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Tissue engineering often uses synthetic scaffolds to direct cell responses during engineered tissue development. Since cells reside within specific niches of the extracellular matrix, it is important to understand how the matrix guides cell response and then incorporate this knowledge into scaffold design. The goal of this review is to review elements of cell–matrix interactions that are critical to informing and evaluating cellular response on synthetic scaffolds. Therefore, this review examines fibrous proteins of the extracellular matrix and their effects on cell behavior, followed by a discussion of the cellular responses elicited by fiber diameter, alignment, and scaffold porosity of two dimensional (2D) and three dimensional (3D) synthetic scaffolds. Variations in fiber diameter, alignment, and scaffold porosity guide stem cells toward different lineages. Cells generally exhibit rounded morphology on nanofibers, randomly oriented fibers, and low-porosity scaffolds. Conversely, cells exhibit elongated, spindle-shaped morphology on microfibers, aligned fibers, and high-porosity scaffolds. Cells migrate with higher velocities on nanofibers, aligned fibers, and high-porosity scaffolds but migrate greater distances on microfibers, aligned fibers, and highly porous scaffolds. Incorporating relevant biomimetic factors into synthetic scaffolds destined for specific tissue application could take advantage of and further enhance these responses.

Synthetic scaffolds for musculoskeletal tissue engineering: cellular responses to fiber parameters