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described in chapter seven preserved native collagen and elastin contents of ear cartilage tissue, as well as cartilage major architecture and shape. Despite recent progress in cartilage decellularization, there are some barriers that limit potential clinical application. First, the ability to revitalise ECM-derived cartilage scaffolds is critical for future clinical implementation. Recellularized ECM-derived scaffolds were non- cytotoxic and had the capability to allow chondrogenic differentiation of human MSCs ( chapter seven ). However, cell migration throughout the scaffold was non-existing and needs to be further improved to actually revitalize and thereby remodel tissue. Secondary, the complexity of cartilage structures in the head and neck area sets high standards to scaffold design. The shortage of (allogeneic) donors and the inability to accurately match cartilage shape of (allogeneic or xenogeneic) donor facial cartilages, impede its translation to clinical therapy. [295] Altogether, we have introduced a method to decellularized cartilage tissue while preserving its native 3D architecture and shape, providing an interesting scaffold for cartilage therapy in the head and neck area. Matrix-inspired scaffolds Another way to - at least partially - mimic structural and functional characteristics of native tissue microenvironment is the generation of ECM-inspired scaffolds. Basic requirements for biomimetic scaffold engineering demand (1) a scaffold with sufficient mechanical strength to retain size and shape ; (2) a 3D structure that allows tissue regeneration and homeostasis ; and (3) a biomaterial that is biocompatible without introducing an inflammatory response. In this thesis we used alginate and bacterial nanocellulose scaffolds for cell-based cartilage repair. Their properties based on these requirements are further discussed below. (1) Biomechanical strength For successful tissue-engineered cartilage, the 3D scaffold must provide sufficient mechanical strength in order to maintain size and shape when subjected to the forces of the implanted environment. Alginate biomechanical properties did not match mechanical stiffness of facial cartilages (1-15 MPa) and ranged from approximately 1 to 1000 kPa. [88] Due to its relatively poor biomechanical strength, alginate itself is not suspected to maintain size and shape after direct subcutaneous implantation. Bacterial nanocellulose, on the other hand, has biomechanical properties that reaches values analogous to facial cartilages. [155] (2) Tissue regeneration and homeostasis Biomimetic scaffold design must provide a natural 3D micro-environment that allows tissue regeneration and homeostasis. Cell-scaffold interactions are critical herein and fundamental for initial cell attachment, subsequent migration, proliferation, differentiation, and later tissue remodelling. Alginate permits the encapsulation of cells rather than actual cell attachment. Alginate encapsulation enables homogeneous 3D cell distribution and prevents cells from floating out. [387] Meanwhile, bacterial nanocellulose provides excellent cell attachment and migration, although cell migration is limited to the surface of the scaffold (i.e. impermeability). In chapter eight a bilayer bacterial nanocellulose scaffold, composed of a dense and a macroporous nanocellulose layer, was designed that enabled 3D cell migration. Both alginate 184 CHAPTER 9