Aug. 31, 2001 DURHAM, N.C. -- Duke University Chemistry Department researchers are creating unique polymers out of naturally occurring building blocks that don't provoke immune reactions and in some cases also biodegrade in the body. The tree-like, globular-shaped substances are being evaluated for a variety of medical uses.
Called biodendrimers, these structures are prepared by systematically reacting acids with alcohols to form what chemists call "esters." The results are branching molecular chains with finger-like ends that can form sticky and tenacious links with other substances.
These characteristics make them "ideal candidates for medical and tissue engineering applications," said Mark Grinstaff, the assistant chemistry professor who heads the Duke team. One potential application, which Duke Medical Center eye researchers are beginning to test, is a glue that could "close a wound and then be dissolved as new tissue grows in to repair the wound site," he added in an interview.
"It could really potentially change the way we do corneal surgery," added Dr. Terry Kim, associate director of the Corneal and Refractive Surgery Service at the Duke Eye Center and a medical center assistant professor of ophthalmology.
Another possibility, which biomedical researchers at Duke's Pratt School of Engineering have also started investigating, would be using such biodendrimers as scaffolding to help induce cells to repair damaged human joints.
"Biodendrimers appear to interact with cells in completely novel manners," said Lori Setton, assistant professor and Harold L. Yoh Faculty Scholar in the Pratt School's Department of Biomedical Engineering. Because of its promise, Grinstaff's research just received $250,000 in funding from the Johnson & Johnson Focused Giving program, established to stimulate exploration in medical science. Other funding sources include the Pew, Sloan and Dreyfus foundations.
In a spring 2001 issue of the Journal of the American Chemical Society, Grinstaff and graduate student Michael Carnahan described the synthesis and characterization of one of these dendrimers, made from glycerol and lactic acid.
He, Carnahan and other graduate students also discussed research on several dendrimers during the American Chemical Society's national meeting in Chicago Aug. 26-30.
"It's an exciting time," he said. "We've finally gotten to the point where we're able to make the molecules, characterize them and understand their physical properties. Now we're exploring opportunities for applications."
Almost all prior work of this type has involved simpler chain-like molecules called linear polymers. Those "constitute a class of materials well suited for research and clinical applications ranging from drug delivery to tissue engineering," Grinstaff and Carnahan noted in their Journal of the American Chemical Society article.
Linear polymers already are being used as surgical sutures that can be degraded and absorbed by the body, their article added. They are candidates for orthopedic applications such as screws, pins and scaffolds, for pharmaceutical uses such as drug delivering hollow spheres, and for surgical applications like staples and dressings.
However, the new compounds offer potential advantages to linear polymers, notably because of biodendrimers' large surface areas and their many finger-like projections, called "end-groups." They are also easily dissolved and mixable, flow easily and can be sticky. And their thickness and degree of solidification can be controlled with laser light.
At Duke Medical Center, Kim's research group is currently evaluating biodendrimers as possible protective sealants for painful perforation wounds to the cornea, the eye's clear protective cover. These perforations represent "full thickness holes in the cornea," Kim said. "Currently as corneal surgeons we have a lot of limitations on how to repair these. They can be very difficult to close with conventional suturing."
Fast and complete wound closure is important to curb pressure-reducing fluid loss and infection, Kim noted. Corneal perforations can also lead to "cataract formation, among other things," he said. "And you can potentially lose the eye if its structural integrity is not restored promptly."
Currently, physicians may use tight-bonding cyanoacrylate glue to seal small perforations, which then heal on their own. But when that glue dries "it gets very hard and can be very difficult to apply on corneal wounds," Kim said. It also becomes opaque. Even though that hard and cloudy coating eventually drops off, it can be uncomfortable in the meantime.
In contrast, solidification rates of biodendrimer glues can be controlled by using an argon laser beam. "We can control how hard we want it," Kim said. "It's a glue that's very soft. And it's very easily put into the wound." This glue also remains clear as it dries. "So far our work looks very encouraging," continued Kim, who also envisions the possibility of using biodendrimer glues to reduce or even eliminate the need for sutures in corneal transplant surgery.
While evaluations at the Pratt School of Engineering are at an earlier stage, Setton's soft tissue engineering group is already finding that Grinstaff's biodendrimers present cells with "a different chemical surface and overall three-dimensional topography" than other polymers do, she said.
Setton hopes further investigation will show that, when applied to damaged joints, these biodendrimers will serve as an effective scaffolding for a matrix of new repair tissue to grow on. "It's too early to tell," she noted.
Grinstaff's group has been creating these biodendrimers by reacting the alcohol glycerol with not only lactic acid but also caproic and succinic acid. "The way we synthesize these is we start from the center and we grow the shell outward," he said.
The biodendrimer thus builds up in step by step increments. In each increment, Grinstaff's team makes additional molecular bonds by freeing some glycerol to interact with acid in an "esterification" reaction. Meanwhile, the rest of the alcohol is kept under chemical lock and key. After more alcohol is freed through a "deprotection" reaction, the next esterification reaction proceeds, making yet more chemical bonds.
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