Clot-Reducing Coats for Blood-Contacting Devices Coating makers take many different paths to hemocompatibility. William Leventon Blood can leave a troublesome mark on a medical device. When blood comes in contact with a device surface, the result can be clotting that impairs the performance of the device — and harms the patient who depends on it. So many manufacturers are looking for ways to improve the blood compatibility of their devices. One option is to add a hemocompatible coating to a device surface. Blood-compatible coatings have been applied to a variety of implants, including stents, sensors, catheters, vascular grafts, and ventricular assist devices. The coatings can also be used on extracorporeal blood-contacting equipment such as heart-lung machines, dialysis machines, and circulation and oxygenation devices. In tests and in use, hemocompatible coatings have shown the ability to reduce surface clotting. But device manufacturers, put off by the downsides of coating use, have been slow to adopt the products. Now, though, 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 Today’s crop of coatings produce blood compatibility in a number of different ways. Some coatings rely on biologically active materials that are loaded into a polymer matrix or bonded to the surface of a device. 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. When exposed to blood, the coating slowly releases heparin, creating 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 mix of polymers in the coating. This way, Medi-Coat can be formulated to release heparin over time periods ranging from days to months. 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 that extend the time that effective drug concentrations can be maintained near the coated surface. A number of device companies have shown interest in Medi-Coat, reports Richard Whitbourne,  chairman and chief technology officer of STS. Next year, the bioactive coating will make its debut on catheters. Meanwhile, the coating is also 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 coating technology binds heparin and other bioactive agents to a matrix polymer. In contact with blood, the coating can remain bioactive for more than a month, according to Margaret Palmer Opolski, president of Surface Solutions. The company’s coatings also offer relatively hassle-free application, Opolski notes. The formulations can be applied in a one- or-two-step dip-coating process, making the job fairly easy for device manufacturers that want to coat products themselves. Long-Lasting Effect For long-lasting hemocompatibility, a number of device manufacturers have opted for a heparin-based treatment called Carmeda BioActive Surface (CBAS) from Cameda Inc. (San Antonio). CBAS was developed to boost the anti- clotting effects of heparin molecules, each of which is a chain of repeating sugar units. This 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 hampers the heparin molecule’s ability to interact with the blood. So 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, attached heparin isn’t used up 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,” notes 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 percent to 15 percent. 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. These growths 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- millimeter Propaten grafts. In one study, thrombus covered the surface of an untreated graft after two hours of implantation. But the treated graft was “almost entirely clean” after a two-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 four 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 two weeks for U.S.-made products. Disguising a Device There are other ways to boost hemocompatibility besides employing clot-fighting agents like heparin. One is to disguise a 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 big 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,” notes Min-Shyan Sheu, vice president of research and development at AST Products Inc. (Billerica, MA). As a result, Sheu says, manufacturers that use bioactive coatings may have to undertake costly and time-consuming clinical studies to satisfy regulators. So 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 and thereby preventing clots. 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. For greater durability, the coating is firmly attached to a device by a covalent bonding process. According to Schult, Camouflage isn’t burdened with a crucial shortcoming of heparin-based coatings. With their highly negative charge, heparin molecules attract blood proteins to the device surface. Soon, the coating is covered by a protein layer that blocks the heparin’s anticoagulant activity. At this point, the hemocompatible coating “doesn’t work anymore,” Schult notes. By contrast, Camouflage doesn’t depend on bioactivity to make a device hemocompatible. “It’s athromobogenic because it’s passive,” Schult says. So far, no medical device firms have marketed Camouflage-coated products. But Schult notes that several device companies 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 platelet activation that causes clotting on blood vessels. To mimic this natural anti-clotting 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 “donors” that release NO when they come in contact with aqueous solutions. Entrapped in a polymer coating on an implanted medical device, these donors interact with blood to produce NO, which 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, MC3 reports. Other tests showed that the performance of blood sensors improved when the sensors were coated with NO-releasing polymers. At present, MC3 is looking for device-manufacturing partners willing to try NO coatings. In the meantime, Meyerhoff's group is trying to determine precisely how much NO release is needed to produce the desired anti-clotting effects. “We don’t want [the coating] to produce too much, because NO is very toxic,” Meyerhoff notes. 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. MC3 has come up with some promising high-temperature candidates, but more research is needed before these materials are ready for the market, says Scott Merz, president of MC3. Since NO and heparin work on different parts of the clotting process, Merz believes the most effective blood- compatibility approach would be to combine both anti-clotting 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 anti- clotting agent runs out. 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 be very low-capacity “reservoirs” of NO donors for release coatings. The Next Step Besides hemocompatibility, coatings can add many useful properties to medical device surfaces. So many coating makers believe their next logical step is to combine two or more attributes in a single surface-enhancing product. For example, some future coating might be hemocompatible as well as lubricious and/or anti-microbial. But there’s much more to creating so-called “combination coatings” than just mixing, say, a hemocompatible substance with an anti- microbial 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, anti-microbial 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 caused patient deaths. Wanted: Users Though 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 manufacturers 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 many 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 large 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 if a manufacturer has a clear view of the regulatory path, it’s probably an unnerving sight. Coatings can add considerable time and cost to the regulatory approval process for a medical 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, according to 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 FDA approval. “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 investment will result in attractive new 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 manufacturers 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 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: coatings of all types 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 onboard 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.” This article was published in Medical Device & Diagnostic Industry magazine.