Originally Published MDDI August 2005
The continued success of drug-eluting stents relies heavily on little-known technologies. Parylene, for example, could have far-reaching applications.
|Drug-eluting stents, although more expensive per unit, may reduce healthcare costs in the long run.|
Coronary artery bypass grafting (CABG) was to be the surgical solution to coronary atherosclerosis. When percutaneous transluminal coronary angioplasty (PTCA) was introduced, it seemed to be the less-invasive alternative to CABG. PTCA with stenting then evolved to solve the issue of post-PTCA artery collapse. But just like its predecessor interventions, PTCA with stenting also revealed a weakness—restenosis, the renarrowing of the stented coronary artery attributed to excessive smooth muscle cell proliferation (scarring) beneath the vessel's endothelium. Restenosis, which occurs in 25–35% of stented patients, is of no small concern to cardiology interventionists as well as to patients who have stents in situ or who are candidates for a stenting procedure.1
In early 2003, the combination technology of drugs and devices brought the drug-eluting stent to the U.S. market. The drug-eluting stent was developed to eliminate (or at least diminish) the occurrence of restenosis in the coronary arteries after stenting. In very simple terms, a drug-eluting stent is one that is overcoated with a pharmaceutical agent that prevents or reduces the undesirable smooth muscle cell proliferation that occurs at the stent-delivery site, and thereby impedes recurrent stenosis. As we have seen, the promise of the drug-eluting stent is being fulfilled many times over. This article examines the evolution of drug-eluting technology, with a particular focus on the role of parylene coatings in their development.
Having delivered on its promise of being highly effective in the fight against restenosis and providing direct delivery of drugs to the coronary artery's wall, drug-eluting-stent use has risen dramatically and shows little sign of slowing down. The drug-eluting Cypher stent from Cordis Corp., followed by Boston Scientific's Taxus stent, have revolutionized treatment possibilities and significantly reduced the frequency of recurrent stenosis. In fact, the U.S. market alone for drug-eluting stents could exceed $6 billion in revenues by the end of 2006, as projected in a study by MarketMavens.com.2
While drug-eluting stents cost more on a per-unit basis, they may actually reduce overall healthcare costs considerably. They have been shown to be more effective than their bare metal counterparts, i.e., they require significantly fewer repeat interventions, including bypass surgery. Additionally, the per-unit cost of drug-eluting stents should continue to drop as other suppliers receive FDA approval for sale of their versions in the United States.
The combination of medical benefits and healthcare cost savings coupled with a lower per-unit cost will likely continue to fuel the growth of drug-eluting stent sales.
All the successes aside, however, coating stents with drugs is not a simple process. To make drug-eluting-stent technology a clinical reality, stent manufacturers had to overcome significant challenges. They had to secure a pharmacologically effective dose of a drug onto the minuscule surface area of a typical stent to make the drug-coated stents therapeutically meaningful in their battle against restenosis. Maintaining adhesion of the drug or drug-polymer combinations to the metal stent before, during, and after delivery to the coronary artery and controlling the rate of drug elution also posed significant hurdles.
One of the little-recognized and little-publicized enabling technologies helping to make the development of the
drug-eluting stent possible is parylene coating, a surface-modification process. The conformal and biocompatible polymeric coating is well suited for drug-eluting stents. A primary example is the Cypher sirolimus-eluting stent from Cordis. According to the stent's instructions for use: “A combination of the two polymers mixed with sirolimus (67%/33%) makes up the basecoat combination, which is applied to a parylene C treated stent….”3
Parylene has been widely used to eliminate problems related to microporosity, biocompatibility, and biofluid corrosion protection in medical devices for nearly 30 years. Although parylene is not a new material to the medical device industry, it is being used in a new way. For coronary stents, it is being used as a bonding, or tie layer, material and as a drug-release control agent. As a bonding agent or tie layer, parylene coatings are applied between the metal stent and the drug or drug-
carrier polymer. As a drug-release control agent, parylene is applied over the drug-coated stent.
|Parylene has enabled stents such as Cypher's sirolimus-eluting stent to reduce problems
related to biocompatibility.
To understand the unique properties that make it so useful in these applications, it is important to understand the characteristics that make parylene so well suited to in vivo devices.
Parylene is a viable coating option for medical devices primarily because of its biocompatibility and biostability. ISO biological evaluation tests have demonstrated very low levels of fibrous capsule formation, nearly nonexistent toxicological responses, and excellent hemocompatibility.4 Parylene has been shown to exhibit nonthrombogenic properties and does not trigger an immunological response. Parylene provides a moisture and chemical barrier, and it is highly resistant to the damaging effects of body fluids, electrolytes, proteins, enzymes, and lipids. Parylene offers dry-film lubricity, with static and dynamic coefficients of friction approaching those of Teflon.
Parylene coatings can be applied to most any material that is vacuum stable. It has been successfully applied to paper, ceramics, plastics, metals, polymers, and even feathers and powders. It is routinely applied to ferrites, nitinol, stainless steel, cobalt chromium, precious metals, rubbers, silicones, printed circuit boards, and silicon wafers. Parylene is used in implantable cardiac defibrillators, pacemakers and neurostimulators, catheters, needles, stents, and components for numerous other medical devices.
The process by which parylene is deposited, vapor deposition polymerization, ensures a truly conformal coating. The film deposits one molecule at a time and faithfully follows the most intricate contours of the stent struts being coated. Whether fully expanded when coated, as in the case of the nitinol stent, or in the neutral state, as with most stainless-steel or cobalt-chromium stents, parylene coats all surfaces conformally and uniformly. Vapor deposition is uniquely suited to coat the intricate structures of stents without webbing or pooling.
Parylene film coatings are free of fillers, stabilizers, solvents, catalysts, and plasticizers. Parylene N is a carbon-hydrogen molecule; parylene C is a carbon-hydrogen molecule with a chlorine atom on the benzene ring. As deposited, parylene is complete, requiring no further curing, cross-linking, or other processes to achieve its inherent properties.
Parylene's deposition process facilitates the precise control of coating thickness and ultimately its ability to serve both as a bonding and as a release-control agent. The deposition of parylene begins with a powdered raw material known as dimer. Sublimated directly to a vapor and cracked to a monomeric state, the resultant parylene coating forms by spontaneous polymerization on the target substrate in an evacuated, room-temperature deposition chamber. The coating grows from the monomeric vapor onto the stent's strut surfaces one molecule at a time, facilitating an intimately conformal and precisely uniform layer on the microstructures of the entire stent from several hundred angstroms to several microns in thickness. Because there is no liquid phase during any part of the deposition process, there are no meniscus or bridging effects between the stent struts, and there is no pooling of the coating due to gravitational forces. The resulting parylene film conforms perfectly to the underlying stent or overlying drug surfaces. It is free of imperfections, forming a thin, transparent film of precisely controlled thickness.
Parylene's conformability characteristics and its ability to penetrate microcrevices are of significant importance to the coating of very fine geometry devices like stents. In fact, its ability to penetrate openings barely larger than the individual molecule size enables parylene to coat inside seemingly closed structures. A recently developed style of stent, for example, includes a plurality of pores, or reservoirs, that are formed in the surface of the stent. When these stents are coated using dip or spray methods, undesirable air pockets can form, because these coatings tend to bridge or film over such small openings. The vapor deposition polymerization of parylene does not encounter such problems, because the molecule-by-molecule growth of the parylene film follows the internal contours of the reservoirs.
Parylene also protects stents from possible corrosion before, during, and after deployment. Galvanic corrosion, for example, can occur whenever two dissimilar metals are in direct contact, such as when a nitinol stent comes in contact with procedural components of another metal, such as platinum. The resulting galvanic electrochemical reaction can corrode of the metals. The excellent moisture barrier properties of parylene prevent fluid conduction of galvanic charge, while the dielectric properties (>5000 V at 25 µm thickness) directly prevent conduction should device-to-device contact of the dissimilar metals occur.
|Parylene can serve as a release control agent when applied over a drug. This Cypher stent delivers the drug sirolimus.|
Another direct benefit of a parylene coating is its ability to provide these attributes to the stent without adding significant weight or dimension to the device. The ability to control thickness and weight at the micron and microgram levels is critical for the continued evolution of drug-eluting stent technology. It is equally important to future applications that call for smaller and more-complex device structures. Minute dimensions and surface geometries—the downfall of dip, brush, and spray coatings—are possible application areas for vapor-deposited parylene.
When a polymer or copolymer being used as the drug carrier or the drug itself does not adhere well to the surface of a bare-metal stent, parylene is often looked to as a necessary precoat primer. Drug-eluting stent manufacturers find that parylene provides bonding properties needed to facilitate drug-polymer combination adhesion to the stent3. In this case, parylene is applied first to the bare-metal stent, and then the drug-polymer carrier combination is applied to the parylene-coated stent.
In addition to the necessary bonding characteristics, inert parylene does not react with the carrier polymers or the drug, it has no leachable or extractable components of its own, and it does not contribute significant mass or dimension to the finished product. It should be noted that the drug is not applied during the parylene vapor-deposition polymerization process, but as a separate manufacturing process.
Parylene can also be applied over a drug to function as a release-control agent.5 In light of the time-dose relationship in pharmacokinetics, a drug-eluting stent requires a mechanism to control or sustain the release of its drugs to achieve the desired therapeutic effect.
Parylene is usually known and used for its pinhole-free and excellent barrier attributes. Manufacturers can also manipulate the thickness of the coating to very thin, porous layers and vary the ratio of drug to parylene in a multiple-layer construct. These attributes enable it to provide control of the drug-delivery rate. The parylene coating can be applied over the drug-coated stent surfaces (drug application is not a part of the vapor-deposition polymerization process) in layers sufficiently thin such that its matrix structure becomes open and porous. At these angstrom thickness levels, parylene allows drug molecules to pass through it at a rate that is a function of film thickness and drug molecule size.
In a multilayer device, for example, a drug-to-carrier polymer ratio that is higher in the interior layers than in the external layers could result in a lower initial dose delivery and in a total dose that would be delivered more uniformly and over a sustained period. By placing the greater concentration of the drug toward the stent strut surfaces, control over the drug's administration rate can be improved significantly. Also, parylene might be used to release multiple drugs to provide more-complex therapeutic activity.6 An example might be the delivery of a combination of active antimicrobial and antithrombogenic agents.7
The medical device and drug industries continue to search for more opportunities in which drug delivery can be combined with devices to enable delivery of the pharmacological agent directly to the target site in a manner similar to that of drug-eluting coronary stents. Opportunities for combined drug-device implants include the treatment of ophthalmic maladies such as macular degeneration or diabetic retinopathy, diseases that are injurious to the retina and threaten vision.
Because of the blood-retinal barrier, it can be quite difficult to deliver drugs by blood circulation to the posterior portions of the eye. Aside from injections via needle, it is also difficult to deliver drugs externally to the eye. As a result, drug-elution technology is being tested on ophthalmic drug-delivery implants, which would be implanted in the eye and left in place until the drug is fully dispensed and then removed.8
As a result of the successful introduction of drug-eluting stent technology, other drug-device combinations are being researched and developed and will ultimately benefit countless millions of people. As the traditional demarcations between devices and pharmaceuticals merge, new technologies will continue to converge with conventional designs to create hybrid products unforeseen only a few years ago. Parylene coatings are playing critical roles in these developments as a biocompatible surface modification, bonding, barrier protection, or drug-release control agents. Devices previously hindered by biological challenges such as inflammation, tissue growth, or foreign-body responses, are now being developed and tested for potential commercial use. These new developments are expected to have a major effect on the medical device industry.
Examples of some devices that might benefit from drug-eluting technologies include the following:
• Neurostimulation devices.
• Anastomosis devices.
• Hearing-assist devices.
• Birth control occlusion devices.
• Spinal repair devices.
• Diabetic devices.
• Dental implants.
• Breast implants.
• Prostate cancer treatments.
• Pacemaker and electrostimulation leads.
• Joint replacements.
With more than 850,000 angioplasties conducted in the United States each year, there is no question that drug-
eluting stents will continue to deliver great promise in the treatment of heart disease. Already, more than 90% of the stents implanted in the United States are drug eluting.
Drug-eluting stent technology represents one of the largest market opportunities in the history of the medical device industry. The success of these stents is the result of their ability to effectively treat patients, reduce restenosis, and contribute to lower healthcare costs. Parylene is playing a role in this process. Moreover, with new biocompatible variants of parylene being developed and embraced, the potential for additional medical applications is continually expanding.
Thanks to the combination device and drug technologies and the science and materials that support them, the future is bright not only for heart disease patients, but for many other patients as well.
1. M Szycher and A Armini, “Microporous Coating Provides Superior Stent,” Membrane & Separation Technology News 21, no. 10, (2003): 12.
2. J McCamant, “Pulse of the Market: ACC Review, Bio-Tech Stocks” [online] (Clearwater, FL: Pinson Communications, 2001 [cited 17 March 2005]); available from Internet: www.marketmavens.com.
3. “Instructions for Use: Cypher Sirolimus-Eluting Coronary Stent on Raptor Over-the-Wire Delivery Systems” [online] (Rockville, MD: FDA, 2005); available from Internet: www.fda.gov/cdrh/pdf3/P020026c.pdf.
4. N Stark, “Literature Review: Biological Safety of Parylene C,” Medical Plastics and Biomaterials 3, no. 2, (1996): 30–35.
5. U.S. Patent 6,299,604.
6. U.S. Patent 5,609,629.
7. M Szycher, PhD, et al., “Drug-Eluting Stents to Prevent Coronary Restenosis” [online] (Wakefield, MA: Implant Sciences Corp., 2002); available from Internet: www.implantsciences.com/pdf/imspaperv2.pdf.
8. AB Anderson, “Drug-Coated Implants for Pinpoint Delivery,” Medical Design News 4, no. 3 (2004): 31, 35–37.
Copyright ©2005 Medical Device & Diagnostic Industry