**1. Introduction**

Multicellular organisms require a framework to delineate functional territories and to pro‐ vide a shelf where the cells can attach to perform their specific functions. The extracellular matrix (ECM) represents this framework for tissues and organs and as such it is an important actor of

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organisms' physiology. The most known examples of ECM-related tissues are the skin, where ECM act as a barrier against the outside environment, and the bones where ECM is strength‐ ened by a mineral phase which allows the body to stand and to move. However, its apparent structural and mechanical properties have hidden more subtle roles of ECM in cell differentia‐ tion and function as ECMs are not restricted to load-bearing organs but are present and required in all types of tissues and organs. During the development of the embryo, neural crest cells lose their cell-cell adhesion properties toward cell–ECM interactions that allow them to move along the dorsal part of the embryo and reach their specific site of function and give birth to the future skeleton. Again, tissue remodeling, as observed during the healing processes, can release messenger molecules that were entrapped in the ECM, waiting for the right moment to trigger their signal and healing functions [1]. Some lack of knowledge on ECM functions remains mainly because of the challenge represented by its comprehensive study. Indeed, ECM is made of several high molecular weight proteins, proteoglycans, and polysaccharides molecules self-arranged into fibers and networks difficult to solubilize and individualize. Basic biochemistry techni‐ ques have led to the identification of the major components of ECMs such as collagens or laminins, but as the investigations are progressing, this results in the constant growing of the constitu‐ ent members of collagen and laminin families and in the discovery of new ECM components with unknown functions [2]. Moreover, understanding the ECM not only means discovering new molecules but also to unravel their organization in the ECM network. So the study of ECM requires the combination of identification and imaging techniques to give a valuable scheme of its composition, organization, and finally function. Interestingly, unraveling ECM complexity meets one of the fundamental questions for biologists: how to recreate and maintain life outside a living organism (literally *ex vivo* but commonly referred as *in vitro*)?

The beginning of the 20th century aroused the possibility to dissociate cells from living tissues and to culture them *ex vivo*. This new technique has triggered the emergence of the new discipline of cell biology which has brought most of the knowledge that we possess today on cell proliferation, differentiation, metabolism, cell fate, and death. However, *ex vivo* cell cultures were restricted to two-dimensional (2-D) culture systems, originally on glass and subsequently on plastic dishes, occasionally supplemented by the coating of ECM molecules to favor cell adhesion. Parallel to the development of cell biology, the broad field of materials science was creating polymers and devices able to bring *ex vivo* cell culture to the third dimension, and to the 21st century. Dedicated to materials that interact with living tissues, the field of biomaterials encompasses several scientific disciplines, from physics and chemistry to biochemistry and medicine. Several types of three-dimensional (3D) materials have been engineered which may represent valuable tools for fundamental cell research, but a lack of knowledge on ECM structures have undermined their use for cell biology. On the other hand, cell biologists are not necessarily aware of the development and possibilities created by extensive research in the field of 3D biomaterials, and this partly compromises the expansion of 3D cell culture models.

In this chapter, we will present basic techniques involved in the investigation of extracellular matrices and data generated by their use to understand ECM composition and organization. Basic knowledge on ECM composition and organization should be useful for biomaterial scientists to propose more biologically relevant materials. Such methodologies are fully transposable for the characterization of biomaterials and 3D models of ECMs. In a second section, we will present a series of biomaterials that were engineered based on the investigation of ECMs composition and organization *in vivo* and could become suitable 3D cell culture models for mechanobiology, aging, cell migration, cell differentiation, and studies on pathologies and their treatments.
