Dynamic Modulation of the Microenvironment Promotes Functional Maturation of Engineered Tissues

While extremely complex interactions between cells and extracellular matrix regulate cellular microenvironments in vivo, the pared-down complexity present in engineered tissues is generally insufficient to recapitulate these dynamics in vitro. Here, a biocompatible small molecule that can diffuse into tissues as they mature to dynamically modulate the cellular microenvironment is utilized. This technology can be deployed in multiple doses to repeatedly and controllably adjust the tissue's microenvironment as it matures. It is observed that deploying precisely the same concentration of the small molecule, but at different stages of a tissue's maturation, led to markedly different outcomes. In particular, it is shown that endothelial cells matured in dynamically modulated microenvironments form thicker, more native-like blood vessels than is possible using traditional, non-dynamic culture. Likewise, engineered cardiac tissues generated stronger contractions and demonstrated a more mature electrophysiology when encapsulated in a soft, dynamically modulated hydrogel matrix that allowed for tissue maturation. Finally, the results of differentiating induced pluripotent stem cells to cardiomyocytes within dynamic matrices and show that coordinating the tissue's stiffness with the differentiating cells' developmental stage maximizes their end functionality is presented. The ability to dynamically control the tissue microenvironment during maturation, in a facile and safe manner, represents a significant step toward achieving a more accurate in vitro recapitulation of complex processes vital for tissue engineering.