REVIEW ARTICLE

Kenneth Ouriel, MD, Review Section Editor

The evolving impact of microfabrication and

nanotechnology on stent design
Jeffrey M. Caves, PhD,a and Elliot L. Chaikof, MD, PhD,a,b,c Atlanta, Ga

Noncoronary atherosclerotic vascular disease, including symptomatic lower extremity peripheral arterial disease (PAD),
promises to extract a steadily rising medical and economic toll over the coming decades. Although drug-eluting stents
have led to substantial advances in the management of coronary atherosclerosis, endovascular treatment of noncoronary,
peripheral arterial lesions continues to yield high restenosis rates and early clinical failures. In this report, we review recent
developments in microfabrication and nanotechnology strategies that offer new opportunities for improving stent-based
technology for the treatment of more extensive and complex lesions. In this regard, stents with microfabricated reservoirs
for controlled temporal and spatial drug release have already been successfully applied to coronary lesions. Microfabri-
cated needles to pierce lesions and deliver therapeutics deep within the vascular wall represent an additional microscale
approach. At the nanoscale, investigators have primarily sought to alter the strut surface texture or coat the stent to
enhance inductive or conductive schemes for endothelialization and host artery integration. Nanotechnology research
that identifies promising strategies to limit restenosis through targeted drug delivery after angioplasty and stenting is also
reviewed. ( J Vasc Surg 2006;44:1363-8.)

Noncoronary atherosclerotic vascular disease affects 18 Of note, despite the success of drug-eluting stents for
million people in the United States, and up to half of these the treatment of coronary artery disease, 24-month data
individuals have symptomatic lower extremity peripheral from the Sirolimus-Coated Cordis SMART Nitinol Self-
arterial disease.1-3 During the next 20 years, it is estimated Expanding Stent for the Treatment of Obstructing Super-
that the number of cases of peripheral arterial disease will ficial Femoral Artery Disease (SIROCCO) trial, which eval-
double, with an anticipated dramatic increase in health care uated sirolimus-coated shape memory alloy recoverable
costs and economic losses due to the rising incidence of technology (SMART) stents for the treatment of superficial
limb loss, disability, and death.4,5 femoral artery lesions, demonstrated restenosis rates of 40%
The endovascular management of vascular disease and 44% for slow and fast-release formulations, respec-
through the use of balloon/laser angioplasty, stenting, or tively. These rates were not significantly different than
atherectomy offers a minimally invasive alternative to sur- those observed in the control group treated with bare metal
gical bypass, but unfortunately, the clinical effectiveness of stents.12
these strategies remains limited by a significant incidence of Apart from biologic differences between coronary and
restenosis.6-9 For example, primary patency rates for percu- peripheral arteries, these data emphasize that lesions repre-
taneous angioplasty and stenting of femoropopliteal lesions sentative of peripheral arterial disease are more complex
averages 61% at 1 year (47% to 86%), with 3-year patency and extensive than those associated with coronary artery
rates ranging from 61% for patients with discrete, focal disease. Thus, the development of endovascular stents with
lesions of the superficial femoral artery to less than 30% for improved clinical performance characteristics remains a
those patients with more complex lesions or occlusions that critical need in the field. The application of evolving micro-
present with critical limb ischemia.10,11 technologies and nanotechnologies in stent design is high-
lighted in this review.

From the Departments of Biomedical Engineering, Georgia Institute of

Technology and Emory University School of Medicine,a Department of IN-STENT RESTENOSIS AND LATE
Surgery, Emory University School of Medicine,b and School of Chemical THROMBOSIS
and Biomolecular Engineering, Georgia Institute of Technology.c
Competition of interest: none. Major limitations of stent technology have included
Correspondence: Elliot L. Chaikof, MD, PhD, 101 Woodruff Circle, Room in-stent restenosis and late thrombosis. Drug elution has
5105, Emory University, Atlanta, GA 30322 (e-mail: echaiko@emory. substantially reduced in-stent restenosis rates, with target
edu).
0741-5214/$32.00
lesion revascularization reduced by 73% after 1 year for
Copyright © 2006 by The Society for Vascular Surgery. paclitaxel-eluting stents13 and 75% after 270 days for
doi:10.1016/j.jvs.2006.08.046 sirolimus-eluting stents.14 The extended durability of these
1363
 JOURNAL OF VASCULAR SURGERY
1364 Caves and Chaikof December 2006

Fig 1. Laser machining methods. A, After the direct-write

method, a pulsed laser is scanned over the workpiece using mirrors.
B, The masked-projection method is used to process larger regions
of the workpiece with a wide, patterned beam. Fig 2. Drug-containing reservoirs permit more advanced drug-
release strategies.

devices remains unproven, however, and some argue that

the initially low restenosis rates may resurge as the effect of is scanned over the workpiece, or the masked-projection
drug elution diminishes. Moreover, restenosis rates remain method where a wide beam is passed through a patterned
higher or unknown in some sites, such as the vertebral mask and regions of the workpiece are processed by the
artery,15 superficial femoral artery,16 and saphenous vein patterned beam (Fig 1). In both methods, the laser is
grafts. Long, heavily calcified, or necrotic lesions also may pulsed at 1 kHz or faster, allowing the substrate to briefly
benefit from more advanced technologies. cool between exposures and avoiding melting. Each pulse
Late stent thrombosis (⬎30 days postprocedure) is a typically removes 0.1 to 0.5 ␮m of material. Polymers and
rare complication (0% to 2% incidence) but leads to fatal metals can be readily cut with channels as thin as 50 to 100
myocardial infarction in an estimated 45% of these cases.17 ␮m to form stents.
Thrombosis in bare metal stents is associated with several Two new stents, the Janus CarboStent (Sorin Bio-
mechanisms that interfere with strut endothelialization and medica Cardio S.p.A., Via Crescentino, Italy) and the
delayed healing, including radiation therapy, stenting of Conor stent (Conor Medsystems, Inc, Menlo Park, Calif),
highly necrotic plaques, disruption of plaques adjacent to contain microfabricated reservoirs for drug release. Com-
the stent, and stenting across the ostia of major arterial pared with polymer-coated stents, the drug reservoir con-
branches.18 cept allows designers to select polymers based primarily on
Concerns that drug-eluting stents may lead to a higher biocompatibility, biodegradation, and drug elution prop-
rate of late thrombosis have been voiced because paclitaxel erties, because the polymer coating adherence and lubricity
and sirolimus slow endothelialization, resulting in subclin- are less critical. In addition, both designs can contain more
ical thrombus formation.19 Indeed, data outside of clinical drug than first-generation drug-eluting stents and release
trials show higher drug-eluting stent thrombosis rates than the drug specifically toward the vascular wall (Fig 2).
observed in clinical trials or with bare metal devices.17 In the Conor stent, distinct reservoirs are cut into
Moreover, premature discontinuation of antiplatelet ther- widened regions of the strut, and in the Janus CarboStent,
apy increases the late thrombosis rate to 29%.17 Hypersen- a continuous groove, or “sculpture,” is cut in the abluminal
sitivity to the poly-n-butyl methacrylate and polyethylene– face of the strut. The widened struts of the Conor stent are
vinyl acetate copolymer coating the Cypher stent (Cordis inflexible, so stent expansion relies on “ductile hinge”
Corporation, Miami Lakes, Fla) also delays healing and has regions between the struts. Although geometrically more
been associated with fatal late thrombosis.20 Many technol- complex, this design permits drug release on both the
ogies to combat thrombosis by promoting stent endothe- abluminal and adluminal sides of the strut, whereas the
lialization or elution of anticoagulants might be envisioned; sculpture of the Janus CarboStent only releases the drug to
several of which are discussed. However, for any new the abluminal side. Also, the distinct reservoirs of the
device, a relatively large clinical data set will be required to Conor stent may be more suitable than the continuous
substantiate any reduction in late thrombosis due to the groove in the Janus CarboStent for the controlled contain-
low occurrence of this complication. ment and elution of multiple drugs. The Conor stent
releases the drug from a fully degradable poly(lactic-
MICROFABRICATED DRUG RESERVOIRS co-glycolic acid) matrix. In the case of the Janus design, the
Microfabrication technologies have improved in con- drug is loaded directly into the sculptures with no polymer
junction with increased demand for minimally invasive matrix.
surgical treatments. The most pervasive microfabrication The Paclitaxel In-Stent Controlled Elution Study
technology in medical device manufacturing appears to be (PISCES) of the Conor platform compared bare stainless
laser machining, used in the fabrication of stents, embolic steel Conor stents to drug-loaded versions with different
filters, stent grafts, catheters, and other devices. Lasers can rates of drug release and different dosages.21 Partly because
be used either via the direct write method where the beam of the high level of control over elution kinetics, it was
JOURNAL OF VASCULAR SURGERY
Volume 44, Number 6 Caves and Chaikof 1365

Fig 3. Left, A fabricated sample as cut from the metal foil with microelectrodischarge machining. Right, Angled and
side views of an expanded stent.24 (Reprinted with the permission of Journal of Microelectromechanical Systems
©2004.)

Fig 4. Production of silicon micro-needles, as described by Henry.26 A silicon wafer is coated with chromium, and
lithographic methods are used to pattern the chromium into dots, approximately the same diameter as the base of the
desired micro-needles (steps 1-3). A reactive ion etching technique is used to erode the silicon. The chromium dot array
protects regions of the silicon wafer, leaving a microneedle pattern (steps 4-5). Silicon microneedles arrays can
subsequently serve as masters to form molds for the fabrication of metal and polymer micro-needles arrays.27

shown that longer durations of drug release impacted in- Other microfabrication technologies may impact stent
stent neointimal hyperplasia more than increased dose. technology in the future. The microelectrodischarge ma-
In vivo studies in pigs have also shown that healing can be chining (␮EDM) technique, for example, removes material
spatially controlled by leaving some reservoirs free of pac- with electrical pulses between an electrode and the work-
litaxel.22 The authors noted “islands” of healed tissue and piece. Any conductive substrate can be machined, with
thickened neointima, which corresponded to regions of the feature sizes as small as 25 ␮m.23 The recent modification
stent that were not loaded with paclitaxel. of the ␮EDM process to use arrays of electrodes in parallel
In vitro, a high degree of control over paclitaxel should allow the efficient batch fabrication of multiple
release kinetics was obtained by loading the polymer and stents in parallel and may offer higher precision and reliabil-
drug in layers within the reservoir, designed to degrade ity than laser machining (Fig 3).24
sequentially.22 For example, biphasic kinetics could be Stents fabricated from planar stainless steel foil dis-
obtained by varying the concentration in subsequent layers. played radial stiffness similar to commercial stents and
Furthermore, use of a drug-free polymer “topcoat” pre- greater bending flexibility. In addition, helical stents with
cluded an initial burst of drug in the first 24 hours.22 The inductive properties can be fabricated by ␮EDM, poten-
CoStar stent, a cobalt chromium version of the original tially enabling the stents to serve as antennas for wireless
Conor platform, has obtained Conformité Européene communication. For example, “stentennas” could be inte-
(CE) mark clearance and is commercially available in grated with implantable microsystems to measure blood
Europe, and the Cobalt Chromium Stent With Antipro- pressure and flow rate.24
liferative for Restenosis (CoSTAR) II clinical trial of the Fabrication techniques to decorate the adluminal face
stent for United States approval completed enrollment in of stent struts with microneedles, capable of piercing dense
late April. atherosclerotic lesions and delivering therapeutics to the
 JOURNAL OF VASCULAR SURGERY
1366 Caves and Chaikof December 2006

advanced microneedle technologies have been devel-

oped,27 but to date, the fabrication of a microneedle stent
has not been announced (Fig 5).

NANOTEXTURED STENT COATINGS

In addition to microscale surface features, nanoscale
texture through the deposition of nanocoatings may be
useful given the observation that surface topography can
promote vascular smooth muscle cell and endothelial cell
adherence and proliferation.28,29 Several such coatings
have been generated using a sol-gel process, in which a
colloidal suspension (sol) of metal or ceramic is applied to a
surface by dipping or spraying and subsequently bonded to
form a porous, highly textured coating. Hydroxyapatite30,31
and titania32 sol-gel coatings are under development. Studies
suggested that these coatings can significantly enhance cell
attachment, and the porosity of these coatings establish them
as potential candidates for drug elution.
Nanotextured coatings fit into a category of design
concepts that enhance endothelialization of stent struts and
may reduce late thrombosis. However, for a significant
impact, these devices will need to recruit and maintain an
endothelial layer under many of the common scenarios
where the risk of thrombosis is typically increased, examples
of which include an intervention that occurs in a previously
irradiated vessel or that which leads to significant plaque
disruption.

NANOPARTICLE-ENCAPSULATED DRUGS
Nanoparticle encapsulation may allow higher arterial
wall concentrations and residence times than traditional
Fig 5. Hollow microneedles fabricated out of silicon, metal, and drugs, two important factors for the prevention of resteno-
glass imaged by optical and scanning electron microscopy. A, sis. In 1996, investigators found that balloon-catheter de-
Straight-walled metal microneedle from a 100-needle array fabri- livery of dexamethasone-loaded nanoparticles in a dog
cated by electrodeposition onto a polymer mold (200 ␮m tall). B,
model resulted in the continued presence of nanoparticles
Tip of a tapered, beveled, glass microneedle made by conventional
in all three layers of the femoral artery wall after 7 days and
micropipette puller (900 ␮m length shown). C, Tapered, metal
microneedle (500 ␮m tall) from a 37-needle array made by elec- in the adventitial layer after 14 days.33 However, plasma
trodeposition onto a polymeric mold. D, Array of tapered metal concentrations of the drug were not detectable after 3 days,
micro-needles (500 ␮m height) shown next to the tip of a 26 suggesting that systemic toxicity effects may be circum-
gauge hypodermic needle. (Reprinted with permission of the vented with localized, drug-laden nanoparticles. Subse-
National Academy of Sciences, USA ©2003.)27 quent work showed that the tissue concentration of similar
systems was increased by seven to ten times when the
surface of the nanoparticles was modified with a cationic
internal elastic lamina, are also under investigation. Ini- chemical species, which was postulated to interact with the
tially, photolithography and chemical etching techniques negatively charged glycosaminoglycans of the arterial
were borrowed from integrated circuits manufacturing to wall.34
construct sharp silicon microneedles that were 80 to 140 In addition to this ionic interaction, nanoparticles func-
␮m tall. When applied in vitro to atherosclerotic rabbit iliac tionalized with antibodies have been shown to bind specif-
artery tissue, the microneedles successfully transected the ically to either cross-linked fibrin in thrombus or tissue
arterial wall.25 factor, a transmembrane glycoprotein up-regulated in
Integrated circuit fabrication methods are most suit- smooth muscle cells after vascular injury. Tissue factor–
able for creating flat features on planar, silicon surfaces targeted nanoparticles, delivered locally with a balloon
(Fig 4).26,27 Thus, cylindrical metal or polymer stents catheter, were shown to enter the tunica media after bal-
cannot be readily obtained using this approach, and alter- loon overstretch injury and may also be useful for sustained
nate technologies will be required to construct stents em- drug delivery.35,36 Local delivery of nanoparticles, com-
bedded with microneedles. Indeed, the planar ␮EDM pro- bined with ionic or antibody targeting strategies, may
cess could provide one strategy to generate a tubular stent therefore permit the sustained, high concentration drug
from flat sheets embedded with microneedles. Several other therapy required to prevent restenosis.
JOURNAL OF VASCULAR SURGERY
Volume 44, Number 6 Caves and Chaikof 1367

Others have noted that balloon catheter delivery may knee arteries with use of the Silverhawk device. J Vasc Interv Radiol
not be required. Endothelial injury after balloon angio- 2004;15:1391-7.
9. Laird JR. Limitations of percutaneous transluminal angioplasty and
plasty creates a state of vascular hyperpermeability that
stenting for the treatment of disease of the superficial femoral and
allows nanoparticles to enter the arterial wall selectively in popliteal arteries. J Endovasc Ther 2006;13(Suppl 2):II30-40.
and around the target lesion.37 These authors showed that 10. Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and
doxorubicin-loaded nanoparticles could be delivered sub- stent implantation for treatment of femoropopliteal arterial disease:
cutaneously to a balloon-injured carotid artery in a rat meta-analysis. Radiology 2001;221:137-45.
model. High-pressure liquid chromatography showed sig- 11. Schillinger M, Exner M, Mlekusch W, Haumer M, Rumpold H, Ah-
madi R, et al. Endovascular revascularization below the knee: 6-month
nificantly higher tissue concentrations of the nanoparticles
results and predictive value of C-reactive protein level. Radiology 2003;
in the injured artery compared with the contralateral con- 227:419-25.
trol, and neointimal hyperplasia was reduced in a dose- 12. Duda SH, Bosiers M, Lammer J, Scheinert D, Zeller T, Tielbeek A,
dependent manner.37 In addition, a nanoparticle formula- et al. Sirolimus-eluting versus bare nitinol stent for obstructive superfi-
tion of paclitaxel, administered intra-arterially immediately cial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol
after iliac artery stent placement in rabbits and again intra- 2005;16:331-8.
13. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT,
venously after 28 days, showed sustained suppression of et al. One-year clinical results with the slow-release, polymer-based,
neointimal growth for 90 days.38 These studies suggest that paclitaxel-eluting taxus stent: The TAXUS-IV trial. Circulation 2004;
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balloon catheter delivery. 14. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR,
O’Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents
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2003;349:1315-23.
Investigation in a variety of areas at the microscale 15. Henry M, Polydorou A, Henry I, Ad Polydorou I, Hugel IM, Anag-
and nanoscale has begun to impact stent design. Stents nostopoulou S. Angioplasty and stenting of extracranial vertebral artery
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