Hydrogels with Reversible Mechanics to Probe Dynamic Cell Microenvironments

The relationship between ECM mechanics and cell behavior is dynamic, as cells remodel and respond to changes in their local environment. Most in vitro substrates are static and supraphysiologically stiff; thus, platforms with dynamic and reversible mechanical changes are needed. Herein, we developed hyaluronic acid‐based substrates capable of sequential photodegradation and photoinitiated crosslinking reactions to soften and then stiffen the hydrogels over a physiologically relevant range of moduli. Reversible mechanical signaling to adhered cells was demonstrated with human mesenchymal stem cells. In situ hydrogel softening (from ca. 14 to 3.5 kPa) led to a decrease in the cell area and nuclear localization of YAP/TAZ, and subsequent stiffening (from ca. 3.5 to 28 kPa) increased the cell area and nuclear localization of YAP/TAZ. Each photoreaction was cytocompatible and tunable, rendering this platform amenable to studies of dynamic mechanics on cell behavior across many cell types and contexts. Hydrogels with reversible mechanics have been developed from hyaluronic acid polymers capable of photodegradation and photopolymerization, capturing dynamic aspects of native microenvironments. Cellular mechanosensing was demonstrated with human mesenchymal stem cells as the substrate mechanics changed in situ.