Journal of Vascular Surgery
Volume 44, Issue 6 , Pages 1363-1368, December 2006

The evolving impact of microfabrication and nanotechnology on stent design

  • Jeffrey M. Caves, PhD

      Affiliations

    • Departments of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Ga
    • ,
  • Elliot L. Chaikof, MD, PhD

      Affiliations

    • Departments of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, Ga
    • Department of Surgery, Emory University School of Medicine, Atlanta, Ga
    • School of Chemical and Biomolecular Engineering, Georgia Institute of Technology, Atlanta, Ga.
    • Corresponding Author InformationCorrespondence: Elliot L. Chaikof, MD, PhD, 101 Woodruff Circle, Room 5105, Emory University, Atlanta, GA 30322.

Received 21 July 2006; accepted 6 August 2006.

Article Outline

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. Microfabricated 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.

 

Noncoronary atherosclerotic vascular disease affects 18 million people in the United States, and up to half of these individuals have symptomatic lower extremity peripheral arterial disease.1, 2, 3 During the next 20 years, it is estimated that the number of cases of peripheral arterial disease will double, with an anticipated dramatic increase in health care costs and economic losses due to the rising incidence of limb loss, disability, and death.4, 5

The endovascular management of vascular disease through the use of balloon/laser angioplasty, stenting, or atherectomy offers a minimally invasive alternative to surgical bypass, but unfortunately, the clinical effectiveness of these strategies remains limited by a significant incidence of restenosis.6, 7, 8, 9 For example, primary patency rates for percutaneous angioplasty and stenting of femoropopliteal lesions averages 61% at 1 year (47% to 86%), with 3-year patency rates ranging from 61% for patients with discrete, focal lesions of the superficial femoral artery to less than 30% for those patients with more complex lesions or occlusions that present with critical limb ischemia.10, 11

Of note, despite the success of drug-eluting stents for the treatment of coronary artery disease, 24-month data from the Sirolimus-Coated Cordis SMART Nitinol Self-Expanding Stent for the Treatment of Obstructing Superficial Femoral Artery Disease (SIROCCO) trial, which evaluated sirolimus-coated shape memory alloy recoverable technology (SMART) stents for the treatment of superficial femoral artery lesions, demonstrated restenosis rates of 40% and 44% for slow and fast-release formulations, respectively. These rates were not significantly different than those observed in the control group treated with bare metal stents.12

Apart from biologic differences between coronary and peripheral arteries, these data emphasize that lesions representative of peripheral arterial disease are more complex and extensive than those associated with coronary artery disease. Thus, the development of endovascular stents with improved clinical performance characteristics remains a critical need in the field. The application of evolving microtechnologies and nanotechnologies in stent design is highlighted in this review.

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In-stent restenosis and late thrombosis 

Major limitations of stent technology have included in-stent restenosis and late thrombosis. Drug elution has substantially reduced in-stent restenosis rates, with target lesion revascularization reduced by 73% after 1 year for paclitaxel-eluting stents13 and 75% after 270 days for sirolimus-eluting stents.14 The extended durability of these devices remains unproven, however, and some argue that the initially low restenosis rates may resurge as the effect of drug elution diminishes. Moreover, restenosis rates remain higher or unknown in some sites, such as the vertebral artery,15 superficial femoral artery,16 and saphenous vein grafts. Long, heavily calcified, or necrotic lesions also may benefit from more advanced technologies.

Late stent thrombosis (>30 days postprocedure) is a rare complication (0% to 2% incidence) but leads to fatal myocardial infarction in an estimated 45% of these cases.17 Thrombosis in bare metal stents is associated with several mechanisms that interfere with strut endothelialization and delayed healing, including radiation therapy, stenting of highly necrotic plaques, disruption of plaques adjacent to the stent, and stenting across the ostia of major arterial branches.18

Concerns that drug-eluting stents may lead to a higher rate of late thrombosis have been voiced because paclitaxel and sirolimus slow endothelialization, resulting in subclinical thrombus formation.19 Indeed, data outside of clinical trials show higher drug-eluting stent thrombosis rates than observed in clinical trials or with bare metal devices.17 Moreover, premature discontinuation of antiplatelet therapy increases the late thrombosis rate to 29%.17 Hypersensitivity to the poly-n-butyl methacrylate and polyethylene–vinyl acetate copolymer coating the Cypher stent (Cordis Corporation, Miami Lakes, Fla) also delays healing and has been associated with fatal late thrombosis.20 Many technologies to combat thrombosis by promoting stent endothelialization or elution of anticoagulants might be envisioned; several of which are discussed. However, for any new device, a relatively large clinical data set will be required to substantiate any reduction in late thrombosis due to the low occurrence of this complication.

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Microfabricated drug reservoirs 

Microfabrication technologies have improved in conjunction with increased demand for minimally invasive surgical treatments. The most pervasive microfabrication technology in medical device manufacturing appears to be laser machining, used in the fabrication of stents, embolic filters, stent grafts, catheters, and other devices. Lasers can be used either via the direct write method where the beam is scanned over the workpiece, or the masked-projection method where a wide beam is passed through a patterned mask and regions of the workpiece are processed by the patterned beam (Fig 1). In both methods, the laser is pulsed at 1 kHz or faster, allowing the substrate to briefly cool between exposures and avoiding melting. Each pulse typically removes 0.1 to 0.5 μm of material. Polymers and metals can be readily cut with channels as thin as 50 to 100 μm to form stents.

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  • 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.

Two new stents, the Janus CarboStent (Sorin Biomedica Cardio S.p.A., Via Crescentino, Italy) and the Conor stent (Conor Medsystems, Inc, Menlo Park, Calif), contain microfabricated reservoirs for drug release. Compared with polymer-coated stents, the drug reservoir concept allows designers to select polymers based primarily on biocompatibility, biodegradation, and drug elution properties, because the polymer coating adherence and lubricity are less critical. In addition, both designs can contain more drug than first-generation drug-eluting stents and release the drug specifically toward the vascular wall (Fig 2).

In the Conor stent, distinct reservoirs are cut into widened regions of the strut, and in the Janus CarboStent, a continuous groove, or “sculpture,” is cut in the abluminal face of the strut. The widened struts of the Conor stent are inflexible, so stent expansion relies on “ductile hinge” regions between the struts. Although geometrically more complex, this design permits drug release on both the abluminal and adluminal sides of the strut, whereas the sculpture of the Janus CarboStent only releases the drug to the abluminal side. Also, the distinct reservoirs of the Conor stent may be more suitable than the continuous groove in the Janus CarboStent for the controlled containment and elution of multiple drugs. The Conor stent releases the drug from a fully degradable poly(lactic-co-glycolic acid) matrix. In the case of the Janus design, the drug is loaded directly into the sculptures with no polymer matrix.

The Paclitaxel In-Stent Controlled Elution Study (PISCES) of the Conor platform compared bare stainless steel Conor stents to drug-loaded versions with different rates of drug release and different dosages.21 Partly because of the high level of control over elution kinetics, it was shown that longer durations of drug release impacted in-stent neointimal hyperplasia more than increased dose. In vivo studies in pigs have also shown that healing can be spatially controlled by leaving some reservoirs free of paclitaxel.22 The authors noted “islands” of healed tissue and thickened neointima, which corresponded to regions of the stent that were not loaded with paclitaxel.

In vitro, a high degree of control over paclitaxel release kinetics was obtained by loading the polymer and drug in layers within the reservoir, designed to degrade sequentially.22 For example, biphasic kinetics could be obtained by varying the concentration in subsequent layers. Furthermore, use of a drug-free polymer “topcoat” precluded an initial burst of drug in the first 24 hours.22 The CoStar stent, a cobalt chromium version of the original Conor platform, has obtained Conformité Européene (CE) mark clearance and is commercially available in Europe, and the Cobalt Chromium Stent With Antiproliferative for Restenosis (CoSTAR) II clinical trial of the stent for United States approval completed enrollment in late April.

Other microfabrication technologies may impact stent technology in the future. The microelectrodischarge machining (μEDM) technique, for example, removes material with electrical pulses between an electrode and the workpiece. Any conductive substrate can be machined, with feature sizes as small as 25 μm.23 The recent modification of the μEDM process to use arrays of electrodes in parallel should allow the efficient batch fabrication of multiple stents in parallel and may offer higher precision and reliability than laser machining (Fig 3).24

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  • 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.)

Stents fabricated from planar stainless steel foil displayed radial stiffness similar to commercial stents and greater bending flexibility. In addition, helical stents with inductive properties can be fabricated by μEDM, potentially enabling the stents to serve as antennas for wireless communication. For example, “stentennas” could be integrated with implantable microsystems to measure blood pressure and flow rate.24

Fabrication techniques to decorate the adluminal face of stent struts with microneedles, capable of piercing dense atherosclerotic lesions and delivering therapeutics to the internal elastic lamina, are also under investigation. Initially, photolithography and chemical etching techniques were borrowed from integrated circuits manufacturing to construct sharp silicon microneedles that were 80 to 140 μm tall. When applied in vitro to atherosclerotic rabbit iliac artery tissue, the microneedles successfully transected the arterial wall.25

Integrated circuit fabrication methods are most suitable for creating flat features on planar, silicon surfaces (Fig 4).26, 27 Thus, cylindrical metal or polymer stents cannot be readily obtained using this approach, and alternate technologies will be required to construct stents embedded with microneedles. Indeed, the planar μEDM process could provide one strategy to generate a tubular stent from flat sheets embedded with microneedles. Several other advanced microneedle technologies have been developed,27 but to date, the fabrication of a microneedle stent has not been announced (Fig 5).

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  • 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

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  • Fig 5. 

    Hollow microneedles fabricated out of silicon, metal, and glass imaged by optical and scanning electron microscopy. A, Straight-walled metal microneedle from a 100-needle array fabricated by electrodeposition onto a polymer mold (200 μm tall). B, Tip of a tapered, beveled, glass microneedle made by conventional micropipette puller (900 μm length shown). C, Tapered, metal microneedle (500 μm tall) from a 37-needle array made by electrodeposition onto a polymeric mold. D, Array of tapered metal micro-needles (500 μm height) shown next to the tip of a 26 gauge hypodermic needle. (Reprinted with permission of the National Academy of Sciences, USA ©2003.)27

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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.

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Nanoparticle-encapsulated drugs 

Nanoparticle encapsulation may allow higher arterial wall concentrations and residence times than traditional drugs, two important factors for the prevention of restenosis. In 1996, investigators found that balloon-catheter delivery of dexamethasone-loaded nanoparticles in a dog model resulted in the continued presence of nanoparticles in all three layers of the femoral artery wall after 7 days and in the adventitial layer after 14 days.33 However, plasma concentrations of the drug were not detectable after 3 days, suggesting that systemic toxicity effects may be circumvented with localized, drug-laden nanoparticles. Subsequent 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 chemical species, which was postulated to interact with the negatively charged glycosaminoglycans of the arterial wall.34

In addition to this ionic interaction, nanoparticles functionalized with antibodies have been shown to bind specifically to either cross-linked fibrin in thrombus or tissue factor, a transmembrane glycoprotein up-regulated in smooth muscle cells after vascular injury. Tissue factor–targeted nanoparticles, delivered locally with a balloon catheter, were shown to enter the tunica media after balloon overstretch injury and may also be useful for sustained drug delivery.35, 36 Local delivery of nanoparticles, combined with ionic or antibody targeting strategies, may therefore permit the sustained, high concentration drug therapy required to prevent restenosis.

Others have noted that balloon catheter delivery may not be required. Endothelial injury after balloon angioplasty creates a state of vascular hyperpermeability that allows nanoparticles to enter the arterial wall selectively in and around the target lesion.37 These authors showed that doxorubicin-loaded nanoparticles could be delivered subcutaneously to a balloon-injured carotid artery in a rat model. High-pressure liquid chromatography showed significantly higher tissue concentrations of the nanoparticles in the injured artery compared with the contralateral control, and neointimal hyperplasia was reduced in a dose-dependent manner.37 In addition, a nanoparticle formulation of paclitaxel, administered intra-arterially immediately after iliac artery stent placement in rabbits and again intravenously after 28 days, showed sustained suppression of neointimal growth for 90 days.38 These studies suggest that targeted nanoparticle therapy may be possible even without balloon catheter delivery.

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Conclusions 

Investigation in a variety of areas at the microscale and nanoscale has begun to impact stent design. Stents equipped with microfabricated drug reservoirs are available in several countries and in clinical trials in the United States. Additional microfabrication strategies may facilitate the efficient batch fabrication of stents from planar foils or the addition of microneedle features to stent struts. Nanoporous and nanotextured coatings may enhance cell adhesion, potentially reducing thrombosis, and may also allow controlled drug elution without a polymer coating. Finally, nanoencapsulated drugs, as an adjunct to stent technology, may provide an alternate approach to drug eluting stents for site-targeted drug delivery.

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References 

  1. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United States: Results from the national health and nutrition examination survey, 1999-2000. Circulation. 2004;110:738–743
  2. Garcia LA. Epidemiology and pathophysiology of lower extremity peripheral arterial disease. J Endovasc Ther. 2006;13(Suppl 2):II3–II9
  3. Centers for Disease Control and Prevention. Lower extremity disease among persons aged > or =40 years with and without diabetes—United States, 1999-2002. MMWR Morb Mortal Wkly Rep. 2005;54:1158–1160
  4. Centers for Disease Control and Prevention. Mobility limitation among persons aged > or =40 years with and without diagnosed diabetes and lower extremity disease–United States, 1999-2002. MMWR Morb Mortal Wkly Rep. 2005;54:1183–1186
  5. McDermott MM, Guralnik JM, Ferrucci L, Criqui MH, Greenland P, Tian L, et al. Functional decline in lower-extremity peripheral arterial disease: Associations with comorbidity, gender, and race. J Vasc Surg. 2005;42:1131–1137
  6. Grimm J, Muller-Hulsbeck S, Jahnke T, Hilbert C, Brossmann J, Heller M. Randomized study to compare PTA alone versus PTA with Palmaz stent placement for femoropopliteal lesions. J Vasc Interv Radiol. 2001;12:935–942
  7. Wissgott C, Scheinert D, Rademaker J, Werk M, Schedel H, Steinkamp HJ. Treatment of long superficial femoral artery occlusions with excimer laser angioplasty: long-term results after 48 months. Acta Radiol. 2004;45:23–29
  8. Zeller T, Rastan A, Schwarzwalder U, Frank U, Burgelin K, Amantea P, et al. Midterm results after atherectomy-assisted angioplasty of below-knee arteries with use of the Silverhawk device. J Vasc Interv Radiol. 2004;15:1391–1397
  9. Laird JR. Limitations of percutaneous transluminal angioplasty and stenting for the treatment of disease of the superficial femoral and popliteal arteries. J Endovasc Ther. 2006;13(Suppl 2):II30–II40
  10. Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis. Radiology. 2001;221:137–145
  11. Schillinger M, Exner M, Mlekusch W, Haumer M, Rumpold H, Ahmadi R, et al. Endovascular revascularization below the knee: 6-month results and predictive value of C-reactive protein level. Radiology. 2003;227:419–425
  12. Duda SH, Bosiers M, Lammer J, Scheinert D, Zeller T, Tielbeek A, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol. 2005;16:331–338
  13. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, et al. One-year clinical results with the slow-release, polymer-based, paclitaxel-eluting taxus stent: The TAXUS-IV trial. Circulation. 2004;109:1942–1947
  14. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’Shaughnessy C, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med. 2003;349:1315–1323
  15. Henry M, Polydorou A, Henry I, Ad Polydorou I, Hugel IM, Anagnostopoulou S. Angioplasty and stenting of extracranial vertebral artery stenosis. Int Angiol. 2005;24:311–324
  16. Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med. 2006;354:1879–1888
  17. Iakovou I, Schmidt T, Bonizzoni E, Ge L, Sangiorgi GM, Stankovic G, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA. 2005;293:2126–2130
  18. Farb A, Burke AP, Kolodgie FD, Virmani R. Pathological mechanisms of fatal late coronary stent thrombosis in humans. Circulation. 2003;108:1701–1706
  19. Kotani J, Awata M, Nanto S, Uematsu M, Oshima F, Minamiguchi H, et al. Incomplete neointimal coverage of sirolimus-eluting stents: angioscopic findings. J Am Coll Cardiol. 2006;47:2108–2111
  20. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious?. Circulation. 2004;109:701–705
  21. Aoki J, Ong AT, Rodriguez Granillo GA, McFadden EP, van Mieghem CA, Valgimigli M, et al. “Full metal jacket” (stented length > or =64 mm) using drug-eluting stents for de novo coronary artery lesions. Am Heart J. 2005;150:994–999
  22. Finkelstein A, McClean D, Kar S, Takizawa K, Varghese K, Baek N, et al. Local drug delivery via a coronary stent with programmable release pharmacokinetics. Circulation. 2003;107:777–784
  23. Murali M, Yeo SH. Rapid biocompatible micro device fabrication by micro electro-discharge machining. Biomed Microdevices. 2004;6:41–45
  24. Takahata K, Gianchandani KT. A planar approach for manufacturing cardic stents: design, fabrication, and mechanical evaluation. J Microelectromech Syst. 2004;13:933–939
  25. Reed ML, Wu C, Kneller J, Watkins S, Vorp DA, Nadeem A, et al. Micromechanical devices for intravascular drug delivery. J Pharm Sci. 1998;87:1387–1394
  26. Henry S, McAllister DV, Allen MG, Prausnitz MR. Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci. 1998;87:922–925
  27. McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, et al. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci U S A. 2003;100:13755–13760
  28. Miller DC, Thapa A, Haberstroh KM, Webster TJ. Endothelial and vascular smooth muscle cell function on poly(lactic-co-glycolic acid) with nano-structured surface features. Biomaterials. 2004;25:53–61
  29. Miller DC, Haberstroh KM, Webster TJ. Mechanism(s) of increased vascular cell adhesion on nanostructured poly(lactic-co-glycolic acid) films. J Biomed Mater Res A. 2005;73:476–484
  30. Liu DM, Troczynski T, Tseng WJ. Water-based sol-gel synthesis of hydroxyapatite: process development. Biomaterials. 2001;22:1721–1730
  31. Liu DM, Yang Q, Troczynski T. Sol-gel hydroxyapatite coatings on stainless steel substrates. Biomaterials. 2002;23:691–698
  32. Areva S, Paldan H, Peltola T, Narhi T, Jokinen M, Linden M. Use of sol-gel-derived titania coating for direct soft tissue attachment. J Biomed Mater Res A. 2004;70:169–178
  33. Guzman LA, Labhasetwar V, Song C, Jang Y, Lincoff AM, Levy R, et al. Local intraluminal infusion of biodegradable polymeric nanoparticles (A novel approach for prolonged drug delivery after balloon angioplasty). Circulation. 1996;94:1441–1448
  34. Labhasetwar V, Song C, Humphrey W, Shebuski R, Levy RJ. Arterial uptake of biodegradable nanoparticles: effect of surface modifications. J Pharm Sci. 1998;87:1229–1234
  35. Lanza GM, Yu X, Winter PM, Abendschein DR, Karukstis KK, Scott MJ, et al. Targeted antiproliferative drug delivery to vascular smooth muscle cells with a magnetic resonance imaging nanoparticle contrast agent: implications for rational therapy of restenosis. Circulation. 2002;106:2842–2847
  36. Wickline SA, Neubauer AM, Winter P, Caruthers S, Lanza G. Applications of nanotechnology to atherosclerosis, thrombosis, and vascular biology. Arterioscler Thromb Vasc Biol. 2006;26:435–441
  37. Uwatoku T, Shimokawa H, Abe K, Matsumoto Y, Hattori T, Oi K, et al. Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats. Circ Res. 2003;92:e62–e69
  38. Kolodgie FD, John M, Khurana C, Farb A, Wilson PS, Acampado E, et al. Sustained reduction of in-stent neointimal growth with the use of a novel systemic nanoparticle paclitaxel. Circulation. 2002;106:1195–1198

 Kenneth Ouriel, MD, Review Section Editor

 Competition of interest: none.

PII: S0741-5214(06)01511-4

doi:10.1016/j.jvs.2006.08.046

Journal of Vascular Surgery
Volume 44, Issue 6 , Pages 1363-1368, December 2006

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