In vivo mechano-tissue engineering by hydrogels capable of transmitting intercellular mechanical stress

Integrating the latest insights from mechanobiology into tissue engineering could lead to innovative technologies. Here we show a method to effectively elicit the regenerative response of transplanted cells by utilizing mechanical stress generated in vivo. The essential feature of our method is that it does not use specific ligands for the vital mechanosensor integrins to mechanically activate them. In our method, azide groups are introduced into the integrin, and the hydrogel is modified with cyclooctyne (DBCO) groups. Thus, bioorthogonal click reaction between the azide groups and the DBCO groups forms direct, stable, irreversible covalent bonds between the cellular integrin and the hydrogel. We demonstrate that the integrin–hydrogel linkage is in ON state regardless of the intensity of the stress, the cell cycle, or the extracellular environment, so that mechanical stress is rapidly and reliably transmitted to the nucleus through the linkage in vivo, resulting in regenerative response of the transplanted cells. Here, authors develop a ligand-free strategy to mechanically activate cells in a hydrogel by utilizing a biorthogonal click reaction to form a covalent bond between azide-modified cellular integrins and the hydrogel. They then apply this strategy in vivo to show that the transmittance of mechanical stress using the hydrogel system promotes regeneration of skeletal muscle.