October 1, 1998

15 Min Read
Coating Science

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

An MD&DI October 1998 Column

In the past, device manufacturers wanted surfaces to be inert. Now, they want them to be more active.

The science of surface modification is entering a new era. The first generation of medical coatings sought to alter characteristics such as wettability and ionization—qualities that are now considered relatively easy to affect. Current researchers, on the other hand, are working to create coatings that will assume a more active role in medical device function. By incorporating bioactive agents such as proteins, drugs, growth factors, and similar substances, researchers are hoping to fine-tune the complex processes that occur at the interfaces of devices and their environment.

A PRIMER

Medical coatings and surface modifications are as diverse as the products they seek to enhance. Some of the more common techniques include plasma deposition, physical vapor deposition, chemical vapor deposition, ion bombardment, ion-beam sputter deposition, ion-beam-assisted deposition, sputtering, thermal spraying, and dipping. Qualities that can be altered include hardness, wear resistance, lubricity, wettability, bond strength, and resistance to bacterial attachment. Orthopedics is naturally a major market, but just about any invasive device can benefit.

Low-voltage scanning electron micrograph (LVSEM) of expanded stainless-steel endoluminal vascular stent with conventional silicone coating showing peeling and delamination of coating. Photo courtesy of the University of Florida (Gainesville).

Advances in coating science have been hindered, at least in part, by poor understanding of surface morphology and materials characterization. Particularly with polymers, mechanical properties at the surface can differ significantly from bulk characteristics. Many researchers have therefore turned their attention—and their atomic-force microscopes—to the molecular composition of surfaces. For example, Thomas Russell, PhD, professor of polymer science and engineering at the University of Massachusetts, has been investigating methods of triggering specific interactions at the surface interface. Most of his work so far has concentrated on binary systems. As he explains it, "If I take two components—A and B—and present them to a surface, in general, A or B will favor the surface. Take any surface that's homogeneous and there'll be a preferential interaction. We've focused on taking those interactions and tuning them to what we want them to be." This "tuning" entails synthesizing molecules that contain both A and B randomly arranged along a polymer chain, which can then be attached to a surface. "All we have to do is coat a layer of this material on the surface and heat it. Specific end groups on the chain migrate to the surface and anchor to it—chemically attach this material to the surface." After washing, everything gets removed except a thin layer, about 4 nm, on the surface. "So the surface is now effectively this 4-nm surface," Russell says, "and it can be anything we want it to be."

Russell and his colleagues have been conducting experiments using block copolymers. "Take a 'white' chain and chemically affix it to a 'black' chain," he explains. "If the surface likes white, then you'll get a layer of white on the surface, and that white is chemically attached to black, which basically converts the surface to black." In this way, multilayer self-assembling structures can be made to form in parallel with the surface, which, he says, make "beautiful diffusion barriers." But the same basic process can be used to make structures that run perpendicular to the surface, forming a latticework of conduits. One obvious application is in separation membranes. But using a substrate such as silicone oxide can yield more interesting results. "We can leave [the membrane] on a surface and fill the holes," Russell explains, combining, for example, nonpolar materials within a polar matrix. The resulting array can be used to trap polymer molecules or other compounds. Alternatively, the holes can be filled with metal to create an array of nanowires.

BONE GROWTH

Russell's research complements current work at Pacific Northwest National Lab (PNNL; Richland, WA), where scientists have achieved preliminary success in developing a process known as surface-induced mineralization. The technique holds potential for depositing calcium-phosphate coatings onto substrates of titanium and other metals. As explained by senior research scientist Allison Campbell, PhD, the underlying theory is pretty simple. "We take a substrate—a metal—and attach organic functional groups to it" in a series of self-assembled monolayers. "And the way these molecules are oriented on the surface, they stand up like trees in a forest rather than lying down flat," she says. The substrate is then immersed in a supersaturated solution of calcium and phosphate, where the functional groups induce precipitation in the form of surface mineralization.

Scanning electron microscope photo of a sputter-textured titanium orthopedic implant surface. Photo courtesy of NASA and GLITeC.

Surface-induced mineralization apparently offers more control and versatility than plasma spraying—the technique currently used to deposit hydroxyapatite on orthopedic implants. To begin with, the water-based process creates an extremely thin coating—on the order of 5–10 µm—that readily penetrates pores and contours without clogging them. Crystallinity can also be controlled, preventing the amorphous structures that can form through some vapor deposition methods. Most importantly, though, the low-temperature process can accommodate growth factors to accelerate bone formation. "We dissolve growth factors into the calcium phosphate and they get codeposited with the coating," Campbell says. "It's an easy thing to do, and it's done at physiological conditions—so pH is physiologic, ionic strength is physiologic. You don't denature the growth factor."

ION BEAMS

Sputter deposition offers another alternative to plasma spraying of hydroxyapatite. Bruce Banks, a researcher at NASA's Lewis Research Center, is hoping to enhance the applicability of the technology. Banks has been working with the Great Lakes Industrial Technology Center (GLITeC) to transfer space-shuttle technologies to commercial use. Ion-beam deposition is one of his core specialties. "The reason we like ion-beam sputter deposition—which is perhaps a little more expensive but adaptable to a variety of medical coatings—is that you can take a surface that is potentially contaminated and you can clean off the oxides and contaminants and deposit a coating all in one process, without breaking vacuum," he explains. Plasma-sprayed coating, on the other hand, generally involves melting particles by an electric arc and blowing them onto the surface. Banks likens this "splatter of molten particles" to throwing mud balls against a wall—they overlap in places and coat over each other, but the result is not entirely uniform. As a result, he says, a plasma coating "is not as adherent as an atomically deposited coating."

Ion-beam sputter deposition can be used to mix or add materials on the molecular level that normally wouldn't combine. The possibilities—and some of the early developments—are intriguing. "You can mix glass molecule by molecule with short-chain Teflon molecules, and it makes a glass-Teflon mixture that has properties of each. It's hydrophobic, stretchy, and transparent," Banks says. This "stretchy glass" could potentially be used to coat catheters, offering an alternative to silicone dioxide, which has a tendency to crack under certain adverse conditions. "We've made it more stretchy by a factor of three—which is big," he notes.

A related technology, ion-beam-assisted deposition (IBAD), has already been embraced by the medical device industry, with companies such as Spire (Bedford, MA) and Implant Sciences (Wakefield, MA) actively promoting it for various applications—particularly orthopedics. But researchers are continuing to extend its versatility. At the Southwest Research Institute (SWRI) in San Antonio, TX, senior research scientist James Arps, PhD, and his colleagues are working with industry to develop coating systems and processes. With IBAD, he explains, the ion bombardment minimizes buildup of internal stresses so the coating sticks better. The bombardment also induces mixing of the coating and substrate molecules, achieving a gradation of coating down into the substrate. For example, coatings combining physical vapor deposition and ion bombardment tend to be denser than their unenhanced counterparts and are applied at lower temperatures, rendering them suitable for more substrates.

Both Banks and Arps believe IBAD and ion-beam sputter deposition overcome some of the more common causes of coating failure—substrate contamination and deforming load stresses. Contaminants in the form of silicone oils, lubricating materials, welding fluxes, and similar compounds can obviously interfere with the coating-substrate bond. Deformation stresses are perhaps more complex. "If you have a high contact load," says Arps, "the Hertzian stresses can deform the substrate, and if the coating is harder or more brittle, you get sort of an ice-on-snow effect—the coating cracks, and as the substrate deforms, it can peel or get torn off." Knees, hips, and spinal disks are all subject to these potentially deforming loads. When a part such as a femoral stem separates from its anchored position because of excess stress, the resulting pistoning action can generate debris and accelerate wear at the interface, says Banks.

PROBLEM STENTS

Designers might find ways around these problems with rigid implants, but what about devices—such as stents—that are designed to deform? Eugene Goldberg, PhD, director of biomedical research at the University of Florida (Gainesville), is among the researchers working to create a suitable coating for stents, vascular grafts, and similar devices. Progress has been slow. One of the most obvious coating materials—silicone—has frustrated coating researchers for some time. "For years, it's been known that silicone coatings are rather good in contact with blood," he explains. "But there are virtually no medical devices—other than tubing used to handle blood—that use silicone coatings because of the problems of peeling and cracking and delaminating." True, he says, some researchers have filed patents for silicone-coated Dacron grafts. "Without any mechanical action, in contact with blood, they do look pretty good. But a vascular graft, especially a small-diameter vascular graft (which to the present doesn't really exist as a satisfactory device), is a mechanical device, subjected to bending and pulsatile pressure and so on, and as a consequence, the state of the art is such that these coatings come off."

Goldberg and his colleagues Chris Widenhouse, PhD, and James Seeger, MD, have also filed patents for a method of applying silicone coatings on vascular grafts and stents. But other techniques might also prove effective. For example, the group has recently been working on combining plasma pretreatments with surface polymerization using gamma or E-beam radiation. "We have an active program in modifying the surface of stainless steel or tantalum or Elgiloy in order to subsequently gamma graft or otherwise chemically couple polymers to the surface, which will be less thrombogenic in the short term and have a potential benefit in the long term to inhibit restenosis." In addition, the team has been working to incorporate biologically active agents into the surface modification. "As a result," Goldberg says, "we can hopefully make a stent surface even less thromobogenic and release agents over a period of maybe three to six months that would be inhibitors of cell growth, which leads to restenosis."

The radiation process involves doses that are too low to affect substances such as heparin or antiinflammatory agents. "That's why we can put various bioactive drugs and even proteins—like basement membrane proteins—into the surface without their being damaged," Goldberg says. The process achieves a covalently bound surface that can't readily be removed. An important application of this technology is the modification of intraocular lens surfaces to inhibit adhesion of bacteria and inflammatory cells. Preclinical studies have been initiated.

AGENTS AND IMAGING

STS Biopolymers (Henrietta, NY) also has a line of biologically active coatings marketed under the name of Medi-Coat. These coatings are mainly applied through dipping, so the main issue is not how to make the agents survive the process, but how to make them perform as intended. As explained by Richard Whitbourne, "We select a polymer matrix and a solvent system that tend to contribute to the stability of the agent, and oftentimes, we make complexes of the pharmaceutical agents to enhance their stability." These agents are then incorporated directly into the dipping mixture, allowing precise control over their amount and their proportion in relation to the polymer binder. The process also allows control over the degree of aqueous diffusion into and out of the coating and drug solubility. "We can produce coatings that have elution profiles that we can control and that leave the drug or pharmaceutical agent stable through sterilization."

Surgical instruments can be difficult to track via ultrasound unless they are held perfectly orthogonal to the transducer. Echo-Coat, developed by STS Biopolymers (Henrietta, NY), allows instruments to be viewed just as well from an angle.

STS has also introduced a coating that is certainly interactive, if not exactly bioactive. The formulation, known as Echo-Coat, enhances the visibility of instruments during ultrasound imaging. "It's a very smooth polymer coating, which, by its structure, allows ultrasound signals to be reflected back in multiple directions," explains Whitbourne. Metal needles, he says, are easy to pick up on ultrasound when they're held perfectly orthogonal to the transducer. But when the angle changes, ultrasound signals bounce off in various directions. Echo-Coat still manages to reflect the signals back to the transducer. "This is something that's unique," Whitbourne claims. "As far as we know, there's not a comparable technology." Currently, the coating cannot be applied in conjunction with any other treatments, although STS is working to expand its versatility. "We are attempting to apply lubricity over it, and we've done it on prototypes, but we're not able to do it in production yet," he says.

DECORATING A CELL

In many ways, the fields of surface science and biomaterials have been moving closer together. It's hardly surprising, then, that some researchers are already trying to take the next step—making coatings out of living cells. Some of the most promising work to date is being conducted at Lawrence Berkeley National Lab (LBNL; Berkeley, CA). The focus there is in taking materials that are well known to have good bulk properties—such as polyethylene—and making them resemble native tissue more closely. Carolyn Bertozzi, PhD, assistant professor of chemistry at the University of California, Berkeley, and a researcher in the materials science division at LBNL, describes two basic approaches—chemical and biological. "The chemical approach is to actually build biological molecules on the surface," she says. The molecules she's working with are oligosaccharides, or more specifically, carbohydrates (human cells are in fact coated with carbohydrates). "The biological approach is to literally coat the material with biological tissue—we take living cells and we attach them to the surface of the material."

The idea of bonding cells to a substrate may seem impractical, but results so far have been encouraging. "We do this trick we call metabolic engineering of reactive sugars," she explains. The process entails feeding an unnatural sugar to the cells, which eat it, metabolize it, and "decorate" their surface with it. "Now, the thing about the unnatural sugar is that it's got a reactive chemical functional group, a chemical anchor that you can use to react the surface," she says. The cell actually becomes reactive, but only with an appropriately modified surface. The cells attach through covalent bonds, rather than forming as they would naturally, by spreading out. The result, says Bertozzi, is a "pretty robust interface."

Bertozzi and her colleagues are hoping to coat synthetic materials with living cells, essentially masking the materials to enhance biological acceptance. Initial applications might include bioreactors, although she notes that biosensor developers have also expressed an interest. The biological approach is still in the basic science stage. "We want to know what happens to these cells when we do this—have we changed their metabolic processes, do they divide, and if they don't divide, how long do they stay alive?" she says. As for the chemical approach, the Berkeley team has already achieved some success in the form of a new material for contact lenses. The material resists nonspecific protein deposition, has a high water content, and is very hydrophilic—all properties of carbohydrates.

CONCLUSION

Where will coating technology go next? In part, surface science will dictate future developments. As NASA's Banks explains, "We've put a lot of effort into understanding what makes a good coating—and what we've discovered is, it's only as good as the smoothness of the substrate." Russell at U. Mass has been investigating length scales—the characteristic periodic nanoscopic features on a surface or material—as they relate to wettability. Though highly theoretical, Russell's work could prove important to surface engineering. "For a system to interact with a surface, it has to wet it," he says, "and if I can control wettability, I've controlled the first step of interaction." At NASA, Banks has been exploring the possibilities of removing fungus, bacteria, viruses, and other substances from surfaces of implants through exposure to room-temperature atomic oxygen.

Most other researchers, though, will probably continue with bioactive agents. "At all the technical meetings I go to," says PNNL's Campbell, "people are trying to find ways to clone naturally occurring growth factors and immobilize them and maintain activity" on a surface. "I think that's the future," she says. Whitbourne at STS leans toward drug-delivery coatings. "This would be across the board, on catheter devices, stent-type products, and some new products that at the moment don't exist," he speculates. Arps at SWRI and Goldberg at the University of Florida agree that stents will foster some interesting developments. "There's some work being done in incorporating radioactive species in the surface of intraluminal stents to introduce beta radiation to prevent restenosis," says Arps, adding that ion implantation might be a suitable means of doping a surface with radioactive species. Earlier this year, in fact, NIH awarded a grant to Implant Sciences to develop this technology, and the use of radioactive stents for inhibiting restenosis is undergoing a clinical trial called the isostent restenosis intervention study (IRIS).

"Bioactive agents that can tune the complex processes that occur on surfaces for implants, small-diameter vascular grafts, and intraluminal stents following angioplasty—those are areas of major clinical importance that are in need of the advances of these technologies," says Goldberg. "We're not there yet, but we are making progress."

Copyright ©1998 Medical Device & Diagnostic Industry

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