For years, University of Washington bioengineer Buddy Ratner has used the metaphor of a lock and key to describe how the body uses specific cell-protein interactions to promote healing. Now, research suggests that the metaphor offers a nifty blueprint for making medical implants that trigger normal healing rather than the body's typical, and often disruptive, foreign material reaction to such devices.
Reporting in the April 15 issue of Nature, Ratner and UW bioengineering graduate student Galen Shi describe a technique they developed for coating a biomaterial surface with tiny keyhole-like indentions that bind specific proteins to potentially unlock the body's natural healing process.
"The ability to make surfaces that can be recognized by the body is a major step forward in our quest for biomaterials and implants that heal," says Ratner, who directs the UW Engineered Biomaterials Center, a $25 million National Science Foundation initiative to create next-generation medical implants. "This is the first coating process that works on the atomically flat surfaces of artificial materials commonly used in implants and that promotes affinity for specific proteins. Our approach potentially can be used for any kind of implant." (See end of release for information on downloading a publication quality image of Professor Ratner and an illustration of the UW coating process.)
More than a half billion medical devices, ranging from simple catheters to heart valves and artificial hips, are implanted in patients every year. While these devices save or improve the lives of millions of people, they often deliver only temporary fixes. The body's natural response to foreign material - whether it's a medical implant or a bullet - is to wall it off with scar-like tissue, Ratner explains. Frequently, this reaction disrupts the device's performance and necessitates further medical intervention.
What's happening at the molecular level, UW researchers suspect, is specific proteins that normally direct the healing process are unable to recognize the artificial materials used to make implants. Instead, Ratner says, implants are bombarded by a jumble of proteins that confuses the macrophage cells responsible for tissue regeneration and triggers the body's inflammatory foreign material reaction.
Ratner's team has devised a complex process for coating artificial materials so their surfaces can attract and bind specific proteins. To begin the process, a layer of the desired proteins is spread over a smooth surface like mica. The proteins and mica are then coated with a thin layer of sugar molecules. Next, a Teflon-like fluoropolymer coating is applied to the surface through a gas-phase plasma deposition process. The coating is then peeled off the mica and dipped into a solution to dissolve the proteins. What's left behind is a Teflon-like polymer coating containing sugar-lined pits in the exact shape of a specific protein.
Laboratory experiments show that coatings prepared in this way have a strong affinity for the protein used to form the pits. It's a combination of the proteins recognizing the shape of the pits and the sugar molecules binding to the surface of the proteins, Ratner says. Tests were done using proteins of similar sizes and only the protein with the appropriate shape and chemistry adhered to the coating.
One of the proteins to be tested next is osteopontin. UW bioengineering professor Cecilia Giachelli discovered osteopontin plays a critical role in preventing calcification of heart valves but typically is not present in high concentrations on artificial valve implants. Ratner and Giachelli will explore whether valve implants coated using the UW process will bind enough osteopontin to inhibit calcification. This may reduce the need for dangerous and expensive valve replacement surgery in tens of thousands of patients.
"We've achieved with ordinary synthetic materials the highly specific lock-and-key fit we see in natural healing, and that has been one of the toughest hurdles," Ratner says. "The next step is to see if an implant coated using our process actually turns on healing in the body."
Shi has been recognized by the Society for Biomaterials and the American Vacuum Society for outstanding Ph.D. research in connection with this project. He is supported by the UW Center for Nanotechnology, which along with the UW Engineered Biomaterials Center is a leader in developing nano-scale molecular engineering techniques for precision control of biology.
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