AbstractCardiopulmonary bypass (CPB) is a standard technique for cardiac surgery, but comes with the risk of severe neurological complications (e.g. stroke) caused by embolisms and/or reduced cerebral perfusion. We report on an aortic cannula prototype design (optiCAN) with helical outflow and jet-splitting dispersion tip that could reduce the risk of embolic events and restores cerebral perfusion to 97.5% of physiological flow during CPB in vivo, whereas a commercial curved-tip cannula yields 74.6%. In further in vitro comparison, pressure loss and hemolysis parameters of optiCAN remain unaffected. Results are reproducibly confirmed in silico for an exemplary human aortic anatomy via computational fluid dynamics (CFD) simulations. Based on CFD simulations, we firstly show that optiCAN design improves aortic root washout, which reduces the risk of thromboembolism. Secondly, we identify regions of the aortic intima with increased risk of plaque release by correlating areas of enhanced plaque growth and high wall shear stresses (WSS). From this we propose another easy-to-manufacture cannula design (opti²CAN) that decreases areas burdened by high WSS, while preserving physiological cerebral flow and favorable hemodynamics. With this novel cannula design, we propose a cannulation option to reduce neurological complications and the prevalence of stroke in high-risk patients after CPB.