Incomplete endothelialization of intracoronary stents has been associated with stent thrombosis and recurrent symptoms, whereas prolonged use of dual antiplatelet therapy increases bleeding-related adverse events. Facilitated endothelialization has the potential to improve clinical outcomes in patients who are unable to tolerate dual antiplatelet therapy. The objective of this study was to demonstrate the feasibility of magnetic cell capture to rapidly endothelialize intracoronary stents in a large animal model. A novel stent was developed from a magnetizable duplex stainless steel (2205 SS). Polylactic-co-glycolic acid and magnetite (Fe3O4) were used to synthesize biodegradable superparamagnetic iron oxide nanoparticles, and these were used to label autologous blood outgrowth endothelial cells. Magnetic 2205 SS and nonmagnetic 316L SS control stents were implanted in the coronary arteries of pigs (n = 11), followed by intracoronary delivery of magnetically labeled cells to 2205 SS stents. In this study, we show extensive endothelialization of magnetic 2205 SS stents (median 98.4% cell coverage) within 3 days, whereas the control 316L SS stents exhibited significantly less coverage (median 48.9% cell coverage, p < 0.0001). This demonstrates the ability of intracoronary delivery of magnetic nanoparticle labeled autologous endothelial cells to improve endothelialization of magnetized coronary stents within 3 days of implantation.

Department of Cardioangiology St Anne's University Hospital Brno Czech Republic

Department of Cardiovascular Medicine Mayo Clinic Rochester Minnesota

Department of Physiology and Biomedical Engineering Mayo Clinic Rochester Minnesota

Division of Engineering Mayo Clinic Rochester Minnesota

School of Medicine University of Adelaide Adelaide Australia

School of Pharmacy and Institute of Cellular Medicine Newcastle University Newcastle upon Tyne United Kingdom

Vascular Research Centre South Australian Health and Medical Research Institute Adelaide Australia

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Gilard M., Barragan P., Noryani A.A., et al. . 6- Versus 24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients nonresistant to aspirin: the randomized, multicenter ITALIC trial. J Am Coll Cardiol 65, 777, 2015 PubMed

Colombo A., Chieffo A., Frasheri A., et al. . Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual antiplatelet therapy: the SECURITY randomized clinical trial. J Am Coll Cardiol 64, 2086, 2014 PubMed

Mauri L., Kereiakes D.J., Yeh R.W., et al. . Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 371, 2155, 2014 PubMed PMC

Duckers H.J., Soullie T., den Heijer P., et al. . Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent). EuroIntervention 3, 350, 2007 PubMed

Jantzen A.E., Lane W.O., Gage S.M., et al. . Use of autologous blood-derived endothelial progenitor cells at point-of-care to protect against implant thrombosis in a large animal model. Biomaterials 32, 8356, 2011 PubMed PMC

Kempe H., Kates S.A., and Kempe M. Nanomedicine's promising therapy: magnetic drug targeting. Expert Rev Med Devices 8, 291, 2011 PubMed

Pan Y., Du X., Zhao F., and Xu B. Magnetic nanoparticles for the manipulation of proteins and cells. Chem Soc Rev 41, 2912, 2012 PubMed

Chorny M., Fishbein I., Adamo R.F., Forbes S.P., Folchman-Wagner Z., and Alferiev I.S. Magnetically targeted delivery of therapeutic agents to injured blood vessels for prevention of in-stent restenosis. Methodist Debakey Cardiovasc J 8, 23, 2012 PubMed PMC

Chorny M., Fishbein I., Forbes S., and Alferiev I. Magnetic nanoparticles for targeted vascular delivery. IUBMB Life 63, 613, 2011 PubMed

Pislaru S.V., Harbuzariu A., Gulati R., et al. . Magnetically targeted endothelial cell localization in stented vessels. J Am Coll Cardiol 48, 1839, 2006 PubMed

Polyak B., Fishbein I., Chorny M., et al. . High field gradient targeting of magnetic nanoparticle-loaded endothelial cells to the surfaces of steel stents. Proc Natl Acad Sci U S A 105, 698, 2008 PubMed PMC

Pislaru S.V., Harbuzariu A., Agarwal G., et al. . Magnetic forces enable rapid endothelialization of synthetic vascular grafts. Circulation 114, I314, 2006 PubMed

Uthamaraj S., Tefft B.J., Klabusay M., Hlinomaz O., Sandhu G.S., and Dragomir-Daescu D. Design and validation of a novel ferromagnetic bare metal stent capable of capturing and retaining endothelial cells. Ann Biomed Eng 42, 2416, 2014 PubMed

Uthamaraj S., Tefft B.J., Hlinomaz O., Sandhu G.S., and Dragomir-Daescu D. Ferromagnetic bare metal stent for endothelial cell capture and retention. J Vis Exp 103, e53100, 2015 PubMed PMC

Tefft B.J., Uthamaraj S., Harburn J.J., Klabusay M., Dragomir-Daescu D., and Sandhu G.S. Cell labeling and targeting with superparamagnetic iron oxide nanoparticles. J Vis Exp 105, e53099, 2015 PubMed PMC

Moore C.G., Carter R.E., Nietert P.J., and Stewart P.W. Recommendations for planning pilot studies in clinical and translational research. Clin Transl Sci 4, 332, 2011 PubMed PMC

Gulati R., Jevremovic D., Peterson T.E., et al. . Diverse origin and function of cells with endothelial phenotype obtained from adult human blood. Circ Res 93, 1023, 2003 PubMed

Lee S.J., Jeong J.R., Shin S.C., et al. . Nanoparticles of magnetic ferric oxides encapsulated with poly(d,l latide-co-glycolide) and their applications to magnetic resonance imaging contrast agent. J Magn Magn Mater 272, 2432, 2004

Lee S.J., Jeong J.R., Shin S.C., et al. . Magnetic enhancement of iron oxide nanoparticles encapsulated with poly(d,l-latide-co-glycolide). Colloid Surface A 255, 19, 2005

Ge G., Wu H., Xiong F., et al. . The cytotoxicity evaluation of magnetic iron oxide nanoparticles on human aortic endothelial cells. Nanoscale Res Lett 8, 215, 2013 PubMed PMC

Yang F.Y., Yu M.X., Zhou Q., Chen W.L., Gao P., and Huang Z. Effects of iron oxide nanoparticle labeling on human endothelial cells. Cell Transplant 21, 1805, 2012 PubMed

Yang J.X., Tang W.L., and Wang X.X. Superparamagnetic iron oxide nanoparticles may affect endothelial progenitor cell migration ability and adhesion capacity. Cytotherapy 12, 251, 2010 PubMed

Ingram D.A., Mead L.E., Tanaka H., et al. . Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood. Blood 104, 2752, 2004 PubMed

Lin Y., Weisdorf D.J., Solovey A., and Hebbel R.P. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 105, 71, 2000 PubMed PMC

Chade A.R., Zhu X., Lavi R., et al. . Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 119, 547, 2009 PubMed PMC

Gulati R., Jevremovic D., Witt T.A., et al. . Modulation of the vascular response to injury by autologous blood-derived outgrowth endothelial cells. Am J Physiol Heart Circ Physiol 287, H512, 2004 PubMed

Zohra F.T., Medved M., Lazareva N., and Polyak B. Functional behavior and gene expression of magnetic nanoparticle-loaded primary endothelial cells for targeting vascular stents. Nanomedicine 10, 1391, 2015 PubMed PMC

Danhier F., Ansorena E., Silva J.M., Coco R., Le Breton A., and Preat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release 161, 505, 2012 PubMed

Kumari A., Yadav S.K., and Yadav S.C. Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf B Biointerfaces 75, 1, 2010 PubMed

Lo C.T., Van Tassel P.R., and Saltzman W.M. Poly(lactide-co-glycolide) nanoparticle assembly for highly efficient delivery of potent therapeutic agents from medical devices. Biomaterials 31, 3631, 2010 PubMed PMC

Shive M.S., and Anderson J.M. Biodegradation and biocompatibility of PLA and PLGA microspheres. Adv Drug Deliv Rev 28, 5, 1997 PubMed

Kwon H.Y., Lee J.Y., Choi S.W., Jang Y.S., and Kim J.H. Preparation of PLGA nanoparticles containing estrogen by emulsification-diffusion method. Colloid Surface A 182, 123, 2001

Lemoine D., Francois C., Kedzierewicz F., Preat V., Hoffman M., and Maincent P. Stability study of nanoparticles of poly(epsilon-caprolactone), poly(d,l-lactide) and poly(d,l-lactide-co-glycolide). Biomaterials 17, 2191, 1996 PubMed

Semete B., Booysen L., Lemmer Y., et al. . In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems. Nanomedicine 6, 662, 2010 PubMed

Corot C., Robert P., Idee J.M., and Port M. Recent advances in iron oxide nanocrystal technology for medical imaging. Adv Drug Deliv Rev 58, 1471, 2006 PubMed

Provenzano R., Schiller B., Rao M., Coyne D., Brenner L., and Pereira B.J. Ferumoxytol as an intravenous iron replacement therapy in hemodialysis patients. Clin J Am Soc Nephrol 4, 386, 2009 PubMed PMC

Schwenk M.H. Ferumoxytol: a new intravenous iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease. Pharmacotherapy 30, 70, 2010 PubMed

Levy M., Luciani N., Alloyeau D., et al. . Long term in vivo biotransformation of iron oxide nanoparticles. Biomaterials 32, 3988, 2011 PubMed

Li L., Jiang W., Luo K., et al. . Superparamagnetic iron oxide nanoparticles as MRI contrast agents for non-invasive stem cell labeling and tracking. Theranostics 3, 595, 2013 PubMed PMC

Nkansah M.K., Thakral D., and Shapiro E.M. Magnetic poly(lactide-co-glycolide) and cellulose particles for MRI-based cell tracking. Magn Reson Med 65, 1776, 2011 PubMed PMC

Granot D., Nkansah M.K., Bennewitz M.F., Tang K.S., Markakis E.A., and Shapiro E.M. Clinically viable magnetic poly(lactide-co-glycolide) particles for MRI-based cell tracking. Magn Reson Med 71, 1238, 2014 PubMed PMC

Yu M., Huang S., Yu K.J., and Clyne A.M. Dextran and polymer polyethylene glycol (PEG) coating reduce both 5 and 30 nm iron oxide nanoparticle cytotoxicity in 2D and 3D cell culture. Int J Mol Sci 13, 5554, 2012 PubMed PMC

Astanina K., Simon Y., Cavelius C., Petry S., Kraegeloh A., and Kiemer A.K. Superparamagnetic iron oxide nanoparticles impair endothelial integrity and inhibit nitric oxide production. Acta Biomater 10, 4896, 2014 PubMed

Wu X., Tan Y., Mao H., and Zhang M. Toxic effects of iron oxide nanoparticles on human umbilical vein endothelial cells. Int J Nanomedicine 5, 385, 2010 PubMed PMC

Huang Z.Y., Pei N., Wang Y.Y., et al. . Deep magnetic capture of magnetically loaded cells for spatially targeted therapeutics. Biomaterials 31, 2130, 2010 PubMed

Yellen B.B., Forbes Z.G., Halverson D.S., et al. . Targeted drug delivery to magnetic implants for therapeutic applications. J Magn Magn Mater 293, 647, 2005

Adamo R.F., Fishbein I., Zhang K., et al. . Magnetically enhanced cell delivery for accelerating recovery of the endothelium in injured arteries. J Controlled Release 222, 169, 2016 PubMed PMC

Polyak B., Medved M., Lazareva N., et al. . Magnetic nanoparticle-mediated targeting of cell therapy reduces in-stent stenosis in injured arteries. ACS Nano 10, 9559, 2016 PubMed

Kempe M., Kempe H., Snowball I., et al. . The use of magnetite nanoparticles for implant-assisted magnetic drug targeting in thrombolytic therapy. Biomaterials 31, 9499, 2010 PubMed

Chorny M., Fishbein I., Yellen B.B., et al. . Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields. Proc Natl Acad Sci U S A 107, 8346, 2010 PubMed PMC

Rathel T., Mannell H., Pircher J., Gleich B., Pohl U., and Krotz F. Magnetic stents retain nanoparticle-bound antirestenotic drugs transported by lipid microbubbles. Pharm Res 29, 1295, 2012 PubMed

Aviles M.O., Chen H.T., Ebner A.D., Rosengart A.J., Kaminski M.D., and Ritter J.A. In vitro study of ferromagnetic stents for implant assisted-magnetic drug targeting. J Magn Magn Mater 311, 306, 2007

Carter A.J., Laird J.R., Farb A., Kufs W., Wortham D.C., and Virmani R. Morphologic characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model. J Am Coll Cardiol 24, 1398, 1994 PubMed

Farb A., Sangiorgi G., Carter A.J., et al. . Pathology of acute and chronic coronary stenting in humans. Circulation 99, 44, 1999 PubMed