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is static, diffusion is passive, constant evaporation alters solute concentrations, frequent media changes are necessary, cell numbers plateau at confluence, the cell experiences stimuli largely unrelated to those it experiences in vivo) are viewed as less important than benefits (cells grow well, the approach is cost effective, 2D planes are easily imaged with inexpensive microscopes, existing body of data is 2D, granting agencies still fund it, and the method enables high throughput).

Yet, as I put it in a recent talk to a group of high school STEM whiz kids, “Your Petri Dish Is So 1887.”

SIGNIFICANCE

Few people ask (and fewer answer) these basic questions: Do the results of Petri dish—type cell culture experimentation mean anything? Are they at all relevant to the intent of the experiment, which in most cases is to model a process that occurs in the human body? Although the assumption is “yes,” in an increasing number of demonstrated cases the answer to these important questions is actually “no.”

A quantitative way to measure the “behavior” of a cell in culture is its gene expression. In a beautiful demonstration that answers the questions above, a comparison was made of key gene expression profiles of primary human cancers with comparative immortalized epithelial cells in 2D (Ridky et al. 2010). Tellingly, the correlation coefficient between the two datasets was 0.0. But there are much easier and cheaper ways to obtain datasets with exactly zero correlation to the behavior one is trying to characterize than to conduct 2D cell culture experiments!

The tremendous opportunity for improvement lies in the fact that cells are living organisms and can respond dynamically to local stimuli provided by and in their environment. The solution is to provide a different environment with more of the “right” physical, mechanical, and biochemical stimuli. Developments that address this challenge will affect much more than in vitro modeling of in vivo physiology. Aside from the desire to model human beings and the need to minimize the very serious consequences of the scientific method for certain kinds of questions, better in vitro systems have enormous implications as both manufacturing methods for implants (e.g., in tissue engineering and regenerative medicine) and as process steps for cell therapy.

ENGINEERING CELL SHAPE THROUGH MATERIAL INTERACTION

As a living entity, each cell has the potential to sense and respond to physical stimulus at each point in all its transecting planes—i.e., its entire surface in three dimensions.

When an adhesion-dependent cell is presented with a flat surface to which it can favorably attach, it tends to maximize its adhesion and adopts a primarily flat morphology. Cells in a 2D paradigm tie up approximately 50% of this interaction capacity with the bottom surface of the well plate, approximately 50% with the



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