New way to create a permanent chemical bond between antibiotics and titanium

Sep 26 2005

Infections associated with inserting a medical device can be devastating, painful, and cause prolonged disability, costing tens of thousands of dollars.

Now, researchers at Jefferson Medical College have found a way to create a permanent chemical bond between antibiotics and titanium, a material used in orthopedic implants. The proof-of-principle study showed that an antibiotic can be connected to the titanium surface in an active form, and can kill bacteria and prevent infection. The work is a critical first step toward developing stable, bacteria-resistant implants to combat infection.

"The biggest benefit of this work is to keep the infection from ever starting," says Eric Wickstrom, Ph.D., professor of biochemistry and molecular biology at Jefferson Medical College of Thomas Jefferson University, who in collaboration with Noreen Hickok, Ph.D., associate professor of orthopedic surgery at Jefferson Medical College and Allen Zeiger, Ph.D., professor of biochemistry and molecular biology at Jefferson Medical College, developed the bonding method.

Infections associated with orthopedic implants are one of the major causes of implant failure. If bacteria grow on an implant, it can't knit properly with bone. "Our technique puts a bed of antibiotic nails on the surface of the implant," Dr. Wickstrom says. "The first time a bacterium lands on those nails, it dies."

The researchers, along with co-authors Binoy Jose, Ph.D., a former postdoctoral fellow now at SK Biopharmaceuticals, and M.D./Ph.D. student Valentin Antoci, Jr., report their results September 23, 2005 in the journal Chemistry and Biology.

In the work, the scientists fastened the antibiotic vancomycin to titanium powder. The vancomycin could then immediately kill bacteria sensitive to vancomycin that landed on the titanium.

The researchers checked to see if vancomycin was indeed attached to the titanium surface using microscopy. Next, they added a fragment of bacterial cell wall to see if the vancomycin on the powder, or beads, could bind to its natural target. The tests proved that the vancomycin was bound and active.

Finally, they added bacteria and showed that titanium beads with vancomycin on the surface killed the bacteria. When the beads were exposed to more bacteria, the vancomycin continued to kill the new infection. The vancomycin was not only chemically bound, but aggressively curtailed re-infection as well.

The researchers, led by Irving Shapiro, Ph.D., professor of orthopedic surgery at Jefferson Medical College, and including collaborators at the Rothman Institute at Jefferson and the University of Pennsylvania are supported by a grant from the U.S. Department of Defense to develop techniques to protect titanium surfaces with antibiotics.

"The recent results are another step toward our ultimate goal of preventing infections in battlefield fractures and hip and knee implants," Dr. Shapiro says.

"This technology bonding antibiotics to the implant surface is analogous to having land mines," says orthopedic surgeon Javad Parvizi, M.D., who treats implant-related infections and works on the project. "Once the organism steps on the surface, the antibiotic mine explodes and kills the bacteria. It holds great promise for our patients."

When a hip or knee implant is infected, physicians give extensive antibiotic treatment and the old implant is replaced. The treatment can include cement-containing antibiotics. "The hope is that the drugs in the glue will protect the implant, but that doesn't always work," Dr. Hickok explains. She notes that while they are infrequent, such infections can occur right after surgery from contamination during the operation. Later, infections can start on the implant from a different source in the body, such as a bladder infection or a dental procedure.

Dr. Wickstrom says the same approach can be used for other antibiotics and other implants. "There are plastic devices – bladder catheters, implants for kidney dialysis, Hickman tubes, pacemakers – every implant you can think of is a magnet for bacteria," he says. "The idea of having a permanent chemical bond to the metal is a new approach. This can be used for every metal and plastic implant, with every antibiotic."

While the current work is proof-of-principle for binding titanium to an antibiotic, the research team has received a new grant for $3 million from the National Institutes of Health for five years to investigate ways of encouraging bone growth on implants bearing permanent antibiotics.

"When an infected implant is taken out, it's usually covered with a slimy layer of bacteria," Dr. Hickok explains. "We're moving from just having a bacteria-killing surface to having one that prevents infection while promoting better bone-implant interactions. The idea is to have the implant last for many more years and avoid infection.

"We expect that the ideal chemical bonds will last for years, ideally as long as the implant," Dr. Hickok says.