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Coronary artery disease is among the primary causes of death worldwide. While synthetic grafts allow replacement of diseased tissue, mismatched mechanical properties between graft and native tissue remains a major cause of graft failure. Multi-layered grafts could overcome these mechanical incompatibilities by mimicking the structural heterogeneity of the artery wall. However, the layer-specific biomechanics of synthetic grafts under physiological conditions and their impact on endothelial function is often overlooked and/or poorly understood. In this study, the transmural biomechanics of four synthetic graft designs were simulated under physiological pressure, relative to the coronary artery wall, using finite element analysis. Using poly(vinyl alcohol) (PVA)/gelatin cryogel as the representative biomaterial, the following conclusions are drawn: (I) the maximum circumferential stress occurs at the luminal surface of both the grafts and the artery; (II) circumferential stress varies discontinuously across the media and adventitia, and is influenced by the stiffness of the adventitia; (III) unlike native tissue, PVA/gelatin does not exhibit strain stiffening below diastolic pressure; and (IV) for both PVA/gelatin and native tissue, the magnitude of stress and strain distribution is heavily dependent on the constitutive models used to model material hyperelasticity. While these results build on the current literature surrounding PVA-based arterial grafts, the proposed method has exciting potential toward the wider design of multi-layer scaffolds. Such finite element analyses could help guide the future validation of multi-layered grafts for the treatment of coronary artery disease.