Release profiles in drug-eluting stents: Issues and uncertainties

Journal of Controlled Release 120 (2007) 149–160www.elsevier.com/locate/jconrel

Review

Release profiles in drug-eluting stents: Issues and uncertainties

Subbu Venkatraman ⁎, Freddy Boey

School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore

Received 25 January 2007; accepted 19 April 2007Available online 22 May 2007

Abstract

This review presents the current data on drug release from drug-eluting stents and the effects of the release profiles on animal and human datafor coronary stenosis. Data for the two most important drugs, sirolimus (rapamycin) and paclitaxel, are presented, the polymers used are describedand the observed release profiles are discussed for various polymer carriers. The current literature on the tissue compatibility of the polymerscommonly used in drug-eluting stents is also discussed.

The range of release rates from stents studied to date is limited for sirolimus, but somewhat broader for paclitaxel. Animal and human data comparingthe different release profiles are limited to about 6 months for animals and 2–4 years for humans. From the data available, it appears that for bothsirolimus and paclitaxel, a slow-releasing drug-eluting stent leads to slightly more favorable angiographic outcomes than more rapid release.

Most of the complications arising from the use of drug-eluting stents are attributed to incomplete healing; one possible clinical consequence ofthis delay in healing is that anti-platelet therapy needs to be maintained over a much longer period than is the case for bare metal stents.© 2007 Elsevier B.V. All rights reserved.

Contents

1. Polymers, drugs and release profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1501.1. Drug release rate and neointimal formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

2. Stents containing sirolimus (rapamycin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512.1. Cypher™ stent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

2.1.1. Polymer biocompatibility. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512.1.2. Drug release characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1512.1.3. Effect of drug release rate on neointimal formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152

3. Stents containing paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533.1. The TAXUS™ stent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

3.1.1. Control of drug release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1533.1.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.1.3. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154

3.2. Other paclitaxel stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.2.1. Poly (caprolactone-co-lactide)-coated paclitaxel-eluting stent . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1543.2.2. Strut-filled paclitaxel-eluting stent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

4. Issues with drug-eluting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1554.1. Healing-related issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

4.1.1. Late stage restenosis and thrombosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1574.2. Inflammatory/hypersensitivity issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159

⁎ Corresponding author. Tel.: +65 67904259; fax: +65 67909081.E-mail address: [email protected] (S. Venkatraman).

0168-3659/$ - see front matter © 2007 Elsevier B.V. All rights reserved.doi:10.1016/j.jconrel.2007.04.022

Table 2Human clinical trial acronyms and details

SIRIUS SIRolImUS Eluting Stent in de Novo Coronary Lesions

RAVEL RAndomized Study with the Sirolimus-eluting Bx VELocity™Balloon Expandable Stent

COSTAR CObalt chromium STent with Antiproliferative for Restenosistrial

ENDEAVOR ABT-578 Eluting Driver Coronary Stent in de Novo nativeCoronary Artery Lesions

HEALING Healthy Endothelial Accelerated Lining Inhibits NeointimalGrowth

ISAR Individualized Drug-eluting Stent System to AbrogateRestenosis

JUPITER Janus Tacrolimus Eluting CarbostentTAXUS Randomized Double-blind Trial of a PacliTAXel-ElUting Stent

for de novo Coronary LesionsSPIRIT I Single-blind study evaluating an everolimus eluting cobalt

chromium MULTI-LINK VISION™STEALTH STent Eluting A9 BioLimus Trial in Humans

150 S. Venkatraman, F. Boey / Journal of Controlled Release 120 (2007) 149–160

The advent of drug-eluting stents has created a revolution ininterventional cardiology practice. The first drug-eluting stent toobtain approval for commercialization was the Cypher™ stent,developed by Cordis Corporation (Miami, FL) in the US. Theapproval was granted in April 2003 by the US FDA, and waslimited to improving coronary luminal diameter in patients whohad discrete de novo lesions≤ 30mm, in vesselswith a diameter of2.5–3.5 mm. The approved drug-eluting stent contained approx-imately 70–300 μg of the drug sirolimus (rapamycin), in total. Thesecond drug-eluting stent granted approval was the TAXUS™family of stents, developed by Boston Scientific (Natick, MA.USA), which contained paclitaxel. This stent was approved inMarch 2004 in the US, barely a year later, for roughly the sameindications, and the drug contents of the stents were approximately50–200 μg. Other drug-eluting stent candidates are nowundergoing clinical trials, including a drug-eluting stent systemdeveloped by Medtronic Inc. and Abbott Laboratories (containingABT-578, also known as zotarolimus). Guidant Corporation/Abbott Vascular (everolimus, a sirolimus derivative), andBiosensors International (Biolimus AF), a sirolimus derivative).

In 2006, the US market for coronary stents was estimated tobe $5 billion; 90% of this revenue was attributed to DES [1].Drug-eluting stents have not only made inroads into the baremetal stent market. but are also being used in patients whowould previously have been treated with bypass surgery.

However, cautionary voices have been raised amidst all theeuphoria over these developments. In particular, some authorshave raised concerns that drug-eluting stents may follow thehistory of brachytherapy [2] where the efficacy of brachytherapywas found to erode significantly in years 4 and 5 after treatment.Additionally, caution is required because drug-eluting stent data todate have come mainly from de novo lesion treatment. Late-stagethrombosis [3] events are now being reported with drug-elutingstents [4,5] and, on a smaller scale, localized hypersensitivity [5].

As we write this review, 4 years after the introduction of thefirst drug-eluting stent into the marketplace, we seek to covertwo important questions related to drug-eluting stents:

1. Are some of the problems encountered with drug-elutingstents related to the way the drug is released? If so. is there an‘optimal’ release profile for the drug in a drug-eluting stent?

Table 1List of DESs in clinical trials

Company System Trial name/acronym

Guidant Corp./Abbott Vascular

Xience™ V, everolimus-eluting stent

SPIRIT

Medtronic Inc Endeavor™, ABT-578 eluting stent ENDEAVORBiosensors International Biolimus™ A9-eluting stent,

bioabsorbable polymerSTEALTH

Conor Medsystems Inc./Johnson and Johnson

Costar™, Paclitaxel-eluting depotstent, bioabsorbable polymer

COSTAR

Orbus/Neisch EPC-capturing stent HEALINGTranslumina GmbH Porous surface, polymer-free

Rapamycin eluting stentISAR

Sorin BiomedicaCardio S.p.A

Tacrolimus eluting stent JUPITER

2. Are the polymers used in drug-eluting stents responsible forsome of the issues now being reported? Is there an ‘ideal’polymer or polymer structure?

We hope this review will inspire more research, thusenabling an already good treatment option to become evenbetter. The emphases of this review are drug delivery andpolymer issues, and not stent design or stent delivery method.Improvements in stent design alone will invariably improve theperformance of either bare metal or coated stents; however, thisreview addresses only possible areas of improvement for thedrug delivery and polymer aspects of coated stents.

1. Polymers, drugs and release profiles

Currently, only two drug-eluting stent products have beenapproved by the US FDA: Cypher™ and TAXUS Express™.The former uses sirolimus, while the latter delivers paclitaxel.Sirolimus is an immunosuppressive agent that inhibits cell cycleprogression at early stage (leading to ∼ cell reversion into aquiescent state). Paclitaxel is a microtubule stabilizing agentthat inhibits cell cycle progression at the late stage (leading tocell death and apoptosis). Other potential products in clinicaltrials in the drug-eluting stent fields are included in Tables 1 and2, along with information on the polymers in Table 3.

Detailed information relating to the materials and processingtechnology behind these products is largely outside of the publicdomain. Most of the clinical trial data and animal data availablerelate to the Cypher and TAXUS stents. Although additionaltrial data from other drug-eluting stent systems are beingreleased, much of the data analysis is not in the public domain.Hence, it is not possible to meaningfully compare and predictthe relative advantages and disadvantages of all the drug-elutingstent products or potential products in this review.

1.1. Drug release rate and neointimal formation

One important issue that is to be addressed in this review ishow the rate at which drug is released from the stent affects

Table 3List of coating materials used in DESs

Polymer/delivery approach Product or company

Poly(n-butyl methacrylate) and poly(ethylene-co-vinyl acetate)

Cypher™ (Cordis)

Phosphorylcholine methacrylate andcopolymers

BiodivYsio™ stent(Abbott,/Biocompatibles)

Poly (acrylate) QuaDS-QP2™ (Quanam Medical,acquired by Boston Scientific)

Holes/depots/porous metals/pyrolyticcarbon

Janus stent (Sorin Biomedica),Conor stent (Conor Medystems)

Poly (L-lactide) Biosensors InternationalPoly (styrene-co-isobutylene-co-

styrene)Taxus™ (Boston Scientific)

Covered Poly (tetra fluoro ethylene) orPTFE

Jostent™ by Jomed International(bought by Abbott Labs); mostlyfor aneurysms

Poly(lactide-co-s-caprolactone) Animal studies, no product [25]Chondroitin Sulfate and Gelatin Animal studies no product [28]Poly(methyl methacrylate) and Poly

(2-hydroxyethyl methacrylate)copolymer

Animal studies no product [48]

Amphiphilic Poly(urethane) Animal studies no product [51]Fibrin Animal studies no product [50]

Fig. 1. Schematic of the Cypher™ coating, for the slow-release (SR)formulation. Top layer starts out drug-free.

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subsequent neointimal formation. The process of restenosisafter stent placement for the treatment of coronary artery diseaseis the result of a complex interplay of several implant-inducedbiologic processes [6].

The acutely occurring processes are:

• Mechanical injury to the arterial wall secondary to balloondilation and stent deployment.

• Activation of platelets in contact with the injured intima and/or the stent material.

• Activation of platelets due to hydrodynamic stagnationpoints and boundary layer separation created by the me-chanical design of the stent.

• Recruitment and activation of neutrophils in contact with theinjured arterial intima, platelets and stent.

• Recruitment and activation of monocytes and macrophagesin contact with the injured intima and stent.

• Activation of endothelium by the mechanical perturbationcaused by stent placement.

Intermediate-term and long-term processes:

• Activation of vascular smooth muscle cells (VSMCs) inresponse to growth factors and cytokines produced byactivated platelets, endothelial cells, and monocyte macro-phages and neutrophils.

• Direct activation of VSMCs in response to the mechanicalinjury and increased wall stress.

• Migration and proliferation of VSMCs within the arterialmedia and intima.

• Synthesis of ECM by the active VSMCs.• Regrowth of the endothelium and return of its normalphysiologic functions.

The temporal drug release profile of any drug candidateshould be tailored to be commensurate with the timing of themechanism being targeted.

Mathematical models are currently being developed todetermine the relative weightage due to some of the abovefactors [6]; such models will help us to understand the temporalsequence of restenosis, and identify the main targets for thissequence. Knowing the target and its temporal behavior willhelp us to identify an “ideal” release profile. The mathematicalmodels are also being developed in the area of predictivebehavior of release rate from a DES coating. The models predictthe time to exhaustion of drug release for a particular DESdesign, and will prove useful for selection of coating materialand thickness.

2. Stents containing sirolimus (rapamycin)

2.1. Cypher™ stent

This stent delivers sirolimus from a coated stent to reducerestenosis. The stent platform is a BX VELOCITY™ stent; thepolymers used for the coating are shown in Fig. 1.

PEVAC is a copolymer of ethylene and vinyl acetate, and hasbeen used extensively in drug-delivery applications, includingan US FDA-approved device on the eye to treat glaucoma [7].However, the use of PEVAC in blood-contacting applicationsis not documented. PBMA, poly (butyl methacrylate), is ahomopolymer that has been used as part of a terpolymer for skincontacting adhesives [8]. Its previous use in an implanteddevice, has not been documented either. The paraylene is a thincoating used expressly to provide an adhesive interface betweenthe metal of the BX VELOCITY™ stent and the two polymercoats above.

2.1.1. Polymer biocompatibilityThere appears to be no history of the previous of these

polymers in blood-contacting implanted devices. As such, mostof the biocompatibility information has come from thecompany's FDA submission itself [9].

2.1.2. Drug release characteristicsFig. 2 puts together [10,11] the in vitro release kinetics for

the two sirolimus drug-eluting stents — the slow and fast-release formulations. The difference in release rates is obtainedby merely coating a drug-free top layer onto the drug reservoirlayer, to create the slow-release formulation. Thus, the slowrelease formulation has a three-layer coating, while the fastrelease formulation has a bilayer coating. With the fast-release

Fig. 2. Plotted release data for a Slow Release (SR) and Fast Release (FR)formulation, for sirolimus-containing Cypher™ DES (based on [10,11]).

152 S. Venkatraman, F. Boey / Journal of Controlled Release 120 (2007) 149–160

formulation, the entire amount of sirolimus (reported loading is∼ 140 μg/cm2) is released within 15 days in an in vitroexperiment; for the slow-release formulation, the time requiredfor complete release is about 90 days.

The three-layer coating configuration for the slow-releaseformulation is a reservoir/membrane system, whereas the two-layer version is a drug-in-matrix (monolith) type system.However, the reported drug release profile does not reallyindicate a zero-order release for the slow release (three layercoating) while the fast-release formulation matrix does. (seeFig. 2) This is contrary to expectations and, is a consequence ofa substantial initial burst effect for the fast-release and possiblyfor the slow-release formulations.

To date, extensive data can be found only for these tworelease patterns for sirolimus. However, one “dose-ranging”study is worthy of mention here [12]. This study utilized a baremetal stent coated with three different concentrations ofsirolimus, without a polymer carrier. The stent is a specializedmicroporous stent capable of holding bare drug. The reporteddrug loadings used were 138, 313 and 479 μg/mm2. Thus forcomparison to the Cypher™ stents, these loadings wereapproximately 100×, 220× and 340× the Cypher™ DESloading (140 μg/cm2), respectively. While the drug releaseprofile was not been reported it was mentioned that completerelease occurred in about 4 weeks, with 66% released in theinitial burst fashion during week 1. From this description, it maybe deduced that the burst effects that occurred with higherloading were proportional to the dose (i.e. 2.2-fold and 3.4-fold,respectively, higher than that occurring with the lowest dose).

2.1.3. Effect of drug release rate on neointimal formulation

2.1.3.1. Animal studies. The animal data reported in theCypher™ documentation submitted to FDA [9] concentratedmostly on the safety aspects, and not on efficacy of differentdosages or release profiles on neointimal formation. An initialporcine study [13] evaluated a bare metal stent, a polymer-coated stent and a drug-eluting stent (without the top coat, henceconsidered fast-release) with 185 μg of sirolimus. The 28-day

data revealed a 50% reduction in neo-intimal area for the drug-eluting stent compared to the bare metal stent. In addition, it isreported that endothelialization was unaffected by the presenceof sirolimus in this porcine model. In view of later findingsregarding paclitaxel, it is significant to note here that efficacyfor the sirolimus drug-eluting stent was established with animalmodels but with no clear indication of the appropriateness ofdosage or of release patterns for efficacy.

However, a more elaborate studying pigs (n = 49) significantcontradicts to the efficacy results quoted in the above study.Carter et al [14] reported no significant difference betweenmetal stents and the slow release Cypher™ drug-eluting stent atthe longer time points of 90 and 180 days. Of interest, this studydid report a 50% reduction in neointimal area at 30 days,corroborating the findings of earlier study. The slow-releaseformulation had a drug loading of 140 μg/cm2. The experi-mental methodology used was quantitative angiography(similar to the first study [13]), which measured the effectiveneointimal area, complemented by histomorphometry. Thesame report also indicated that there is no difference in theextent of endothelialization between bare metal and drug-eluting stent, approximately 100% coverage occurring by30 days.

The Carter et al. study [14] rationalized the findings asfollows:

• The lack of efficacy of the drug-eluting stent at longer timepoints was due to delayed cellular proliferation, presumablydue to lack of a critical concentration of sirolimus.

• The discrepancy between the porcine and human data (whichshow maintenance of neointimal reduction for as long as2 years) might be due to the difference in the response ofdifferent species to sirolimus, and/or due to the fact thedelayed proliferation may occur at a later time (3–5 years)for humans compared to the animal species.

2.1.3.2. Human data. An 8-month human study in 30 patientstreated with de novo coronary lesions treated with the slow- andfast-release formulations of Cypher™ (n = 15 each) wasreported in 2001 [10]. A 4-month quantification of neointimalformation and lumen loss was done with intravascularultrasound (IVUS) and quantitative coronary angiography(QCA); a clinical follow-up was carried out at 8 months. At4 months, very little neo-intimal formation was seen with eitherformulation (∼ 15% by volume) and there was no differencenoted between the fast-and slow-release stents.

Clearly, a longer time period of observation is needed tomore accurately assess the drug-eluting stent. However, similarresults were reported from 12-month follow-up of the same 30patients, with virtually no difference noted between the fast-andslow drug-eluting stents [15]. Data for neointinmal volume wassimilar at 12 months as at the 4 months demonstrating thesustained effect of the drug-eluting stents, in spite of therelatively low number of patients involved in the study.

In the 2-year follow-up of the same patients [16], neointimalvolume had not increased significantly (remaining at around10%). In-stent stenosis was not observed in any patient; one

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patient experienced proximal stenosis. If lumen loss isconsidered, the slow-release drug-eluting stents appeared tohave a somewhat better performance and in general, a lightlybetter angiographic outcome overall.

The trial above remains the only study comparing the relativeeffect of slow and fast release formulations for stents in humans;all subsequent studies have only reported on the slow-releasedrug eluting stents. However, the impressive findings showing0% restenosis in stented segments in this study [16] have notbeen reproduced to the same extent in larger patient popula-tions. We will focus here on just a few of the most significantresults. In SIRIUS-I (Sirolimus-eluting stent in de novocoronary lesions), 1058 patients were evaluated in multicentertrials [17]. All patients had de novo lesions, including high-risklong lesions (mean 14.4 mm) occurring in small vessels (mean2.80 diameter). At 240 days, in-segment restenotic rates were36.3% for bare metal stents and 8.9% for the Cypher™ stent(SR). A 2-year follow-up of 944 patients [16] showed a TLR of5.8% for the drug eluting stents and 21.3% for the bare metalstent, clearly demonstrating sustained benefit at 2 years with theSR formulation.

The 2-year follow-up of these 944 patients [18], showed atarget lesion revasculazation rate of 5.8% for the drug-elutingstents and 21.3% for the bare stents, clearly demonstratingsustained benefits at 2 years with the slow-release Cypher™formulation.

However, the data for bifurcated lesions are not as im-pressive. Restenosis rate was 25.7% for one study in whichpatients with coronary bifurcation lesions were treated withsirolimus-eluting stenting of both branches or of main branchonly with provisional stenting of the side branch [19]. However,it must be mentioned that this rate of restenosis was notedmostly in the side branch rather than the main branch of theaffected coronary artery.

As more and more data emerge for longer lesions, it appearsthat the restenosis rates will be in double digits. In all thesestudies, the drug-eluting stents showed better results than wasobserved or historically reported with bare metal stents.Nevertheless, many researchers have noted that drug elutingoutcomes are less favorable for lesions other than de novo in thereal world.

Against this background, there was one body of work [12]that sought to shed some light on appropriate dosing drug-eluting stent. These researchers pointed to the shortcomings ofthe two drug-eluting stent types (with sirolimus and paclitaxel),and conducted a trial enrolling 602 patients with complexlesions, diabetes and with an average vessel diameter of about2.9 mm. The interesting approach taken by these researcherswas to coat sirolimus directly on to a microporous stent surface[20]. Stainless steel stents were sandblasted to obtain themicroporous surface, on to which sirolimus solutions of variousconcentrations were coated directly. In this particular study thesirolimus loadings were 138, 313 and 479 μg/mm2, which mostof the drug being released a burst effect by the end of the week1. With such a high loading of sirolimus, the resulting humandata showed some interesting trends. The patients were dividedinto four groups, one group received drug-eluting stents loaded

with sirolimus doses of 138, 313, and 479 μg/mm2. In-segmentand in-stent restenosis were monitored angiographically at amedian time interval of 198 days ± results are tabulated in tableIII). For both these outcomes (p values of 0.024 and 0.012,respectively), there appears to be a reduction in restenosis withdose.

The data above seemed to support a dose-dependentreduction in restenosis, but not necessarily release-kineticsdependence. The dose-dependence might point to the need for abetter control and delivery of drug locally, as short term deliveryappeared to have long-term consequences. This is furtherelaborated below.

3. Stents containing paclitaxel

In contrast to sirolimus-containing stents, there is a largerbody of literature on paclitaxel-containing stents. In part thismay be because more companies are using or evaluating the useof paclitaxel than sirolimus in their stent program. The onlyapproved drug-reluting stent containing paclitaxel is the Bostonscientific stent, TAXUS™.

3.1. The TAXUS™ stent

The TAXUS™ stent uses a fairly well-known blockcopolymer of styrene-b-isobutylene-b-styrene (SIB), whichcan be considered as a thermoplastic elastomer. There do notappear to be any previous medical reports of this polymerhaving been used in a medical device, although one of co-polymer blocks poly (isobutylene) has been used as acomponent of skin-contact adhesives [8]. However, bothmaterials separately or otherwise have not been reported tohave been evaluated for any blood-contacting application.The major reason for the selection of this polymer appears tobe its flexible character at room temperature and, to somedegree, its ease of processing [21]. Different drug loadingsmay be used.

3.1.1. Control of drug releaseThree different release profiles have been reported for this

system [21], dictated only by drug concentration in polymer.The concentrations are 8.8%, 25% and 35% by weight ofpaclitaxel in the polymer. The measured in vitro release intobuffer is shown in Fig. 3. This is clearly a drug-in-matrix ormonolithic system, whereby the overall drug release profile(square root of time dependence) is modulated by startingconcentration changes, as per the Higuchi equation:

M tð Þe

A 2DCSC0ð Þ1=2t1=2 for C0NNCS : ð1Þ

WhereM(t) is the amount of drug released at time t, C0 is thestarting concentration, Cs is the solubility of drug in the matrix(polymer), A is the surface area of the matrix, and D is thediffusion coefficient.

At the above concentrations, it is expected that paclitaxel iswell above the solubility limit, which is typically around 2–5%in hydrocarbon-based polymers. Clearly, in Fig. 3, the early

Fig. 4. Release of paclitaxel from a biodegradable coating (Poly (caprolactone-co-lactide)). Adapted from reference [26].

Fig. 3. Plotted release data for paclitaxel from a coated TAXUS™ stent, basedon [21], for 3 different coating thicknesses (Slow release, moderate release andfast release).

154 S. Venkatraman, F. Boey / Journal of Controlled Release 120 (2007) 149–160

release was due to an initial burst effect at the two higherconcentrations. The remainder was released via a diffusionprocess, as per the Higuchi equation, with rates that increasedwith increasing C0. This pattern of release has been observed inother work by the authors as well [22].

It is of particular interest to contrast the very low amounts ofpaclitaxel released for the so-called slow release formulation inFig. 3, to the corresponding period for sirolimus in the slow-release formulation (Fig. 2), where as much as 50% was alreadyreleased by day 10.

It is generally accepted that a substantial portion of the drug(paclitaxel) is retained in the polymer even after a considerablelength of time for the moderate-and slow-release formulations;this could be largely due to matrix construction and/or anyspecific interaction of paclitaxel with the polymer. However,extensive specific drug-polymer interaction is probably ruledout due to the fact the fast-release formulation does release mostof the drug over 30 days [21].

3.1.2. Animal studiesOther than the animal studies are reported in the FDA

document, very few animal studies have been reported onTAXUS™ stent, those that have been reported largely theaddress safety issues rather than efficacy issues.

3.1.3. Human studiesA series of studies involving the TAXUS Express™ stent has

been reported, these are the TAXUS I, II and IV studies.The first study [23] used just the slow-release formulation on

the drug-eluting stent, which was placed in 31 patients, while 30patients received the bare metal stents. For both groups ofpatients, the lesions were ≤ 12 mm(the study included de novoand restenotic lesions). Six-month results showed no restenosisfor the drug-eluting stent and 10% restenosis for the bare metalstents. This clearly showed the efficacy of even small amount ofpaclitaxel released slowly over several days; incomplete releaseis expected at 6 months, with perhaps 90% of drug remaining inthe stent.

The TAXUS II study [24] compared the slow-releasewith the moderate-release formulation of TAXUS™ paclitaxeldrug-eluting stent in patients with a single de novo coronarylesion ≤ 12 mm. A total of 538 patients were randomly assignedto 2 cohorts (slow ormoderate release), each with its own controlgroup who were treated with bare metal stent. The 12-monthendpoint for major adverse cardiac events was 9.9% for themoderate-release and 10.9% for the slow-release TAXUS stent,while their respective controls had tares of 22% and 21.4%,respectively. The efficacy was shown not have been improvedby increasing the release rate of paclitaxel.

The TAXUS IV [25] study involved 1314 patients, all withde novo lesions. They were treated with bare metal stent (n =652) and a slow-release TAXUS™ stent (n = 662); the meanlesion length was about 13 mm. At 9 months, the restenosisrates were 26.6% and 7.9%, for the bare metal stent and drug-eluting stent, respectively. This again confirmed the goodefficacy of the slow-release formulation and probably led to thesubsequent choice of the slow-release formulation for allclinical studies and submissions.

3.2. Other paclitaxel stents

3.2.1. Poly (caprolactone-co-lactide)-coated paclitaxel-elutingstent

One of the earliest reports is of a paclitaxel-eluting stents of astent coated with paclitaxel in a degradable polymer matrix[26]. In this study, NIR stents made by Medinol, Inc. werecoated with a copolymer of poly (caprolactone) and poly(lactide) and loaded at 200 μg/stent. The report did not makeclear what this loading was in terms of concentration by weightconcentration, as neither the coating thickness nor weight wasreported. It was likely to have been comparable to theTAXUS™ stent (slow-release) weight percentage, for a 3 mmdiameter and 18 mm long stent.

Surprisingly, the data for release (Fig. 4) shows completerelease of drug in 60 days, without an evident onset ofdegradation-controlled release. Release from degradable poly-mer matrices are usually tri-phasic (early burst, diffusionalphase and degradation-controlled phase). Clearly, the reportedrelease kinetics was entirely different from what has beenobserved in vitro for TAXUS™ at this loading. The authors alsoreported complete polymer degradation by 60 days, a faster ratethat may be due to an overall lower crystallinity of the

Fig. 5. Various configurations of the Conor strut-filled stent, giving rise todifferent release profiles of paclitaxel in vitro; redrawn according to reference[27]. a: Top-coat, and barrier on lumen side. c: No top-coat, no lumen barrier.b: Top-coat, lumen barrier and drug-free layer.

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copolymer. The release showed a burst effect at day 1, followedby a subsequent diffusion-controlled release up to 2 months (seeFig. 4), suggesting that the polymer released almost its entirepayload (200 μg) over about 60 days. These results are perhapsindicative of degradation occurring as early as 30 days with thisthin coating, due possibly to the low crystallinity of thisparticular copolymer.

In the study of this stent, 23 iliac arteries of New Zealandwhite rabbits underwent endothelial denudation and receivedbare metal stents, 10 received polymer-coated stents, andanother 15 received paclitaxel/polymer coated stents. At the 6-month time point, the result showed that the localized deliverytranslated to substantial reduction of neointima formation of upto 60% with the drug-containing coated stents. However, ofconcern, there was evidence of incomplete healing as long as180 days after stent implantation for the drug-eluting stent, andpersistence of macrophages in the neointima. In addition, theendothelial cell coverage appeared to be retarded for the drug-eluting stent at 180 days in a denuded model.

3.2.2. Strut-filled paclitaxel-eluting stentAnother paclitaxel-eluting stent design was developed at

Conor MedSystems Inc [27]. This very interesting design usesductile hinges that connect the stent struts to sinusoidal “bridges”.The struts do not deform with balloon expansion because theductile hinges carry the full deformation during expansion. Hencethe “passive” struts, illustrated in Fig. 5, could be filled with drug-containing polymers. Drug release and directionality is thenprogrammed by means of the top or barrier coat.

However, in the 30-day pig study [27], only one releaseprofile was evaluated: one that released 60% of drug on day 1,and the rest by day 25 to 20. The porcine data showedconsiderable reduction in intimal thickness, from 0.45 mm withbare metal stent to 0.16 mm drug eluting stent. However,delayed healing was also noted at 30 days for the area aroundthe drug-containing struts.

A study using six different paclitaxel formulations wasundertaken in humans [28]. Two hundred and forty-fourpatients with de novo lesions b17 mm received bare metalstent (n=53) or one of six different formulations of paclitaxelbased on variations in paclitaxel dose, duration of elution anddirectionality of drug release (bidirectional [b] or monodirec-tional abluiminal only [m]) as follows: D1=10/5/b, where 10represents the paclitaxel dose in μg per 17 mm stent, 5represents the duration of elution in days, and b representsdirectionality; D2=10/10/m; D3=10/10/M; D4=30/10/b;D5=10/30 m; D6=30/30/m.

On the basis of IVUS at the 6-month follow-up, thefollowing tentative trends were observed:

(a) Shorter duration of delivery (b10 days) resulted in noimprovement over bare metal stent

(b) Directionality of release also did not seem to be critical(c) where the greater inhibition of in-stent neointimal

hyperplasia was achieved with paclitaxel-eluting stentcompared with the bare stent, this was due to longerduration of release (30 days).

It is interesting to compare these results to the TAXUS IIstudy (where the slow-release (SR) formulation appeared todo as well as the moderate-release formulation in humans[24]). In the TAXUS II study which used the slow-release andmedium-release formulations, no difference was found interms of restenosis rates for these two cohorts; the amount ofpaclitaxel released showed at 30 days were about 7.5 μg andabout 21.9 μg respectively [28]. Thus the slow-release andmedium-release formulations of TAXUS II study are compa-rable to the D5 and D6, respectively, in this study. Therefore,the merit of this Conor first-in-man study is that it showed forthe first time, an effect on the restenosis rates, due todifferences in release kinetics. In addition, the local effects ofbiodegradation, such as increased inflammatory response,were not detected, even at 6 months, when most of thepolymer had presumably degraded. However, this needs to befurther investigated with longer-term studies.

4. Issues with drug-eluting stents

The problems reported with polymer-coated drug-elutingstents may be classified as either healing-related issue orhypersensitivity reactions.

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4.1. Healing-related issues

By far, the majority of problems experienced with drug-eluting stents appear to be attributable to either delayed orincomplete healing. As noted above already, many of the studiesindicate delayed healing when a drug-eluting stent is used, andthere appears to be strong evidence linking these problems tostents loaded with paclitaxel, [26,29], paclitaxel derivates [30]and for sirolimus [13,14]. It must be emphasized that much ofthe evidence for delayed healing has come from animal studies,where extensive histology has been possible. It is now wellacknowledged that these drugs do delay healing, but withunknown clinical consequences.

In one small human study of 12 patients [31], endothelialdysfunction was monitored prospectively in 7 patients with asirolimus stent (Cypher™, Cordis Corp) and 5 with a bare metalstent (Conor Medsystems). The endothelium-dependent vaso-motion of segments distal to the stent was studied (the stentitself prevents vasomotion of any kind within the segment). Itwas found that 6 months after insertion, there was a greaterdysfunction in endothelium-dependent vasomotion for theCypher™-stented patients than for the patients with baremetal stent. This has been attributed to delayed endothelialcoverage (at a section distal to the stent, and presumably withinthe stent as well) at 6 months, possibly caused by prolongedretention of sirolimus in tissue, followed by lateral migration.Again, the clinical relevance of this finding is not clear, and inaddition, the study population was small.

In another study with 25 patients [32], vasodilation wasevaluated in patients with stent during exercise and withnitroglycerine treatment. As vasodilation in response toincreased blood flow is regulated by endothelial cells, lack ofthe normal vasodilation reflects a dysfunctional endothelium.This study specifically found that the Cypher™-stent treatedpatients showed vasoconstriction in segments adjacent to thestent, while there was the normal dilatory response adjacent tothe bare metal stent segments. The study was done approxi-mately 6 months after implantation. The vasoconstrictive effectswere found in the so-called “peri-stent region”, approximately5–10 mm proximal and distal to the stent, and not in regionsfurther distant. Thus there appeared to be incomplete endothe-lial coverage or improper function close to the DES, even6 months after implantation, and presumably long after the drughas been released completely from the stent.

One report of histopathology in a human stented vascularsegment has been reported [33]. Four years after a Cypher™stent implantation, one male patient (aged 60 years) developedcardiac arrest, and subsequently died. Histological examinationrevealed minimal in-segment stenosis (b50%), and about 95%coverage of the stented segment by endothelium. The report didnot attribute either the cardiac arrest or the subsequent death toproblems with the stented artery.

In an animal study involving paclitaxel-eluting stents [29],New Zealand white rabbits were implanted with bare metal stent(n=6), metal stent with a coating of chondroitin sulfate A andgelatin (CSG, n=18), and with varying amounts of paclitaxel inCSG-coated stents (42 μg, n=6; 20.2 7 μg, n=7; 8.6 μg, n=5;

and 1.5 μg, n=6). At 28 days, the lower doses did not reduceneo-intimal thickness more than the bare metal stent, whereasthe 42 μg stent reduced thickness by 49% and the 20.2 μg stentby 35% over bare metal stent. However, this inhibitory effectdisappeared by 90 days. The residual drug measurementshowed no drug in either stent 2 weeks after implantation.The arterial tissue also did not show detectable paclitaxel after1 week. Thus the study showed dose-dependent suppression ofneo-intimal formation, although at 90 days, the effect seemed tobe absent.

In a study of paclitaxel-eluting stents [34], the follow-up tothe TAXUS II study, 161 patients (bare metal stents, n=77;slow-release, n=43; moderate-release TAXUS, n=41) under-went IVUS at 2 years. Neo-intimal suppression was maintainedat 2 years in patients with the slow-and moderate-release;however, between 6 months and 2 years, the slow-andmoderate-release stented segments showed an increase in neo-intimal area, in contrast to the bare metal stent-stented segmentswhich showed a decrease. Thus, contrary to the animal studyabove[7], neo-intimal suppression was sustained at 2 years,although there was a trend towards increased neo-intima at2 years for the drug-eluting stents segments. The regression ofneo-intimal tissue with bare metal stent has been welldocumented [35], and is attributed to cellular protein changesthat are associated with normal healing.

Some important conclusions can be made from theseobservations as follows:

1. Most of the evaluated sirolimus-containing stents deliveredtheir drug payload in 30 days or less; in animal models(pigs), neo-intimal suppression was better for sirolimus-eluting stents at 30 days, but this effect disappeared at90 days [14].

2. Most of the paclitaxel-containing stents (TAXUS™) deliv-ered part of their drug payload at 30 days, with the restretained over several months (TAXUS™ Stents). For thesestents in New Zealand white rabbits, neo-intimal suppressionwas seen at 30 days and also disappeared at 90 days.

3. Even assuming a suggested [36] 1:6 ratio for time effects inpig to humans (i.e., 90 days in pigs is equivalent to18 months in man), there is still some discrepancy betweenanimal data for efficacy and human data. Whether this is dueto the difference in species, artery conditions, concurrentdrug therapy etc, is not clear. Nevertheless, it must bementioned that animal studies appeared to better reflectsafety than efficacy.

4. With the above constraint, we turn to the effect of drug ondelayed healing in human patients. Evidence is nowaccumulating regarding observations of endothelial dysfunc-tion as early as 6 months after stent placement; but theclinical significance of this finding is far from clear. It maybe safe to surmise that endothelial coverage of the stents islower in DES than in BMS, and the clinical consequences ofthis are just emerging (see information below, on late-stagethrombosis).

5. Data to date show no effect of drug loading or releasekinetics on neo-intimal formation, except for one study using

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the Conor-paclitaxel stent system [28], where a slowerrelease of paclitaxel appears to be more beneficial. However,it is fair to say that currently there is no coated system wherea substantial portion of drug is delivered measurably beyond30 days irrespective of the drug involved (paclitaxel orsirolimus).This restriction comes from the limitations of thincoatings. This problem is being addressed by fully polymericstents containing larger drug payloads and better controlmechanisms. [22]

4.1.1. Late stage restenosis and thrombosisMore recently, reports have surfaced regarding late-stage

thrombosis and restenosis in DES-stented patients. For exam-ple, approximately a year after stenting, four patients, two withCypher™ and the other two with TAXUS™ stents, werereported to have angiographic thrombosis in the stentedsegments [37]. Three out of the four patients had anti-platelettherapy stopped prior to another surgery, and shortly thereaftersuffered occlusion of the stented segment in the DES. Theywere all treated with percutaneous intervention and recovered.The inference is that incomplete endothelialization was re-sponsible for the occlusion after stoppage of anti-platelettherapy. This inference was reinforced in the one remainingpatient, who also had 2 bare metal stents in other vessels, andthese vessels did not occlude.

Two cases of TAXUS™ patients suffering late-stage throm-bosis were also reported in 2005 [38]. In these two instances,both patients had discontinued anti-platelet therapy, approxi-mately 6 months after stent insertion. Thrombi were detected inboth cases. According to the authors, such a “late-stage” event(defined as occurring 3 months after stent insertion) has neverbeen reported for patients with BMS.

The issue of late-stage stent thrombosis continues to becontroversial. In a study of 746 patients (about 2/3 of thepatients stented with DES (both sirolimus-and paclitaxel-eluting) and the rest stented with BMS), patients surviving at6 months were followed for 1 year after discontinuation ofclopidogrel therapy [39]. This study pointed to a statisticallysignificant increase in late stage thrombosis in the DES cohort(2.6% vs 1.3%). Similarly, clopidogrel discontinuation has beenassociated with higher risk of cardiac events with DES-stentedpatients [40], but this study did not compare BMS-stentedpatients. One study that did compare both types of DES (SESand PES) with bare metal stents was that by Stone et. al [41]which analyzed 4-year thrombosis rates from 9 trials involving atotal of 5261 patients. Their findings pointed to a statisticallysignificant higher thrombosis rate for SES (1.2%) and PES(1.3%) compared to BMS (∼0.6-0.9%). On the other hand, atleast 2 data analyses [42,43] have reported statistically-insignificant differences in thrombosis rates between bothpaclitaxel-and sirolimus-eluting stents and BMS, over the entireperiod of observation (∼4 years). A third analysis [44] of 4958patients in 14 randomized trials comparing SES with BMS, didhowever point to a slight increase in the risk of thrombosis afterthe first year for SES-stented patients. Regardless of the actualincidence rates, it is now evident that DES do delay healing,which may contribute to the increased thrombosis risk [45,46].

Two cases of late-stage restenosis were reported undercircumstances different from the cases above [47]. In one of thecases, recurrent angina pectoris occurred 6 months afterantiplatelet therapy was discontinued; coronary angiographyperformed on the patient showed in-stent resteosis in a drugeluting stent that had been inserted 13 months earlier. The samepatient also had a bare metal stent inserted, but this showed littlerestenosis. In the second case, restenosis occurred in the drug-eluting stent 17 months after insertion, while the same patientwith a bare metal stent and there no angiographic restenosis inthe BMS-stented vessel. In both cases, the earlier angiographicresults at 7 month after insertion of drug-eluting stents had beenexcellent.

The above reports clearly send out a cautionary signal: thewhole story on the efficacy of drug-eluting stents may not haveyet fully unfolded. In all of these cases reported, the evidencepoints to the cause of these problem being incomplete healing indrug-eluting stent segments, most likely caused by the presenceof drug itself. These reports suggest that antiplatelet therapymay need to be maintained over a much longer period afterimplantation of drug drug-eluting stents than is the case for baremetal stents.

4.2. Inflammatory/hypersensitivity issues

An article published in 2004 by Virmani et. al. [48] cites aUS FDA Public Health notification that reported 50 “possible”hypersensitivity reactions related to the Cypher™ stent. Thearticle itself described a case of late-stage thrombosis in apatient who had two overlapping Cypher™ stents, deployedwith an 18 months gap between their insertion of first andsecond stent. Three weeks after the second stent implantation,the patient developed skin rashes in several places with itchingand irritation. The use of clopidrogel was suspected to be thecause of the problem, and this was replaced by ticlopidine. Therashes were resolved in a few days; at 8 months and 12 months,the patient remained asymptomatic. However, at 18 months, thepatient complained of chest pain and died while being treated.

Post-mortem analysis of this patient showed thrombus at theentrance to one of the two stents; the distal stent had someevidence of inflammatory cells in the subluminal tissue. In theproximal stent, a few small polymer pieces had separated fromthe stent (whether this due to the preparation procedure or notwas unclear) and were surrounded by giant cells. Based on thisfinding, and noting no reported incidences of hypersensitivity tosirolimus, the authors concluded that localized hypersensitivityto the polymer was responsible for the occlusion. The inferenceappeared plausible, especially as it was backed up by known orreported hypersensitivity to synthetic polymers. In particular, itappears that n-butyl methacrylate (one of the polymers used inthe Cypher™ coating) had been reported to have inducedhypersensitivity in rabbits [49], although this was not a polymerof n-butyl methacrylate, but the monomer mixed witholigomers.

In a later article [50], a more comprehensive survey ofhypersensitivity cases is reported. Out of 5783 cases, about 17could be attributed definitively to drug-eluting stents; this

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translates to about 0.3% cases so far. This is contrast to another(more limited) survey [51], where a 10% allergic reaction ratewas reported for chromium and molybdenum steels used instents. While noteworthy, perhaps the incidences are nodifferent from those for bare metal stents.

While there are few reports of inflammatory responses to thepolymers in human studies, there have been several reports ofsuch reactions in animals. The most extensive, and in manyrespects pioneering, study was carried out by W.J. van derGissen et. al. [52], and is a study that is quoted widely in thiscontext. Five degradable and three non-degradable polymerswere studied. Metal stents were dip-coated with “longitudinal”strips of the polymer, from solutions. (It is not clear whether thepolymer strips were dried to get rid of most of the solvent,whose residual levels and types are not disclosed in the study).The stents with the polymer strips (of thickness about 75–100microns) were implanted in porcine coronary arteries, andexplanted at 4 weeks to evaluate local tissue reactions. Of thepolymers studied, Poly (ortho ester), Poly (caprolactone), Poly(hydroxy butyrate valerate), as well as the non-degradable poly(urethane) and poly (dimethyl siloxane) were found to causesevere inflammatory reactions. Less severe responses wereobserved for the biodegradable PLGA and a copolymer of Poly(ethylene oxide) and poly (butylenes terephthalate). This studywas pioneering and extensive, and has been quoted extensivelyby other researchers when rationalizing polymer-free DES.There are some concerns with this study that must be borne inmind when generalizing from it:

(a) It is not clear whether the solvent types differed; in fact,given the nature of the polymers, it is likely that differentsolvents were used.

(b) The study was carried out to 4 weeks, and it is not clearwhat the extent of degradation was at this stage for theseveral biodegradable polymers: in all likelihood, it wasnot extensive for most of them.

(c) No bare metal stent controls were used; the area next tothe uncoated stent was used as bare metal control.

(d) None of the stent samples were sterilized.

It is interesting to note that in the review by Zidar [53],quoted above, the authors have reported favourable cellularresponse for a PLLA monofilament-derived stent with adiamond-braided pattern, even at 18 months, when appreciablepolymer degradation is likely to have occurred. However, acanine femoral artery model was used for this study, and it isgenerally agreed that the canine model is less likely to produceinflammatory reactions.

In another study [54] that compared coated and uncoatedstents, some interesting observations were reported. This studyis particularly noteworthy in that it reported cellular response toa stent coated with low-MW PLLA (80,000 Da) and high-MWPLLA (320,000 Da). Both the polymers were spray-coated on tometal stents (Tantalum) from a chloroform solution. Neverthe-less, the stent coated with high-MW PLLA exhibited much lessneo-intimal inflammatory response, the vessel remaining patentat 28 days in the porcine coronary artery. It is not clear why the

high-MW PLLA behaves differently, but most likely thefavourable results are due to a combination of low solventlevel and slow degradation. It is well-known that the decrease inlocal pH from a degrading PLLA polymer is higher with lowerMW.

Other studies on Poly (caprolactone)/poly (lactide) [PCL-PLA] copolymers [26], Poly L-(lactide) PLLA in pigs [51], andPLLA in humans [55] or a blend of poly(methyl methacrylate)and poly(2-hydroxyethyl methacrylate) [56], have not shownsimilar inflammatory responses in either rabbit or pig studies.On the other hand, Poly (ethylene terephthalate) or PET [57]and Poly (urethane) or PU [58] have been studied and foundto cause inflammatory responses in pigs. For the poly (eth-ylene terephthalate), a woven mesh was used, presumably ofDacron ® fibers, and found to cause severe neo-intimal pro-liferation at 4–6 weeks. In the poly (urethane) study, the PU wassolution-cast on to a metal stent, dried and then inserted intoporcine coronary artery. Both thrombotic occlusion andextensive hyperplasia were detected at 48 h and at 28 days,respectively. In contrast, a fibrin-coated stent in the same studywas found to produce significantly less cellular proliferation.

In contradiction to the poly(urethane) result quoted above,another study [59] used an “amphiphilic” PU made using ahydrophilic polyether, diisocyanate and a butane diol. At6 weeks in porcine coronary arteries, the PU-coated (coatedusing a chloroform solution) stent showed the same level ofvessel wall narrowing as the bare metal stent.

So what sense can one make of this vast array of data on thecellular response to various polymers? Clearly, the guidingprinciples seem to be:

• Use a high-molecular weight, slow-degrading polymer tominimize inflammatory response.

• Both solvent-cast and solvent-less polymers have also beenfound to cause cellular proliferation, hence being solvent-free does not guarantee a tissue-compatible coating

• Generally, hydrophilicity appears to be a desirable charac-teristic; of course this has to be balanced by the tendency toswell or dissolve too quickly in vivo.

5. Conclusions

An optimal release profile is yet to be found for drug-elutingstents. The main reason for this is that most, if not all, of theanimal data pertain to coated stents, for which the thinness ofthe coating precludes a wide range of release profiles. Althoughin principle, release profiles extending over a few months ispossible with coated stents, in practice the release rate will betoo slow to be meaningful. At least for studies that help us tounderstand the optimum release profiles, thicker coatings orfully polymeric stent formulations would be useful.

We expect that the optimum release profile may be differentfor different drugs, as the drugs target different events leading torestenosis, which may also occur at different temporal stages.Only a prolonged pharmacokinetic animal study with drug-eluting stents of different release profiles will identify thedesirable release profile. Such a study should include

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measurements of drug concentrations in tissue adjacent to thestent, its clearance rate, and the consequent biological effects.Such as study has been attempted for paclitaxel deliveredlocally via infusion [60,61]. Detailed studies of drug transportand distribution in tissue have been advocated by Edelman'sgroup [62]. Questions to be answered in such studies include:

(a) How long is the drug retained in arterial tissue, for variousdrug release profiles (rapid infusion, fast, moderate andslow release)?

(b) Is there a benefit to cyclical drug release?(c) What are the effects of arterial drug distribution on events

such as endothelialization and smooth muscle cellproliferation?

In order to fully understand the long-term implications ofdrug-eluting stents, it is imperative to carry out such studieswith systems that can sustain the release over a wider range ofrates. Such a study may be carried out best with fully polymericstents that have higher drug-carrying capacity, and the abilityfor programming the drug release rates over a wide range.However, from the data available to date, it is safe to say thatcomplete release of the drug from the carrier in about 2-3months is a desirable feature.

A number of problems have been observed with drug-elutingstents, including late-stage thrombosis, which is associated withdelayed or incomplete healing. The various polymers used indrug-eluting stents appear to cause occasional hypersensitivity,but the incidence reported to date is perhaps comparable toreported hypersensitivity to metals used in bare metal stents.

From the animal data (and to some extent human data) to date, itappears that many polymers will be acceptable in drug-elutingstents, from the point of view of tissue compatibility. The followingis a list of some of the polymers that appear to be acceptable:

Biostable polymers:

• Poly (styrene-co-isoprene-co-styrene) or SIS triblockcopolymer

• Poly (n-butyl acrylate) and poly (vinyl-co-acetate)• Polyacrylates (selected classes: eg. Poly (methyl methacry-late and Poly (2-hydroxyethyl methacrylate))

• Phosphoryl choline methacrylate and copolymer

Biodegradable Polymers:For the case of biodegradable polymers, there is conflicting

data. However, many studies have shown the following to causeminimal cellular responses:

• Poly (caprolactone), PCL and copolymers (PCL-co-PLLA)• Poly (L-lactide), high molecular weight• Fibrin• Tyrosine-derived polycarbonate [63].

Acknowledgements

The authors gratefully acknowledge the assistance of Ms.Luciana Lisa Lao for redrawing some of the figures.

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