Getting Out the Thorn

Biomaterials become friendlier to the body

The practice of replacing injured or worn-out body parts with something other than flesh and blood goes back centuries. But not until recently have doctors been inserting completely humanmade materials into their patients, and today, it’s downright routine. Each year, millions of patients are fitted with temporary or permanent parts, such as plastic heart valves and catheters and silicon breast implants. To be sure, it’s a medical marvel.

Fewer Staphylococcus bacteria (large green spots) adhere to poly(ether urethane) samples releasing the antibiotic ciprofloxacin (top) or monoclonal antibodies (middle) than to the unimproved material (bottom). Bryers

Micrographs show less adhesion by Pseudomonas aeruginosa bacteria (dark spots) on a material that releases nitric oxide (above) than on one that doesn’t (below). The American Chemical Society

However, although these medical insertions are often referred to as biomaterials, they’re often invaders as far as the patient’s body is concerned. Bodies treat an artificial implant “just like a thorn,” says James Bryers of the University of Connecticut in Farmington. They try to get rid of it.

Frequently, tissue won’t heal correctly around an artificial object. Often, the location of the implant becomes infected or inflamed. Or, the body creates a capsule of tissue around the implanted materials. That makes it difficult for, say, a glucose sensor to make accurate measurements for its diabetic host.

Because of the body’s unwelcoming reception, biomaterials developers have worked in recent years to create sophisticated materials that might interact with inner-body environments in a less provocative way. One of the most promising strategies, researchers say, is to apply coatings that alter the chemistry of an implant’s surface. These coatings can release various drugs, for example, to treat conditions such as bacterial infections. Also, coatings of cells or certain molecules might trick the body into thinking that an artificial material is its own flesh and blood.

There already are a few biomaterials of this sort in development, and basic research in chemistry, biology, and materials science is opening up new possibilities. Among recent developments, some researchers have found improved ways to control the release of antibiotics preloaded into biomaterials. Other scientists have designed polymers that produce nitric oxide, which can prevent fouling by bacteria and formation of blood clots. Even more visionary are the investigators working on biomaterials that would chemically communicate with the body’s cells and tissues.

When patients receive implants, “it’s a battle between what our body will tolerate and what the material will tolerate,” says David Grainger of Colorado State University in Fort Collins. Now, researchers are trying to negotiate a peace between the implants and the body.

Infection problems

Infection is often the final blow for medical implants. Although prescriptions of oral antibiotics can sometimes eliminate such infections, more often the implant must be removed to save the patient’s life.

Even when oral antibiotics work and the implant can remain in place, this treatment is a far-from-perfect solution, says Bryers. When patients take large doses of antibiotics, the drug eliminates good bacteria all over the body, not just bad ones at the site of the infection. Such treatment can also contribute to the development of antibiotic-resistant bacteria. A new generation of biomaterials might reduce these risks.

Bryers and his colleagues, including Buddy P. Ratner of the University of Washington in Seattle, are among the many researchers who decided that it would be much better if biomaterials released antibiotic themselves. Less of the drug would be needed because it would be released at exactly the site of infection.

With this in mind, a couple of years ago, the researchers loaded a polymer full of the antibiotic ciprofloxacin, or Cipro, a powerful broad-spectrum drug now widely known for its use in combating anthrax. The polymer was also designed so that it could release a protein that binds to certain receptors on infecting bacteria. When the polymer was exposed to bacteria, the protein prevented bacteria from attaching to the surface (SN: 4/26/97, p. 253: In patients, many implants suffer from surface fouling by microbes.

One of the big challenges for scientists designing antibiotic-loaded implant materials is to control the drug’s release so that it doesn’t spurt out all at once. Bryers, Ratner and their colleagues found that they could slow cipro release by covering their polymer with a finely porous coating that makes it harder for the antibiotic to escape.

Now, Ratner has taken these materials a step further. He and his colleagues have devised a biomaterial that releases a drug only when zapped with an ultrasound pulse, the same sort of signal used in sonograms. In their experiments, reported in the November 2001 Journal of Biomedical Materials Research, a specialized polymer coating on a cipro-loaded polymer base prevented the antibiotic from leaking out prematurely. Then, the researchers showed that a pulse of ultrasound temporarily made the membrane porous enough to let the drug through. When the researchers stopped the ultrasound, the membrane “healed,” says Ratner, and drug release ceased.

Eventually, a doctor might use ultrasound to direct an implant to release antibiotic just when it’s needed, he says.

Another experiment showed that the ultrasound technique also works when the coated material was infused with insulin, says Ratner. So, doctors might someday design devices that would enable diabetics to administer insulin doses with a painless pulse of ultrasound rather than a needle, he suggests.

Bacterial films

Infection often takes hold after bacteria form a film on an implant. In one new approach to the problem of bacterial adhesion, Mark Schoenfisch of the University of North Carolina in Chapel Hill used nitric oxide gas (SN: 9/15/01, p. 165: Materials use nitric oxide to kill bacteria).

Nitric oxide release is a logical addition to biomaterials because it’s produced naturally by the body for many functions, such as killing bacteria and dilating blood vessels, says Mark Meyerhoff of the University of Michigan at Ann Arbor. It was in Meyerhoff’s laboratory that Schoenfisch began doing nitric oxide research. “We’re mimicking what nature’s already doing,” says Meyerhoff.

He and Schoenfisch both make polymers that contain chemical groups called diazeniumdiolates. On contact with water, the groups produce and release nitric oxide gas. These groups can be tailored to produce nitric oxide that breaks down after anywhere from 1.8 seconds to 20 hours, says Larry Keefer of the National Cancer Institute’s laboratory in Frederick, Md. He was among the earliest researchers to study the fundamental chemistry of diazeniumdiolates, and his team was the first to disperse them in polymers. This quick breakdown of nitric oxide is imperative to prevent the gas from migrating to places where it might have unintended consequences, such as dilating blood vessels, says Keefer.

In Schoenfisch’s recent work, described in the Oct. 3, 2001 Journal of the American Chemical Society, he showed that the nitric oxide-releasing polymers can actually reduce bacterial adhesion. Schoenfisch points out that he still needs to determine how long the materials can store and release nitric oxide and how a device coated with them will behave in the body.

Before Schoenfisch’s work, Meyerhoff had found that the nitric oxide-producing groups are useful in biomaterials for preventing blood clotting. Unintended blood clotting has thwarted the development of implanted biological sensors, such as those for detecting gases and acidity in blood, says Meyerhoff. In the body’s defense efforts, platelets aggregate on implanted sensors and form clots that result in inaccurate measurements, he says.

To solve this problem, Meyerhoff created polymers containing nitric oxide-producing diazeniumdiolates. Then, in work reported in 2000, he used such nitric oxide-releasing coatings to create gas sensors that measure oxygen but avoid the clotting problem. The materials prevented the adhesion of platelets around sensors implanted in dogs’ arteries and also seemed to dilate those blood vessels, helping blood to flow more freely.

In more recent work, Meyerhoff has made nitric oxide-emitting polymers for equipment that doctors use to transport and filter blood outside the body during procedures such as heart surgery and kidney dialysis.

Lifelike materials

Some researchers suggest that materials found in medical implants will become ever more lifelike in their behavior. Rather than releasing compounds such as antibiotics or imitating natural bodily processes such as the generation and release of nitric oxide, commercial biomaterials might actually communicate with the body the way real tissues do. In other words, they’ll send out chemical signals to tell the body to produce nitric oxide or assimilate the artificial object as though it were made of the host’s own tissues, says Ratner.

Grainger is one of many researchers exploring this approach. In his laboratory, researchers are studying the body’s own cell-to-cell signaling systems. After adding certain chemical groups to the surfaces of implantable materials, the researchers examine which modified materials adsorb proteins and cells in ways that promote an environment conducive to further cell attachment and natural tissue growth.

This type of research is “at the interface where the cells and the proteins touch the materials surface and tries to understand the signaling responses that initiate either a rejection response or an integrating response on that surface,” says Grainger.

In other work, Grainger has recently shown in mice that antibodies can be released from a gel at the site of an implanted material to counteract abdominal infections. This strategy might serve as an alternative to loading antibiotics into biomaterials.

Today, biomaterials researchers have to pay attention to biology much more than they did 30 years ago, Grainger says.

“Anybody who deals with a material as being a dumb, inanimate object–with an arrogance that we can just stick it in the body, sew it into place, and the body has to accept it–is really a dinosaur,” he says.

In the near future, notes Bryers, researchers might actually combine anti-fouling, drug-releasing, and chemical-communications properties into advanced biomaterials that are more compatible with the body than today’s materials are.

“The body is a very interactive system, and the materials that we implant have to be just as interactive,” says Grainger. “It’s just like a marriage: It’s a two-way street, and if one person reacts and the other one doesn’t, then it’s a dead issue. It’s the same way with biomaterials.”

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