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Stent Designers Think Zinc

The most advanced absorbable stents available today are made from polylactic acid (PLLA). Based on nearly five years of clinical trial data, for example, Abbott Vascular's bioresorbable Absorb scaffold compares favorably to the company's metal-based XIENCE stent, the current industry standard for nonabsorbable drug-eluting stents.

But what about absorbable metal stents? Based on magnesium, current state-of-the-art absorbable metal stents could eventually give bioresorbable polymeric stents a run for their money because they are thinner, less prone to inflammation, easier to implant, free from the risk of thrombosis, and more. However, some researchers argue that magnesium is less than ideal 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 (Houghton) are conducting studies on a stent design made from zinc. This material, the scientists say, offers better degradation rates than magnesium and can be processed in such a way as to increase its mechanical properties. In the following conversation, Jaroslaw Drelich, professor in the department of materials science engineering, and Patrick Bowen, PhD candidate in materials science and engineering, share their insights into zinc as a potential candidate for next-generation absorbable stents. Drelich specializes in applied surface chemistry and biomaterials, while Bowen, a materials scientist and metallurgist, is working in the area of biomaterials and corrosion science. They work in close collaboration with Jeremy Goldman, an associate professor in the department of biomedical engineering specializing in material biocompatibility and animal studies.

At this year's BIOMEDevice Boston, Drelich will hold a seminar on "Utilizing Zinc for Bioresorbale Stents" on Thursday, March 27 from 3:00 to 3:45 p.m.

MPMN: Please go into zinc's properties and why it is suitable for absorbable stent applications? What is its absorption rate and how does it affect the body as it absorbs?

Michigan Technical University zinc stent
Because of its biocompatibility and its penetration rate in the range of 10 to 20 µm per year, zinc is a prime candidate for future absorbable metal stents.

Drelich: We don't yet have data on the behavior of zinc in the human body. Thus far, we have performed only in vitro and in vivo studies, the latter of which was limited to small-animal models. While we have some indication of zinc's effects on the human body, we cannot yet say for certain.

The starting points for determining a metal's suitability for use in stents are biocorrosion and biocompatibility. In the case of zinc, our data indicate that the penetration rate is in the range of 10 to 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. Thus, the rate for our zinc stent is the best reported so far in the research literature. That's why our findings are exciting and have generated a lot of discussion.

MPMN: What happens to the zinc after absorption? How does the metal affect the body?

Drelich: We are in the middle of a study to determine how quickly zinc implants disappear from the body over the period of more than one year. We want to know whether implant dissolution is uniform and whether it generates by-products or dissolves completely in the body.

Bowen: Based on our current knowledge, we can make some general statements about zinc levels in the body. Because the amount of zinc present in a stent is in the range of tens of milligrams, it is comparable to the amount of zinc one ingests everyday in a multivitamin. Thus, in terms of the systemic effects of zinc stents, we are not concerned. But the intermediate steps between the metal and how it winds up--most likely as ions--are not yet clear.

Drelich: As a biological process, the effects of zinc are difficult for us to analyze. We are not sure whether some of the zinc is consumed by the body or whether it is removed as a toxin through bodily fluids.

MPMN: What are the physical and mechanical properties of zinc, and what are its advantages over other candidate absorbable metals for stent applications, such as iron and magnesium?

Drelich: The study into the use of metals in stents started about 12 years ago, when scientists suggested that the long-term negative effects of permanent stents could be reduced by replacing them with a technology that could function for six months to a year and then disappear in the body. Because iron is present in the blood, researchers began their quest by studying the use of iron as a perfect biocompatible absorbable material. But unfortunately, it was recognized very quickly that iron degrades too slowly. Our own research indicated that it also produces rust around the implantation site, which slowly increases in volume and causes problems. Iron, in our opinion, is therefore out of the question for use in absorbable stents. Perhaps the addition of alloying elements could eventually help the iron dissolve fully, but there is nothing in the literature indicating that researchers have succeeded in improving the absorption performance of iron stents significantly.

After considering iron, researchers jumped to magnesium because this metal is a very good biocompatible material. Unfortunately, magnesium dissolves very quickly, disappearing in the body after a maximum of three months. As a result, in the last 10 to 12 years, researchers have been on the hunt for alloying elements that can reduce magnesium's degradation rate in the biological environment. And while improvements have been made, there is no magical alloy available at this time for manufacturing biodegradable stents based on magnesium.

MPMN: What about zinc's mechanical strength?

Drelich: While iron does not degrade quickly enough to be used in absorbable stent applications, it offers good mechanical properties. Magnesium, on the other hand, does not exhibit enough ductility. In stent applications, zinc offers good ductility--even better than required. As for pure zinc, the only problem is that it doesn't have enough mechanical strength. Generally, however, this deficiency is not a big deal because zinc alloys can be formulated with improved mechanical properties. However, it is necessary to find alloying elements that are nontoxic and biocompatible and that increase the metal's strength twofold. At the same time, while such elements may slightly reduce zinc's ductility, they cannot be allowed to destroy it altogether.

In addition to using alloying elements to improve zinc's mechanical properties, the material can be strengthened significantly by processing and manipulating its microstructure. But whatever approach we decide to use, we have to ensure that the biodegradation rate will remain approximately the same as that of pure zinc.

Currently, two of our graduate students are working to alloy zinc with different elements, and we are trying to get more funding from the National Institutes of Health and the National Science Foundation to expand this activity. Unfortunately, this type of research is very time-consuming. Because in vivo data are more reliable than in vitro data, we are focusing on performing in vivo animal studies, but the results from such studies become available only after six months to a year and a half. Although our first paper, published in Advanced Materials and titled "Zinc Exhibits Ideal Physiological Corrosion Behavior for Bioabsorbable Stents," was published in March 2013, we are still analyzing the results of tests involving the use of pure zinc and a first set of alloys. Tests involving a second set of alloys will follow. The results from these follow-up tests should be available in the next couple of years.

MPMN: What is the potential of using a zinc-based stent as a drug-eluting platform? Can a drug-eluting coating be deposited on the zinc substrate?

Bowen: Yes, it is very possible to use a zinc platform to elute drugs. In fact, 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.

Drelich: We are not sure that a drug-eluting coating will be needed on a zinc-based stent because we don't see much of an inflammation effect associated with the use of pure zinc. Pure zinc and zinc alloys also exhibit pretty good tissue compatibility. 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.

Bowen: An antiatherogenic material, zinc can also prevent arteriosclerosis, or arterial plaque. Biochemical and cell biology researchers have recognized that zinc is a critical nutrient for the inner lining of the arteries, which is composed of endothelial cells. Nevertheless, despite its antiatherogenic properties, zinc cannot reduce already existing plaque.

Bob Michaels is senior technical editor at UBM Canon.

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