Journal of Biotechnology 164 (2013) 151–170

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Journal of Biotechnology
journal homepage: www.elsevier.com/locate/jbiotec

Review

Inception to actualization: Next generation coronary stent coatings incorporating nanotechnology
Aaron Tan a,e , Yasmin Farhatnia a , Achala de Mel a , Jayakumar Rajadas b , Mohammad S. Alavijeh c , Alexander M. Seifalian a,d,∗
a

Centre for Nanotechnology & Regenerative Medicine, UCL Division of Surgery & Interventional Science, University College London (UCL), London NW3 2QG, UK Biomaterials & Advanced Drug Delivery Laboratory, School of Medicine, Stanford University, Stanford, CA 94305, USA Pharmidex Pharmaceutical Services Ltd., London W1S 1YH, UK d Royal Free London NHS Foundation Trust, London NW3 2QG, UK e UCL Medical School, University College London, London WC1E 6BT, UK
b c

a r t i c l e

i n f o

a b s t r a c t
Percutaneous coronary intervention (PCI) is used to treat blocked coronary arteries. Bare-metal stents (BMS) were first used in PCI but often necessitated repair procedures due to in-stent restenosis. Drugeluting stents (DES) were developed to address this problem as the stent-incorporated anti-proliferative drugs prevented restenosis. However late-stent thrombosis arose with the use of DES due to polymer hypersensitivity and impaired re-endothelialization. Evidence suggests that using a combination of biofunctionalized polymers and antibody/peptide motifs can prevent thrombosis while ensuring in situ endothelialization. The advent of nanotechnology has engendered techniques like layer-by-layer selfassembly, and localized drug and gene delivery using nanoparticles. Therefore, this review seeks to explore the convergence of biotechnology and nanotechnology for the next generation coronary stent coatings, with an emphasis on its development from bench to beside. © 2013 Elsevier B.V. All rights reserved.

Article history: Received 30 September 2012 Received in revised form 9 January 2013 Accepted 11 January 2013 Available online 30 January 2013 Keywords: Drug-eluting stent Nanotechnology Biofunctionalized polymer Control drug release Endothelial progenitor cell capture

Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Percutaneous coronary intervention for atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Bare metal stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Drug-eluting stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. First generation DES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Second generation DES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Design considerations in stent coating technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Polymers for coating stents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Non-biodegradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Biodegradable polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Interfacing advanced pharmacologic agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Achieving anti-thrombogenicity & anti-proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Layer-by-layer (LbL) self-assembly for controlled release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. An imperative for in situ endothelialization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.1. Antibody conjugation for endothelial progenitor cell capture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3.2. Functional peptide incorporation for endothelialization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Biofunctionalization via nitric oxide integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Localized drug delivery & targeted gene therapy using nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 152 153 153 155 155 155 155 156 156 157 157 157 158 158 158 158 159

3.

4.

∗ Corresponding author at: Centre for Nanotechnology & Regenerative Medicine, University College London, London NW3 2QG. Tel.: +44 207 830 2901. E-mail address: a.seifalian@medsch.ucl.ac.uk (A.M. Seifalian). 0168-1656/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jbiotec.2013.01.020

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Inception to actualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. In vitro chemical & engineering tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Animal models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Clinical trials in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future directions and concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

159 159 162 162 163 167

1. Introduction Cardiovascular disease is one of the leading causes of mortality and morbidity in the world. According to the World Health Organization (WHO), 17.3 million people died from cardiovascularrelated diseases in 2008, and this number is projected to rise to an estimated 23.6 million by 2030 (WHO, 2011). Atherosclerosis is a subset of cardiovascular disease, and can be treated using percutaneous coronary intervention (PCI) as a less invasive alternative to coronary artery bypass graft (CABG) surgery (Cohen et al., 2011). Early stents were made from stainless steel (previously referred to as wallstent), and were, for all intents and purposes, classified as bare metal stents (BMS). As metal stents are perceived as foreign objects, the body mounts an immunological response with an upregulation of inflammatory mediators, ultimately causing neointimal hyperplasia, where the proliferation of vascular smooth muscle cells causes a re-narrowing of the vessel (Curcio et al., 2011) (in-stent restenosis). Drug-eluting stents (DES) were developed in response to the problems associated with BMS use. The anti-proliferative effects of DES resulted in lower rates of instent restenosis compared to BMS. However, due to a distinct lack of endothelialization around the vessel wall, yet another problem arose with DES: late-stent thrombosis (Pfisterer et al., 2006) (ST). ST is a serious complication, with mortality rates of up to 30%. Although the exact mechanism of ST is still unclear, it is postulated that polymer coatings on DES and the lack of endothelialization contribute to an increased risk of late ST. This is further compounded by endothelial injury during stenting, and turbulent blood flow in the presence of stent struts in the luminal area of the vessel. In the realm of fluid shear stress, evidence also suggests that laminar flow promotes a healthy endothelium, while turbulent flow is associated with atherosclerosis (Fig. 1) (Niccoli et al., 2010; Tan et al., 2010). Hence, there is an urgent need for a new breed of stents that would not inherit the problems seen with BMS and DES. The advent of nanotechnology in medicine has witnessed a range of innovations tailored to addressing present-day clinical challenges. For instance, the development of biologically-friendly polymers for artificial organs (Jungebluth et al., 2011); functionalized nanoparticles for targeted drug delivery (Chan et al., 2011) and the controlled release of drugs from polymers, exemplified by techniques like layer-by-layer self-assembly (Wong et al., 2010). Indeed, special nanocomposite polymers like polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane (POSSPCU, trade named UCL-NanoTM ) have been developed specifically to tailor to an unmet need for functional nanomaterials in clinical medicine. The multi-faceted applicability of POSS-PCU has allowed it to be used as a scaffold in the world’s first artificial trachea transplant (Jungebluth et al., 2011), synthetic bypass grafts (Baguneid et al., 2011), heart valves (Ghanbari et al., 2010), and more recently, protective coatings for drugs and medical devices. Apart from appropriate polymer coatings, stents with novel features like endothelial progenitor cell (EPC)-specific antibodies for cell capture (Beijk et al., 2010), and gene-eluting stents (Walter et al., 2004a) have been developed, in hopes of achieving in situ endothelialization to circumvent problems of restenosis and thrombosis. Furthermore, the biological significance of nitric

oxide (NO) in the cardiovascular system is widely recognized, and has been hailed as a “guardian” for cardiovascular implants (de Mel et al., 2011). NO precursors can be integrated into nanocomposite polymers, optimizing them for regenerative cardiovascular applications (Naghavi et al., 2013). We envisage the future generation of cardiovascular stents would incorporate nanotechnology-based features like biofunctionalized polymers for enhanced biocompatibility, antibody/peptide conjugation for attracting endothelial progenitor cells, and multiple coating layers for controlled and sustained drug delivery (Tan et al., 2012) (Fig. 2). The journey of a coronary stent from bench to bedside entails not only developing a viable product, but it also has to pass a battery of industry-standard tests, animal studies and human clinical trials. Therefore, this review focuses on new developments in stent coating technologies, and with a particular focus on various tests required before gaining regulatory approval for clinical use.

2. Percutaneous coronary intervention for atherosclerosis Atherosclerosis is a hallmark of cardiovascular disease, characterized by calcification and the build up of fatty deposits, cellular debris and cholesterol in arteries, resulting in stenosis (narrowing) of the vessels (O’Donnell et al., 2011). If this occurs in coronary arteries, insufficient delivery of oxygenated blood to the heart would result in cardiac ischemia, ultimately leading to myocardial infarction (a heart attack). The atherosclerotic plaque consists mainly of cellular debris and cholesterol, with a concomitant upregulation of pro-inflammatory mediators produced by immune cells (Hansson and Libby, 2006). While stable atherosclerotic lesions (plaque) may be relatively asymptomatic until complete vessel closure, unstable (or vulnerable) lesions are prone to rupture and thrombus formations, leading to life-threatening complications like thromboembolism. Blocked coronary arteries can be treated either by a coronary artery bypass graft or a less invasive technique called percutaneous coronary intervention (Park et al., 2011b). PCI involves inserting a catheter with a guide wire to locate the site of the occluded vessel using real-time X-ray visualization. A balloon angioplasty is then performed, whereby the inflation of the balloon encased within a metal stent “cage” unblocks the occluded vessel. The deployed stent would then be a permanent fixture, eventually becoming part of the vessel wall. Balloon angioplasty was developed in 1978 by Andreas Gruntzig in Switzerland (Gruntzig, 1978), and was the mainstay of PCI. Although balloon angioplasty was a pioneering technique in the field of interventional cardiology, there were problems associated with it as well, like vessel closure due to elastic recoil and stenosis due to neointimal hyperplasia, which limited its use (Grüntzig et al., 1979). The idea of introducing a more permanent structure in conjunction with the balloon during angioplasty to maintain patency in the blood vessel led to the development of stents in 1986 by Ulrich Sigwart (Sigwart et al., 1987). These metal struts provided the necessary radial force on the vessel wall, circumventing the problem of vessel closure seen in balloon angioplasty. The acceptance of stenting as a method of choice for PCI has seen a dramatic rise since the 1990s (Fischman et al., 1994; Serruys

. BMS = bare metal stent.. there are concerns that PCI is associated with a higher incidence of MACE. Post PCI treatment normally involves dual anti-platelet therapy (aspirin and clopidogrel/prasugrel) to protect patients against stent thrombosis and major adverse cardiovascular and cerebrovascular events (MACE). (2010). 2006) and everolimus (Grube et al. As BMS are perceived as foreign objects. which occurs in around 30% of patients (Stettler et al. which requires the patient be hospitalized a few days post-surgery. . 2009). its exorbitant cost and long patient recovery time has led to a move towards adopting PCI as a first line treatment for appropriate cases. 2006). Anti-proliferative drugs like sirolimus (Rensing et al. 2. with the rapid advancement of interventional cardiology. PCI allows the patient to go home often within a day. In contrast to PCI. collectively termed as neointimal hyperplasia (Kornowski et al.2. primarily caused by repeat revascularization (Brilakis et al. to provide an alternative route for blood flow. 1994)... 2011). with newer versions featuring zotarolimus (Fajadet et al. Drug-eluting stents As its name suggests. strong evidence suggests that endpoint results of PCI can match those of CABG (Boudriot et al. DES = drug-eluting stent. The ascension of BMS as an integral part of PCI saw the birth of a new breed of stents designed to solve its predecessor’s problems: the drug-eluting stent. As opposed to CABG. polymer hypersensitivity and the lack of proper endothelialization result in late stent thrombosis. By 1999. classified as bare-metal stents. Copyright© 2010 American College of Cardiology Foundation. while PCI is usually under the remit of interventional cardiologists/radiologists. A common problem associated with BMS implantation is in-stent restenosis. 2002) were first used in DES. 1998). This then necessitates a repair procedure (revascularization).. resulting in intimal hyperplasia. A landmark randomized controlled trial of CABG versus PCI concluded that CABG remained the gold standard in patients with left main or 3 vessel coronary artery disease (Serruys et al. which could involve another round of PCI. 1. et al.1. CRP = C-reactive protein. drug-eluting stents carry anti-proliferative agents on its surface with the purpose of inhibiting cell proliferation to prevent neointimal hyperplasia and restenosis...A. At time of writing.. there are currently 11 DES approved by the US Food and Drug Administration (FDA) for clinical use (Table 1). anti-proliferative drugs prevent in-stent restenosis. 2001) and paclitaxel (Liistro et al. Bare metal stents Early stents were mostly made of either stainless steel or cobalt chromium.. 2007). 2. vascular smooth muscle cell proliferation. However. / Journal of Biotechnology 164 (2013) 151–170 153 Fig. 2011). Although PCI may afford benefits similar to CABG (Capodanno et al. 2011). CABG is a surgical procedure. the body mounts and immune response against it.. and were for all intents and purposes. Immunological responses after BMS and DES implantation. coronary stenting accounted for almost 80% of all PCI procedures (Serruys et al.. Tan et al. which occurs due to inflammation and proliferation of vascular smooth muscle cell in the luminal area. However. Reproduced with permission from Niccoli et al. which is a potentially life-threatening event. or even CABG. and ultimately in-stent restenosis. which involves harvesting a suitable autologous blood vessel (blood vessel from another part of the body) and grafting it onto the diseased area.. ECP = eosinophil cationic protein. However. Cardiac surgeons often perform CABG. In the case of DES.

controlled drug release. 2001). Late stent thrombosis in DES. NO = nitric oxide. 2002. 2002. RCA = right coronary artery. Cx = circumflex coronary artery. Multiple drugs could be incorporate using layer-by-layer coating technology. POSS-PCU is non-biodegradable. Stent thrombosis. a potentially fatal phenomenon. DES = drug-eluting stent. EPC = endothelial progenitor cell. / Journal of Biotechnology 164 (2013) 151–170 Fig. POSS-PCU = polyhedral oligomeric silsesquioxane poly(carbonate-urea) urethane.154 A. POSSPCL is biodegradable.. LAD = left anterior descending artery. 2008). Morice et al. Early evidence demonstrating the safety and superiority of DES over BMS made DES the treatment of choice in PCI (Degertekin et al.. 2004). PES = paclitaxel-eluting stent. Stent thrombosis is virtually absent in BMS. 2. NO is essential for maintaining a healthy endothelium and preventing thrombosis. POSS-PCL = polyhedral oligomeric silsesquioxane poly caprolactone. the next generation cardiovascular stent could involve coating with special nanocomposite polymers like POSS-PCU. and can be used together with drugs for controlled release. and so is used as the base coat to prevent bare metal from coming into contact with blood. and NO-eluting polymers could also be developed. DES were first used in early 2000s (Sousa et al. Despite the initial fanfare and promise of DES. 3. is seen on PES when implanted in various coronary arteries. By 2005. (2009). To address the problems seen in BMS and DES.. 2002). Reproduced with permission from Chen et al. Tan et al. EPC-specific antibodies could be attached to the polymer. Convergence of bio-functionalized polymers. Serruys et al. BMS = bare metal stent. To enhance endothelialization. Fig. use of DES accounted for almost 90% of all PCI procedures (Jeremias and Kirtane. Copyright © 2009 American College of Cardiology Foundation. and the CYPHERTM (Cordis) sirolimus-eluting stent gained FDA approval in 2003. and EPC capture. concerns about a potentially fatal phenomenon called late stent ..

. First generation DES Sirolimus was the first drug incorporated onto DES seen in the FDA-approved CYPHERTM stent (Cordis)..6%). Polymers can be broadly divided into two categories: biodegradable and nonbiodegradable.HFP PBMA PVDF-HFP PBMA PVDF-HFP PBMA SIBS Hydrophobic C10 (for drug release) Hydrophilic C19 (for bio-compatibility) PVP Zotarolimus Everolimus Everolimus Everolimus Paclitaxel Zotarolimus 1 Feb 2008 2 Jul 2008 1 Nov 2011 24 May 2011 4 Mar 2004 17 Feb 2012 Key: PBMA = poly-n-butyl methacrylate. Zotarolimus is also a derivative of sirolimus.2.0% vs 26. 2007. Design considerations in stent coating technology 3. Stone et al. calling into question the actual long-term benefits of DES over BMS (Fig.. PEVA = polyethylene co-vinyl acetate.1. Leon et al... 2005.. 2007. PVP = polyvinyl pyrrolidone. The idea was based on the premise that the degradation of the polymer in tandem with drug release would eventually leave behind a BMS. Tan et al. Non-biodegradable (or durable) polymers were first used in DES.. 2008). thrombosis were raised. Meta-analyses comparing both sirolimus and paclitaxel DES with BMS revealed that DES afforded a reduction in restenosis and repeat revascularization. 3. The Xience V® stent (Abbott Vascular) is an everolimus-eluting stent (EES). which could potentially mitigate late ST (as late ST was rarely seen in BMS). 2009). Stettler et al. Manufacturer Cordis Model CYPHER Polymer PEVA PBMA Boston Scientific Boston Scientific Boston Scientific TAXUS Liberté Atom TAXUS Liberté Long ION SIBS SIBS SIBS Paclitaxel Paclitaxel Paclitaxel 21 May 2009 13 Jul 2009 22 Apr 2011 Boston Scientific’s flagship model Captures 20% of US stent market Boston Scientific’s flagship model Captures 20% of US stent market Drug Sirolimus Date Approved 24 Apr 2003 Comments 155 Manufacturing will stop by end of 2012 due to quality control lapses Platinum chromium stent struts promises increased strength. PVDF-HFP = polyvinylidene fluoride co-hexafluoropropylene. 2002) (0. Given the increased risk of late ST. and is also used as an immunosuppressant for transplant patients.. / Journal of Biotechnology 164 (2013) 151–170 Table 1 FDA-approved drug-eluting stents/polymer-coated stents... The Endeavor® stent has been shown to be effective in treating coronary artery diseases. Published . Polymers for coating stents DES often utilize polymers as a foundation on which to incorporate pharmacologic agents (Costa et al. The TAXUS® Express (Bostin Scientific) and TAXUS® Liberté stent (Boston Scientific) contain paclitaxel.2. PC = phosphorylcholine. Due to the observation of late ST in DES. 2007. patients implanted with DES often have to undergo dual antiplatelet therapy (a combination of aspirin and clopidogrel/prasugrel) for a longer time (6–12 months post-stenting) compared to patients implanted with BMS (1 month post-stenting) (Musumeci et al.htm. 2007). has similar mechanism of action. It has also been shown that both EES and ZES have comparable safety and efficacy outcomes (Silber et al. possibly due to immunological response mounted against the polymer coating on DES. SIBS = poly(styrene-b-isobutylene-b-styrene).. 2011).gov/MedicalDevices/ProductsandMedicalProcedures/ DeviceApprovalsandClearances/Recently-ApprovedDevices/default. Kuchulakanti et al.. 2007. Iakovou et al..fda. As second generation DES was only introduced recently. 2. and a multi-center randomized controlled trial demonstrated that everolimus-eluting stents had superior outcomes compared to first generation paclitaxel-eluting stents (PES) (Stone et al.. as shown by favorable results in various clinical trials and multicenter registries (Eisenstein et al. 2006). Lotan et al. it was hypothesized that biodegradable polymers might serve as “second generation” polymers.. and gained FDA approval following studies which confirmed its safety and efficacy.1.. Chen et al. CYPHERTM was first evaluated in the RAVEL trial. and the Endeavor® stent (Medtronic) is an FDAapproved zotarolimus-eluting stent (ZES). 2008. 3) (Camenzind et al.2.A.. 2009). Second generation DES Everolimus is a derivative of sirolimus. there is still no conclusive evidence as to whether they are superior to first generation DES (Fig. 2008. 2009. which demonstrated superior antirestenotic effects when compared to BMS (Morice et al.. 2007.. which showed significantly less in-stent restenosis compared to BMS (Turco et al. 2011) 2. Spaulding et al. Thus. it was postulated that the prolonged presence of a non-biodegradable polymer contributed to late ST via an immunological response. 2007). 4) (Dani et al. 2011b). 2010. deliverability and visibility Utilizes same technology platform as Abbott’s Xience V Biomemetic PC coating is also found on outer membrane of red blood cells Abbott Vascular’s flagship model Abbott Vascular’s flagship model Abbott Vascular’s flagship model Boston Scientific’s flagship model Captures 20% of US stent market First DES to be approved by FDA for use in diabetic patients Boston Scientific PROMUS Element PBMA PVDF-HFP Everolimus 22 Nov 2011 Medtronic Abbott Vascular Abbott Vascular Abbott Vascular Boston Scientific Medtronic Endeavor Xience V Xience Prime Xience Nano TAXUS Express2 Resolute MicroTrac & Resolute Integrity PC PVDF. 2009. compared to BMS (Kastrati et al. * Information compiled using data obtained from US FDA website on recently-approved devices: http://www. Wykrzykowska et al.. Mauri et al.

C19 and polyvinyl pyrrolidone (PVP) for a controlled release of drug elution. A newer version. A mixture of SIBS and paclitaxel is applied directly to the bare-metal stent without a basecoat (primer) or a topcoat layer. The hydrophilic PVP increases the initial drug burst. 2011a).. which is a hydrophobic elastomeric tri-block copolymer (Stone et al. and polyvinylidene fluoride hexafluoropropylene (PVDF-HFP) (Krucoff et al.1. Hence. 2011). which also mimics biological phospholipid bilayer membranes. It has a molecular weight of 80. with a drug load of 100 ␮g/cm2 .. problems like late stent thrombosis and impaired endothelial healing have been reported. 2011a). The C19 polymer is hydrophilic (contact angle = 91◦ ). since there are currently no FDA-approved DES with biodegradable polymers.. The Xience V® stent (Abbott Vascular) is coated with PBMA which adheres to the metal surface and drug coating. but uses platinum chromium instead of stainless steel for the stent strut. Tan et al. SIBS is composed of styrene and isobutylene units built on 1. The CYPHERTM stent (Cordis) contains parylene C. The Xience stent consists of a fluoropolymer mixed with everolimus and a basecoat. thus minimizing restenosis. 2011).. PVDF-HFP serves as a drug matrix layer containing everolimus.3-di(2-methoxy-2-propyl)-5-tert-butylbenzene. Non-biodegradable polymers are currently still the preferred coating of choice for stents. and no topcoat is used. The TAXUS® stent (Boston Scientific) is coated with poly(styrene-b-isobutylene-b-styrene) (SIBS.2. Furthermore. The C10 polymer is hydrophobic (contact angle = 118◦ ) and aids in the control for drug release. sirolimus. Biodegradable polymers DES with biodegradable polymers have been developed. 4. The Endeavor stent contains zotarolimus and uses a PC base coat. PVDF-HFP is a non-biodegradable semi-crystalline random copolymer with a molecular weight of 254–293 kDa. 2011). DES = drug-eluting stent.1. based on the hypothesis that it may offer both the anti-restenotic effects . Parylene C is used as a basecoat (primer) to the bare-metal stent as it is an excellent moisture barrier.000–130. PBMA = Poly-n-butyl methacrylate.000 g/mol and a polydispersity index of 1. trade name Translute).0. for enhanced biocompatibility (Kandzari et al. an objective clinical comparison between non-biodegradable and biodegradable polymers cannot be definitively established. one issue that warrants attention is that of late stent thrombosis. The parylene C-treated stent is then coated with a combination of PEVA and PBMA mixed with sirolimus (67%/33%). The TAXUS stent consists of a mixture of SIBS polymer and paclitaxel. A drug-free topcoat of PBMA is then applied for controlled release of sirolimus. and poly n-butyl methacrylate (PBMA) (Park et al. Copyright © 2009 Informa UK Ltd. Reproduced with permission from Wykrzykowska et al. and is designed to confer biocompatibility. These studies largely demonstrated that biodegradable polymers share similar safety and efficacy as non-biodegradable polymers (Navarese et al. Two variants. The BioLinx polymer system encompasses a combination of C10. Non-biodegradable polymers The current range of FDA-approved DES employs nonbiodegradable polymers. enhancing the elution rate. the Endeavor® RESOLUTE (Medtronic) uses a proprietary BioLinx polymer system. The PROMUSTM ElementTM (Boston Scientific) uses the same drug and polymer coating as the Xience stent. LST = late stent thrombosis.1. This ensures that metal struts would not come into contact with blood.156 A. there is still a lack of conclusive evidence to show that biodegradable polymers are superior to non-biodegradable polymers (Park et al. 3. PVDF-HFP is mixed with everolimus in a 83%/17% ratio and applied to the PBMA-treated metal surface. SIBS = Poly(styreneb-isobutylene-b-styrene).. reports indicate that biodegradable polymers were non-inferior to non-biodegradable polymers (Kandzari et al. 2011a). The IONTM stent (Boston Scientific) uses the same drug and coating as the TAXUS stent..0–2. (2009). / Journal of Biotechnology 164 (2013) 151–170 Fig. The Endeavor® stent (Medtronic) uses a phosphorylcholine (PC) polymer which is seen in biological membranes. 3. Xience PrimeTM (Abbott Vascular) and Xience NanoTM (Abbott Vascular) are also available. The CYPHER stent consists of a PBMA topcoat. However. The current range of FDA-approved DES. PC = phosphorylcholine. 2011).. polyethyleneco-vinyl acetate (PEVA). However. studies documenting long term follow up (more than 10 years) are few and far between. and a parylene C primer basecoat. Considering that the FDA only approved the first DES in 2003.

1.2. A macrolide that inhibits mTOR (mammalian target of rapamycin). its breakdown products and monomers must be non-toxic and easily excreted from biological systems. 2011. the lack of endothelialization and polymer hypersensitivity contribute to late ST seen in DES. Reproduced with permission from Daemen and Serruys (2007). Slow release of genistein and sirolimus in middle layer B will prevent cell proliferation from day 10 to day 49. 5) (Thanigaraj et al. mTOR = mammalian target of rapamycin. 6. poly lactide-cocaprolactone (PLC). Stella et al. Currently. 1996). Reproduced with permission from Thanigaraj et al. rendering them non-functional and thus prevents chromosome segregation. genistein which has anti-platelet and anti-proliferative properties can be layered with sirolimus. Garg and Serruys. DESyneTM BD (Elixir Medical). which could potentially be useful in developing the next generation of DES (Hammond. Abluminal coating is a way of minimizing exposure of polymers to the luminal area of the vessel. Inc. 4. while simultaneously encouraging endothelial cell regeneration. Sirolimus is a cytostatic agent that causes the cell to arrest at G1 phase by inhibiting mTOR. sirolimus causes cells to arrest in the G1 phase (Fig. Initial high does of genistein release in top layer D will prevent platelet aggregation in the first 2 days. 2006). 2008. with evidence suggesting that they can cause more severe vessel inflammation compared to nonbiodegradable polymers (van der Giessen et al. which is then used as a coating for the metal stent struts. 2007). 2009). Serruys et al. Layer-by-layer (LbL) self-assembly for controlled release of multiple pharmacologic agents. 2008. Copyright © 2006 Lippincott Williams & Wilkins. Paclitaxel is a cytotoxic agent that disrupts the G2 phase by binding to mitotic spindles and prevent chromosome segregation.. Sirolimus is an immunosuppressant normally used in renal transplant patients to prevent organ rejection. various drug types can Fig.. Verheye et al. / Journal of Biotechnology 164 (2013) 151–170 157 of a standard DES. Release of genistein and sirolimus in middle layer C will prevent thrombus formation and intimal cell proliferation. is a sirolimus-eluting (SES) coated with poly-L-lactic acid (PLLA).. Sustained release of genistein in base layer A will prevent late stent thrombosis. and JACTAX Liberté (Boston Scientific) utilizes the concept of abluminal coating with PLA (Chevalier et al. 2010.. a process for coating medical devices called layerby-layer self-assembly has emerged as a viable technique. The current range of FDA-approved DES contains either sirolimus (and its derivatives) or paclitaxel dissolved in a polymer matrix. Ostojic et al.. Layer-by-layer (LbL) self-assembly for controlled release With the emergence of nanotechnology targeted for medical applications. 4. Nobori® (Terumo). (2006). It binds to ␤-tubulin in the mitotic spindle. resulting in cell death.A. The Excel stent (JW Medical System). The disruption of cell cycle by anti-proliferative drugs. For example. Furthermore. Paclitaxel is a microtubule inhibitor. 5. This method involves the “stacking” of thin films carrying an alternation of positive and negative polyelectrolyte charges. 2009. Copyright © 2007 American Heart Association. Multiple layers made up of drugs and polymers harbor the potential of achieving sustained and controlled release of pharmacologic Fig. LbL allows for controlled release of drug molecules. and poly lactide-co-glycolide (PLGA) (Dani et al. the use of biodegradable polymers are largely experimental and not approved by FDA. 6). . Vranckx et al. 2011). Guagliumi et al. and the actual benefits of having a biodegradable polymer coating over a non-biodegradable one remains to be seen. polyvinyl pyrrolidone... Interfacing advanced pharmacologic agents 4. preventing both smooth muscle cell proliferation and thrombosis (Daemen and Serruys. Tan et al. A combination of different drugs can be incorporated onto different layers to match healing times. normally used in the treatment of advanced ovarian cancer and metastatic breast cancer. SYNERGYTM (Boston Scientific). and the safety profile of a BMS (Table 3).. Achieving anti-thrombogenicity & anti-proliferation An ideal polymer coating would prevent thrombosis and smooth muscle cell proliferation. AxxessTM (Biosensors International). Given that sirolimus and paclitaxel are antiproliferative agents. 2006). which completely degrades after 6–9 months (Han et al. 2010.. the concept of biodegradable polymers in stents should be proceeded with caution. it is also vital to ensure adequate endothelialization to prevent late ST. Stents like BioMatrixTM (BioSensors International). XTENT (Xtent). 2010).. However. while it is important to prevent in-stent restenosis by curbing vascular smooth muscle proliferation. The Supralimus® and Infinnium® stent (Sahajanand Medical Technologies) is a DES coated with biodegradable polymers consisting of poly-L-lactide (PLA). In order for a biodegradable polymer to be feasible. while retaining the bare-metal strut in the luminal area. This method of coating ensures that the drug and polymer matrix is in contact with the vessel wall. 2010.. Hence. agents (Fig.

2010a) and prevent platelet aggregation (Luo et al. developments for stents combining anti-CD34 antibody and drugelution are currently underway (Nakazawa et al. there is some evidence supporting the use of other EPC-specific antibodies like anti-CD133 (Langer et al. highlighting its potential use in stents. RGD is an integrin-binding motif. and a customizable bioactive epitope (Sargeant et al. 2011). 2011). Ren et al. The GenousTM stent is coated with anti-CD34 antibodies. Stefanadis et al. Conversely. An imperative for in situ endothelialization 4. DNA for gene therapy (Jewell et al. was propounded as an alternative to RGD as it binds to ␣5 ␤1 integrin. Apart from anti-CD34.. 2005) and anti-thrombogenic (Lin et al. However. 2007). ␣v ␤3 is also found on platelets.3.. (B) The GenousTM stent uses EPC capture technology. Recently. It has been shown that incorporation of GP IIb/IIIa inhibitors onto stents can prevent platelet aggregation and thrombosis (Wang et al. 2010. donors and even gene encoding for NO production are often used to confer controlled and sustained release . 2006. a more specific ligand-binding sequence. be incorporated into different layers corresponding to its therapeutic use in different phases in vessel healing. 2010) and VEGF (Webber et al. EPC = endothelial progenitor cell. it is imperative for re-endothelialization to occur in order to restore physiological vascular homeostasis (Padfield et al. 2010)... and monoclonal antibodies to encourage endothelialization (Lin et al. and clinical follow-up reports indicated its safety even after 3 years implantation (Klomp et al. 2009). RRETAWA. 2010)..158 A. and plays a role in platelet activation (Yin et al. a deficiency of NO is associated with in-stent restenosis and thrombosis (Gorchakova et al. NO precursors. and binds to the ␣v ␤3 integrin on endothelial cells (Blindt et al.. PA nanofibers can be functionalized with NO-releasing molecules (Kushwaha et al. PA nanofibers are self-assembling materials made up of 3 domains: a hydrophobic alkyl chain covalently attached to a peptide segment. 2011). 4. 2003). In addition. NO is formed from l-arginine via NO synthase. 2011). This underscores the importance of combining both aspects of anti-proliferation and anti-thrombogenicity for stent technologies of the future. 2005... which induces cyclic guanosine monophosphate (cGMP)-dependent vasodilation and inhibits vascular smooth muscle cell proliferation as well as preventing platelet adhesion and aggregation (Do et al. However..1. circumventing problems like instent restenosis and late ST inherent in current ranges of BMS and DES. 2010b) agents incorporated into multilayers can be finetuned to match the healing time and re-endothelialization of the vessel wall (Meng et al. which is present on endothelial cells but not platelets (Meyers et al. 4. The inhibition of platelet activation is also another way of achieving anti-thrombogenicity (Luo et al. Reproduced with permission from Garg and Serruys (2010). arginineglycine-aspartic acid (RGD) and peptide amphiphile (PA) nanofibers also harbor the potential to augment the rate of re-endothelialization on stent surfaces.. 2011).. 2006). (A) Anti-CD34 antibodies are attached onto the stent to capture circulating EPCs to promote endothelialization. these multilayers can be functionalized with a plethora of bioactive molecules like nitric oxide (NO) donors to reduce platelet adhesion (Thierry et al. due to the short half-life of NO (2–5 s)... 2011). Coating via LbL self-assembly is still currently in the experimental phase. Tan et al. EPC capture using antibodies. However. Copyright © 2010 American College of Cardiology Foundation. Glycoprotein (GP) IIb/IIIa is an integrin complex found on platelets. which could increase the risk of thrombosis.2. Functional peptide incorporation for endothelialization Other molecules like synthetic functional peptides. 2004).3. 2007).. Biofunctionalization via nitric oxide integration Nitric oxide (NO) functions as a signaling molecule in biological organisms. Issues like maintaining batch-to-batch consistency and its advantage over conventional spray coating/dip coating still remains to be seen. 2011). 8) (Ceylan et al.. and plays a significant role in maintaining homeostasis in the cardiovascular system.. respectively. 2008). 2006. while thrombosis was seen in the TAXUS stent (Beijk et al. The notion of achieving in situ endothelialization via the capture of circulating EPCs is exemplified by the GenousTM stent (OrbusNeich). 4.... 2008). 2009... Kammerer et al. Hence.3. Yamauchi et al. 7. which capture circulating EPCs (Fig. a study comparing the GenousTM stent with a TAXUS LibertéTM (Boston Scientific) DES revealed that restenosis was observed in the GenousTM stent... 2010) and vascular endothelial growth factor receptor-2 (VEGFR-2) (Plouffe et al.. 2011) to promote and maintain endothelial cell growth and integrity.. PA nanofibers were also evaluated as promising platforms on which to promote endothelial cell adhesion and proliferation by mimicking the extracellular matrix (Fig. and there are no large animal or human trials being conducted as yet. 2007).. The release of anti-proliferative (Chen et al.4. 7).. Antibody conjugation for endothelial progenitor cell capture The process of stent implantation in PCI damages the vessel wall and disrupts the endothelium. Indeed. / Journal of Biotechnology 164 (2013) 151–170 Fig.. 2003). Promoting re-endothelialization in the stented vessel wall by mobilizing endothelial progenitor cells (EPCs) is recognized as a measure to prevent both restenosis and thrombosis (Duckers et al..

. It has also been reported that tagging endothelial cells with magnetic nanoparticles. 2010). S-nitrosoglutathione (GSNO) was similarly incorporated into a polymer and displayed anti-thrombogenic and anti-proliferative effects (Sorragi et al. Reproduced with permission from Ceylan et al.. 2003). Furthermore. 2010). 2010). and extracellular matrix production. 2004b).. Gene-eluting stents have also been experimentally developed via the attachment of an adenovirus expressing inducible nitric oxide synthase (iNOS) on the stent surface to mitigate neointimal hyperplasia following stent injury (Fig. a bioabsorbable polymeric nanoparticle-eluting stent was developed to encapsulate therapeutic agents for the purpose of sustained intracytoplasmic release (Fig. (f) Rheology studies reveal gelation due to nanofibrous network formation by the mixture of REDV-PA and Dopa-PA at physiological pH. 2003). iNOS is a potent inhibitor of smooth muscle cell proliferation and migration. 2008). These diazeniumdioated particles function as a reservoir for NO molecules. TEM (b) and SEM (c) images of PA nanofibers. evidence suggests that a gene-eluting stent with plasmid DNA encoding for human vascular endothelial growth factor (VEGF-2) could reduce neointimal hyperplasia while simultaneously enhancing re-endothelialization (Walter et al. (2011). magnetic nanoparticles could also be loaded with paclitaxel and magnetically guided to the stented area for enhanced drug localization and delivery (Chorny et al.A. 2011). NOreleasing polymers can also be developed by diazeniumdiolating fumed silica. and was shown to be effective in mitigating in-stent restenosis (Fishbein et al.. 2002). (a) Skeletal formula of Dopa-PA and REDV-PA. Furthermore. 4. Wang et al. Inception to actualization 5. PA = peptide amphiphile. Tan et al. and inhibited neointimal thickening in a porcine model (Yoon et al. 2006. Linsidomine (SIN-1) is a NO donor. (e) Circular dichroism spectroscopy of the PA nanofiber matrix. 2008). / Journal of Biotechnology 164 (2013) 151–170 159 Fig. A study reported that local gene delivery was achieved using dodecylated chitosanplasmid DNA nanoparticles coated onto stents (Zhu et al. Sodium nitroprusside (SNP).. .. Another NO donor. a NO donor.. while the REDV bioactive epitope interact with endothelial cells.. In addition. platelet activation.5. 2004). Dopa = 3. SEM = scanning electron microscopy. which was then subsequently coated onto a stent. 2011).. In vitro chemical & engineering tests After initial research and development (R&D).. and it was shown to inhibit platelet aggregation on metal stents (Jung et al. Endothelial nitric oxide synthase (eNOS) catalyzes the production of NO from l-arginine.. 8. and this method was shown to prevent in-stent restenosis by inhibiting vascular smooth muscle cell proliferation (Brito et al. It has been demonstrated that gene therapy holds potential promise for treating in-stent restenosis. 2008). Lipopolyplexes with eNOS-expressing plasmid DNA were immobilized onto metal stent struts using a mixture of type B gelatin coating and PLGA. Localized drug delivery & targeted gene therapy using nanoparticles Using a novel cation electrodeposition coating technology. Catechol groups of Dopa residues adsorb onto the metal surface. was incorporated into a polyurethane polymer. 2003). In terms of targeting drug delivery to specific cells.. (d) PA nanofiber coated on stainless steel promotes endothelial cell adhesion and proliferation.4-dihydroxyphenyl-L-alanine. releasing it upon contact with physiological fluids (Keefer. An in vivo study using a non-viral method of encapsulating eNOS in liposomes also showed accelerated re-endothelialization of the blood vessel wall (Sharif et al. 5.. Promoting endothelial cell adhesion and proliferation using a mixture of two PA nanofibers. 10) (Fishbein et al. Adenovirus-mediated gene delivery of eNOS to the vasculature was shown to inhibit restenosis and augment re-endothelialization (Sharif et al. and then incorporating it into a nanocomposite polymer. TEM = transmission electron microscopy. liposomal formulations of eNOS were demonstrated to be effective against smooth muscle cell proliferation (Muhs et al. A therapeutic combination of NO donors and paclitaxel coated onto stents showed synergistic anti-restenotic effects (Lin et al. 2003)... Copyright© 2011 Elsevier Ltd.1. and subsequently guiding them to stents using magnetic field gradients expedited the process of cell mobilization and re-endothelialization (Polyak et al. 9) (Nakano et al. this aspect of nano-encapsulation of pharmacologic agents appear most promising in nanotechnology-based stent coatings. 2009). robust test have to be conducted prior to clinical use and FDA-approval. localized in a biofunctionalized polymer..

160 Table 2 In vitro engineering tests. / Journal of Biotechnology 164 (2013) 151–170 Stent material specification conformance testing Chemical analysis Material characterization Meet specifications for ASTM F-138 Surface contamination Mechanical properties: tensile strength & elongation Stent corrosion resistance SEM analysis to detect surface contaminants or impurities Determine yield strength. to ensure that stent would not fail due to fatigue (as determined by modified Goodman analysis) FEA evaluated stent designs “deployed in a straight or bend configuration” when subjected to loading conditions expected in coronary arteries Fatigue failure should not occur over 400 million cycles of loading 500 million cycles conducted on stent. Tan et al. Stent material specification conformance testing encompasses: material characterization.and post tracking through a tortuous anatomy using microscopy and SEM Using finite element analysis (FEA) Addition of coating to stent should not change critical location of stresses during expansion and during in vivo loading Critical stress location within coating should be in the same location as found on bare (uncoated) stent Analysis of bare stent. For coronary stents. In vitro engineering tests Description A. and deployed to maximum diameter conditions using microscopy Qualitative comparison of coating integrity is performed pre. and stent integrity/dimensional and functional attributes.5 mm Stents are examined under magnification for potential cracks Determine stent resistance to radial load Stents deployed to nominal stent diameter and placed in radial crush tester Qualitative comparison of coating in pre-deployed. to demonstrate ability of stent to maintain structural integrity SEM used to assess surface of stent to check for fatigue-induced surface defects Accelerated in vivo testing (up to 400 million cycles) when expanded beyond nominal diameter Static magnetic field of 3-Tesla Spatial gradient field of 525 Guass/cm Maximum whole-body averaged specific absorption rate (SAR) of 2 W/kg for 20 min of scanning Stent temperature rise should be less than 0. mechanical properties (tensile strength and elongation). surface contamination. and galvanic . and percent elongation of tubing sizes used to fabricate stent Conform to ASTM F562 Conform to ASTM F2129 “Standard Test Method for Conducting Cyclic Potentiodynamic Measurements to Determine the Corrosion Susceptibility of Small Implant Devices” Test conducted to evaluate relative susceptibility to pitting/crevice corrosion using corrosion techniques outlined in ASTM F746 and using sample preparation techniques conforming to ASTM F2129 Post fatigue testing for overlapped stents to determine potential for fretting corrosion Different stents are overlapped with one another to determine potential for galvanic corrosion Fretting corrosion Galvanic corrosion Stent integrity testing/dimensional & functional attributes Measure and optically inspect stent dimensions correspond to product specifications Stent dimensional verification Calculated using stent nominal dimensional values and is based on ratio of stent area to area of vessel Percent surface area Length changes upon expansion: foreshortening Stent expansion uniformity Percentage change in stent length measured to determine amount of length reduction the stent may experience after expansion to the nominal inflation pressure Foreshortening is calculated by subtracting expanded length from the length while crimped on catheter Units are inflated to nominal inflation pressure. when expanded beyond nominal maximum diameter. balloon deflated. when expanded beyond nominal maximum diameter. and measurements of stent diameter taken along expanded stent length Product must be within 10% of the labeled diameter at nominal pressure along stent length To quantify the amount of stent diameter reduction experience after removal of inflated balloon to correlate this parameter to the recommended sizing procedures System is inflated to rated burst pressure (RBP) and balloon removed Recoil calculated by subtracting internal diameter after balloon deflation from internal stent diameter still mounted on inflated balloon To determine if plastic deformation experienced by the stent when expanded from compressed profile to the final maximum deployed diameter can produce crack initiation of the stent Stents are deployed to their largest possible diameters by inflating each delivery system to nominal plus 0. deployed to nominal. ultimate tensile strength. fretting corrosion. in vitro engineering tests comprises of 2 main parts: stent material specification conformance testing. stent corrosion resistance.5 ◦ C at a maximum whole body averaged SAR of 2 W/kg for 20 min of MR scanning in a 3-Tesla MR scanner Stent should not move or migrate when exposed to MR scanning immediately post-implantation Determine image artifact extension from device/lumen centerline when scanned in non-clinical testing using 3-Tesla MR system with a send-receive RF body coil Radiopacity Addition of coating should not add or detract from the radiopacity of stent Stent Recoil Stent integrity/crack initiation Radial stiffness & radial strength Stent expansion/coating evaluation Coating stress analysis Finite element analysis (FEA) Accelerated fatigue testing Magnetic resonance imaging (mri) safety & compatibility The benchmark to use would be to closely adhere to tests that were conducted on FDA-approved devices.

C Release profile of nanoparticle-eluting stent. stent recoil. Scale bar = 1 mm. Stent integrity testing includes: stent dimensional verification. PAA-BP modified steel surface shows P(2p) and persistent Fe(2p) signals. monomer content. A summary and description of these tests can be found in Table 2. magnetic resonance imaging (MRI) safety and compatibility.A. Reproduced with permission from Fishbein et al. corrosion. SEM = scanning electron microscopy. B SEM of nanoparticle eluting stent. A Light and fluorescence microscopy of FITC encapsulated in nanoparticles via cationic electrodeposition coating technology. XPS = X-ray photoelectron spectroscopy. High magnification on right. 10. / Journal of Biotechnology 164 (2013) 151–170 161 Fig. with peak changes indicating bisphosphonate addition. finite element analysis. scale bar = 1 ␮m. Copyright© 2005 The National Academy of Sciences of the USA. stent expansion/coating evaluation. further tests regarding the polymer matrix coating and drug release kinetics would have to be ascertained as well. coating stress analysis. PAA-BP = polyallylamine bisphoaphonate. SPDP = N-succinimidyl 3-(2-pyridyldithio) propionate. radial stiffness and radial strength. polydispersity. percent surface area. Tan et al. Coating characterization tests Material analysis—polymer Chemical analysis—polymer Chemical analysis—drug Total drug content Dose density Drug content along stent length Total drug related substances Coating thickness Coating uniformity/reproducibility In vitro elution Particulates Description Testing of polymer components to ensure conformity to raw materials specifications and incoming inspection procedures Appropriate assays conducted to determine Mw. chemical analysis of polymer. Reproduced with permission from Nakano et al. (2009). If a DES is being developed. length changes upon expansion (foreshortening). Fig. Coating characterization test generally involves: material analysis of polymer. (2006). Table 3 Coating characterization test. Low magnification on left. Gene-eluting stents. NMR = nuclear magnetic resonance. Nanoparticle-eluting stents. and radiopacity. Copyright© 2009 American College of Cardiology Foundation. Mn. FITC = fluorescein-isothiocyanate. 9. scale bar = 100 nm. stent integrity/crack initiation. stent expansion uniformity. presence/formation of oligomers & free monomers Drug substance tested to ensure conformity to incoming Certificate of Analysis Quantitatively determine total amount of drug substance on stent Dose per unit area is calculated Characterize uniformity of distribution of drug along length of stent Quantitatively determine type and amount of impurities and degradation products on stent Measure thickness of coating on stent Determine coating uniformity and reproducibility from stent to stent and from batch to batch Measure release kinetics of drug Determine particulate levels after stent deployment Must be within USP < 788 > specification for small volume injections . XPS detection of phosphorus (D) and iron (E). (A) PAA-BP synthesis with the corresponding peaks (B and C) using NMR spectroscopy to show chemical shifts. iNOS = inducible nitric oxide synthase. accelerated fatigue testing. (F) Adenovirus containing iNOS gene tethered on PAA-BP modified metal surface.

and how accurately its data can be extrapolated to humans. For stents. 5. Apolipoprotein E (apoE) deficient mouse is a particularly useful model for studying atherosclerosis. as they are bred to spontaneously develop atherosclerotic lesions (Meir and Leitersdorf. and therefore have a high level of serum LDL. Table 7 provides a comparison between the different biological characteristic and responses to stent implantation between various animal models. Animal models Animal model studies are an integral part of the R&D process before the medical device in question can be brought to clinical trials (Fig. in vitro mouse lymphoma/part 3. acute systemic toxicity/part 11. hemolysis (extract method)/part 4. material-mediated pyrogenicity (rabbit)/part 11. drug content uniformity. Although not strictly a requirement prior to FDA-approval. manufacturing. Stages Platelet aggregation. thrombus formation at injury site Elastic and vasotonic recoil Inflammation Proliferation: re-endothelialization. manufacturing & controls (CMC) testing. 13-week systemic toxicity following subcutaneous implantation in rats/part 6 and 11. 11. Inception to Actualization. ames mutagenicity/part 3. 2004). small transgenic animal models can serve as useful tools in studying atherosclerosis. Further supportive analytical chemistry tests include chemical characterization of extractables via ICP analysis. hemolysis (direct contact)/part 4. Small animal studies tend to be preliminary studies conducted to obtain the necessary data and endpoints before progressing into large animal studies.2. Perhaps the most important aspect for any medical devices before animal implantation studies would be to assess its biocompatibility. manufacturing. cytotoxicity (direct contact)/part 5. (a) Newly developed coronary stent. A battery of tests have to be conducted. the Watanabe Heritable Hyperlipidaemic (WHHL) rabbit lack receptors for low density lipoprotein (LDL). target vessel Box 1: Comparing pigs and humans. In addition. For example. A plethora of animal studies pertaining to stents have been conducted. Tan et al. it has to conform to the industry standard of ISO 10993. and large animal studies. and residuals and leachables. Large animal studies include pigs. 1998). and non-human primates. and controls (CMC) testing would have to be done as well. drug identity. A description of these tests can be found in Table 5. Clinical trials in humans A crucial step in bringing a product from bench to bedside is conducting clinical trials. smooth muscle cell formation. total drug content. 11). and Box 1). and complement activation (C3a and SC5b-9)/part 4. and they are generally classified into small animals studies. dogs. and particulates (Table 4). the use of pigs is the most widely studied animal model.162 Table 4 Chemistry. Also. target vessel revascularization (TVR). and particulates (Table 3). / Journal of Biotechnology 164 (2013) 151–170 Description Polymers tested to ensure conformity to specifications Verify identity of drug substance Quantitatively verify amount of drug and types of impurities on stent Multiple stents are assayed to verify uniformity of drug content between individual stents Verify that residual levels of solvents used in manufacturing process are below acceptable limits established for finished goods release Measure in vitro release profile of drug on stent Specification based on elution characteristics of stents evaluated in clinical investigation Particulate levels are monitored to verify that they remain below acceptable levels as established in product specifications chemical analysis of drug. and all FDA-approved stents have used pigs as its definitive animal model (Table 6. coating uniformity/reproducibility. drug content along stent length. coating thickness. sensitization (guinea pig maximization)/part 10. which include: cytotoxicity (L929 MEM elution)/part 5. (d) In vivo animal studies. in vitro elution. Chemistry. intracutaneous reactivity/part 10. dose density. fibrin deposition. (c) In vitro chemical tests. total drug-related substances. Stents have to undergo rigorous testing before being approved for clinical use. This involves: material analysis of polymer. 5. in vitro drug elution. Chemistry. residual solvents. in vivo mouse micronucleus/part 3. thus serving as a useful model for familial hypercholesterolaemia in humans Fig.3. This is also where most products fail to gain regulatory approval for clinical use. drug content/impurities. sheep. (Burnstock and Aliev. The type of animal to be used largely depends on how similar its biology is to humans. (b) Mechanical and in vitro engineering tests. and rabbits. & controls (CMC) testing Material analysis—polymer Drug identity Drug content/impurities Drug content uniformity Residual solvents In vitro elution Particulates A. extracellular matrix production Arterial remodeling Pig 0–14 days Human 0–30 days 0–3 days 0–14 days 3–28 days 0–3 days 0–30 days 14 days–6 months 14–90 days 2 months–3 years . the main clinical endpoints to be evaluated are: target lesion revascularization (TLR). For coronary stents. (e) Clinical trials in humans. Some examples of small animal studies include rats/mice.

it is therefore hardly surprising that major industry players like Boston Scientific and Abbott Vascular continue to dominate the stent market. 2000). subchronic (90 days or 10% of animal lifespan). Recent toxicology studies of metal hip implants reported the leaching of metal nanoparticles into the bloodstream. degeneration and lysis of cells are observed around the test material Intradermal injection conducted on guinea pigs This is to determine if device causes a delayed dermal contact sensitization reaction 163 Cytotoxicity (Direct Contact)/Part 5 Sensitization (Guinea Pig Maximization)/Part 10 Intracutaneous Reactivity/Part 10 To determine tissue reaction to extracts made from the device Used when irritation tests are inappropriate for the device. More clinical studies investigating the potential of coating BMS with a biocompatible polymer without any pharmacologic agents should be conducted. platelets and platelet functions. Interestingly. Although there is no evidence to suggest that metal debris from BMS would cause inflammation or cancer. The BiodivYsioTM (Biocompatibles Cardiovascular Inc) is the only FDA-approved phosphorylcholinecoated stent. Despite the anti-restenotic benefits of DES. some form of non-biodegradable and biocompatible coating on bare metal should be advocated. hematology and immunology Exposure of serum to a test sample results in production of these fragments. frameshift and small deletions To test for genotoxic compounds Increase in frequency of micronucleated polychromatic erythrocytes would indicate chromosomal damage Assesses thrombosis. degeneration and lysis of cells observed under microscope Recommended for low density materials Test material is placed directly onto cells and incubated in suitable condition Leachable chemicals from test materials can diffuse into culture medium during incubation and make contact directly with cell layer The chemicals released are concluded to be cytotoxic if malformation. there are calls for metal hip implants to be coated with non-biodegradable polymers to prevent these potentially fatal complications. Hence. without any drug formulation (Galli et al. hematology and immunology Assesses thrombosis. and chronic (anything longer) Comprises of administering extracts intravenously into rabbits and monitoring their rectal temperatures over the course of several hours A significant rise in temperature indicates presence of pyrogens Determines the effects after implantation of biomaterials intended for use in medical devices Determines the potential mutagenic activity of an extract from a medical devices/material/chemical Test is performed as part of the genotoxicity battery of tests to determine if leacheables from a medical device/material or chemical are mutagenic Detects mutations at the thymidine kinase locus caused by base pair changes.A.0 billion by 2015 (Inc. which can be characterized quantitatively under standard conditions Acute Systemic Toxicity/Part 11 Material-Mediated Pyrogenicity (Rabbit)/Part 11 13-week Systemic Toxicity following Subcutaneous Implantation in Rats/Part 6 and 11 Ames Mutagenicity/Part 3 In vitro Mouse Lymphoma/Part 3 In vivo Mouse Micronucleus/Part 3 Hemolysis (Direct Contact) Part 4 Hemolysis (Extract Method)/Part 4 Complement Activation (C3a and SC5b-9)/Part 4 Supportive analytical chemistry tests Chemical characterization (extractables—ICP analysis) Chemical characterization (residuals and leachables) failure (TVF). subacute closure. major hemorrhagic vascular complication. major adverse cardiac events (MACE). cancer (Polyzois et al. this concept has been largely neglected due to the popularity of DES. subacute (14–28 days). Taking into account that considerable resources are needed for bringing stents from the experimental phase. there is also evidence supporting the creation of nanotopograhpy or nanowires on the metal struts themselves. Tan et al. Test/ISO 10993 part no. the issue which still needs to be addressed is the problem of late ST. major bleeding complications. platelets and platelet functions. Table 8 shows the clinical trials of various FDA-approved stents.b). to clinical trials and FDA-approval. Smith et al. / Journal of Biotechnology 164 (2013) 151–170 Table 5 Biocompatibility tests. The popularity of DES has largely overshadowed the use of BMS.. This could well form a viable alternative “middle ground” for patients who might develop adverse reaction to drugs seen in DES. 2012). e.. Although the introduction of stents has revolutionized interventional cardiology. 2012. The layer of polymer coating that remain even after the drug had completely eluted contributed to hypersensitivity and subsequent stent . devices having blood or compromised tissue contact Evaluates potential adverse effects of medical device on the body’s organs and tissues that are remote from the site of contact There are 4 categories: acute (24 h)... Inc.g. and a recent report by Global Industry Analysts. Although the idea of having a plain polymer coating without any drug formulations is appealing. cerebrovascular accident. The question of using non-biodegradable or biodegradable polymers for coating medical devices or implants is still open to debate. which enhanced endothelialization (Loya et al.. 6. Cytotoxicity (L929 MEM Elution)/Part 5 Description Determines cytotoxic effect of extracts of the test device using different extracting media and conditions Extracts are transferred to cell layer and incubated Malformation. using radio frequency plasma surface texturing. Future directions and concluding remarks Around one million stenting procedures are done each year in the US. late thrombosis. coagulation. 2010). due to its anti-restenotic effects. much still remains to be improved upon. causing inflammation and in some cases. coagulation. valued the coronary stent market to exceed US $8. stent thrombosis. 2010a.

TEM & immunohistochemistry Dose response relationship for various SES Evaluation of high-dose SES Drug release kinetics (evaluated in hours to a few weeks) Arterial & systemic drug levels Histological & histomorphometric evaluation Chronic vascular response and acute delivery Subacute tissue reaction in vessel and myocardium Thrombogenicity evaluation of stent at 11 days Angiographic patency Cell proliferation 10. 2.5. 3. MI Angiographic vessel patency Visual fracture analysis Histological & histomorphometric evaluation Acute device handling & deliverability Chronic vascular response Angiography Degree of re-endothelialization using SEM 8. 3. 30. 60.5.25.0 Lengths: 8. 14.5. 3. 12 Diameters: 3. 90. Manufacturer Cordis Model CYPHER Date approved 24 Apr 2003 Animals Yucatan Mini-swine Domestic swine Vessels LAD LCX RCA Stent dimensions (mm) Diameter: 3 Lengths: Time (days) 1. 90.0. 3. 180.0. 12 Boston Scientific PROMUS 22 Nov 2011 Swine LAD LCX RCA . 30. 90. / Journal of Biotechnology 164 (2013) 151–170 Juvenile Yorkshire swine Yucatan Mini-swine LCX RCA 2. 12. 3.75.0. 5. 3.164 Table 6 Animal (porcine) studies in FDA-approved drug-eluting stents.0 Lengths: 8. 45.5. 180. morphometry. myocardial effects Drug release kinetics 28. 2. 2 years Drug release kinetics (evaluated in hours to a few weeks) Arterial & systemic drug levels Effects of high dosage drug on platelet function Morbidity. 7.0. 4. stent thrombosis. 18 Boston Scientific ION 22 Apr 2011 Porcine Rabbit (Iliac artery) LAD LCX RCA Iliac artery Diameters: 2. 2. Lengths: 8. morphology.0. 4. 180 Endpoints Drug release kinetics (evaluated in hours to a few weeks) Arterial & systemic drug levels Histological & histo-morphometric evaluations coupled with angiography Chronic vascular response & acute delivery Evaluation of re-endothelialization by SEM. 10. mortality. 15. 90. 18 Medtronic Vascular Endeavor 1 Feb 2008 Domestic swine LAD Diameters: 1. 270 Establish safety Mortality. 11. 180 A. Tan et al. 28.

25. 12. 2. 12 Diameters: 2. 3.0 Lengths: 1–5 days Long term: 1. 365 Drug release kinetics (evaluated in hours to a few weeks) Arterial & systemic drug levels Angiography Histological & histomorphometric evaluation Degree of endothelialization using SEM Acute delivery Chronic vascular response Evaluation of polymer safety Abbott Vascular XIENCE PRIME 1 Nov 2011 Farm swine Yucatan swine LAD LCX RCA Diameters: 3 Lengths: 12 28.0 Lengths: 38 Diameters: 2.0. Tan et al. 300 Drug release kinetics (evaluated in hours to a few weeks) Chronic vascular response Quantitative coronary angiography Histological & histomorphometric evaluation Degree of endothelialization using SEM Early and late patency rates A. 4.0. 12 28. 3. 3.75.50.5. 3. 4. 180.0 Boston Scientific TAXUS Liberté Long 13 July 2009 Not stated Not stated Diameters: 2.0 Lengths: 8.5. 3. 2. Not stated Biological response of vessel to stent Ability to deliver hand crimped stents using a variety of balloon catheters Histological and pathological studies Not stated Boston Scientific TAXUS Liberté Atom 21 May 2009 Not stated Not stated Not stated Not stated Abbott Vascular XIENCE nano 24 May 2011 Not stated Not stated Not stated Not stated Medtronic Resolute 17 Feb 2012 Domestic Farm Swine Yucatan Mini Swine Not stated 165 .Abbott Vascular XIENCE V 2 Jul 2008 Farm swine New Zealand white rabbit (iliac artery) Yucatan swine LAD LCX RCA Iliac artery Diameters: 2. 3.5. 240. Bio-divYsio 29 Sep 2000 Not stated Not stated Diameters: Short term: 3. 16. 20.25 Lengths 8. 24. 90. / Journal of Biotechnology 164 (2013) 151–170 Bio-compatibles Cardiovascular Inc.5 Lengths: 8. 6 months 15.5. 28. 3.75. 32 Diameters: 2. 180.

This would perhaps involve some form of antibody/functional peptide targeting which would be specific for smooth muscle cells but not endothelial cells. The next challenge in this topic of stent technology would be to develop methods that would specifically target the elimination of smooth muscle cell proliferation. the material itself has to be a favorable platform on which endothelial cells can adhere to and proliferate on. pathophysiology mimics humans High cost Inconvenience due to large size Highly susceptible to inflammation with implanted devices Neointimal growth peaks at 1 month post-stenting. achieving the maximum therapeutic benefit using the minimum dosage to minimize side effects. The topic of nanotechnology has gained considerable foothold in the basic sciences as well as applied and clinical medical research. Biodegradable polymer coatings on DES were thus designed to erode in tandem with the drug release. However. This is evident not only in the proliferation of various research journals dedicated to the subject of nanotechnology. the potential for nanotechnology in stent coatings appears promising. Hence. The importance of NO for maintaining a healthy endothelium must be emphasized. and would be well poised to address the current challenges faced today. To increase the probability of capturing endothelial cells. while the subsequent “BMS phase” would circumvent the problem of late ST. useful as atherosclerosis model Pig Large Coronary artery Accepted as the most appropriate model for preclinical evaluation Used for stent device approval by FDA Coronary anatomy. essentially leaving behind a BMS. Tan et al. the polymer platform must be one that is highly compatible with biological systems while harboring the ability to interface with nanotechnology-based drug delivery systems. but also the volume and rate at which they are published (Rogach. 2012). . Furthermore. hence not a good approximation Elastic nature of iliac arteries less prone to injury compared to muscular coronary arteries Rabbit Small Iliac artery Low cost First animal studies regarding DES were used in rabbits Complete endothelialization occurs after 21 days Flow dynamics of rabbit iliac artery similar to pig coronary artery Readily susceptible to dietary-induced hypercholesterolemia. increased therapeutic index. physiology. / Journal of Biotechnology 164 (2013) 151–170 Advantages Low cost Availability Reduced ethical concerns Well-defined genetic characterization Transgenic and gene knock-out mice Disadvantages Lack efficacy in predicting restenosis in humans Little thrombus formation Neointimal hyperplasia bears little resemblance to human pathology specimens Vessels less prone to injury compared to humans Only morphometric analysis can be conducted due to small size. it still remains to be seen if this is indeed a viable method. while encouraging the growth of endothelial cells. controlled drug release and endothelial progenitor cell capture technology would form the cornerstone of the next generation cardiovascular stent coatings. This was predicated on the hypothesis that the initial “DES phase” would prevent restenosis. In conclusion.166 Table 7 Comparison of different animal models. Apart from a biocompatible and haemocompatible polymer. but would not itself elicit an immunological response from the body. Nano-encapsulation of cell-specific drugs would also aid in the targeted delivery of pharmacologic agents. as the current range of FDA-approved DES are coated with non-biodegradable (durable) polymers. specific antibodies and peptides can be incorporated into the polymer. From targeted drug delivery. localized delivery of pharmacologic agents using nanoparticles would mean a higher therapeutic index. Developing NO-eluting polymers could well pave the way for the next generation of stent coatings. Animal model Rat/Mouse Animal type Small Vessel Aorta A. it is of paramount importance to have a highly biocompatible polymer that would not only serve as a protective coating against the stent. no angiographic endpoints Different vessel physiology in iliac artery and coronary artery. This would minimize the risk of proliferation of vascular smooth muscle cells that can cause restenosis. compared to 6 months in humans Resistant to neointimal formation High fibrinolytic activity and coagulation system distinctive from that of humans Fails to predict thrombotic complications in humans Not many studies done Dog Large Coronary/peripheral arteries Low cost Availability Ease of handling Sheep Large Coronary artery Docile Similar fibrinolytic and coagulation system to humans Similar coronary anatomy to humans Phylogenetic proximity Very similar to humans Non-human primates Large Coronary artery Ethical considerations High cost Very few studies conducted thrombosis. and controlled/sustained drug release. Taking a “nano” perspective allows one to delve deeper into the mechanisms of various problems in biology and medicine. Finally. the convergence of biofunctionalized polymers.

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