Passive and Active Polymer Coatings for Intracoronary Stents: Novel Devices to Promote Arterial Healing

Authors


Address for reprints: Refat Jabara, M.D., F.A.C.C., Saint Joseph's Translational Research Institute, Saint Joseph's Hospital of Atlanta, 5673 Peachtree Dunwoody Rd., Suite 675, Atlanta, GA 30342. Fax: 404-843-6051; e-mail: rjabara@sjha.org.

Abstract

Coronary stent implantation is the second great advance in the treatment of obstructive coronary artery disease since the introduction of balloon catheter angioplasty. However, in-stent restenosis (ISR) caused by neointimal hyperplasia has been a major limitation of stents, occurring in up to 30% of cases. Advances in coronary stent technology both in terms of stent design and function and especially drug-eluting stents (DES) have significantly improved the safety and efficacy of percutaneous coronary intervention (PCI) with stenting, including marked reduction in ISR. This has led to use of DES for increasingly challenging clinical and lesional subsets, with potential for increased risk of stent-associated complications, especially late stent thrombosis (LST). Because restenosis and stent thrombosis are caused by multiple and often interrelated factors, ideal agents for stent coatings should inhibit thrombus formation, inflammatory reaction, and cellular proliferation, while supporting reendothelialization. To avoid undesirable effects of currently applied (durable) polymers, biocompatible, and bioabsorbable polymers as well as DES delivery systems that minimize polymer burden have been produced and tested. Bioabsorbable stents, both polymeric and metallic, have been developed to decrease potential late complications after stent implantation. Novel strategies to address some of these challenges are in various stages of research and development. In this article we outline developments in the field of passive and active stent coatings and evaluate the ongoing role of such coatings in the contemporary era of DES.

Introduction

Coronary artery disease (CAD) remains the leading cause of morbidity and mortality in the United States, accounting for 1 in every 5 deaths.1 In 1975, the invention of a double-lumen catheter fitted with a polyvinylchloride balloon by Andreas Gruentzig revolutionized therapy for CAD. Since then, the field of interventional cardiology has witnessed vast improvement in techniques and an increase in research designed to eliminate some of the limitations associated with percutaneous transluminal coronary angioplasty (PTCA). Restenosis is the major limitation of PTCA, in rates up to 30% to 60% of patients within the first 6 months.2–4 Postangioplasty restenosis primarily results from negative remodeling with contraction formation, which accounts for more than 60% of late luminal loss.5,6 Bare metal stents (BMS) have effectively reduced the restenosis by functioning as a mechanical scaffold that eliminates the elastic recoil and negative remodeling.2,3,7 BMS demonstrated significant reduction of the major adverse cardiac events (MACE), death, and myocardial infarction (MI). Currently coronary stents are used in more than 90% of PCI procedures worldwide for treatment of CAD.8,9

The dramatic increase in the use of BMS identified a new problem, restenosis occurring within the stent: In-stent restenosis (ISR) is defined as lumen diameter loss of greater than 50% within the stent. ISR is also clearly correlated with the degree of stent-induced injury to the vessel wall, strut thickness, patient factors (diabetes, acute coronary syndromes, etc.), and lesion characteristics (small luminal diameter vessel, bifurcation, ostial, restenotic as well as venous graft lesions). In addition, chronic foreign-body inflammatory response as well as gradual long-term corrosion of the metallic stent may have roles in the process of ISR.

Mechanical strategies, systemic pharmacotherapy, and intravascular brachytherapy are methods previously used to reduce the frequency of ISR. These strategies have achieved some reduction in restenosis rates but either failed to demonstrate a significant benefit in large randomized, controlled trials or were subject to increased complications such as late sudden stent thrombosis in the case of brachytherapy.10–14 Drug-eluting stents (DES) have reduced ISR and target lesion revascularization (TLR) compared with BMS and launched a revolution in the interventional treatment of symptomatic CAD.15,16 However, enthusiasm for this technology has recently been dampened by concerns about late stent thrombosis (LST), incomplete endothelialization, coronary artery spasm, and abnormal vasomotor function,17–19 in some ways similar to complications that arose with brachytherapy.

Thus, focus has been brought onto the structure and composition of stents and stent coatings with particular interest in how the vessel responds to the foreign device and development of devices with improved biocompatibility and long-term patient outcomes. In this paper we evaluate developments in passive thrombo-resistant stent coatings, and also new active stent coatings and totally absorbable stents that show promise for advancements in the contemporary era of DES.

Metal Characteristics of Bare Metal Stents

Before discussing stent coatings, it is useful to review the characteristics of different metals and associated host response to the BMS. Stent implantation is associated with early thrombus deposition on the strut surfaces, acute inflammation, granulation tissue development, foreign-body giant cell infiltration, and smooth muscle cell neointimal proliferation and extracellular matrix synthesis.20 The severity of arterial injury during stent deployment correlates with increased inflammation and late neointimal growth. The majority of current stents are manufactured with 316 L stainless steel alloy, composed primarily of iron (60–65%), nickel (12–14%), and chromium (17–18%), the latter providing excellent anticorrosion properties in addition to radial strength.21 The first-generation DES were composed of a 316 L stainless steel platform, since this material is radiopaque with adequate radial strength. However, cobalt–chromium alloy (CoCr) exhibits superior radial strength and improved radiopacity allowing for thinner stent struts (to ∼50 μm), which may reduce restenosis in BMS,22 while maintaining or even improving deployment characteristics and acute procedural outcome. CoCr is the stent platform for the second-generation Xience V® (Abbott Laboratories, Abbott Park, Illinois) and Endeavor® (Medtronic, Minneapolis, MN) stents. Recently platinum chromium alloy stents were designed specifically for increased flexibility while improving radial strength, recoil, and radiopacity. TAXUS PERSEUS Workhorse trial is currently under way to evaluate the safety and efficacy of the next-generation platinum-based paclitaxel-eluting coronary stent system (TAXUS® Element™, Boston Scientific, Natick, MA) for the treatment of de novo atherosclerotic lesions.

Stent Coatings

Stent coating is an important factor for stent design, influencing both angiographic and clinical outcomes. Some materials exhibit excellent mechanical properties but have an unfavorable biocompatibility and other compounds with good biocompatibility are not suitable for stent mass production. Stent coating requires combining desirable characteristics of different materials. Using this approach stent coating can be applied as passive or active coatings. Whereas passive coatings serve only as a barrier between the bloodstream or tissue and metal with good biocompatibility on a backbone material, active coatings directly interfere with intimal proliferation. Active coatings are generally based on the effect of therapeutic compounds. They are either chemically bonded onto the surface of the stent or the drug is trapped in three-dimensional polymers which function as a sponge. Polymer coatings are needed for most drugs because they do not adhere appropriately to the metallic stent surface to insure controlled release of sufficient drug quantities in a beneficial manner. The polymer coating thus must provide a platform for appropriate drug elution kinetics, which can be varied by using multiple polymer layers to achieve optimal drug release over time (Fig. 1). Biocompatible coatings should at least provide a surface that minimizes adverse tissue reactions, or preferably mimic a biologic substrate that can guide stent healing in a favorable pattern.

Figure 1.

Components of drug-eluting stent. The Taxus® stent consists of a bare metal stent coated with Translute™ hydrocarbon-based copolymer to allow for biphasic release of paclitaxel, providing a burst release of 2 days, followed by lower-level release for 10 days. The Cypher® stent is produced by coating a stainless steel stent with a dual layer polymer with a poly n-butyl methacrylate (PBMA) diffusion barrier that allows release of 50% of its sirolimus content during the first week after implantation and 85% of the drug over 30 days.

Passive Stent Coatings

One strategy for reducing the occurrence of LST and late ISR is enhancing the blood and tissue compatibility of the stent by surface coatings. Passive coatings of polymeric inorganic chemical composition (silicon carbide, carbon, or gold) provide a biologically inert barrier between the stent surface, vessel wall, and circulating blood, in an attempt to curb thrombotic and inflammatory reactions and thus prevent LST and reduce neointimal hyperplasia.

Gold One of the first coatings to be tested, gold, provides excellent fluoroscopic visibility with reduced thrombogenicity; however, trials have not demonstrated clinical benefit over conventional stents.23

Heparin Heparin has been evaluated predominately as a fixed (passive) stent coating, although it may also be actively released from a drug-eluting platform (active stent coatings). Multiple non-randomized studies have shown that fixed heparin-coated stents such as Hepacoat with end-point attached heparin are well-tolerated.24 The incidence of stent thrombosis with the Hepacoat™ stent (Cordis Corporation, Miami, Florida) in clinical trials has ranged from 0.1% in elective cases, to 0.7% in acute MI, with similar rates reported from “real world” registry data.25,26

Carbon Preclinical evaluation of a diamond-like carbon nanocomposite film coating has suggested reduced thrombogenicity. However, in a recent randomized trial comparing CarboStent® (Sorin Biomedica Cardio, Saluggia, Italy) with stainless steel stent implantation in 329 patients undergoing single-lesion PCI, no differences in major adverse events or binary restenosis were reported.27

Silicon Carbide Hydrogen-rich amorphous silicon carbide (a-SiC:H) coating may also improve thromboresistance. Recent randomized trials showed no improvement in angiographic and clinical outcomes compared with BMS group.28

Phosphorylcholine Phosphorylcholine (PC), a major component of the outer layer of the cell membrane, seems a natural choice for a biomimetic polymer. PC stent coating technology is based on a co-polymer design. The coating consists of a polymer composed of methacryloyloxyethyl lauryl methacrylate, and a synthetic form of PC, the zwitterionic phospholipid found in the outer layer of cell membranes (Fig. 2). The resulting PC coating is a polymeric material that has been shown to have biologically favorable effects on reduction of platelet activation and thrombus deposition, and rate of reendothelialization.29 PC exhibits certain features of an ideal polymer for device implantation.30 It is the only stent coating that has been shown to be safe to undergo magnetic resonance imaging immediately after stent implantation.31 The PC coating is compatible with a range of chemical compounds, including biomolecules for gene therapy,32 which are notoriously difficult to incorporate and elute at prescribed rate for therapeutic benefit. Preclinical studies of coronary stenting have shown that histologically, PC-coated stents are reendothelialized rapidly without excessive inflammatory response.33 These findings are consistent with reduced expression of markers of endothelial activation after PC-coated stent deployment when compared to BMS in patients.34 Preclinical data confirm that PC-coated stents do not elicit increased inflammatory reaction, even during elution of zotarolimus when compared to BMS.35 The hydrophilic outer layer of PC coating (high biocompatibility with reduced thrombogenic potential) combined with a lipophilic inner layer (drug carrier for slow elution) makes PC a favorable inert long-term coating for coronary stents after elution of drugs.36

Figure 2.

Schematic representation of phosphorylcoline. Phosphorylcholine (PC) is a zwitterionic phospholipid and a major component of the outer layer of the cell membrane. As a component of their structure, these polymers contain an exact chemical copy of the predominant phospholipid head group (PC) found in the outer leaflet of red blood cell membranes.

Clinical Experience with Phosphorylcholine Coating

Zotarolimus-eluting stents (Endeavor®, ZoMaxx®), release the rapamycin (sirolimus) analogue zotarolimus loaded on a CoCr alloy stent known for its enhanced flexibility as compared to stainless steel stents; furthermore, the drug is eluted from a PC polymer, which has the potential advantage of reduced hypersensitivity reactions from improved vascular biocompatibility. In the ENDEAVOR II study, the primary end-point of target vessel failure at 9 months was reduced by 52% (7.9% vs. 15.1%, P = 0.0001) with the Endeavor® stent as compared to the Driver-BMS, and the rate of MACE was reduced by 51% (7.3% vs. 14.4%, P = 0.0001); the differences in clinical outcome were maintained at 12 and 24 months (P < 0.0001).37 The ENDEAVOR III follow-up study, however, failed to meet the primary end-point of angiographic in-segment late lumen loss at 9 months compared to the Cypher group.38 The ZoMaxx® (Abbott Laboratories, Abbott Park, Illinois) stent equally elutes zotarolimus from a biocompatible PC coating but with a different drug elution profile.

Active Stent Coatings

Active coatings are biologically active because the coatings are loaded with drugs (paclitaxel, sirolimus, biolimus), which are released (at a certain rate) to prevent the occurrence of thrombosis or restenosis.

Anti-thrombotic

Several antithrombotic agents have been or are undergoing clinical evaluation. Heparin, while mainly evaluated as a passive fixed coating, has also been studied as an active coating using a DES platform. Worhle et al.39 assigned 277 moderate- to high-risk patients to an active heparin-coated stent (with heparin elution from a polyamine platform) or control stent, and did not note any difference in sub-acute ST (1.9% vs. 1.3%; P = NS), major adverse events (25.2% vs. 25.7%; P = NS), or rates of restenosis at six-month angiographic follow-up (33.1% vs. 30.3%; P = NS).

Anti-inflammatory

Since inflammation plays an important role in both thrombosis and restenosis post-PCI, use of anti-inflammatory agents on DES is a desirable goal. The STRIDE study demonstrated the feasibility and safety of a dexamethasone-eluting stent in patients with de novo single-vessel disease with a MACE rate of 3.3% after 6 months and binary restenosis rate of 13.3%.40 In a recent study of patients with acute coronary syndromes, however, implantation of a dexamethasone-eluting stent was not associated with a reduction in combined incidence of TVR, MI, and death.41

Anti-proliferative

Coating with anti-proliferative drugs with or without polymer has proven to be highly effective against ISR in clinical trials. Multiple polymers have been used for the coating of the stent surface, which can provide slow drug elution as a drug reservoir. The benefits of stent-based drug delivery include maximizing the local tissue levels of therapeutic agents while minimizing local arterial wall toxicity. First-generation DES were coated with either rapamycin (Cypher® stent, Cordis Corporation, Warren, NJ) or paclitaxel (Taxus® stent, Boston Scientific, Natick, MA). After implantation, restenosis rates and the need for TVR dropped to below 10% as compared to BMS.15

Problems with Current-Generation Stent Coatings

Drug Both sirolimus and paclitaxel used in the current generation of DES are thought to primarily inhibit migration and proliferation of vascular smooth muscle cells (VSMC), which represent the crucial events in the development of ISR.17 However, these agents not only inhibit VSMC migration and proliferation, but also affect other cell types such as vascular endothelium. Among the available compounds, sirolimus and paclitaxel have been studied extensively. Indeed, it was shown that both agents decrease migration and proliferation of mature endothelial cells42 as well as proliferation, differentiation, and homing of endothelial progenitor cells (EPCs).43 Furthermore, sirolimus and paclitaxel induce the arterial wall expression of tissue factor, a key factor in the initiation of coagulation and thrombus formation.44,45 All of these effects appear particularly important, as they are likely responsible for increased risk of LST with DES. Recently published human autopsy studies have implicated delayed arterial healing and reendothelialization, as characterized by persistence of thrombus/fibrin deposition, as potential mechanisms in the pathogenesis of LST.17,46 In a recent publication from our institute Shinke et al. quantitatively correlated in vivo angioscopic findings with post mortem macroscopic and microscopic histology following overlapping PES implant in pig coronary arteries. The study has shown that although both stent types were thoroughly covered by neointima, there is clear evidence, both angioscopically and histopathologically, that a high incidence of intramural thrombus occurred only in overlapping PES segments (Figs. 3 and 4).

Figure 3.

Angioscopic grading for neointimal coverage of stent strut and mural thrombi: Neointimal coverage was more complete with BMS compared to PES (P < 0.001). PES showed varying degrees of mural thrombus (especially concentrated at overlap segments), which was greater than BMS (P < 0.001).

Figure 4.

Microscopic images of PES- and BMS-stented coronary arteries: Low magnification (20×) microscopic images of H&E-stained sections from coronary segments implanted with PES and BMS, demonstrating overall vessel morphologies. Neointimal growth was less in PES, and neointima formation was greater in overlap areas compared to non-overlap sections. High magnification (200×) microscopic images of Movat-stained sections showing, in PES, the neointima is attenuated, with thrombus and fibrinoid deposits juxtaposed to stent struts. BMS segments exhibited well-healed, thick fibrocellular neointima, completely covered with endothelial or endothelial-like cells.

Polymer Permanent polymer platforms such as ethylene vinyl acetate/acrylate or isobutylated styrene used in current DES have been shown to trigger chronic inflammation and hypersensitivity reactions which may contribute to increased risks of LST and progressive rebound restenosis.46–48 Therefore, optimal polymer platform selection (type and composition) and the use of completely absorbable but biocompatible polymers are expected to minimize these risks. Li and co-workers from our institute have shown that the sirolimus-eluting stent with a permanent polymer platform adversely affected the vasomotor function of downstream coronary segments compared to BMS at a 1-month postimplant time point. This endothelial dysfunction could be attributable to either the chronic local drug effect on arterial tissue at the implant site, chronic reaction to the polymer coating, or their combination.49

The Next Generation of Coronary Stents and Coatings Despite the success of first-generation DES (Cypher®, Taxus®) in reducing ISR and the need for TVR, several concerns have arisen since their first application, including the risk of LST, undesired effects due to the polymer as well as the stent itself, and incomplete inhibition of restenosis (especially in complex lesions).

Novel Drugs The Xience V® (Abbott, Abbott Park, Illinois) everolimus-eluting stent (EES) consists of a CoCr platform with a durable polymer and 100 μg/cm2 everolimus, a synthetic analogue of sirolimus (40-O-[2-hydroxyethyl]-rapamycin).50 The EES has shown favorable results when compared to both BMS and PES in randomized controlled trials.51,52

The Endeavor® (Medtronic, Minneapolis, MN) zotarolimus-eluting stent (Table 1) is currently in use in Europe and recently FDA-approved in the USA. This is also a CoCr platform loaded with a permanent polymer (PC) and another sirolimus analogue, and is therapeutically beneficial when compared to BMS.37,38,53

Table 1.  Up to Date List of Current and Future Stents and Stent Coatings
DrugStent nameStent platformCoatingCharacteristics
  1. SS = stainless steel; CoCr = cobalt chromium; PLLA = poly-L-lactic acid.

SirolimusCypherSSDurable polymerFirst-generation DES
SirolimusSupralimusSSBiodegradable polymerBiodegradable polymer
SirolimusYukonSSNo polymerMicroporous surface
PaclitaxelTaxusSSDurable polymerFirst-generation DES
PaclitaxelCostarCoCrBioabsorbable polymerReservoir design, bioabsorbable polymer
PaclitaxelV-flex PlusSSNo polymerDirect application
EverolimusXience VCoCrPhosphorylcholineBiocompatible PC polymer, new drug
EverolimusAbsorb (BVS)PLLABioabsorbable polymerResorbable stent, bioabsorbable polymer
EverolimusChampionSSBioabsorbable polymerBioabsorbable polymer, new drug
ZotarolimusEndeavorCoCrPhosphorylcholineBiocompatible PC polymer, new drug
ZotarolimusZoMaxxSS + tantalumPhosphorylcholineBiocompatible PC polymer, new drug
ZotarolimusEndeavor ResoluteCoCr3-layer polymerBiocompatible PC polymer, new drug
BiolimusBiomatrixSSBiodegradable polymerBiodegradable polymer, new drug
BiolimusNoboriSSBiodegradable polymerBiodegradable polymer, new drug
BiolimusXtentCoCrBiodegradable polymerBiodegradable polymer, new drug
TacrolimusJanusSSNo polymerReservoir design
PimecrolimusProlimusCoCrBiodegradable polymerBiodegradable polymer, new drug
PimecrolimusDreamsMagnesiumBiodegradable polymerResorbable stent, biodegradable polymer
Anti-CD34GenousSSDurable polymerBioactive, pro-endothelial healing
Titanium-NOHexacathSSNo polymerBioactive, pro-endothelial healing
No drugIgaki-TamaiPLLABioabsorbable polymerResorbable stent, bioabsorbable polymer
No drugAMSMg-alloyNo polymerMetallic bioabsorbable stent

Novel Polymers

Biocompatible Polymers The durable polymers used for coating of first-generation DES have been implicated as causing hypersensitivity reactions in some patients, leading to pronounced inflammatory reaction and, in some cases, contributing to LST.46 In order to overcome this limitation of first-generation DES, biocompatible polymer coatings were developed. On the Endeavor Resolute® stent, the novel BioLinx™ polymer is used for drug elution. This system has three constituents: a hydrophobic polymer (“C10”) to retain the drug and control drug release, another polymer (“C19”) to improve biocompatibility, and finally (outer-most side of the stent) a polyvinyl pyrrolidinone hydrophilic polymer which increases the initial drug burst and is thought to further enhance biocompatibility. These characteristics should optimize the drug elution profile while at the same time minimizing the risk of eliciting an inflammatory response in the vessel wall.

Bioabsorbable Polymers Using bioabsorbable polymers for coating represents another attempt to overcome the problems encountered with first-generation DES polymers mentioned above. However, absorption of the polymer may itself trigger increased inflammatory reaction in the vessel wall.54 In a study to evaluate a new DES comprising a bioabsorbable polylactide coglycolide (PLGA) polymer eluting a moderate dose of paclitaxel (0.3–0.35 μg/mm2), Jabara and co-workers from our institute have shown that despite in vitro data showing slow, sustained release of paclitaxel from a bioabsorbable polymer, in porcine coronary arteries a sequence of medial necrosis at 1 week, stent malapposition at 1 month, and rebound neointimal thickening at 3 months occurred (Fig. 5). This study suggests that the therapeutic window for paclitaxel may not be as broad as currently inferred and that efforts to improve DES technology should consider early vessel wall toxicity as well as chronic neointima suppression.55 Hence, only an inert bioabsorbable polymer, which is degraded slowly and without augmented inflammation, is suitable. In a subsequent study Jabara et al.56 evaluated a new second-generation device of the same type, but comprising a slow-release (12–16 weeks) biodegradable PLGA polymer and low-dose paclitaxel (0.15 μg/mm2) on a thin-strut cobalt chromium stent platform, and found favorable vascular compatibility and efficacy for this novel DES in porcine coronary arteries (Fig. 6). Their results support the notion that slowing the release rate and lowering the dose of paclitaxel favorably influences the vascular biological response to DES implant, decreasing early toxicity and promoting stable healing while still suppressing neointima formation. In a recent article by Hamilos et al.,57 the investigators report the results of a second-generation DES with a bioabsorbable polymer that may eliminate the endothelial dysfunction produced by earlier stent designs. In this clinical study evaluating the new Nobori® biolimus A9-eluting stent (Terumo Corporation, Tokyo, Japan), vascular reactivity at 9 months was preserved in the biolimus stent compared with the Cypher® stent. The Nobori® stent is different from the Cypher® stent in several ways; it has different drug, biolimus A9, the drug is placed only on the vessel side of the stent, and the Nobori® stent coating itself is not permanent and is expected to be absorbed within a few months, leaving a simple BMS. Which of these differences between the Nobori® and Cypher® stents is most important to the present study's findings related to long-term vasomotor function is not known, but it is certainly possible that timely resorption of the polymer is critical to the maintenance or restoration of normal vascular physiology. In a recently published article from our institute Jabara et al.58 studied a novel and unique bioabsorbable salicylate-based polymer as a DES coating and demonstrated a favorable vascular compatibility and efficacy in a porcine coronary artery model. The elution profile of sirolimus from salicylic acid/adipic acid + sirolimus (SA/AA + S) and Cypher™ stents was similar, exhibiting a “burst” over the first 48 hours, followed by more gradual elution over the next 6 days of testing (Fig. 7). In addition, salicylic acid eluted from the SA/AA and SA/AA + S stents in a gradual, linear fashion, matching the overall degradation of the drug layer. The authors also concluded that the specific type, composition, and formulation of a bioabsorbable polymer and the associated drug elution profile are critical components for any new DES technology. Shinke et al. also studied a novel bioerodible sol–gel film coated with low dose of paclitaxel (sol-gel-PES, 3 μg per stent) in a porcine coronary artery model and showed less toxicity to the coronary tunica media, while retaining effective inhibition of neointima formation at 28 days.59

Figure 5.

Microscopic images of BMS, polymer only, and polymer + paclitaxel stented coronary arteries: Low-magnification microscopic images of Movat-stained sections from 1- and 3- month samples demonstrating comparative overall vessel morphologies. Note stent malapposition at 1 month (1-mo) and thick neointima at 3 months (3-mo), in paclitaxel stent.

Figure 6.

Low-magnification microscopic images of sections from 1- and 3-month samples: Low-magnification microscopic images of Movat-stained sections from 1- and 3-month samples demonstrating comparative overall vessel morphologies, with thinner neointima for the paclitaxel-eluting stent at 1 month.

Figure 7.

Elution profile of sirolimus from bioabsorbable coating: In vitro elution profile of sirolimus from salicylate-based bioabsorbable polymer and biostable polymeric sirolimus-eluting stent (Cypher™). Note early burst release during the first 48 hours followed by plateau phase.

Reservoir Stents While using biocompatible or bioabsorbable polymers represents one possibility to reduce hypersensitivity reactions and/or LST encountered in first-generation DES systems, avoidance or reduction of the polymer burden altogether represents a potentially even more promising approach to tackle this problem. Modifications to the design of the stent surface may lead to (theoretically) safer “no-polymer” or minimal-polymer approaches for drug delivery. These efforts include the use of porous stent surfaces, designed to function as reservoirs for the continuous release of antirestenotic agents.

The CoStar® (Conor Medsystems, Menlo Park, CA) stent represents one such stent, in which the agent is loaded in reservoirs and is subsequently released toward both the luminal and/or abluminal side of the vessel; the drug, paclitaxel, is loaded on a bioresorbable polymer, which is located only within the wells in the stent, resulting in a polymer-free stent surface.

Coating with Pro-endothelial Agents (“bioactive stents”) As mentioned, one major problem encountered with first-generation DES is the risk of LST. In order to overcome this problem, several novel approaches have used coating strategies to enhance endothelial healing thereby reducing thrombogenicity of the stent and consequently the risk of LST; because the “pro-healing” substances are in fact not eluted from the stent but instead attract endothelial cells, this type of stent may be referred to as a “bioactive stent.”60 EPCs are involved in reendothelialization after angioplasty.61 Antiproliferative agents on DES, such as rapamycin, inhibit proliferation, migration, and differentiation of human EPCs in vitro,62 potentially resulting in impaired endothelial healing. Indeed, a decrease in circulating CD34 + cells is observed after sirolimus as compared to BMS implantation.63 In an attempt to promote reendothelialization, the “Genous capture R stent®” (OrbusNeich, Wanchai, Hong Kong) is covered with a CD34-binding antibody to capture circulating EPCs.

Statins have a pronounced antiproliferative effect on VSMC;64 furthermore, they inhibit tissue factor expression in endothelial cells,65 and may thus represent an interesting candidate for DES coating. Animal studies assessing the effect of a simvastatin-eluting stent are currently ongoing.66

Bioabsorbable Stents As the stent itself represents a foreign body in the vasculature with an inherent prothrombogenic potential, employment of an entirely absorbable, or biodegradable stent which dissolves after the initial phase of vessel recoil and constrictive remodeling appears to be a logical and attractive approach. Another advantage of such a stent would be the fact that it would not interfere with non-invasive imaging modalities (in particular computed tomography and magnetic resonance imaging), especially after implantation of a large number of stents (“full metal jacket”); also, bypass grafting, if required, would potentially be more feasible. Polymeric (e.g., Igaki-Tamai (Igaki Medical Planning Co., Kyoto, Japan), BVS® (Abbott, Abbott Park, Illinois), Sahajanand® (Surat, India), REVA® (REVA Medical, Inc., San Diego, CA)) and metallic bioabsorbable/biodegradable stent systems (e.g., magnesium alloy, Biotronik, Berlin, Germany) have been developed. The Igaki-Tamai stent, which is constructed from a poly-L-lactic acid polymer, was one of the first bioabsorbable stents employed in humans. In contrast to this passive stent, the BVS® stent releases everolimus from a bioresorbable polylactic acid polymer. In the ABSORB trial, in-stent late loss was 0.44 ± 0.35 mm at 6-month angiographic follow-up after implantation of the BVS® stent; the binary restenosis rate was 11.5%, and there was only one non-Q wave infarction requiring TVR: (corresponding to a MACE rate of 3.3%); no LST were recorded.67

The principal drawback of polymeric biodegradable stents is early recoil after implantation due to their lower radial strength compared to metal stents; with respect to the implantation procedure, both limited flexibility as well as missing radio-opacity can make accurate placement difficult. Furthermore, severe inflammatory reactions have been observed during degradation, which is likely to promote development of restenosis.54,55 Hence, larger studies, long-term follow-ups of presently available trials, as well as further technical improvements are required. The absorbable metal stent (AMS®, Biotronik) is a metallic alloy stent made of 93% magnesium and 7% rare-earth metals, which induces rapid endothelialization, has low thrombogenicity, and a degradation time of 2–3 months.

Finally, a novel, potentially anti-inflammatory, fully bioabsorbable sirolimus-eluting stent synthesized entirely from salicylic acid polymer, is under investigation in our laboratory. Initial preclinical results are highly encouraging and support progress into more extensive studies.

Conclusions

Although first-generation DES achieved efficacy against ISR, long-term safety issues have arisen, making these DES stand in an exquisite balance among the occasionally conflicting key properties of deliverability, efficacy, and safety. However, the provision of a permanent mechanical scaffold with inhibition of ISR no longer seems sufficient. A large number of devices are currently under investigation, with particular emphasis on new metallic platforms, biocompatible stent coatings, new drug combinations, and fully biodegradable stents. The optimal composition of the next generation of DES has yet to be resolved. The ideal DES should inhibit restenosis while at the same time expediting reendothelialization, all on the basis of a bioabsorbable (and fully biocompatible) polymer. Of the systems currently investigated, elution of an anti-restenotic agent combined with a “pro-healing” platform to enhance reendothelialization appears to be a favorable and feasible strategy. By combining novel stent coating and design improvements with optimal mechanical, pharmacologic, and manufacturing approaches, the development of an ideal DES appears to be within reach.

Ancillary