Advanced Review Drug-eluting stent coatings

Advanced Review

Drug-eluting stent coatingsJudit E. Puskas,1∗ Lyn G. Munoz-Robledo,1 Robert A. Hoerr,2 JohnFoley2, Steven P. Schmidt3, Michelle Evancho-Chapman3, JinpingDong 4, Chris Frethem4 and Greg Haugstad4

This paper reviews the development of coronary stents from a polymer scientist’sview point, and presents the first results of an interdisciplinary team assembledfor the development of new stent systems. Poly(styrene-b-isobutylene-b-styrene)block copolymer (SIBS), a nanostructured thermoplastic elastomer, is used inclinical practice as the drug-eluting polymeric coating on the Taxus coronarystent (trademark of Boston Scientific Co.). Our group has been developingnew architectures comprising of arborescent (dendritic) polyisobutylene cores(D SIBS), which were shown to be as biocompatible as SIBS. ElectroNanospray(Nanocopoeia Inc.) was used to coat test coupons and coronary stents withselected DSIBS polymers loaded with dexamethasone, a model drug. The surfacetopology varied from smooth to nanosized particulate coating. This paper willdemonstrate how drug release profiles were influenced by both the molecularweight of the polyisobutylene core and spraying conditions of the polymer-drugmixture. 2009 John Wiley & Sons, Inc. WIREs Nanomed Nanobiotechnol

INTRODUCTION

This interdisciplinary paper intends to discuss drug-eluting coronary stents (DES) and novel stent

coatings mostly from the perspective of a polymerscientist who has been involved in the developmentof a polymer currently in clinical practice. Developingimproved polymeric coatings will require close col-laboration between medical professionals and expertsin natural science and engineering. Communication iscritical but difficult when even the vocabulary is vastlydifferent. This paper first will give an overview of thehistory of stent development, followed by a glimpseinto the first results coming from our interdisciplinarygroup. It is not intended to be an exhaustive review,and it may be lacking from some perspectives.It is hoped, however, that it will contribute to a

Additional Supporting Information may be found in the onlineversion of this article.∗Correspondence to: [email protected] University of Akron, Akron, OH 44325-3909, USA2Nanocopoeia, Inc., St. Paul, MN 55104, USA3Division of Surgical Research, Summa Health System, Akron, OH44304, USA4Characterization Facility, University of Minnesota, 12 ShepherdLabs, 100 Union St. SE, Minneapolis, MN 55455, USA

DOI: 10.1002/wnan.038

better understanding of this topic, and hence someterminology will be ‘translated’ for the benefit of all.

Overview of coronary stentsCoronary stents revolutionized interventional cardiol-ogy to treat the narrowing of coronary arteries causedby the build-up of atherosclerotic plaque (heart dis-ease), which is the leading cause of death for bothwomen and men in the United States.1–7 If this con-dition goes untreated, it can result in heart attacksor angina (pain in the chest, arms, or lower jawthat occurs when insufficient blood flows to theheart muscle). Before Andreas Gruntzig introducedballoon angioplasty to treat arterial narrowings in1977,8 bypass grafts utilizing the patient’s own arter-ies were used. During angioplasty (some prefer theterm ‘percutanueous transluminal coronary angio-plasty’ or PTCA) a balloon-tipped catheter is inflatedinside the artery (Figure 1(a) and (b)). Stretching theintima (innermost layer of an artery) causes injury,leaving a ragged interior surface after deflation of theballoon, which triggers a healing response. A signif-icant problem is the elastic recoil or collapse of theartery after stretch injury. This collapse can occurduring the procedure after the balloon is deflated andalso after the angioplasty when the patients are in therecovery room. After such a collapse, the only optionfor the patient is emergency bypass graft surgery to

2009 John Wiley & Sons, Inc.

Advanced Review www.wiley.com/wires/nanomed

Stent deployed

CollapsedBallonCatheter Dilated

ballon catheter

Dilatedballoncatheterand stent

Plaque

(a) (b) (c) (d)

FIGURE 1 | Balloon angioplasty and stenting (Reprintedwith permission from www.applesnail.net Copyright 2007Boston Scientific Corporation).

repair the problem. Moreover, ∼30% of all coronaryarteries begin to ‘restenose’ (close back) as a result ofcellular proliferation in response to the stretch injury.In other words, overstretch shearing of the diseasedwall with PTCA leads to vascular spasm and, in someinstances, severe vessel wall weakening or dissection,both of which could require emergent salvage revas-cularization. By the mid-1980s, various cardiologistsand radiologists were working on solutions to theseproblems, designing new devices that would providemore safety and durability to the procedures. Onesuch device was the stent—an expandable metal tubeor ‘scaffold’. The metallic stents are crimped onto aballoon-tipped catheter and positioned in the coro-nary artery at the site of the narrowing (Figure 1(b)).The balloon is inflated, and the stent expands andpresses against the arterial wall (Figure 1(c)). Theballoon is deflated and removed. The stent remainspermanently in place, helping to keep the artery open(Figure 1(d)). Within a few weeks, new tissue willgrow over the stent. In 1985, Palmaz et al. implantedthe first balloon-mounted stent in a peripheral artery.9

Others in Europe were developing their own designs.In 1986, Puel and Sigwart10 inserted the first stentinto a human coronary artery. With the modificationsby Schatz et al. of the original Palmaz stent,11 the firstcoronary stent became commercially available in theUnited States (Palmaz–Schatz stent). The first devicewas implanted in 1987 at Brooke Army Medical Cen-ter. In 1994 the Palmaz–Schatz stent was approvedfor use in the United States.12 Since their approval,over 1.5 million coronary stents have been implantedinto patients each year. Over the years, several gen-erations of bare metal stents (BMSs) were developed,and it has been shown that they can significantlydecrease the chance of vessel restenosis at the site oftreatment. However, ∼20–30% of patients still devel-oped significant scar formation at the site of the stentplacement, which in turn caused restenosis.7 Thus the

introduction of these bare metal endoluminal scaf-folds, i.e., stents, provided a convenient and effectiveapproach to prevent acute arterial closure followingPTCA, but the technique was plagued by a 30%restenosis rate within 6 months, resulting from anexuberant vascular tissue neointimal growth aroundthe stent and within the lumen. Many investigatorshave tried to prevent restenosis by administering drugssystematically, but this has had little success despitepromising preliminary work in animal models. A newsolution to the problem of restenosis has been thedevelopment of DES.2–5,13 DES are made by coatinga standard coronary stent with a thin polymer filmcontaining a drug, which is released in controlledamounts directly into the region of the injury, therebypreventing the formation of scar tissue at the site ofcoronary intervention. BMS reduce the incidence ofclinically significant restenosis by expanding the ves-sel lumen area; restenosis still occurs in virtually allinstances. With DES, the remodeling is often positive(vessel expansion) because the vessel wall retracts fromthe stent because of the drugs. Comparative studieshave shown that DES are better than BMS for treat-ing coronary diseases.13–16 For example, the Taxus(coronary stent trademark of Boston Scientific Co.) Vclinical trial reported 13.7% verus 31.9% restenosiswith DES and BMS, respectively.14 Since the Food andDrug Administration (FDA) approval of the first DES,the market has grown explosively. The current U.S.market is dominated by two DES: the Taxus by BostonScientific Co. (BSC) and the Cypher (Coronary stenttrademark of Johnson&Johnson Inc.) by Johnson &Johnson Inc. (J&J) The worldwide market was pre-dicted to reach 6.1 billion by 2010. Table 1 comparesvarious DES technologies under development.


WIREs Nanomedicine and Nanobiotechnology Drug-eluting stent coatings

TABLE 1 DES Technologies

Manufacturer Trade name Stent Polymer Drug

Abbott ZoMaxx Tantalum/SS Durable Zotarolimus

Boston Scientific Taxus SS Durable Taxus

Cordis J&J Cypher Cobalt chromium/SS Durable Sirolimus

Guidant Champion SS Bioabsorbable Everolimus

Terumo Nobori SS Bioabsorbable Biolimus-A9

SS, Stainless steel.

Polymers used in drug eluting stentsThe biocompatibility of the polymers used for coatingstents in contact with the blood is vital. Biocom-patibility is hard to define, especially for a polymerscientist, but the term describes how cells respondbiologically to the presence of a material in theirenvironment.17 The polymer must not stimulate aninflammatory response. In addition, for DES applica-tions it must be capable of being stretched withoutflaking or delaminating. Secondly, the polymer needsto be able to deliver the drug at a sustained, con-trolled, and predictable rate. Only a few polymersmeet these requirements. These polymers may bebiodegradable or non-biodegradable (durable). Somebiodegradable polymers investigated as coatings instents include polyglycolic or polylactic acid or theircopolymers, and poly(ethylene glycol-block-ethyleneterephthalate). Examples of durable polymers testedin DES are methacryloyl phosphorylcholine–lau-rylmethacrylate, poly(ε-caprolactone), poly(ethyleneterephthalate), silicone, and polyurethane.18 Theexact polymeric compositions are usually propri-etary. Unfortunately, the polymers listed above haveshown less than optimal biocompatibility in a porcinemodel.18,19 Polyurethanes are classified as ‘durable’but in fact they are not biostable over an extendedperiod of time and the degradation products havebeen shown to be toxic.20 However, thermoplasticpolyurethanes with shape memory properties wereinvestigated as DES.21

Pinchuk recently advanced a hypothesis ofbiostability and biocompatibility on the basisof the analysis of the degradation mechanism ofpolyurethanes combined with an understanding oforganic chemistry principles.18 According to thishypothesis, the long-term stability of a polymericmaterial in living tissue can be jeopardized when thepolymer contains unprotected ester, amide, ether, car-bamate, urea, or any other groups that are proneto oxidation, hydrolysis, or enzymatic cleavage. Fur-ther, secondary carbon-containing polymers such aspolyethylene, and secondary and tertiary carbon-containing polymers such as polypropylene, are also

to be avoided, as double bond formation leads toembrittlement and stress-cracking. Clinical evidenceseems to support this hypothesis.

In addition to effective suppression of inti-mal growth, the ideal DES polymer shouldbe non-thrombotic, non-inflamatory, non-toxic tocells, and should encourage arterial healing byre-endotheliatization. Long-term safety and efficacyis important; therefore incidences of late thrombosisled to controversy over DES versus BMS, which willbe discussed in more detail in a later section.22

The two DES approved by the FDA employpoly(ethylene-co-vinyl acetate) (PEVA) and poly(n-butyl methacrylate) (PBMA) (J&J), and poly(styrene-b-isobutylene-b-styrene) (SIBS) (BSC).

DES approved by the FDAThe Cypher is manufactured by Cordis (J&J). Itis made of 316 L stainless steel (SS) (low-magnetic,low-carbon) and coated with a mixture of polymers(PEVA:PBMA 67:33) containing the sirolimus drug.A drug-free top coat of PBMA is also applied to thestent surface to control drug release.

Sirolimus is a natural macrocyclic lactone, whichis a fermentation product of Streptomyces hygro-scopicus originally identified in a soil sample fromPara Nui (Easter Island) to combat restenosis. Thisantibiotic has potent immunosuppressant propertiesand is used as an oral agent to prevent rejectionin patients who have undergone renal transplant.Furthermore, this drug has the ability to inhibitcytokine- and growth-factor-mediated proliferationof lymphocytes and smooth muscle cells.23 Severalstudies have been conducted with this drug and theresults were reportedly excellent. It was demonstratedthat for up to 24 months neointimal hyperplasia, asdetected by intravascular ultrasound, was virtuallyabsent, and there was no late thrombosis close tothe stent area. The Ravel Trial24 demonstrated thereduction of restenosis and associated clinical events.In addition to the Ravel study, the results of the Siriusstudy25 showed that after 9 months the patients whoreceived DES had significantly lower rates for repeat



procedures than those who received BMS (4.2% vs.16.8%).14 Thus, the FDA decided to approve thesestents on April 24, 2003.

The Taxus stent is made of 316 L SS andis coated with SIBS or Translute produced underlicense from the University of Akron, where SIBSwas invented,26 mixed with paclitaxel (PTx). PTx(Taxus brevifolia) was originally isolated from thebark of the Pacific yew tree and has been usedto treat several types of cancer (e.g., breast andovarian cancer). SIBS belongs to the family ofnovel thermoplastic elastomeric (TPE) biomaterialsbased on polyisobutylene (PIB) soft segments withphase-separated glassy (amorphous) domains suchas polystyrene (PS) or PS derivatives.26–40 In TPEs,nano-sized discrete glassy phases embedded in acontinuous elastomer phase provide ‘thermolabilecrosslinks’, giving rise to rubbery properties. TPEsdo not need to be chemically crosslinked like siliconerubber, and therefore offer many advantages overchemically crosslinked rubbers while being processibleas thermoplastics. SIBS is transparent and resemblessilicone rubber, whereas it is much stronger and hasbetter fatigue properties.

Multiple clinical trials have been performedto investigate the efficacy and the safety of thisstent,16,41–43 and because of the excellent results fromthese trials the FDA approved the use of the Taxusstent on March 6, 2004. Extensive testing in vitroand in vivo18,44 as well as clinical evidence showsthat this polymer has excellent vascular compatibility.In the smooth stent coating, the PTx was shown toexist as discrete particles, mostly in the PS domainsdue to weak π–π interactions between the aromaticrings of PS and PTx.45 The release kinetics of the drugfrom the polymer matrix was shown to correlatewith drug-to-polymer ratio. However, in vivo, atthe clinically relevant dosage only about 10% ofthe drug is eluted from the matrix in about 3 days,and the rest remains practically entrapped as a resultof the extreme impermeability of the polymer.44,45

Eventually, the entrapped drug will be released veryslowly by diffusion, which may take years, but‘permanent’ entrapment would be against the lawsof physics.

Stent controversyDES technology was the fastest introduction andscale-up of a combination medical device therapyever introduced. In late 2006, there were only twodomestic products approved by the FDA for usein the United States. Many more were poised forintroduction with international trials in progress.

Then, the market for the product crashed because ofunanticipated complications with the devices. Recentstudies indicate that the rapamycin- and PTx-elutingstents may be accompanied by rare, but serious, late-term thrombotic events.

In April 2003 FDA’s Manufacture and UserDevice Experience (MAUDE) (center received unfa-vorable event reports from patients implanted withDES. The problems associated with using the Taxusand Cypher stents were hypersensitivity (includingrashes), dyspnea (labored breathing), hives, and ana-phylaxis. Additionally, in other studies it was reportedthat patients were suffering thrombocytopenia (notenough platelets), itching, arthralgia (pain in thejoints), joint swelling, myalgia (muscle pain), or fever.These symptoms started within 1 day of the stentimplantation (20%), or manifested at later times(2–7 days (46%), 8–14 days (19%) and > 14 days(15%)).15,46–48 In spite of these problems, 88% ofpatients had favorable outcomes from the placementof DES—compared to BMS which have a higher per-centage of restenosis (∼40%)—and claimed DES tobe a better option. However, concerns were raisedthat while DES might reduce restenosis significantly inthe first few months, post-procedure (9–12 months)rates for DES and BMS were found to be essentiallythe same, and it was suggested that DES posed andan increased risk of thrombosis (ST-segment elevationand myocardial infarction) or death.46–49 However,it was pointed out that thrombosis was typicallyoccurring when the patient discontinued anticoagu-lant/antiplatelet therapy (the Swedish study47 did notinclude this factor).

Early thrombotic events are a well-knowncomplication of stent therapies. Combination anti-platelet regimens have reduced the incidence ofthese events from as high as 24% to below 1%for BMSs.50,51 DES were thought to be especiallysusceptible to late thrombosis events because ofdelayed re-endothelialization caused by the drugs.There are conflicting reports on whether or not thisis the case. Randomized trials of DES did not show adifference in thrombosis events at 1 year.52,53 Follow-up on patients from the initial clinical trials (4–5 years)has not shown any increased risk of major cardiacevents for DES versus BMS. However, these studieslack the statistical power to identify rare events.

Meta-analyses were performed in the hopeof gaining statistical significance by pooling dataacross multiple studies. It should also be notedthat meta-analysis studies are controversial, as therewere no consensus on the validity of makingpooled comparisons across existing methodologies.54

However, these studies are routinely reported in the



medical literature indicating general acceptance ofthe approach. The 1-year findings of no differencebetween DES and BMS were confirmed by meta-analyses.55,56 While the initial studies showed nodifference in thrombosis out to 1 year, other studiesat longer time points were conflicting. For example,in 2006 Pfisterer et al. reported that in patients whostopped anti-coagulation therapies, late thromboticevents were two to three times more frequent amongthose who had received DES than among those whohad received BMS and that these events carriedfour times greater risk of cardiac death/myocardialinfarction versus non-thrombosis-related events.57

Another important study suggested an increased rateof death or Q-wave myocardial infarction with DES.58

The Camenzind analysis was based on publishedstudies. However, another set of studies based on rawdata from the two major stent companies concludedthat long-term mortality did not differ for patientswith DES or BMS.59,60

What is one to make of all of this controversy?Consensus is emerging that the decision to implantBMS versus DES needs to be made after carefulconsideration of whether the benefits of a reductionin restenosis outweigh the potential risks of long-termanti-platelet treatment to prevent late thrombosis.61

BMS are an appropriate choice for some patientsbut not others. What is clear, however, is that thereis a need for new stent alternatives. The ideal stentcoating would be one that inhibits smooth muscle cellproliferation in response to the stenting injury whilepromoting rapid re-endothelialization. New polymers,drugs, and biological agents are being screened inpreclinical studies in the hope that the next-generationstents can alleviate potential pitfalls of the currentstents.

What is most surprising to the polymer scientistis that the long-term clinical effects of the polymerhave not been investigated separately. At presentthere is no evidence that the presence of the polymerleads to thrombosis, which happens with both theJ&J and BSC DES62 in spite of the very differentpolymers. Poly(isobutylene) has alternating secondaryand quaternary carbons and no labile pendantgroups, and hence the excellent biocompatibility andbiostability of SIBS-type biomaterials. In comparison,methacrylate polymers have unprotected ester sidegroups. The corresponding author of the present paperbelieves that the impermeability of the PIB may also bea contributing factor since enzymes cannot penetratethe film. On the other hand, this may lead to drugentrapment, as discussed before.

It would be ideal to have long-term clinical dataon the behavior of polymers used in DES coating,

or a comparative study involving BMS and stentscoated with the polymer in question. Barring thispossibility, the role of polymers in the controversyremains unclear.

Whatever the outcome of the controversy,62–64

it appears that the problems related to the first gener-ation of DES will inspire scientists to develop newtechnologies. This will necessitate close interdisci-plinary efforts among polymer and surface scientists,medical professionals, and clinicians.

A personal note from the corresponding author:most likely all polymers eventually suffer degradationin the body, and therefore the term ‘biodegradable’polymer appears to be an oxymoron. The differenceis only in the rate of degradation—one polymer maydegrade in vivo in a day, while another in 10 years.The real question is what the degradation productsare and how the body can deal with them. Therefore‘biodegradable stents’ may not be magic bullets either.

This paper will discuss the hypothesis thatthe synergistic combination of ElectroNanospraycoating technology65 and a new generation of SIBS-type polymers28,37,40 could open new avenues intocontrolled drug release in general and improved DEStechnologies in particular. We will present data of invitro drug release from the new generation of SIBScopolymers electronanosprayed with the model drugdexamethasone (DXM).

RESULTS AND DISCUSSION

New polymers for stent coatingWith the development of various controlled/livingpolymerization techniques, we are in the positionto synthesize a wide variety of architectures, e.g.,stars, brush-like chains, centipedes, dendritic (hyper-branched and arborescent) structures, self-assemblingblock copolymers, and supramolecular structures.Figure 2 compares the architecture of linear tri-blocks and dendritic (arborescent) blocks (DIBs forshort).37,39,40 Structurally, all these constructs com-prise a rubbery (soft) inner segment (core) bound totwo or more glassy (hard) outer segments (corona).The spatial arrangement of the rubbery/glassy moieties(i.e., linear, star, dendritic), the molecular parametersof the segments (i.e., molecular weight, Tg, relativeamounts of rubbery/glassy components, degree of seg-mental incompatibility), and the micro-morphologyof the constructs control the ultimate TPE propertiesand processibility. Macroscopically, these materialsare transparent rubbers. For our studies, we selectedto use three different DIBS: TPE1, TPE4, and TPE5,which differed in molecular weight, PS content, and



SIBS

D_SIBS all architectures

FIGURE 2 | Polyisobutylene (PIB)-based Thermoplastic elastomers(TPEs); architecture and macroscopic appearance, where = PIB and=glassy segments.

TABLE 2 Industrial Stent Coating Technologies

Method Comments

Atomization Single layer; large particle size

Dipping Inside coverage may be difficult

Ultrasound Single layer; large particle size

Inkjet printinga Difficult to get complete coverage

Gas-Phase Depositiona Not suitable for biodegradablepolymers

aSpecific applications.

the average number of PS blocks (see Table 3). Theaverage number of PS blocks at the end of each branchof the PIB was 3 and 4, but the high molecular weightfractions had up to 15–20 end blocks. These materialscan be synthesized very reproducibly and were foundto be as biocompatible as SIBS (to be published).

ElectroNanosprayCommonly used industrial coating methods suchas ion beam deposition, chemical vapor deposition,plasma vacuum technology, etc. are not compatiblewith the coating of DESs. Table 2 lists industrialtechnologies currently used for stent coating.

Electrohydrodynamic atomization, commonlycalled ‘electrospray’, has been used in traditionalapplications such as surface coating, agricultural treat-ments, emulsion or supermicron aerosol production,fuel spraying, micro-encapsulation, ink-jet printers,and colloid micro-thrusters. However, in this appli-cation we will be referring to a particular mode ofelectrospray operating in the ‘cone jet’ mode. In thismode it can be used to produce airborne nanoparti-cles from a solution or colloidal suspension of desired

drug loaded nanoparticles

target to be coated

solventevaporation

+

–

FIGURE 3 | Schematic of the ElectroNanospray process.

solute materials, typically in a size range of 2–100 nm,hence the term ‘ElectroNanospray’.65 In its simplestconfiguration, a syringe pump is used to deliver asolution or suspension into a capillary tube. The liq-uid exiting through the capillary tube is exposed to ahigh electric field established between the tip of thecapillary, to which a high voltage is applied, and atarget that is grounded or oppositely charged. Thenonuniform electric field causes the liquid meniscus toassume a conical shape (see Figure 3) established bythe balance between the surface tension force and theelectrical force on the cone. The liquid is dispensedthrough the cone tip in the form of a liquid jet ofnanometer diameter. The instability of the liquid jetcauses it to fragment into nanoparticles, each carryinga very high charge level—on the order of 80–90% ofthe Rayleigh limit. Since the particles are positivelycharged, they repel each other in the gas phase allow-ing solidification as discrete nanometer-sized objects.The key variables that govern particle size when theelectrospray is operated in the cone jet mode are theflow rate and the conductivity of the solution. Otherfactors, such as the diameter of the feed capillary, vis-cosity of the fluid, and volatility of the carrier solvent,also affect particle size. A unique configuration of thissystem is a spray nozzle comprised of coaxial cap-illaries. This configuration produces highly uniformparticles and provides significant process flexibility.The spray process can accommodate a broad range



TPE 4

TPE 1

TPE 5

FIGURE 4 | Scanning electron microscope images of continuous(5000 × magnification) and particulate (20,000 × magnification) filmssprayed onto SS plates.

of chemical and biological agents as well as multipleand potentially incompatible solvents. The ability tomerge streams at the spray tip enables particle engi-neering: for example, to give coated drug particles withcore–shell architecture. Spraying conditions have beendeveloped with more than 60 different solvents andseveral different model pharmaceutical compoundsand biomedically relevant polymer systems. Particlescan be delivered into liquid media or deposited ontosolid surfaces to produce nanocomposite films. Whenthe spray nozzle and cone jet are positioned near agrounded or oppositely charged target, the particlescan be collected in a dry, or nearly dry, or viscous liq-uid. This results in a variety of reproducible surfacesand drug-release profiles.

Figure 4 shows the scanning electron microscope(SEM) images of a smooth (continuous) and partic-ulate films with DXM sprayed onto SS plates. Thesmooth film of TPE4 shows ‘islands’ of DXM par-ticles on the surface, similar to the PTx particlesreportedly seen in the Taxus stent coating.45 The con-tinuous films sprayed with TPE1 and TPE5 seem tohave fully encapsulated/coated particles and no DXMexposed on the surface. The particulate films also seemto have encapsulated DXM, and the size of the fea-tures increases in the order of TPE4 < TPE1 < TPE5.

0102030405060708090

100

0 7 14 21 28

Days

DX

M %

C

umul

ativ

e re

leas

eD

XM

%

Cum

ulat

ive

rele

ase

DX

M %

C

umul

ativ

e re

leas

e

0102030405060708090

100

0 7 14 21 28

Days

010203040506070

8090

100

0 7 14 21 28

Days

(a)

(b)

(c)

FIGURE 5 | DXM release from TPE4, TPE1 and TPE5.• smooth film;o particulate film.

These plates were used to obtain the release profilesshown in Figure 5.

Drug releaseThe smooth film of TPE4 showed a burst releaseof 20.3% in 6 h of the DXM loaded into the film,followed by a very slow release reaching 26.7% by day28 (Figure 5(a)). The particulate film of TPE4 showed3.3% burst release in 6 h, followed by continuousrelease reaching 23.2% by day 28. In the case ofTPE1, both films showed ∼3% burst release in 6 h,followed by a slower release reaching 20% by day 28(Figure 5(b)).

In case of TPE5, the continuous film showed lessburst release (2.6%) than the particulate film (6.3%).



Both films displayed gradual release, but the rate wasmuch slower for the continuous film. The cumulativerelease was ∼14% for the smooth film and 25% forthe particulate film in 28 days, see Figure 5(c). Table 4summarizes the drug release data.

Neither the burst nor the cumulative releasefrom either film correlated with the PS content ofthe blocks (Table 4). In spite of the nearly 10 wt%higher PS content of TPE4 than TPE1, the formerhad a higher cumulative release than the latter, incontrast to that reported for the Taxus stent where thedrug was shown to preferentially segregate in the PSphases where it remained trapped.45 However, boththe burst and cumulative release from the continuousfilms were inversely correlated with the Mn of thePIB inner core (Table 4). It can be theorized that moreDXM is being fully encapsulated by the materials withhigher molecular weight PIB. It has been demonstrated

by X-ray photoelectron spectroscopy analysis thatthe surface of PIB-based styrenic block copolymersis covered with a layer of pure PIB, on accountof its lower surface energy compared to PS.36 PIBhas very low permeability, so diffusion of the DXMfrom the matrix through the PIB layer is expected tobe slow. With increasing PIB molecular weight, thethickness of the outer PIB layer might increase, orhigher extensibility during electrospraying may leadto better encapsulation.

The high initial burst release in Taxus wasattributed to the drug particles exposed on thesurface.45 We have investigated this aspect using insitu confocal Raman spectroscopy. Figure 6 shows theRaman spectra of DXM and TPE4.

The carbonyl resonance of DMX at ∼1660 cm−1

and the alkyl group resonances (in both the PIB and PS,and-CH3 in the PIB) of the polymer at ∼2920 cm−1

TABLE 3 Properties of the D SIBS Used

ID Block Mn (kg/mol) Mw/Mn PS (wt%) PIB Mn (kg/mol) Avg. # PS blocks

TPE4 70 4.5 32.8 47 4.1

TPE1 110 2.4 23.1 85 3.2

TPE5 220 1.8 29.4 154 3.2

D SIBS, SIBS with a dendritic (branched) polyisobutylene core and polystyrene end blocks; Mw/Mn, Molecularweight distribution; Mn, Number average molecular weight, Da or g/mol.

TABLE 4 DXM Release from D SIBS

ID Block Mn (kg/mol) PIB Mn (kg/mol) PS wt% % Release

Smooth Particulate

Burst Total Burst Total

TPE4 70 47 32.8 20.3 26.7 3.3 23.2

TPE1 110 85 23.1 3.2 20.2 3.1 19.7

TPE5 220 154 29.4 2.6 14.0 6.3 26.7

D SIBS, SIBS with a dendritic (branched) polyisobutylene core and polystyrene end blocks; Mn, Numberaverage molecular weight, Da or g/mol.

3500300025002000150010005000

400

800

1200

1600

2000

2400

rel. 1/cm

CC

D c

ts

3500300025002000150010005000

340

360

380

rel. 1/cm

CC

D c

ts

FIGURE 6 | Raman spectra of DXM powder and a TPE4 film.



FIGURE 7 | Raman images (z and x–yscans) of TPE4/DXM smooth films.

Before incubation After 10 hrs incubation in water

DXMPolymerDXMPolymer

FIGURE 8 | Optical images of TPE4/DMX continuousfilms. Before incubation After 10 hrs incubation in water

Openmatrix

SmoothFilm

StainlessSteelPlate

FIGURE 9 | Hybrid coating.

were used to monitor changes due to incubation inpure water. Figures 7 and 8 summarize the findings.

In Figure 7, the left image is the cross-sectionscan of the film (scan size 30 × 6 µm2). The top darkregion is air, and the bottom dark region is the SSsubstrate. The middle bright region is the coatingfilm (∼4µm). Lateral scans were performed at threedifferent levels (three black lines corresponding tolateral planes close to the surface, in the middle of thefilm and close to the substrate). The two columns ofthe images on the right show the polymer and drugcontrast (brighter meaning higher concentration) fromthe three layers (scan size 30 × 30 µm2). The Raman

Continuous Particulate

FIGURE 10 | Stents coated with TPE4/DXM.

images in Figure 7 reveal that DXM particles (2–6 µm)are distributed evenly within the polymer film. After10 h incubation in pure water, holes appeared inthe polymer, from where the drug particles wereremoved. The optical images (Figure 8) also showthe presence of holes on the surface of the polymerfilm after incubation. In contrast, the surface of theparticulate TPE4/DXM coating shown in Figure 4appeared unchanged and did not become porous.These results support the conclusion that burst releasecomes from the drug particles exposed on the surface.Figure 9 shows a hybrid film of TPE4/DXM, with25% particulate film on top of the smooth coating.



Burst release was reduced to 10% from 20% mea-sured with the smooth coating, while the cumulativerelease decreased to 22.2% (only a 16% relative drop,see Table 4).

Figure 10 shows examples of coated stents.Coatings were remarkably uniform on both inter-nal and external surfaces with no visible webbing.DXM release profiles from coated stents were verysimilar to those from SS plates (Figure 5). Followingincubation in buffered saline for 28 h, the continuouscoating became porous, whereas the appearance ofthe particulate coating did not change.

The results presented here demonstrate that drugrelease profiles can be influenced by both the molecularweight of the dendritic PIB block of the polymer sam-ples and spraying conditions of the polymer–drugmixture. Future work will include precision synthe-sis of new biocompatible polymers and fine controlof drug release profiles via both bulk and surfacematerial properties. Polyisobutylene-based polymersas a platform will remain strong because of their inert-ness in the body. Search for more effective drugsor drugs with different modus operandi will alsocontinue.

ACKNOWLEDGEMENTS

This material is based upon work supported by the National Science Foundation under DMR-0509687 andSBIR Phase II: 0620563 and the National Institutes of Health SBIR Phase I: 1R43HL079690-01A1. The authorswould like to acknowledge the contribution of Reza Lalani to this work.

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