Coronary stent CD31-mimetic coating favours endothelialization and reduces local inflammation and neointimal development in vivo Sergio Diaz-Rodriguez 1†, Charlotte Rasser 2†, Jules Mesnier 2, Pascale Chevallier 1, Romain Gallet 3, Christine Choqueux 2, Guillaume Even 2, Neila Sayah 2, Frédéric Chaubet 2, Antonino Nicoletti 2, Bijan Ghaleh 3, Laurent J Feldman 2,4, Diego Mantovani1, and Giuseppina Caligiuri 2,4* 1 Laboratory for Biomaterials and Bioengineering (CRC-I) Department of Min-Met-Mat Engineering and the CHU de Québec Research Center, Laval University, PLT-1745G, Québec, QC G1V 0A6, Canada; 2 Laboratory for Vascular Translational Science, Université de Paris, Inserm U1148, 46 rue Henri HUCHARD, Paris 75018, France; 3 Institut Mondor de Recherche Biomédicale, école nationale vétérinaire de Maisons-Alfort (ENVA), Institut National de la Santé et de la Recherche Médicale U955, GHU (Groupe Hospitalo-Universitaire) A. Chenevier, Henri Mondor Faculty of Medicine Paris Est, 8 Rue du Général Sarrail, Créteil 94010, France; and 4 Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Nord Val-de-Seine, Site Bichat, 46 rue Henri Huchard, Paris 75018, France † These authors are co-first authors. *Corresponding author. Tel: +33 1 40 25 75 56, Fax: +33 1 40 25 86 02, Email: [email protected] Aims The rapid endothelialization of bare metal stents (BMS) is counterbalanced by inflammation-induced neointimal growth. Drug-eluting stents (DES) prevent leukocyte activation but impair endothelialization, delaying effective device integration into arterial walls. Previously, we have shown that engaging the vascular CD31 co-receptor is crucial for endothelial and leukocyte homeostasis and arterial healing. Furthermore, we have shown that a soluble synthetic peptide (known as P8RI) acts like a CD31 agonist. The aim of this study was to evaluate the effect of CD31-mimetic metal stent coating on the in vitro adherence of endothelial cells (ECs) and blood elements and the in vivo strut coverage and neointimal growth. Methods and results We produced Cobalt Chromium discs and stents coated with a CD31-mimetic peptide through two procedures, plasma amination or dip-coating, both yielding comparable results. We found that CD31-mimetic discs significantly reduced the extent of primary human coronary artery EC and blood platelet/leukocyte activation in vitro. In vivo, CD31-mimetic stent properties were compared with those of DES and BMS by coronarography and microscopy at 7 and 28 days post-implantation in pig coronary arteries (n = 9 stents/group/timepoint). Seven days post-implantation, only CD31-mimetic struts were fully endothelialized with no activated platelets/leukocytes. At day 28, neointima development over CD31-mimetic stents was significantly reduced compared to BMS, appearing as a normal arterial media with the absence of thrombosis contrary to DES. Conclusion CD31-mimetic coating favours vascular homeostasis and arterial wall healing, preventing in-stent stenosis and thrombosis. Hence, such coatings seem to improve the metal stent biocompatibility. Figure 3 In vivo stent endothelialization at day 7 post-implantation. Representative examples of scanning electron microscopy imaging of the luminal surface of pig coronary arteries implanted with either bare metal or drug-eluting stent vs. CD31-mimetic plasma aminated or dip-coated stents (n = 9 stents/group), taken at low (top), medium (middle) or high (bottom) magnification. Arrowheads point at the absence of endothelialization over the drug-eluting stent struts. Note the presence of activated leukocytes (numerous pseudopods at their surface) tangled in a dense fibrin mesh over the endothelialized struts of bare metal stents. Non-activated (round-shaped) leukocytes can be identified over drug-eluting stent struts but there endothelial cells appeared detached one from another and covered with platelets and fibrin. Instead, the absence of leukocyte activation (round shape) was combined with the presence of a smooth and continuous endothelium, free from platelets and fibrin, over CD31-mimetic stent struts.