Titanium and stainless steel are still the workhorse stent materials, but some manufacturers and researchers are developing bioresorbable metals.
More than 20 years ago, FDA approved the first coronary stent—a balloon-expandable and coil-type device made from a flat Type 316 L stainless-steel wire coil attached to a single longitudinal strut. Since then, millions of patients have benefited from the implantation of such bare-metal stents to prevent incidences of arterial restenosis.
“The most critical properties for metals used in medical implantables are biocompatibility and corrosion resistance,” explains Mike Vincent, president of M. Vincent & Associates Ltd., a supplier of specialty metals. Secondarily, implantable-grade metals must also offer high strength and be able to withstand sterilization. “Put these properties together, and you’ve narrowed the range of metals that are acceptable for stent applications,” Vincent adds.
The two most common metals used in current-generation stent applications include titanium and various grades of vacuum-melted stainless steel, the most prevalent of which is Type 316LVM. Primarily used to produce stent tubing, these metals are available in bar, rod, and wire configurations.
The primary advantage of titanium, according to Vincent, is its weight. Weighing less than a third as much as stainless steel and exhibiting high strength, titanium is an attractive option for stent applications. However, stainless steel is more commonly used to manufacture stent tubing because it is less expensive and more readily available. Because stent-compatible grades of small-diameter titanium tubing are primarily manufactured in Europe, they are four to five times more expensive than stainless steel.
While traditional bare-metals stents have dominated the industry for a generation, they are designed to remain in the body for many years, if not permanently. However, because of their longevity, they can cause such side effects as chronic inflammation, thrombosis, and vascular injury. And while a new generation of polylactic acid (PLLA)–based stents has been developed to prop open arteries for a limited period of time and then dissolve in the body, such bioresorbable polymeric designs are thicker than their metal counterparts, more prone to fractures, and associated with a heightened risk of inflammation and thrombosis.
Addressing these concerns, medical device manufacturers and university researchers alike are returning to metals. Only this time, their goal is to design metal-based stents that will dissolve in the body after they have completed their mission. Among the most promising candidates are magnesium and zinc—biocompatible materials that offer a range of advantages in stent applications.
Zorion’s ZMED wire-form stent prototype is made from a proprietary magnesium alloy.
A dozen or so years ago, researchers thought they could reduce the long-term negative effects of permanent stents by replacing them with a technology that could function for six months to a year and then dissolve in the body. The first candidate they studied was iron, a biocompatible, absorbable material that is present in blood. However, because iron degrades too slowly and also results in accumulation of rust around the implantation site, it turned out to be unsuitable for absorbable stent applications.
In response, the quest for the ideal stent metal led to magnesium. Among its proponents is Zionsville, IN–based Zorion Medical, a medical device manufacturer that is developing the ZMED stent, a fully absorbable medical device platform for treating coronary and peripheral artery disease.
“One of the objectives for the development of our proprietary magnesium alloy was to completely avoid rare-earth elements and utilize known bioabsorbable metals,” says David Broecker, Zorion’s president and CEO. “We have not disclosed the exact composition of our alloy, but we can say that in early animal-model testing, the magnesium alloy is extremely well tolerated and has little to no adverse or inflammatory response.” Animal models, he continues, indicate that the bare magnesium alloy wire is completely absorbed in approximately 90 days.
Broecker says that, while most polymer-based scaffolds take 24–36 months or more to absorb into the body completely, testing suggests that magnesium alloys will degrade in approximately one-half to one-third the time. “Faster is better,” he adds. Furthermore, a metal-based alloy will ultimately offer better performance characteristics than polymers, especially with regard to low profile, flexibility, and conformability.
While current-generation polymeric stents such as Abbot Vascular’s bioresorbable Absorb scaffold are drug-eluting platforms, the ZMED stent is currently not being evaluated for its drug-release properties. “We will be doing this in our next preclinical study,” Broecker notes. “However, we know that standard drug-delivery techniques will work. Our plan, therefore, is to deliver known drugs using a bioabsorbable polymer-based delivery system.”
Meanwhile, in order to complete clinical trials of its prototype, the company’s goal is to establish baseline performance characteristics in preclinical models and proceed to the first human clinical study in in 2016.
Zinc is a prime candidate for future absorbable metal stents because of its biocompatibility and its penetration rate in the range of 10–20 µm per year.
Some researchers argue that magnesium is a less than ideal stent material because it absorbs too quickly in the body and can thereby pose structural integrity issues. Seeking an alternative to magnesium-based stents, researchers at Michigan Technological University (MTU) are conducting studies on a stent design made from zinc.
Jaroslaw Drelich, professor in MTU’s department of materials science engineering and a specialist in applied surface chemistry and biomaterials says, in contrast to zinc, magnesium dissolves very quickly, disappearing in the body after a maximum of three months. While researchers are hunting for alloying elements that can reduce magnesium’s degradation rate in the biological environment, there is no magical alloy available at this time for manufacturing magnesium-based biodegradable stents, he says.
“The starting points for determining a metal’s suitability for use in stents are biocorrosion and biocompatibility,” Drelich says. “In the case of zinc, our data indicate that the penetration rate is in the range of 10–20 µm per year. This is the rate at which the thickness of the zinc stent disappears in the bodies of small animals.” The benchmark value for bioabsorbable stents is a penetration rate of slightly below 20 µm per year, making the zinc stent’s rate the best reported so far in research literature, Drelich says.
Pure zinc’s sole problem, Drelich says, is its lack of sufficient mechanical strength. To remedy this, alloying elements can be added to the pure zinc. Alternatively, zinc can also be strengthened significantly by processing and manipulating its microstructure. Nevertheless the alloying elements must be nontoxic and biocompatible, and they must increase the metal’s strength twofold. At the same time, while such elements may slightly reduce pure zinc’s good ductility, they cannot be allowed to destroy it altogether. “Whatever approach we decide to use, we have to ensure that the biodegradation rate will remain approximately the same as that of pure zinc,” Drelich says.
Like polymer- and magnesium-based stents, a zinc-based stent can also be designed to elute drugs, says Patrick Bowen, a PhD candidate in materials science and engineering at MTU. “Manufacturers of magnesium-based stents that are currently in preclinical and first-stage clinical trials have already done a lot of trailblazing in the area of biodegradable drug-eluting coatings. Many of the same principles can be applied to zinc-based stents. However, if we choose to go down that road, we will also have to keep the interplay between the coating and zinc corrosion in mind.”
According to Drelich, a zinc-based stent may not need a drug-eluting coating because the pure metal is not associated with an appreciable inflammation effect. Pure zinc and zinc alloys also exhibit pretty good tissue compatibility, he adds. “However, in order to improve the performance and biocompatibility of a zinc-based stent in the first few months after implantation, we may decide to use coatings, including drug-eluting coatings, that are already available on the market.”
Bob Michaels is senior technical editor at UBM Canon.