a liver is well underway.

The process goes like this:

Through a technique pioneered at MIT, induced pluripotent stem cells — adult skin or blood cells that have been modified to have the capacity to become any kind of cell— are programmed to become all the different types of liver cells. (Soon, researchers hope to be able to genetically engineer those cells to also evade immune rejection by patients, making them universally compatible.)

Burdick’s team takes clusters of those cells, or liver organoids, and amasses them into larger, tissue-like structures. Then they deploy a novel 3D-printing technique called ‘suspension printing’, pioneered in his lab.

“Rather than building up a three-dimensional structure layer by layer, like most 3D printers do, we can now take a bath of material— in this case organoids suspended within a hydrogel — and print an ink directly into that three-dimensional volume,” said Burdick.��

Once the ‘ink’ is washed away and cells migrate to those channel walls, it leaves intricate webs of blood vessels behind.��

Producing liver tissue at scale

Ultimately, when a patient needs a new liver, that tissue could then be implanted and sutured in place, its vessels lining up with those connecting it to the rest of the body.

Much like patients seeking a knee replacement today, those seeking a new liver could basically order the part off the shelf.

Of the up to $25 million allocated to the team, about $3.5 million will go to CU ������ý����.

Within a few years, the team hopes to be embarking on animal studies.��

Meanwhile, collaborators at Columbia will be developing new bioreactor technologies and manufacturing processes to produce liver cells, organoids and tissues at scale.

If all goes according to plan, clinical trials could be underway within five to 10 years, said Burdick.

“We are all experts in our own fields with many years of research behind us,” said Burdick. “Now that we can combine all of our expertise with enough funding and support to really push the program forward, I’m confident that we can develop new therapies based on 3D printed livers to truly help patients.”��

"Research reported in this publication was supported by the Advanced Research Projects Agency for Health (ARPA-H) under Award Number D25AC00322-00. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Advanced Research Projects Agency for Health."��