Immobilized-on-Metal Peptide Layer for Arterial NexT generation Stents – IMPLANTS

Metallic stents are widely used in endovascular treatment of coronary stenosis (balloon-expandable stents) and cerebral aneurysms (self-expandable flow diverters). In spite of the different design, both types of device are hampered by potentially life-threatening complications linked to the reaction of the blood elements and of the arterial wall in contact with the foreign body. Neointima formation (restenosis) and endoluminal thrombosis are associated with coronary stenting, while unstable sac occlusion and progressive dilation/fissuring of the aneurysmal wall are associated with flow diverters, but all are caused by the lack of a complete endothelial coverage of the metallic device/arterial wall which allows further activation and accumulation of blood leukocytes and platelets in the stented arterial segment. The use of “Active” stents has partially solved these issues because the associated anti-inflammatory/cytostatic drugs limit the processes leading to the proliferation of vascular stromal cells and neointima formation (restenosis). Unfortunately, their use requires a strengthening and an indefinite continuation of the antithrombotic treatment because these drugs also prevent the growth of endothelial cells and thus prevent the homeostatic endothelial covering of the stent meshes which can therefore persist in activating the platelets of the blood, even long-time (>1 year) after their implantation.
Thus, the scientific and industrial community of arterial stents extensively pursues the research to identify innovative biomimetic coverings, which can prevent the local development of inflammation and thrombosis and promote endothelial cells covering allowing the integration of the medical device at the blood/vessel interface.
In this context, CD31 is a very interesting biological target, because this homophilic cell-cell regulatory receptor, highly expressed by resting endothelial cells, is necessary in order to prevent the activation of circulating leukocytes and platelets.
The aim of our project is to evaluate the improvement carried by directly coating stent surfaces with a CD31 biomimetic peptide, named P8RI. Preliminary data show that the covalent grafting of P8RI on superalloy sample surfaces is capable of conferring them the regulatory functions of CD31 such as survival and growth of endothelial cells and inhibition of leukocytes and platelet activation.
The specific objectives of this project are:
1) to optimize the procedure of modification of the metallic surfaces and grafting of P8RI in order to be compatible with the development of an arterial stent (preservation of the physico-chemical and biological properties of the covering upon different storage and manipulation conditions);
2) to analyze the biological properties of superalloys samples (flat CoCr and 316L discs and NiTi filaments) covered with the P8RI, as compared to control samples made of the same material, in terms of growth and continuity of endothelial cells, anti-inflammatory properties and anti-thrombotic properties, in vitro;
3) to transfer the method of the modification of surface and grafting of the peptide to commercially available stents, made by the same material, and compare their biocompatibility in vivo (implantation in farm sheep coronary and rabbit carotid arteries), as assessed by histological analysis of the stented arteries, in terms of endothelial cell covering of the stent struts, degree of vascular stromal cells’ hyperplasia, signs of inflammation (leukocyte infiltration / expression of pro-inflammatory molecules) and signs of thrombosis (presence of platelets / fibrin/ plasmin).