“In America today, and across the world, we are at a severe shortage of transplantable organs,” explained Jeff Ross, PhD at the Bay Area Biomedical Device Conference held on March 28. In the United States, there are about 900,000 individuals die of heart disease each year. The number of hearts that are transplanted in this country is much lower: approximately 2300 annually.

Brian Buntz

April 3, 2012

5 Min Read
Moving Tissue Engineering to the Next Level by Creating Whole Organs

For lung cancer patients, lung transplants are similarly hard to come by. In 2007, 6494 U.S. patients were recipients of lung transplants. That same year, lung cancer claimed the lives of 158,683 people in the United States in 2007, according to the CDC. The situation for patients in need of liver, kidney, and pancreas transplants is similarly bleak.

perfusion decellurization

The above image from Miromatrix shows the ability of perfusion decellurazation to preserve structure of a porcine heart. 

Tissue engineering could prove to be an alternative to organ harvesting by enabling the creation of whole organs with vasculature that is intact. Typical tissue engineered products rely on angiogenesis—the body’s own capacity to regrow blood vessels from pre-existing vessels. An example of such a product are tissue scaffolds from porcine or bovine origin that have been completely decellurized. These scaffolds can be implanted in procedures such as hernia repair and breast reconstruction. The body then resorbs them.

While there are tissue-engineered products on the market that are more complex than such scaffolds, they too rely on angionesis, said Ross, who is the vice president of product development of Miromatrix Medical (Eden Prairie, MN).

A Different Approach

To engineer complex tissues, a different approach is needed than the traditional approach, which is is based on isolating cells, growing them in cell culture, and then having a matrix that they are reseeded back onto. “We are still incredibly limited in how revascularized we can create a tissue itself,” Ross said. But to take tissue engineering to the next level to create whole organs and tissues requires that they have a functional vascular network. “From early on in development, one of the first thing that grows and innervates as all of our organs develop is the vascular supply,” Ross said.

Organs, however, are, not surprisingly, complex. And engineering organs from scratch would be a feat. It would require understanding how the organ is composed, including the ratios of collagens, concentrations of the cytokines, thorough understanding of the vascular network, and so forth. “Unfortunately, we don’t understand that yet,” Ross said.

But nature is so good at creating vascularized organs, why not tap into her power to help create them? That is the strategy behind perfusion decellularization. Take an organ with natural vasculature intact, flow a solution through it that only removes the cellular material, leaving the extracellular matrix in its wake. The matrix can then have the organ recipient’s stem cells seeded back onto it.

There is a severe shortage of donated organs in the world. This image, dran from Wikipedia, shows a transplanted heart positioned in the thorax of patient.

The researchers generally use porcine organs because of their similarity to human organs and the fact that harvesting organs from that source offers tighter controls than from human cadavers. “We can get six-month-old swine each and every time, and this technology could still be used for a [human cadaver] but with a cadaver you are going to be getting tissue from 20-year olds all the way to 80 with every disease state in between,” Ross said. “From a quality control standpoint, it is going to be very variable.”

Researchers at Miromatrix have performed this procedure with a porcine heart and then reattached it back up to the vascular supply. Blood was able to flow through the heart because the vascular network is still intact.

The company has also used to process in a number of other organs, including liver, lung, kidney, and pancreas. “We can use this technology for pretty much any vascularized tissue and decellularize it,” Ross said.

 A number of different methods have been explored to recellurize tissue or organs in the procedure. “But the way that has been the most beneficial at this point, which has actually been somewhat of a surprise, is to perfuse the cells back in back through the vasculature.” When introduced in this manner, cells naturally home to their native micro-environment. “If you put in five different cell populations in the heart or the twelve cell populations in the lung, you start to find them [distributed] where you would normally find them [in nature].” This isn’t entirely surprising, Ross explained, because cells are programmed to like certain environments.

Budding Interest 

In the last four years, more than 20 publications and many major universities are investigating the use of the technology. “For the first time, it really enables tissue engineering to the next level. It is the ultimate scaffold. We’ve spent a lot of time characterizing stem cells. We know all of the surface markers, we know all of these populations, now this is a scaffold to try to sort of enable this.”

“A future without organ waiting lists is really possible, I believe.” 

Some of the early feasibility and proof of concept of the technology have been impressive, confirming the technology’s ability to preserve vascular organs’ mechanics, Ross said. In studies at, Massachusetts General Hospital (Boston) have decellurized a rat lung, perfuse cells back into it, and keep that in a bioreactor for 14 days. Afterwards, and transplant it back into a rat model and have it function for 14 days. Similar pancreas studies have also been promising. 

Miromatrix is currently investigating the use of the decellular vascularization to treat liver disorders. At present, the company is working on vascular liver grafts that could be linked up with the liver's native vasculature. 

Once such grafts are on the market, whole organs are likely to follow. 

"A future without organ waiting lists is really possible, I believe," Ross said. 

Brian Buntz is the editor-at-large at UBM Canon's medical group. Follow him on Twitter at @brian_buntz.

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