Schematic representation of the main players within the extracellular matrix (ECM), including inputs derived from neural and supportive cells, blood vessels and secreted and paracrine factors and ECM components that need to be captured in advanced biomaterial design to reestablish ECM-stem cell interactions [297]. The ECM offers a highly specialized and dynamic microenvironment encompassing different length scales; in this context, the matrix elasticity/topography and a number of inputs combine and control cell fate commitment. The ECM may act by soluble factor presentation (a) and be remodeled by the action of enzymes that produce functional fragments (b). More importantly, the ECM may directly bind cell surface receptors or co-receptors (c, d and e), thereby potentially regulating cell anchoring and mediating diverse pathways involved in mechanotransduction and intracellular signaling.