Directing Stem Cell Activity through Mechanical Stimulation of Metamaterial 3D Scaffolds

Regenerative medicine aims at repairing damaged tissues in our body. To do so, stem cells are often used. My research has been focused on biofabrication innovations for tissue engineering, which aims to direct stem cell fate to steer tissue regeneration. While mechanical loading play a determinant role in the organization of adult cells and tissue development, and my past work with 3D scaffolds demonstrated the importance of mechanical cues to direct stem cell fate, very little is known about its influence on pluripotent stem cells (PSCs). PSCs are a powerful resource for tissue engineering whose application currently suffers from many limitations. One such limitation is the reliance on added biological factors to induce iPSC differentiation, which do not reflect accurately what occurs in vivo. MECCANO aims to establish a new research program that focuses on the systematic understanding of the influence of mechanical loading on tissue development from PSCs in 3D cultures. I will design mechanically active metamaterial scaffolds, which are porous 3D materials that can morph their shape in response to mechanical loading, thus providing defined dynamic stresses and deformations to cells hosted on them. I will then develop a library of mechanical metamaterial scaffolds able to maintain PSCs undifferentiated or to direct their differentiation into the three germ layers of embryological development (ecto-, meso-, endoderm lineages) through mechanical loading. This knowledge will be fed back into a mathematical model to enable the rational design and fabrication of scaffolds for the regeneration of a targeted tissue, here vascularized and conductive cardiac tissue, which has not yet been accomplished and provides a proof of concept. MECCANO will deliver a new paradigm for PSC differentiation, based on the optimization of 3D scaffolds' mechanical and structural properties. This solution holds the potential to generate more targeted, complex products for tissue replacement.