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Biocompatibility Aspects of New Stent Technology

OLIVIER F. BERTRAND, MD,* RAJENDER SIPEHIA, PHD, ROSAIRE MONGRAIN, PHD,JOSEP RODES, MD,* JEAN-CLAUDE TARDIF, MD,* LUC BILODEAU, MD,*

GILLES COTE, MD, FACC,* MARTIAL G. BOURASSA, MD, FACC*

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 biocompatibil-

ity issues appears critical. Persisting challenges to the use of

intracoronary stents include the prevention of early thrombus

formation and late neointima development. Different metals anddesigns 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. Con-

tinuous 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 un-doubtedly contribute to the improvement of stent biocompatibility

in the future.

(J Am Coll Cardiol 1998;32:56271)

1998 by the American College of Cardiology

During the last 20 years, major technologic advances have beenachieved and new devices for coronary interventions have beentested. Among these, stents recently modified standard prac-tice by affording a highly effective and safe method to tackle

dissections occurring after balloon angioplasty. Two landmarkstudies have shown that slotted tube, stainless steel, balloon-expandable stents could significantly decrease restenosis ratesin selected lesions (1,2). Multidisciplinary efforts have subse-quently been put into stent research and as a result, newdesigns and different materials and coatings have been pro-posed to further improve the performance of these prostheses.The purpose of this review is to address some issues of stentdesign and materials, to review recent experience with variousstent coatings and biodegradable* stents and to describe recentresearch data involving surface modifications to increase bio-

compatibility and possibly reduce neointima formation.Coronary stents: material and design. Metallic character-

istics, bulk and surface properties, design and chemistry are allimportant factors to consider in the conception of an optimal

stent. Materials to be used as stent backbone must fulfillstringent physical, mechanical and chemical properties. Themetal of an expandable stent must have enough plasticity toremain at the required size when deployed. Self-expanding

stents, in addition, must be prepared from metals with suffi-cient elasticity so they can be compressed and then expandedand retain sufficient radial hoop strength to prevent vesselrecoil or closure once in place (3). First-generation coronarystents were made of surgical grade stainless steel or tantalum,although several investigators have also suggested the use oftemporary or permanent nitinol stents due to the superelasticand thermal shape memory properties of that alloy (46).

Among chemical characteristics, corrosion properties areparamount. Formation of a surface metal oxide-film retardscorrosion, and for some metals, such as chromium and tita-

nium, this passivation is highly effective.However, saline liquids (such as blood) will destabilize the

oxide layer on many metals. Although not yet investigated withstents, it has been shown that corrosion particles may migratefrom metallic implants to other parts of the body (3). To date,long-term results with stainless steel or tantalum coronaryprostheses do not suggest any signs of local or distant toxicity(7). The most recent available stents are manufactured in 316Lstainless steel, with L indicating the low (0.03% weight) carboncontent. 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 protec-tion in addition to contributing to strength and hardness (8,9).Thus, 316L stainless steel provides good resistance to corro-sion, and excellent mechanical properties but biocompatibilityremains limited by the thrombosis issue (3,8,9). Nickel(55%)-titanium (45%) (Nitinol) stents may offer some

From the *Research Center, Montreal Heart Institute; Division of Exper-imental Medicine and Artificial Cells and Organs Research Centre, McGillUniversity; and Department of Biomedical Engineering, Montreal HeartInstitute, Montreal, Quebec, Canada. Dr. Bertrand is a Clinical and ResearchFellow of the Fonds de la Recherche en Sante du Quebec. This study wassupported in part by Medtronic Inc., Minneapolis, Minnesota, and by Merck-Frosst 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 Cardi-ology Laboratories, Montreal Heart Institute, Belanger East, 5000, Montreal,Quebec, Canada H1T 1C8. E-mail: [email protected].

*Used in a broad meaning that the polymer will eventually disappear afterintroduction in the body without references to mechanisms of degradation.

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1998 by the American College of Cardiology 0735-1097/98/$19.00Published by Elsevier Science Inc. PII S0735-1097(98)00289-7

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advantages that have not yet been fully explored in the clinicalsetting (9). Nitinol alloy has also proved to have good earlybiocompatibility. Some concern exists that nickel leakage fromthese alloys could lead to immunogenic reactions (8,10,11).Tantalum confers several theoretical advantages over stainlesssteel in terms of radiopacity, biocompatibility, mechanicalproperties and lack of ferromagnetism. It is regarded as a

biologically inert material. After implantation, the tantalumstent wire undergoes oxidation, resulting in an oxide that isvery stable and extremely resistant to degradation (3). In thecirculation, the thin layer of inert tantalum peroxide creates anelectrically negative charge that could reduce adhesion ofnegatively charged platelets (12). However, in clinical practice,tantalum has not been shown to decrease stent thrombosiscompared with stainless steel stents. This may be partly due tothe activation of the coagulation cascade by negatively chargedsurfaces (13). Therefore, whether the metallurgic propertiesmay confer an advantage in vivo is still unknown. Scott et al.(14) found no difference in platelet deposition and fibrin

accumulation between identical coil stents made of tantalumor stainless steel in baboon arteriovenous shunts and inporcine coronary arteries. Rogers and Edelman (15) compared

vascular injury, thrombosis rates and neointima formationbetween stainless steel slotted tube (Palmaz-Schatz) and stain-less steel corrugated ring stents (Multilink) in rabbit iliacarteries. These two stents have distinct designs but identicalmetals and metal-to-surface ratios. Overall neointima forma-tion was proportional to vessel injury and corrugated ringstents created 42% less arterial injury and 38% less neointimalhyperplasia than slotted tube stents. Polymer coating (Throm-

boshield) had no effect on vessel injury or neointima formationbut significantly decreased thrombosis rates. Altering the stentsurface with a polymer coating virtually eliminated thromboticocclusion in corrugated ring stents and significantly reducedthrombosis rates in coated versus uncoated slotted-tube stents(8% vs. 42%, respectively). Barth et al. (16) performed pairedcomparisons of vascular wall reactions after implantation of 3different stents in dog peripheral arteries. Neointima forma-tion was significantly higher with Strecker stents than withWallstent or Palmaz stents. Sheth et al. (17) described lessthrombosis and vessel injury after implantation of slotted tubenitinol stents in rabbit carotid arteries compared with Palmaz-Schatz stents. In an attempt to separate the multiple factorsinvolved in stent performance, Fontaine et al. (18) comparedsimilarly designed tantalum coil stents with different rigidity.The more rigid stents induced more vessel injury and createdmore neointima than the flexible design. Buchwald et al. (19)

compared regular and short-wave Wiktor stents implanted inminipig coronary arteries. Although neointimal area was re-duced at 4 weeks in the short-wave group, no differencesubsisted in neointimal or lumen area between the 2 groups at12 weeks. Therefore, the increased metal mass (15%) associ-

ated with the short-wave design did not lead to increasedneointima formation. Many factors such as blood rheology,longitudinal flexibility, metal hoop-strength and coverage mayinterfere with and complicate the objective evaluation of stents

with different designs.Furthermore, surface treatment has also been shown to

modify the performance of stents. Sheth et al. (20) comparedthe effects of mechanical polishing to decrease surface irregu-larities on thromboses in an ex vivo porcine arteriovenousshunt model. Polished nitinol slotted-tube and Palmaz-Schatzstents exhibited a drastic reduction in thrombus formation

compared with unpolished nitinol stents. De Scheerder et al.(21), using electrochemical polishing of stainless steel stents,showed a significant reduction in early thrombosis in a ratarteriovenous shunt model and less neointima formation in apig coronary model compared with untreated stents. Otherinvestigators have also tested noble metal coatings to improvethe corrosion properties (22,23). However, no distinct advan-tages in terms of thrombus or neointima formation were foundbetween metal coatings by galvanization or ion implantationcompared with uncoated stents. Thus, experimental data sug-gest that stent design and surface properties may influenceearly and late results of stenting in animal models. Ongoing

randomized trials comparing various stent designs will soonconfirm whether this translates into different clinical outcomes.

Polymer coatings (Table 1). Polymers are long-chain mol-ecules that consist of small repeating units (8). Several poly-mers with previous medical or dental use have been evaluatedto cover stents or to coat stent struts.

Nonbiodegradable synthetic polymers. Van der Giessen etal. (24) compared thrombosis rates and neointima formationusing uncoated and coated Wallstents with Biogold (PlasmaCarb Inc.). Despite suppression of early thrombosis with thecoating, neointima formation remained similar in both groups

after 12 weeks. A large group of investigators have evaluated 3synthetic nonbiodegradable coatings partially covering coiltantalum stents (25). Three different nonsterile polymers wereimplanted in a pig coronary model: polyurethane, poly (di-methyl) siloxane (silicone) and polyethylene terephtalate (Da-cron). All but one of the 20 silicone-coated stents remainedpatent at 4 weeks. All polymers elicited intense inflammatoryresponses with presence of multinucleated giant cells andmacrophages surrounding proteinaceous debris and thrombusremnants. De Scheerder et al. (26) compared 2 differentpolymer coatings of stainless steel slotted tube stents in normalporcine coronary arteries. Stents were coated with either abiodegradable poly(organo)phosphazene (POP) or a biostablepolyurethane. Although 3 of 6 pigs with uncoated stents died ofacute stent occlusion, only one of four POP-coated stents wasfound occluded at follow-up angiography. No difference inneointima proliferation was found between bare and polyure-

Abbreviations and Acronyms

PEO/PBTP polyethylenoxide/polybutylene terephtalate copolymerPLLA poly-l-lactic acid

PHBV polyhydroxy-butyrate-valerate copolymer

POP poly(organo)phosphazene

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thane stents. However, in the POP-coated stent group, severe

intimal proliferation of histiolymphocytic tissue was noted.Fontaine et al. (27) compared platelet adhesion betweenuncoated and polyurethane-coated tantalum stents implantedin a swine arteriovenous shunt. Radiolabeled platelet accumu-lation in the uncoated stent group was already more severeafter 5 min and remained higher after 60 to 120 min. In rabbitcarotid arteries, Rechavia et al. (28) observed identical tissuereaction between polyurethane-coated and uncoated nitinolstents. Chronos et al. (29) used a copolymer of methacryl-phosphorylcholine and laurylmethacrylate to coat stainlesssteel stents. In a baboon arteriovenous shunt model, theyobserved an early decrease in platelet deposition at 60 and120 min compared with bare stents. Subsequently, Malik et al.(30) evaluated phosphorylcholine (a component of cell mem-brane) or cross-linked phosphorylcholine coated on stainlesssteel stents in a pig coronary model. No stent thrombosisoccurred in any group and there was no excess neointimaformation in coated versus uncoated stents. Identical results

have been obtained in rabbit iliac arteries with phosphotidyl-

choline by Nordrehaug and colleagues (31). Amon et al. (32)used a newly designed tantalum stent with a silicon carbidecoating. In vivo testing in a pig model showed the absence ofthrombus formation. Ozbek et al. (33), using the same coatingapplied on stainless steel stents reported the first clinical use inbail-out stenting. Among 44 patients who received 58 silicon-carbide coated stents, 21% (9 of 42) had restenosis at 6-monthfollow-up and stent thrombosis was suspected in two patients.Thus, these results do not seem to suggest a clinical advantagefor these silicone-carbide coated stents. Therefore, it remainsunclear whether any polymer coating may improve the stentbiocompatibility per se, but recent data suggest that somepolymers such as polyurethane or phosphorylcholine couldserve as effective drug delivery systems.

Biodegradable synthetic polymers. Van der Giessen et al.(25) studied 5 polymer-coated stents implanted in pig coronaryarteries. Polyglycolic/polylactic acid copolymer, polycaprolac-tone, polyhydroxy-butyrate/valerate copolymer (PHBV), poly-

Table 1. Polymers Used as Stent Coatings

Author (ref) Stent Material Polymer Biodeg.

Thickness

(m) Model

Van Der Giessen et al. (24) Wallstent Stainless steel Biogold No Pig coronary

Van Der Giessen et al. (25) Wiktor Tantalum PGLA Yes 75125 Pig coronary

PCL YesPHBV Yes

POE Yes

PEO/PBTP Yes

PUR No

SIC No

PETP No

de Scheerder et al. (59) Wiktor Tantalum POP No 20 Pig coronary

de Scheerder et al. (26) NA Stainless steel POP No 23 Pig coronary

PUR

Fontaine et al. (27) Fontaine-Dake Tantalum PUR No Pig shunt

Rechavia et al. (28) NA Niti PUR No Rabbit carotid

Chronos et al. (29) NA NA MPC/LM No Arteriovenous baboon shunt

Malik et al. (30) Dyvisio Stainless steel PC No Pig coronaryXL-PC

Nordrehaug et al. (31) NA Stainless steel PC No Rabbit iliac

Amon et al. (32) NA Tantalum Silicone carbide No Pig femoral

Ozbek et al. (33) NA Stainless steel Silicone carbide No Human coronary

Lincoff et al. (34) Wiktor Tantalum PLLA Yes 1127 Pig coronary

Schwartz et al. (35) Wiktor Tantalum PPE Pig coronary

Holmes et al. (36) Wiktor Tantalum FIB Yes 120 Pig coronary

PUR No 70 120

Kipshidze et al. (38) NA Titanium FIB Yes 40 6 Dog iliac artery

Barber et al. (37) Palmaz-Schatz Stainless steel FIB Yes 40 6 Dog iliac artery

Lambert et al. (57) Harts Niti PUR No 50 Rabbit carotid

Cox et al. (53) Coil Tantalum CEL Yes Pig coronary

Folts et al. (69) Palmaz-Schatz Stainless steel PSNO/BSA Yes 80 1000 Pig carotidPrietzel et al. (63) Palmaz-Schatz Stainless steel PLLA Yes 10 Pig coronary

Aggarwal et al. (66) Cook Stainless steel CEL Yes 30 Rabbit iliac

Biodeg. biodegradable; CEL cellulose; COLLLAM collagene/laminin; FIB fibrin; H heparin; MPC/LM methacrylphosphorylcholine/laurymethacrylate; NA not available; Niti nitinol/titanium; PC phosphorylcholine; PCL polycaprolactone; PEO/PBT polyethyleneoxide/polybutylene

terephtalate; PETP polyethylene terephtalate; PGLA polyglycolic/lactic acid; PHBV polyhydroxybutyrate/valerate; PLLA poly-l-lactic acid; POE

polyorthoester; POP polyorganophosphazene; PPE polyphosphate ester; PSNO/BSA polynitrosated nitric oxide albumin; PUR polyurethane; SIL silicone;XL-PC cross-linked phosphorylcholine.

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orthoester and polyethyleneoxide/polybutylene terephtalatecopolymer (PEO/PBTP) were used as strips covering 90 de-grees of a Wiktor stent circumference. In contrast to similarstudies using nonbiodegradable polymers, 3 of 7 stents withPHBV and 3 of 10 with PEO/PBTP occluded within hoursafter implantation. A wide range of inflammatory response wasalso demonstrated. Lincoff et al. (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. In thegroup with low molecular weight PLLA, severe acute andchronic signs of inflammation were recognized with a variable

destruction of the vessel architecture. In contrast, in the groupwith high molecular weight PLLA (slower degradation), therewas no evidence of acute or chronic inflammation, and theneointima was similar to that noticed in the control group. Asingle preliminary study reported no thrombosis and littleinflammation after polyphosphate ester coated tantalumstents were implanted in pig coronary arteries (35). Amongthese biodegradable polymers, PLLA remains high on the listto serve as a temporary matrix for drug release.

Natural coated and covered stents. Natural products offerthe theoretical advantage of minimizing the inflammatory

response. Holmes et al. (36) compared fibrin-covered withpolyurethane-covered tantalum stents in a pig coronary arterymodel. Polymerization of fibrin produced a film completelyencasing the stent. In addition, fibrin-covered stents weresoaked in a heparin solution for 3 hours. In the other group,stents were covered with biostable medical grade polyure-thane. Three of 34 fibrin-covered stents occluded within 48hours. After 4 weeks, all stents were endothelialized. Incontrast, in the group with polyurethane covering, 6 of 12stents occluded within 48 hours. In addition, after 4 weeks,neointimal proliferation in the group with polyurethane coat-ing completely obliterated the lumen of the remaining stents.Histology documented an intense foreign-body reaction withmultinucleated giant cells. Baker et al. (37) using a similarfibrin coating on self-expanding titanium stents and balloon-expandable Palmaz-Schatz stents, reported a significant reduc-tion in platelet deposition after 2 hours in an in vitro model.

Subsequently implanted in canine iliac arteries, 3 of 7 uncoatedstents thrombosed after 8 weeks, whereas no coated stentpresented signs of thrombosis. In addition, foreign body reac-tion was observed in 2 uncoated stents but not in fibrin-coatedstents. Endothelial coverage was also higher in the fibrin-coated group, suggesting that fibrin could also allow rapidendothelialization of the stent struts (38). Stefanidis et al. (39)introduced the concept of a conventional stent completelycovered by an autologous vein or arterial graft. In a pig iliacartery model, they inserted 27 regular or vein-covered stents.Two uncovered stents developed subacute thrombosis. With a

follow-up extending up to 6 months, covered stents showedonly minimal hyperplasia (39). These results prompted theinvestigators to use the same technique in patients and prelim-inary clinical results are encouraging (40,41). Because of itsrelative complexity, the potential long-term benefit will be theprimary factor that will determine the place of this technique.

Heparin-coated stents (Table 2). Bonan et al. (41) werefirst to use heparin-coated (a preliminary version of Carmedacoating) zig-zag stents in canine coronary arteries. Neitherthrombosis nor neointima formation was different betweencoated and uncoated groups. Several preliminary reports,

however, suggested that heparin coating could reduce earlythrombosis (4244). The Rotterdam group reported experi-mental and early clinical results with heparin-coated (Car-meda) Palmaz-Schatz stents (45,46). In their experimentalseries, stent thrombosis occurred in 37% of pigs receivinguncoated stents, whereas no thrombosis was seen in any coatedstent with either moderate or high heparin activity. After 4

weeks, histomorphometric analysis showed a slight but signif-icant increase in neointimal thickness in the group with highestheparin activity. However, after 12 weeks, the difference wasno longer significant. Heparin coating induced a decreasedendothelial cell covering of the coated stents, possibly by aneffect of heparin on cell attachment and growth. The Carmedacoating also appears to be highly effective in reducing plateletdeposition when stents are not completely deployed (47).Using heparin-bonded tantalum coil stents, Chronos et al.(48,49) showed similarly less early thrombosis and subsequent

Table 2. Heparin-Coated Stents

Author (ref) Model Stent Coating Control

Thrombosis

Reduction

Neointima

Reduction

Bonan et al. (41) Dog coronary Zig-Zag NA Bare stent No No

Stradienko et al. (42) Rabbit iliac Palmaz-Schatz Bare stent Yes

Bailey et al. (43) Rabbit iliac Palmaz-Schatz Proprietary Bare stent Yes NoSheth et al. (44) Rabbit carotid Harts SPUU-PEO-hep Bare stent Yes

Hardhammar et al. (45) Pig coronary Palmaz-Schatz Carmeda Bare stent Yes No

Serruys et al. (46) Human coronary art. Palmaz-Schatz Carmeda Yes

Chronos et al. (47) Baboon carotid Cordis NA Bare stent Yes Yes

Chronos et al. (48,49) Baboon A-V Palmaz-Schatz Carmeda Bare stent Yes

Zidar et al. (50,51) Dog coronary Cordis NA Bare stent No

de Scheerder et al. (52) Pig coronary Self designed Duraflow Bare stent Yes No

Jeong et al. (54) Porcine carotid Wallstent NA Bare stent Yes NA

Vrolix et al. (56) Human coronary art. Wiktor Hepamed

Art. artery; A-V arteriovenous; NA not available; SPUU-PEO-hep polyurethaneurea-polyethylene oxide-heparin.


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neointima formation in baboon carotid arteries. In contrast,Zidar et al. (50,51) implanted heparin-bonded tantalum coilstents in dog coronary arteries and found no difference in earlythrombosis or neointima formation between coated and un-

coated stents. De Scheerder et al. (52) performed a detailedexperimental study to evaluate the immediate and delayedeffects of heparin coating. After 30 min in a rat arteriovenousshunt model, thrombus weight, radiolabeled platelets andfibrinogen were significantly reduced in the Duraflo II coatedstent group (52). However, when subsequently implanted inpig coronary arteries, there was no reduction in neointimaproliferation in the group with heparin coating compared withcontrol stents. Cox et al. (53) evaluated the potential ofheparin release from a cellulose-coated coil stent to reduceneointima formation. In porcine coronary arteries, there was

no significant difference at 4 weeks between coated anduncoated stents. Jeong et al. (54) evaluated heparin releasefrom coated Wallstents in a porcine carotid model. After 1

week, all uncoated stents were occluded, whereas all coatedstents remained widely patent. Therefore, in animal models,

various heparin coatings have been shown to be effective inreducing thrombosis, although a beneficial effect on neointimaformation remains to be established. Serruys et al. (46) re-ported initial clinical experience with Carmeda heparin-coatedPalmaz-Schatz stents. Overall, this study showed no stentthrombosis, and restenosis rates remained low, decreasingfrom 15% in the group with conventional anticoagulation to6% in patients taking a combination of ticlopidine and aspirin.In the recently completed Benestent II trial comparingheparin-coated stents with balloon angioplasty, 413 patientsreceived a stent and thrombosis occurred in only 1 case (55).Vrolix et al. (56) also reported preliminary results with a

heparin covalent bound (Hepamed) Wiktor stent in 100 pa-tients. Given the better stent deployment technique and theclinical effectiveness of the ticlopidine-aspirin regimen, both of

which helped to dramatically reduce stent thrombosis, the

exact role of heparin coating for stents remains to be estab-lished.

Drug-eluting stents (Table 3). Much interest has beenfocused on loading a drug onto a stent to limit the earlythrombogenicity and late neointima formation. Drugs may bereleased by diffusion mechanisms or during polymer break-down. Lambert et al. (57) by using forskolin loaded into apolyurethane (Tecoflex)-coated nitinol stent, reported a de-crease in thrombosis in rabbit carotid arteries. The same groupcompared drug release between forskolin and etedrinate (58).Levels of etedrinate in the vessel wall peaked at 24 hours and

remained high up to 72 hours after placement. Levels offorskolin peaked within 2 hours of stent placement but rapidlyfell during the first 24 hours. About 50% of the originaletedrinate remained in the stent at 72 hours compared withabout 5% of forskolin at 24 hours. Ratios of drug levels in the

vessel wall to that in blood peaked at 6,000 for etedrinate andat 780 for forskolin. This study confirmed the feasibility andefficiency of the concept of a drug-eluting stent and demon-strated the variability in release kinetics according to thechemical characteristics of the selected compounds. DeScheerder et al. (59,60) showed an improved biocompatibilityof POP coating by loading the polymer with methylpred-nisolone or angiopeptin. Cellulose ester has been used in onestudy as a coating for tantalum stents with heparin and/ormethotrexate bound to the polymer (53). In porcine coronaryarteries, there was no difference in neointima formation be-tween drug-coated and uncoated stents. Lincoff et al. (34)

Table 3. Drug-Eluting Stents

Author (ref) Polymer Drug Amount Release/Kinetics Control

Thrombosis

Reduction

Neointima

Reduction

Lambert et al. (57) PUR Forskolin 1.58 mg 95% in 24 h Yes

Dev et al. (58) PUR Forskolin 1.5 mg 95% in 24 h

Etedrinate 2.8 mg 50.5% in 72 hde Scheerder et al. (59,60) POP Methylprednisolone 300 g 86% in 24 h POP stent Yes

Cox et al. (53) CEL H, Metho,HMetho

Bare No

Lincoff et al. (34) PLLA Dexamethasone 0.8 mg 50% in 23 d PLLA No

Bare stent

Eccleston et al. (61) PLLA Colchicine 3.96 mg 50% in 28 d

0.99 mg 10% in 28 d

Schmidmaier et al. (64) PLLA PEG-hirudin PG12 52.8% in 30 d Bare stent Yes

11.8% in 30 d

Alt et al. (62 65) PLLA PEG-hirudin PG12 10 g Bare stent Yes

2 g

Aggarwal et al. (66) CEL IIb-IIIa inhibitors 60% in 14 d CEL anti-CMV Yes No

Aggarwal et al. (67) CEL IIb-IIIa-UK CEL Yes Folts et al. (69,70) PSNO/BSA NO Bare stent Yes Yes

Baker et al. (71) FIB RGD Bare stent Yes

Santos et al. (72) PLLA L 703,801 40 w % PLLA No

Bare stent Yes

Metho methotrexate; PEG polyethylene glycol; UK urokinase; other abbreviations as in Table 2.


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loaded dexamethasone onto a PLLA matrix that were coatedon Wiktor stents. In a low molecular weight PLLA group,dexamethasone reduced the inflammatory response observedin the PLLA group, whereas there was no difference inneointima formation between polymer-coated and bare stentsin the high molecular weight PLLA group. At 28 days, thetissue concentration in dexamethasone was still 3,000 higherthan in the blood, confirming the possibility of slow drugrelease from a polymer matrix coated on a stent. Eccleston etal. (61), using the same model-eluting colchicine, also obtainedsimilar results at 28 days. More recently, other investigators

using PLLA matrix loaded with prostacyclin and PEG-hirudincoated onto stainless steel stents described less early thrombo-sis and neointima formation in porcine coronary arteries thanin uncoated stents (6265).

Aggarwal et al. (66,67) showed decreased early stent throm-bogenicity using cellulose matrix loaded with glycoproteinIIb-IIIa inhibitors or a complex of glycoprotein IIb-IIIa uroki-nase. No reduction in neointima formation was subsequentlydemonstrated. However, recent data showed that increasedloading could be achieved, and it is thus possible that higherlocal doses can produce a greater biological effect (68). Folts et

al. (69,70) used a polynitrosated albumin nitric oxide donorcoated onto Palmaz-Schatz stents that were implanted in pigcoronary arteries. Preliminary results suggest an early decreasein thrombosis and less neointimal hyperplasia. Baker et al.(71), using a fibrin-covered peak stent loaded with an arginineglycine aspetic acid peptide in an atherosclerotic rabbit modeldescribed significantly less smooth muscle cell proliferation,inflammation and neointima formation in the coated group.Santos et al. (72) used a composite polymer-metal stent loaded

with a nonpeptide tirofiban analog and showed a significantreduction in platelet deposition after 2 h compared with barestents in canine coronary arteries. Although the concept of adrug delivery stent is appealing, the challenges to define theright pharmacologic agent and its release kinetics furthercomplicate the polymer issues.

Polymeric stents (Table 4). The group from the MayoClinic first reported initial results using a Dacron tubing mesh

self-expanding stent (73). Two animals killed after 24 hoursconfirmed the correct mechanical stent deployment within thecoronary vessel. However, all animals killed 4 to 6 weeks afterimplantation showed a stent occluded by neointimal prolifer-ation. In addition, there was a marked chronic foreign bodyinflammatory response with lymphocytes, eosinophils and gi-ant cells. In contrast, the Rotterdam group, using a similarstent implanted in peripheral porcine arteries, describedhigher patency rates at 4 weeks (74). Histologic analysisdisplayed complete endothelial cell coverage and minimalintimal thickness. A foreign body inflammatory response was

noted in the neointima of all vessels and additional inflamma-tion was noted in the media of the occluded vessels. It istherefore possible that a contaminant was present in thenonsterilized stents used by the group at the Mayo Clinic.Investigators at Kyoto University developed a biodegradablestent in polyglycolic acid. All stents were successfully im-planted in 15 dogs (75). Fresh thrombus was present in somestruts at 3 h. Endothelialization of the stent surface occurredbetween 2 and 8 weeks. However, at 1 and 2 weeks, stentdegradation began to occur and foreign body reaction wasrecognized. Zidar and colleagues (76) at Duke University have

accumulated a wide experience in the development of biode-gradable stents. Using PLLA designs, their stents have shownpromising in vitro mechanical properties. In vivo testing in dogfemoral arteries confirmed excellent scaffolding properties.The degradation was nearly complete by 9 months withminimal inflammatory response. To assess thrombogenicityand biocompatibility, 11 polymeric stents, sterilized by poly-ethylene oxide, were implanted after 5 minutes of heparinsoaking, in a canine femoral artery model. Only 2 stentocclusions were observed due to traumatic implantation. After18 months, limited neointima formation was present, but there

was no chronic inflammatory response. Bier et al. (77) devel-oped bioabsorbable stents in collagen I. Preliminary in vitrodata showed that most of these stents could be expandedagainst porcine arteries when correctly matched to vessel size.Gregory and Grunkemeier (78) evaluated an elastin-basedmaterial as a means to seal the artery. Absorption of the

Table 4. Polymeric Stents

Author (ref) Design

Self-Expanding

Balloon-Expandable Polymer Model Evaluation Remarks

Murphy et al. (73) Mesh Auto PETP Porcine coronary 24 h, 4 6 w All stents occluded at 6 w

van der Giessen et al. (74) Mesh Auto PETP Porcine periph. 4 w 7/8 patentSusowa et al. (75) Knitted Balloon PGA Dog coronary 3 h, 1 w, 2 w, 8 w 15/15 patent at 3 h

Zidar et al. (76) Diamond braided Auto PLLA Dog femoral 2 h, 2 d, 4 d, 1 w,2 w, 12 w, 18 mo

10/11 patent at 18 mo

Bier et al. (77) Balloon Collagen I In vitro

Gregory et al. (78) Sheet-tube Laser energy Elastin Porcine aorta

Gao et al. (79) Film PCL/D,L PLA Porcine carotid 1 mo, 2 mo

Landau et al. (80) Tubular coil Balloon PLLA-PCL Rabbit carotid

arteries

5 d Carriers for adenovirus

vectors

PCL/D,L-PLA polycaprolactone/D,L-lactic acid; periph peripheral arteries; PETP polyethylene terphtalate; PLLA/PCL poly-l-lactic acid/polycaprolactone; other abbreviations as in Table 2.


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material into porcine arterial wall was obtained using thermalbonding with laser energy. Gao et al. (79) developed aballoon-expandable biodegradable stent made of a copolymerof coprolactone and D,L lactide impregnated with heparin.This stent could withstand collapse pressures of 300 to

700 mm Hg at 38C. After preheating at 51C, stents wereimplanted in mini-swine carotid arteries. No thrombosis orforeign body reaction was noticed after 2 months. Recently,Landau and his group (80) developed coil and tubular stents incopolymers of poly-l-lactic acid and polycoprolactone. Theyserved also as carriers for recombinant adenovirus vectors and

were implanted in rabbit carotid arteries. Clearly, the efforts todevelop a fully biodegradable stent have been slowed down bythe technical complexities and by the positive long-term resultsof metallic stents. The concept, however, together with thepossibility to deliver locally large amounts of drug for an

extended period of time remains appealing.Endothelial cell seeding. Another interesting approach isto provide a natural coating by using genetically engineeredendothelial cells. This technique has previously been used forendovascular graft coatings. In addition, these cells may begenetically modified to generate increased local fibrinolyticactivity (81,82). However, initial results were marked by lim-ited cell retention after stent expansion and pulsatile flowexposure (82,83). To overcome some technical limitations ofcells seeding, Bailey et al. (84) used local delivery of endothe-lial cells after stent implantation in rabbit iliac and porcinecoronary arteries. After 4 h, both models displayed a large

number (75%) of attached endothelial cells onto implantedstents. By 14 days, endothelial cell coverage was 90% in bothtreated and untreated segments. Interestingly, it has recentlybeen shown that local delivery of vascular endothelial growthfactor165 could increase endothelial regeneration after vesselinjury (85). Van belle et al. (86) showed that a single dose of

vascular growth factor administered locally could enhanceendothelial regeneration after stent implantation in rabbit iliacarteries. Moreover, this accelerated endothelialization wascorrelated with a decrease in thrombosis and intimal thicken-ing after 28 days (86).

Radioactive stents. Besides the use of single doses ofgamma or beta rays delivered at high dose rates by intravas-cular catheters, radioactive stents present the radiobiologicaladvantage of delivering radiation at continuous low-dose rates(87). Using stents radioactivated by particle bombardment,Herhlein et al. (88) showed a significant reduction in neointimaformation in a rabbit iliac artery model, despite the fact thatextended follow-up revealed that neointima formation wasonly delayed in the low-activity stent groups. Later, the samegroup and investigators at Walter Reed Army Medical Centerdeveloped a beta-emitting stent by ion implantation of 32P(89,90). Studies in pig coronary arteries and rabbit iliac arteriesconfirmed earlier positive results, although they also noticeddelayed reendothelialization of the stented segments andincreased neointima formation with certain radioactivities(89,90). Ion implantation of noble metals has been proposed toimprove the corrosion properties of metal alloys (8,23). How-

ever, to obtain the required initial radioactivity with an isotopesuch as 32P, would raise the quantity of phosphorus above therecommended maximum limit of 316L stainless steel (91). Asa consequence, the corrosion properties of the resulting stentsurface would be changed. Thus, it is possible that the surface

characteristics of32

P ion-implanted or particle bombardedPalmaz-Schatz stents would be modified, leading to reducedlong-term biocompatibility. Another alternative would be touse an eluting system to deliver a chosen isotope from a stentplatform (92).

Discussion

Biocompatibility has evolved from the previous notion of inertmaterial to a more recent concept based on the ability of amaterial to perform with an appropriate host response in a

specific environment (93). Stent implantation adds to tissuecompatibility the enormous challenge of hemocompatibility.As we have described, there are several important factorsinvolved in the design of an optimal coronary stent. Most of themechanical properties are related to the bulk characteristics ofthe metal or polymer, and those related to biocompatibility arelinked to surface properties. Early biocompatibility problems

with stents are associated with thrombosis, inflammation andneointima formation. Late problems with stents can be dividedin two broad categories: mechanical failure due to materialfatigue resulting from the considerable stress imposed to stentsby cardiac contractions, and chemical failure where corrosion

or depolymerization can release potential toxic substancessuch as nickel, degradation products or contaminants (8,94).To date, long-term clinical follow-up of first-generation stentshas not revealed signs of mechanical failure or toxicity, al-though some longer stent designs showed early fatigue whenimplanted in animal models and during in vitro testing (un-published results).

Stent implantation leads to greater vessel injury than bal-loon dilatation and can be followed by inflammation, woundhealing and sometimes foreign body reaction. Recent datasuggest that the stent design itself may influence the extent of

injury (15,17). Metallic stents have elicited a rather limitedinflammatory response, whereas coated and polymeric stentshave shown more severe responses with histiolymphocyticinfiltrates, macrophages and giant cells typical of foreign bodyreaction (25,26). Reports, however, suggest that this inflam-matory response can be modulated by drug release or polymermodification. In addition, the accumulation of inflammatorycells may stimulate growth factor and cytokine release and inturn promote neointima formation. Drug eluting stents couldtherefore provide an ideal tool to limit the inflammatoryreaction and possibly the neointima formation.

The basic tenet of blood-stent interactions is that circulat-ing cells do not react directly with the coating or the metallicstent surface (8,13,95). Within minutes after stent implanta-tion, soluble proteins will adhere to it and rapidly form amonolayer at the surface of the foreign material. It is thereforefundamental to understand, at the molecular level, the dy-


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namic process that regulates protein adsorption. Indeed, pro-teins will adhere according to their plasma concentrations butalso depending on their surface affinity (13,95). Therefore,there will be a competition between numerous proteins toadhere to the foreign surface. Some surfaces may preferen-

tially absorb albumin, whereas others will tie fibrinogen. Theformer may promote passivation of the stent surface while thelatter may lead to thrombus accumulation. Protein adhesionleads to conformational changes in the protein structureinitiating cell adhesion, whereas soluble proteins do not inter-act with circulating cells (13,95). This field is currently underactive investigation, especially since the discovery of the inte-grin family.

Heparin coatings have been developed to provide perma-nent fixation or slow release from the material surface (8).There are basically three different approaches to achieve

heparin coating. First, heparin may be bound by ionic interac-tion (49). Then, heparin is slowly released and interacts withantithrombin III to neutralize thrombin. A second approach isto incorporate heparin by blending it with a polymer. In thiscase, heparin is released by leaching or biodegradation of thepolymer (53). The third approach, such as that developed byCarmeda, consists of heparin immobilization using end-pointattachment of heparin fragments to polyamine-dextran sulfatelayers that have absorbed on the stent surface (45,46). TheMedtronic (Hepamed) coating uses a similar approach whereunfractionated heparin is attached to a polyamine layer. This

layer has been previously covalently linked to a hydrogeldeposited on the stent surface (M Verhoeven, personal com-munication). With the first two techniques, the release kineticsand concentration of heparin determine the clinical lifetime ofthe coating. With the last technology, the active site of heparinremains free and heparin functions as a catalyzer to permitrepetitive inactivation of thrombin by antithrombin III. It hasbeen shown that immobilized heparin retains its ability to bindthrombin for more than 4 months (8). Other anticoagulantssuch as hirudin have been tested, although immobilized hiru-din binds thrombin indefinitely and therefore a cycle of

inactivation cannot be entertained. Other research avenuesinvolve slow-release hirudin, immobilized fibrinolytic enzymesor new antiplatelet agents such as glycoprotein IIb-IIIa inhib-itors or glycoprotein Ib antagonists. Whether early reduction inthrombogenicity will translate into reduction in neointimaformation and ultimately restenosis remains, however, to bedemonstrated.

Conclusions. Stents represent a major advance since theintroduction of coronary angioplasty. As stents may be im-planted in smaller vessels and in more complex lesions in thenear future, the biocompatibility aspects will need to be furtheranalyzed and mastered. There is little doubt that the nextdecade will witness the emergence of much less thrombogeniccoronary endoprostheses capable of being accepted and toler-ated by the body environment. Indeed, the research in thedirection of reduction in stent thrombogenicity and in provid-ing better tissue compatibility may have a significant impact on

stent effectiveness in a variety of clinical conditions and mayfurther expand the use of stents.

References

1. Fischman D, Leon M, Baim D, et al. A randomized comparison ofcoronary-stent placement and balloon angioplasty in the treatment ofcoronary artery disease. N Engl J Med 1994;331:496501.

2. Serruys P, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients withcoronary disease. N Engl J Med 1994;331:48995.

3. Taylor A. Metals. In: Sigwart U, ed. Endoluminal Stenting. London,Philadelphia, Toronto, Sydney, Tokyo: WB Saunders, 1996:2833.

4. Dotter C. Transluminally placed coilspring endarterial tube grafts, long termpatency in canine popliteal artery. Invest Radiol 1969;4:32932.

5. Beyar R, Roguin A. Self expandable nitinol stent for cardiovascular appli-cations: canine and human experience. Cathet Cardiovasc Diagn 1994;32:16270.

6. Eigler N, Litvak F, Whitlow P. Temporary stents. In: Topol E, ed. Textbook

of Interventional Cardiology. Philadelphia, London, Toronto, Montreal,Sydney, Tokyo: WB Saunders, 1994:76675.

7. Robinson K, Roubin G, King S. Long-term intracoronary stent placement:arteriographic and histologic results after 7 years in a dog model. CathetCardiovasc Diagn 1996;38:327.

8. Ratner B, Hoffman A, Schoen F, Lemons J, eds. An introduction tomaterials in medicine. San Diego, London, Boston, New York, Sydney,Tokyo, Toronto: Academic Press, 1996.

9. Park JB. Metallic Biomaterials. In: Branzino JD, ed. The BiomedicalEngineering Handbook. Boca Raton: CRC Press, 1995:53771.

10. Ryhanen J, Niemi E, Serlo W, Niemela E, Sandvik P, Pernu H, Salo T.Biocompatibility of nickel-titanium shape memory metal and its corrosionbehavior in human cell cultures. J Biomed Mater Res 1997;35:4517.

11. Castelman L, Motzkin S, Aricandri F, et al. Biocompatibility of nitinol alloyas an implant material. J Biomed Mater Res 1976;10:695731.

12. Zitter H, Plenk H. The electromechanical behavior of metallic implantmaterial as an indicator of their biocompatibility. J Biomed Mater Res1987;21:88196.

13. Salzman EW, Merrill EW, Kent KC. Interaction of blood with artificialsurfaces. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, eds. Hemo-stasis and Thrombosis: Basic Principles and Clinical Practice. Philadelphia:J.B. Lippincott, 1994:1469 85.

14. Scott N, Robinson K, Nunes G, et al. Comparison of the thrombogenicity ofstainless steel and tantalum coronary stents. Am Heart J 1995;129:86672.

15. Rogers C, Edeman E. Endovascular stent design dictates experimentalrestenosis and thrombosis. Circulation 1995;91:29953001.

16. Barth K, Virmani R, Froelich J, et al. Paired comparison of vascular wallreactions to Palmaz stents, Strecker tantalum stents, and Wallstents incanine iliac and femoral arteries. Circulation 1996;93:21619.

17. Sheth S, Litvak F, Dev V, Fishbein M, Forrester J, Eigler N. Subacutethrombosis and vascular injury resulting from slotted-tube nitinol andstainless steel stents in a rabbit carotid artery model. Circulation 1996;94:173340.

18. Fontaine A, Spigos D, Eaton G, et al. Stent-induced intimal hyperplasia: arethere fundamental differences between flexible and rigid stent designs?J Vasc Interv Radiol 1994;5:73944.

19. Buchwald A, Stevens J, Zilz M, et al. Influence of increased wave density ofcoil stents on the proliferative response in a minipig coronary stent-angioplasty model [abstract]. Eur Heart J 1997;18:152.

20. Sheth S, Litvak F, Fishbein M, Forrester J, Eigler N. Reduced thromboge-nicity of polished and unpolished nitinol vs stainless steel slotted-tube stentsin a pig coronary artery model [abstract]. J Am Coll Cardiol 1996;27:197A.

21. De Scheerder I, Sohier J, Wang K, et al. Metallic surface treatment usingelectrochemical polishing decreases thrombogenicity and neointimal hyper-

plasia after coronary stent implantation in a porcine model [abstract]. EurHeart J 1997;18:153.

22. Hermann R, Schmidmaier G, Alt E, et al. Comparison of the thromboge-nicity of steel and gold-surface coronary stents with a biodegradable drugreleasing coating in a human stasis model [abstract]. Eur Heart J 1997;18:152.

23. Hehrlein C, Zimmerman M, Metz J, Ensinger W, Kubler W. Influence of


7/27/2019 1-s2.0-S0735109798002897-main

9/10

surface texture and charge on the biocompatibility of endovascular stents.Coronary Artery Dis 1995;6:5816.

24. van der Giessen W, van Beusekom H, van Houten C, van Woerkens L,Verdouw P, Serruys P. Coronary stenting with polymer-coated and uncoatedself-expanding endoprostheses in pigs. Coronary Artery Dis 1992;3:63140.

25. van der Giessen W, Lincoff A, Schwartz R, et al. Marked inflammatorysequelae to implantation of biodegradable and nonbiodegradable polymersin porcine coronary arteries. Circulation 1996;94:16907.

26. De Scheerder I, Wilczek K, Verbeken E, et al. Biocompatibility of polymer-coated oversized metallic stents implanted in normal porcine coronaryarteries. Atherosclerosis 1995;114:10514.

27. Fontaine A, Koelling K, Clay J. Decreased platelet adherence of polymer-coated tantalum stents. J Vasc Interv Radiol 1994;5:56772.

28. Rechavia E, Fishbien M, DeFrance T, Nakamura M, Litvak F, Eigler N.Vascular injury triggered by temporary and permanently implanted polyure-thane coated and uncoated stents in rabbit carotid arteries [abstract].Circulation 1996;94:I88.

29. Chronos N, Robinson K, Kelly A, et al. Thromboresistant phosphorylcholinecoating for coronary stents [abstract]. Circulation 1995;92:I685.

30. Malik N, Gunn J, Sheperd L, Newman C, Crossman D, Cumberland D.Phosphorylcholine-coated stents in porcine coronary arteries: angiographic

and morphometric assessment [abstract]. Eur Heart J 1997;18:152.31. Nordrehaug J, Chronos N, Sigwart U. A biocompatible phosphotidylcholine

coating applied to metallic stents [abstract]. J Am Coll Cardiol 1994;23:5A.

32. Amon M, Winkler S, Dekker A, Bolz A, Mittermayer C, Schaldach M.Introduction of a new coronary stent with enhanced radioopacity andhemocompatibility. IEEE Engin Med Biol Soc 1995;7:1201.

33. Ozbek C, Heisel A, Grob B, Bay W, Schieffer H. Coronary implantation ofsilicone-carbide-coated Palmaz-Schatz stents in patients with high risk ofstent thrombosis without oral anticoagulation. Cathet Cardiovasc Diagn1997;41:718.

34. Lincoff A, Furst J, Ellis S, Tuch R, Topol E. Sustained local delivery ofdexamethasone by a novel intravascular eluting stent to prevent restenosis inthe porcine coronary injury model. J Am Coll Cardiol 1997;29:80816.

35. Staab ME, Holmes DR, Schwartz RS. Polymers. In: Sigwart U, ed. Endolu-

minal Stenting. London: WB Saunders, 1996:3444.36. Holmes D, Camrud A, Jorgenson M, Edwards W, Schwartz R. Polymeric

stenting in the porcine coronary artery model: differential outcome ofexogenous fibrin sleeves versus polyurethane-coated stents. J Am CollCardiol 1994;24:52531.

37. Baker J, Horn J, Nikolaychik V, Kipshidze N. Fibrin stent coatings. In:Sigwart U, ed. Endoluminal Stenting. London, Philadelphia, Toronto,Sydney, Tokyo: WB Saunders, 1996:849.

38. Kipshidze N, Baker J, Nikolaychik N. Fibrin coated stents as an improvedvehicle for endothelial cell seeding [abstract]. Circulation 1994;90:I597.

39. Stefanidis C, Toutouzas K, Vlachopoulos C, et al. Stents wrapped inautologous vein: an experimental study. Circulation 1996;28:103946.

40. Stefanidis C, Toutouzas K, Tsiamis E, et al. Preliminary results by using theautologous arterial graft-coated stent for the treatment of coronary arterydisease [abstract]. Eur Heart J 1997;18:154.

41. Bonan R, Bhat K, Lefevre T, et al. Coronary artery stenting after angioplastywith self-expanding parallel wire metallic stents. Am Heart J 1991;121:152230.

42. Stratienko A, Zhu D, Lambert C, Palmaz J, Schatz R. Improved thrombo-resistance of heparin coated Palmaz-Schatz coronary stents in an animalmodel [abstract]. Circulation 1993;88:I596.

43. Bailey S. Coating of endovascular stents. In: Topol E, ed. Textbook ofInterventional Cardiology. 1994:754765.

44. Sheth S, Dev V, Jacobs H, Forrester J, Litvak F, Eigler N. Prevention ofsubacute stent thrombosis by polymer-polyethylene oxide-heparin coating inthe rabbit carotid artery [abstract]. J Am Coll Cardiol 1995;25:348A.

45. Hardhammar P, Van Beusekom H, Emanuelsson H, et al. Reduction inthrombotic events with heparin-coated Palmaz-Schatz stents in normalcoronary arteries. Circulation 1996;93:42330.

46. Serruys P, Emanuelsson H, Van der Giessen W, et al. Heparin-coatedPalmaz-Schatz stents in human coronary arteries: early outcome of theBenestent-II pilot study. Circulation 1996;93:41222.

47. Chronos N, Robinson K, White D, et al. Heparin coating dramaticallyreduces platelet deposition on incompletely deployed Palmaz-Schatz in thebaboon A-V shunt [abstract]. J Am Coll Cardiol 1996;27:84A.

48. Chronos N, Robinson K, Kelly A, et al. Thrombogenicity of tantalum stents

is decreased by surface heparin bonding: scintigraphy of 111In-plateletdeposition in baboon carotid arteries [abstract]. Circulation 1995;92:I490.

49. Chronos N, Robinson K, Kelly A, et al. Neointima formation in stentedbaboon carotid arteries is reduced by bonded heparin: correlation withdecreased thrombogenicity [abstract]. J Am Coll Cardiol 1996;27:85A.

50. Zidar J, Virmani R, Culp S, et al. Quantitative histopathologic analysis of thevascular response to heparin coating of the Cordis stent [abstract]. J Am CollCardiol 1993;21:336A.

51. Zidar J, Jackman J, Gammon R, et al. Serial assessment of heparin coatingon vascular responses to a new tantalum stent [abstract]. Circulation1992;89:I185.

52. de Scheerder I, Wang K, Wilczek K, et al. Experimental study of thrombo-genicity and foreign body reaction induced by heparin-coated coronarystents. Circulation 1997;95:154953.

53. Cox D, Anderson P, Roubin G, Chou C, Agrawal S, Cavender J. Effects oflocal delivery of heparin and methotrexate on neointimal proliferation instented porcine coronary arteries. Coron Artery Dis 1992;3:23748.

54. Jeong M, Owen W, Staab M, et al. Does heparin release coating of theWallstent limit thrombosis and platelet deposition? Results in a porcinecarotid injury model [abstract]. Circulation 1995;92:I37.

55. Legrand V, Serruys PW, Emanuelsson H, et al. Benestent II trialfinal

results of visit 1:a 15-day follow-up [abstract]. J Am Coll Cardiol 1997;29:170A.

56. Vrolix M, Grollier G, Legrand V, et al. Heparin-coated wire coil (Wiktor)for elective stent placement-The MENTOR trial [abstract]. Eur Heart J1997;18:155.

57. Lambert T, Dev V, Rechavia E, Forrester J, Litvak F, Eigler N. Localizedarterial wall drug delivery from a polymer-coated removable metallic stent:kinetics, distribution, and bioactivity of forskolin. Circulation 1994;90:100311.

58. Dev V, Eigler N, Sheth S, Lambert T, Forrester J, Litvak F. Kinetics of drugdelivery to the arterial wall via polyurethane-coated removable nitinol stent:Comparative study of two drugs. Cathet Cardiovasc Diagn 1995;34:2728.

59. de Scheerder I, Wang K, Wilczek K, et al. Local methylprednisoloneinhibition of foreign body response to coated intracoronary stents. Coronary

Artery Dis 1996;7:1616.60. de Scheerder I, Wilczek K, Van Dorpe J. Angiopeptin loaded stents inhibit

the neointimal reaction induced by polymer coated stents implanted inporcine coronary arteries [abstract]. Circulation 1994;90:I597.

61. Eccleston D, Lincoff A, Furst J. Administration of colchicine using a novelprolonged delivery stent produces a marked local biological effect within theporcine coronary artery [abstract]. Circulation 1995;92:I67.

62. Alt E, Beilharz C, Preter G, et al. Biodegradable stent coating with polylacticacid, hirudin and prostacyclin reduces restenosis [abstract]. J Am CollCardiol 1997;29:238A.

63. Prietzel K, Pasquantonio J, Fliedner T, Stemberger A, Janczewski M.Inhibition of neointimal proliferation with a novel hirudin/prostacyclinanalog eluting stent coating in an animal overstretch model [abstract].Circulation 1996;94:I260.

64. Schmidmaier G, Stemberger A, Alt E, Gawaz M, Neumann F, Schomig A. Anew biodegradable polylactic acid coronary stent-coating, releasing PEG-Hirudin and a prostacycline analog, reduces both platelet activation andplasmatic coagulation [abstract]. J Am Coll Cardiol 1997;29:354A.

65. Schmidmaier G, Stemberger A, Alt E, Gawaz M, Schomig A. Time releasecharacteristics of a biodegradable stent coating with polylactic acid releasingPEG-hirudin and PGI2-analog [abstract]. J Am Coll Cardiol 1997;29:94A.

66. Aggarwal R, Ireland D, Azrin M, Ezekowitz M, De Bono D, Gershlick A.Antithrombotic potential of polymer-coated stents eluting platelet glycopro-tein IIb/IIIa receptor antibody. Circulation 1996;94:33117.

67. Aggarwal R, Ireland D, Azrin M, de Bono D, Gershlik A. Reduction inthrombogenicity of cellulose polymer-coated stents by immobilisation ofplatelet-targeted urokinase [abstract]. J Am Coll Cardiol 1997;29:353A.

68. Baron J, Aggrawal R, de Bono D, Gershlick A. Adsorption and elution ofc7E3 Fab from polymer-coated stents in-vitro [abstract]. Eur Heart J

1997;18:503.69. Folts J, Maalej N, Keaney J, Loscalzo J. Coating Palmaz-Schatz stents with

a unique NO donor renders them much less thrombogenic when placed inpig carotid arteries [abstract]. Circulation 1995;92:I670.

70. Folts J, Maalej N, Keaney J, Loscalzo J. Palmaz-Schatz stents coated with aNO donor reduces reocclusion when placed in pig carotid arteries for 28 days[abstract]. J Am Coll Cardiol 1996;27:86A.


7/27/2019 1-s2.0-S0735109798002897-main

10/10

71. Baker J, Nikolaychik V, Zulich A, Komorowski R, Kipshidze N. Fibrincoated stents as depot to deliver RGD peptide inhibit vascular reaction inatherosclerotic rabbit model [abstract]. J Am Coll Cardiol 1996;27:197A.

72. Santos R, Tanguay J, Kruse K, et al. Local administration of L-703,801 witha composite polymer stent reduces platelet deposition in canine coronaryarteries [abstract]. J Am Coll Cardiol 1997;29:418A.

73. Murphy J, Schwartz R, Edwards W, Camrud A, Vliestra R, Holmes D.Percutaneous polymeric stents in porcine coronary arteries. Circulation1992;86:15961604.

74. Van der Giessen W, Slager C, Gussenhoven E, et al. Mechanical featuresand in vivo imaging of a polymer stent. Int J Card Imag 1993;9:21926.

75. Susawa T, Shiraki K, Shimizu Y. Biodegradable intracoronary stents in adultdogs [abstract]. J Am Coll Cardiol 1993;21:483A.

76. Zidar J, Lincoff A, Stack R. Biodegradable stents. In: Topol E, ed. Textbookof Interventional Cardiology. Philadelphia, London, Toronto, Montreal,Sydney, Tokyo: WB Saunders, 1994:787802.

77. Bier J, Zalesky P, Sasken H, Williams D. A new bioabsorbable intravascularstent: in vitro assessment of hemodynamic and morphometric characteristics[abstract]. Circulation 1991;84:II197.

78. Gregory K, Grunkemeier J. Internal elastic lamina replacement with a newelastin stent biomaterial [abstract]. Circulation 1994;90:I596.

79. Gao R, Shi R, Qiao S, Song L, Li Y. A novel polymeric local heparin deliverystent: initial experimental study [abstract]. J Am Coll Cardiol 1996;27:85A.

80. Ye Y, Landau C, Meidell RS, et al. Improved bioresorbable microporousintravascular stents for gene therapy. ASAIOJ 1996;42:M823M827.

81. Dichek D, Neville R, Zwiebel J, Freeman S, Leon M, Anderson W. Seedingof intravascular stents with genetically engineered endothelial cells. Circu-lation 1989;80:134753.

82. Flugelman M, Virmani R, Leon M, Bowman R, Dichek D. Geneticallyengineered endothelial cells remain adherent and viable after stent deploy-ment and exposure to flow in vitro. Circulation 1992;70:34854.

83. Scott N, Candal F, Robinson K, Ades E. Seeding of intracoronary stents with

immortalized human microvascular endothelial cells. Am Heart J 1995;129:8606.

84. Bailey SR, Decento YJ, Sprague E. Endothelial sodding: intraproceduralreplacement of endothelial cells on endovascular stents [abstract]. Circula-tion 1997;94:I261.

85. Van Belle E, Tio F, Couffinhal T, Maillard L, Passeri J, Isner J. Stentendothelialization. Time course, impact of local catheter delivery, feasibilityof recombinant protein administration and response to cytokine expedition.Circulation 1997;95:438 48.

86. Van Belle E, Tio F, Chen D, et al. Passivation of metallic stents after arterialgene transfer ofphVEGF165 inhibits thrombus formation and intimal thick-ening. J Am Coll Cardiol 1997;29:13719.

87. Bertrand OF, Mongrain R, Lehnert S, et al. Intravascular radiation therapyin atherosclerotic disease: promises and premises. Eur Heart J 1997;18:138595.

88. Hehrlein C, Gollan C, Donges K, et al. Low-dose radioactive endovascularstents prevent smooth muscle cell proliferation and neointimal hyperplasiain rabbits. Circulation 1995;92:15705.

89. Hehrlein C, Stintz M, Kinscherf R, et al. Pure -particle emitting stentsinhibits neointima formation in rabbits. Circulation 1996;93:6415.

90. Carter A, Laird J, Bailey L, et al. Effects of endovascular radiation from a

-particle-emitting stent in a porcine coronary restenosis model. A dose-response study. Circulation 1996;94:23648.

91. American Society for Testing and Materials, eds. Annual Book of ASTMStandards, 1992;13:F139F86.

92. Bertrand OF, Mongrain R, Bilodeau L, Tanguay JF. Radioactivity localdelivery system. In: PCT patent application (W097/38730).

93. Williams D. Definitions in Biomaterials. Consensus Conference of theEuropean Society for Biomaterials. Chester: Elsevier, 1987.

94. Stokes K. Biodegradation. Cardiovasc Pathol 1993;2:111S9S.95. Horbett T. Principles underlying the role of adsorbed plasma proteins in blood

interactions with foreign materials. Cardiovasc Pathol 1993;2:137S48S.


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