What is the difference between ECM-based and ECM-free systems in 2D and 3D cell culture? When are ECM-derived cues required for tissue organization and differentiation in 3D models? How do researchers choose between ECM-based and ECM-free culture formats for their experiments? When setting up a 3D cell culture experiment, one of the first choices researchers face is whether to use an extracellular matrix (ECM) scaffold or an ECM-free format. ECM-based materials such as Matrigel and Geltrex have long been used to provide basement membrane signals that support adhesion, polarity, and tissue organization. At the same time, ECM-free ultra-low-attachment (ULA) approaches have gained...