Approaches for prevention of restenosis

Approaches for Prevention of Restenosis

Amir Kraitzer,1 Yoel Kloog,2 Meital Zilberman1

1 Department of Biomedical Engineering, Faculty of Engineering, Tel-Aviv University, Tel-Aviv 69978, Israel

2 Department of Neurobiochemistry, Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel

Received 9 March 2007; revised 14 June 2007; accepted 26 July 2007Published online 20 December 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jbm.b.30974

Abstract: Coronary artery disease is characterized by a narrowing (stenosis) of the arteries that

supply blood to the tissue of the heart. Continued restriction of blood flow manifests itself as

angina and ultimately myocardial infarction (heart attack) for the patient. Heart bypass was once

the only treatment for this condition, but over the years percutaneous coronary intervention (PCI)

has become an increasingly attractive alternative to medical therapy and surgical revasculariza-

tion for the treatment of coronary artery disease. A vascular stent is a medical device designed to

serve as a temporary or permanent internal scaffold, to maintain or increase the lumen of a blood

vessel. Metallic coronary stents were first introduced to prevent arterial dissections and to

eliminate vessel recoil and intimal hyperplasia associated with PCI. Further advancement in the

treatment of coronary artery disease is the development of drug-eluting stents that dramatically

reduce the incidence of in-stent restenosis to less than 5%. Local drug delivery offers the

advantages of allowing a relatively high local concentration of drug at the treatment site while

minimizing systemic toxic effect. This review describes approaches for prevention of restenosis. It

focuses on drugs for prevention of restenosis, bare metal stents, and drug-eluting stents. It also

describes recent advances in bioresorbable stents. One of the chapters is dedicated to our novel

composite bioresorbable drug-eluting fibers, designed to be used as basic elements in drug-eluting

stents. ' 2007 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 85B: 583–603, 2008

Keywords: restenosis; stent; drug delivery; bioresorbable polymers; paclitaxel

INTRODUCTION: RESTENOSIS

Restenosis is the renarrowing of a blood vessel causing a

reduction of the luminal size, consequently restricting blood

flow after intravascular procedure. Restenosis is mainly char-

acterized by intimal hyperplasia and vessel remodeling.1 The

intima is the innermost coat of a blood vessel consisting usu-

ally of an endothelial layer backed by connective tissue and

elastic tissue. The hyperplasia is an abnormal or unusual

increase in the cells composing the intima.

Restenosis is a combined result of a biological response

and mechanical reaction to percutaneous coronary interven-

tion (PCI). At the early phase of restenosis, elastic recoil

takes place due to the mechanical response of the elastic

fibers of vascular wall to overstretching by balloon cathe-

ter. The recoil occurs within minutes following balloon

deflation; the recoil may cause up to a 40% lumen loss.2

However, this phase may be totally eliminated by introduc-

ing a stent. The biological response to the procedure is

more complicated to eliminate, and it may consist of the

following four phases, as described in Figure 12–6:

Platelet Aggregation: Immediately after stent placement,

endothelial denudation and medial dissection results due to

the mechanical injury of PCI [Figure 1(a)]. The injury

causes platelets aggregation and activation, producing a

countless number of various cell-signaling factors initiating

an inflammatory cascade and releasing adhesion molecules

that cause a thrombus formation.2,3

Inflammatory Phase: Over the next few days to weeks, avariety of white cells will gather at the injury site, secretetheir own factors, and exert their own influence on the heal-ing tissue. The inflammatory response can persist for months[Figure 1(b)].

Proliferation Phase: The inflammatory phase stimulates

smooth muscle cells (SMCs) migration and proliferation, in

an attempt to repair the wound. This process is enabled by

leukocytes cells releasing and activating tissue-digesting

enzymes, forming a path for the SMCs to move. SMCs

migrate to the thrombus that acts as a scaffold, providing

the substrate for neointimal formation. The migrating

SMCs form an overgrown, obstructing scar [Figure 1(c)].

Late Remodeling Phase: The final mechanism of reste-

nosis response is the late remodeling of the vessel. This

produces a neointimal layer, which is mainly formed by

proliferating SMC and extracellular matrix (ECM). Inflam-

matory mediators and cellular elements contribute to trigger

Correspondence to: M. Zilberman (e-mail: [email protected])

� 2007 Wiley Periodicals, Inc.

583

a complex array of events that modulates matrix production

and cellular proliferation. As the amount of scar develops

[Figure 1(d)], blood flow is gradually reduced. Addition-

ally, there is evidential reendothelialization of partial seg-

ments of the injured vessel surface.

A more detailed description of restenosis pathophysio-

logy as well as restenosis-related terminology definition

can be found elsewhere.5 The timeframe of each phase is

described in Figure 2.

In-Stent Restenosis

Stenting, introduced in 1993, was one of the advances that

significantly reduced the procedural complication rates of

balloon angioplasty. Stents mitigate the complications of

acute and subacute vessel closure, intimal dissection, elastic

recoil of the vessel wall, and reduce angioplasty-related

restenosis rates.7 In most of the centers in the United States

and Europe, stents are being used in over 70% of PCI.4

However, despite their advantages, early enthusiasm for

stents was somewhat diminished by the complications of

stent thrombosis and in-stent restenosis.7 Stent placement

has failed to achieve acceptable restenosis rates, especially

in challenging patient groups.6 Of �1 million patients who

underwent PCI worldwide in 1999, in-stent restenosis has

developed in �250,000.6 The incidence of ISR may vary

from 8% to as high as 80% at 6 months, according to both

anatomic and clinical risk factors.6,8

In-stent restenosis is most commonly defined as stenosis

or lumen loss of over 50% caused following stent place-

ment.6,9 The rate of lumen loss is the same in value to that

of restenosis due to PCI.9 The problem of in-stent restenosis

has been more difficult to overcome and made PCI a less

definitive treatment.7 The process of in-stent restenosis peaks

at about the third month and reaches a plateau between the

third and sixth months after procedure.10 Angiographic fol-

low-up studies have shown no further reduction in minimal

lumen diameter between 6 months and 1 year.11

Studies12,13 using intravascular ultrasound (IVUS) have

demonstrated that stents virtually eliminate vessel recoil

and negative remodeling. Moreover, according to these

studies, in-stent restenosis is mainly caused by neointimal

proliferation. In addition, the stent has a chronic indwelling

impact on the vascular biological response causing an

inflammatory response thus incurring a greater neointimal

growth.5 The neointimal hyperplasia is more pronounced

and exaggerated with stent placement than with balloon

angioplasty.9,14 Several studies evaluated the effect of

patients, lesions, and procedure-related predictors of angi-

ography after stent placement on in-stent restenosis. In

these studies, diabetes mellitus, lesion length, lesion plaque

burden, number of stents, stent design, acute lumen gain,

and the final obtained lumen diameter were found to have

a significant impact on in-stent restenosis rates.15

STRATEGIES FOR PREVENTION OF RESTENOSIS

A considerable amount of research was invested in the pre-

vention of in-stent restenosis due to the substantial rate of the

phenomenon. This interest prompted various strategies that

Figure 1. A schematic representation of the restenosis process. (a) Platelet Aggregation: Immediate

result of stent placement with endothelial denudation and platelet/fibrinogen (not shown) deposi-

tion. (b) Inflammatory Phase: A variety of white cells will gather at the injury site. (c) ProliferationPhase: Smooth muscle cells migrate and proliferate, creating the neointima in an attempt to repair

the wound. (d) Late Remodeling Phase: The neointima is changed from predominantly cellular to a

less cellular and more extracellular matrix-rich plaque. [Color figure can be viewed in the online

issue, which is available at www.interscience.wiley.com.]

584 KRAITZER, KLOOG, AND ZILBERMAN

Journal of Biomedical Materials Research Part B: Applied Biomaterials

have been investigated and employed at the treatment of

restenosis. The stent strategy reduced restenosis caused by

balloon angioplasty from �50% to �15%.2 Early attempts at

the prevention of restenosis focused on the administration of

antithrombotic agents, but there was limited success in trials.8

With technologic advances and greater understanding of vas-

cular pathobiology, novel therapeutic strategies, such as local

delivery of ionizing radiation, pharmacological agents, and

gene therapy, have been deployed to prevent coronary reste-

nosis.8,9 It became clear that although coronary stenting com-

bined with antithrombotic therapies had essentially eli-

minated the problem of elastic recoil, thrombus formation,

and vessel remodeling, in-stent restenosis remained a major

problem.2 Today, it is obvious that vascular SMC (VSMC)

growth and migration trigger intimal hyperplasia, which is

the main cause of in-stent restenosis.9

The following paragraphs briefly describe the strategies

for reducing restenosis. These strategies are presented in a

chronologic order, while each strategy’s failure to prevent re-

stenosis has prompted the development of the next strategy.

Stents

Stents are inserted into the lumen of a vessel to keep a for-

merly blocked passageway open. The stent provides a ra-

dial support to the vascular wall while healing takes place

after an invasive procedure. Stents are usually made of

metal or polymer filamentous tube. Their diameter may

vary from 2.5 to 3.5 mm, and their length is typically in

the range of 15–18 mm.15,16 In 1993, the FDA approved

the balloon-expandable stent to treat acute or threatened

closure. One year later, two randomized trials showed an

impressive reduction of restenosis in patients treated with

stents when compared to patients treated with balloon

angioplasty.17,18 The acute and long-term benefits of stents

over balloon angioplasty have been demonstrated in several

studies.19 Today, stents are used in over 70% of the cases

of coronary angioplasty.14,19 Vascular stents will be broadly

discussed in this review.

Mechanical Strategy

Several mechanical techniques were used, including the use

of high-pressure stent deployment20 to achieve larger final

luminal diameter, direct stenting without predilatation,21

and placing an additional stent (stent sandwich).22 These

techniques failed to present benefit over stenting alone.

Another approach to prevent in-stent restenosis was to

mechanically reduce plaque volume using an Atherectomy

procedure. This catheter-based procedure was originally

developed as a potential replacement for balloon angio-

Figure 2. Four phases of restenosis that occur poststent implantation: (a) Immediately after stent

placement, the injury causes platelets aggregation and activation; (b) A variety of white cells gatherat the injury site over the next few days to weeks; (c) SMCs migrate and proliferate to form the

neointima and this process decays after a month from the procedure; (d) Late remodeling begins at

about the third week.3 [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

585APPROACHES FOR PREVENTION OF RESTENOSIS


plasty, but it was used in conjunction to stenting or balloon

angioplasty eventually. The most studied forms of atherec-

tomy are rotational atherectomy and directional coronary

atherectomy.

Two randomized trials compared angioplasty to rota-

tional atherectomy plus balloon angioplasty in the treatment

of in-stent restenosis. In the multicenter European ARTIST

trial,23 angioplasty alone produced a significantly better

long-term outcome than atherectomy followed by adjunc-

tive low-pressure angioplasty. In the smaller single-center

US randomized ROSTER24 trial, rotational atherectomy

resulted in less residual intimal hyperplasia, lower repeat

stent use, decreased target lesion revasculazation, and simi-

lar complications rate compared to angioplasty alone.

The CAVEAT25 randomized trial compared directional

coronary atherectomy with angioplasty and demonstrated a

small reduction in angiographic restenosis in the atherec-

tomy group. However, atherectomy led to a higher rate of

early complications, increased cost, and no apparent clini-

cal benefit after 6 months of follow-up. The BOAT26 trial

used an optimal directional coronary atherectomy method

that resulted in significantly lower restenosis rate in the

atherectomy group (32 vs. 40% in angioplasty) with no

increase in major complications after 6 months. Yet, the

trial failed to reach a statistical significance for clinical

events after 1 year.

The AMIGO27 trial was designed to compare the angio-

graphic restenosis rates between stenting with or without

prior directional coronary atherectomy. The study failed to

demonstrate the superiority of the combined approach com-

pared to stenting alone in regard to restenosis rate. Con-

versely, a recently published meta-analysis28 reveals that

directional coronary atherectomy before stenting is advanta-

geous over stenting alone with regard to angiographic

results. Nonetheless, the study demonstrated higher rates of

major adverse cardiac events mainly due to higher peripro-

cedural myocardial infarction.

These trials caused interventional cardiologists to ques-

tion the value of directional atherectomy. Accordingly,

atherectomy treatment shifted from routine to discretionary,

primarily for problematic lesions.29

Systemic Drugs

When stents alone failed to eliminate restenosis, systemic

drugs were administrated in conjunction.2 The majority of

the drugs used and studied were antiplatelets and were antith-

rombogenic.30 The principal systemic administrated drugs

and their effects are presented in Table I. Although there is

some evidence that controlling thrombus formation may

decrease neointimal hyperplasia, systemic administration of a

variety of agents has not had a significant impact on post-

PCI restenosis rates in clinical trials.31 Similarly, the systemic

administration of drugs that inhibit inflammatory process31

and proliferation and migration of SMC have failed on tri-

als.5,14 The lack of effect of systemically administrated

agents may be due to their potential toxicity8 and inadequate

drug concentrations at the site of stent insertion.31

Temporary Local Delivery

Trials using the concept of a temporary local delivery

administration of an antiproliferative agents, such as with

use of microperforated balloons, produced vascular damage

and were associated with fast washout and a delayed effect

of the drug.6,8,32

Radioactive Stents

The first approved form for local delivery used to prevent

in-stent restenosis was Brachytherapy. This is a form of

radiation treatment in which radioactive material is

implanted directly into the tumor-containing organ. By

using this concept, high dose of radiation is delivered to a

specific organ while limiting the exposure to the adjacent

organs. The energy emitted from an active isotope is

believed to block the cell division by causing a double-

stranded break in the cell’s DNA, therefore inhibiting the

hyperplasia process.33

The first randomized clinical trials to show significant

reduction of restenosis, the SCRIPPS trial and the

GAMMA I trial, used a c-emitter, 192Ir, as the radioisotope.

The 3-year angiographic follow-up of the SCRIPPS trial

showed that the restenosis rate reduction observed during

TABLE I. Summary of Relevant Systemic Administrated Drugs

Name Description

Aspirin Aspirin inhibits platelet activation and

reduces atherothrombotic complications

in patients at risk of myocardial infarction

and stroke.6

Clopidogrel Clopidogrel is an inhibitor of platelet

aggregation.6

Ticlopidin Ticlopidine is a platelet-inhibiting drug.6

Troglitazone Successfully inhibited neointima

proliferation in human study.9

Tanilast Reduced in-stent restenosis in the porcine

model, failed in human studies.9

Cilostazol Cilostazol is an antiplatelet drug that has

been used after implantation of

coronary stents. It was found that a

combination of Aspirin and Cilostazol

might be an effective regimen for

prevention of not only stent thrombosis

but also Restenosis. Results are inconsistent.9

Abciximab The drug inhibits platelet aggregation.

It prevents fibrinogen from binding

to activated platelets. It is given as

an intravenous bolus followed by

infusion over 12 h followed by

angioplasty. It can cause major

bleeding complications.2



the first year persisted in the long-term follow-up in the

treated group (33 vs. 66%, p 5 0.05); however, delayed

restenosis was suspected.34 More recent studies were per-

formed with b-emitters, which are considered to be more

safety than c-emitters.9 The START trial used a 90Sr/90Y

b-emitters. The target vessel revascularization rate at 9-

month follow-up was reduced from 24% in the placebo

patients to 16% in the treated patients.35

The radioactive approach has shown its capability of

effectively suppressing tissue growth within the stent, but

in long-term follow-ups, edge restenosis and late thrombo-

sis were evident.36 In addition, it has been postulated that

the combination of vessel wall injury with suboptimal radi-

ation dosage may promote excessive intimal hyperplasia.9

Passive Coating

Evidence shows that restenosis following stent placement

entails a series of interrelated host responses: thrombosis,

inflammation, and SMC proliferation.37 The adhesion of

cells to surfaces is believed to be mediated in the

first instance by the adsorption of a protein layer onto the

surface, altering their conformation and encourage further

adhesion of blood components.3 It is known that the throm-

bogenic potential of bare metal stent prompting protein to

rapidly cover the high energy surface eventually results in

restenosis.3 Therefore, less thrombogenic and inflammatory

stent coatings have been developed for reducing neointimal

hyperplasia. These passivation methods alter selected pro-

perties of the stent surface without delivery of drugs or

other agents. These techniques are expected to remove sur-

face initiators of the host response, although less intense

cellular responses to the surface may continue. The coating

materials, both organic and inorganic compounds, have

generally caused slight decreases in thrombosis without

substantially decreasing in-stent restenosis.37 Comparing to

the systemic drug approach, the advantage of passive coat-

ing was questionable.6 Moreover, results of animal trials

TABLE II. Inorganic and Organic Passive Stent Coatings

Name Description

Inorganic Elements

Titanium nitrite/oxide Reduce adherent thrombus in a short-term porcine study reduce neointimal

proliferation.37

Silicon carbide Patients implanted with silicon carbide coating showed less acute stent thrombosis, but

it did not significantly inhibit neointimal hyperplasia.4,6,37

Hydrogenated diamond-like carbon Reduce adherent thrombus in a short-term porcine study.37

Gold Prevents corrosion,6 chemically inert, and noninflammatory.1 Considered to be

biocompatible; however, trials presented either Restenosis equivalency with

uncoated stents or increased neointimal hyperplasia compared to uncoated

stents.4,15,32

Carbon Reduces thrombosis. Trials suggest that carbon-coated stents are well tolerated in vivoand possibly inhibit neointimal hyperplasia, especially in high-risk patients.31

Chromium, Titanium, Platinum Prevents corrosion.6

Aluminum oxide One Trail38 shows that nanoporous aluminum oxide coronary stent coating has

favorable tissue compatibility.

Organic Elements

Phosphorylcholine (PC) PC had the most attention as a stent passivation method. It mimics phosphatidyl

choline, a major component of a red cell’s outer membrane layer, and thus inhibits

the activation of blood elements.37 BiodivYisio PC-coated stent is biocompatible

and does not elicit inflammatory reaction, offering[90% endothelial recovery.1,3,31

Hyaluronic acid (HA) HA is an ever-present, nonsulfated glycosaminoglycan component of the extracellular

matrix. Both HA and immobilized sulfated HA-coated stents have been shown to

inhibit platelet aggregation and platelet adhesion in baboon models.39

Biostable polymers Expanded polytetrafluoroethylene (ePTFE), polyester (Dacron), a blend of

methylmethcrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA), fluorine-

acryl-styrene-urethane-silicone (FASUS) copolymer, parylene, and amphiphilic

polyurethane. These materials present variable success rates in reducing Restenosis

rates.37 Several polymer coatings have shown to stimulate inflammation and increase

neointima formation. However, the long-term effect has not been studied.

Biodegradable polymer Poly-(organo)phosphazene and poly(L-lactic acid) (PLLA)-coated stents37 were

reported to be less thrombotic, but their long-term effect has not been studied. Poly-

bis-trifluorethoxy phosphazene (PTFEP)-coated stents show good biocompatibility in

porcine model up to 6 months, offering complete endothelial recovery at 5 days.40 A

porcine artery study of a newly developed poly(ester-amide) elastomers suggests

that this slow degrading material is suitable for stent-based local-delivery.41



with polymer-coated stents have been diverse, with many

of the so-called biocompatible polymer coatings (both

resorbable and nonresorbable) invoking severe inflamma-

tory reactions coupled with abnormally high neointimal

proliferation that can be directly attributable to the presence

of the coating.3,37 Table II presents the biocompatibility

properties of stents coated with various materials.

Active Stent Coating

The goal of drug-eluting stents is to place the right amount

of drug at the site of injury in the time of injury. Also, it is

difficult to achieve desired drug levels in the artery without

undesired side effects when releasing drugs with a narrow

therapeutic window.2 Two of the most important active

coating methods currently available are as follows:

� Drug-Eluting Stents: Stents coupled with local delivery

of drugs demonstrated a tremendous effect on reducing

restenosis rates. Drug-eluting stents will be further dis-

cussed in this review.

� Gene Therapy: Stents may serve as carriers for gene

therapy. Three known gene therapy approaches are as

follows: stents seeded with cells that are transfected with

the desired gene, stents loaded with recombinant adeno-

virus gene transfer vectors,6 and stents loaded with naked

DNA impregnated in various matrices.37 Gene therapy

directly released from stents in animal studies shows a

dramatic improvement in neointima proliferation.9 Yet,

human trials present unsuccessful results. Moreover,

gene therapy potential side effects are of concern.37,42

DRUGS FOR PREVENTION OF RESTENOSIS

The ideal biological agent should have potent antiprolifer-

ative effects but also to preserve vascular healing. Such a

compound should contain hydrophobic elements to ensure

high local concentrations, as well as hydrophilic proper-

ties, to allow homogeneous drug diffusion. In addition,

the drug should have a wide therapeutic to toxic ratio and

should not provoke thrombosis or inflammation.8 Other

factors such as molecular weight, charge, and degree of

protein binding may also affect drug kinetics and ulti-

mately influence the biological success.8 On the basis of

the mechanism of action of the biological compound and

its target in the restenotic process, drugs loaded in stents

may be generally classified as follows: anticoagulants,

antiplatelet drugs, antiproliferative drugs, and immunosup-

pressive drugs (Table III).1,8 To date, the immunosuppres-

sant drug rapamycin and the antiproliferation drug

paclitaxel have achieved significant efficacy in preventing

stent restenosis in clinical trials and have been approved

for clinical use as stent coating. These drugs are described

in detail in the following sections. There is a long list of

agents that have failed to prevent in-stent restenosis or

TABLE III. Classification of Drugs for Prevention of Restenosis

Type Drug Name Way of Action

Anti Coagulants Heparin Antithrombotic and possibly direct inhibition

of SMC proliferation

Hirudin Antithrombotic and potentially antiproliferative

Iloprost Prostacyclin analog that is antithrombotic

and potentially antiproliferative

Anti Platelet Sodium nitroprusside NO donor

Abciximab GP IIb/IIIa inhibitor

AZ1 GP IIb/IIIa receptor antibody

Eptifibatide GP IIb/IIIa inhibitor

L-703081 GP IIb/IIIa antagonist

Argatroban Inhibitor of thrombin-induced platelet activation

Anti-proliferation ST638 Tyrosine kinase inhibitor

Angiopeptin Inhibitor of SMC proliferation

Paclitaxel Microtubular inhibitor

Taxane (QP2) Microtubular inhibitor

Antinomycin D Inhibits RNA synthesis

Immunosuppressant Methylprednisolone Anti-inflammation

Dexamethasone Anti-inflammation

Sirolimus (Rapamycin) Immunosuppressant and antiproliferative

Everolimus Immunosuppressant and antiproliferative

ABT 578 Inhibitor of SMC proliferation

Tacrolimus (FK 506) Immunosuppressant

Mycophenolic Acid An antibiotic derived from Penicillium species

Refs. 1, 4, 8, 37, 43.



shown only limited efficacy compared to rapamycin and

paclitaxel.2

Antiproliferation Drugs

These drugs directly inhibit vessel SMC proliferation and

migration. Stents coated with such drugs proved to reduce

neointimal growth in both animal and clinical studies.

Paclitaxel is the most popular drug in this group. Other

drugs include Texane, Isotaxel 2, and Tyrphostin.

Paclitaxel. Paclitaxel is a potent inhibitor of cell prolif-

eration and therefore is known to be very effective in treat-

ment of cancer as well as neointimal hyperplasia, which is

known as the main cause of restenosis. Paclitaxel was orig-

inally isolated from a trace compound found in the bark of

the Pacific Yew (Taxus brevifolia).44 Paclitaxel’s antitumor

activity was detected in 1967 in the US National Cancer

Institute (NCI), and later it was found to be a novel, prom-

ising antineoplastic drug. It was approved by FDA for

ovarian cancer in 1992, for advanced breast cancer in

1994, and for early stage breast cancer in October 1999.

Today, it is synthetically produced as Taxol� and became a

standard medication in oncology.44,45

Paclitaxel acts to inhibit mitosis in dividing cells by

binding to microtubules and cause the formation of

extremely stable and nonfunctional microtubules. Since

microtubule disassembly is essential for the transition from

the G2 to the M phase in the mitotic cycle, stabilization

arrests mitosis and cell proliferation.44 G2-M is the transi-

tion in the cell division cycle from the state G2, where the

cell produces enough proteins to divide, to the state, mito-

sis (M), where the cell is divided into two daughter cells.

Therefore, it inhibits VSMC proliferation, migration, secre-

tion of extracellular matrix, and angiogenesis, eventually

reducing restenosis.44

Slow release of paclitaxel applied perivascularly totally

inhibits intimal hyperplasia and prevents luminal narrow-

ing following balloon angioplasty. Paclitaxel is very

potent at low concentrations and can be loaded in high

doses into polymers.6 The drug interacts with arterial tis-

sue elements as it moves under the forces of diffusion and

convection and can establish substantial partitioning and

spatial gradients across the tissue.45–47 Studies indicate

the need for a controlled drug release of paclitaxel due to

the narrow toxic-therapeutic window and high hydropho-

bic character of this compound.43 Paclitaxel is excellent

for sustained delivery from cardiovascular devices when a

prolonged deposition is necessary due to its insolubility in

water. Its hydrophobic nature minimizes loss to the blood,

but promotes tissue uptake after contact with the arterial

wall compared to hydrophilic drugs. The lipophilic nature

of paclitaxel favors partitioning into the organic phase of

the encapsulating polymer48 as well as enables it to pass

though the hydrophobic barrier of the cell membrane.48 A

significant fraction of the drug may also be retained by

membrane lipids and remain there as a depot for continu-

ous release.49 As a result, new dosage forms are studied,

such as biodegradable polymeric devices for controlled

and local drug delivery taking advantage of therapeutic ef-

ficacy enhancement of paclitaxel.50 Paclitaxel’s permea-

tion into the vessel wall is significant; it increases with

time47,51,52 and concentration32 and is accumulated at

regions of proximity to the origin of the drug.46

There are several limitations in clinical application of

paclitaxel. The first limitation is related to its limited

occurrence in nature and high production costs.44 Second,

endothelialization is delayed within 90 days after treat-

ment6; therefore, antiplatelet therapy with aspirin and ticlo-

pidine/clopidogrel is necessary.50 Third, paclitaxel is

susceptible to solvolysis of its ester linkage leading to loss

of its cytotoxic activity with maximum stability in the

range of pH 3–5 at 378C.53 Finally, paclitaxel is highly

hydrophobic (Figure 3 and Table IV), causing a limited

drug delivery; therefore, it must be delivered in conjunction

to supplementary materials (such as Cremophor for treat-

ment of cancer). This additive is believed to cause serious

side effects.50 The hydrophobic nature of paclitaxel is a

serious obstacle for in-vitro studies, since it adsorbs to

glass and plastic vials.

Paclitaxel release mechanism using several biomaterials

was studied extensively. The conclusions can be summar-

ized as follows50:

� When surface-eroding polymers were used, erosion was

found to be the main mechanism by which paclitaxel

was released. However, diffusion is the main mechanism

of release through slow bulk degrading polymers.

� The release profile is mainly affected by the molecular

weight and relative hydrophilicity of the polymers. SinceFigure 3. Paclitaxel’s chemical structure.

TABLE IV. Paclitaxel’s Properties

Water Solubility 5 mg/mL40

Solvents DMSO, methanol, ethanol, acetonitrile,

methylene chloride

Melting temperature 216–2178CMolecular weight 853.93 g/mol

Molecular formula C47H51NO14



paclitaxel is extremely hydrophobic, hydrophilic bioma-

terials are required to shorten the release rate. Moreover,

hydrophobic polymers will sustain paclitaxel’s diffusion

and therefore will decrease the release rate.

� The presence of additives with appropriate hydrophilic–

lipophilic balance (HLB) can help in achieving the

desired paclitaxel release rate.

Taxane (QP2 or 7-Hexanoyltaxol). The structure of this

drug is similar to paclitaxel.48 Results of the SCORE trail

using stent coated with this drug were discouraging because

of an unacceptable rate of subacute thrombosis and a high

rate of acute myocardial infarction.54

Isotaxel 2. This compound is a synthesized water-solu-

ble paclitaxel prodrug.55 This prodrug has no additional

functional auxiliaries released during conversion to pacli-

taxel. This is a great advantage in toxicity and medical eco-

nomics, since the potential side effects caused by reported

auxiliaries and the use of detergent for solubilization can

be omitted.

Tyrphostin (AGL-2043). Tyrphostin is a potent, syn-

thetic, inhibitor of several intracellular protein tyronsine

kinases. A series of experiments show selective inhibition

of SMC proliferation in culture and attenuation of the out-

growth of SCMs from porcine and human arterial explant

tissue.56 This drug was found to reduce SMC proliferation

and migration in vitro and in balloon-injured porcine femo-

ral arteries, and reduce restenosis in stented porcine coro-

naries administrated within biodegradable particles. Also,

stents coated with PLGA-encapsulated Tyrphostin reduced

neointimal hyperplasia in porcine coronary arteries by 50%

after 28 days.56

Salirasib (S-trans, trans-farnesylthiosalicylic Acid,

FTS). Salirasib (FTS) is a potent Ras inhibitor acting selec-

tively on the active GTP-bound form of Ras. Salirasib is a

nontoxic Ras inhibitor with no adverse side effects in ani-

mal models.57,58 Ras proteins are critically involved in the

control of cell proliferation and migration through the acti-

vation of signaling pathways including the Raf/MEK/ERK

MAP kinase and the PI3K/Akt/mTOR cascades.57,58 There-

fore, Ras inhibitors could be expected to ameliorate reste-

nosis to the extent of targeting mTOR by rapamycine and

possible even more. Salirasib (FTS) was found to inhibit

intimal thickening in rat carotid artery injury model.59 FTS

inhibited VSMC and splenocytes proliferation, reduced the

levels of active Ras and active ERK in balloon injured rat

arteries, and reduced the number of NFkB- and iNOS-posi-

tive cells in sections of the injured arteries.59 Salirasib

went through phase I clinical trials with no reported

adverse side effects. The hydrophobic nature of FTS, which

also contains a hydrophilic carboxyl group, may suggest

that it could be an appropriate drug for stents.

Immunosuppressive and Anti-Inflammatory Drugs

The immunosuppressive agents attack neointimal growth

by possessing both anti-inflammatory effects as well as

immunosupresssive effects. The inflammatory cells seem to

be an optimal target in the fight against restenosis, due to

their role in restenosis.8 Anti-inflammation agents have

long been shown to reduce the influx of mononuclear cells,

to inhibit monocyte and macrophage function, and to influ-

ence SMC proliferation. However, clinical trials have failed

to demonstrate any benefit of systemic steroid therapy.8

Sirolimus. This drug was originally known as Rapamy-

cin, which was discovered in 1977, and found to have

potent cell cycle inhibitory activity, which inhibits VSMC

proliferation.7 It was approved by the FDA in 1999 as

Rapamune (Wyeth, NJ) as immunosuppressive drug for

transplant rejection.8 The properties are presented in Table

V. From a therapeutic point of view, Sirolimus is a natu-

ral macrocyclic, lipophilic lactone with immunosuppres-

sive antibiotic activity.6 Sirolimus blocks cell cycle

progression at the G1-S transition and inhibits VSMC pro-

liferation.62 G1-S is the transition in the cell division

cycle between the phase G1, where the cell increase with

size producing proteins and RNA, to the phase S in which

the DNA replication occurs. Studies show that Sirolimus

is capable of abolishing T-cell proliferation as well as

SMC proliferation and migration, which are the main

sources of restenosis.6 Trials show that the drug should be

present in the vessel wall for at least the first 7–14 days

to be efficacious.6

Everolimus (40-O-(2-Hydroxyethyl)-Rapamycin). This

drug is an immunosuppressive drug that has been shown to

inhibit cell proliferation. Animal studies have shown a

potent antirestenotic effect of Everolimus given orally or

via a drug-eluting stent. However, its immunosuppressive

activity is 2- to 3-fold lower than Sirolimus in vitro.8 The

S-Stent (Biosensor) has been impregnated with a blend of

Everolimus and slowly biodegradable Hydroxyacid Polylac-

tic acid polymer. Low (180 mg/stent) and high-dose (360

mg/stent) Everolimus-eluting stents were implanted in pig

coronary arteries. Percent area stenosis by histomorphomet-

ric analysis was 62% in bare stents, 70% in polymer-coated

stents, 39% in low-dose Everolimus-eluting S-stents, and

38% in high-dose Everolimus-eluting S-stents.8,39

ABT-578 (Methyl Rapamycin). This drug is a synthetic

analog of Sirolimus. Preliminary animal studies have

shown significant inhibition of intimal proliferation

after stenting.8 The clinical ENDEAVOR I trail, N 5 100,

using a cobalt alloy stent platform presented in-stent late

lumen loss of 0.33 mm at 4 months. One-year follow-up

results, however, showed an increase in in-stent late lumen

loss to 0.58 mm.7 The ENDEAVOR II Pivotal Clinical

Trial completed enrollment of 1200 patients and presented

impressive results. The Endeavor stent is produced by



TABLE

V.ClinicalTrials

UsingDrug-E

lutingStents

Stent/Platform

Coating

Manufacturer

Drug

Clinical

Trials

Follow-up

BinaryRestenosisRate

Measuredat

Follow-up

(MACEarenotincluded)

Cypher

TM/

BX

Velocity

6,7,8,9

Nondegradable

Poly(n-butyl

methacrylate/Poly

(ethylenevinylacetate)

[PEVA/PBMA]

(50/50)coated

stainless

steelstent

Cordis,

Johnson&

Johnson

Sirolimus

(Rapam

ycin)

FIM

(N5

45)

24m

0%

(SRDES),0%

(FRDES)

RAVEL(N

5238)

6m

0%

(DES)vs.26.6%

(BS)

SIRIU

S(N

5l,100)

9m

2%

(DES)vs.31.1%

(BS)

E-SIRIU

S(N

5352)

9m

5.9%

(DES)vs.42.3%

(BS)

QuaD

DS-Q

P26,43,60

Nonbiodegradable

polyacrylate

sleeves

Quanam

7-hexanoytaxol

(QP2)

SCORE(N

5266)

6m

Trailhaltedprematurely

dueto

highincidence

of

stentthrombosis6.4%

(DES)vs.

36.9%

(BS)at

6months

TaxusT

M/

NIRxConform

er6,43,60

Poly(Lactide-co-S

-

caprolactone)

BostonScientific

Paclitaxel

TAXUSI(N

561)

6m

0%

(DES)vs.10.3%

(BS)

TAXUSII(N

5536)

6m

2.3%

(DES)vs.17.9%

(BS)in

(SR)

4.7%

(DES)vs.20.2

(BS)in

(MR)

TAXUSTM/

Express

2

BostonScientific7

,60

BostonScientific

Paclitaxel

TAXUSIII(N

528)

6m

16%

(DES)16

TAXUSIV

(N5

1,326)

9m

5.5%

(DES)vs.24.4%

(BS)

TAXUSV

(N5

1,172)

12m

OverallTLR:11.2%

(DES)vs.19.0

(BS)

TAXUSVI(N

5448)

9m

OverallTLR:6.8%

(DES)vs.18.9%

(BS)

Endeavor/

Driver

Medtronic

Phosphorylcholine

Medtronic

Inc

ABT-578

ENDEAVORI(N

5100)

48m

TLR:3.1%

(DES)

ENDEAVORII

(N5

1,197)

36m

TLR:7.3%

(DES)vs.14.7%

(BS)

ENDEAVORIII(N

5436)

9m

TLR:6.3%

(Endeavor)

vs.3.5%

(Cypher)

ENDEAVORIV

(N5

1,548)

9m

Enrolling

Supra

G1,43

Directlyim

pregnated

Cook,Inc

Paclitaxel

ASPECT(N

5177)

6m

4%

(highdose

DES),

12%

(low

dose

DES)vs.27%

(BS)

V-FlexPlus

PTXTM

1,9,43,60

Directlyim

pregnated

Cook,Inc

Paclitaxel

ELUTES(N

5192)

6m

3.1%

(2.7

mg/m

m2DES),

13.5%

(1.4

mg/m

m2DES),

11.8%

(0.7

mg/m

m2DES),

20%

(0.2

mg/m

m2DES)vs.20.6%

(BS).

Logic

PTXTM

43,60

Directlyim

pregnated

Cook,Inc

Paclitaxel

PATENCY

(N5

50)

9m

38.1%

(DES)vs.35.3%

(BS)

Multi-LinkTetra

6,43,60

Proprietary

Guidant

ActinomycinD

ACTIO

N(350)

6m

Trial

halteddueto

highMACE,

TLR

ratesat

30days

Multi-LinkPenta2,43,60

Directlyim

pregnated

Guidant

Paclitaxel

DELIV

ER(N

51,043)

9m

14.9%

(DES)vs.20.6%

(BS)

ACHIEVETM

61

Directlyim

pregnated

Guidant–Cook

Paclitaxel

DELIV

ERII(N

550)

6m

Inlesion:20%

(DES)vs.

16%

intracoronaryradiation



MedtronicTM is coated with a Phosphorylcholine (PC) poly-

mer, and received CE Mark approval in July 2005.

Tacrolimus (FK506). This drug is a potent immunosup-

pressive drug with proven inhibitory activity on human

VSMC by leading to G1 cell cycle arrest. The drug exerts

inhibitory effect in T-lymphocyte activation by binding

specifically to FK506-binding protein 12 (FKBP12) in the

cytoplasm. The tacrolimus-FKBP12 complex inhibits calci-

neurin, which interrupts signal transduction pathways in

T-cells as well as SMC growth. The drug has been used

clinically to prevent renal transplant rejection. One trail38

had shown a significant reduction (around 50%) in neoin-

tima thickness using ceramic-coated stents loaded with

tacrolimus compared to bare stents.

Dexamethasone. Dexamethasone is a glucocorticoid

that interferes with macrophages and reduces growth fac-

tors and cytokines, thus producing potent anti-inflammatory

properties. BiodivYsio Dexamethasone-eluting stent was

studied on the STRIDE trail. The stents were immersed on

site in a solution of Dexamethasone. At 6-month follow-up,

angiographic binary restenosis was 13.3%, and late loss

was 0.45 mm. The stent have been approved for clinical

use in Europe.8

Tranilast (N-[3,4-dimethoxycinnamoyl]anthranilic Acid).

This drug has been shown to inhibit proliferation and

migration of VSMC in experimental models.8 This drug is

an antiallergic drug that also inhibits the migration and

proliferation of VSMCs induced by platelet-derived

growth factor and transforming growth factor b1.63,64

Tranilast was found to significantly suppress vascular inti-

mal hyperplasia in rabbit artery after balloon injury65,66

and in pig coronary arteries after balloon angioplasty and

stent implantation.67

Anticoagulants

Early studies of drug-eluting stents examined stents coated

with anticoagulants or thrombin inhibitors such as heparin

and hirudin. These studies indicated reduced thrombosis.

However, these stents do not seem to have a significant

long-term impact on restenosis rates during clinical trials,

when compared to uncoated stents used in conjunction

with systemically administrated antiplatelet drugs.4,31,37

Animal studies have revealed that heparin is the inherent

modulator of vascular repair after injury due to its anti-

proliferative and anti-inflammatory properties. However,

human trials using Heparin after PCI have proven ineffec-

tiveness in preventing restenosis.31 Hirudin-coated stents

are believed to reduce neointima formation in the same

way as Heparin. Alt et al.68 implanted stents coated with

a layer of poly(lactic acid), which contained the drugs hir-

udin and iloprost in pigs and sheep. They demonstrated a

significant restenosis reduction after 4 weeks without

inflammatory reactions.68TABLE

V.(continued)

StentPlatform

Coating

Manufacturer

Drug

Clinical

Trials

Follow-up

BinaryRestenosisRate

Measuredat

Follow-up

(MACEarenotincluded)

SStent60

Proprietary

Biosensor/Guidant

Everolimus

FUTUREI(N

542)

6m

0%

(DES)vs.9.1%

(BS)

FUTUREII(N

564)

6m

0%

(DES)vs.19.1%

(BS)

XIENCETM

VMulti-Link

VisionAbott

Abbottvascular

Everolimus

SPIRIT

II(N

5300)

6m

Latestentthrombosisrate

0%

(XIENCE)vs.1.3%

(TAXUS)

BiodivYsio6,43

Phosphorylcholine

Biocompatibles/

Biopolymerix

17-b-estradiol

EASTER

(N5

120)

6m

Lateloss

0.57mm

instent,

0.32mm

inlesion

Batim

astat

BRILLANTI(N

5173)

6m

21%

(DES),Lateloss

0.88mm

BiodivYsio6

Phosphorylcholine

Biocompatibles/

Biopolymerix

Dexam

ethasone

STRID

E(N

570)

6m

13.3%

(DES),Lateloss

0.45mm

BS,barestent;DES,drugelutingstent;SR,slow

releasestent;MR,moderatereleasestent;FR,fast

releasestent;TLR,target

lesionrevascularization;MACE,majoradverse

cardiacevent.



Antiplatelet Drugs

Nitric oxide donors, glycoprotein IIIb/IIIa receptor antago-

nist/antibodies, and Angiopeptin V significantly reduce

platelet deposition in animal studies.37 The platelet

glycoprotein IIb/IIIa receptor is involved in the final com-

mon pathway of platelet aggregation, and antibodies against

this receptor have recently proven their efficacy in the

treatment of unstable angina.4 Unfortunately, no indication

has revealed that the reduction of thrombosis by these

means resulted in the inhibition of intimal growth.37

Research of antithrombotic therapies led to great excite-

ment over the possibility that blocking platelet aggregation

would eliminate in-stent restenosis.2 One such agent, the

antibody Abciximab, which targets glycoprotein IIIb/IIIa

on platelets, seems to have the potential to reduce in-stent

restenosis to insignificant levels.2

VASCULAR STENTS

Metal Stents

Since their introduction, in 1993, vascular stents signifi-

cantly reduced restenosis as well as other balloon proce-

dural related complication rates. It has been shown to

reduce late restenosis relative to conventional balloon

angioplasty.17,18,69 Early designs, including the Wallstent

(Schneider), Palmaz-Schatz (Johnson and Johnson), Wiktor

(Medtronic), and Gianturco-Roubin (Cook) stents, have

been replaced by the Micro (AVE), Multilink (ACS), and

other designs.70–72 The metals used to prepare these stents

are selected for strength, elasticity, and malleability or

shape memory. Stainless steel, tantalum, and nitinol alloys

are among the most commonly used materials.72,74,75 Niti-

nol offers superelastic and thermal shape memory proper-

ties, which allow self-expansion of the stent during

deployment and thermally-induced collapse for theoretical

removal procedures.76 Several metal stent designs are pre-

sented in Figure 4.

Stent design (i.e., struts thickness, number of struts per

cross-section, and strut design), stent material, and surface

smoothness have been shown in histological restenosis

studies to have an important impact on the amount of inti-

mal hyperplasia. A thin strut thickness with a corrugated-

ring stent design was found to induce the smallest intimal

hyperplasia thickness between tested metal stents.15 Studies

show that surface irregularities could serve as sites for

thrombus attachment and growth.3 Smooth surfaces tend to

be less thrombogenic than textures in irregular device.

Monocytes and macrophages attracted to the implant site

are known to form foreign body giant cells to isolate the

prostheses from the surrounding tissue. The substantial rate

of in-stent restenosis led to redesigning stents to improve

their antithrombotic properties.

Metal stents are available as either balloon-expandable

or self-expandable. The balloon-expandable stents expand

by the balloon catheter, while the self-expandable stents

employ a shape memory alloy that acts over a mild temper-

ature range. The metal stent expansion principle is based

on the plastic deformation of metal beyond its elastic limit.

The metals currently used in stents demonstrated several

Figure 4. Examples for Metal stent designs: (a) TAXUS Express 2, Paclitaxel eluting stent (Boston

Scientific); (b) Cypher – sirolimus eluting stent (Johnson and Johnson); (c) Cordis minicrown – slot-

ted tube design (Cordis Corporation); (d) ChromoFlex – thin struts design (DISA Vascular).



disadvantages. First, their electropositivity results in throm-

bogenicity, since blood elements that are mostly negatively

charged, and also proteins, will rapidly cover the high

energy surface. This may also be an advantage, since endo-

thelial cells are able to migrate and cover the exposed

metal surface within a number of days after implantation,

encasing the stent in a cellular sheath. Second, the presence

of the metallic material is permanent and irritates the

immunological response occurring at the injury site.15

Third, sensitization is a concern to those who are hypersen-

sitive to metals.77 And finally, metal stents are considered

to hold limited capacity for local drug delivery.37,42 There-

fore, the current tendency is to coat stents with less throm-

bogenic materials such as polymer or biodegradable

polymer coating.3

Bioresorbable Polymeric Stents

The rationale for bioresorbable stents is to support the vas-

cular wall during the vessel healing process alone; while

gradually transferring the mechanical load to the vessel

wall as stent mass and strength decreases over time. Reste-

nosis commonly occurs within 3–6 months after coronary

intervention, and it rarely occurs thereafter. Therefore, the

clinical need for stents is limited after this period.77,78

These stents can present longer term of drug delivery from

an internal reservoir. In addition, there is no need for a sec-

ond surgery to remove the device.

Several early designs of expandable bioresorbable stents

have been developed as alternatives to metallic vascular

stents.79,80 The first biodegradable stent was developed by

Stack and Clark of Duke University in the early 1980s.79,81

They investigated several biodegradable polymers and

chose PLLA as the stent material. This Duke University

stent was constructed of a specialized PLLA polymer

woven into a diamond-braided pattern from eight polymeric

strands. It was designed to withstand compression pressures

of up to 1000 mmHg (the Palmaz-Schatz stent can with-

stand pressures of 300–500 mmHg and maintain its radial

strength for 1 month). In vivo studies demonstrated mini-

mal thrombosis and inflammatory responses, and moderate

neointimal growth. Gao et al.82 reported the Tianjin/Beijing

stent, a PDLLA/PCL stent with an inner heparin layer,

deployed with a balloon catheter and employing heating

and pressurization. This stent produced mild neointimal

proliferation in swine carotid artery models at 2 months.

Yamawaki et al.83 reported a Kyoto University PGA coil

stent, which exhibited thrombus deposition in canine

implant studies, but no subacute closure. Nuutinen et al.84

developed knitted PLLA and 80/20 PDLGA stents with

mechanical properties similar to those of commercially

available metallic stents. They found that the knitting ge-

ometry has a marked effect on the stents’ mechanical pro-

perties. Such knitted bioresorbable stents are more suitable

for urological, gastrointestinal, and tracheo-bronchial indi-

cations, where the size of the delivery device is not critical,

as opposed to peripheral vascular or even coronary indica-

tions, for which a small-diameter delivery device is critical.

Tamai et al.78,85 described the Igaki/Tamai stent, a biore-

sorbable balloon-expandable zigzag coil design, based on a

PLLA monofilament. The thickness of the stent strut is 0.007

inches (0.17 mm) and the stent surface area is 24% at an

arterial diameter of 3.0 mm. The stent has a self-expanding

capacity, with an expansion range of up to 4.5 mm. This bio-

resorbable stent combines the features of a thermal self-

expandable and a balloon-expandable stent. The stent initially

autoexpands in response to the heat transmitted by a delivery

balloon inflated with a 708C contrast-water mixture (508C at

the balloon site). Subsequent expansion is obtained by infla-

tion at a moderate to high pressure (6–14 atm). This stent

will continue to expand to its nominal size within the follow-

ing 20–30 min at 378C. The most important and unique

innovation made by these authors, compared with prior

investigators, is the change in stent design from a knitted pat-

tern to a zigzag helical coil design.

Vessel wall injury causes neointimal proliferation,86 and

the severity of vessel injury is strongly correlated with neo-

intimal thickness and the percentage of stenosis after bal-

loon angioplasty or stenting.87 The stent design may reduce

the extent of vessel wall injury caused by the stent implan-

tation and may influence the neointimal proliferation and

the inflammatory response. Animal studies of the Igaki/

Tamai stents have demonstrated that the PLLA coil stent

reduced the percentage of stenosis in porcine coronary

arteries at 2 weeks from 64% to 19%, compared with the

PLLA-knitted type stent.88 Minimal neointimal hyperplasia

was found within the PLLA coil stents, whereas moderate

to severe neointimal hyperplasia was observed in knitted

PLLA stents. The PLLA coil stents also exhibited long-

term biocompatibility with a minimal inflammatory res-

ponse in porcine coronary arteries after 16 weeks.85,89

Unlike stents used in previous studies, the Igaki/Tamai

stent was made from a high molecular weight PLLA that

resulted experimentally in a minimal inflammatory

response, compared with that observed in previous reports.

In this study, 25 stents were deployed successfully in 15

patients. No stent thrombosis or major cardiovascular

adverse events occurred within 30 days. After 6 months, re-

stenosis occurred in 10.5% of the patients and target lesion

revascularization occurred in 6.7%. This study actually

provided the first report on immediate and 6-month results

following implantation of a bioresorbable PLLA stent in

humans. The Igaki-Tamai and the double-spiral helical

stent designs are presented in Figure 5.

The multiple-lobe vascular stent (Figure 6) was devel-

oped and studied by us.37,92,93 This fiber was prepared

using a linear, continuous coil array principle, by which

four furled lobes convert to a single large lobe upon bal-

loon expansion. Melt-extruded PLLA fibers with a 0.15

mm diameter were woven continuously around a four-man-

drel array (one central, three peripheral) into a four-lobe

configuration. Three longitudinal fibers were interwoven

and glued to the coil for mechanical support. The fully



expanded stent has a helical coil structure with three longi-

tudinal reinforcing fibers. The stents’ initial and final diam-

eters in this stent design are adjustable.

Stents of 15 mm length, 3 mm final (dilated) diameter,

and 1.8 mm predilated diameter were fabricated. The initial

radial compression strength of the stent in its dilated form

was higher than 200 kPa. The stents were immersed in

PBS at 378C to investigate the effect of their in vitro deg-

radation on mechanical properties. The mode of failure

observed was rapture of binding points, between the coils

and the longitudinal support fibers. The stents did not

undergo any failure after applying 200 kPa throughout the

first 8 weeks. Then, the radial compression pressure

required to create a rupture at binding points showed a lin-

ear decrease with time and the number of ruptures was

increased with time.92 We demonstrated that these stents

generally exhibited good radial compression endurance.

They resisted at least 150 kPa (�75% of the initial

strength) and exhibited only few rupture points, while most

of the binding points remained intact. The combination of

the suggested design and the relatively high molecular

weight PLLA may thus be applicable for supporting blood

vessels for at least 20 weeks and was chosen for further

studies.

DRUG-ELUTING VASCULAR STENTS

Drug-Eluting Metal Stents

A drug-eluting stent is a device releasing single or multiple

bioactive agents into bloodstream. The agent can deposit in

or affect tissue adjacent to the stent eventually eliminating

in-stent restenosis. Drug-eluting stents offer relatively high

drug concentration at the site of stent deployment and mini-

mal systemic side effects. Using this method, drugs are grad-

ually and locally released from the coating matrix and taken

up by the surrounding tissue. Most of the released drugs are

via a polymer matrix such as silicone, cellulose esters, poly-

urethane, polyethylene vinyl alcohol, and copolymers of pol-

yethylene glycol. The matrices control the drug released over

a certain period of time. Unfortunately, many of these syn-

thetic polymers induce exaggerated inflammatory response

and neointimal hyperplasia in animal models.31,37

The drug should interfere with SMC proliferation, the

main source of restenosis, thus a sufficient drug amount

should be released by the appropriate kinetics.2 This effect

must be maintained throughout the first 3–4 weeks after pro-

cedure. Also, a confluent endothelial coverage of the stent

must be achieved. A reduction of neointimal hyperplasia is

expected during the period that the drug actions remain in

effect and beyond (Figure 7). The drug is usually incorpo-

rated in a polymeric coat, but sometimes it is bound directly

to the metal stent. When using the first method, the agent is

usually loaded in the polymer coat by physical entrapment or

sometimes by chemical bonding to the polymer chain. A

schematic representation of various types of drug-loaded

coatings is presented in Figure 8. By altering the physio-

chemical properties of the polymer matrix, one can control

the kinetics of the drug elution so that the drug is released in

a sustained fashion over a period of weeks after implanta-

tion.7 An optimal combination of drug and coating polymer,

and the kinetics of release determines the safety and opti-

mizes the local therapeutic benefit, and therefore enables pat-

ency of the stented vessel.6,8 Various important drug-eluting

metal stent developments and their clinical trials results are

summarized in Table V. We will focus below on paclitaxel-

eluting stents and on sirolimus-eluting stents.

Paclitaxel-Eluting Stents. Paclitaxel-coated stents re-

ceived CE approval on September 2002 and FDA approval

on April 2004 under the name TAXUSTM following exten-

sive successful clinical trials [49]. TAXUS is a 15 mm

NIRxTM stent (316L stainless steel, Boston Scientific

coated with poly(lactide-co-e-carpolactone) copolymer

loaded with either ‘‘low’’ dose of 85 mg or a ‘‘moderate’’

dose of 171 mg of paclitaxel.16,45 The release profile is

characterized by an initial release over the first 48 h

followed by slow release over the next 10 days.16 Clinical

trials of paclitaxel-eluting stents have been encouraging.

Early studies were performed using a variety of stent plat-

forms, drug concentrations, polymer matrix, or without a

matrix. Although the early human and animal trials of

Figure 5. Examples for bioresorbable fiber-based stents: (a) The

double helical PDLLA stent90; (b) The Igaki-Tamai PLLA stent78; (c)

The knitted 96L/4D PLA stent, the arrows indicate the loop height.84



paclitaxel-coated stents had mixed results, more recent

results using TAXUS-eluting stents are very promising.7

Recently, Boston Scientific developed its next generation

paclitaxel-eluting coronary stent, the TAXUS Liberte’,

which is based on the TAXUSTM Express 2.

Animal Studies. Various animal studies using paclitaxel-

eluting stents reported that inhibition of restenosis is associ-

ated with delayed or incomplete intimal healing character-

ized by increased local arterial inflammation and fibrin

deposition. The coating polymers and their degree of steri-

lization may be the cause of these reactions.2,49,77

Paclitaxel-eluting Palmaz-Schatz coronary stent trial in

pigs49 has shown to significantly reduce restenosis in a dose-

dependent manner with the largest reduction in neointima at the

high dose group. This stent was coated with a range of paclitaxel

doses by dipping the stent into Ethanolic paclitaxel and evaporat-

ing the solvent. No hyperplastic edge effects were found in any

of the groups; however, the trail did raise concerns regarding

vascular complication (aneurysm, wall rapture).

Stents coated with a crosslinked biodegradable polymer,

Chondroitin Sulfate A and Gelatin (CSG) containing pacli-

taxel, were examined on rabbits.94 The results have shown

a suppressed neointimal formation at 28 days in a dose-de-

pendent manner (42.0, 20.2, 8.6, or 1.5 mg of paclitaxel per

stent) without systemic toxicity. Higher dose produced

higher reduction in restenosis rates. However, findings sug-

gested that paclitaxel delayed neointimal growth, and the

healing was incomplete. Studies of Conor Med stent

implanted in porcine coronary for 30 days exhibited inhibi-

tion of restenosis and delayed healing.95

Clinical Studies. Paclitaxel-eluting stents presented very

promising preclinical and clinical results. A graded dose

response is observed, where restenosis rates are lower in

the higher dose groups. TAXUS, which is a paclitaxel-

coated stent, was found effective and safe in a wide range

of complex patients and lesions, including small vessels,

long lesions, and diabetic patients.8 More details can be

found in Table V.

Sirolimus (Rapamycin)-Eluting Stent. Cypher (Cordis,

Miami, FL, a Johnson and Johnson Company) was

approved in April 2002 for use in Europe and FDA

approved it in April 2003.7 The Cordis Cypher is a tubular

stainless steel stent coated with a 5-mm-thick layer of non-

erodable polymer (50:50 mixture of polyethylene-vinyl-ace-

tate and poly-n-butyl methacrylate) containing 140 mg/cm2

Sirolimus (Rapamycin). The drug is released slowly over

4–6 weeks; approximately 80% is released after 4 weeks

and 100% after 6 weeks.2

Bioresorbable Drug-Eluting Stents

Several drug-eluting fiber-based and film-based vascular

stents have been reported lately. In these stent designs, the

drug molecules were located within the fibers or films, or

in a coating.

Fiber-Based Stents. Drug-mixed polymer stents can be

loaded with larger amounts of drug than drug-coated stents

can, because the polymer stent struts can contain the drug.

The tranilast-eluting Igaki-Tamai stent was made of a

PLLA monofilament mixed with tranilast, and its shape

was similar to that of the regular Igaki-Tamai stent without

the drug. The radial compression strength of the drug-

loaded stent was �10% lower than that of the neat stent.

Figure 6. The design concept of our vascular fiber-based bioresorbable stent: (a) predilated; (b)

dilated; (c) predilated, side view; (d) dilated, side view.91 [Color figure can be viewed in the onlineissue, which is available at www.interscience.wiley.com.]



Tsuji et al.96 compared the tranilast content in the tranilast-

eluting Igaki-Tamai stent with that in a tranilast-coated

Palmaz-Schatz stent that was coated with a 20–40 mm layer

of tranilast-mixed PCL. The tranilast content of the former

was found to be at least four times higher than that of the

latter. The authors developed three types of tranilast-eluting

stents: a noncoated stent, which can release tranilast rap-

idly, a PCL-coated stent for relatively slow release of trani-

last through the PCL barrier layer, and a stent with a

tranilast-loaded PCL coating designed to rapidly release the

drug from the PCL coating followed by a slower release

through the PCL layer. The authors stated that clinical

experiments are necessary to elucidate these stents’ safety

and efficacy.

Figure 7. The response to PCI and methods for restenosis prevention. Beginning with a coronary

artery that has already stenosed owing to plaque formation, PCI is performed either with or without

stent implantation. With PCI alone, the artery is subject to elastic recoil, thrombus formation, neoin-

timal growth, and late vessel remodeling. If a stent is implanted, the effects of elastic recoil andlate vessel remodeling are limited, but the artery is still at risk of neointimal hyperplasia. If a drug-

eluting stent is implanted, neointimal hyperplasia can be nearly abolished by blocking cell-cycle pro-

gression.2 [Color figure can be viewed in the online issue, which is available at www.interscience.

wiley.com.]



Uurto et al.97 evaluated in-vivo a new fiber-based drug-

eluting bioresorbable vascular stent, with respect to bio-

compatibility, neointimal hyperplasia formation, and reli-

ability. Monofilaments made of a polymer consisting 96%

L-lactic acid and 4% D-lactic acid were manufactured by

melt-spinning. The stents were formed from a mesh design

consisting of 16 monofilaments braided over a mandrel.

These stents were coated with 50/50 two bioactive agents:

dexamethasone or simvastatin. Both, PCL and a polymer

containing 50% L-lactic acid and 50% D-lactic acid, were

used as coating materials. The in-vivo results (pig experi-

ments) indicated that all stented arteries were angiographi-

cally patent. The dexamethasone-loaded stents decreased

the mean luminal diameter compared to other stents, and

they induced minimal intimal hyperplasia. The vascular

injury scores demonstrated only mild vascular trauma for

all studied stents. Hence, the authors concluded that biore-

sorbable polymer stents appear to be biocompatible and

reliable, and can be used as local drug delivery vehicle.

The findings showed a need for further investigation to

prove the efficacy and safety of this new biodegradable

drug-eluting stent.

The two fiber-based drug-eluting bioresorbable vascular

stents described above demonstrated promising results.

Other fiber-based vascular stents were developed by com-

panies, and their studies are in progress. The growing num-

ber of such stents includes for example the paclitaxel-

loaded REVA stent (developed by REVA company) and a

stent developed by TissueGen and Endovasc companies.

PLLA stents coated with drug-loaded microspheres were

developed and studied by us.92 Drug-loaded bioresorbable

microspheres were developed and bound to the PLLA

fibers and to our multiple-lobe stents.92,98 These micro-

sphere reservoirs, which were prepared by the double

emulsion technique, can be loaded with biologically

active aqueous or nonaqueous molecules. Since mild

materials and processing steps are used, these micro-

spheres can be loaded with all drugs, proteins, and gene

transfer vectors. The processing conditions can be con-

trolled to yield single-reservoir or multiple-reservoir

microspheres. The initial radial compression strength of

all types of microsphere-loaded stents exceeded 200 kPa.

This indicates that the partial dissolution of the

surface layers that was performed to enable microsphere

attachment to the fiber had practically no effect on the

strength of the stent. It has been demonstrated that the

microsphere structure strongly affects the release profile

of the agent from the microspheres and from the micro-

sphere-loaded stents.92,96 In fact, the release profile from

the microsphere-loaded fibers and stents is determined

by the chemical structure of the microsphere’s polymer,

and its initial molecular weight and the processing

conditions.

Film-Based Stents. Vogt et al.90 reported a novel

PDLLA double-helical stent designed according to the

material’s properties, based on a finite element method.

Figure 8. A schematic representation of different models for drug-eluting stent platforms (black

represents stent strut; gray, coating): (A) Drug–polymer blend release by diffusion; (B) Drug diffusionthrough additional polymer coating; (C) Drug release by swelling of coating; (D) Nonpolymer-based

drug release; (E) Drug loaded in stent reservoir; (F) Drug release by coating erosion; (G) Drug

loaded in nanoporous coating reservoirs; (H) Drug loaded between coatings (coating sandwich); (I)

Polymer–drug conjugate cleaved by hydrolysis or enzymic action.8



This stent was manufactured using the controlled expansion

of saturated polymers (CESP) for molding the PDLLA.

This method is characterized by a low process temperature

that enables the processing of thermally sensitive polymers

and the incorporation of biologically active substances.

This stent exhibited sufficient mechanical stability and a

significant potential to reduce restenosis after vascular

intervention was observed following the incorporation of

paclitaxel. Paclitaxel was shown to effectively inhibit pro-

liferation and coronary stenosis in a pig model after vascu-

lar injury in a long-term course. The authors suggest that

invitro pharmacokinetics with a very slow release pattern

of paclitaxel over a time span of more than 2 months might

contribute to this favorable outcome. The authors also

reported that paclitaxel loading did not increase toxicity, as

reflected by media necrosis or delayed healing of endothe-

lial cells.

Alexis et al.77 studied the in vitro release kinetics of

paclitaxel and rapamycin from solution-cast PDLLA and

PDLGA films and from nonexpandable helical stents pre-

pared from strips cut from the films. The results demon-

strated that the release mechanism for both drugs combined

diffusion and degradation. The films and stents exhibited

the same release profiles, indicating homogenous degrada-

tion kinetics. No burst effect was observed for either drug.

This is especially important during paclitaxel administra-

tion, where cardiotoxicity is sometimes a concern. The

authors also demonstrated that the release period can vary

from 1 month to several months, depending on the matrix

polymer.

Ye et al.99 demonstrated the successful transfer and

expression of a nuclear-localizing ß-Gal reporter gene in

cells in the arterial wall of rabbits after the implantation of

biodegradable stents made of bioresorbable PLLA/PCL

films creating a porous tubular structure impregnated with

a recombinant adenovirus carrying that gene. Although

they used a nonexpandable stent design, they demonstrated

the exciting possibility of transferring genes that encode for

key proteins in the central regulatory pathways of cell pro-

liferation inside arterial wall cells, using bioresorbable

stents as vehicles.

Novel Composite Fiber Structures Used as Basic

Stent Elements. As have already stated, bioresorbable

stents can simultaneously support blood vessels and serve

as drug/protein delivery platforms. Certain drugs, such as

steroids, can be incorporated into the PLLA fiber during

melt processing. However, only small drug quantities can

be incorporated in dense polymeric structures such as fibers

without having an adverse effect on the mechanical proper-

ties of the fiber and the stent. Furthermore, most drugs and

all proteins are destroyed when exposed to the high melt

processing temperature. To solve these problems, we devel-

oped and studied novel drug-loaded composite fibers61,91

that can be used as basic elements of stents such as the

multiple-lobe stent (described above). These unique fibers,

which resemble sutures, actually contain two sections: (a) a

dense core fiber with good tensile mechanical properties

(high strength and good flexibility) and (b) a porous shell,

i.e. a bioresorbable ‘‘coating’’ that contains the drug mole-

cules. This section is prepared via freeze drying of inverted

emulsions using mild processing conditions, and can there-

fore include any bioactive agent, while preserving its acti-

vity. This new concept of composite fiber structures is

schematically presented in Figure 9(a), and a SEM fracto-

graph of a fiber’s cross section is presented in Figure 9(b).

We prepared fiber structures with porous shell loaded with

the antiproliferative agent paclitaxel. Investigation of these

composite fibers focused on the effects of the emulsion’s

composition (formulation) and processing conditions on the

drug release profile from the fibers and on the fibers’ ten-

sile mechanical properties.

In general, extremely porous ‘‘shell’’ structures (mean

porosity of �85% and mean pore size 6 mm) were obtained

with good adhesion to the core fiber [Figure 9(c)]. These

new fibers demonstrated good mechanical properties with a

Figure 9. The structure of the core/shell composite fibers: (a) A

schematic representation showing the concept; (b, c) SEM fracto-graph of a specimen; (d) The effect of paclitaxel content on its

release profile from core/shell fiber structures. Red suqare, 0.7% w/w;

Pink circle, 1.4% w/w; Blue triangle, 2.9% w/w; Turquoise square,

7.1% w/w.89 [Color figure can be viewed in the online issue, which isavailable at www.interscience.wiley.com.]



versatile drug release profile. The porous PDLGA shell

contained 1.6–6 mg of paclitaxel per 1 cm of fiber (16–60

mg/cm2). The fibers released a maximum of 40% of the

paclitaxel, and most of the release occurred during the first

30 days. Paclitaxel release from the porous shell was rela-

tively slow due to its extremely hydrophobic nature, and

the main release mechanism during the tested period was

diffusion rather than polymer degradation.

The release rate and quantity increased with the increase

in drug content or the decrease in polymer content, whileother emulsion’s formulation parameters and processing

conditions showed a minor effect on the release profile.

The effect of drug content on the paclitaxel’s release pro-file from the fibers is presented as an example in Figure

9(d). Incorporation of surfactants in the organic phase ofthe emulsion increased the rate of drug release through a

microstructure with a larger surface area for diffusion.

Although our new fibers exhibited versatile drug releaseprofiles, the paclitaxel release profile obtained for most

studied structures during the test period demonstrated avery low initial burst effect, accompanied by a decrease in

release rate with time. It is clear that a second release

phase should occur after more than 4 months. This meansthat during the first release phase, most of the drug is

released within the first month and a second release phaseshould occur later as the polymer undergoes degradation

into very small fragments. Such a release profile can be ad-

vantageous for our application, especially since it is knownthat restenosis may occur within 6 months after the proce-

dure. It should be mentioned that the specimens maintainedtheir mechanical integrity throughout the entire test period,

without visible cracking or discharge of degradation pro-

ducts to the medium. Our results indicate also that the newcomposite fibers are strong and flexible enough to be used

as basic elements for stents. We have demonstrated that

proper selection of processing conditions, based on kineticand thermodynamic considerations, can yield polymer/drug

systems with desired drug release behaviors and good me-chanical properties. Our novel coating technique can be

used on bioresorbable core fibers to get totally bioresorb-

able stents, and it can also be used for bare metal stents,where only the drug-loaded coat degrades with time.

CONCLUSION

This review presents an extensive overview of approaches

for prevention of restenosis. It focuses on drugs for preven-

tion of restenosis, metal stents, and drug-eluting stents. It

also describes published studies of new bioresorbable stents

with drug delivery. These stents are actually used as drug

delivery platforms in addition to their support function,

releasing drugs for prevention of restenosis from the stent

in a desired controlled manner. Basic elements, such as our

new composite core/shell fiber structures, can be used to

build new bioresorbable drug-eluting stents. New drugs and

stent designs may thus advance the therapeutic field of

restenosis prevention.

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Approaches for prevention of restenosis