The biochemical and biophysical cues of the stem cell environment that act in a concerted and spatiotemporal manner lead to the formation of the 200 cell types and organs of the human body, but how this precisely occurs remains unclear and it is necessary to guide their production for use in the biomedical area. Standard differentiation protocols in vitro mimic known stages in development by the timed addition of biochemical cues on 2D substrates, however these protocols lack the complexity of the 3D natural extracellular matrix (ECM), with its mechanical character that evolves in time. Supramolecular materials can recapitulate the structural and dynamic character of the ECM being based on non-covalent interactions. Their mechanical soft character can mimic embryonic microenvironment for induced pluripotent stem cell (iPSC) culture but renders them unable to mimic stiff and tough tissues.
Double networks using covalent polymers have demonstrated to achieve such mechanical properties, however these materials lack the cytocompatibility for use in 3D cell culture. The ERC project will address these challenges through objectives that include the synthesis of hybrid covalent-supramolecular polymer networks using biocompatible chemical and light-activated ligation approaches and the application of the materials to guide the fate of iPSCs to cardiomyocytes by controlling their mechanical properties in time. Subsequently, the cell laden materials will be interfaced with biomechanical devices to exploit their unique mechanical properties, and the materials will also be 3D-bioprinted with cells to prepare an actuatable culture platform in the form of a miniature beating heart ventricle. These advanced culture platforms based on hybrid-covalent supramolecular materials that go from soft to stiff and tough in time and space with shifting-shapes, with the potential to decouple the presentation of bioactive cues in an integrated manner, will provide uncharted opportunities to understand the spatiotemporal evolution of active and passive mechanical cues in development from cell to organ. The developed strategies within this ERC project will be essential for the development of cardiac models at various length scales with improved accuracy for in vitro drug screening, toxicity testing and disease modeling that will have societal impact on healthcare.
