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Acta Biomaterialia 5 (2009) 945958 www.elsevier.com/locate/actabiomat

Review

The evolution of cardiovascular stent materials and surfaces in 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 2008 Available 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 been developed in response to these drivers. The review is generally chronological and outlines how stent materials have evolved from initial basic stainless steel devices all the way through to the novel biodegradable devices currently being explored. Where appropriate, pre-clinical or clinical data that inuenced decisions and selections along the way is referenced. Opinions are given as to the merit and direction of various ongoing and future developments. 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
Keywords: Stent; Materials; Coatings; Cardiovascular; Restenosis

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Thinner struts needed for improved deliverability and reduced restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Higher-strength materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Radio-opaque coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Future needs for higher strength and radio-opacity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative inorganic coatings for improved vascular compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Metal ion release and restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Carbon coatings for reduced restenosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Silicon carbide and the semiconductor theory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Titanium-nitride-oxide coating: leveraging titaniums track record . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Iridium oxide and the catalytic theory. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6. Future clinical needs for inorganic bare metal stent coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alternative stent materials for improved vascular compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polymer coatings for improved vascular compatibility and drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Biomimetic phosphorylcholine-based coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. First-generation drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Second-generation drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Biodegradable polymers for drug-eluting coatings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . New surfaces for direct loading of drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Nanoporous aluminium oxide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946 946 946 947 947 948 948 948 949 949 950 950 950 951 951 951 952 952 952 952

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4. 5.

6.

Corresponding author. Tel.: +353 87 2934292. E-mail address: j.obrien9@nuigalway.ie (B. OBrien).

1742-7061/$ - see front matter 2008 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.actbio.2008.11.012

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6.2. Microtextured stainless steel surfaces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Porous carboncarbon coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4. Hydroxyapatite ceramic coating . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.5. Drug delivery from strut macro reservoirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6. Future clinical needs for a direct drug-loading surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stent materials for alternative imaging compatibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biodegradable stent materials the need to disappear . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Polymeric stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Magnesium alloy stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Iron stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4. The future for biodegradable stents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The treatment of coronary and peripheral artery disease using metallic stents has been one of the most revolutionary and most rapidly adopted medical interventions of our time. During early development much of the investigation and debate revolved around stent design, including assessment of dierent materials and surface treatments. In recent years, the introduction of drug-eluting stents has seen the debate, and sometimes controversy, shift to the merits of one pharmacological agent or carrier over another. The current most signicant issue is concern about increased risks of late stent thrombosis when using drug-eluting stents [1,2]. However, development of stent materials and non-pharmacological coatings has continued steadily. In fact, as we move forward, there are several reasons why the development focus is likely to return to bare metal stent technologies, including materials and coatings. This review describes some of the clinical and biological factors that drive stent material selection and presents the evolution of material developments that has resulted and the direction in which these developments may go in the future. 2. Thinner struts needed for improved deliverability and reduced restenosis 2.1. Higher-strength materials Early in stent development, key characteristics were the ease with which a device could be tracked through to the target vessel and then cross through lesions. These features were signicantly aected by strut thickness, with thinner struts leading to more exible devices and reduced crosssectional proles. There was also a hypothesis that thinner struts would lead to reduced restenosis rates. However, it was not until the ground-breaking ISAR-STEREO clinical trial results were released in 2001 that data was available to prove this theory [3]. Using two comparable stent designs, with strut thicknesses of 50 and 140 lm, the trial showed that 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 designs and strut thicknesses, also concluded that thinner struts resulted in lower restenosis rates [4]. While both studies only tentatively linked this eect to thinner struts causing lower vascular trauma (and therefore less neointima growth), the longer-term eect was a drive to higherstrength stent materials which would enable designed reductions in strut thickness. This led to the initial introduction of cobaltchromium materials for balloon-expandable stents. It is worth noting that cobaltchromium alloys were already being used for stents for many years before this [5], where the high elastic modulus enabled the creation of the self-expanding Wallstent (Boston Scientic Corp., Natick, MA). One of the rst balloon-expandable stents utilizing cobaltchromium alloys was the Multi-Link VisionTM coronary stent (Abbott Laboratories, Abbott Park, IL). In this device, the L605 alloy (Co20Cr15W10Ni) provided both increased strength and increased X-ray attenuation compared to stainless steel, allowing for thinner struts without impairing radio-opacity [6]. Subsequently, the Driver coronary stent was introduced (Medtronic Inc., Minneapolis, MN), made from the MP35N alloy (Co 20Cr35Ni10Mo), again with increased strength and radio-opacity compared to stainless steel. The struts of this device were of a similar thickness to those of the VisionTM stent and an initial clinical trial showed the two devices to have comparable performance [7]. While many devices are now available, all exploiting the higher strength of these materials, the inherent corrosion resistance of cobaltchromium alloys is also worth mentioning. In general they behave at least as passively as stainless steel, with a similar chromium-rich oxide developing. In fact in the case of alloys containing molybdenum, it has also been shown that the molybdenum contributes further to oxide stability [8]. While the focus on this discussion is on reducing strut thickness, these higher-strength alloys have also enabled more novel stent designs such as the CoStar stent (Johnson & Johnson, New Brunswick, NJ), with its unique drug reservoirs within the stent struts such a design would not have been possible with lower-strength materials. While the initial drug-eluting study results were not

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as promising as expected, there is no doubt that this reservoir concept will continue to be developed [9]. Returning to the theme of higher-strength materials and thinner struts, another unique development has been the composite sandwich structure of the TriMaxxTM stent (Abbott Laboratories, Abbott Park, IL). This device is comprised of a thin layer of tantalum sandwiched between two layers of 316L stainless steel; the composite structure provides sucient strength and radio-opacity to allow strut thicknesses even lower than the aforementioned cobalt chromium devices. The rst clinical results from this stent (in conjunction with a phosphorylcholine thromboresistant coating) showed it to be safe and comparable to other bare metal stents [10]. Table 1 presents details on a range of coronary stents summarizing this trend of reduced strut thicknesses through use of higher-strength materials and composite structures. Among the more recent and novel alloying eorts, capturing both improved strength and radio-opacity requirements, has been the development of stainless steel with platinum additions. The platinum provides both solid solution strengthening and increased radio-opacity, allowing signicant reductions in strut thickness compared to conventional stainless steel. Early versions of this platinum chromium alloy contained up to 10% platinum [11], but higher levels of platinum have also been explored [12]. A clinical study is underway employing the ElementTM stent (Boston Scientic Corp., Natick, MA), made from this material, though the exact platinum level has not been specied [13]. 2.2. Radio-opaque coatings As described, the drive towards thinner struts has also been intrinsically tied to maintaining or improving device radio-opacity. Prior to the new alloy and composite work described, some of the earlier eorts to improve radioopacity utilized gold coatings on conventional stainless steel devices. These merit mention here, primarily due to the unexpectedly poor clinical outcomes that resulted. A randomized clinical study comparing the InowTM stent design (InFlow Dynamics AG, Munich, Germany), in bare stainless steel and gold-coated congurations, showed that the gold-coated devices were associated with a higher risk

of restenosis [14]. A later study comparing the NIRTM stent design (Medinol Ltd., Jerusalem, Israel), in bare metal and gold-coated conditions, showed very similar trends with the gold-coated devices again giving higher restenosis rates [15]. At the time, neither study was able to determine the cause of the poor performance from gold surfaces, though both alluded to possible defects and impurities in the goldplated layers. Related to this, an interesting animal study was performed by Edelman et al. exploring the possibility of a post-plating heat treatment to modify gold surface topography and remove any residual impurities [16]. However, the damage had already been done and interest in gold coatings declined rapidly, giving added impetus to the cobaltchromium and other alloying eorts. 2.3. Future needs for higher strength and radio-opacity As an overview, Table 2 presents summary data for the key materials-related clinical trials described. (Readers are advised to refer to the sources of information indicated to obtain full details of study design and statistical signicance data for the outcomes listed.) Moving forward, it is dicult to see a need for new materials with further increases in strength or radio-opacity, beyond the developments described. There is a practical limit to which strut thickness can be readily reduced. Stents made from higher-strength materials will have a tendency to increased elastic recoil, as it becomes increasingly dicult to induce plastic deformation at equivalent device expansion strains. Furthermore, as strut thickness reduces and stent exibility improves, a point is being reached where device trackability and crossing prole is becoming more dependent on the mechanical characteristics and dimensions of the balloon and delivery system than on the stent itself. Finally, some of the drivers for improved radio-opacity are also becoming less relevant. The quality and resolution of X-ray uo-

Table 2 Summary of clinical trial data for design and materials-related studies. Study description ISAR-STEREO, 316L In-stent restenosis in small coronary arteries (2.762.99 mm) Angiographic restenosis rates 15.0% in thin strut group (50 lm) 25.8% in thick strut group (140 lm) 23.5% in thin strut group (<100 lm) Ref. [3] [4]

Table 1 Correlation of typical yield strength values with strut thickness for a sample of devices. Stent name/ manufacturer BX Velocity/Johnson & Johnson Express/Boston scientic Driver/Medtronic VisionTM/Abbott TriMaxxTM/Abbott Material 0.2% Yield strength (MPa) 340 340 415 510 Not applicable Strut thickness (lm) 140 132 91 81 74

37.0% in thick strut group (P100 lm) Registry for VisionTM stent Registry for Driver stent TriMaxxTM trial InFlowTM: gold vs. stainless steel NIR : gold vs. stainless steel
TM

316L 316L CoCr MP35N CoCr L605 316L/Ta/316L

15.7% for this L605 CoCr alloy 15.7% for this MP35N CoCr alloy 25% for 316L/Ta/316L stent with PC coating 49.7% for gold-plated group 38.1% for stainless steel group 37.7% for gold-plated group 20.6% for stainless steel group

[6] [7] [10] [14]

[15]

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roscopy images obtained in the catheterization laboratory is being signicantly improved with the introduction of at-panel detector technology. These systems are making it easier to resolve detail on small devices such as stents [17]. In other imaging developments, the rapid uptake of computed tomography (CT) for angiographic screening and follow-ups may also have an impact. Materials with high radio-opacity have a tendency to produce more image artefact, such that lumen patency assessment can be dicult in some stents [18]. In light of this, it is most unlikely that further increases in radio-opacity will be needed for current conventional stent designs. 3. Alternative inorganic coatings for improved vascular compatibility In parallel with the developments in material strength and radio-opacity, increasing attention was also being given to optimizing the stent surface to improve compatibility with its vascular environment. While no strong scientic evidence existed, it was believed that surface optimization could help reduce restenosis rates for bare metal stents below the typical levels of 2030%. A wide variety of surface modications and inorganic coatings were explored, targeting a range of objectives such as reduced metal ion release, reduced surface thrombogenicity and 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 and chromium oxide, enhance biocompatibility by minimizing metal ion release. While there had been many in vitro studies of ion release from implant materials, no clinical evidence was available with regard to the impact for patients with vascular stents. The rst tentative link was from a study by Ko ster et al. investigating correlations between metal allergies and in-stent restenosis [19]. This study suggested that patients with a sensitivity to nickel and molybdenum, based on a skin patch test, had a higher frequency of in-stent restenosis than patients without sensitivity. While the investigators recognized limitations in their study, the work did raise questions about the potential impact of metal ion release from stainless steel, which was still the predominant material in use. The debate focused on nickel due to it being present at higher levels than molybdenum in 316L nominally 12% compared to 2.5%, respectively. While the subject did fuel ongoing developments of inorganic stent coatings, to prevent ion release, subsequent studies have failed to establish an eect [20]. It is also worth noting that the introduction of cobalt chromium alloy stents was not impeded by the discussion; L605 contains 10% nickel while MP35N contains 35% nickel and 10% molybdenum. However, metal ion release is not necessarily related to the elemental proportions in an alloy and is more inuenced by stability and regenera-

tion potential of the oxide. A review of this subject by Hanawa describes how nickel is disproportionately released from stainless steel and also how cobaltchromium repassivates much faster than stainless steel [21]. These may be important factors when considering the disruption experienced by oxide lms during stent deployment and therefore the likelihood of ion release from the respective materials. The behaviour of nitinol (NiTi), which contains approximately 50 at.% nickel, is also worth mentioning in relation to ion release. Though many in vitro, in vivo and explant studies have been performed, there is no evidence to suggest that release of nickel ions from NiTi is a signicant clinical problem. This can be attributed to two basic metallurgical eects. First, it is important to note that the nickel present in NiTi is bonded intermetallically to the titanium, i.e. typically each nickel atom is strongly bonded to a titanium atom. The nickel is therefore more chemically stable than, 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 oxidizes more readily that nickel, creating what is predominantly a titanium oxide surface. While there may be very small quantities of nickel or nickel oxide present, surface passivation treatments can further enhance the titanium oxide, creating a surface that is typically as stable as titanium materials. Of course, situations involving wear or signicant oxide disruption may alter such stability, but such conditions are not usually present for the majority of cardiovascular devices. 3.2. Carbon coatings for reduced restenosis Carbon coatings were explored early in the development of alternative surfaces, with a number of dierent approaches examined including diamond-like carbon (DLC) and pyrolytic carbon. An early in vitro study showed that BioDiamond DLC-coated stainless steel stents (BioDiamond, Mainz, Germany) exhibited reduced metal ion release and lower platelet activation compared to uncoated stents [22]. While the investigators naturally concluded that this should lead to improved biocompatibility, results of subsequent studies did not always demonstrate this. Airoldi et al. reported on a study comparing the Diamond Flex AS stent (Phytis Medical Devices GmbH, Berlin, Germany) in its DLC-coated conguration against a bare stainless steel version [23]. At sixmonth follow-up, no dierence was detected in restenosis rates between the two groups. Thus while the DLC may indeed reduce acute and subacute thrombosis, its benet with respect to longer-term vessel patency was not evident. A similar study reported by Meireles et al. compared the PhytisTM DLC-coated stent (Phytis Medical Devices GmbH, Berlin, Germany) with the Multi-Link PentaTM stainless steel stent (Abbott Laboratories, Abbott Park, IL) [24]. Angiographic restenosis rates at six months showed no signicant dierence between the two groups.

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Interestingly, despite such ndings, some DLC-coated stents are still on the market, and while they can make no claim to being able to reduce restenosis, their ability to reduce metal ion release is probably still a marketable advantage over bare metal stents. Research continues into further optimizing DLC coatings; a study by Hasebe et al. investigated a uorine-doped DLC [25]. The uorinedoped material had a higher ratio of albumin to brinogen adsorption and lower platelet adhesion and activation than non-doped DLC. It was therefore concluded that the uorine-doped DLC would have a much lower tendency to induce thrombus formation. Pyrolytic carbon has a longer and arguably more successful history of vascular implant experience than DLC. It has been used for many years as a coating for articial heart valves, where high haemocompatibility has been critical. Sorin Biomedica (Saluggia, Italy) was one of the pioneers of pyrolytic carbon heart valves and was also behind the development of one of the rst carbon-coated stents, the CarbostentTM. Pyrolytic carbon requires high temperatures for deposition and is usually applied in relatively thick layers; these conditions are not particularly suited for stents. Sorin therefore developed a modied process to vapour deposit a carbon layer at low temperatures and in thin layers. The deposited layer is similar to pyrolytic carbon in structure. An early clinical study showed the CarbostentTM to have an angiographic restenosis rate of 14.1%; however, this study had no control arm and therefore primarily just demonstrated safety and ecacy [26]. The authors did, however, note that the low number of diabetic patients in the study may also have contributed to the relatively low restenosis rates observed. A further study, which included higherrisk patients (including those with diabetes and those over 75 years of age) demonstrated an angiographic restenosis rate of 25% at six months [27]. This value is more typical for bare metal stents and the absence of thrombotic events is also of merit. In another variation of carbon surfaces, the ARTHOSInert stent (amg International GmbH, Raesfeld-Erle, Germany) has a surface with ion-implanted carbon, rather than coated carbon the rationale being that the ion-implanted carbon would adhere better, therefore giving a superior barrier against ion release. However, a study comparing this device with an equivalent stainless steel stent failed to show any signicant dierence between the two congurations [28]. In summary, while carbon surfaces may be safe and less thrombogenic, they appear to do little with regard to reducing restenosis rates. An interesting study by Tomai et al. measured inammatory markers, platelet activation and thrombin generation at various timepoints post-implantation and concluded that there was no dierence between carboncoated stents and stainless steel stents [29]. While both groups showed signicant increases due to the stenting procedure, the absence of a dierence between them may in part explain the ndings of the other clinical studies.

3.3. Silicon carbide and the semiconductor theory Another early unique approach to address the restenosis issue was the exploration of silicon carbide surfaces. The theory behind this approach revolved around electron transfer between proteins in the blood and the stent metallic surface, i.e. interactions between brinogen and the stent surface leading to brin deposition and ultimately platelet adhesion and thrombus formation. It was proposed that this electron interaction could be limited through application of a semiconductor layer tuned to an appropriate conductivity [30]. The coating selected was an amorphous, phosphorous-doped, hydrogen-rich silicon carbide applied by a chemical vapour deposition process. However, while in vitro studies showed promise, an initial clinical study (using a tantalum stent substrate) resulted in a restenosis rate of 26.8%, again typical for bare metal stents with no major advantage evident [31]. A later iteration of the device utilized a stainless steel substrate, but in a comparison with a commercial stainless steel stent, the silicon carbide again failed to show a restenosis advantage over stainless steel [32]. So what appears to have been a well-investigated strategy again failed to live up to expectations and became another coating casualty in the pre-drugeluting stent era. 3.4. Titanium-nitride-oxide coating: leveraging titaniums track record This coating has been developed on the rationale that a titanium oxide surface should be highly biocompatible and should also act as a barrier to metal ions. The addition of some nitrogen into the oxide structure is an interesting aspect that has not been widely addressed. Endotheliumderived nitric oxide is of course known to be important in regulating endothelial function, helping suppress platelet aggregation, cellular adhesion to the endothelium and even inhibiting smooth muscle cell proliferation [33]. While there is no scientic evidence to suggest that a nitrogen-containing oxide should have a similar benet, the eects are nevertheless promising. An early porcine study employed a stainless steel stent with a titanium coating applied by physical vapour deposition, in an oxygennitrogen gas mixture [34]. Histology showed that neointimal area and thickness were signicantly less in the TiNOX samples compared to bare stainless steel. Unlike many of the earlier coatings, in vitro and pre-clinical ndings seem to subsequently translate into real clinical benets. A study comparing the coated stents with stainless steel devices recorded 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 eective in a number of subsequent studies, including an unrestricted clinical study that included high-risk patients and complex lesions [36]. The titanium-nitride-oxide coating has also been compared against drug-eluting stents (DESs) and

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B. OBrien, W. Carroll / Acta Biomaterialia 5 (2009) 945958 Table 3 Summary of clinical trial data for inorganic coating-related studies. Study description DLC vs. stainless steel DLC vs. stainless steel Phantom IV study: carbon coating Carbon coating: high-risk patients Ion-implanted carbon vs. stainless steel Angiographic restenosis rates 31.8% for Diamond Flex AS stent 35.9% for bare Flex AS stent 24.3% for PhytisTM Diamond 21.8% for PentaTM stainless steel 14.1% for CarboSTENTTM No control arm 25.0% for CarboSTENTTM No control arm 11.0% for ArthosInert carbon implanted stent 16.1% for Arthos stainless steel stent (NS) 26.8% for SiC-coated tantalum No control arm 30.0% for SiC-coated stainless steel stent 26.7% for NIRTM stainless steel stent 15.0% for titanium-nitride-oxide coated stent 33.0% for same design stainless steel stent 13.8% for iridium oxide-coated stent No control arm [28] [27] Ref. [23] [24] [26]

while restenosis rates were not measured, the rate of MACEs was much lower for the TITANOXTM (Hexacath, Rueil-Malmaison, France) than the DESs [37]. In summary, this seems to be one of the few non-DES coatings that is surviving on its own merit, even if it does not have a very signicant market share. 3.5. Iridium oxide and the catalytic theory Iridium oxide has long been used as a coating for electrodes involved in neural stimulation and pacing applications. Its rst use as a stent coating was explored in the MOONLIGHT clinical study which employed a gold-plated stainless steel stent, covered with a layer of iridium oxide [38]. The study yielded an angiographic restenosis rate of 13.8% which is certainly attractive for a nonDES device, but the absence of a control arm makes it dicult to put any signicance on the outcome. As a result of the demise of gold coatings described earlier, further iterations of this technology have been explored without the gold interlayer. Coatings are applied directly to stent substrates by reactive sputtering of iridium in an oxygen-rich atmosphere. While it is proposed that the iridium oxide acts as a barrier layer against metal ions, its vascular compatibility is also attributed to a catalytic eect at the surface of the stent and the manner by which this disrupts the restenosis process [39]. In particular, it is understood that hydrogen peroxide (H2O2) is created by leukocytes in response to the stent-induced vessel injury. This H2O2 plays a signicant role in restenosis as it inhibits endothelial cell growth and promotes smooth muscle cells. The theory behind iridium oxide suggests that the oxide surface acts as a catalyst for the decomposition of the peroxide to oxygen and water, thereby reducing the stimulus for smooth muscle cell growth. While this catalytic eect has been demonstrated in vitro, there is no clinical evidence to support its occurrence or eect in vivo. 3.6. Future clinical needs for inorganic bare metal stent coatings As reviewed, and summarized in Table 3, most inorganic stent coatings have provided ineective or inconclusive performance in terms of reducing restenosis, which was the primary driver behind their development. (The exception may be the titanium-oxide-nitride coatings which appear to be the most promising.) Despite the many novel and well-engineered approaches, these coatings will not be signicant players in the eorts to reduce restenosis rates, in their existing congurations. They may, however, have an ongoing role to play in the bare metal stent market segment if they can truely demonstrate reduced thrombosis rates and in individual cases where metal allergy is a genuine concern. While the links between metal ion release, metal allergy and restenosis have never been clearly established, inorganic coatings can certainly eliminate the doubt where

Silicon carbide coating TenaxTM SiC vs. NIR 316L TiNOX trial

[31] [32]

[35]

MOONLIGHT study

[38]

appropriate. Going forward, there is, however, a signicant role for inorganic coatings in the eld of polymer-free drug delivery and potentially in delivery of other biological and genetic agents. This topic is reviewed in a later section of this article. 4. Alternative stent materials for improved vascular compatibility While the majority of eorts to improve vascular compatibility have naturally involved coatings, a brief mention needs to be given to work involving the development of new platform stent materials. Such material developments have indeed been fewer than the eorts to increase strength and radio-opacity, but this is understandable given the more tentative nature of any potential benet and the investment already going into higher-strength and radio-opacity needs. Tantalum was explored early during stent development and was used in both the coronary Wiktor stent (Medtronic Inc., Minneapolis, MN) [40] and the peripheral Strecker stent (Boston Scientic Corp., Natick, MA) [41]. These were helical wound wire and knitted wire structures, respectively. While the radio-opacity of tantalum was a factor in its selection, there was also evidence to suggest that the inert nature of tantalum oxide surfaces would lead to improved vascular compatibility and in particular

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reduced thrombogenicity. Specically relevant was data suggesting that the biocompatibility should be high due to excellent performance in a variety of electrochemical studies [42]. While these stents were reasonably successful, wire coiled and woven structures were eventually superceded by slotted tube/laser-cut designs, giving improved compression behaviour with reduced device foreshortening upon deployment. A laser-cut tantalum stent, the Tensum (Biotronik GmbH, Berlin, Germany), was briey introduced in a silicon carbide-coated design, as described earlier. However, the stent design and material appear not to have been optimized and the device was only briey available. Much more recently, the use of niobium has been explored, again based on the rationale that niobium would have a highly inert oxide surface and that there would also be no release of nickel, chromium or molybdenum ions. The stents were made from a niobium-1% zirconium alloy and were anodized to further ensure a high-integrity niobium oxide. These devices were compared against stainless steel stents in a clinical study with six-month follow-up [43]. The results, however, failed to show an advantage for the niobium, which produced higher neointimal ingrowth. The investigators suggest that the thicker struts of the niobium stent (in comparison to the stainless steel control) may have contributed to its poorer performance. Higher-strength niobium alloys may overcome this aspect. Looking to the future for materials with improved vascular compatibility, nickel-free stainless steels certainly deserve mention. Nickel-free steels have been in development for many years and some are now on the market, having been driven primarily by the orthopaedic implant sector where larger devices, with bigger surface areas and greater wear, have made the nickel toxicity issue more signicant. Nickel is present in austenitic steels like 316L, to enhance strength, corrosion resistance and to stabilize the austenite phase which is critical for durability and formability. The new nickel-free steels have low-level additions of nitrogen (1.0%) which provide all these benets [44]. While much work would be needed to verify that the corrosion resistance and oxide stability of these new materials is suitable for stent applications, it would seem to be a suitable incremental step in the development of stent materials. Having reviewed several traditional and novel materials, at this point it is worth mentioning a study by Sprague and Palmaz, which assessed a wide spectrum of materials using a number of bioassays relevant to cardiovascular applications [45]. This study investigated brinogen, platelet and monocyte binding, as well as endothelial cell migration, and used the data to establish a vascular biocompatibility 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 performed poorly. This trend reects some of the overall observations reported here and points towards some potentially

useful correlations between data from such assays and real-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 limited success in improving vascular response, polymeric surfaces were also being explored. Among the most interesting approach in this respect was the use of phosphorylcholine (PC)-based coatings to mimic the phospholipids on the outer surfaces of red blood cells, thereby aiming to provide a highly compatible implant surface [46]. Several studies and registries were performed with the BiodivYsioTM stent (Abbott Laboratories, Abbott Park, IL) and while safety and reduced thrombogenicity was demonstrated, the benet in terms of signicantly reduced restenosis rates was not evident [47]. The PCcoated device, however, also demonstrated both long-term stability [48] and the ability to deliver drug compounds [49], and therefore the coating has attracted much interest for drug delivery. Most prominent among these has been the successful use of PC coatings for delivery of the ABT578 (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 drugeluting coatings (DECs) was not specically selected or designed for vascular compatibility. Availability, drug miscibility, durability and release kinetics were key drivers in the initial development of polymer-based carriers for the commercially successful Cypher (Johnson & Johnson, New Brunswick, NJ) and Taxus (Boston Scientic Corp., Natick, MA) devices. The Cypher stent has three dierent layers. An initial parylene tie-layer is applied to the stent surface, followed by a polyethylene-co-vinyl acetate (PEVA) and poly-n-butyl methacrylate (PMBA) mixture which contains the Sirolimus drug. Finally, a top coat of PEVA/PMBA (without drug) is applied to control the drug elution rate. The Taxus device has a single polymer/Paclitaxel drug mixture layer, using the SIBS triblock copolymer poly(styrene-b-isobutylene-b-styrene). While several trials and investigations have supported the early and mid-term safety and ecacy of these stents, doubts have been raised about long-term safety, particularly in relation to the risk of late stent thrombosis [51,52]. The exact cause for late stent thrombosis has not been conrmed, but there is a general concensus that the continued presence of the polymer carrier is a key factor, especially after drug release has diminished. Therefore, going forward, there is a drive to use either biodegradable polymer drug carriers or nonpolymeric surfaces for direct loading of drugs.

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5.3. Second-generation drug-eluting coatings With the benet of an ever-increasing library of clinical data, second-generation DEC device development has already seen the commercial introduction of new polymer carriers. The PC-based coating for the Endeavor stent has already been described, while most recently the Xience V Everolimus-eluting stent (Abbott Laboratories, Abbott Park, IL) has been introduced [53]. This uses poly-n-butylmethacrylate (PMBA) as a tie-layer to the metal surface and a polyvinylideneuorohexauoropropylene (PVDF HFP) copolymer as the drug-carrier layer. No top coat is used. Clinical results for this new system have been promising, showing superiority to initial devices in terms of restenosis rates and reduced late events [54]. Whilst this cannot be attributed solely to the polymer surface, it at least points towards the successful design and selection of a surface with good vascular compatibility, even if it is non-erodible and will remain in place indenitely. 5.4. Biodegradable polymers for drug-eluting coatings Biodegradable polymers oer a potentially ideal solution in terms of initially providing a carrier to retain and release the required drug quantity and then to fully degrade away, eliminating doubts about long-term eects of the polymer. There are many biodegradable polymers, but the most widely used for medical applications come from the polyester family and include polylactic acid (PLA), polyglycolic acid (PGA) and the copolymer polylactic-coglycolic acid (PLGA).1 Drug compounds mixed with these polymer matrices are gradually released as the polymer degrades within the vessel wall. Biodegradation of PLA, PGA and PLGA involves random hydrolysis of their ester bonds. The lactic acid and glycolic acid degradation products are subsequently converted to water and carbon dioxide through the action of enzymes and then excreted [55]. It must be noted, however, that the biodegradable route is not without its own challenges. In addition to these fundamental degradation products, the host environment must deal with polymer processing aids such as initiators, catalysts and solvents, all of which may impact biocompatibility. A number of devices with biodegradable drug-eluting layers are currently in clinical trials. These include the SparrowTM NiTi stent system from CardioMind Inc. (Sunnyvale, CA), which uses the SynBiosysTM biodegradable PLGA polymer from Surmodics Inc. (Eden Prairie, MN) to release Rapamycin [56,57], and the CE-approved BioMatrix 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
Note that polylactic acid (PLA) is often interchangeably referred to as poly-L-lactic acid (PLLA), to allow more accurate dierentiation from poly-DL-lactic acid (PDLA), which has a dierent molecular orientation on the polymer chain.
1

devices will be in the long term, but the approach is certainly a logical step in the evolution of polymeric drug-eluting surfaces. 6. New surfaces for direct loading of drugs As mentioned earlier, the increased risk of late thrombosis is one of the biggest challenges facing current DES technology. It has been well demonstrated that such thrombosis is most frequently associated with poor endothelialization of stent struts [60,61]. The exact cause of poor endothelialization has not been established, but, as indicated, the potential for the polymeric drug carriers to induce a local inammatory reaction is considered to be one of the factors [62]. There is therefore now a signicant driver for the development of technologies to load drugs onto the stent surface without the use of either absorbable or non-absorbable polymers. One of several early eorts in this regard involved the loading of Paclitaxel directly to a conventional stainless steel stent surface. However, this approach was not entirely successful, with no signicant dierences recorded between this DES and a bare metal stent [63]. While issues with drug dose density were highlighted as being possible causes for the poor performance, the study is a good illustration of the simple fact that release kinetics of pure drug, from a conventional surface, is not optimum. In summary, modied surfaces to retain and release the drug in a more controlled manner are essential for such polymer-free approaches. A number of these surface technologies are described here. 6.1. Nanoporous aluminium oxide This was one of the rst eorts at developing a porous surface for loading of drug onto a stent surface. The process involved application of a thin layer of aluminium over the stainless steel stent, using physical vapour deposition. Following this, the coated stent was anodized to convert the aluminium layer to a porous aluminium oxide, with pores in the nanometer range. An early animal study showed the coated stents to have good vascular compatibility and also demonstrated the possibility of drug loading and elution from the porous structure [64]. However, clinical trials with this concept have not been successful and the approach is not currently being pursued [65]. It is most likely that diculties with control of loading and release of drug from the nanometer-sized pores (515 nm) is a significant challenge due to their small size. In a fundamental drug-loading and drug-release study of such structures it has been shown that uncontrolled release occurs when drug adhered to the outer surface rather than being deposited within 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

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this surface in the catheterization laboratory, just before implantation. The Yukon stent (Translumina GmbH, Hechingen, Germany) is roughened by a basic grit-blasting process detailed quantication of this surface has not been reported, but early in vitro and animal work demonstrated that the surface retained drug and released it over an extended period [67]. A related clinical study compared the safety of smooth and roughened stents (without drug) and, interestingly, the roughened surfaces showed lower late 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 established no signicant dierences between them at nine-month follow-up [69]. Such results are indeed interesting, but there are some signicant challenges ahead for this device. Firstly, the manner of drug loading on-site, just prior to implantation, will cause logistic, quality and regulatory challenges for all involved from manufacturers through to physicians and patients. Secondly, though probably less important, will be the need to alter the mindset in regard to stent surface roughness. For many years, highly polished stent surfaces have been desired, in order to reduce risk of thrombosis and minimize the risk of ination balloon damage. Exploration of nanoporous textures has only marginally infringed on such thinking; however, the concept of a grit-blasted rough surface is a dierent scenario. The idea most certainly has merit as the inuence of textures on endothelialization has long been explored, but extensive research on aspects such as acute thrombogenicity and long-term fatigue performance will be needed, as well as being able to demonstrate tight surface roughness control. 6.3. Porous carboncarbon coating Details on this new technology are scarce but merit mention as animal studies have already been completed and clinical studies are in progress. The coating is described in company literature (Cinvention GmbH, Wiesbaden, Germany) as having a glassy polymeric carbon matrix and pyrolytic carbon compounds. It appears that the coating is initially a polymer-based slurry with carbon particles dispersed; subsequent pyrolysis converts the mixture to this carboncarbon matrix, with porosity controlled by the carbon particle size and the extent of pyrolysis. A porcine study using this drug-loaded coating, on a cobalt chromium stent, showed the concept to be both safe and eective, though the study did lack a suitable control arm [70]. Going forward, it will be interesting to see the significance of any residual polymer that may be present in the structure, i.e. to ascertain that it has no thrombogenic eect when assessed clinically in a larger population. 6.4. Hydroxyapatite ceramic coating The biocompatibility of hydroxyapatite (HAp) coating has long been successfully demonstrated in orthopaedic applications where it acts as a support for bone growth

and osseointegration. This proven biocompatibility, combined with the ability to tune porosity, has resulted in these calcium phosphate-based materials now being explored for drug retention and elution. Initial porcine studies have been completed with HAp-coated devices (without drug) showing equivalency to bare metal stents [71]. Solgel technology is used to apply an initial relatively dense thin layer, with electrochemical deposition being used to apply a more porous outer layer for drug retention. Detailed analyses of early clinical studies are not available, but initial reports claim promising results for the drug-eluting version of this device [72]. As this technology moves forward, signicant engineering challenges will be faced with ensuring durability and integrity of these ceramic coatings. These will be critical issues, not only after implantation, but during device manufacture, tracking through dicult anatomy and also when being deployed by direct stenting against hard lesions. 6.5. Drug delivery from strut macro reservoirs A number of signicant drug-delivery approaches merit mention in this category even though they are not utilizing any new materials or coatings that have not already been mentioned. The CoStar stent (Johnson & Johnson, New Brunswick, NJ), as described earlier [9], utilizes reservoirs machined from within the stent struts, for the storage and elution of drug. These reservoirs are laser cut from the cobaltchromium struts and penetrate completely through the strut thickness. Drug elution rate is controlled by a capping layer of biodegradable polymer over the drug. Control of degradation of this capping layer will be critical to the success of this concept going forward. As reviewed earlier, carbon coatings have been widely explored and while they have proven to be safe and nonthrombogenic, oered no signicant advantage in terms of reducing restenosis rates. However, the CarbostentTM concept is now being taken a step further with the use of this coating technology in a polymer-free drug-eluting design. The JanusTM stent (Sorin Biomedica, Saluggia, Italy) has slots cut on the abluminal face of the stent struts; this slotted device is then coated with the same coating technology as the CarbostentTM and subsequently these slots are lled with pure drug, i.e. with no polymer matrix. A number of clinical trials have commenced. Interestingly, results from a trial comparing this DES against a bare carboncoated device showed only marginal advantage for the drug-eluting version [73]. 6.6. Future clinical needs for a direct drug-loading surface As long as the concern exists that current non-absorbable polymers are contributing to late stent thrombosis in DES systems, then there is a signicant need for direct drug-loading surfaces. Those reviewed here, which are summarized in Table 4, have many merits and challenges as discussed. There are also many other approaches, for

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Table 4 Summary of current technologies for direct drug loading. Technology Aluminium oxide Microtextured stainless steel Porous carboncarbon Hydroxyapatite Reservoirs in CoCr struts Carbon-coated slotted struts Company Abbot (Jomed) Translumina Cinvention MIV Therapeutics Johnson & Johnson (Conor Medsystems) Sorin group Description Anodizing of aluminium layer applied to stent Grit blasting to create a roughened texture Carbon particles in porous carbon matrix Calcium phosphate-based layer by electrodeposition Laser-cut reservoirs through strut thickness Non-penetrating slots within struts Status Inactive Clinical data Animal data. Clinical in progress Animal data. Clinical in progress Clinical data Clinical data Ref. [64,65] [67 69] [70] [71,72] [9] [73]

which clinical data is not available, but which will no doubt highlight further options to physicians and patients. As with any novel technology, a whole array of general challenges need to be addressed. These include engineering aspects, such how these surface modications impact on device integrity and durability, while extensive scientic exploration is needed to understand and control the kinetics and pharmacological mechanisms for such delivery systems. At this point some of the bigger challenges appear to be in achieving controlled loading of drug into these surfaces and subsequently getting controlled release. Therefore development of materials surfaces must not be in isolation, but must done in conjunction with developments in drug-loading and drug-release technologies. Similarly, material developments must address cell biology requirements such as maximizing endothelial cell growth and proliferation and minimizing platelet adhesion. 7. Stent materials for alternative imaging compatibility This topic has already been partly addressed, at the start of this review, where radio-opacity requirements for X-ray uoroscopy were described. For the foreseeable future, Xray uoroscopy will continue to be used during stent implantation to monitor location and deployment. However, for screening and follow-up procedures, alternative imaging technologies have been introduced in recent years and these are seeing increased utilization. Computed tomography (CT) has seen rapid take up, especially for evaluation of coronary vessels, while magnetic resonance imaging (MRI) is being increasingly used for peripheral vessels such as carotid, iliac, femoral and renals. Looking rst at compatibility of stents for CT imaging, it is important to note that there is a somewhat conicting requirement between optimum radio-opacity for X-ray uoroscopy and the optimum level for CT angiography. In summary, materials with high radio-opacity generate signicant artefacts when imaged using CT, as mentioned earlier [18]. Therefore conventional materials like stainless steel and cobaltchromium produce image artefacts that can prevent clinical interpretation of the data. In the case of stents, the artefact usually manifests itself as a thickening of the struts, giving the impression of a reduced stent lumen. This can prevent identication of in-stent restenosis, particularly if it is not a severe stenosis and is easily

obscured by the articial wall thickening. Radio-opaque marker bands and highly radio-opaque stents are particularly problematic, while devices with thinner struts obviously perform better [74,75]. Clearly, the conicting requirements for X-ray uoroscopy and CT create an interesting material selection challenge. For example, optimum CT image compatibility may be a material with an X-ray attenuation in the range of titanium, but of course this would be nearly invisible when viewed under uoroscopy, during the critical stages of tracking and stent deployment. So the ideal material would have high radio-opacity initially to aid implantation under uoroscopy, but radioopacity would degrade subsequently so that vessel followups can be accurately performed by CT. In the long term it may not be necessary to meet such a design requirement; imaging software may ultimately be able to lter out or reduce the metal artefact. Alternatively the introduction of biodegradable stents, which will be reviewed later, may indirectly solve this problem. However, at this point neither of these scenarios can be guaranteed and a material solution that oers diminishing radio-opacity with time would indeed be interesting. The imaging compatibility problem is even more significant when considering MR angiography. MR oers significant advantages over CT (or uoroscopy) in that it involves no ionizing radiation and also avoids the use of iodine-based contrast agents, which can be toxic for some patients. Diculties with image resolution and image capture speed have so far hindered wider use of the technology for imaging of coronary vessels, but these are less critical issues for peripheral vessels where the technique is now being widely used. However, for both coronary and peripheral stents, the major challenge for MR angiography arises due to the paramagnetic nature of the majority of the commercial materials such as stainless steel and cobaltchromium. This paramagnetism leads to local distortion of the magnetic imaging eld, ultimately leading to an artefact on the image that is typically proportional to the magnetic susceptibility of the material. In the case of stainless steel and cobaltchromium this artefact is relatively large and, in addition to obscuring the vessel lumen, extends well beyond the stent boundary [76]. Nitinol devices tend to perform better due to this materials lower magnetic susceptibility. It must be noted that eddy currents, induced in the stent by the RF signal of the scanner, also contribute to

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artefacts within the stent lumen [77]. However, this is primarily a stent design issue and is not addressed in this review. There has been a number of attempts, though largely unsuccessful, at developing new stent materials to optimize MR image compatibility. One of the early eorts involved development of a Cu14Au8Ag2Pt1Pd alloy with low magnetic susceptibility [78,79]. While this copper-based material did eliminate image artefact, it was not an appropriate stent material from a vascular compatibility and mechanical strength perspective and did not make it past initial feasibility studies. Similarly, a novel palladiumsilver alloy may have had ideal imaging characteristics [80] but also failed to get into development, most likely again due to its inability to meet mechanical and vascular compatibility requirements. One of the more successful developments has been the introduction of a platinum stent for biliary applications [81]. This device has been shown to have good MR imaging behaviour; however, this approach has not been used for coronary stents, most likely because the material would be too radio-opaque even for X-ray uoroscopy. The tantalum peripheral devices described earlier [40,41] also had reduced susceptibility artefact but this was purely incidental. While these stents became obsolete for design reasons, use of pure tantalum did not successfully carry through to newer coronary designs, due to lack of mechanical property optimization and also as the high radio-opacity would again be unsuitable for smaller stent sizes. One of the more recent research eorts has been the development of an Nb28Ta3.5W 1.3Zr alloy specically for MR image compatibility. Coronary stents made from this material have been shown to provide suitable mechanical performance [82], with initial data for imaging behaviour and vascular compatibility also showing promise [83]. In summary, from a clinical imaging perspective, the most challenging requirement going forward is likely to be MR compatibility. Currently, however, this is a low development driver; there is a current need for MR compatibility in peripheral stenting, but until such time as MR becomes widely used for coronary imaging, it is unlikely that sucient investment and development will take place. 8. Biodegradable stent materials the need to disappear . . . Many arguments have been put forward on the potential benets of having the stent removed once its job is done. Most obvious amongst these is of course the fact that the stent is indeed a foreign object within the vessel and its presence is associated with the potential for inammatory reactions, progressive neointima development, damaged endothelium and associated thrombosis risks. In addition, problems with blockage of side-branches would be reduced and diculties with overhang at ostial lesions would be minimized. There has therefore been signicant interest and development in recent years in the eld of biodegradable stents.

8.1. Polymeric stents There are several polymeric degradable stents in development but just a couple merit mention at this stage on the basis of clinical data. The BVS stent (Abbott Laboratories, Abbott Park, IL) is made from poly-L-lactic acid (PLLA) and results from an initial clinical trial were recently published [84]. While the study demonstrated feasibility, it was a very small patient population (30) and, interestingly, at one-year follow-up the stent was only partially degraded. This appears to be one of the drawbacks of polymeric biodegradable stents, i.e. long degradation times presumably to minimize the rate at which any by-products are released. One of the earliest devices in this eld was the Igaki-Tamai stent (Kyoto Medical Planning Co., Kyoto, Japan), which is also manufactured from PLLA [85]. A small trial with these stents showed that while some acute stent recoil occurred, this stabilized fast and at six months follow-up performance was satisfactory with initial hyperplasia comparable to bare metal stents. A four-year followup showed the devices to have completely degraded with no further hyperplasia development. 8.2. Magnesium alloy stents The relative ease with which magnesium corrodes and its role as an essential element in the biological system makes it an excellent candidate for the biocorrosion concept. The rst animal study utilized the AE21 magnesium alloy which contained 2% aluminium and 1% rare earths (Ce, Pr, Nd) [86]. There were a number of key ndings from this study: neointima formation decreased signicantly once strut thickness started to reduce; struts endothelialized readily; and biocorrosion occurred within this endothelium. Follow-up at 56 days showed strut material to be still present and extrapolation suggested that full corrosion would have occurred at 89 days this was much faster than expected and this rapid degradation is still an issue today for this technology. In any event, the results were promising and subsequent clinical studies have been performed in both peripheral and coronary vessels [87,88]. These studies used the WE43 alloy (<5% Zr, <5% Y, <5% rare earths) which was selected to give a reduced corrosion rate compared to the initial AE21 alloy. This work showed that the stents were fully degraded at a four-month follow-up, with overall performance comparable to that of bare metal stents. However, the small study size and short follow-up prevents any conclusions being made with regard to late, low-incidence events such as thrombosis. It is also worth noting that the while the magnesium has corroded, much of the by-product remains within the vessel wall as calcium and phosphorus compounds; these are, however, considered to be biocompatible and also compatible with a range of imaging modalities which may even be useful to conrm initial stent location [89]. In summary, however, the most important outcome from the clinical studies is that the rate of biocorrosion is still too rapid and there is a desire to

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slow it down, to ensure that the scaolding function of the device remains for longer, preventing negative remodelling from taking place. 8.3. Iron stents Although this technology has not progressed as far as magnesium stents, the rst animal work was actually completed some years earlier. In this initial study, pure iron stents were implanted in rabbit aortas with follow-ups extending to 18 months [90]. While histology revealed signicant damage to the vessel media and internal elastic membrane, no aneurysm damage occurred and no signicant neointimal hyperplasia developed. However, corrosion was deemed to be too slow, as major portions of the struts were still present at 18 months. A subsequent study by the same group implanted larger-diameter iron stents into porcine aortas and determined that neointima proliferation was comparable to that found with stainless steel; no local or systemic toxicity was recorded [91]. However, large portions of these stent struts also remained and while this slow degradation was noted to reduce the risk of fragment embolization, it was also acknowledged that the rate was too slow for such biodegradable strategies. A recent trial with iron stents implanted in porcine coronary arteries was limited to a 28-day follow-up, but claimed to have less neointima formation than cobaltchromium stents at this timepoint [92]. 8.4. The future for biodegradable stents All of the degradable technologies reviewed here have many specic challenges ahead of them, but, to date, common to all is the lack of clinical evidence demonstrating a clear advantage to this approach. Polymer systems face specic challenges in achieving adequate strength and resistance to recoil, as well as a need to reduce degradation times. Magnesium systems appear to oer the most promise with degradation times being closer to what may be required. Iron stents face big diculties in terms of establishing that the degradation products would be acceptable after years of striving to avoid corrosion of stainless steel devices, the mindset will take some time to change, even if the data is good. In summary, the eld of biodegradable devices may in theory oer the ideal solution, but with many challenges ahead, there should be a focus of continued materials and clinical research in the coming years. 9. Concluding remarks This review has covered a wide range of material science and engineering developments which have been driven by clinical needs within the cardiovascular stent eld. New alloys have been developed specically for stent applications and existing alloys have been leveraged from other elds. 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 the developments have failed to achieve their objectives, but even these outcomes have contributed to the vast body of knowledge which has been gained in the eld of materials performance in biological environments. Even as the cardiovascular stent market matures, there is a continued need for investigation and development. At this point, the areas which would appear to be worthy of the most eort include development of inorganic drug-eluting coatings, materials and designs for image compatibility and biodegradable stents. References
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