Defending implants from diabetes
James Chow and Aggie Simionescu examine a heart valve. Photo by Craig Mahaffey.
It is difficult enough to engineer a matrix populated with stem cells, and use it to replace a body part. It is difficult enough to design that matrix to fade slowly away as the patient’s own tissues and cells take over and make the part their own. But if the patient has diabetes, the degree of difficulty goes way, way up.
“We can barely make this work in a healthy, normal patient,” says James Chow, a Ph.D. student in Agneta Simionescu’s lab. “In a patient with diabetes it would fail catastrophically.”
Chow, who plans to finish his Ph.D. in May, has been working with Aggie Simionescu for years, ever since he took a course from her in bioengineering. In the simplest terms, his goal has been to develop matrix-based constructs that can resist the onslaught of diabetes, to help patients survive.
To understand what’s at stake, consider what diabetes does. It attacks tissues and cells with inflammation and oxidation, crosslinking proteins and disrupting the functions of cells. Chaos ensues. “The cells lose their identity and their function,” Chow says.
He finds evidence that this onslaught may also involve a Maillard reaction, the same chemical process that browns meat in a frying pan. In a diabetic body, sugars react with amino acids, crosslinking in a way that stiffens the tissues. Blood vessels are especially vulnerable, so a classic symptom of diabetes is circulation failure that damages or kills tissue. Today, the ravages of diabetes are so widespread that demand is huge for replacement veins, arteries, and other components of the circulatory system.
But against a monster like diabetes, a vulnerable new implant would stand very little chance. Chow and Aggie Simionescu think they may have found a silver bullet. It’s an antioxidant known as PGG (pentagalloyl glucose), a natural polyphenol similar to the antioxidant compounds in green tea. At Aggie’s suggestion, Chow found ways to introduce PGG into the extracellular matrix the team uses to engineer a construct. PGG, he found, could attach itself to the matrix and hang out there long enough to protect the scaffold from attack while the wound healed and tissue regenerated. After several months, PGG detaches itself and gets out of the way.
“We’ve shown that PGG inhibits harsh inflammation,” Chow says. “It’s like this perfect antioxidant that can slow down or fight the reactive oxygen species that damage tissue.”
He has tested this process by preparing constructs with and without PGG and implanting them under the skin of laboratory rats. In the implants treated with PGG, the matrix survived, and PGG-treated constructs populated with stem cells developed normally.
It’s the combination of PGG and stem cells that shows the most promise, Chow says. The stem cells, he explains, not only help form new tissue; they also help integrate the implant into the body by modulating the immune response and promoting anti-inflammatory agents that enable the growth of new tissue.
For all of this work, Chow says, he depends on collaborating surgeons and clinicians, especially those from the Greenville Health System, who keep the work grounded in the real-world practicalities of patients and treatments. He works closely with Dr. John Bruch, an endocrinologist, and with Dr. Christopher Wright, a cardiovascular surgeon, and several other clinicians contribute, as well.
“We’re trying to make tangible, off-the-shelf products,” Chow says. “This is what we call translational medicine, not just science for science’s sake.”
Chow plans a career in industry, developing medical devices, and he says his experience running a project in the lab has prepared him well. It’s an entrepreneurial endeavor, with many of the complications of running a business.
“You learn to manage a project through all of its cycles, meeting goals, training the students, writing grants, and presenting your work,” he says. “Aggie and the clinicians are there to advise me, but it’s truly my own project.”