Biotechnology and Applied Biochemistry In situ endothelialization of intravascular stents from progenitor stem cells coated with nanocomposite and functionalized biomolecules Meghna S. Motwani, 1 Yasmin Rafiei, 1 Aphrodite Tzifa, 2 and Alexander M. Seifalian 1,3∗ 1 Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, UK 2 Department of Congenital Heart Disease, Evelina Children’s Hospital Guy’s and St Thomas’ Hospital, Rayne Institute London, UK 3 Royal Free Hampstead NHS Trust Hospital, London, UK Abstract. Owing to their noninvasive nature, coronary artery stents have become popular demand for patients undergoing percutaneous coronary intervention. Late restenosis, in-stent restenosis, and late thrombosis, all mediated by the denuded endothelium, represent the most recurrent failures of vascular stent induction. Higher patency rates of stents can be achieved by restoring the native internal environment of the vessel—an endothelium monolayer. This active organ inhibits the inflammatory reaction to injury responsible for thrombus and intimal hyperplasia, thereby providing a novel therapeutic option to combat the unacceptably high prevalence of restenosis. As the climax of the nanotechnology era approaches, tissue engineering is being explored by means of exploiting the multipotent abilities of stem cells and their adherence to bioactive surface nanocomposite polymers. The endothelium can be reconstructed from neighboring intact endothelium and adherence of circulating endothelium progenitor cells. The latter takes place via a series of signaling events: mobilization, adhesion, chemoattraction, migration, proliferation, and finally their differentiation in mature endothelial cells. A nanotopography surface can orchestrate endothelium formation, attributable to cellular interactions promoted by its nanosize. This review encompasses the prospect of in situ endothelialization, the mechanisms regulating the process, and the advantages of using a new generation of bioactive nanocomposite materials for coating metal stent scaffolds. C  2011 International Union of Biochemistry and Molecular Biology, Inc. Volume 58, Number 1, January/February 2011, Pages 2–13 • E-mail: a.seifalian@ucl.ac.uk Keywords: coronary artery stents, nanocomposite material, POSS–PCU, polymer, endothelium progenitor cells, in situ endothelialization, stem cells, medical device, intervention 1. Introduction Hyperlipidemia often leads to formation of multiple occlusive plaques within the arteries, a condition known as atheroscle- rosis. It is a chronic vascular disease with numerous complica- tions, the most common being stenosis (concentric narrowing of the luminal cross-sectional area) and thrombosis (aggrega- tion of platelets to form blood clots) [1]. Endothelial cells (ECs) Abbreviations: CEPCs, circulating endothelial progenitor cells; DLC, diamond-like carbon; ECs, endothelial cells; ECGF, endothelial cell growth factor; ECM, extracellular matrix; eNOS, endothelial nitric oxide synthase; EPCs, endothelial progenitor cells; G-CSF, granulocyte colony stimulating factor; IH, intimal hyperplasia; MMP, matrix metalloprotease; NO, nitric oxide; PCU, poly(carbonate-urea)urethane; PEG, polyethylene glycol; POSS, polyhedral oligomeric silsesquioxane; SCF, stem cell factor; SDF-1, stromal cell-derived factor-1; SMCs, smooth muscle cells; SQS, silsesquioxane; TGFβ-1, transforming growth factor β-1; UV, ultraviolet; VEGF, vascular endothelial growth factor. ∗ Address for correspondence: Professor Alexander M. Seifalian, FIoN, Professor of Nanotechnology and Regenerative Medicine, Centre for Nanotechnology and Regenerative Medicine, Division of Surgery and Interventional Science, University College London, London, UK. Tel.: + 44 20 7830 2901, Fax: + 44 20 7472 6444; e-mail: a.seifalian@ucl.ac.uk. Received 21 December 2010; accepted 5 January 2011 DOI: 10.1002/bab.10 Published online 30 March 2011 in Wiley Online Library (wileyonlinelibrary.com) maintain homeostasis in the vessel wall and serve as a barrier between the vessel wall and the flowing blood; hence, endothe- lial dysfunction is thought to be a major event in development of atherosclerotic lesions [2]. Stent implantation has replaced traditional angioplasty procedures and the alternative graft im- plantation for the treatment of coronary heart disease in the past decade. The range of strategies offered by this noninvasive device has transformed the field of interventional cardiology forever [3]. Stents are cylindrical metal or metal–alloy meshes made from 316L stainless steel, tantalum, nitinol, cobalt alloy, or plat- inum iridium. The ideal stent should be biocompatible, resist thrombosis and other immune responses, and simultaneously enhance vascular tissue regeneration. Stents should be flexible enough to expand, yet hard enough for durability. Polymers have been used to coat stents to enhance their biocompatibility. Nu- merous polymer coatings for stents have been tested, such as polyurethane, polyethylene terephthalate, and polydimethyl- siloxane (silicone). The latest addition to this large family of biological conduits is nanocomposite polymers, which will be reviewed later [4],[5]. 2