Abstract
Mechanobiological-based control of mesenchymal stromal cells (MSCs) to facilitate engineering and regeneration of load-bearing tissues requires systematic investigations of specific dynamic mechanical stimulation protocols. Using deformable membrane microdevice arrays paired with combinatorial experimental design and modeling, we probed the individual and integrative effects of mechanical stimulation parameters (strain magnitude, rate at which strain is changed, and duty period) on myofibrogenesis and matrix production of MSCs in three-dimensional hydrogels. These functions were found to be dominantly influenced by a previously unidentified, higher-order interactive effect between strain magnitude and duty period. Empirical models based on our combinatorial cue-response data predicted an optimal loading regime in which strain magnitude and duty period were increased synchronously over time, which was validated to most effectively promote MSC matrix production. These findings inform the design of loading regimes for MSC-based engineered tissues and validate a broadly applicable approach to probe multifactorial regulating effects of mechanobiological cues.