Scientists have been working diligently to create engineered tissue implants to repair or replace damaged or diseased tissue and organs; but their success hinges on the ability to build a sturdy connection linking the implant’s blood vessels and the patient’s existing vasculature. National Institute of Biomedical Imaging and Bioengineering (NIBIB)-funded researchers at Boston University have created segments of engineered blood vessels to address this often overlooked, but critically important issue. The new bioengineered blood vessels are the smallest yet that are also strong enough to be used in parts of the body where exceptionally tiny blood vessels are needed, such as the fingers. The technique was reported online in January in the journal Tissue Engineering.
 
“The ability to link an engineered tissue to a patient’s circulatory system is as important as creating the implant itself,” said Rosemarie Hunziker, Ph.D., director of the NIBIB program in Tissue Engineering. “The plumbing fails unless all of the pipes are effectively connected. So, this study is key because they have developed a “linker” that has properties compatible with natural human blood vessels and is also easy to manipulate. It is an important accomplishment.”
 
The Boston University team developed a method that uses collagen tubes to make these critical connections. They demonstrated that their collagen constructs were compatible with a rat’s vascular system and connected seamlessly, without leaking or causing blockage. In addition, the research focuses on connecting very small arteries, which is particularly difficult and is needed for attaching artificial implants as well as delicate replantation surgeries where a patient’s damaged tissue must be reconnected or repaired. Tissue damage from traumatic injuries often leaves many small stubs of blood vessels that need a linking segment to successfully reconnect the tissue to the vasculature.
 
The new technique is able to produce grafts with diameters smaller than previously possible, allowing them to be connected to tiny arteries in the body, like those in the fingers. “If you needed some sort of bridge to connect the circulation of a severed finger to the intact circulation of the patient then you need to be able to create grafts at around the one millimeter scale,” says Joe Tien, Ph.D., professor of biomedical engineering at Boston University and senior author of the paper. “And there’s not really much known about trying to create an artificial graft that small.”


 
Using collagen, Tien and his team discovered an easy way to make such a graft; it’s a matter of drying. Collagen is a natural substance found in the body, so it’s compatible, and cells are able to adhere and grow on it with less risk of an adverse reaction compared to synthetic materials.
 
Because collagen is normally very dilute—it’s 99 percent water—a common technique that binds proteins to each other to add stability and strength, known as crosslinking, didn’t work since there weren’t enough solid materials to connect. But Tien’s group discovered that drying a large piece of collagen on a small, rotating rod, “like a rotisserie for a chicken,” said Tien, makes it shrink down to the very small diameter of the rod, becoming more dense in the process. The resulting structure can then be crosslinked, adding the critical additional strength.
 
The combination of drying and crosslinking was the key to the team’s success. When they implanted the collagen tubes in rats, they were able to attach them to the rat’s circulation and demonstrate that the tubes sustained normal blood flow for twenty minutes and displayed strengths similar to an artery in a rat’s leg.
 
“It’s actually a very simple technique,” said Tien.
 
“Dr. Tien is being modest here,” said Hunziker. “While the answer may have been ’simple,’ getting there required a thorough understanding of the physics and physiology of the body.”
 
Next, the team hopes to extend the time the grafts can maintain unobstructed blood flow. Bare, empty tubes are likely to lead to blood clot formation, but tubes lined with endothelial cells, which naturally line blood vessels, reduce the risk of clotting. The team has already demonstrated the ability to line the tubes with endothelial cells, which grow well on the collagen. They will next test to see how the system responds to lined tubes long term and if these artificial vessels display irregularities, degrade, or fail for any reason.
 
Tien is excited about being able to implant—and connect—engineered tissue that has its own vessels. “To us that is the Holy Grail,” he said. “It is what we have been working to achieve for the last fifteen years: to be able to create engineered, vascularized tissues that can be surgically connected to a host circulation.”