The Mechanobiologist’s dilemma: Force, stiffness, and the illusion of adaptation

Mechanoadaptation, a process by which living cells adjust to the mechanical properties of the environment, is fundamental to their function and behavior. Generating mechanical forces is the main way a cell can acquire information about the physical nature of the immediate micro-environment. Crucially, mechanical force during this interaction is the sole stimulus upon which the cell performs mechanoadaptation. However, quantifying this mechanical interaction is notoriously challenging due to the interdependent relationship between mechanical force, mechanical substrate stiffness, and the resulting spatial displacements. A critical issue, often overlooked in common measurement techniques like traction force microscopy, is that a change in substrate stiffness inherently alters measurement sensitivity. This perspective argues that this oversight can lead to misinterpretation of cellular function and behavior, creating an ’illusion of adaptation.’ We present a conceptual framework to highlight the importance of accounting for the measurement sensitivity and advocate for a more accurate quantification of the biological processes governing mechanoadaptation to avoid pitfalls and advance the field of mechanobiology.