(Circulation. 1996;94:1494-1495.)
© 1996 American Heart Association, Inc.
Articles |
Polymer Coatings for Stents
Can We Judge a Stent by Its Cover?
the Heart Institute at Borgess Medical Center, Kalamazoo, Mich.
Correspondence to Tim A. Fischell, MD, Director of Cardiovascular Research, Heart Institute at Borgess, 1722 Shaffer St, Kalamazoo, MI 49001.
Key Words: Editorials • stents • biocompatibility • polymers
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The article by van der Giessen et al1 in this issue of Circulation provides an important perspective on the challenges associated with the development of a truly biocompatible polymeric stent coating.
A number of investigators have worked diligently over the past several years to explore the feasibility of a completely bioabsorbable stent.2 The impetus for this approach was the perception that the long-term implantation of metallic stents might provide a chronic inflammatory stimulus and/or lead to medial atrophy with aneurysm formation that could negate the immediate- and intermediate-term (6 months) advantages of stenting compared with the use of balloon angioplasty in the coronary circulation.3 4 However, recent studies have suggested that concerns about "late" restenosis and aneurysm formation with metallic stents in atherosclerotic human coronary arteries are likely unfounded.5 The excellent long-term biocompatibility of stainless steel stents, combined with the substantive difficulties in developing a polymeric stent with a high-performance delivery system, radiopacity, and competitive structural characteristics (eg, radial hoop strength) have led previously enthusiastic polymer stent proponents to focus their efforts on developing biocompatible polymeric coatings for metal stents. Such a hybrid device (metal backbone plus polymer coating) would provide the mechanical advantages of stenting, including reduction in early elastic recoil and the elimination of unfavorable late remodeling, and at the same time provide a platform for local drug delivery to decrease stent thrombogenicity and/or neointimal hyperplasia.
Although appealing in concept, the potential difficulties in the successful development of a biocompatible hybrid (polymer/metal) stent are highlighted by the present study. In this study using an animal model performed at three leading interventional cardiology centers, the investigators examined the histological responses to five biodegradable (polyglycolic acid/polylactic acid, polycaprolactone, polyhydroxybutarate valerate, polyorthoester, and polyethylenoxide/polybutylene terepthalate) and three nonbiodegradable (polyurethane, silicone, and polyethylene terephthalate) polymers applied to a 90° arc of the balloon-expandable Wiktor tantalum stent. These particular polymers were selected due to their potential for excellent biocompatibility based on previous in vitro and in vivo testing.1 The vessel wall responses at the (noncoated) tantalum wire implantation sites were used as the control and compared with the histopathological responses seen surrounding the polymer. The authors found that all of the implanted polymer coatings were associated with a significant inflammatory and exaggerated neointimal proliferative response. In addition, their data suggest that at least some of the polymer coatings may have provoked an enhanced thrombotic response.
As pointed out by the authors, the inflammatory response evoked by these polymers demonstrates the limitations of screening compounds with the use of in vitro or subcutaneous implant assays for biocompatibility. The intravascular environment is indeed unforgiving and does not readily tolerate foreign bodies. In addition to the usual tissue biocompatability issues, the exposure to flowing blood with the potential for activation of platelets, the extrinsic clotting cascade, or both provide a challenge to identify a compound that could be used in a hybrid stent design without aggravating the thrombotic risks. These challenges are exaggerated in the coronary circulation due to the potential for enhanced platelet activation at high shear rates in smaller vessels.6 In the present study, the potentially prothrombotic behavior of the polymer-coated stents may be only partially attributable to the polymer per se. One of the limitations of the present study was that the polymer was applied in a nonuniform manner with a comparatively thick layer (75 to 125 µm). The rheology of such a thick and eccentric polymer coating may have predisposed the polymer-coated segment to platelet activation and thrombus formation. In a study by De Scheerder et al,7 who used a thinner (23 µm) and more uniformly applied polyurethane stent coating, there appeared to be a favorable effect on stent thrombosis. In the present study, the possibility that the marked inflammatory response observed with most of the polymers may also have contributed to enhance the thrombogenicity of these stents cannot be excluded.
Although the results of the present study raise concerns regarding an exaggerated thrombogenic potential for polymer-coated stents, the recently reported in vivo and clinical experience with the polymer-coated (polyamine plus dextran sulfate trilayer) Palmaz-Schatz stent with covalently bound heparin from the Benestent II trial suggests that it is possible to find a biocompatible polymeric coating that, when combined with an active agent (eg, heparin), can be successfully used to reduce the thrombogenic potential of stents.8 9 The success of this particular coating may be related to the biocompatibility of this polymer, the very thin and uniform application of the coating, and the antithrombin and secondary antiplatelet effects of the covalently bound heparin.
The acute and chronic inflammatory responses and the accelerated neointimal proliferative responses observed with all of the polymers in the present study raise important questions with regard to the use of a polymer-coated stent as a drug-delivery vehicle to inhibit neointimal hyperplasia. These data should, however, be interpreted with the caveat that the stents used were not sterilized and may have harbored nonbacterial or, less likely, bacterial pyrogens.
There are several challenges to the development of a stent coating that will inhibit neointimal hyperplasia. If a biodegradable compound is chosen as the drug delivery vehicle, the degradation of such a compound is typically mediated by a low-level inflammatory response. Such an inflammatory response is mediated by macrophages, lymphocytes, and other inflammatory cell subtypes and has the capability to incite greater neointimal hyperplasia and negate some or all of the antiproliferative effect of the "drug." Although there may be a theoretical advantage to the use of a nonbiodegradable polymer as a reservoir for drug delivery, the present study demonstrates that the use of nonbiodegradable polymers does not necessarily eliminate the potential for inflammation and an associated aggravation of the neointimal hyperplastic response after stenting. The other challenge to the development of a hybrid stent to inhibit restenosis is related to the choice of the active agent (drug). Despite a wealth of potential drugs that might be incorporated into the ideal, but yet-to-be-identified, noninflammatory polymer, it remains unclear which agent, if any, can be delivered locally in adequate concentrations and over an appropriate period of time to achieve a favorable antiproliferative effect. If and when a promising drug/polymer/stent combination is developed, the regulatory pathway for the approval of such a combination of device plus drug is likely to be an arduous one. We should not expect to see such a device available for widespread clinical use in the near future.
Finally, although the eight agents tested in the present study appear to be problematic, other polymers, such as a high-molecular-weight poly-L-lactic acid,2 fibrin,10 and the polyamine plus dextran sulfate trilayer coating used in the recent Benestent II trial9 show some promise. Newer drug choices, including nitric oxide synthase or nitric oxide donors may prove to have desirable antiplatelet and antiproliferative properties.11 Other hybrid stent concepts, including a ß-particle–emitting radioisotope stent, with P32 incorporated beneath the surface of a metal stent, also show promise as a method of modulating the neointimal proliferation observed after stenting.12 13 Ultimately, the clinical results obtained through the use of these hybrid stent technologies will need to be compared in terms of efficacy, time efficiency, and cost efficiency with conventional stenting and with other approaches, including stenting plus local drug delivery, stenting plus catheter-based irradiation, and systemic delivery of potent antiplatelet agents such as c7E3.14
Despite the negative results of the present study, the concept of a hybrid stent composed of a state-of-the-art metallic backbone with a thin layer of a biocompatible polymeric coating containing an active agent to inhibit thrombosis and/or restenosis remains appealing. In the future, it is likely that we will evaluate stents not only by their ease of delivery and structural characteristics but also by their long-term biocompatibility, antithrombogenicity, and antiproliferative capabilities.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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TopIntroductionReferences |
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1. van der Giessen WJ, Lincoff AM, Schwartz RS, van Beusekom HMM, Serruys PW, Holmes DR Jr, Ellis SG, Topol EJ. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation. 1996;94:1690-1697.
2. Tanguay JF, Zidar JP, Phillips HR III, Stack RS. Current status of biodegradable stents. Cardiol Clin. 1994;12:699-713.[Medline] [Order article via Infotrieve]
3.
Fishman, DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S, for the Stent Restenosis Study investigators. A randomized comparison of coronary stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med. 1994;331:496-501.
4.
Serruys PW, De Jaegere P, Kiemeney F, Macaya C, Rutsch W, Heyndrickx, G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy J, van den Heuvel P, Delcan J, Morel M, for the Benestent Study Group. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489-495.
5.
Kimura T, Yokoi H, Nakagawa Y, Tamura T, Kaburagi S, Sawada Y, Sato Y, Yokoi H, Hamasaki N, Nosaka H, Nobuyoshi M. Three-year follow-up after implantation of metallic coronary-artery stents. N Engl J Med. 1996;334:561-566.
6. Turrito VT, Weiss HJ, Baumgartner HR. Physical factors influencing platelet deposition on subendothelium: importance of blood shear rate. Ann N Y Acad Sci. 1977;283:293-309.
7. De Scheerder IK, Wilczek KL, Verbeken EV, Vandorpe J, Lan PN, Schacht E, De Geest H, Piessens J. Biocompatability of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries. Atherosclerosis. 1995;114:105-114.[Medline] [Order article via Infotrieve]
8.
Hardhammar PA, van Beusekom HMM, Emanuelsson H, Hofma SH, Albertsson PA, Verdouw PD, Boersma E, Serruys PW, van der Giessen WJ. Reduction in thrombotic events with heparin-coated Palmaz-Schatz stent in normal porcine coronary arteries. Circulation. 1996;93:423-430.
9.
Serruys PW, Emanuelsson H, van der Giessen WJ, Lunn A, Kiemeney F, Macaya C, Rutsch W, Heyndrickx G, Suryapranata H, Legrand V, Goy JJ, Materne P, Bonnier H, Morice MC, Fajadet J, Belardi J, Colombo A, Garcia E, Ruygrok P, De Jaegere P, Morel MA. Heparin-coated Palmaz-Schatz stents in human coronary arteries: early outcome of the Benestent II pilot study. Circulation. 1996;93:412-422.
10. Holmes DR, Camrud AR, Jorgenson MA, Edwards WD, Schwartz RS. Polymeric stenting in porcine coronary artery model: differential outcome of exogenous fibrin sleeves versus polyurethane-coated stents. J Am Coll Cardiol. 1994;24:525-531.[Abstract]
11. Folts JD, Maalej N, Keaney JF, Loscalzo J. Palmaz-Schatz stents coated with a NO donor reduces reocclusion when placed in pig carotid arteries for 28 days. J Am Coll Cardiol. 1996;27:86A. Abstract.
12.
Laird JR, Carter AJ, Kufs WM, Hoopes TG, Farb A, Nott S, Fischell RE, Fischell DR, Virmani R, Fischell TA. Inhibition of neointimal proliferation with a ß-particle–emitting stent. Circulation. 1996;93:529-536.
13.
Hehrlein C, Stintz M, Kinscherf R, Schlosser K, Huttel E, Friedrich L, Fehsenfeld P, Kubler W. Pure ß-particle–emitting stents inhibit neointima formation in rabbits. Circulation. 1996;93:641-645.
14. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med. 1994:330:956-961.
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