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Flow fields and particle trajectories evolving in geometric perturbations were studied by Computational Fluid Dynamics (CFD) simulation and the model was verified experimentally also. The development of cell-depleted layer near the channel walls due to lift and shear forces were analyzed considering the applied flow rates and the geometric variation of singularities. An optimal flow rate was defined to avoid cell recirculation in the extractions to be deteriorating purity of the proposed plasma. The branch-to-branch development of the cell-depleted layer thickness was studied to prove the improvement of the separation technique due to the integrated inertial subsystems. The separation efficiencies of different geometries were defined and calculated and the optimal singularity shape was selected for further development the proposed Zweifach-Fung effect driven plasma separation system. © 2015 The Authors. 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