## 2 Fn as a Pertinent Key Actor in the ECM
### Fn's Role and the Structure-Function Relationship within the ECM and Cells  
Cells' behaviors are under the control of their interactions with their surrounding extracellular microenvironment. Cells are very sensitive to the mechanical and biophysicochemical properties of this ECM environment, and cell receptors and integrins are mainly solicited. Via the integrins, cells literally \"feel\" the specificity of their environment and respond to crucial parameters such as mechanical properties. For instance, a lack of rigidity, as in a very soft environment, compromises cell adhesion and, subsequently, induces a lack of intracellular tension and non-performant intrinsic signaling pathway. Conversely, the ECM that presents a relatively high stiffness plays a pivotal role in provoking appropriate cell behaviors such as correct differentiation, the generation of intrinsic signals, the leading of focal adhesions and, thus, cell engagement in appropriate signaling pathways. Moreover, in addition to the fact that cells respond to their biochemical environments via integrins, they also mainly employ GF receptors. Indeed, GFs, delivered to cells, are essential factors that govern part of their response. These GFs must be delivered specifically to the cells. In physiological conditions, they are present throughout the ECM, where they bind to the GF receptors. When scientists and engineers design and generate biomaterials with interfacial properties capable of controlling cell behavior, it is of crucial interest to implicate and mobilize specific receptors' integrins and GF receptors, respectively. In other words, ECM models must consider both integrins and GF receptors. Moreover, integrins mediate adhesion related to the mechanical or viscoelastic properties of the environment. The ECM presents dynamic viscoelasticity, and biomaterials developed by engineers must also integrate these viscoelastic properties. Thus, there are two crucial questions regarding the aim of satisfying and optimizing the dialogue between cells and their surrounding environments: (i) How do cells sense this viscoelasticity, and how can this viscoelasticity be incorporated into materials? (ii) How can GFs' presentation and their accessibility be maximized? [PERSON] et al., in a recent review, synthetized the different possibilities for presenting GFs [21], from uploading GFs in  
Figure 2: (**A**) Representation of the modular composition of an Fn chain with details of the electrostatic net charge for each of individual 32 domains. A red–blue scale illustrates the gradual change in the charge from –11 to +11. (**B**) Schematic representation of the structural organization adopted by the chain in solutions, essentially mediated by electrostatic domain interactions in the type III–1–III–14 central domains. (**C**) Representation of an Fn dimer stabilized by disulfide cross-links at the C-terminus and Fn–Fn interactions in the N-terminal domain. interfacial films to increasing GFs' affinity, specific chemical binding, or affinity in the ECM. Among these strategies, the development of materials with both integrin binding and GF binding represents a highly interesting way to solve these problems. Fn appears to be the most pertinent protagonist of the ECM for satisfying the latest requirements and addressing this interesting dual specificity. First, as presented above, among the different modules that contain specific properties, the modules III-10 and III-9 contain the well-known RGD and PHRRN sequences that are, highly specific and a well-known region for integrin binding, respectively (especially \(\alpha\)v\(\beta\)3 and \(\alpha\)5\(\beta\)1). Second, in the vicinity of this region, there exists a row of three specific type III modules (III-12-III-14 heparin-binding site) that exhibit a specific affinity for binding GFs (Figure 1A). [PERSON] and [PERSON] showed that Fn III-12-III-14 from Fn promote the binding of GFs including BMP2 [22]. Thus, within Fn, integrin binding can be simultaneously optimized with GF binding.