Ten years ago, two US researchers attempted to create a totally human-derived substitute to the synthetic blood vessels commonly used in dialysis patients. Since then, they have accomplished that and have developed a range of medical-textile-making techniques to weave together blood vessels.
“There were a lot of doubts in the field that you could make a blood vessel, which is something that needs to resist pressure constantly, 24-7, without any synthetic materials in it,” explained Dr. Nicolas L'Heureux, a co-founder and the chief scientific officer of Cytograft Tissue Engineering, Inc. (Novato, CA, USA). “They didn’t think that was possible at all.” But that was not the case. Cytograft, which Dr. L'Heureux and Todd McAllister co-founded in 2000, has indeed developed vessels that are “completely biological, completely human, and living, which is the Cadillac of treatments...and it seems to work really well,” Dr. L'Heureux stated.
The researchers first created blood vessels from patients’ own skin cells. Then, in June 2011, the company reported that three dialysis patients had received the world’s first lab-grown blood vessels made from skin cells from donors, which eliminates the long lead time needed for making vessels from a patient’s own cells. Moreover, now Cytograft has developed a new technique for making human textiles that promises to reduce the production cost of these vessels by half.
Dr. L'Heureux presented his team’s latest findings April 23, 2012, at the annual meeting of the American Association of Anatomists, which was held in conjunction with the Experimental Biology 2012 meeting in San Diego, CA, USA.
Cytograft’s new application builds on what already has been shown to be effective. In 2005, the scientists started extracting fibroblasts from patients’ own skin, cultured those cells into thin sheets, rolled up those sheets, cultured them some more so that they would fuse together, and implanted the lab-grown cylindrical vessels. The vessel-growing process was long, approximately seven months, but, because the vessels were derived from the patients’ own cells, the implants were easily accepted by the patients’ bodies, and they held up to the rigors of dialysis process, which requires repeated punctures with large-gauge needles.
Then the researchers created allogeneic vessels with the hope that they were laying the foundation for an off-the-shelf stockpile of 100% human replacement parts. “By combining these two methods we could make something that is allogeneic, cheaper to produce, and that you could store forever, meaning that the clinician can pull it off the shelves whenever they want,” Dr. L'Heureux explained. “If it is frozen and allogeneic, that is kind of the homerun.”
Those donor-based vessels were implanted into three patients in Poland, and they have performed well with no signs of rejection. That achievement was huge, from a manufacturing perspective, Dr. L'Heureux noted, because “it is very, very costly to segregate all the patients’ cells at all the steps with all the material and all the media and the culturing zones.”
Although using donor cells drastically decreases costs, putting the price tag of a lab-grown human vessel somewhere between USD 6,000 to USD 10,000 (although this will drop with automation and volume), it does not shorten the manufacturing time all that much, because the culturing of the cells so that they fuse together takes many months. Therefore, the researchers determined it was time to try out an idea they had been putting together for some years: human textiles.
Today, the Cytograft team is deconstructing the sheets of cultured cells into threads and then using a range of medical-textile-making techniques to weave together blood vessels. Most medical textiles used today are made of permanent synthetic fibers, such as polyester.
“They weave synthetic threads to create patches, for example, for blood vessels ... and they can make a large blood-vessel replacement conduit that they use for arterial repair. They can use patches for hernia repair,” Dr. L'Heureux explained. “What we are doing here is using a completely biological, completely human--and chemically nonprocessed in any way--fiber from which we can now build all kinds of structures by weaving, knitting, braiding, or a combination of techniques.”
According to Dr. L'Heureux, once the cell sheets are grown, the weaving of these human textiles into a vessel takes only a couple of days, even with the prototype loom currently in use at the Cytograft lab. Additionally, the threads of cells, while more delicate than synthetic fibers, are strong. “It is not like your grandmother with the little knitting pins,” Dr. L'Heureux stated. “It is much faster than that. Basically, the time it takes for making the threads and assembling them in a blood vessel is negligible compared to the time that it took you to make the sheet.”
Dr. L'Heureux noted that, having demonstrated that vessels grown from donor cells are a good, natural alternative to synthetic vessels, it’s time to roll out “a treatment that is more streamlined and more cost effective,” and this third-generation woven allogeneic blood vessel could be the solution. “We just came to a point where we had proved a lot of what we could do with our blood vessels and it made sense to find a way to make it faster. And this weaving method that makes the vessel out of the same material that we used in the sheet makes it ready in about a third of the time that it took before,” he said.
Moreover, weaving actually produces a more robust vessel than one that has been cultured in a cylindrical shape. “There is no seam, which is a problem when you roll something--there’s always a flap on the inside and a flap on the outside, and you need to be sure that these flaps are really well fused with the rest, and that takes a long time for the cells to do,” Dr. L'Heureux remarked. The research is still in the early stages, and an animal trial revealed promising findings. For one thing, the woven vessel has proved to resist puncture, “which is important for dialysis.”
From the beginning, Cytograft’s team has focused primarily on the lab-grown vessels’ use in dialysis patients, “because that’s where the largest need is,” Dr. L'Heureux said. But they could be used in a variety of patients. Babies with congenital heart defects, for instance, need replacement vessels that can grow and change. Heart bypass patients now endure the frequently painful recovery associated with removing a vessel from one part of the body for implantation elsewhere, and a lab-grown and -woven one could eliminate the need for the first surgery.
Furthermore, human-based replacement vessels are far less prone to infection than synthetic ones, Dr. L'Heureux emphasized. “With synthetics, one of the big drawbacks is that they get easily infected. What happens is that the synthetic harbors microbes, and immune cells can’t deal with the synthetic. They can’t grab it. It’s like chasing a dog on an ice rink.” Immune cells, meanwhile, can recognize and interact with the lab-grown tissue since it is completely biologic.
In spite of the uncertainties about Cytograft’s research in the early days, there is a move now for finding natural alternatives to synthetics, in part because of the infection risk, Dr. L'Heureux said. “Today, 15 years later, the goal of eliminating synthetic materials from tissue-engineered products has become pretty mainstream.”
Cytograft Tissue Engineering