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Hemocompatible Coatings for Blood-Contacting Devices


Posted by mddiadmin on August 1, 2003

Originally Published MDDI August 2003

Coatings

Coating makers take many different paths to ensure the blood compatibility of medical products.

William Leventon

Digital micrograph of polyurethane catheter tubing coated with Medi-Coat on both the lumen and outside surface. The dyed coating was uniform with a measured polymer thickness of 11 µm.

Blood can leave a troublesome mark on a medical device. When blood contacts a device surface, the result can be clotting that impairs device performance and can harm a patient depending on the product. 

David E. Babcock, an associate research scientist with SurModics Inc. (Eden Prairie, MN), says “Materials used to fabricate medical devices can possess different surface chemistries that can influence how aggressively blood will respond to the surface of the device.” He explains that most synthetic polymers and metal substrates are thrombogenic. Even when the materials that comprise a device are all blood compatible, the finished product may not be. This can be the result of factors such as complex device geometry.

Many manufacturers are exploring ways to improve the blood compatibility of their devices. One option is to coat device surfaces with a hemocompatible material. In tests and in use, hemocompatible coatings have been shown to reduce surface clotting. Device manufacturers put off by the challenges of coating use, however, have been slow to adopt the products. Now coatings may be poised for a surge in popularity, thanks to several developments that could accentuate the positives and mitigate the negatives of surface-enhancing products. 

An Active Approach

The current crop of coatings use a number of methods to ensure blood compatibility. Some coatings rely on biologically active materials loaded into a polymer matrix or bonded to the device surface. These bioactive materials prevent clot formation by altering the physiological responses of blood.

In many coatings, the bioactive agent is heparin, a widely used drug that inhibits blood clot formation. Heparin plays a key role in the activity of Medi-Coat, a hemocompatible coating developed by STS Biopolymers Inc. (Henrietta, NY). Medi-Coat technology entraps heparin in hybrid polymer layers. The coating slowly releases heparin when exposed to blood. This creates an environment of high drug concentration near the surface of the medical device. To suit different applications, STS can vary the release rate by changing the polymer mix. In this way, the coating can be formulated to release heparin over time periods ranging from days to months.

Digital micrograph of polyurethane catheter tubing coated with Medi-Coat on both the lumen and outside surface. The dyed coating was uniform with a measured polymer thickness of 11 µm.

Polymers used in Medi-Coat formulations include cellulose esters, polyurethanes, methacrylates, and polyvinylpyrrolidone. The polymer layers serve as a reservoir capable of holding high heparin loads, which extends the time that effective drug concentrations can be maintained near the coated surface. 

A number of device companies have shown interest in Medi-Coat, says Richard Whitbourne, chairman and chief technology officer of STS. Next year, the bioactive coating will make its debut on catheters. Meanwhile, the coating is being evaluated for use on vascular stents.

Like Medi-Coat, a formulation from Surface Solutions Laboratories Inc. (Carlisle, MA) combines heparin and various plastics to produce bioactive coatings. The company's patented technology binds heparin and other bioactive agents to a matrix polymer. The coating can remain bioactive for more than a month while in contact with blood, according to Margaret Palmer Opolski, president of Surface Solutions.

The company's coatings also offer relatively hassle-free application, Opolski says. The formulations can be applied in a one- or two-step dip-coating process. This simplifies the job for device manufacturers that want to coat products in-house. 

Long-Lasting Effects

For long-lasting hemocompatibility, a number of device manufacturers have opted for a heparin-based treatment called Carmeda BioActive Surface (CBAS) from Carmeda Inc. (San Antonio, TX). CBAS was developed to boost the anticlotting effects of heparin molecules, which are chains of repeating sugar units. Each chain includes an active sequence of five sugar residues that bind to and accelerate the activity of antithrombin, a clot-preventing agent in the blood. If a coating process attaches this active sequence to a device surface, it will hamper the heparin molecules' ability to interact with the blood.

Therefore, CBAS features end-point attachment of heparin molecules. Fastened at their end points to a device surface, the molecules “sway in the bloodstream like seaweed in water,” according to Carmeda. This maximizes the interaction between the active sequence and the flowing blood, the company claims.

For greater durability, CBAS covalently bonds heparin to a device surface. Unlike heparin-release coatings, which are effective only as long as the drug supply lasts, the bonded heparin isn't depleted over time. Thus, a fixed amount of the drug can continue to fight clotting for as long as several months, according to Carmeda.

To prove the effectiveness of CBAS, the company points to studies showing that it reduces the amount of thrombus formation and various blood components on medical device surfaces. Like other surface-enhancement products, however, CBAS offers improvement—not perfection. “You're still going to have growth on a coated surface,” says Andrew Jacobson, Carmeda's director of business development. “What you want is less growth—and less-harmful growth—than what you'll get on an uncoated surface.” For example, he says, an effective surface-enhancement product might reduce the clot rate on a medical device from 25 to 15%.

Today, CBAS is reducing the clot rate on a number of commercial medical devices. One of these is Propaten, a vascular graft sold in Europe by W.L. Gore & Associates. CBAS combats clot formation on the inside surface of Propaten grafts. Such clots can cause blockage that reduces blood flow through the grafts, explains Robert Thomson, a product specialist at W.L. Gore's Flagstaff, AZ, facility.

To test CBAS, Gore conducted animal studies that compared the performance of treated and untreated versions of 3.0-mm Propaten grafts. In one study, thrombi covered the surface of an untreated graft within 2 hours of implantation. But the treated graft was “almost entirely clean” after a 2-hour implantation, according to Thomson. “The difference was very striking,” he recalls.

On the downside, CBAS carries a hefty price tag. In addition, “it's a difficult process,” Jacobson admits. Unlike dip-and-dry coating methods that can take minutes or even seconds, CBAS is applied to devices in a batch treatment process that lasts 4 hours. Normally, Carmeda performs the process at its facility in Sweden. So devices must be shipped to Sweden and back, a journey that can take 2 weeks for products made in the United States. 

Disguising a Device

There are other ways to boost hemocompatibility besides employing clot-fighting agents like heparin. One is to disguise the device surface so blood can't detect the presence of foreign material and trigger clot formation.

Such a passive approach to blood compatibility may offer device manufacturers a significant advantage over bioactive approaches: a shorter, simpler, and less-expensive journey to regulatory approval. “FDA is very conservative if you make a claim of some kind of bioactivity,” says Min-Shyan Sheu, vice president of research and development at AST Products Inc. (Billerica, MA). As a result, Sheu emphasizes, manufacturers that use bioactive coatings may have to undertake costly and time-consuming clinical studies to satisfy regulators.

Digital micrograph of polyurethane catheter tubing coated with Medi-Coat on both the lumen and outside surface. The dyed coating was uniform with a measured polymer thickness of 11 µm.

AST is working on a bioinert coating designed to provide blood compatibility without bioactive agents like heparin. Instead, the coating will include a substance that attracts and binds blood proteins to a device surface. The proteins will cover the coated surface, hiding it from the blood-stream and thereby preventing clot formation.

Development of the AST coating is still in the early stages, but another surface-disguising coating has already reached the market. Developed by Hemoteq GmbH (Würselen, Germany), the appropriately named Camouflage coating provides hemocompatibility by mimicking endothelial cells that line human blood vessels.

Hemoteq makes Camouflage using a patent-pending process to synthesize carbohydrates that mimic inert endothelial cell surfaces. By relying on synthetic carbohydrates rather than organic materials (which were the basis of a previous version of the coating), the new Camouflage should accelerate the regulatory approval process, according to product manager Ingolf Schult.

Camouflage consists of a single layer of molecules with a thickness measured in nanometers. To ensure durability, the coating is attached to a device by a covalent bonding process.

According to Schult, Camouflage isn't burdened with one limitation of heparin-based coatings. With their highly negative charge, heparin molecules actually attract blood protein to the device surface. The coating is quickly covered by a protein layer that can block the heparin's anticoagulant 
activity. Once that occurs, the hemocompatible coating “doesn't work anymore,” Schult asserts.

By contrast, Camouflage doesn't depend on bioactivity to make a device hemocompatible. “It's athrombogenic because it's passive,” says Schult.
So far, no device firms have marketed Camouflage-coated products but Schult notes that several are interested in the coating. He expects coronary stents to be the first commercial application, with other Camouflage-coated implants following soon after.

Like Camouflage, a coating from MC3 Inc. (Ann Arbor, MI) mimics human endothelial cells. But the MC3 coating takes a more active approach to mimicry. According to MC3, tests have shown that endothelial cells generate nitric oxide (NO), which prevents the platelet activation that causes clotting in blood vessels. To mimic this natural anticlotting action, the company is developing NO-releasing polymers that can be used to coat medical devices. In this effort, MC3 is collaborating with Mark Meyerhoff, professor of chemistry at the University of Michigan. Meyerhoff's group works with “donor molecules” that release NO when they contact aqueous solutions. Entrapped in a polymer coating on an implanted device, these donors will interact with blood, producing NO that inhibits platelet adhesion to the surface of the plastic.

In animal testing, polyvinylchloride with entrapped NO donors significantly reduced the incidence of thrombus formation and platelet activation, according to MC3. Other tests showed that the blood sensor performance improved when the sensors were coated with NO-releasing polymers.
MC3 is now looking for device-manufacturing partners willing to try the new coatings. In the meantime, Meyerhoff's group is attempting to determine precisely how much NO release is needed to produce the desired anticlotting effect. “We don't want [the coating] to produce too much, because NO is very toxic,” Meyerhoff adds.

In living organisms, he adds, the toxicity of small amounts of NO doesn't present a problem because the molecules quickly react with elements in the blood. “There's no systemic effect because [the NO] never makes it very far from the surface of the polymer,” he says.

MC3 is also trying to develop materials that can be used in high-temperature manufacturing processes. A number of NO donors decompose when exposed to excessive heat, making them unsuitable for some manufacturing operations. Although MC3 has identified some promising high-temperature candidates, more research is needed before these materials are ready for the market, says Scott Merz, president of MC3. Because NO and heparin work on different parts of the clotting process, Merz believes the most effective blood-compatibility approach would be to combine both anticlotting agents in a single coating. To that end, he says, MC3 is looking at ways to incorporate heparin into its NO coatings.
Like their heparin-based counterparts, NO-release coatings provide hemocompatibility only until the supply of anticlotting agent is depleted. So Meyerhoff's group is trying to develop a coating capable of generating NO from elements inside the body. These NO-generating polymers could provide sustained hemocompatiblity on the surfaces of permanent implants. In addition, they could be used on devices that require extremely thin coatings, which would provide very-low-capacity reservoirs of NO donors for release coatings.

The Next Step

Coatings can add many useful properties to medical device surfaces aside from hemocompatibility. Many coating makers believe their next logical step is to a single surface-enhancing product that combines two or more attributes. For example, a future coating might be lubricious and antimicrobial as well as hemocompatible. But developing these so-called combination coatings will entail much more than simply mixing a hemocompatible substance with an antimicrobial substance. “It's not like making soup,” says Jacobson, whose company plans to develop such coatings.

Coating experts are also looking at new factors that might enhance hemocompatibility. For example, antimicrobial additives may kill bacteria that cause thrombus formation, Opolski notes. Or a potentially troublesome blood substance may be less likely to adhere to a hydrophilic surface. “People are finding things that expand the definition of hemocompatibility and how you impact it,” she says.

According to Opolski, some of her colleagues in the coating field are also considering the use of genes that give hemocompatibility-enhancing instructions to the body. For instance, she says, genes in a coating “could signal the endothelium to get cranking real fast” or trigger the production of cells that mask an implanted device from the blood.

Opolski knows of no company close to introducing a hemocompatible product based on gene therapy, which she calls the “Star Wars” idea in the coating field. She believes such products may have been pushed even farther into the future by recent gene-therapy mishaps that resulted in patient deaths.

Wanted: Users

Though the makers of hemocompatible coatings sound hopeful about the future, current sales figures must be a disappointment to at least some of them. As Jacobson sees it, there are a number of reasons that device manufacturers have been slow to adopt coatings. For one thing, proprietary coatings offering long-term hemocompatibility can be very expensive. In addition, he says, device makers must spend large amounts of money—often millions of dollars—on studies showing that a coated device is better than an uncoated one. “And end-users often balk at this proof anyway,” he notes. “They say, ‘That's nice, but we like our low-cost device.'”

Another factor working against coating makers is that some of their products haven't lived up to claims made for them. Worse, Jacobson adds, the products have actually caused harm in some cases. As a result, he says, “people just don't believe in coatings.”

Then there's the issue of regulatory approval. Many device companies may not have a clear idea of how to get a coated device past regulators. “If you don't know the regulatory path for a coating, it creates a lot of anxiety and uncertainty,” Jacobson says.

Even manufacturers with a clear view of the regulatory path may find it an unnerving sight. Coatings can add considerable time and cost to the regulatory approval process for a device. Companies with coated devices can spend several years and millions of dollars gathering enough test data to satisfy U.S. and European regulatory bodies, says Thomson.

Regulatory approval hasn't come easy for Gore's CBAS-coated Propaten product — despite the fact that both the coating and the graft are well-established products. “It's been a protracted process,” says Thomson, whose company has won approval to sell the coated Propaten version in Europe but is still awaiting an FDA decision. “This isn't something any company is going to take on lightly.”

Dramatic Growth Ahead?

Despite these negatives, Jacobson predicts “dramatic” growth for the coating market in the next few years. He cites several reasons for his optimism:

• Investment in coatings. In the near future, increased supplier in R&D investment will result in attractive coating products. “You're going to see new technologies, and I think the supply will [stimulate] demand as these new technologies are developed and introduced,” he says.
• Better coatings, lower prices. Carmeda and other coating suppliers are working on ways to make their products more affordable. In time, he says, “I think people will come up with higher-quality coatings at lower coated-devices costs.”
• A boost from drug-eluting stents. The attention attracted by drug-eluting stents—and the high prices these stents will probably command—should benefit manufacturers of coatings that offer hemocompatibility and other properties. The reason is that coatings add value to products, “which is very attractive to mature markets,” he says. “When you have a mature product line, you're just fighting for market share. But with a coating, the whole pie expands.”
• Easier approval over time. As coated devices become more common, U.S. and European regulators will establish guidelines that clarify the approval process.
• Adoption leads to more adoption. For example, once stents and grafts with Carmeda coatings hit the market, other device manufacturers showed more interest in CBAS, Jacobson reports. At that point, adoption “required less of a leap of faith,” he says. “People said, ‘Wow, this stuff must really work. I don't have to be as big a risk taker.'”
• Competitive pressures. “If there are five players in a mature market and one of them gets a coating, the other four will have to jump on board to keep up,” he asserts.

Thomson seems to agree with the last point. In the medical device industry, he notes, people are starting to realize that coatings provide the best solutions to physiological problems like clotting. As a result, he says, executives at Gore and other device companies have two choices when considering whether or not to embrace coatings: “Either we play now and get our feet wet, or we get left behind.”

Processes to Consider

To improve hemocompatibility and performance with a coating, manufacturers must consider what processes will best integrate the material with the device. Use of such processes as plasma polymerization and surface characterization can help optimize functionality while potentially reducing the time to market.

Although using polymerized plasma to coat materials and devices is not new, it's steadily gaining usefulness and popularity in the medical field. The process is performed by pumping a monomer gas into a vacuum chamber, where plasma polymerizes the gas into a coating. The process is unique, according to Stephen Conover, CEO of Applied Membrane Technology (AMT; Minnetonka, MN), in that it “opens up and creates sites on the substrate—a piece of tubing for a pacemaker, for example—and you can attach to that site a layer of whatever it is you're trying to create.”  The result, Conover says, is an “intimately bonded” layer of coating, even if you're using materials that normally don't combine, such as Teflon, polypropylene, or polyethylene. “The plasma polymerization process creates free radicals, or free-radical active sites, on both the material you're going to coat and the coating. That creates the bonds,” and makes possible the combination of materials that are normally incompatible, he says. 
Conover's company uses plasma polymerization to coat implantables, such as sensors that are left inside the body, as well as tubing, catheters, and membranes. Additionally, AMT is currently coating fibrous membranes for firms that are developing artificial organs. In addition to their biocompatibility, Conover says, plasma polymerized coatings are flexible and resistant to radiation. 

But what about the cost? According to Conover, it's less than you might guess. “Plasma polymerization is not necessarily more expensive than some other coating processes,” he says. 

Surface modification has become an equally important process in coating devices. Klaus R. Wormuth, PhD, of SurModics, says the firm has “developed a PhotoLink surface-modification technology platform that improves medical device surface characteristics,” such as hemocompatibility. The method provides the basis for time-controlled elution of drugs from device surfaces—a development that has been critical to the current generation of coronary stents.

Conclusion

Hemocompatible coatings prevent the formation of harmful clots on medical device surfaces. Some of the coatings include bioactive agents that interfere with the clotting process; others attempt to prevent clots by concealing the device surface from the bloodstream. 

Nevertheless, device makers have been reluctant to adopt the coatings, despite their usefulness. This is due in part to the cost and complexity the coatings can add to the regulatory approval process. But competitive pressures, the commercial success of drug-eluting stents, and other factors may soon push hemocompatible coatings into the medical mainstream. 

Copyright ©2003 Medical Device & Diagnostic Industry


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