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Mechanical and morphological anisotropy play key roles in the function of native cardiac tissues. In the current study, finite element simulations, morphological and mechanical analysis were used to investigate interactions between the geometry of accordion-like honeycomb poly(glycerol sebacate) scaffolds and cardiomyocytes seeded via a collagen solution gelled within the pores. Specifically, the mechanical behavior of the accordion-like honeycomb scaffold itself, as well as the statistical arrangement of the collagen fibrils within the pores, were determined from uniaxial tensile testing, finite element simulations, and image analysis of confocal reflectance micrographs. Further, the shape, orientation, and deformation of individual, fluorescently labeled cardiomyocytes within the collagen gel-filled accordion-like honeycomb pores, were measured from 3-D reconstructions of laser scanning confocal z-stacks and compared with finite element predictions. Collectively, these results contribute toward our understanding of how scaffold microarchitecture imparts at both the macro-and micro-scales in promoting the formation of anisotropic engineered tissues mimicking myocardial structural-mechanics.