CD&D National Editor

What causes thrombosis in drug-eluting cardiovascular stents (DES)? What's the primary culprit – stent, drug, polymer? What's to blame for this unhappy side effect?

That's a question that has dogged this sector for some time now. Early on, DES devices were presented as the "gold standard" in stent technology, but they have been plagued by a very small rate of thrombosis that, while miniscule, is sometimes highly fatal.

So how to prevent this side effect?

Rather than providing an easy answer, engineering researchers at the Massachusetts Institute of Technology (MIT; Cambridge) have developed work providing a mathematical approach to stent turbulence – a sort of mechanical culprit – saying that all three elements of DES must be considered to produce the best, safest devices.

Elazer Edelman, MD, PhD, the Thomas D. and Virginia W. Cabot Professor of Health Science and Technology at MIT and senior author of a paper on the work, told Cardiovascular Devices & Drugs that he has been looking at stent design since the 1980s, with particular focus on the "kinetics" created by these devices, with blood flow "a very important part of the equation."

"We look at elements at stent design, elements of arterial geometry, the elements of blood flow – we need to match all three of those things" to determine clinical relevance, he said. "What happens to the drug as it's released with a certain set of kinetics?"

Adding to this equation, he said, is still "a fourth element – the physical/chemical properties of the drug and how these penetrate and bind" in the artery to potentially impact flow.

Edelman said that the basis of the research was to put these factors "into the computational model and asked fundamental questions."

The resultant model, he said, "helps explain why some stents are better than others, and could predict which stents are predisposed to cause clotting." Edelman and HST postdoctoral associates Vijaya Kolachalama and Abraham Tzafriri designed the model – appearing in an early January issue of the Journal of Controlled Release – to predict how the size and shape of a stent affects blood flow and drug distribution.

Edelman used the analogy of white water rafting to explain what happens in a stent.

"I do love white-water rafting, which is similar the issues we looked at," he said. "But I must confess that the idea of occluded flow probably evolved subconsciously."

He said that just like the turbulence experienced by a white water rafter, the same types of action occurs when blood flows across a stent: Drugs tend to accumulate and spin around in the "recirculation zone." And this, he said, is most likely to happen with stents that protrude further into the artery.

"Until now, the degree to which recirculation zones impact the distribution of drugs was not appreciated," said Edelman.

The mathematical model developed is considered the first to successfully predict stent performance, based on changes in arterial blood flow and design, and the researchers hope the model and concepts it establishes could aid efforts to design stents that allow drugs to be more evenly distributed throughout the area.

The research did not compare the architecture of current stents on the market, Edelman told CD&D, but rather was intended to help the FDA in assessing and understanding the safety of future devices, based on their size and shape, which controls how they will affect blood flow.

So what about the thrombosis question – and what part of the DES is to blame?

Calling that a "wonderful question," Edelman said that there is no one culprit or simple answer.

"One of the things that we've shown, in particular, is that it's not stent, not the coating, it's not the drug, but all of the things" that may result in injury to the artery. "Indeed, that is one of the very important part of what we've found."

"Everyone would like to believe that there's a simple solution to these issues, but it's far more complicated," particularly in understanding how stent design, polymer and drug all impact blood flow and resultant turbulence.

But Edelman went on to say that in determining drug efficacy, stent architecture may be the most important feature in the equation of stent/polymer/drug/turbulence.

"What we have shown is that the elution of drug makes the design of the stent that much more critical. A stent design that disrupts blood flow, rather than one that does not, will have the likelihood of potential complication," he said.

"Assuming you need it to release a drug [from a stent], and assuming that you were going to do so from a polymer coating, then stent design becomes the distinguishing feature of how that unit will respond." And: "Depending on which you would prefer to do – change the drug or change the [stent] design – you should pay most attention to changing the design."

The research was funded by the National Institutes of Health.

Edelman is an intensive care unit cardiologist who runs an integrated physiology research laboratory and directs the Harvard-MIT Biomedical Engineering Center (Cambridge, Massachusetts).

His research also recently resulted in a study describing the healing of airway injuries in rabbits, using a technique that might eventually apply to the trachea and other parts of the human body.

The technique is designed to heal airway injuries by placing new tracheal cells around the injury site. Two types of tracheal cells, embedded within a 3-D gelatin scaffold, take over the functions of the damaged tissue.

"We can begin to replicate the regulatory role cells play within tissues by creating engineered constructs with more than one cell type," Edelman said.

Patents on the technique have been licensed to Pervasis Therapeutics (also Cambridge), a company co-founded by Edelman and on which he is a board member, which develops cell-based therapies that induce repair and regeneration in an array of tissues.

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