Advanced cell culture platforms: a growing quest for emulating natural tissues

In the body, cells inhabit within a complex three-dimensional (3D) extracellular matrix that provides physical and chemical signals to regulate the cell fate. Cultured cells in Petri dishes and tissue culture flasks (2D) receive completely different environmental cues compared to natural tissues, causing radical alterations in cell morphology and function. Three-dimensional culture models have been able to revolutionize biomedical applications by better emulating natural tissues. However, sample handling and high-throughput screening can be challenging with 3D cell culture. Moreover, most 3D matrices are unable to quantify intracellular mechanics due to their structurally undefined surface characteristics. Therefore, highly structured surfaces (21/2D) comprising various micro- and nano-patterns were introduced to address these limitations. The topographical substrates have also been shown to retain in vivo cell functionalities, such as proliferative capacity. Here, we review recent advancements in modulation of surface patterns that have been able to control cell adhesion in two or three dimensions, and their impacts on the cell behavior. Finally, we provide a comparison between 2D, 21/2D and 3D systems and present several clinical applications of non-planar substrates.