Construction Of Multifunctional Stent Coatings And Study On Biocompatibility

Preventing restenosis and late-stage thrombosis (LST) are crucial to the success of vascular stents. The advent of drug eluting stent (DES) systems has revolutionized coronary intervention therapy due to their abilities of dramatically reducing the possibility of restenosis through inhibiting vascular smooth muscle cells (SMCs) proliferation. While solving one problem, the use of DES has been associated with a small but increased risk of LST due to a failure of vessel wall healing. Since the value of a functional and intact endothelium in the prevention and attenuation of restenosis and LST has been preliminary proved, rapid endothelialization of stent has been proposed. Unfortunately, most of efforts only aimed at partially enhancing the endothelial cells (ECs) growth, while ignoring anti-proliferative or anticoagulant properties, which were limited in their clinical application. Hereon, we proposed and highlighted that an ideal vascular stent should have multiple functions, with the specific abilities to improve hemocompatibility and encourage endothelialization, while inhibit SMC proliferation.To engineer such multiple functions on stent, this thesis focused on developing new surface coating modification strategies. The work described in this thesis concerns the plasma polymerized coating and bioinspired catecholic chemistry used for coupling a kind of bioactive molecules or agents with multiple biological functions. The first part of this thesis focused on the evaluation on vascular compatibility of the newly introduced materials, plasma polymerized films especially mussel-inspired coating of polydopamine that were used for coupling bioactive molecules. Good resistance to the deformation behavior of compression and expansion of a stent and cytocompatibility were found in both coatings, indicating potential application as a stent coating.Next, based on chemical coupling technique, bioactive molecules or agents including heparin, bivalirudin (BVLD), Gallic acid (GA) and nitric oxide (NO)-generating agent of 3,3-diselenodipropionic acid (SeDPA) were immobilized on plasma polymerized allylamien (PPAam) coatings rich in amine groups. Inspired by the formation of polydopamine, NO-catalytic adherent polymer coatings were synthesized through simple one-step surface dip-coating of objects into a mixed aqueous solution consist of NO-generating agent of cystamine (CySA) or selenocystamine (SeCA) and phenolic compounds such as GA, dopamine (Dopa), epigallocatechin gallate (EGCG) or catechol (Ca).Systemic evaluations on biocompatibility showed that all of the functional coatings had the ability to enhance ECs growth. Meanwhile the BVLD-functionalzed PPAam (BVLD-PPAam) coating exhibited excellent anticoagulation by inhibiting the activity of adsorbed thrombin. For the GA-functionalzed PPAam (GA-PPAam) coating, it significantly inhibited SMCs proliferation. Among these functional coatings, heparin-functionalzed PPAam (Hep-PPAam) coating and NO-catalytic coatings of SeDPA-functionalzed PPAam (SeDPA-PPAam) and adherent polymer coupling CySA and SeCA showed substantial effects on improving hemocompatibility, enhancing ECs growth, and inhibiting SMCs proliferation. It was found that the fate of ECs grown on heparin-functionalzed coating was closely dependent on the amount of heparin bound to the surface. The enhancement of ECs growth by heparin-functionalized surface occurred in a level of binding-heparin lower than about 3μg/cm2. Both NO-catalytic coatings were found to have the long-term and continuous ability to catalytically decompose endogenous S-nitrosothiols (RSNO) for generating NO, in which the generation of NO showed endothelium-like functions, with specific abilities to substantially inhibit collagen-induced platelet activation and aggregation and SMCs adhesion and proliferation and to stimulate EC growth. More importantly, NO-catalytic coatings created a favorable microenvironment of competitive growth of HUVECs over HASMCs for promoting re-endothelialization. It was noteworthy mentioned that the NO-catalytic coatings of adherent polymer coupling CySA and SeCA also showed the controlled the release rates of NO, and can strongly adhere on a wide variety of material surfaces.In addition to demonstrating the feasibility of strategy for multifunctional stent platform by coupling bioactive molecules with multiple functions, the results of this work help to further deciphering the biological responses to blood, ECs or SMCs, and will likely serve as a guide for the design of the new generation of vascular stents. Among these functional stent coatings, the Hep-PPAam, especially the NO-generating coatings are the most promising for developing the new generation of stent due to their versatile abilities to improve vascular compatibility.