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Researchers bond antibiotics to titanium, making new anti-infective implants possible
Bonding vancomycin to titanium surfaces may produce implants with sustained antibiotic activity over the long-term.
Pennsylvania researchers have created a way to covalently bond vancomycin to the surface of titanium. The work lays the ground for the possible development of orthopedic implants with sustained antibiotic activity to reduce postoperative infection risks.
Eric Wickstrom, PhD, a professor of biochemistry and molecular biology at Thomas Jefferson University's Jefferson Medical College in Philadelphia, and colleagues at the college published their proof-of-principle study in the journal Chemistry & Biology. The results show that vancomycin, after being covalently bonded to titanium, can remain capable of killing bacteria. Specifically, vancomycin-bonded titanium killed cultured Staphylococcus aureus (S. aureus), a Gram-positive bacterium, according to the study.
Gram-positive bacteria are the most common causes of nosocomial and hematogenous periprosthetic infections, the authors noted.
�Our technique puts a bed of antibiotic nails on the surface of the implant,� Wickstrom said in a press release. �The first time a bacterium lands on those nails, it dies.�
Sustained antibiotic activity
COURTESY ERIC WICKSTROM |
Infections that follow orthopedic implant procedures are difficult to treat because the implants become surrounded by a fibrous coating. Although this is a natural response to a foreign body, some bacteria, such as S. aureus, readily adhere to the implant surfaces and this coating provides an ideal growing environment that is largely inaccessible to the immune system resulting in biofilm-encased bacterial colonies, according to the study.
Current practices for treating such infections, such as antibiotic-impregnated bone cements, only deliver antibiotics from the time of implantation and last only through the immediate postop period, the authors said.
�A new paradigm to interdict deep-seated bone infection both in the immediate postoperative period and throughout the life of the implant would have great clinical importance for implant surgery,� they said. �We hypothesized that permanent covalent bonding of drugs to implants would provide the desired protection,� they added.
To test this, the researchers used solid phase peptide synthesis to bond vancomycin to aminopropylated titanium. Using a specific anti-vancomycin antibody visible under indirect immunofluorescence, they found that vancomycin evenly covered titanium surfaces, with only some areas of focal concentrations, according to the study.
They then incubated control samples of normal titanium and the vancomycin-bonded titanium at room temperature. At three weeks, the researchers found that anti-vancomycin antibodies remained significantly bound to vancomycin-bonded titanium. In contrast, control samples showed only minimal binding.
�Taken together, these images imply stability of [vancomycin] on the [titanium] surface for at least three weeks,� the authors said.
The researchers next used static incubation to test antibiotic activity against S. aureus. After one hour of incubation, the vancomycin-bonded titanium reduced bacterial colony formation by 76% � 15% compared to controls. This increased to 88% � 16% after two hours of incubation, according to the study.
Staining showed that most S. aureus cells remained alive on control samples, but had predominantly died on vancomycin-bonded titanium samples, the authors noted.
�When beads that had been exposed the day before to S. aureus were washed, rechallenged, and stained, [vancomycin-bonded titanium] retained its ability to kill S. aureus preferentially,� they added.
Multiple implant possibilities
The approach to bonding vancomycin and titanium used in this study could also be used for bonding other antibiotics and other implant types, Wickstrom noted in the press release.
�There are plastic devices � bladder catheters, implants for kidney dialysis, Hickman tubes, pacemakers � every implant you can think of is a magnet for bacteria. 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,� he said.
The research was led by Irving Shapiro, PhD, a professor of orthopedic surgery at Jefferson Medical College and was supported by a grant from the U.S. Department of Defense.
The current work is proof-of-principle for binding titanium to an antibiotic. The researchers have received a new five-year $3 million grant from the National Institutes of Health to investigate ways of encouraging bone growth on implants bearing permanent antibiotics.
For more information:
- Jose B, Antoci V, Zeiger AR, et al. Vancomycin covalently bonded to titanium beads kills Staphylococcus aureus. Chem Biol. 2005:12;1041-1048.