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Review

The evolution of cardiovascular stent materials and surfacesin response to clinical drivers: A review

Barry OBrien *, William Carroll

National Centre for Biomedical Engineering Science, National University of Ireland, Galway, Ireland

Received 25 July 2008; received in revised form 26 October 2008; accepted 20 November 2008Available online 6 December 2008

Abstract

This review examines cardiovascular stent materials from the perspective of a range of clinical drivers and the materials that have beendeveloped in response to these drivers. The review is generally chronological and outlines how stent materials have evolved from initialbasic stainless steel devices all the way through to the novel biodegradable devices currently being explored. Where appropriate, pre-clin-ical or clinical data that influenced decisions and selections along the way is referenced. Opinions are given as to the merit and directionof various ongoing and future developments. 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Keywords: Stent; Materials; Coatings; Cardiovascular; Restenosis

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9462. Thinner struts needed for improved deliverability and reduced restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946

2.1. Higher-strength materials. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9462.2. Radio-opaque coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9472.3. Future needs for higher strength and radio-opacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947

3. Alternative inorganic coatings for improved vascular compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9483.1. Metal ion release and restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9483.2. Carbon coatings for reduced restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9483.3. Silicon carbide and the semiconductor theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9493.4. Titanium-nitride-oxide coating: leveraging titaniums track record . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9493.5. Iridium oxide and the catalytic theory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9503.6. Future clinical needs for inorganic bare metal stent coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950

4. Alternative stent materials for improved vascular compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9505. Polymer coatings for improved vascular compatibility and drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 951

5.1. Biomimetic phosphorylcholine-based coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9515.2. First-generation drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9515.3. Second-generation drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9525.4. Biodegradable polymers for drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952

6. New surfaces for direct loading of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9526.1. Nanoporous aluminium oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 952

1742-7061/$ - see front matter 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

doi:10.1016/j.actbio.2008.11.012

* Corresponding author. Tel.: +353 87 2934292.E-mail address: [email protected] (B. OBrien).

Available online at www.sciencedirect.com

Acta Biomaterialia 5 (2009) 945958

www.elsevier.com/locate/actabiomat
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6.2. Microtextured stainless steel surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9526.3. Porous carboncarbon coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9536.4. Hydroxyapatite ceramic coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9536.5. Drug delivery from strut macro reservoirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9536.6. Future clinical needs for a direct drug-loading surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 953

7. Stent materials for alternative imaging compatibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9548. Biodegradable stent materials the need to disappear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955

8.1. Polymeric stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9558.2. Magnesium alloy stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9558.3. Iron stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9568.4. The future for biodegradable stents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956

9. Concluding remarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 956

1. Introduction

The treatment of coronary and peripheral artery diseaseusing metallic stents has been one of the most revolution-

ary and most rapidly adopted medical interventions ofour time. During early development much of the investiga-tion and debate revolved around stent design, includingassessment of different materials and surface treatments.In recent years, the introduction of drug-eluting stentshas seen the debate, and sometimes controversy, shift tothe merits of one pharmacological agent or carrier overanother. The current most significant issue is concernabout increased risks of late stent thrombosis when usingdrug-eluting stents [1,2]. However, development of stentmaterials and non-pharmacological coatings has continuedsteadily. In fact, as we move forward, there are several rea-

sons why the development focus is likely to return to baremetal stent technologies, including materials and coatings.This review describes some of the clinical and biologicalfactors that drive stent material selection and presents theevolution of material developments that has resulted andthe direction in which these developments may go in thefuture.

2. Thinner struts needed for improved deliverability and

reduced restenosis

2.1. Higher-strength materials

Early in stent development, key characteristics were theease with which a device could be tracked through to thetarget vessel and then cross through lesions. These featureswere significantly affected by strut thickness, with thinnerstruts leading to more flexible devices and reduced cross-sectional profiles. There was also a hypothesis that thinnerstruts would lead to reduced restenosis rates. However, itwas not until the ground-breaking ISAR-STEREO clinicaltrial results were released in 2001 that data was available toprove this theory [3]. Using two comparable stent designs,with strut thicknesses of 50 and 140 lm, the trial showedthat the thinner strut device resulted in lower restenosis

rates. A similar study published in 2002, but in smaller

coronary vessels and using a larger variety of device designsand strut thicknesses, also concluded that thinner strutsresulted in lower restenosis rates [4]. While both studiesonly tentatively linked this effect to thinner struts causing

lower vascular trauma (and therefore less neointimagrowth), the longer-term effect was a drive to higher-strength stent materials which would enable designedreductions in strut thickness. This led to the initial intro-duction of cobaltchromium materials for balloon-expand-able stents. It is worth noting that cobaltchromium alloyswere already being used for stents for many years beforethis [5], where the high elastic modulus enabled the creationof the self-expanding Wallstent (Boston Scientific Corp.,Natick, MA).

One of the first balloon-expandable stents utilizingcobaltchromium alloys was the Multi-Link VisionTM coro-

nary stent (Abbott Laboratories, Abbott Park, IL). In thisdevice, the L605 alloy (Co20Cr15W10Ni) providedboth increased strength and increased X-ray attenuationcompared to stainless steel, allowing for thinner strutswithout impairing radio-opacity [6]. Subsequently, the Dri-ver coronary stent was introduced (Medtronic Inc.,Minneapolis, MN), made from the MP35N alloy (Co20Cr35Ni10Mo), again with increased strength andradio-opacity compared to stainless steel. The struts of thisdevice were of a similar thickness to those of the VisionTM

stent and an initial clinical trial showed the two devicesto have comparable performance [7]. While many devicesare now available, all exploiting the higher strength of thesematerials, the inherent corrosion resistance of cobaltchro-mium alloys is also worth mentioning. In general theybehave at least as passively as stainless steel, with a similarchromium-rich oxide developing. In fact in the case ofalloys containing molybdenum, it has also been shown thatthe molybdenum contributes further to oxide stability [8].While the focus on this discussion is on reducing strutthickness, these higher-strength alloys have also enabledmore novel stent designs such as the CoStar stent(Johnson & Johnson, New Brunswick, NJ), with its uniquedrug reservoirs within the stent struts such a designwould not have been possible with lower-strength materi-

als. While the initial drug-eluting study results were not

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as promising as expected, there is no doubt that this reser-voir concept will continue to be developed [9].

Returning to the theme of higher-strength materials andthinner struts, another unique development has been thecomposite sandwich structure of the TriMaxxTM stent(Abbott Laboratories, Abbott Park, IL). This device is

comprised of a thin layer of tantalum sandwiched betweentwo layers of 316L stainless steel; the composite structureprovides sufficient strength and radio-opacity to allow strutthicknesses even lower than the aforementioned cobaltchromium devices. The first clinical results from this stent(in conjunction with a phosphorylcholine thromboresistantcoating) showed it to be safe and comparable to other baremetal stents [10]. Table 1 presents details on a range of cor-onary stents summarizing this trend of reduced strut thick-nesses through use of higher-strength materials andcomposite structures.

Among the more recent and novel alloying efforts, cap-turing both improved strength and radio-opacity require-

ments, has been the development of stainless steel withplatinum additions. The platinum provides both solid solu-tion strengthening and increased radio-opacity, allowingsignificant reductions in strut thickness compared to con-ventional stainless steel. Early versions of this platinumchromium alloy contained up to 10% platinum [11], buthigher levels of platinum have also been explored [12]. Aclinical study is underway employing the ElementTM stent(Boston Scientific Corp., Natick, MA), made from thismaterial, though the exact platinum level has not beenspecified [13].

2.2. Radio-opaque coatings

As described, the drive towards thinner struts has alsobeen intrinsically tied to maintaining or improving deviceradio-opacity. Prior to the new alloy and composite workdescribed, some of the earlier efforts to improve radio-opacity utilized gold coatings on conventional stainlesssteel devices. These merit mention here, primarily due tothe unexpectedly poor clinical outcomes that resulted. Arandomized clinical study comparing the InflowTM stentdesign (InFlow Dynamics AG, Munich, Germany), in barestainless steel and gold-coated configurations, showed thatthe gold-coated devices were associated with a higher risk

of restenosis [14]. A later study comparing the NIRTM stentdesign (Medinol Ltd., Jerusalem, Israel), in bare metal andgold-coated conditions, showed very similar trends with thegold-coated devices again giving higher restenosis rates[15]. At the time, neither study was able to determine thecause of the poor performance from gold surfaces, though

both alluded to possible defects and impurities in the gold-plated layers. Related to this, an interesting animal studywas performed by Edelman et al. exploring the possibilityof a post-plating heat treatment to modify gold surfacetopography and remove any residual impurities [16]. How-ever, the damage had already been done and interest ingold coatings declined rapidly, giving added impetus tothe cobaltchromium and other alloying efforts.

2.3. Future needs for higher strength and radio-opacity

As an overview, Table 2 presents summary data for thekey materials-related clinical trials described. (Readers are

advised to refer to the sources of information indicated toobtain full details of study design and statistical signifi-cance data for the outcomes listed.) Moving forward, it isdifficult to see a need for new materials with furtherincreases in strength or radio-opacity, beyond the develop-ments described. There is a practical limit to which strutthickness can be readily reduced. Stents made fromhigher-strength materials will have a tendency to increasedelastic recoil, as it becomes increasingly difficult to induceplastic deformation at equivalent device expansion strains.Furthermore, as strut thickness reduces and stent flexibilityimproves, a point is being reached where device trackability

and crossing profile is becoming more dependent on themechanical characteristics and dimensions of the balloonand delivery system than on the stent itself. Finally, someof the drivers for improved radio-opacity are also becom-ing less relevant. The quality and resolution of X-ray fluo-

Table 1Correlation of typical yield strength values with strut thickness for asample of devices.

Stent name/manufacturer

Material 0.2% Yieldstrength (MPa)

Strutthickness(lm)

BX Velocity/Johnson &Johnson

316L 340 140

Express/Boston scientific 316L 340 132Driver/Medtronic CoCr MP35N 415 91VisionTM/Abbott CoCr L605 510 81

TriMaxx

TM

/Abbott 316L/Ta/316L N ot applicable 74

Table 2Summary of clinical trial data for design and materials-related studies.

Study description Angiographic restenosis rates Ref.

ISAR-STEREO, 316L 15.0% in thin strut group (50 lm) [3]25.8% in thick strut group (140 lm)

In-stent restenosis in smallcoronaryarteries (2.762.99 mm)

23.5% in thin strut group (

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roscopy images obtained in the catheterization laboratoryis being significantly improved with the introduction offlat-panel detector technology. These systems are makingit easier to resolve detail on small devices such as stents[17]. In other imaging developments, the rapid uptake ofcomputed tomography (CT) for angiographic screening

and follow-ups may also have an impact. Materials withhigh radio-opacity have a tendency to produce more imageartefact, such that lumen patency assessment can be diffi-cult in some stents [18]. In light of this, it is most unlikelythat further increases in radio-opacity will be needed forcurrent conventional stent designs.

3. Alternative inorganic coatings for improved vascular

compatibility

In parallel with the developments in material strengthand radio-opacity, increasing attention was also beinggiven to optimizing the stent surface to improve compati-

bility with its vascular environment. While no strong scien-tific evidence existed, it was believed that surfaceoptimization could help reduce restenosis rates for baremetal stents below the typical levels of 2030%. A widevariety of surface modifications and inorganic coatingswere explored, targeting a range of objectives such asreduced metal ion release, reduced surface thrombogenicityand texturing to promote endothelialization.

3.1. Metal ion release and restenosis

It had long been considered that implant materials with

corrosion-resistant oxide surfaces, i.e. titanium oxide andchromium oxide, enhance biocompatibility by minimizingmetal ion release. While there had been many in vitro stud-ies of ion release from implant materials, no clinical evi-dence was available with regard to the impact forpatients with vascular stents. The first tentative link wasfrom a study by Koster et al. investigating correlationsbetween metal allergies and in-stent restenosis [19]. Thisstudy suggested that patients with a sensitivity to nickeland molybdenum, based on a skin patch test, had a higherfrequency of in-stent restenosis than patients without sensi-tivity. While the investigators recognized limitations intheir study, the work did raise questions about the poten-tial impact of metal ion release from stainless steel, whichwas still the predominant material in use. The debatefocused on nickel due to it being present at higher levelsthan molybdenum in 316L nominally 12% compared to2.5%, respectively. While the subject did fuel ongoingdevelopments of inorganic stent coatings, to prevent ionrelease, subsequent studies have failed to establish an effect[20]. It is also worth noting that the introduction of cobaltchromium alloy stents was not impeded by the discussion;L605 contains 10% nickel while MP35N contains 35%nickel and 10% molybdenum. However, metal ion releaseis not necessarily related to the elemental proportions in

an alloy and is more influenced by stability and regenera-

tion potential of the oxide. A review of this subject byHanawa describes how nickel is disproportionatelyreleased from stainless steel and also how cobaltchro-mium repassivates much faster than stainless steel [21].These may be important factors when considering the dis-ruption experienced by oxide films during stent deployment

and therefore the likelihood of ion release from the respec-tive materials.The behaviour of nitinol (NiTi), which contains approx-

imately 50 at.% nickel, is also worth mentioning in relationto ion release. Though many in vitro, in vivo and explantstudies have been performed, there is no evidence to sug-gest that release of nickel ions from NiTi is a significantclinical problem. This can be attributed to two basic metal-lurgical effects. First, it is important to note that the nickelpresent in NiTi is bonded intermetallically to the titanium,i.e. typically each nickel atom is strongly bonded to a tita-nium atom. The nickel is therefore more chemically stablethan, for example, the nickel present in stainless steel or

cobaltchromium alloys, which is present in solid solution.Secondly, at the surface of NiTi, exposed titanium oxidizesmore readily that nickel, creating what is predominantly atitanium oxide surface. While there may be very smallquantities of nickel or nickel oxide present, surface passiv-ation treatments can further enhance the titanium oxide,creating a surface that is typically as stable as titaniummaterials. Of course, situations involving wear or signifi-cant oxide disruption may alter such stability, but suchconditions are not usually present for the majority of car-diovascular devices.

3.2. Carbon coatings for reduced restenosis

Carbon coatings were explored early in the develop-ment of alternative surfaces, with a number of differentapproaches examined including diamond-like carbon(DLC) and pyrolytic carbon. An early in vitro studyshowed that BioDiamond DLC-coated stainless steelstents (BioDiamond, Mainz, Germany) exhibited reducedmetal ion release and lower platelet activation comparedto uncoated stents [22]. While the investigators naturallyconcluded that this should lead to improved biocompati-bility, results of subsequent studies did not always demon-strate this. Airoldi et al. reported on a study comparingthe Diamond Flex AS stent (Phytis Medical DevicesGmbH, Berlin, Germany) in its DLC-coated configura-tion against a bare stainless steel version [23]. At six-month follow-up, no difference was detected in restenosisrates between the two groups. Thus while the DLC mayindeed reduce acute and subacute thrombosis, its benefitwith respect to longer-term vessel patency was not evi-dent. A similar study reported by Meireles et al. com-pared the PhytisTM DLC-coated stent (Phytis MedicalDevices GmbH, Berlin, Germany) with the Multi-LinkPentaTM stainless steel stent (Abbott Laboratories, AbbottPark, IL) [24]. Angiographic restenosis rates at six months

showed no significant difference between the two groups.


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Interestingly, despite such findings, some DLC-coatedstents are still on the market, and while they can makeno claim to being able to reduce restenosis, their abilityto reduce metal ion release is probably still a marketableadvantage over bare metal stents. Research continues intofurther optimizing DLC coatings; a study by Hasebe et al.

investigated a fluorine-doped DLC [25]. The fluorine-doped material had a higher ratio of albumin to fibrino-gen adsorption and lower platelet adhesion and activationthan non-doped DLC. It was therefore concluded that thefluorine-doped DLC would have a much lower tendencyto induce thrombus formation.

Pyrolytic carbon has a longer and arguably more suc-cessful history of vascular implant experience thanDLC. It has been used for many years as a coating forartificial heart valves, where high haemocompatibilityhas been critical. Sorin Biomedica (Saluggia, Italy) wasone of the pioneers of pyrolytic carbon heart valves andwas also behind the development of one of the first car-

bon-coated stents, the CarbostentTM. Pyrolytic carbonrequires high temperatures for deposition and is usuallyapplied in relatively thick layers; these conditions arenot particularly suited for stents. Sorin therefore devel-oped a modified process to vapour deposit a carbon layerat low temperatures and in thin layers. The depositedlayer is similar to pyrolytic carbon in structure. An earlyclinical study showed the CarbostentTM to have an angio-graphic restenosis rate of 14.1%; however, this study hadno control arm and therefore primarily just demonstratedsafety and efficacy [26]. The authors did, however, notethat the low number of diabetic patients in the study

may also have contributed to the relatively low restenosisrates observed. A further study, which included higher-risk patients (including those with diabetes and those over75 years of age) demonstrated an angiographic restenosisrate of 25% at six months [27]. This value is more typicalfor bare metal stents and the absence of thromboticevents is also of merit. In another variation of carbon sur-faces, the ARTHOSInert stent (amg International GmbH,Raesfeld-Erle, Germany) has a surface with ion-implantedcarbon, rather than coated carbon the rationale beingthat the ion-implanted carbon would adhere better, there-fore giving a superior barrier against ion release. How-ever, a study comparing this device with an equivalentstainless steel stent failed to show any significant differ-ence between the two configurations [28]. In summary,while carbon surfaces may be safe and less thrombogenic,they appear to do little with regard to reducing restenosisrates. An interesting study by Tomai et al. measuredinflammatory markers, platelet activation and thrombingeneration at various timepoints post-implantation andconcluded that there was no difference between carbon-coated stents and stainless steel stents [29]. While bothgroups showed significant increases due to the stentingprocedure, the absence of a difference between themmay in part explain the findings of the other clinical

studies.

3.3. Silicon carbide and the semiconductor theory

Another early unique approach to address the restenosisissue was the exploration of silicon carbide surfaces. Thetheory behind this approach revolved around electrontransfer between proteins in the blood and the stent metal-

lic surface, i.e. interactions between fibrinogen and thestent surface leading to fibrin deposition and ultimatelyplatelet adhesion and thrombus formation. It was pro-posed that this electron interaction could be limitedthrough application of a semiconductor layer tuned to anappropriate conductivity [30]. The coating selected wasan amorphous, phosphorous-doped, hydrogen-rich siliconcarbide applied by a chemical vapour deposition process.However, while in vitro studies showed promise, an initialclinical study (using a tantalum stent substrate) resulted ina restenosis rate of 26.8%, again typical for bare metalstents with no major advantage evident [31]. A later itera-tion of the device utilized a stainless steel substrate, but in a

comparison with a commercial stainless steel stent, the sil-icon carbide again failed to show a restenosis advantageover stainless steel [32]. So what appears to have been awell-investigated strategy again failed to live up to expecta-tions and became another coating casualty in the pre-drug-eluting stent era.

3.4. Titanium-nitride-oxide coating: leveraging titaniums

track record

This coating has been developed on the rationale that atitanium oxide surface should be highly biocompatible and

should also act as a barrier to metal ions. The addition ofsome nitrogen into the oxide structure is an interestingaspect that has not been widely addressed. Endothelium-derived nitric oxide is of course known to be importantin regulating endothelial function, helping suppress plateletaggregation, cellular adhesion to the endothelium and eveninhibiting smooth muscle cell proliferation [33]. While thereis no scientific evidence to suggest that a nitrogen-contain-ing oxide should have a similar benefit, the effects are nev-ertheless promising. An early porcine study employed astainless steel stent with a titanium coating applied byphysical vapour deposition, in an oxygennitrogen gasmixture [34]. Histology showed that neointimal area andthickness were significantly less in the TiNOX samplescompared to bare stainless steel. Unlike many of the earliercoatings, in vitro and pre-clinical findings seem to subse-quently translate into real clinical benefits. A study com-paring the coated stents with stainless steel devicesrecorded angiographic restenosis rates of 15% and 33%,respectively, with lower major adverse cardiac events(MACEs) also measured for the titanium-nitride-oxide[35]. The device has proven to be safe and effective in anumber of subsequent studies, including an unrestrictedclinical study that included high-risk patients and complexlesions [36]. The titanium-nitride-oxide coating has also

been compared against drug-eluting stents (DESs) and

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while restenosis rates were not measured, the rate ofMACEs was much lower for the TITANOXTM (Hexacath,Rueil-Malmaison, France) than the DESs [37]. In sum-mary, this seems to be one of the few non-DES coatingsthat is surviving on its own merit, even if it does not havea very significant market share.

3.5. Iridium oxide and the catalytic theory

Iridium oxide has long been used as a coating for elec-trodes involved in neural stimulation and pacing applica-tions. Its first use as a stent coating was explored in theMOONLIGHT clinical study which employed a gold-pla-ted stainless steel stent, covered with a layer of iridiumoxide [38]. The study yielded an angiographic restenosisrate of 13.8% which is certainly attractive for a non-DES device, but the absence of a control arm makes itdifficult to put any significance on the outcome. As aresult of the demise of gold coatings described earlier, fur-

ther iterations of this technology have been explored with-out the gold interlayer. Coatings are applied directly tostent substrates by reactive sputtering of iridium in anoxygen-rich atmosphere. While it is proposed that theiridium oxide acts as a barrier layer against metal ions,its vascular compatibility is also attributed to a catalyticeffect at the surface of the stent and the manner by whichthis disrupts the restenosis process [39]. In particular, it isunderstood that hydrogen peroxide (H2O2) is created byleukocytes in response to the stent-induced vessel injury.This H2O2 plays a significant role in restenosis as it inhib-its endothelial cell growth and promotes smooth muscle

cells. The theory behind iridium oxide suggests that theoxide surface acts as a catalyst for the decomposition ofthe peroxide to oxygen and water, thereby reducing thestimulus for smooth muscle cell growth. While this cata-lytic effect has been demonstrated in vitro, there is noclinical evidence to support its occurrence or effectin vivo.

3.6. Future clinical needs for inorganic bare metal stent

coatings

As reviewed, and summarized in Table 3, most inorganicstent coatings have provided ineffective or inconclusive per-formance in terms of reducing restenosis, which was theprimary driver behind their development. (The exceptionmay be the titanium-oxide-nitride coatings which appearto be the most promising.) Despite the many novel andwell-engineered approaches, these coatings will not be sig-nificant players in the efforts to reduce restenosis rates, intheir existing configurations. They may, however, have anongoing role to play in the bare metal stent market segmentif they can truely demonstrate reduced thrombosis ratesand in individual cases where metal allergy is a genuineconcern. While the links between metal ion release, metalallergy and restenosis have never been clearly established,

inorganic coatings can certainly eliminate the doubt where

appropriate. Going forward, there is, however, a significant

role for inorganic coatings in the field of polymer-free drugdelivery and potentially in delivery of other biological andgenetic agents. This topic is reviewed in a later section ofthis article.

4. Alternative stent materials for improved vascular

compatibility

While the majority of efforts to improve vascular com-patibility have naturally involved coatings, a brief men-tion needs to be given to work involving thedevelopment of new platform stent materials. Such mate-rial developments have indeed been fewer than the effortsto increase strength and radio-opacity, but this is under-standable given the more tentative nature of any poten-tial benefit and the investment already going intohigher-strength and radio-opacity needs. Tantalum wasexplored early during stent development and was usedin both the coronary Wiktor stent (Medtronic Inc.,Minneapolis, MN) [40] and the peripheral Strecker stent(Boston Scientific Corp., Natick, MA) [41]. These werehelical wound wire and knitted wire structures, respec-tively. While the radio-opacity of tantalum was a factorin its selection, there was also evidence to suggest thatthe inert nature of tantalum oxide surfaces would lead

to improved vascular compatibility and in particular

Table 3Summary of clinical trial data for inorganic coating-related studies.

Study description Angiographic restenosis rates Ref.

DLC vs. stainless steel 31.8% for Diamond Flex AS stent [23]35.9% for bare Flex AS stent

DLC vs. stainless steel 24.3% for PhytisTM Diamond [24]

21.8% for PentaTM

stainless steelPhantom IV study:

carbon coating14.1% for CarboSTENTTM [26]

No control arm

Carbon coating: high-riskpatients

25.0% for CarboSTENTTM [27]

No control arm

Ion-implanted carbon vs.stainless steel

11.0% for ArthosInert carbonimplanted stent

[28]

16.1% for Arthos stainlesssteel stent (NS)

Silicon carbide coating 26.8% for SiC-coated tantalum [31]No control arm

TenaxTM SiC vs.NIR 316L

30.0% for SiC-coated stainlesssteel stent

[32]

26.7% for NIRTM stainless steel stent

TiNOX trial 15.0% for titanium-nitride-oxidecoated stent

[35]

33.0% for same design stainlesssteel stent

MOONLIGHT study 13.8% for iridium oxide-coated stent [38]No control arm


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reduced thrombogenicity. Specifically relevant was datasuggesting that the biocompatibility should be high dueto excellent performance in a variety of electrochemicalstudies [42]. While these stents were reasonably success-ful, wire coiled and woven structures were eventuallysuperceded by slotted tube/laser-cut designs, giving

improved compression behaviour with reduced deviceforeshortening upon deployment. A laser-cut tantalumstent, the Tensum (Biotronik GmbH, Berlin, Germany),was briefly introduced in a silicon carbide-coated design,as described earlier. However, the stent design and mate-rial appear not to have been optimized and the devicewas only briefly available.

Much more recently, the use of niobium has beenexplored, again based on the rationale that niobium wouldhave a highly inert oxide surface and that there would alsobe no release of nickel, chromium or molybdenum ions.The stents were made from a niobium-1% zirconium alloyand were anodized to further ensure a high-integrity nio-

bium oxide. These devices were compared against stainlesssteel stents in a clinical study with six-month follow-up[43]. The results, however, failed to show an advantagefor the niobium, which produced higher neointimalingrowth. The investigators suggest that the thicker strutsof the niobium stent (in comparison to the stainless steelcontrol) may have contributed to its poorer performance.Higher-strength niobium alloys may overcome this aspect.

Looking to the future for materials with improved vas-cular compatibility, nickel-free stainless steels certainlydeserve mention. Nickel-free steels have been in develop-ment for many years and some are now on the market,

having been driven primarily by the orthopaedic implantsector where larger devices, with bigger surface areasand greater wear, have made the nickel toxicity issuemore significant. Nickel is present in austenitic steels like316L, to enhance strength, corrosion resistance and tostabilize the austenite phase which is critical for durabilityand formability. The new nickel-free steels have low-leveladditions of nitrogen (1.0%) which provide all thesebenefits [44]. While much work would be needed to verifythat the corrosion resistance and oxide stability of thesenew materials is suitable for stent applications, it wouldseem to be a suitable incremental step in the developmentof stent materials.

Having reviewed several traditional and novel materi-als, at this point it is worth mentioning a study bySprague and Palmaz, which assessed a wide spectrum ofmaterials using a number of bioassays relevant to cardio-vascular applications [45]. This study investigated fibrino-gen, platelet and monocyte binding, as well as endothelialcell migration, and used the data to establish a vascularbiocompatibility ranking for the materials. Interestingly,materials such as stainless steel, nitinol, titanium,cobaltchromium and tantalum ranked highly in this list,while gold, DLC, carbon and silicon carbide performedpoorly. This trend reflects some of the overall observa-

tions reported here and points towards some potentially

useful correlations between data from such assays andreal-world clinical experience.

5. Polymer coatings for improved vascular compatibility and

drug delivery

5.1. Biomimetic phosphorylcholine-based coatings

While inorganic coatings were proving to have limitedsuccess in improving vascular response, polymeric sur-faces were also being explored. Among the most interest-ing approach in this respect was the use of phosphorylcholine (PC)-based coatings to mimic thephospholipids on the outer surfaces of red blood cells,thereby aiming to provide a highly compatible implantsurface [46]. Several studies and registries were performedwith the BiodivYsioTM stent (Abbott Laboratories, AbbottPark, IL) and while safety and reduced thrombogenicitywas demonstrated, the benefit in terms of significantly

reduced restenosis rates was not evident [47]. The PC-coated device, however, also demonstrated both long-termstability [48] and the ability to deliver drug compounds[49], and therefore the coating has attracted much interestfor drug delivery. Most prominent among these has beenthe successful use of PC coatings for delivery of the ABT-578 (Zotarolimus) drug from the Endeavor stent(Medtronic Inc., Minneapolis, MN) [50].

5.2. First-generation drug-eluting coatings

Unlike PC coatings, which have now transitioned to

drug-delivery applications, the initial generation of drug-eluting coatings (DECs) was not specifically selected ordesigned for vascular compatibility. Availability, drug mis-cibility, durability and release kinetics were key drivers inthe initial development of polymer-based carriers for thecommercially successful Cypher (Johnson & Johnson,New Brunswick, NJ) and Taxus (Boston Scientific Corp.,Natick, MA) devices. The Cypher stent has three differentlayers. An initial parylene tie-layer is applied to the stentsurface, followed by a polyethylene-co-vinyl acetate(PEVA) and poly-n-butyl methacrylate (PMBA) mixturewhich contains the Sirolimus drug. Finally, a top coat ofPEVA/PMBA (without drug) is applied to control the drug

elution rate. The Taxus device has a single polymer/Pac-litaxel drug mixture layer, using the SIBS triblock copoly-mer poly(styrene-b-isobutylene-b-styrene). While severaltrials and investigations have supported the early andmid-term safety and efficacy of these stents, doubts havebeen raised about long-term safety, particularly in relationto the risk of late stent thrombosis [51,52]. The exact causefor late stent thrombosis has not been confirmed, but thereis a general concensus that the continued presence of thepolymer carrier is a key factor, especially after drug releasehas diminished. Therefore, going forward, there is a driveto use either biodegradable polymer drug carriers or non-

polymeric surfaces for direct loading of drugs.


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5.3. Second-generation drug-eluting coatings

With the benefit of an ever-increasing library of clinicaldata, second-generation DEC device development hasalready seen the commercial introduction of new polymercarriers. The PC-based coating for the Endeavor stent

has already been described, while most recently the XienceV Everolimus-eluting stent (Abbott Laboratories, AbbottPark, IL) has been introduced [53]. This uses poly-n-butyl-methacrylate (PMBA) as a tie-layer to the metal surfaceand a polyvinylidenefluorohexafluoropropylene (PVDFHFP) copolymer as the drug-carrier layer. No top coat isused. Clinical results for this new system have been prom-ising, showing superiority to initial devices in terms ofrestenosis rates and reduced late events [54]. Whilst thiscannot be attributed solely to the polymer surface, it atleast points towards the successful design and selection ofa surface with good vascular compatibility, even if it isnon-erodible and will remain in place indefinitely.

5.4. Biodegradable polymers for drug-eluting coatings

Biodegradable polymers offer a potentially ideal solu-tion in terms of initially providing a carrier to retain andrelease the required drug quantity and then to fully degradeaway, eliminating doubts about long-term effects of thepolymer. There are many biodegradable polymers, butthe most widely used for medical applications come fromthe polyester family and include polylactic acid (PLA),polyglycolic acid (PGA) and the copolymer polylactic-co-glycolic acid (PLGA).1

Drug compounds mixed with these polymer matrices aregradually released as the polymer degrades within the ves-sel wall. Biodegradation of PLA, PGA and PLGA involvesrandom hydrolysis of their ester bonds. The lactic acid andglycolic acid degradation products are subsequently con-verted to water and carbon dioxide through the action ofenzymes and then excreted [55]. It must be noted, however,that the biodegradable route is not without its own chal-lenges. In addition to these fundamental degradation prod-ucts, the host environment must deal with polymerprocessing aids such as initiators, catalysts and solvents,all of which may impact biocompatibility.

A number of devices with biodegradable drug-elutinglayers are currently in clinical trials. These include theSparrowTM NiTi stent system from CardioMind Inc.(Sunnyvale, CA), which uses the SynBiosysTM biodegrad-able PLGA polymer from Surmodics Inc. (Eden Prairie,MN) to release Rapamycin [56,57], and the CE-approvedBioMatrix 316L device from Biosensors International(Singapore), which elutes Biolimus A9 from PLA [58,59].It is too early to know how successful these or other similar

devices will be in the long term, but the approach is cer-tainly a logical step in the evolution of polymeric drug-elut-ing surfaces.

6. New surfaces for direct loading of drugs

As mentioned earlier, the increased risk of late thrombo-sis is one of the biggest challenges facing current DES tech-nology. It has been well demonstrated that suchthrombosis is most frequently associated with poor endo-thelialization of stent struts [60,61]. The exact cause of poorendothelialization has not been established, but, as indi-cated, the potential for the polymeric drug carriers toinduce a local inflammatory reaction is considered to beone of the factors [62]. There is therefore now a significantdriver for the development of technologies to load drugsonto the stent surface without the use of either absorbableor non-absorbable polymers. One of several early efforts inthis regard involved the loading of Paclitaxel directly to a

conventional stainless steel stent surface. However, thisapproach was not entirely successful, with no significantdifferences recorded between this DES and a bare metalstent [63]. While issues with drug dose density were high-lighted as being possible causes for the poor performance,the study is a good illustration of the simple fact thatrelease kinetics of pure drug, from a conventional surface,is not optimum. In summary, modified surfaces to retainand release the drug in a more controlled manner are essen-tial for such polymer-free approaches. A number ofthese surface technologies are described here.

6.1. Nanoporous aluminium oxide

This was one of the first efforts at developing a poroussurface for loading of drug onto a stent surface. The pro-cess involved application of a thin layer of aluminium overthe stainless steel stent, using physical vapour deposition.Following this, the coated stent was anodized to convertthe aluminium layer to a porous aluminium oxide, withpores in the nanometer range. An early animal studyshowed the coated stents to have good vascular compatibil-ity and also demonstrated the possibility of drug loadingand elution from the porous structure [64]. However, clin-ical trials with this concept have not been successful andthe approach is not currently being pursued [65]. It is mostlikely that difficulties with control of loading and release ofdrug from the nanometer-sized pores (515 nm) is a signif-icant challenge due to their small size. In a fundamentaldrug-loading and drug-release study of such structures ithas been shown that uncontrolled release occurs when drugadhered to the outer surface rather than being depositedwithin the pores [66].

6.2. Microtextured stainless steel surfaces

One of the more individual approaches involves use of a

roughened stent surface and attaching a drug solution to

1 Note that polylactic acid (PLA) is often interchangeably referred to aspoly-L-lactic acid (PLLA), to allow more accurate differentiation frompoly-DL-lactic acid (PDLA), which has a different molecular orientation on

the polymer chain.


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this surface in the catheterization laboratory, just beforeimplantation. The Yukon stent (Translumina GmbH,Hechingen, Germany) is roughened by a basic grit-blastingprocess detailed quantification of this surface has notbeen reported, but early in vitro and animal work demon-strated that the surface retained drug and released it over

an extended period [67]. A related clinical study comparedthe safety of smooth and roughened stents (without drug)and, interestingly, the roughened surfaces showed lowerlate loss and also a trend for lower restenosis rates [68].A more recent trial compared the drug-loaded Yukon

stent against a commercially available DES and establishedno significant differences between them at nine-month fol-low-up [69]. Such results are indeed interesting, but thereare some significant challenges ahead for this device.Firstly, the manner of drug loading on-site, just prior toimplantation, will cause logistic, quality and regulatorychallenges for all involved from manufacturers throughto physicians and patients. Secondly, though probably less

important, will be the need to alter the mindset in regard tostent surface roughness. For many years, highly polishedstent surfaces have been desired, in order to reduce riskof thrombosis and minimize the risk of inflation balloondamage. Exploration of nanoporous textures has only mar-ginally infringed on such thinking; however, the concept ofa grit-blasted rough surface is a different scenario. The ideamost certainly has merit as the influence of textures onendothelialization has long been explored, but extensiveresearch on aspects such as acute thrombogenicity andlong-term fatigue performance will be needed, as well asbeing able to demonstrate tight surface roughness control.

6.3. Porous carboncarbon coating

Details on this new technology are scarce but merit men-tion as animal studies have already been completed andclinical studies are in progress. The coating is describedin company literature (Cinvention GmbH, Wiesbaden,Germany) as having a glassy polymeric carbon matrixand pyrolytic carbon compounds. It appears that thecoating is initially a polymer-based slurry with carbon par-ticles dispersed; subsequent pyrolysis converts the mixtureto this carboncarbon matrix, with porosity controlled bythe carbon particle size and the extent of pyrolysis. A por-cine study using this drug-loaded coating, on a cobaltchromium stent, showed the concept to be both safe andeffective, though the study did lack a suitable control arm[70]. Going forward, it will be interesting to see the signif-icance of any residual polymer that may be present in thestructure, i.e. to ascertain that it has no thrombogenic effectwhen assessed clinically in a larger population.

6.4. Hydroxyapatite ceramic coating

The biocompatibility of hydroxyapatite (HAp) coatinghas long been successfully demonstrated in orthopaedic

applications where it acts as a support for bone growth

and osseointegration. This proven biocompatibility, com-bined with the ability to tune porosity, has resulted in thesecalcium phosphate-based materials now being explored fordrug retention and elution. Initial porcine studies havebeen completed with HAp-coated devices (without drug)showing equivalency to bare metal stents [71]. Solgel tech-

nology is used to apply an initial relatively dense thin layer,with electrochemical deposition being used to apply a moreporous outer layer for drug retention. Detailed analyses ofearly clinical studies are not available, but initial reportsclaim promising results for the drug-eluting version of thisdevice [72]. As this technology moves forward, significantengineering challenges will be faced with ensuring durabil-ity and integrity of these ceramic coatings. These will becritical issues, not only after implantation, but duringdevice manufacture, tracking through difficult anatomyand also when being deployed by direct stenting againsthard lesions.

6.5. Drug delivery from strut macro reservoirs

A number of significant drug-delivery approaches meritmention in this category even though they are not utilizingany new materials or coatings that have not already beenmentioned. The CoStar stent (Johnson & Johnson, NewBrunswick, NJ), as described earlier [9], utilizes reservoirsmachined from within the stent struts, for the storageand elution of drug. These reservoirs are laser cut fromthe cobaltchromium struts and penetrate completelythrough the strut thickness. Drug elution rate is controlledby a capping layer of biodegradable polymer over the drug.

Control of degradation of this capping layer will be criticalto the success of this concept going forward.

As reviewed earlier, carbon coatings have been widelyexplored and while they have proven to be safe and non-thrombogenic, offered no significant advantage in termsof reducing restenosis rates. However, the CarbostentTM

concept is now being taken a step further with the use ofthis coating technology in a polymer-free drug-elutingdesign. The JanusTM stent (Sorin Biomedica, Saluggia, Italy)has slots cut on the abluminal face of the stent struts; thisslotted device is then coated with the same coating technol-ogy as the CarbostentTM and subsequently these slots arefilled with pure drug, i.e. with no polymer matrix. A num-ber of clinical trials have commenced. Interestingly, resultsfrom a trial comparing this DES against a bare carbon-coated device showed only marginal advantage for thedrug-eluting version [73].

6.6. Future clinical needs for a direct drug-loading surface

As long as the concern exists that current non-absorb-able polymers are contributing to late stent thrombosis inDES systems, then there is a significant need for directdrug-loading surfaces. Those reviewed here, which aresummarized in Table 4, have many merits and challenges

as discussed. There are also many other approaches, for


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which clinical data is not available, but which will no doubthighlight further options to physicians and patients. Aswith any novel technology, a whole array of general chal-lenges need to be addressed. These include engineeringaspects, such how these surface modifications impact ondevice integrity and durability, while extensive scientificexploration is needed to understand and control the kinet-

ics and pharmacological mechanisms for such delivery sys-tems. At this point some of the bigger challenges appear tobe in achieving controlled loading of drug into these sur-faces and subsequently getting controlled release. There-fore development of materials surfaces must not be inisolation, but must done in conjunction with developmentsin drug-loading and drug-release technologies. Similarly,material developments must address cell biology require-ments such as maximizing endothelial cell growth and pro-liferation and minimizing platelet adhesion.

7. Stent materials for alternative imaging compatibility

This topic has already been partly addressed, at the startof this review, where radio-opacity requirements for X-rayfluoroscopy were described. For the foreseeable future, X-ray fluoroscopy will continue to be used during stentimplantation to monitor location and deployment. How-ever, for screening and follow-up procedures, alternativeimaging technologies have been introduced in recent yearsand these are seeing increased utilization. Computedtomography (CT) has seen rapid take up, especially forevaluation of coronary vessels, while magnetic resonanceimaging (MRI) is being increasingly used for peripheralvessels such as carotid, iliac, femoral and renals.

Looking first at compatibility of stents for CT imaging,it is important to note that there is a somewhat conflictingrequirement between optimum radio-opacity for X-rayfluoroscopy and the optimum level for CT angiography.In summary, materials with high radio-opacity generatesignificant artefacts when imaged using CT, as mentionedearlier [18]. Therefore conventional materials like stainlesssteel and cobaltchromium produce image artefacts thatcan prevent clinical interpretation of the data. In the caseof stents, the artefact usually manifests itself as a thicken-ing of the struts, giving the impression of a reduced stentlumen. This can prevent identification of in-stent resteno-

sis, particularly if it is not a severe stenosis and is easily

obscured by the artificial wall thickening. Radio-opaquemarker bands and highly radio-opaque stents are particu-larly problematic, while devices with thinner struts obvi-ously perform better [74,75]. Clearly, the conflictingrequirements for X-ray fluoroscopy and CT create an inter-esting material selection challenge. For example, optimumCT image compatibility may be a material with an X-ray

attenuation in the range of titanium, but of course thiswould be nearly invisible when viewed under fluoroscopy,during the critical stages of tracking and stent deployment.So the ideal material would have high radio-opacity ini-tially to aid implantation under fluoroscopy, but radio-opacity would degrade subsequently so that vessel follow-ups can be accurately performed by CT. In the long termit may not be necessary to meet such a design requirement;imaging software may ultimately be able to filter out orreduce the metal artefact. Alternatively the introductionof biodegradable stents, which will be reviewed later, mayindirectly solve this problem. However, at this point neither

of these scenarios can be guaranteed and a material solu-tion that offers diminishing radio-opacity with time wouldindeed be interesting.

The imaging compatibility problem is even more signif-icant when considering MR angiography. MR offers signif-icant advantages over CT (or fluoroscopy) in that itinvolves no ionizing radiation and also avoids the use ofiodine-based contrast agents, which can be toxic for somepatients. Difficulties with image resolution and image cap-ture speed have so far hindered wider use of the technologyfor imaging of coronary vessels, but these are less criticalissues for peripheral vessels where the technique is nowbeing widely used. However, for both coronary and periph-eral stents, the major challenge for MR angiography arisesdue to the paramagnetic nature of the majority of the com-mercial materials such as stainless steel and cobaltchro-mium. This paramagnetism leads to local distortion ofthe magnetic imaging field, ultimately leading to an artefacton the image that is typically proportional to the magneticsusceptibility of the material. In the case of stainless steeland cobaltchromium this artefact is relatively large and,in addition to obscuring the vessel lumen, extends wellbeyond the stent boundary [76]. Nitinol devices tend to per-form better due to this materials lower magnetic suscepti-bility. It must be noted that eddy currents, induced in the

stent by the RF signal of the scanner, also contribute to

Table 4Summary of current technologies for direct drug loading.

Technology Company Description Status Ref.

Aluminium oxide Abbot (Jomed) Anodizing of aluminium layer applied to stent Inactive [64,65]Microtextured stainless steel Translumina Grit blasting to create a roughened texture Clinical data [67

69]Porous carboncarbon Cinvention Carbon particles in porous carbon matrix Animal data. Clinical in progress [70]

Hydroxyapatite MIV Therapeutics Calcium phosphate-based layer by electrodeposition Animal data. Clinical in progress [71,72]Reservoirs in CoCr struts Johnson & Johnson

(Conor Medsystems)Laser-cut reservoirs through strut thickness Clinical data [9]

Carbon-coated slotted struts Sorin group Non-penetrating slots within struts Clinical data [73]


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artefacts within the stent lumen [77]. However, this is pri-marily a stent design issue and is not addressed in thisreview. There has been a number of attempts, though lar-gely unsuccessful, at developing new stent materials tooptimize MR image compatibility. One of the early effortsinvolved development of a Cu14Au8Ag2Pt1Pd alloy

with low magnetic susceptibility [78,79]. While this cop-per-based material did eliminate image artefact, it wasnot an appropriate stent material from a vascular compat-ibility and mechanical strength perspective and did notmake it past initial feasibility studies. Similarly, a novel pal-ladiumsilver alloy may have had ideal imaging character-istics [80] but also failed to get into development, mostlikely again due to its inability to meet mechanical and vas-cular compatibility requirements. One of the more success-ful developments has been the introduction of a platinumstent for biliary applications [81]. This device has beenshown to have good MR imaging behaviour; however, thisapproach has not been used for coronary stents, most likely

because the material would be too radio-opaque even forX-ray fluoroscopy. The tantalum peripheral devicesdescribed earlier [40,41] also had reduced susceptibilityartefact but this was purely incidental. While these stentsbecame obsolete for design reasons, use of pure tantalumdid not successfully carry through to newer coronarydesigns, due to lack of mechanical property optimizationand also as the high radio-opacity would again be unsuit-able for smaller stent sizes. One of the more recent researchefforts has been the development of an Nb28Ta3.5W1.3Zr alloy specifically for MR image compatibility. Coro-nary stents made from this material have been shown to

provide suitable mechanical performance [82], with initialdata for imaging behaviour and vascular compatibility alsoshowing promise [83].

In summary, from a clinical imaging perspective, themost challenging requirement going forward is likely tobe MR compatibility. Currently, however, this is a lowdevelopment driver; there is a current need for MR com-patibility in peripheral stenting, but until such time asMR becomes widely used for coronary imaging, it is unli-kely that sufficient investment and development will takeplace.

8. Biodegradable stent materials the need to disappear . . .

Many arguments have been put forward on the potentialbenefits of having the stent removed once its job is done.Most obvious amongst these is of course the fact that thestent is indeed a foreign object within the vessel and itspresence is associated with the potential for inflammatoryreactions, progressive neointima development, damagedendothelium and associated thrombosis risks. In addition,problems with blockage of side-branches would be reducedand difficulties with overhang at ostial lesions would beminimized. There has therefore been significant interestand development in recent years in the field of biodegrad-

able stents.

8.1. Polymeric stents

There are several polymeric degradable stents in devel-opment but just a couple merit mention at this stage onthe basis of clinical data. The BVS stent (Abbott Laborato-ries, Abbott Park, IL) is made from poly-L-lactic acid

(PLLA) and results from an initial clinical trial wererecently published [84]. While the study demonstrated fea-sibility, it was a very small patient population (30) and,interestingly, at one-year follow-up the stent was only par-tially degraded. This appears to be one of the drawbacks ofpolymeric biodegradable stents, i.e. long degradation timespresumably to minimize the rate at which any by-productsare released. One of the earliest devices in this field was theIgaki-Tamai stent (Kyoto Medical Planning Co., Kyoto,Japan), which is also manufactured from PLLA [85]. Asmall trial with these stents showed that while some acutestent recoil occurred, this stabilized fast and at six monthsfollow-up performance was satisfactory with initial hyper-

plasia comparable to bare metal stents. A four-year follow-up showed the devices to have completely degraded with nofurther hyperplasia development.

8.2. Magnesium alloy stents

The relative ease with which magnesium corrodes and itsrole as an essential element in the biological system makesit an excellent candidate for the biocorrosion concept. Thefirst animal study utilized the AE21 magnesium alloy whichcontained 2% aluminium and 1% rare earths (Ce, Pr, Nd)[86]. There were a number of key findings from this study:

neointima formation decreased significantly once strutthickness started to reduce; struts endothelialized readily;and biocorrosion occurred within this endothelium. Fol-low-up at 56 days showed strut material to be still presentand extrapolation suggested that full corrosion would haveoccurred at 89 days this was much faster than expectedand this rapid degradation is still an issue today for thistechnology. In any event, the results were promising andsubsequent clinical studies have been performed in bothperipheral and coronary vessels [87,88]. These studies usedthe WE43 alloy (

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slow it down, to ensure that the scaffolding function of thedevice remains for longer, preventing negative remodellingfrom taking place.

8.3. Iron stents

Although this technology has not progressed as far asmagnesium stents, the first animal work was actually com-pleted some years earlier. In this initial study, pure ironstents were implanted in rabbit aortas with follow-upsextending to 18 months [90]. While histology revealed sig-nificant damage to the vessel media and internal elasticmembrane, no aneurysm damage occurred and no signifi-cant neointimal hyperplasia developed. However, corro-sion was deemed to be too slow, as major portions of thestruts were still present at 18 months. A subsequent studyby the same group implanted larger-diameter iron stentsinto porcine aortas and determined that neointima prolifer-ation was comparable to that found with stainless steel; no

local or systemic toxicity was recorded [91]. However, largeportions of these stent struts also remained and while thisslow degradation was noted to reduce the risk of fragmentembolization, it was also acknowledged that the rate wastoo slow for such biodegradable strategies. A recent trialwith iron stents implanted in porcine coronary arterieswas limited to a 28-day follow-up, but claimed to have lessneointima formation than cobaltchromium stents at thistimepoint [92].

8.4. The future for biodegradable stents

All of the degradable technologies reviewed here havemany specific challenges ahead of them, but, to date, com-mon to all is the lack of clinical evidence demonstrating aclear advantage to this approach. Polymer systems facespecific challenges in achieving adequate strength and resis-tance to recoil, as well as a need to reduce degradationtimes. Magnesium systems appear to offer the most prom-ise with degradation times being closer to what may berequired. Iron stents face big difficulties in terms of estab-lishing that the degradation products would be acceptable after years of striving to avoid corrosion of stainless steeldevices, the mindset will take some time to change, even ifthe data is good. In summary, the field of biodegradabledevices may in theory offer the ideal solution, but withmany challenges ahead, there should be a focus of contin-ued materials and clinical research in the coming years.

9. Concluding remarks

This review has covered a wide range of material scienceand engineering developments which have been driven byclinical needs within the cardiovascular stent field. Newalloys have been developed specifically for stent applica-tions and existing alloys have been leveraged from otherfields. Surface coatings have been developed for objectives

ranging from acting as a metal ion barrier through to being

a carrier for storage and elution of drugs. Some of thedevelopments have failed to achieve their objectives, buteven these outcomes have contributed to the vast body ofknowledge which has been gained in the field of materialsperformance in biological environments. Even as the car-diovascular stent market matures, there is a continued need

for investigation and development. At this point, the areaswhich would appear to be worthy of the most effort includedevelopment of inorganic drug-eluting coatings, materialsand designs for image compatibility and biodegradablestents.

References

[1] Lusher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC,Virmani R, et al. Drug-eluting stent and coronary thrombosis:Biological mechanisms and clinical implications. Circulation2007;115:10518.

[2] Daemen J, Wenaweser P, Tsuchida K, Abrecht L, Vaina S, Morger C,

et al. Early and late coronary stent thrombosis of sirolimus-elutingand Paclitaxel-eluting stents in routine clinical practice: data from alarge two-institutional cohort study. Lancet 2007;369:66778.

[3] Kastrati A, Mehilli J, Dirschinger J, Dotzer F, Schuehlen H,Neumann FJ, et al. Intracoronary stenting and angiographic results:strut thickness effect on restenosis outcome (ISAR-STEREO) trial.Circulation 2001;103:281621.

[4] Briguori C, Sarais C, Pagnotta P, Liistro F, Montorfano M, ChieffoA, et al. In-stent restenosis in small coronary arteries: impact of strutthickness. J Am Coll Cardiol 2002;40:4039.

[5] Clerc CO, Jedwab MR, Mayer DW, Thompson PJ, Stinson JS.Assessment of wrought ASTM F1058 cobalt alloy properties forpermanent surgical implants. J Biomed Mater Res (Appl Biomater)1997;38:22934.

[6] Kereiakes DJ, Cox DA, Hermiller JB, Midei MG, Bachinsky WB,

Nukta ED, et al. Usefulness of a cobalt chromium coronary stentalloy. Am J Cardiol 2003;92:4636.

[7] Sketch MH, Ball M, Rutherford B, Pompa JJ, Russell C, KereiakesDJ. Evaluation of the Medtronic (Driver) cobalt-chromium alloycoronary stent system. Am J Cardiol 2005;95:812.

[8] Metikos-Hukovic M, Pilic Z, Babic R, Omanovic D. Influence ofalloying elements on the corrosion stability of CoCrMo implant alloyin Hanks solution. Acta Biomaterialia 2006;2:693700.

[9] Krucoff MW, Kereiakes DJ, Petersen JL, Mehran R, Hasselblad V,Lansky AJ, et al. A novel bioresorbable polymer Paclitaxel-elutingstent for the treatment of single and multivessel coronary disease. JAm Coll Cardiol 2008;51:154352.

[10] Azibad A, Popma JJ, Tanajura LF, Hattori K, Solberg B, LarracasC, et al. Clinical and angiographic results of percutaneous coronaryrevascularization using a trilayer stainless steel-tantalum-stainless

steel phosphorylcholine-coated stent: The TriMaxx trial. CatheterCardiovasc Interv 2007;70:9149.

[11] Craig CH, Friend CM, Edwards MR, Cornish LA, Gokcen NA.Mechanical properties and microstructure of platinum enhancedradiopaque stainless steel (PERSS) alloys. J Alloy Comp2003;361:18799.

[12] Craig C, Friend C, Edwards M, Gokcen N. Tailoring Radiopacity ofAustenitic Stainless Steel for Coronary Stents. In: Proceedings fromthe Materials and Processes for medical devices Conference, Ana-heim, CA. Materials Park, OH: ASM International; 2003. p. 2947.

[13] Boston scientific, press release. Boston scientific announces firstimplant of TAXUS elementTM platinum chromium Stent, 20 July2007.

[14] Kastrati A, Schoemig A, Dirschinger J, Mehilli J, von Welser N,Pache J, et al. Increased risk of restenosis after placement of gold-

coated stents. Circulation 2000;101:247883.


7/29/2019 1-s2.0-S1742706108003668-main

13/14

[15] Reifart N, Morice MC, Silber S, Benit E, Hauptmann KE, de SousaE, et al. The NUGGET study: NIR ultra gold-gilded equivalencytrial. Catheter Cardiovasc Interv 2004;62:1825.

[16] Edelman ER, Seifert P, Groothuis A, Morss A, Bornstein D, RogersC. Gold-coated NIR stents in porcine coronary arteries. Circulation2001;103:42934.

[17] Spahn M. Flat detectors and their clinical applications. Eur Radiol2005;15:193447.

[18] Maintz D, Seifarth H, Raupach R, Flohr T, Rink M, Sommer T,et al. 64-slice multi-detector coronary CT angiography: in vitroevaluation of 68 different stents. Eur Radiol 2006;16:81826.

[19] Koster R, Vieluf D, Kiehn M, Sommerauer M, Kahler J, Baldus S,et al. Nickel and molybdenum contact allergies in patients withcoronary in-stent restenosis. Lancet 2000;365:18957.

[20] Norgas T, Hobikoglu G, Serdar ZA, Aksu H, Alper AT, Ozer O,et al. Is there a link between nickel allergy and coronary stentrestenosis? Tohoku J Exp Med 2005;206:2436.

[21] Hanawa T. Metal ion release from metal implants. Mater Sci Eng C2004;24:74552.

[22] Gutensohn K, Beythien C, Bau J, Fenner T, Grewe P, Koester R,et al. In vitro analysis of diamond-like carbon coated stents: reductionof metal ion release, platelet activation, and thrombogenicity.Thromb Res 2000;99:57785.

[23] Airoldi F, Colombo A, Tavano D, Stankovic G, Klugmann S,Paolillo V, et al. Comparison of diamond-like carbon-coated stentsversus uncoated stainless steel stents in coronary artery disease. Am JCardiol 2004;93:4747.

[24] Meireles GCX, de Abreu LM, da Cruz Forte AA, Sumita MK,Sumita JH, Aliaga J. Randomized comparative study of diamond-likecarbon coated stainless steel stent versus uncoated stent implantationin patients with coronary artery disease. Arc Bras Cardiol2007;88(4):3437.

[25] Hasebe T, Yohena S, Kamijo A, Okazaki Y, Hotta A, Takahashi K,et al. Fluorine doping into diamond-like carbon coatings inhibitsprotein adsorption and platelet activation. J Biomed Mater Res A2007;83:11929.

[26] Danzi GB, Capuano C, Sesana M, Baglini R, Bartorelli AL,Trabattoni D, et al. Six-month clinical and angiographic outcomesof the tecnic carbostentTM coronary system: the phantom IV study. JInv Cardiol 2004;16:6414.

[27] Antoniucci D, Valenti R, Migliorini A, Moschi G, Trapani M,Bolognese L, et al. Clinical and angiographic outcomes followingelective implantation of the carbostent in patients at high risk ofrestenosis and target vessel failure. Catheter Cardiovasc Interv2001;54:4206.

[28] Kim YH, Lee CW, Hong MK, Park SW, Tahk SJ, Yang JY, et al.Randomized comparison of carbon ion-implanted stent versus baremetal stent in coronary artery disease: the asian pacific multicenterarthos stent study (PASS) trial. Am Heart J 2005;149:33641.

[29] Tomai F, Ghini AS, Ferri C, Desideri G, Versaci F, Gaspardone A,et al. Effects of carbon-coated coronary stents on the markers ofinflammation, thrombin generation and platelet and endothelial

activation. Ital Heart J 2003;4(1):238.[30] Rzany A, Schaldach M. Smart material silicon carbide: reducedactivation of cells and proteins on a-SiC:H-coated stainless steel. ProgBiomed Res 2001;3:18294.

[31] Heublein B, Pethig K, Ozbek C, Elsayed M, Bolz A, Schaldach M.Silicon carbide coatinga new hybrid design of coronary stents. ProgBiomed Res 1998;1:339.

[32] Unverdorben M, Sippel B, Degenhardt R, Sattler K, Fries R, Abt B,et al. Comparison of a silicon carbide-coated stent versus a noncoatedstent in human beings: the Tenax versus NIR Stent Studys long termoutcome. Am Heart J 2003;145:e17.

[33] Vallence P, Chan N. Endothelial function and nitric oxide: clinicalrelevance. Heart 2001;85:34250.

[34] Windecker S, Mayer I, De Pasquale G, Maier W, Dirsch O, De GrootP, et al. Stent coating with titanium-nitride-oxide for reduction of

neointimal hyperplasia. Circulation 2001;104:92833.

[35] Windecker S, Simon R, Lins M, Klauss V, Eberli FR, Roffi M, et al.Randomized comparison of a titanium-nitride-oxide-coated stentwith a stainless steel stent for coronary revascularization. The TiNOXTrial. Circulation 2005;111:261722.

[36] Karjalainen PP, Ylitalo AS, Airaksinen KEJ. Real world experiencewith the TITAN stent: a 9-month follow-up report from The TitanPORI Registry. EuroInterv 2006;2:18791.

[37] Karjalainen PP, Ylitalo A, Airaksinen KEJ. Titanium and nitrideoxide-coated stents and Paclitaxel-Eluting stents for coronary revas-cularization in an unselected population. J Inv Cardiol 2006;10:4628.

[38] Di Mario C, Grube E, Nisanci Y, Reifert N, Colombo A, RodermannJ, et al. MOONLIGHT: a controlled registry of an iridium oxide-coated stent with angiographic follow-up. Int J Cardiol2004;95:32931.

[39] OBrien B, Chandrasekaran C. Development of iridium oxide as acardiovascular stent coating. In: Proceedings from the materials andprocesses for medical devices conference, St Paul, MN. MaterialsPark, OH: ASM International; 2004. p. 3016.

[40] Vaishnav S, Aziz S, Layton C. Clinical experience with the Wiktorstent in native coronary arteries and coronary bypass grafts. Br HeartJ 1994;72:28893.

[41] Long AL, Sapoval MR, Beyssen B, Auguste MC, Le Bras Y,Raynaud AC, et al. Strecker stent implantation in iliac arteries:patency and predictive factors for long-term success. Radiology1995;194:73974.

[42] Zitter H, Plink H. The electrochemical behavior of metallic implantmaterials as an indicator of their biocompatibility. J Biomed MaterRes 1987;21:88196.

[43] Beier F, Gyongyosi M, Raeder T, v Eckardstein-Thumb E, SperkerW, Albrecht P, et al. First in human randomized comparison of ananodized niobium stent versus a standard stainless steel stent. ClinRes Cardiol 2006;95:45560.

[44] Sumita M, Hanawa T, Teoh SH. Development of nitrogen-containingnickel-free austenitic stainless steels for metallic biomaterialsreview.Materials Science and Engineering C 2004;24:75360.

[45] Sprague EA, Palmaz JC. A model system to assess key vascularresponses to biomaterials. J Endovasc Ther 2005;12:594604.

[46] Whelan DM, van der Giessen WJ, Krabbendam SC, van Vliet EA,Verdouw PD, Serruys PW, et al. Biocompatibility of phosphorylcho-line coated stents in normal porcine coronary arteries. Heart2000;83:33845.

[47] Babapulle MN, Eisenberg MJ. Coated stents for the prevention ofrestenosis: part II. Circulation 2002;106:285966.

[48] Lewis AL, Furze JD, Small S, Robertson JD, Higgins BJ, Taylor S,et al. Long-term stability of a coronary stent coating post-implanta-tion. J Biomed Mater Res (Appl Biomater) 2002;63:699705.

[49] Lewis AL, Vick TA, Collias ACM, Hughes LG, Palmer RR, LeppardSW, et al. Phosphorylcholine-based polymer coatings for stent drugdelivery. J Mater Sci Mater Med 2001;12:86570.

[50] Garcia-Touchard A, Burke SE, Toner JL, Cromack K, Schwartz RS.Zotarolimus-eluting stents reduce experimental coronary neointimalhyperplasia after 4 weeks. European Heart Journal 2006;27:98893.

[51] Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T,et al. Localized hypersensitivity and late coronary thrombosissecondary to a sirolimus-eluting stent: should we be cautious?Circulation 2004;109:r3842.

[52] Ellis SG, Colombo A, Grube E, Popma J, Koglin J, Dawkins KD,et al. Incidence, timing, and correlates of stent thrombosis with thepolymeric Paclitaxel drug-eluting stent. J Am Coll Cardiol2007;49:104351.

[53] Sheiban I, Villata G, Bollati M, Sillano D, Lotrionte M, Biondi-Zoccai G. Next-generation drug-eluting stents in coronary arterydisease: focus on everolimus-eluting stent (Xience V). Vasc HealthRisk Manage 2008;4(1):318.

[54] Serruys PW, Ruygrok P, Neuzner J, Piek JJ, Seth A, Schofer JJ, et al.A randomized comparison of an everolimus-eluting coronary stentwith a Paclitaxel-eluting coronary stent: the SPIRIT II trial.

EuroInterv 2006;2:28694.


7/29/2019 1-s2.0-S1742706108003668-main

14/14

[55] Commandeur S, van Beusekom HMM, van der Giessen WJ.Polymers, drug release, and drug-eluting stents. J Interv Cardiol2006;19:5006.

[56] Surmodics, press release. Surmodics announces first human use ofsynbiosys biodegradable polymer on CardioMind. 31 March 2008.

[57] Abizaid AC, de Ribamar Costa Jr J, Whitbourn RJ, Chang JC. TheCardioMind coronary stent delivery system: stent delivery on a 0.014 00

guidewire platform. EuroInterv 2007;3:1547.[58] BioMatrix drug eluting coronary stent system. Biosensors interna-

tional brochure reference 10351-000-Rev 02, BMXBRO-03-08-EN.[59] Biosensors, press release. Biosensors drug-eluting stent demonstrates

superior strut coverage to industry-leading drug-eluting stent, 14October 2008.

[60] Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC,et al. Pathological correlates of late drug-eluting stent thrombosis:strut coverage as a marker of endothelialization. Circulation2007;115:243541.

[61] Guagliumi G, Virmani R, Musumeci G, Motta T, Valsecchi O,Bonaldi G, et al. Drug-eluting versus bare metal coronary stents:long-term human pathology. Findings from different coronaryarteries in the same patient. Ital Heart J 2003;10:71320.

[62] Steffel J, Eberli FR, Luscher T, Tanner FC. Drug-eluting stents: whatshould be improved? Ann Med 2008;40:24252.

[63] Lansky AJ, Costa RA, Mintz GS, Tsuchiya Y, Midei M, Cox DA,et al. Non-polymer-based Paclitaxel-coated coronary stents for thetreatment of patients with de novo coronary lesions. Circulation2004;109:194854.

[64] Wieneke H, Dirsch O, Sawitowski T, Gu YL, Brauer H, Dahman U,et al. Synergistic effects of a novel nanoporous stent coating andtacrolimus on intima proliferation in rabbits. Catheter CardiovascInterv 2003;60:399407.

[65] Tsujino I, Ako J, Honda Y, Fitzgerald PJ. Drug delivery via nano-,micro and macroporous coronary stent surfaces. Exp Opin DrugDeliv 2007;3:28795.

[66] Kang HJ, Kim DJ, Park SJ, Yoo JB, Ryu YS. Controlled drug releaseusing nanoporous anodic aluminum oxide on stent. Thin Solid Films2007;515:51847.

[67] Wessely R, Hausleiter J, Michaelis C, Jaschke B, Vogeser M, Milz S,et al. Inhibition of neointima formation by a novel drug-eluting stentsystem that allows for dose-adjustable, multiple, and on-site coating.Arterioscler Thromb Vasc Biol 2005;25:74853.

[68] Dibra A, Kastrati A, Mehilli J, Pache J, von Oepen R, Dirschinger J,et al. Influence of stent surface topography on the outcomes ofpatients undergoing coronary stenting: a randomized double-blindcontrolled trial. Catheter Cardiovasc Interv 2005;65:37480.

[69] Mehilli J, Kastrati A, Wessely R, Dibra A, Hausleiter J, Jaschke B,et al. Randomized trial of a nonpolymer-based Rapamycin-elutingstent versus a polymer-based Paclitaxel-eluting stent for the reductionof late lumen loss. Circulation 2006;113:2739.

[70] Bhargava B, Reddy NK, Karthikeyen G, Raju R, Mishra S, Singh S,et al. A novel Paclitaxel-eluting porous carbon-carbon nanoparticlecoated, nonpolymeric cobalt-chromium stent: evaluation in a porcine

model. Catheter Cardiovasc Interv 2006;67:698702.[71] Rajtar A, Kaluza GL, Yang Q, Hakimi D, Liu D, Tsui M, et al.Hydroxyapatite-coated cardiovascular stents. EuroInterv 2006;2:1135.

[72] MIV press release. MIV presents positive preliminary data for itspolymer-free DES, 16 April 2008.

[73] Morice MC, Bestehorn HP, Carrie D, Macaya C, Aengevaeren W,Wijns W, et al. Direct stenting of de novo coronary stenoses withtacrolimus-eluting versus carbon-coated carbostents. The randomizedJUPITER II trial. EuroInterv 2006;2:4552.

[74] Mahnken AH,Buecker A, WildbergerJE, Ruebben A, Stanzal S, VogtF, et al. Coronary artery stents in multislice computed tomography:in vitro artifact evaluation. Invest Radiol 2004;39:2733.

[75] Schlosser T, Scheuermann T, Ulzheimer S, Mohrs OK, Kuehling M,Albrecht P, et al. In vitro evaluation of coronary stents and in-stentstenosis using a dynamic cardiac phantom and a 64-detector row CTscanner. Clin Res Cardiol 2007;96:88390.

[76] Hug J, Nagel E, Bornstedt A, Schnackenburg B, Oswald H, Fleck E.Coronary arterial stents: safety and artifacts during MR imaging.Radiology 2000;216:7817.

[77] Bartels LW, Smits HFM, Bakker CJG, Viergever MA. MR imagingof vascular stents: effects of susceptibility, flow, and radiofrequencyeddy currents. J Vasc Interv Radiol 2001;12:36571.

[78] Buecker A, Spuentrup E, Ruebben A, Mahnken A, Nguyen TH,Kinzel S, Gunther RW. New metallic MR stents for artifact-freecoronary MR angiography: feasibility study in a swine model. InvestRadiol 2004;39:2503.

[79] Spuentrup E, Ruebben A, Mahnken A, Stuber M, Koeller C, NguyenTH, et al. Artifact-free coronary resonance magnetic angiographyand coronary vessel wall imaging in the presence of a new, metallic,coronary magnetic resonance imaging stent. Circulation2005;111:101926.

[80] van Dijk LC, van Holten J, van Dijk BP, Mathelijssen NAA,Pattynama PMT. A precious metal alloy for construction of MRimaging-compatible balloon-expandable vascular stents. Radiology2001;219:2847.

[81] Hagspiel KD, Leung DA, Nandalur KR, Angle JF, Dulai HS,Spinosa DJ, et al. Contrast-enhanced MR angiography at 1.5 T afterimplantation of platinum stents: in vitro and in vivo comparison withconventional stent designs. AJR 2005;184:28894.

[82] OBrien B, Stinson J, Carroll W. Development of a new niobium-based alloy for vascular stents. Journal Mech Behav Biomed Mater2008;1:30312.

[83] OBrien BJ, Stinson JS, Boismier DA, Carroll WM. Characterizationof an NbTaWZr alloy designed for magnetic resonance angiographycompatible stents. Biomaterials 2008;29:45405.

[84] Ormiston JA, Serruys PW, Regar E, Dudek D, Thuesen L, WebsterM, et al. A bioabsorbable everolimus-eluting coronary stent systemfor patients with single de-novo coronary artery lesions (ABSORB): aprospective open-label trial. Lancet 2008;371:899907.

[85] Griffiths H, Peeters P, Verbist J, Bosiers M, Deloose K, Heublein B,et al. Future devices: bioabsorbable stents. Br J Cardiol (Acute IntervCardiol) 2004;11:AIC80=0?>AIC84.

[86] Heublein B, Rohde R, Kaese V, Niemeyer M, Hartung W, HaverichA. Biocorrosion of magnesium alloys: a new principle in cardiovas-cular implant technology? Heart 2003;89:6516.

[87] Di Mario C, Griffiths H, Gotekin O, Peeters N, Verbist J, Bosiers M,et al. Drug-eluting bioabsorbable magnesium stent. J Interv Cardiol2004;17:3915.

[88] Erbel R, Di Mario C, Bartunek J, Bonnier J, de Bruyne B, Eberli F,et al. Temporary scaffolding of coronary arteries with bioabsorbablemagnesium stents: a prospective, non-randomised multicentre trial.Lancet 2007;369:186975.

[89] Barlis P, Tanigawa J, Di Mario C. Coronary bioabsorbable magne-sium stent: 15-month intravascular ultrasound and optical coherency

findings. Eur Heart J 2007;28:2319.[90] Peuster M, Wohlsein P, Brugmann M, Ehlerding M, Seidler K, FinkC, et al. A novel approach to temporary stenting: degradablecardiovascular stents produced from corrodible metalresults 618months after implantation into New Zealand white rabbits. Heart2001;86:5639.

[91] Peuster M, Hesse C, Schloo T, Fink C, Beerbaum P, von Schnak-enburg C. Long-term biocompatibility of a corrodible peripheral ironstent in the porcine descending aorta. Biomaterials 2006;27:495562.

[92] Waksman R, Pakala R, Baffour R, Seabron R, Hellinga D, Tio FO.Short-term effects of biocorrodible iron stents in porcine coronaryarteries. J Interv Cardiol 2008;21:1520.

958 B. OBrien, W. Carroll / Acta Biomaterialia 5 (2009) 945958

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