The main goal of this proposal is to develop coatings for the membrane of ECMO that dynamically interact with blood to suppress coagulation mediated by the activation of factor XII (FXII) upon adsorption to the membrane. Currently, heparin is used as anticoagulant to prevent clot formation at the cost of increasing the risk of hemorrhage. Recently, the systemic inhibition of FXII and FXI has emerged as a promising and safer strategy to prevent thrombosis with little or no risk of bleeding. However, this strategy fails to address the negative effect of the membrane surface in other blood components which also activate coagulation. To address these challenges, we will develop ultra-thin coatings for ECMO membrane that are non-thrombogenic, specifically interact, capture and inhibit activated FXII and FXI (FXIIa and FXIa) generated in situ, preventing the propagation of coagulation. Further, we will combine these inhibitory functions with fibrinolytic activity. First, we will develop a library of hydrogel coatings with an interface that display a brush-like structure which do not activate blood coagulation by prohibiting protein adsorption and cells adhesion. We will investigate how the physicochemical properties of the coatings influence the repellency to blood components. The main challenge is to minimize the adsorption-induced activation of FXII, but if some adsorption occurs, we need a mechanism to rapidly inhibit this process. We will decorate these coatings with biomolecules that specifically bind to FXIIa and FXIa and inactivate them, suppressing the propagation of coagulation. We will investigate different strategies to immobilize these inhibitors, maintaining their activity when confined to the coatings as well as their synergistic action. Because activation of coagulation may also occur at other parts of the circuit of the ECMO, we will also immobilize tissue plasminogen activator (tPA) allowing local fibrinolysis. tPA will simultaneously bind fibrin clots and plasminogen which is converted to plasmin that disintegrates the clot. We will investigate if tPA can enhance the action of the immobilized inhibitors. The final steps of the projects will be committed to study whether these coatings can improve hemocompatibility in animal models without interfering with hemostasis. We envision that this project will generate a broad scientific basis for the design and fabrication of hemocompatible coatings for ECMO and other blood contacting devices in which long-term application is of key importance.