Biomedical researchers at Purdue University have developed a material from pigs' intestines that, when inserted into the human body, may help it reconstruct a variety of damaged tissues, such as torn ligaments or tendons, diseased urinary bladders, or severely burned skin.
"The fundamental principle behind this material is that once inserted into the body, it gets broken down and rebuilt into something that resembles the original tissue or organ," says Dr. Stephen F. Badylak, director of research for Purdue's Hillenbrand Biomedical Engineering Center and coordinator for the project.
The Purdue group, in conjunction with Methodist Hospital in Indianapolis, has received four patents to use the material in human beings. The researchers also are working with several companies to develop these applications. Human trials on some applications may begin within a year.
Badylak will present results from recent laboratory and animal studies at the meeting of the Society of Basic Urological Research at Stanford University Oct. 20-23.
The new material, called SIS for small-intestinal submucosa, is derived from a middle layer of the small intestine of pigs. Once this layer of intestine is removed, it can be sterilized and molded into different forms, such as tubes or sheets, or stored for future use.
Though SIS comes from a biological source, the studies to date indicate there are no problems with rejection.
"Although the tissue is certainly foreign to the recipient, our research group has been unable to measure any cellular or clinical adverse response," Badylak says.
What sets SIS apart from other biomaterials is that its structure, the unique arrangement of proteins and other molecules, is taken directly from nature, Badylak says.
"We're using a mixture of molecules developed and organized by Mother Nature," he says. "SIS is a composite of connective tissues that include collagen and proteins and various other bioactive molecules that we have not fully characterized."
Animal studies show that, when inserted into a body, these molecules are capable of interacting with host cells, sending and receiving signals that tell the material how to "perform" like the original tissue and encouraging neighboring cells to migrate.
This interaction may be what allows SIS to remodel itself once it is implanted in the body, Badylak adds, noting that studies are now under way to analyze this signal-sending process and identify the properties that allow remodeling to occur.
Though the intestinal lining that gives rise to the raw material for SIS is very thin -- 80 microns, or about 15 red blood cells thick -- the material is extremely strong, Badylak says.
Once the material is rebuilt within a body, it has the ability to strengthen in response to stress, much like natural tissue. This ability to gain strength makes SIS ideal in orthopedic applications such as replacement material for damaged ligaments and tendons, says Badylak, who also serves as head physician for Purdue's athletes. Torn or damaged ligaments and tendons, the fibrous tissues that connect bone, cartilage and muscle, make up the bulk of sports-related injuries.
The Purdue research team now is working with DePuy Inc. of Warsaw, Ind., to develop SIS ligaments that would be suitable for human trials.
Such ligaments may be used to treat "blowouts," knee injuries that involve damage to a ligament that runs from the femur, or thigh bone, to the tibia, which is the bone below the knee.
"This can be a career-ending injury for many athletes," Badylak says. "The surgical procedure used to treat this problem usually involves taking a piece of connective tissue, or tendon, from a separate location in the same knee and replacing the injured ligament. This procedure can be as traumatic to the patient as the ligament tear."
Other treatments currently used for this type of knee injury include replacing damaged ligaments with synthetic fibers. Badylak says synthetic implants tend to fail or weaken over time.
Studies in dogs and rabbits have shown that with SIS, the opposite is true. When damaged ligaments are removed and replaced with long, thin strands of SIS material, the replacements form fibrous bundles of cells and become stronger over time. The SIS material is anchored to the bones through small holes drilled for this purpose.
"The SIS implants start out weaker than synthetic ligaments, but become heavier and stronger with use, just like natural muscle," Badylak says.
Once they have developed a ligament for knee injuries, the Purdue-DePuy team plans to expand applications for SIS into other orthopedic areas such as tendons and other muscular and skeletal soft tissue applications.
"We may even get into some hard-tissue applications like bone or cartilage," Badylak says.
The Purdue group also is exploring uses for the material in treating urological problems. Animal studies in dogs, pigs and rats indicate the material may be liquefied and injected into sphincter muscles to help strengthen or add bulk to such muscles in patients with incontinence. The material also has been used in animals to create replacement bladders.
The idea of using small intestines to develop biological materials was born eight years ago, when biomedical researchers at Purdue were studying ways to build new types of vascular grafts, or blood vessels, Badylak says.
"Synthetic materials have been used for decades to replace blood vessels, but these materials are foreign to the body and can induce blood clots," he explained. "While brainstorming ways to overcome this problem, someone in the group recalled that blood rarely clots in the small intestine."
The group investigated various ways of applying material from the small intestine, and found that the middle layer, stripped of its mucosal and muscle layers, could be used to form blood vessels that resist clotting in most locations. That application still is being pursued, Badylak says.
The group then went on to pursue other applications. The possibilities include:
SIS also might be used to connect synthetic implants to the body, Badylak says.
"In many cases, the body will develop scar tissue or 'wall off' a synthetic implant once it has been introduced into the body," he explains, "Such scars can interfere with nerves, blood vessels and muscles. SIS might be used to incorporate implants into the body's own tissue, thus avoiding scarring and any subsequent problems."
Badylak says the cell-signaling process that occurs in remodeling may be similar to that which occurs during embryonic development, when cells use biochemical signals to take on a particular form and create tissues and organs for specific tasks.
"Each cell contains a tremendous set of instructions within the DNA, and, given the proper signal from a neighboring cell or molecule, a cell can summon forth instructions to differentiate into a specific type of cell," Badylak says. "Embryonic cells are especially adept at using these signals to heal wounds and construct new tissues."
At some point in development, generally after a cell has become specialized, this ability to remodel itself into different forms is limited, Badylak says.
"Even though we don't fully understand this process, our studies indicate that the SIS material is utilizing some of those signals that have been dormant for a long time," he says.
Badylak received his doctor of veterinary medicine, master's and doctoral degrees from Purdue, and his doctor of medicine degree from Indiana University.
The research at Purdue's Hillenbrand Biomedical Engineering Center is funded by Purdue and a variety of sources, including the National Institutes of Health and Human Services, DePuy, Methodist Hospital, Senmed Medical Ventures of Cincinnati, and Eli Lilly and Co.
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