**Background:** Tissue Engineering (TE) and Regenerative Medicine (RM) aim to restore damaged tissues using scaffolds, growth factors, and cells. The extracellular matrix (ECM) is a sophisticated nanoarchitecture of proteins (collagen, elastin, fibronectin), macromolecules (glycosaminoglycans, proteoglycans), and soluble factors that provides structural support and biophysical/biochemical cues regulating cell functions. Understanding cell–ECM interactions is crucial for designing biomimetic scaffolds that promote regeneration. This review summarizes ECM organization, cell–matrix interactions, and how scaffold physical, chemical, and biological properties can be tailored to improve cell–biomaterial interactions.
**Methods:** This is a narrative review that synthesizes existing literature on ECM composition, structure, and properties, as well as scaffold fabrication and functionalization techniques. It discusses the concept of Unit Cell Processes (UCPs) to describe cell–biomaterial interactions. The review covers physical properties (orientation, porosity, topography, stiffness), chemical properties (surface functional groups, charge, wettability), and biological properties (biomolecule functionalization, biocompatibility, biodegradability) of scaffolds, citing numerous specific studies and their findings.
**Key Results:** The ECM is composed of two layers: pericellular matrix (e.g., basement membrane with collagen IV, laminins, nidogens) and interstitial matrix (collagens, elastin, fibronectin). Collagens represent up to 30% of total human proteins, with 28 types; collagen fibres have a strength of ~0.12 GPa and elastic modulus of ~1.2 GPa in mammalian tendons. ECM stiffness influences cell behaviour via durotaxis, and viscoelasticity affects cell migration. Scaffold physical properties: oriented structures (e.g., aligned PCL fibres) promote cell alignment and differentiation; porosity (e.g., porous Mg scaffolds) enhances cell migration and viability; topography (e.g., microgrooves on PS scaffolds) guides cell orientation; stiffness modulation (e.g., EDC-crosslinked collagen-GAG scaffolds) increases chondrocyte proliferation and GAG synthesis. Chemical properties: -NH2 functional groups promote osteogenic differentiation of MSCs and hDPSCs; surface charge (positive from -NH2 groups) enhances MC3T3-E1 cell adhesion; moderate wettability (contact angle 40–70°) improves cell adhesion; hydrophilic surfaces (e.g., SLActive implants) encourage osseointegration with superior bone-to-implant contact after 4 weeks. Biological functionalization: RGD peptide immobilization enhances endothelial cell adhesion; laminin-modified PLGA/CNT scaffolds promote neurite outgrowth; biocompatibility is demonstrated for various modified scaffolds (e.g., PDAM/HD coatings reduce inflammatory cell infiltration). Biodegradability can be increased by functionalization with ascorbic acid (1.6-fold increase) or sucrose (1.5-fold increase).
**Clinical Implications:** The review provides a comprehensive framework for designing biomimetic scaffolds by mimicking native ECM properties. Key strategies include: (1) matching scaffold stiffness to target tissue to guide stem cell differentiation; (2) using oriented structures for anisotropic tissues like muscle, blood vessels, and nerves; (3) optimizing porosity for nutrient transport and cell infiltration; (4) incorporating specific functional groups (e.g., -NH2) to enhance osteogenesis; (5) tuning surface wettability to improve cell adhesion and protein adsorption; (6) functionalizing with ECM-derived peptides (e.g., RGD) to promote cell attachment and differentiation. Despite promising in vitro and preclinical results, clinical translation remains limited due to the complexity of cell–ECM interactions and fabrication challenges. The authors emphasize the need for continued research to better understand ECM mechanisms and develop advanced fabrication techniques to create scaffolds that fully recapitulate the native microenvironment for successful tissue regeneration.