Drug Eluting Stents

Matt Osten, osten055@umn.edu Dan Rosenbush, rosen855@umn.edu Andrew Asmus, asmus025@umn.edu Scott Ajax, ajaxx003@umn.edu

BMEn 3301 Biomaterials

Prof. Wei Shen

Friday, May 4th, 2012

Introduction Stents are hollow tubes usually made out of a wire mesh that are placed into narrowed arteries. These stents are implanted via a catheter through an artery. Once the stent is in the proper position a balloon is inflated which expands the stent and sets it in place. The balloon is then deflated and taken back out. This procedure is known as coronary stenting, it is the most common procedure for treating coronary artery disease, also known as atherosclerosis. Bare metal stents were the first stents to reach the market, but they tended to cause restenosis fairly quickly due to the bodys natural defense system to fight a foreign object in the body. Restenosis is a multistep process in which smooth muscle cell migration, extracellular matrix formation and other tissues start to form on the newly stented segment. For these reasons, the drug-eluting stent was developed. The drug-eluting stent is coated with drugs that are slowly released to inhibit the biological processes. The drug eluting stent has become greatly popular because of their high success rates. (Burt 2006) Shown below in figure 1 is a common stent placed in a thrombosed artery. Figure 1: Common Stent

Background In the early years of treating coronary arterial stenosis, cardiologists used angioplasty balloons. The balloons would successfully open up the artery, but a short time after the balloon was deflated and taken out, the artery would collapse. Since there were no other options at the time, bypass graft surgery was the only fix. Because of this problem, many doctors came out with various devices to treat the problem, one of which was the stent. The stent became a very popular choice because it was a good solution in stopping sudden restenosis. The early stent was inserted much like it is today. The first stent to be used in a human was in 1986 in France by Jacques Puel and Lrich Sigwart, and by 1994, the first stent was approved in the United States. Over the next ten years many new bare metal stents came out on the market that were much more durable and flexible. Although the stents stopped arteries from suddenly closing, thrombosis was a common theme. Bare metal stents cause thrombosis in about 20-40% of the cases in the first six months they were in. This reoccurring theme caused the switch from only structural devices to new drug-eluting ones. New stents coated with drugs slowly released and inhibited the bodys natural defense processes leading to less thrombosis. (Cohen 2008) Deliverability Stents are implanted using catheters inserted usually through the femoral artery. The first step of this process involves using a contrast agent to identify proper placement of the stent. Once the thrombosis location is found, an angiogram (or detailed ultrasound image) is used to look at the blood vessel. Next, the catheter is positioned correctly and a balloon is inflated to clear the thrombosed area. Once the

artery is fully dilated, the catheter is retrieved, and a stent is placed on the balloon. The catheter is then re-inserted to the thrombosed location where the balloon is again inflated and the stent is set in place. Another method of stent insertion involves nitinol stents, which self-expand once a temperature threshold is reached, eliminating the need for a balloon. Biocompatibility Implantation of any biomaterial is an invasive procedure that initiates a cascade of events whose outcome ultimately determines the biocompatibility of the material. In implantation of biomaterials foreign body reaction responses can occur. These cellular events include protein adsorption, inflammation, macrophage adhesion, and macrophage fusion into foreign body giant cells. There are three possible outcomes of the continued presence of a biomaterial. The body can either reabsorb the biomaterial, create a fibrous encapsulation around the foreign object, or be integrated with the body and become a successful biocompatible implant. Biomaterial surface properties play an important role in modulating foreign body reactions. By design, the drug-eluting stent delays the formation of a new endothelium cover over the stent and inhibits clot formation. These effects can limit the rate of restenosis and limit life-threatening effects.(Anderson 2009) Drug-eluting stents do not come without problems though. There is some evidence emerging that suggests that this late-stent thrombosis may be a result of a delayed healing process or a delay in re-endothelialization leading to cases of increased platelet aggregation and inflammation at the sight of the implantation. Patients who receive a stent need to take both aspirin and anti-clotting medications to decrease the

risk of thrombosis. Another problem that drug-eluting stents can have is that the drug can actually inhibit the good healing that needs to take place in-order for restenosis not to occur. The drug can prevent the inner lining of blood vessels from forming over the stent which prevents blood clotting. (Cohen 2008) Structure The drug-eluting stent consists of three parts; the stent framework, the coating, and the drug. The framework of the stent is an expandable metal mesh tube usually made out of nitinol or stainless steel. The stents can be anywhere from 2.25mm to 4mm in diameter and 8mm to 38mm in length depending on the size of the artery. The shapes of the stents can take on different forms, such as diamond shapes, rings with links, and many other complex shapes. These different forms allow for the stent to be strong yet still flexible when expanded. Deliverability, strength, diameter, and length are just some of the factors that are taken into account when choosing a stent. (Burt 2006) Mechanical Properties Mechanical properties of stents are very important to the life of the material. Increased success of the devices has prompted their implantation into regions that would have previously been viewed as too narrow. Stents subjected to these regions are put under a high amount of stress and there have been several reports of fracture. In order to limit device fracture many studies have been performed on flexibility, pressure-diameter relationships, and size-dependent tensile strength. In one such study, F. J. Harewood and P.E McHugh studied the size dependent failure in cardiovascular stent struts under tension and bending. At the microscopic size scale

they showed that the tensile failure strain is size dependent. Shown in figure 2 and figure 3 is the relationship between strut diameter and failure strength.(Harewood 2007) Figure 2. Comparison of the failure strain vs. strut thickness

Figure 3. Macroscopic stress-strain relationship of four different strut thicknesses

Coating Drug-Eluting stents are covered with a coating, usually a polymer. The coating holds on to and delivers a drug onto the wall of a vessel; it does so by contact transfer. The coating is applied by either submersion of the stent in the coating or by a spray-on application, and there can be multiple coatings on each stent. The multiple coats are used to slow the elution of the drug. The first drug-eluting stents used durable coatings,

but new innovations have led to coatings that biodegrade once the drug has been released. The reason why the biodegradable coatings are preferred is because the durable coatings have been known to cause late stent thrombosis. The degradation time of a biodegradable polymer can be altered by changing the ratio of monomers that make up the polymer. Drug releasing from biodegradable polymer coated stent is mainly through two mechanisms: (1) drug diffusion and (2) polymers degradation (Ma, 2011). The drug release is also influenced by blood flow, pH level, temperature, and other cellular events found in the newly stented segment. More testing still needs to be done, but the biodegradable coatings appear to be solving the problem of restenosis. (Huang 2010) In one study, researchers investigated a metal stent sprayed with multiple layers of collagen and sirolimus, an immunosuppressive agent. (Chen 2005) In the study they used a spray-coating method on a 316L stainless-steel stent (13mm in length.). Layer by layer the stents were coated with aqueous bovine type I collagen, a biocompatible and biodegradable film, and sirolimus. The biocompatible collagen film is key in preventing an inflammatory response and hyperplasia. A dip-coating method was first used to apply the coating, but it was found that the collagen did not evenly distribute. To ensure the drug would not dissolve, a cross-linking agent, genipin, was added to the collagen. Mei-Chin Chen performed many tests on this particular stent to see how it was affected. (Chen 2005) Chen studied the amount of adhered platelets as a function of percent collagen crosslinking by genipin. Platelet adherence was evaluated at a 0%, 35%, 50%, 70%, and at 85% degree of cross-linking. The test samples were immersed in a collagen solution and incubated at 37 degrees for 28 days. Figure 4 shows these

results below. The test showed that a proper degree of collagen cross-linking increases stent hemocompatability as platelet adsorption is reduced. This is consistent with past findings that biological fixation of genipin significantly increases hydrophilicity and surface tension, thus decreasing the amount of adsorbed proteins and platelets in vivo. The study also showed that treating stents with genipin via biological fixation for crosslinking does not adversely affect other stent functions, such as increasing the amount of deformation of the collagen layer. (Chen 2005) Figure 4: Effect of Collagen Crosslinking Platelet

The amount of enzymatic collagen degradation was also examined as a function of collagen crosslinking. A collagen film was placed in a collagenase solution for 28 days and the degradation of collagen was recorded. It was found that resistance to degradation increased as the amount of crosslinking increased. This likely resulted from the cleavage sites of the collagen molecules being hidden or altered by cross-linking, thus limiting the effect of collagenase. The results from this test are shown below in figure 5.

Figure 5: Effect of Crosslinking on Collagenase Degradation

Angioplasty balloon expansion was also tested to determine the integrity of the collagen coating. The genipin cross linked collagen stent was mounted on a balloon angioplasty catheter and was expanded to a maximum pressure of 10 atmospheres for 30 seconds, and then deflated. After the test, a SEM was taken to examine the collagen. No damage of the collagen coat had occurred. This showed that the collagen coating exhibited enough flexibility on the stent to avoid cracking or peeling upon expansion. (Chen 2005) This follows our previous knowledge that polymers such as collagen exhibit low elastic modulus and can deform easily without approaching mechanical failure. Figure 6 below shows a genipin treated stent before (a) and after (b) expansion from an angioplasty balloon. The stent retains its smoothness upon deformation and does not exhibit mechanical failure. Figure 6: Effect of Deformation on Genipin treated Stent

Currently, dual drug-eluting stents look to combine drugs to outperform the single coated stents available. Dual-drug eluting stents have both an anti-proliferative drug (sirolimus) and an anti-thrombotic drug (triflusal) incorporated in a biodegradable coating that release concurrently (Huang, 2010). The anti-proliferation drug, sirolimus, is a lipid soluble drug which favors elusion into the newly stented segment and limits the amount of drug that is released into the bloodstream. The localized delivery of sirolimus also limits the amount of smooth muscle cell migration and reduces the risk of restenosis. While the anti-thrombotic drug, triflusal, is a chemical relative to acetylsalicylic acid (aspirin). Its chemical structure works to inhibit cycloygenase-1 in platelets and increases nitric oxide and the concentration of cyclic nucleotides. When these two drugs are coated on a stent, anti-proliferation and anti-thrombus drugs are able to be directly delivered to the endothelial wall. A dual drug-eluting stent is able to be uniformly coated on the biodegradable polymer by dissolving the polymer, PLGA 80/20, with dichloromethane and mixed into a homogeneous solution before both sirolimus and triflusal are added. The mixed polymer is cast on a glass panel using an automatic film applicator and dried in a vacuum oven at 37C for 7 days to evaporate the dichloromethane (Huang, 2010). To prepare the stents for the polymer coating, they are sterilized with an ultrasonic cleaner using acetone. Dual drug-eluting stents have an inner layer made of the mixed drug polymer while an outer coating contains only the polymer and is sirolimus and triflusal free. It is this outer layer that controls the rate at which the two drugs will be released. The release profiles of triflusal and sirolimus can reduce thrombus formation even further than a single coated drug-eluting stent, but again more testing needs to be conducted to

ensure that these biomaterials are as safe as the FDA approved stents being currently used.(Huang 2010) Figure 7 shows the properties of the dual drug-eluting stent. Figure 7: Dual drug-eluting stent

Areas of Improvement Even considering how groundbreaking and important the development of drugeluting stents has been for the medical world, there are still improvements that can made to make stents even more impactful. Obviously, one route would be to continue to find new materials and alloys that are lighter, stronger, and more flexible than anything that is being used now. These new materials would allow for the stents to be smaller and less bulky, causing them to be less intrusive to the blood flow in the artery. However, we feel that the ultimate progression of stents would lead to a stent material that is itself biodegradable. After all of the drug has been released and the polymer coating has degraded, the once drug-eluting stent is more or less a normal bare metal stent, which leads to an increased risk of restenosis in the artery. Having a stent

scaffold that degrades after the initial thrombus has been removed would eliminate the threat of restenosis associated with bare metal stents. Since metals are not biodegradable, this new class of stents would most likely have to be some type of polymer, either synthetic or natural. Conclusion The drug-eluting stent is a high-impact biomedical device that is used in the medical field to treat patients with coronary artery disease. Since the first drug-eluting stent was approved, stents have dominated the market. Drug-eluting stents release an anti-proliferative drug that suppresses smooth-muscle cell proliferation, reducing the risk of restenosis. Drug-eluting stents are superior to their counter-parts, the bare metal stents, although the drug-eluting stents can cause restenosis, their restenosis rates are significantly better than the bare metal stent. With further investigation into dual drugeluting stents along with research into biodegradable stents the outlook looks bright for drug-eluting stents. References Chen, Mei-Chin. "A novel drug-eluting stent spray-coated with multi-layers of collagen and sirolimus ." Journal of Controlled Release 108.1 (2005): 178-189. Web. 7 Mar 2010. Canan, Timothy. "Drug-Eluting Stent Fracture." Wiley InterScience 75. (2010): 237-245. Web. 25 Apr 2010. Cohen, Burt. "Drug-Eluting Stent Overview." Angioplasty.org 2008: n. pag. Web. 25 Apr 2010. Harewood, F.J. "Modeling of Size Dependent Failure in Cardiovascular Stent Struts under Tension and Bending." Annals of Biomedical Engineering. 35.9 (2007): 1539-1553. Print.

Burt, Helen. "Drug-eluting stents: A multidisciplinary success story." ScienceDirect 58.3 (2006): 350-357. Web. 25 Apr 2010. Huang, Yingying . "In vitro and in vivo performance of a dual drug-eluting stent (DDES) ." ScienceDirect 31.15 (2010): 4382-4391. Web. 25 Apr 2010. Anderson, James. "FOREIGN BODY REACTION TO BIOMATERIALS." PubMed Central. NIH, 2009. Web. 28 Apr 2012. Ma, W. e. (2011). Paclitaxel/sirlimus combination coated drug-eluting stent:In vitro and in vivo drug release studies. Journal of Pharmaceutical and Biomedical Analysis, 807-811.