Introduction

Stents were first developed in the late 1970s out of a need to keep coronary arteries open after balloon angioplasty (Cohen, 2006). Balloon angioplasty can weaken the arteries, sometimes causing them to collapse within a few days (Cohen, 2006). At that time, the only treatment available was emergency bypass graft surgery (Cohen, 2006). Further, angioplasty was causing restenosis in almost one-third of all patients (Cohen, 2006). Bare metal stents were developed in the mid 1980s out of a need to prevent or lower the incidences of restenosis due to angioplasty.

While bare metal stents solved the problem of artery closure during the hospital stay, restenosis continued to occur in patients who received bare metal stents. In one-fourth of all cases, the stent experienced reblocking at around six months and had to be reimplanted (Cohen, 2006). Drug eluting stents were next developed in the hope that the pharmaceutical would prevent restenosis. Drug eluting stents have the same structure as a bare metal stent but are coated with a pharmaceutical. The pharmaceutical can also be contained within a thin polymer on the scaffolding of the stent to slow the release (Cohen, 2006). Drug eluting stents, in comparison to bare metal stents, decrease the risk of restenosis. However, drug elucting stents may increase the risk of stent thrombosis. Still searching for a solution that would reduce the risk of restenosis and stent thrombosis, a few companies are developing biomimetic stents. Biomimetic stents are coated with a biologic in order to improve biocompatibility. Thus far, biomimetic stents are showing great promise in reducing occurrences of restenosis, stent thrombosis, and even neointimal hyperplasia.

Stenting

Stenting is the process through which a stent is inserted into an artery. A catheter which includes a balloon covered by a stent is inserted into an access site. The access site can be a small puncture located in the arm or groin. The catheter is guided by imaging technology such as a camera through the artery to the site of blockage. Once the catheter is at the site of blockage, the balloon is inflated. As the balloon inflates, plaque and calcium that are clogging the artery are pressed against the wall of the artery and held in place by the stent. The balloon is then deflated, and the catheter is retracted out through the access site.

Bare Metal Stents

Bare metal stent inserted onto a balloon catheter (Cohen 2006).

Bare metal stents were developed in the mid 1980s in an attempt to prevent artery collapse and restenosis in patients receiving an angioplasty. Bare metal stents are cylindrical and developed in a mesh pattern and is made primarily of stainless steel, but can also consist of metals such as titanium alloy and nickel and titanium alloy, platinum and platinum iridium alloys, some cobalt chromium alloys, and other metals that have a high biocompatibility with low memory. Throughout the 1990s, incremental improvements were made by various companies such as using different types of metal or changing the structure of the stent. However, restenosis was still occurring in a significant number of patients who had bare metal stents implanted.

Drug Eluting Stents

Drug eluting stents were developed in an attempt to reduce the occurrence of restenosis at the site of stent implantation. Drug eluting stents have a metal framework that is coated with the pharmaceutical mixed with a polymer surface matrix, covered by a polymer matrix to slow the release of the pharmaceutical. Pharmaceuticals that are used in drug eluting stents include sirolimus and paclitaxol. Sirolimus reduces neointimal hyperplasia by reducing the number of cells that grow around the stent. Sirolimus is used in the Cypher® stent developed by Cordis and is the first drug eluting stent. Paclitaxol is a pharmaceutical that is used to treat cancer, but is used to improve the luminal diameter in the artery where the stent is implanted. Paclitaxol is pharmaceutical agent used in the Taxus® stent developed by Boston Scientific. Other companies such as Medtronic are also developing drug eluting stents that are currently in clinical trials. Abbott Laboratories is currently developing a drug eluting stent that is bioabsorbable after three years. This characteristic may decrease the possible of restenosis in patients. While drug eluting stents do decrease restenosis, they increase the occurrence of stent thrombosis. Additionally, drug eluting stents do not significantly improve the rate of occurrence of complications due to angioplasty in comparison to pharmaceuticals alone.

Restenosis

Restenosis is defined as the reoccurrence of stenosis. It is a medical term that refers to the gradual re-narrowing of the artery during several months following a medical procedure. The term is used most commonly in relation to cardiac procedures such as angioplasty.
Several mechanisms can lead to restenosis. An important one is the inflammatory response, which induces tissue proliferation around an angioplasty site.

Sometimes, restenosis is caused by blood clots occurring at or near the site of the treatment. Aspirin, heparin, or combinations of anti-clotting drugs are generally used before and after the procedures to try and prevent this. Restenosis may be caused by the walls of the artery gradually ‘caving in’ to their original position. Use of catheters to broaden artery may cause local injury to tissue and the healing of cracks by platelet accumulation may cause the artery to block again. Blood clot formation produces thrombin, which can cause cell proliferation. While this is an essential healing process, unnecessary cell proliferation can narrow the artery further obstructing blood flow.

Cathetarization versus Stenting

A catheter is a tube that can be inserted into a body cavity or vessel. The process of inserting a catheter is called catheterization. In most cases a catheter is a thin, flexible tube that allows access to various body parts and organs that are not easily accessible with surgery.

The use of catheters was first implicated in coronary angioplasty surgery also known as
Percutaneous Transluminal Coronary Angioplasty (PTCA). The method was first developed in 1977 by Andreas Gruentzig and was quickly adopted by many cardiologists, as a method to avoid Coronary Artery Bypass Grafting surgery (CABG). Catheters are used commonly in surgical procedures such as angioplasty to gain access to a clogged blood vessel. First, an introducer needle is used to gain access into the femoral artery in the leg3. Once access into the artery is gained, a sheath introducer is placed in the opening to keep the artery open and control bleeding. Then, through this sheath, a long, flexible, soft plastic tube or guiding catheter is pushed. The tip of the guiding catheter is placed at the mouth of the coronary artery. In balloon catheterization, the balloon in inflated at the site of stenosis leading to compression of plaque (figure 1).

More recently, however, a small mesh tube, or stent, is introduced into a blood vessel or artery to prop it open using percutaneous methods. Angioplasty with stenting is a viable alternative to heart surgery over balloon catheter angioplasty. Bare metal coronary stents provide a mechanical framework that holds the artery wall open, preventing stenosis. PTCA with stenting has been shown to be superior to angioplasty alone in patient outcome by keeping arteries unblocked for a longer period of time.
Newer drug-eluting stents coated with drugs release certain medications over time and further decrease the possibility of fatal restenosis. It has been shown that these types of stents help prevent restenosis of the artery through several different physiological mechanisms, most of which rely upon the suppression of tissue growth at the stent site. Three drugs, sirolimus, everolimus and paclitaxel, have been successfully used for this purpose. Antisense knockdown of c-myc, a protein critical for progression of cell replication, is another approach to inhibit cell proliferation in the artery. Clinical trials are underway to investigate this prospect further.
The Regulatory Requirements for Combination Products

The use of biomimetic stents has proven to be an area where the regulatory process can be both extensive and cumbersome. This is in part due to the fact that both the regulatory requirements of a biologic and a medical device must be considered. All biomimetic stents or drug-eluting stents (DES) are class III devices requiring the submission of a Pre-Market Approval (PMA). The Food and Drug Administration (FDA) has defined a combination product in 21 CFR § 3.2(e), to be compromised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity. Biomimetic stents would fall under the regulation of a biologic/device. Depending upon the type of combination product, its approval, clearance or licensure may be obtained through a submission of either a single marketing application or through two marketing applications for the individual constituent parts of the combination product. If for example one of constituent parts of a combination product, like heparin coating is already approved for another use, the labeling of the already approved product will have to reflect it new intended use in the combination product, so the FDA may determine that two applications are necessary. The Office of Combined Products (OCP) is developing guidance documents for public review and comment addressing the factors FDA expects to consider whether a single or multiple marketing application(s) should be submitted for a combination product (FDA, accessed 4 May 2007).

There are three departments in which the FDA center can oversee a product’s regulation: Center for Drug evaluation & Research (CDER), Center for Biologics Evaluation & Research (CBER), and the Center for Devices & Radiological Health (CDRH). Of these three a company would prefer to through CDRH, because it is less stringent and easier to get a product approved and on the market. There has been a debate with the FDA as to what department is assigned for review of combination product PMA’s, this is in part the reason of the inception of the OCP. The OCP is to act under a set of defined ‘mode of action (MOA) and ‘primary mode of action’ (PMOA), in which it is to ensure the prompt assignment of combination products to agency components, the timely and effective pre-market review of such products, and the consistent and appropriate post-market regulation of combined products. The single mode of action of a combination product is that it provides the most important therapeutic action of the combination product (FDA, accessed 4 May 2007). Due to the heavy regulation of combination products many companies have opted to just provide the biologic or drug through licensing while, the device company takes on the responsibility of the combination regulatory requirements.

Industry examples of Regulatory Stents and Coating Manufacturers

The use of biomimetic and biological materials like heparin coating for anticoagulation in combination with the stent can be a powerful tool against diseases like restenosis, thrombosis, myocardial ischemia, myocardial infraction, stroke, and other coronary heart disease. This is a lucrative market in which the main players consists of Guidant (a division of J&J), Cordis, Boston scientific, Medtronic, Allvivo, Advanced Bio Prosthetic Surfaces, Biosensors International, Biotronik, Conor Medsystems, Design and Performance Corporation, Devax, Endovasc, Hemoteq, OrbusNeich, REVA Medical, Surmodics, and Translumina (Chadwick, 2006). While some of these companies are in the business of both the production and regulation of the drug or biological in conjunction with the stent, just Allvivo, Hemoteq and Surmodics are in the market for biomimetic coatings and have elected to develop only the coating and leave the stent manufacturing to others like J&J. All three companies, Allvivo, Surmodics, and Hemoteq do assist its customers with resources and support through the regulatory process and maintain their device master files with the FDA to expedite the regulatory approval of new products (Allvivo, Hemoteq, SurModics, accessed on 4 May 2007) (figure 2).

Figure 2. Five Basic Steps to begin utilizing SurModics technology to enhance the product.

While drug eluting stents are similar in fashion to biomimetic stents and they often get regarded as the same, they are different; one lies under regulatory requirements of a drug and the other a biologic. As of late 2003, the only drug-eluting coronary stent that has been granted US FDA approval is the Cypher sirolimus-eluting coronary stent from Cordis Corporation (Medical Device Link, accessed on 4 May 2007). There are certain specifications and physiological parameters that must be proven during clinical trials for indications of use. For example, the Cypher sirolimus-eluting coronary stent is indicated for the use of improving coronary luminal diameter in patients with symptomatic ischemia disease due to discrete de novo lesions of length < 30 mm in native coronary arteries with a reference vessels diameter of > 2.5 to < 3.5 mm. While Cordis manufactured the stent, Surmodics provided the coating for the stent. The regulatory strategy employed by Cordis was to perform the necessary research upfront, and provide reimbursement for Cypher upon market approval by approaching Medicare and Medicaid before FDA approval. Another company that came out with an approved combination product was Boston Scientific, who in 2004 came out with their own stent, the Taxus stent, that was coated with Placlitaxel also known as SIBS or poly (styrene-b-isobutylene-b-styrene). It was approved for the taxus express2 paclitaxel-eluting coronary stent system (monorail and over-the-wire), and the device is indicated for improving the luminal diameter for the treatment of de novo lesions <28 mm in length in native coronary arteries > 2.5 to < 3.5 mm in diameter (Baura, 2007). While these two are the only examples of approved coated stents in the market, it is important to keep in mind that these are approved drug coated stents, to date there are no approved biomimetic stents.

FDA Regulatory Hurdles with Combination Products

Are the drug-eluting stents really better than bare metal stents and drug treatments? The FDA and other cardiology departments have conducted studies to test the effectiveness of DES, and have found that under certain parameters there is a statistically significant increase of stent thrombosis with the use of DES as opposed to bare metal stents in conjunction with a drug regimen (Stone et al., 2007). This study also found that there was an increase in death with use of the Cypher and Taxus stents as compared to bare stents, however, these results were not significant. The consequences of this study have prompted the FDA to conduct their own study on the safety and efficacy of the use of coated stents. The Circulatory Systems Devices Advisory Panel met and the FDA has made statements in both 2006 and 2007, stating that larger and longer pre-market clinical trials along with longer follow-up post-approval studies are needed (FDA, accessed on 7 May 2007]. This has put many constraints on the combination product market, to which there is there is not a present solution (Baura, 2007). Another issue is the cost of a coated stents which is $22,000 as opposed to $700 for a bare metal stent, prompting the questioning of its cost-effectiveness in light of the recent studies (Baura, 2007).

Biomimicry

Biomimicry is the process through which devices, pharmaceuticals, and processes are designed to imitate that which occurs in nature. In the instant case, biomimicry would apply to developing a biologic that would coat the stent in order to prevent complications such as restenosis or neointimal hyperplasia and promote greater biocompatibility between the stent and artery walls.

Prevention of Neointimal Hyperplasia by Re-endothelialization The lack of an endothelium on the luminal surface of the grafts has been implicated as a stimulus for the activation of smooth muscle cells, the development of intimal hyperplasia, and the late failure of grafts. The formation of an endothelium provides a non-thrombogenic and anti-inflammatory barrier between the stent-graft and the circulating blood.

Glycocalyx Coated Stents

Hemoteq, a German company, is a leading provider of surface modification solutions for medical devices. The company designs customized nanocoatings for a variety of devices and applications. Its proprietary Camouflage® coatings are ultra-thin synthetic imitations of the endothelial cell glycocalyx. Glycocalyx is a general term that refers to the charged carbohydrates of the outermost layer of cell surfaces. Since the glycocalyx is permanently in contact with the coagulation system in nature, it doesn’t interact with or activate the coagulation system. Hemoteq’s product, Camouflage® is a synthetic imitation of the glycocalyx lining endothelial cells. The surfaces on which it is coated are masked as endothelial cells. Camouflage® confers excellent hemocompatibility to coated surfaces and hence should make a very good coating for biomimetic stents. The Camouflage® coating can also be used on other medical devices such as grafts, valves tubing and catheters. It is available in several covalent bonding types and can thus be coated on a variety of surfaces.

Besides this, Hemoteq also makes a drug eluting coating under the brand Repulsion®, which prevents restenosis. Advantages for both Camouflage® and Repulsion® are combined in a another product which is marketed as a drug-eluting stent platform called Ouverture®, which consists of Repulsion® coated on a base coat of Camouflage®.

Peritoneum Lined Stents

Despite the enthusiasm for drug eluting stents, they haven’t proven to be efficacious in the superficial femoral artery (SFA). Stent grafts and bare metal stents are also not effective at treating SFA disease. The primary reasons for these failures are neointimal hyperplasia and stent fractures. Recently, at the Cleveland Clinic Foundation, peritoneum lining has been demonstrated to show improved patency when used for stent-grafts placed in a canine iliac artery balloon injury model. Since the canine iliac artery is similar to human SFA in diameter and the lesion length to be treated, this shows possible utility of peritoneum lined stents in SFA occlusion disease. Peritoneum lined stents were found to be more thrombo-resistant than dacron lined stents. The peritoneum lined stent showed lesser progression of intimal hyperplasia and thus a greater lumen size. One reason for this might be that the peritoneum serves as a scaffold for rapid re-endothelialization. Peritoneum offers several advantages over other synthetic materials that are commonly used in stent grafts such as Dacron and ePTFE. Peritoneum is the serous membrane that forms the lining of the abdominal cavity of higher vertebrates. It is composed of a single confluent layer of mesothelial cells with an underlying basement membrane that is derived from embryonic endoderm (similar to endothelium). It is similar to pericardium and pleura in that it functions as a frictionless interface between visceral surfaces. It is often used in combination with prosthetic tissue, the theory being that the biological peritoneum tissue provides physiological benefits while the prosthetic tissue provides structural integrity.

PeriTec Biosciences, a spin-off of the Cleveland Clinic Foundation, is focusing on producing a peritoneum lined stent graft for the treatment of peripheral artery disease, particularly the SFA. After success in canine trials they are in the process of filing for an IDE.

P15-coated stents Collagen-coated Stents Though studies of stent-grafts that were placed into the large arteries of the aortoiliac system had promising results, the stent-grafts placed into small arteries did not have high patency rates due to reactions to the synthetic stent-graft materials, such as polyurethane and PTFE, that were used. Thus, the development of biomaterials is critical to the success of using stent-grafts in small arteries.

A natural biologic polymer, such as collagen, is potentially more biocompatible than the synthetic polymers. Collagen also possesses sufficient tensile strength to exclude blood flow into an aneurysm at systemic blood pressures. In a study done using nitinol-collagen stent grafts implanted in abdominal aorta of rabbits, collagen as a stent-graft material was found to be biocompatible for at least 3 months. It was found to be rapidly endothelialized and didn’t cause restenosis.

Heparin-coated stents Heparin is a proteoglycan that has been shown to inhibit smooth muscle cell proliferation in vitro. Its inhibitory effect on the smooth muscle cell is mediated in part through interactions with cell receptors, growth factors, adhesion molecules, and proteinase inhibitors. Because of heparin’s antiproliferative and anticoagulant properties, researchers have examined various strategies of administering heparin after intraluminal stent placement in an effort to reduce intimal hyperplasia. These strategies include local intraluminal infusion of heparin, adventitial administration and coating the stent with the heparin polymer. Clinical studies have demonstrated that heparin-coated stents result in less acute thrombus formation after coronary placement. In another study, it was demonstrated in that heparin-coated balloon-expandable stents offer at least short-term benefits in maintaining luminal patency and reducing intimal hyperplasia after iliac artery placement in baboons.

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