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JACC Vol. 32, No. 3 September 1998:562–71

Biocompatibility Aspects of New Stent Technology
OLIVIER F. BERTRAND, MD,*† RAJENDER SIPEHIA, PHD,‡ ROSAIRE MONGRAIN, PHD,§ ´ S, MD,* JEAN-CLAUDE TARDIF, MD,* LUC BILODEAU, MD,* JOSEP RODE ˆ ´ , MD, FACC,* MARTIAL G. BOURASSA, MD, FACC* GILLES COTE
Montreal, Quebec, Canada

Stent implantation represents a major step forward since the introduction of coronary angioplasty. As indications continue to expand, better understanding of the early and late biocompatibility issues appears critical. Persisting challenges to the use of intracoronary stents include the prevention of early thrombus formation and late neointima development. Different metals and designs have been evaluated in animal models and subsequently in patients. Polymer coatings have been proposed to improve the biocompatibility of metallic stents or to serve as matrix for drug delivery and they are currently undergoing clinical studies. The

promises of a biodegradable stent have not yet been fulfilled although encouraging results have recently been reported. Continuous low dose-rate brachytherapy combining the scaffolding effect of the stent with localized radiation therapy has witnessed the development and early clinical testing of radioactive stents. The combined efforts of basic scientists and clinicians will undoubtedly contribute to the improvement of stent biocompatibility in the future. (J Am Coll Cardiol 1998;32:562–71) ©1998 by the American College of Cardiology

During the last 20 years, major technologic advances have been achieved and new devices for coronary interventions have been tested. Among these, stents recently modified standard practice by affording a highly effective and safe method to tackle dissections occurring after balloon angioplasty. Two landmark studies have shown that slotted tube, stainless steel, balloonexpandable stents could significantly decrease restenosis rates in selected lesions (1,2). Multidisciplinary efforts have subsequently been put into stent research and as a result, new designs and different materials and coatings have been proposed to further improve the performance of these prostheses. The purpose of this review is to address some issues of stent design and materials, to review recent experience with various stent coatings and biodegradable* stents and to describe recent research data involving surface modifications to increase biocompatibility and possibly reduce neointima formation. Coronary stents: material and design. Metallic characteristics, bulk and surface properties, design and chemistry are all important factors to consider in the conception of an optimal

From the *Research Center, Montreal Heart Institute; †Division of Experimental Medicine and ‡Artificial Cells and Organs Research Centre, McGill University; and §Department of Biomedical Engineering, Montreal Heart Institute, Montreal, Quebec, Canada. Dr. Bertrand is a Clinical and Research Fellow of the Fonds de la Recherche en Sante ´ du Que ´bec. This study was supported in part by Medtronic Inc., Minneapolis, Minnesota, and by MerckFrosst Inc., Montreal, Quebec, Canada. Manuscript received October 9, 1997; revised manuscript received May 4, 1998, accepted May 15, 1998. Address for correspondence: Dr. Olivier F. Bertrand, Interventional Cardiology Laboratories, Montreal Heart Institute, Belanger East, 5000, Montreal, Quebec, Canada H1T 1C8. E-mail: ofbert@icm.umontreal.ca. *Used in a broad meaning that the polymer will eventually disappear after introduction in the body without references to mechanisms of degradation.
©1998 by the American College of Cardiology Published by Elsevier Science Inc.

stent. Materials to be used as stent backbone must fulfill stringent physical, mechanical and chemical properties. The metal of an expandable stent must have enough plasticity to remain at the required size when deployed. Self-expanding stents, in addition, must be prepared from metals with sufficient elasticity so they can be compressed and then expanded and retain sufficient radial hoop strength to prevent vessel recoil or closure once in place (3). First-generation coronary stents were made of surgical grade stainless steel or tantalum, although several investigators have also suggested the use of temporary or permanent nitinol stents due to the superelastic and thermal shape memory properties of that alloy (4 – 6). Among chemical characteristics, corrosion properties are paramount. Formation of a surface metal oxide-film retards corrosion, and for some metals, such as chromium and titanium, this passivation is highly effective. However, saline liquids (such as blood) will destabilize the oxide layer on many metals. Although not yet investigated with stents, it has been shown that corrosion particles may migrate from metallic implants to other parts of the body (3). To date, long-term results with stainless steel or tantalum coronary prostheses do not suggest any signs of local or distant toxicity (7). The most recent available stents are manufactured in 316L stainless steel, with L indicating the low (0.03% weight) carbon content. This alloy is predominantly iron (60% to 65%) mixed with chromium (17% to 18%) and nickel (12% to 14%) (8). The chromium content affords a very good corrosion protection in addition to contributing to strength and hardness (8,9). Thus, 316L stainless steel provides good resistance to corrosion, and excellent mechanical properties but biocompatibility remains limited by the thrombosis issue (3,8,9). Nickel (Х55%)-titanium (Х45%) (Nitinol) stents may offer some
0735-1097/98/$19.00 PII S0735-1097(98)00289-7

Rogers and Edelman (15) compared vascular injury. (14) found no difference in platelet deposition and fibrin accumulation between identical coil stents made of tantalum or stainless steel in baboon arteriovenous shunts and in porcine coronary arteries. 32. Stents were coated with either a biodegradable poly(organo)phosphazene (POP) or a biostable polyurethane. no distinct advantages in terms of thrombus or neointima formation were found between metal coatings by galvanization or ion implantation compared with uncoated stents. Several polymers with previous medical or dental use have been evaluated to cover stents or to coat stent struts. the thin layer of inert tantalum peroxide creates an electrically negative charge that could reduce adhesion of negatively charged platelets (12). neointima formation remained similar in both groups after 12 weeks. After implantation. Altering the stent surface with a polymer coating virtually eliminated thrombotic occlusion in corrugated ring stents and significantly reduced thrombosis rates in coated versus uncoated slotted-tube stents (8% vs. Nitinol alloy has also proved to have good early biocompatibility. Sheth et al. However.). (17) described less thrombosis and vessel injury after implantation of slotted tube nitinol stents in rabbit carotid arteries compared with PalmazSchatz stents. (20) compared the effects of mechanical polishing to decrease surface irregularities on thromboses in an ex vivo porcine arteriovenous shunt model. in clinical practice. Polished nitinol slotted-tube and Palmaz-Schatz stents exhibited a drastic reduction in thrombus formation compared with unpolished nitinol stents. surface treatment has also been shown to modify the performance of stents. only one of four POP-coated stents was found occluded at follow-up angiography. Fontaine et al. No difference in neointima proliferation was found between bare and polyure- . Furthermore. (19) compared regular and short-wave Wiktor stents implanted in minipig coronary arteries. Three different nonsterile polymers were implanted in a pig coronary model: polyurethane. respectively). Scott et al. All but one of the 20 silicone-coated stents remained patent at 4 weeks. This may be partly due to the activation of the coagulation cascade by negatively charged surfaces (13). thrombosis rates and neointima formation between stainless steel slotted tube (Palmaz-Schatz) and stainless steel corrugated ring stents (Multilink) in rabbit iliac arteries. Ongoing randomized trials comparing various stent designs will soon confirm whether this translates into different clinical outcomes. Although neointimal area was reduced at 4 weeks in the short-wave group.23). In an attempt to separate the multiple factors involved in stent performance. STENT BIOCOMPATIBILITY 563 Abbreviations and Acronyms PEO/PBTP ϭ polyethylenoxide/polybutylene terephtalate copolymer PLLA ϭ poly-l-lactic acid PHBV ϭ polyhydroxy-butyrate-valerate copolymer POP ϭ poly(organo)phosphazene advantages that have not yet been fully explored in the clinical setting (9). No. mechanical properties and lack of ferromagnetism.10. (16) performed paired comparisons of vascular wall reactions after implantation of 3 different stents in dog peripheral arteries. However. Tantalum confers several theoretical advantages over stainless steel in terms of radiopacity. It is regarded as a biologically inert material. The more rigid stents induced more vessel injury and created more neointima than the flexible design. A large group of investigators have evaluated 3 synthetic nonbiodegradable coatings partially covering coil tantalum stents (25). Although 3 of 6 pigs with uncoated stents died of acute stent occlusion. De Scheerder et al. (18) compared similarly designed tantalum coil stents with different rigidity. longitudinal flexibility. In the circulation. (21). metal hoop-strength and coverage may interfere with and complicate the objective evaluation of stents with different designs. the tantalum stent wire undergoes oxidation.JACC Vol. experimental data suggest that stent design and surface properties may influence early and late results of stenting in animal models. the increased metal mass (15%) associated with the short-wave design did not lead to increased neointima formation. 3 September 1998:562–71 BERTRAND ET AL. De Scheerder et al. Therefore. Some concern exists that nickel leakage from these alloys could lead to immunogenic reactions (8. Thus. Many factors such as blood rheology. (24) compared thrombosis rates and neointima formation using uncoated and coated Wallstents with Biogold (Plasma Carb Inc. Despite suppression of early thrombosis with the coating. Other investigators have also tested noble metal coatings to improve the corrosion properties (22. Barth et al. These two stents have distinct designs but identical metals and metal-to-surface ratios. Overall neointima formation was proportional to vessel injury and corrugated ring stents created 42% less arterial injury and 38% less neointimal hyperplasia than slotted tube stents. using electrochemical polishing of stainless steel stents. Van der Giessen et al. All polymers elicited intense inflammatory responses with presence of multinucleated giant cells and macrophages surrounding proteinaceous debris and thrombus remnants. 42%. Nonbiodegradable synthetic polymers. Neointima formation was significantly higher with Strecker stents than with Wallstent or Palmaz stents. (26) compared 2 different polymer coatings of stainless steel slotted tube stents in normal porcine coronary arteries. biocompatibility. Buchwald et al. whether the metallurgic properties may confer an advantage in vivo is still unknown. Polymers are long-chain molecules that consist of small repeating units (8). resulting in an oxide that is very stable and extremely resistant to degradation (3). no difference subsisted in neointimal or lumen area between the 2 groups at 12 weeks. Polymer coatings (Table 1). Polymer coating (Thromboshield) had no effect on vessel injury or neointima formation but significantly decreased thrombosis rates. showed a significant reduction in early thrombosis in a rat arteriovenous shunt model and less neointima formation in a pig coronary model compared with untreated stents. Therefore. Sheth et al. tantalum has not been shown to decrease stent thrombosis compared with stainless steel stents.11). poly (dimethyl) siloxane (silicone) and polyethylene terephtalate (Dacron).

Niti ϭ nitinol/titanium. NA ϭ not available. (33). thane stents. MPC/LM ϭ methacrylphosphorylcholine/ laurymethacrylate. However. Polymers Used as Stent Coatings Author (ref) Van Der Giessen et al. severe intimal proliferation of histiolymphocytic tissue was noted. POP ϭ polyorganophosphazene. SIL ϭ silicone. FIB ϭ fibrin. (30) Nordrehaug et al. H ϭ heparin. Subsequently. Polyglycolic/polylactic acid copolymer. Thus. (31) Amon et al. (33) Lincoff et al. STENT BIOCOMPATIBILITY JACC Vol. PPE ϭ polyphosphate ester. using the same coating applied on stainless steel stents reported the first clinical use in bail-out stenting. Biodegradable synthetic polymers. PSNO/BSA ϭ polynitrosated nitric oxide albumin. (27) Rechavia et al. (36) Kipshidze et al. polycaprolactone. (66) Wiktor NA Fontaine-Dake NA NA Dyvisio NA NA NA Wiktor Wiktor Wiktor NA Palmaz-Schatz Harts Coil Palmaz-Schatz Palmaz-Schatz Cook Tantalum Stainless steel Tantalum Niti NA Stainless steel Stainless steel Tantalum Stainless steel Tantalum Tantalum Tantalum Titanium Stainless steel Niti Tantalum Stainless steel Stainless steel Stainless steel 20 23 — — — — — — — 11–27 — 120 70 –120 40 Ϯ 6 40 Ϯ 6 50 — 80 –1000 10 30 Pig coronary Pig coronary Pig shunt Rabbit carotid Arteriovenous baboon shunt Pig coronary Rabbit iliac Pig femoral Human coronary Pig coronary Pig coronary Pig coronary Dog iliac artery Dog iliac artery Rabbit carotid Pig coronary Pig carotid Pig coronary Rabbit iliac Biodeg. (35) Holmes et al. (37) Lambert et al. (32) used a newly designed tantalum stent with a silicon carbide coating. CEL ϭ cellulose. these results do not seem to suggest a clinical advantage for these silicone-carbide coated stents. (34) Schwartz et al. In a baboon arteriovenous shunt model. (38) Barber et al. No. polyhydroxy-butyrate/valerate copolymer (PHBV). Fontaine et al. (30) evaluated phosphorylcholine (a component of cell membrane) or cross-linked phosphorylcholine coated on stainless steel stents in a pig coronary model. Van der Giessen et al. Therefore. (28) Chronos et al. poly- .564 BERTRAND ET AL. PETP ϭ polyethylene terephtalate. PGLA ϭ polyglycolic/lactic acid. POE ϭ polyorthoester. Radiolabeled platelet accumulation in the uncoated stent group was already more severe after 5 min and remained higher after 60 to 120 min. (26) Fontaine et al. (69) Prietzel et al. PC ϭ phosphorylcholine. Amon et al. (59) de Scheerder et al. (27) compared platelet adhesion between uncoated and polyurethane-coated tantalum stents implanted in a swine arteriovenous shunt. but recent data suggest that some polymers such as polyurethane or phosphorylcholine could serve as effective drug delivery systems. (63) Aggarwal et al. PEO/PBT ϭ polyethyleneoxide/polybutylene terephtalate. in the POP-coated stent group. Identical results have been obtained in rabbit iliac arteries with phosphotidylcholine by Nordrehaug and colleagues (31). PUR ϭ polyurethane. (25) studied 5 polymer-coated stents implanted in pig coronary arteries. 32. No Yes Yes Yes Yes Yes No No No No No No No No No No No No Yes — Yes No Yes Yes No Yes Yes Yes Yes Thickness (␮m) — 75–125 Model Pig coronary Pig coronary de Scheerder et al. 3 September 1998:562–71 Table 1. it remains unclear whether any polymer coating may improve the stent biocompatibility per se. Chronos et al. PCL ϭ polycaprolactone. Malik et al. Among 44 patients who received 58 siliconcarbide coated stents. 21% (9 of 42) had restenosis at 6-month follow-up and stent thrombosis was suspected in two patients. XL-PC ϭ cross-linked phosphorylcholine. COLLϩLAM ϭ collagene/laminin. (29) Malik et al. PHBV ϭ polyhydroxybutyrate/valerate. Rechavia et al. In rabbit carotid arteries. (57) Cox et al. In vivo testing in a pig model showed the absence of thrombus formation. (29) used a copolymer of methacrylphosphorylcholine and laurylmethacrylate to coat stainless steel stents. ϭ biodegradable. (28) observed identical tissue reaction between polyurethane-coated and uncoated nitinol stents. (53) Folts et al. they observed an early decrease in platelet deposition at 60 and 120 min compared with bare stents. (32) Ozbek et al. PLLA ϭ poly-l-lactic acid. Ozbek et al. (24) Van Der Giessen et al. No stent thrombosis occurred in any group and there was no excess neointima formation in coated versus uncoated stents. (25) Stent Wallstent Wiktor Material Stainless steel Tantalum Polymer Biogold PGLA PCL PHBV POE PEO/PBTP PUR SIC PETP POP POP PUR PUR PUR MPC/LM PC XL-PC PC Silicone carbide Silicone carbide PLLA PPE FIB PUR FIB FIB PUR CEL PSNO/BSA PLLA CEL Biodeg.

SPUU-PEO-hep ϭ polyurethaneurea-polyethylene oxide-heparin. (48.51) de Scheerder et al. in the group with high molecular weight PLLA (slower degradation). Heparin-Coated Stents Author (ref) Bonan et al. Bonan et al. In addition. suggesting that fibrin could also allow rapid endothelialization of the stent struts (38). Neither thrombosis nor neointima formation was different between coated and uncoated groups. Two uncovered stents developed subacute thrombosis. (54) Vrolix et al. Endothelial coverage was also higher in the fibrincoated group. A wide range of inflammatory response was also demonstrated. they inserted 27 regular or vein-covered stents. Baboon carotid Baboon A-V Dog coronary Pig coronary Porcine carotid Human coronary art. The Carmeda coating also appears to be highly effective in reducing platelet deposition when stents are not completely deployed (47). whereas no thrombosis was seen in any coated stent with either moderate or high heparin activity. After 4 weeks. (52) Jeong et al. (43) Sheth et al. PLLA remains high on the list to serve as a temporary matrix for drug release. Using heparin-bonded tantalum coil stents. stent thrombosis occurred in 37% of pigs receiving uncoated stents. (41) Stradienko et al. However. NA ϭ not available.49) Zidar et al. Chronos et al. (45) Serruys et al. STENT BIOCOMPATIBILITY 565 Table 2. and the neointima was similar to that noticed in the control group. Natural coated and covered stents.49) showed similarly less early thrombosis and subsequent . 3 of 7 stents with PHBV and 3 of 10 with PEO/PBTP occluded within hours after implantation. neointimal proliferation in the group with polyurethane coating completely obliterated the lumen of the remaining stents. (48. possibly by an effect of heparin on cell attachment and growth. ϭ artery. suggested that heparin coating could reduce early thrombosis (42– 44).41). Three of 34 fibrin-covered stents occluded within 48 hours. In the other group. after 12 weeks. (34) evaluated low (80 kD) and high (321 kD) molecular weight poly-l-lactic acid (PLLA) coated onto Wiktor stents again in pig coronary arteries. Baker et al. No. Histology documented an intense foreign-body reaction with multinucleated giant cells. in the group with polyurethane covering. foreign body reaction was observed in 2 uncoated stents but not in fibrin-coated stents. there was no evidence of acute or chronic inflammation. In the group with low molecular weight PLLA. after 4 weeks. however. (56) Model Dog coronary Rabbit iliac Rabbit iliac Rabbit carotid Pig coronary Human coronary art. (41) were first to use heparin-coated (a preliminary version of Carmeda coating) zig-zag stents in canine coronary arteries. histomorphometric analysis showed a slight but significant increase in neointimal thickness in the group with highest heparin activity. (44) Hardhammar et al. Several preliminary reports. 3 September 1998:562–71 BERTRAND ET AL. Heparin-coated stents (Table 2). (47) Chronos et al. (50.JACC Vol. After 4 weeks. (46) Chronos et al. 3 of 7 uncoated stents thrombosed after 8 weeks. Stent Zig-Zag Palmaz-Schatz Palmaz-Schatz Harts Palmaz-Schatz Palmaz-Schatz Cordis Palmaz-Schatz Cordis Self designed Wallstent Wiktor NA — Proprietary SPUU-PEO-hep Carmeda Carmeda NA Carmeda NA Duraflow NA Hepamed Coating Control Bare stent Bare stent Bare stent Bare stent Bare stent — Bare stent Bare stent Bare stent Bare stent Bare stent — Thrombosis Reduction No Yes Yes Yes Yes Yes Yes Yes — Yes Yes — Neointima Reduction No — No — No — Yes — No No NA — Art. In a pig iliac artery model. Among these biodegradable polymers. covered stents showed only minimal hyperplasia (39). fibrin-covered stents were soaked in a heparin solution for 3 hours. Natural products offer the theoretical advantage of minimizing the inflammatory response. Polymerization of fibrin produced a film completely encasing the stent. In contrast to similar studies using nonbiodegradable polymers. Stefanidis et al. In their experimental series. In addition. the potential long-term benefit will be the primary factor that will determine the place of this technique. stents were covered with biostable medical grade polyurethane. The Rotterdam group reported experimental and early clinical results with heparin-coated (Carmeda) Palmaz-Schatz stents (45. the difference was no longer significant. In contrast. orthoester and polyethyleneoxide/polybutylene terephtalate copolymer (PEO/PBTP) were used as strips covering 90 degrees of a Wiktor stent circumference. Holmes et al. Subsequently implanted in canine iliac arteries. 32. severe acute and chronic signs of inflammation were recognized with a variable destruction of the vessel architecture. (37) using a similar fibrin coating on self-expanding titanium stents and balloonexpandable Palmaz-Schatz stents. In contrast. Heparin coating induced a decreased endothelial cell covering of the coated stents. A single preliminary study reported no thrombosis and little inflammation after polyphosphate ester– coated tantalum stents were implanted in pig coronary arteries (35). (39) introduced the concept of a conventional stent completely covered by an autologous vein or arterial graft. whereas no coated stent presented signs of thrombosis. all stents were endothelialized. reported a significant reduction in platelet deposition after 2 hours in an in vitro model. (42) Bailey et al. A-V ϭ arteriovenous. Lincoff et al. These results prompted the investigators to use the same technique in patients and preliminary clinical results are encouraging (40. Because of its relative complexity. 6 of 12 stents occluded within 48 hours.46). In addition. (36) compared fibrin-covered with polyurethane-covered tantalum stents in a pig coronary artery model. With a follow-up extending up to 6 months.

70) Baker et al. (56) also reported preliminary results with a heparin covalent bound (Hepamed) Wiktor stent in 100 patients. radiolabeled platelets and fibrinogen were significantly reduced in the Duraflo II coated stent group (52). (59.801 Amount 1. Levels of forskolin peaked within 2 hours of stent placement but rapidly fell during the first 24 hours. 413 patients received a stent and thrombosis occurred in only 1 case (55). (71) Santos et al. HϩMetho Dexamethasone Colchicine PEG-hirudin PG12 PEG-hirudin PG12 IIb-IIIa inhibitors IIb-IIIa-UK NO RGD L 703.8 mg 3. In porcine coronary arteries. there was no difference in neointima formation between drug-coated and uncoated stents. there was no significant difference at 4 weeks between coated and uncoated stents.60) showed an improved biocompatibility of POP coating by loading the polymer with methylprednisolone or angiopeptin. thrombus weight. Lincoff et al. Metho. although a beneficial effect on neointima formation remains to be established. (34) Eccleston et al. Therefore.8% in 30 d — — 60% in 14 d — — — — Control — — POP stent Bare PLLA Bare stent — Bare stent Bare stent CEL Ϯ anti-CMV CEL Bare stent Bare stent PLLA Bare stent Thrombosis Reduction Yes — — — — — Yes — Yes Yes Yes — No Yes Neointima Reduction — — Yes No No — — Yes No — Yes Yes — — Metho ϭ methotrexate. Serruys et al. (53) Lincoff et al. Overall. (50. In contrast. other abbreviations as in Table 2. both of which helped to dramatically reduce stent thrombosis. PEG ϭ polyethylene glycol. 32. reported a decrease in thrombosis in rabbit carotid arteries. Ratios of drug levels in the vessel wall to that in blood peaked at 6. Zidar et al. (66) Aggarwal et al. (58) de Scheerder et al. (34) .8% in 30 d 11.000 for etedrinate and at 780 for forskolin. De Scheerder et al. the exact role of heparin coating for stents remains to be established. (62– 65) Aggarwal et al.5% in 72 h 86% in 24 h — Ͼ50% in 2–3 d 50% in 28 d Ͻ10% in 28 d 52. (57) by using forskolin loaded into a polyurethane (Tecoflex)-coated nitinol stent. No. (64) Alt et al. (46) reported initial clinical experience with Carmeda heparin-coated Palmaz-Schatz stents. this study showed no stent thrombosis. Drug-Eluting Stents Author (ref) Lambert et al. when subsequently implanted in pig coronary arteries. (59. 3 September 1998:562–71 Table 3. Drugs may be released by diffusion mechanisms or during polymer breakdown. (57) Dev et al. UK ϭ urokinase. Lambert et al.51) implanted heparin-bonded tantalum coil stents in dog coronary arteries and found no difference in early thrombosis or neointima formation between coated and uncoated stents.8 mg 300 ␮g — 0. Jeong et al. decreasing from 15% in the group with conventional anticoagulation to 6% in patients taking a combination of ticlopidine and aspirin. neointima formation in baboon carotid arteries. (54) evaluated heparin release from coated Wallstents in a porcine carotid model. in animal models. About 50% of the original etedrinate remained in the stent at 72 hours compared with about 5% of forskolin at 24 hours. various heparin coatings have been shown to be effective in reducing thrombosis.566 BERTRAND ET AL. (52) performed a detailed experimental study to evaluate the immediate and delayed effects of heparin coating. This study confirmed the feasibility and efficiency of the concept of a drug-eluting stent and demonstrated the variability in release kinetics according to the chemical characteristics of the selected compounds. The same group compared drug release between forskolin and etedrinate (58). whereas all coated stents remained widely patent. Cellulose ester has been used in one study as a coating for tantalum stents with heparin and/or methotrexate bound to the polymer (53).99 mg — 10 ␮g 2 ␮g — — — 40 w % Release/Kinetics 95% in 24 h 95% in 24 h 50. Drug-eluting stents (Table 3).96 mg 0. Levels of etedrinate in the vessel wall peaked at 24 hours and remained high up to 72 hours after placement. Much interest has been focused on loading a drug onto a stent to limit the early thrombogenicity and late neointima formation. all uncoated stents were occluded. However. (61) Schmidmaier et al.60) Cox et al. Given the better stent deployment technique and the clinical effectiveness of the ticlopidine-aspirin regimen. De Scheerder et al. After 1 week.58 mg 1. In porcine coronary arteries. there was no reduction in neointima proliferation in the group with heparin coating compared with control stents. STENT BIOCOMPATIBILITY JACC Vol. (69.5 mg 2. (53) evaluated the potential of heparin release from a cellulose-coated coil stent to reduce neointima formation. In the recently completed Benestent II trial comparing heparin-coated stents with balloon angioplasty. Cox et al. Vrolix et al. After 30 min in a rat arteriovenous shunt model. (67) Folts et al. (72) Polymer PUR PUR POP CEL PLLA PLLA PLLA PLLA CEL CEL PSNO/BSA FIB PLLA Drug Forskolin Forskolin Etedrinate Methylprednisolone H. and restenosis rates remained low.

(61). In vivo testing in dog femoral arteries confirmed excellent scaffolding properties. Baker et al. confirming the possibility of slow drug release from a polymer matrix coated on a stent. Zidar and colleagues (76) at Duke University have accumulated a wide experience in the development of biodegradable stents. (73) van der Giessen et al. Absorption of the . 2 w. However. 11 polymeric stents. No reduction in neointima formation was subsequently demonstrated. (66. using a similar stent implanted in peripheral porcine arteries.JACC Vol. The group from the Mayo Clinic first reported initial results using a Dacron tubing mesh self-expanding stent (73). (74) Susowa et al. (77) developed bioabsorbable stents in collagen I. the Rotterdam group. Polymeric Stents Self-Expanding BalloonExpandable Auto Auto Balloon Auto Balloon Laser energy — Balloon Author (ref) Murphy et al. also obtained similar results at 28 days. (69. other abbreviations as in Table 2. in a canine femoral artery model. Two animals killed after 24 hours confirmed the correct mechanical stent deployment within the coronary vessel. However. their stents have shown promising in vitro mechanical properties. (79) Landau et al. In contrast. Using PLLA designs. Gregory and Grunkemeier (78) evaluated an elastin-based material as a means to seal the artery. Preliminary in vitro data showed that most of these stents could be expanded against porcine arteries when correctly matched to vessel size. 3 September 1998:562–71 BERTRAND ET AL. (75) Zidar et al. Only 2 stent occlusions were observed due to traumatic implantation. Although the concept of a drug delivery stent is appealing.L-lactic acid. Investigators at Kyoto University developed a biodegradable stent in polyglycolic acid. using a fibrin-covered peak stent loaded with an arginine glycine aspetic acid peptide in an atherosclerotic rabbit model described significantly less smooth muscle cell proliferation. 18 mo — — 1 mo. the tissue concentration in dexamethasone was still 3. The degradation was nearly complete by 9 months with minimal inflammatory response. It is therefore possible that a contaminant was present in the nonsterilized stents used by the group at the Mayo Clinic. To assess thrombogenicity and biocompatibility. In addition. Santos et al. Dog coronary Dog femoral In vitro Porcine aorta Porcine carotid Rabbit carotid arteries Evaluation 24 h. After 18 months. other investigators using PLLA matrix loaded with prostacyclin and PEG-hirudin coated onto stainless steel stents described less early thrombosis and neointima formation in porcine coronary arteries than in uncoated stents (62– 65). A foreign body inflammatory response was noted in the neointima of all vessels and additional inflammation was noted in the media of the occluded vessels. (71). inflammation and neointima formation in the coated group. At 28 days. 2 d. No. loaded dexamethasone onto a PLLA matrix that were coated on Wiktor stents. there was a marked chronic foreign body inflammatory response with lymphocytes. were implanted after 5 minutes of heparin soaking. all animals killed 4 to 6 weeks after implantation showed a stent occluded by neointimal proliferation. In a low molecular weight PLLA group.L PLA PLLA-PCL Model Porcine coronary Porcine periph. eosinophils and giant cells. Folts et al. 1 w. stent degradation began to occur and foreign body reaction was recognized. at 1 and 2 weeks. Bier et al. Polymeric stents (Table 4). Fresh thrombus was present in some struts at 3 h. STENT BIOCOMPATIBILITY 567 Table 4. Aggarwal et al. (80) Design Mesh Mesh Knitted Diamond braided — Sheet-tube Film Tubular coil Polymer PETP PETP PGA PLLA Collagen I Elastin PCL/D. 4 d. limited neointima formation was present. PLLA/PCL ϭ poly-l-lactic acid/ polycaprolactone. (72) used a composite polymer-metal stent loaded with a nonpeptide tirofiban analog and showed a significant reduction in platelet deposition after 2 h compared with bare stents in canine coronary arteries. (77) Gregory et al. Histologic analysis displayed complete endothelial cell coverage and minimal intimal thickness.L-PLA ϭ polycaprolactone/D. 12 w. 4 – 6 w 4w 3 h. Eccleston et al. 2 w. 32. periph ϭ peripheral arteries. but there was no chronic inflammatory response. All stents were successfully implanted in 15 dogs (75). and it is thus possible that higher local doses can produce a greater biological effect (68). whereas there was no difference in neointima formation between polymer-coated and bare stents in the high molecular weight PLLA group. (76) Bier et al. However. Endothelialization of the stent surface occurred between 2 and 8 weeks. using the same model-eluting colchicine.000 higher than in the blood. 2 mo 5d Remarks All stents occluded at 6 w 7/8 patent 15/15 patent at 3 h 10/11 patent at 18 mo — — — Carriers for adenovirus vectors PCL/D.67) showed decreased early stent thrombogenicity using cellulose matrix loaded with glycoprotein IIb-IIIa inhibitors or a complex of glycoprotein IIb-IIIa urokinase. dexamethasone reduced the inflammatory response observed in the PLLA group. the challenges to define the right pharmacologic agent and its release kinetics further complicate the polymer issues. 8 w 2 h. Preliminary results suggest an early decrease in thrombosis and less neointimal hyperplasia. described higher patency rates at 4 weeks (74). recent data showed that increased loading could be achieved. More recently. sterilized by polyethylene oxide. PETP ϭ polyethylene terphtalate. 1 w.70) used a polynitrosated albumin nitric oxide donor coated onto Palmaz-Schatz stents that were implanted in pig coronary arteries. (78) Gao et al.

suggest that this inflammatory response can be modulated by drug release or polymer modification. to obtain the required initial radioactivity with an isotope such as 32P. It is therefore fundamental to understand. Gao et al. however. However. STENT BIOCOMPATIBILITY JACC Vol. initial results were marked by limited cell retention after stent expansion and pulsatile flow exposure (82. these cells may be genetically modified to generate increased local fibrinolytic activity (81. Another interesting approach is to provide a natural coating by using genetically engineered endothelial cells.83). They served also as carriers for recombinant adenovirus vectors and were implanted in rabbit carotid arteries. The basic tenet of blood-stent interactions is that circulating cells do not react directly with the coating or the metallic stent surface (8. After preheating at 51°C. Herhlein et al. Interestingly. (86) showed that a single dose of vascular growth factor administered locally could enhance endothelial regeneration after stent implantation in rabbit iliac arteries. Drug eluting stents could therefore provide an ideal tool to limit the inflammatory reaction and possibly the neointima formation. however. Van belle et al. In addition. Radioactive stents. Reports. the efforts to develop a fully biodegradable stent have been slowed down by the technical complexities and by the positive long-term results of metallic stents. Stent implantation leads to greater vessel injury than balloon dilatation and can be followed by inflammation. Thus. it has recently been shown that local delivery of vascular endothelial growth factor165 could increase endothelial regeneration after vessel injury (85).90). would raise the quantity of phosphorus above the recommended maximum limit of 316L stainless steel (91). and those related to biocompatibility are linked to surface properties.95). endothelial cell coverage was Ͼ90% in both treated and untreated segments.13. Besides the use of single doses of gamma or beta rays delivered at high dose rates by intravascular catheters. despite the fact that extended follow-up revealed that neointima formation was only delayed in the low-activity stent groups. Recently. although they also noticed delayed reendothelialization of the stented segments and increased neointima formation with certain radioactivities (89. Recent data suggest that the stent design itself may influence the extent of injury (15. This technique has previously been used for endovascular graft coatings. Clearly. this accelerated endothelialization was correlated with a decrease in thrombosis and intimal thickening after 28 days (86). both models displayed a large number (Ͼ75%) of attached endothelial cells onto implanted stents. together with the possibility to deliver locally large amounts of drug for an extended period of time remains appealing. wound healing and sometimes foreign body reaction. although some longer stent designs showed early fatigue when implanted in animal models and during in vitro testing (unpublished results). Late problems with stents can be divided in two broad categories: mechanical failure due to material fatigue resulting from the considerable stress imposed to stents by cardiac contractions. the same group and investigators at Walter Reed Army Medical Center developed a beta-emitting stent by ion implantation of 32P (89. the dy- . degradation products or contaminants (8.23). Discussion Biocompatibility has evolved from the previous notion of inert material to a more recent concept based on the ability of a material to perform with an appropriate host response in a specific environment (93). Ion implantation of noble metals has been proposed to improve the corrosion properties of metal alloys (8. As a consequence. Another alternative would be to use an eluting system to deliver a chosen isotope from a stent platform (92). it is possible that the surface characteristics of 32P ion-implanted or particle bombarded Palmaz-Schatz stents would be modified. Using stents radioactivated by particle bombardment. Moreover. How- ever. To overcome some technical limitations of cells seeding. whereas coated and polymeric stents have shown more severe responses with histiolymphocytic infiltrates. Bailey et al. Metallic stents have elicited a rather limited inflammatory response. After 4 h. No thrombosis or foreign body reaction was noticed after 2 months. Early biocompatibility problems with stents are associated with thrombosis. As we have described. By 14 days. This stent could withstand collapse pressures of 300 to 700 mm Hg at 38°C. To date. 3 September 1998:562–71 material into porcine arterial wall was obtained using thermal bonding with laser energy. Within minutes after stent implantation. Endothelial cell seeding. In addition. Stent implantation adds to tissue compatibility the enormous challenge of hemocompatibility. there are several important factors involved in the design of an optimal coronary stent. long-term clinical follow-up of first-generation stents has not revealed signs of mechanical failure or toxicity. The concept. stents were implanted in mini-swine carotid arteries. (88) showed a significant reduction in neointima formation in a rabbit iliac artery model. Studies in pig coronary arteries and rabbit iliac arteries confirmed earlier positive results. Landau and his group (80) developed coil and tubular stents in copolymers of poly-l-lactic acid and polycoprolactone. (79) developed a balloon-expandable biodegradable stent made of a copolymer of coprolactone and D.L lactide impregnated with heparin. Most of the mechanical properties are related to the bulk characteristics of the metal or polymer. the accumulation of inflammatory cells may stimulate growth factor and cytokine release and in turn promote neointima formation. radioactive stents present the radiobiological advantage of delivering radiation at continuous low-dose rates (87). at the molecular level.17). Later. 32.94). macrophages and giant cells typical of foreign body reaction (25. the corrosion properties of the resulting stent surface would be changed.26). No. soluble proteins will adhere to it and rapidly form a monolayer at the surface of the foreign material. (84) used local delivery of endothelial cells after stent implantation in rabbit iliac and porcine coronary arteries.90).82). and chemical failure where corrosion or depolymerization can release potential toxic substances such as nickel.568 BERTRAND ET AL. leading to reduced long-term biocompatibility. inflammation and neointima formation.

Tokyo: WB Saunders. 8. Conclusions. With the first two techniques. Hoffman A. Philadelphia: J. Textbook of Interventional Cardiology. Pernu H. Froelich J. J Biomed Mater Res 1997. 18. Paired comparison of vascular wall reactions to Palmaz stents. Interaction of blood with artificial surfaces. Endoluminal Stenting. J Am Coll Cardiol 1996. Aricandri F. et al. First. Temporary stents. 9.32: 162–70. et al.129:866 –72.91:2995–3001. Influence of increased wave density of coil stents on the proliferative response in a minipig coronary stentangioplasty model [abstract]. Salo T. et al. London. 3. Stent-induced intimal hyperplasia: are there fundamental differences between flexible and rigid stent designs? J Vasc Interv Radiol 1994.95). Philadelphia. personal communication).5:739 – 44. 22. STENT BIOCOMPATIBILITY 569 namic process that regulates protein adsorption. Invest Radiol 1969. Comparison of the thrombogenicity of steel and gold-surface coronary stents with a biodegradable drug releasing coating in a human stasis model [abstract]. Baim D. The third approach. Circulation 1995. King S. Litvak F. the biocompatibility aspects will need to be further analyzed and mastered. Other anticoagulants such as hirudin have been tested. Circulation 1996. Buchwald A. There is little doubt that the next decade will witness the emergence of much less thrombogenic coronary endoprostheses capable of being accepted and tolerated by the body environment. The former may promote passivation of the stent surface while the latter may lead to thrombus accumulation. the research in the direction of reduction in stent thrombogenicity and in providing better tissue compatibility may have a significant impact on stent effectiveness in a variety of clinical conditions and may further expand the use of stents. Metals.95). although immobilized hirudin binds thrombin indefinitely and therefore a cycle of inactivation cannot be entertained. Philadelphia. et al. 15. This field is currently under active investigation. Castelman L. N Engl J Med 1994. Subacute thrombosis and vascular injury resulting from slotted-tube nitinol and stainless steel stents in a rabbit carotid artery model. Tokyo. eds. 12. Stevens J. Serruys P.93:2161–9. Metallic surface treatment using electrochemical polishing decreases thrombogenicity and neointimal hyperplasia after coronary stent implantation in a porcine model [abstract]. Indeed. Biocompatibility of nitinol alloy as an implant material. Long-term intracoronary stent placement: arteriographic and histologic results after 7 years in a dog model. Eigler N. 20. Tokyo: WB Saunders. Schoen F. Hermann R.18:153. Boston.B. Barth K. Park JB. Robinson K. Merrill EW. Roubin G. In: Topol E. Plenk H.18:152. London. 1994:1469 – 85. Whitlow P.JACC Vol. Forrester J. 6. 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