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network in the ECM. In fact, compressive biomechanical integrity appears mainly assigned by elastin, whereas in hyaline cartilage this is principally provided by a complex relationship between the collagen network entrapping glycosaminoglycans. [202] Biomechanically, elastin is responsible for the physical properties of elasticity, reversible extensibility and elastic recoil. [144] Moreover, elastin is localized in close proximity to proteoglycans, altering the proteoglycan-ECM binding paradigm we know from hyaline cartilage, and thereby influencing biomechanical behaviour. [202] Therefore, elastic cartilage displays a distinctly different response to load compared to hyaline nasal cartilage which exhibits high resistance to instantaneous loads. [202] In chapter three it appeared that cell density was significantly higher in alar cartilage than in cartilage obtained from the ear or septal cartilage. Besides, alar chondrocytes were larger, occupying a considerable part of the ECM. Although high cell density does not directly influence cartilage biomechanical behavior [162], lower volume of ECM fraction (due to higher cell fraction) is likely to affect biomechanics. [176] Knowledge of the biochemical and biomechanical properties of the cartilage ECM in the head neck area will benefit future tissue engineering therapies. However, biomechanical properties of the ECM are not only determined by the amount of ECM components, but is also considerably influenced by ECM fiber orientation as well as binding between components. [301] Better insight into the three-dimensional (3D) interconnected ECM network will provide valuable information for future cell-based therapies. Especially when selecting and preparing a 3D scaffold (see below). Altogether, we have set a benchmark against which to evaluate cartilage tissue-engineering strategies in the head and neck area. Cell sources Q2 Which cells or combination of cells are most suitable for cell-based cartilage repair in the head and neck area? Monoculture Defining an appropriate cell source for successful cell-based cartilage repair in the head and neck area, is crucial. The goal of creating clinically relevant tissue-engineered cartilages places specific requirements on the cell source. The ideal cell source should meet specific requirements, including the availability of large quantities of cells with minimal invasive accessibility and the ability to produce cartilage ECM that resembles cartilage both in form and function. The most obvious cell source for cartilage repair are chondrocytes themselves. However, to generate a cartilage construct of reasonable size, large numbers of chondrocytes are required, necessitating the use of culture-expansion. In chapter four , the cartilage-forming capacity of human culture-expanded chondrocytes from several anatomical locations (i.e. articular joint, ear, and nose) were studied. Independent on their origin, culture-expanded chondrocytes dedifferentiate; they change phenotypically to a fibroblast-like morphology and lose their chondrogenic potential. [61] As a result, chondrogenic gene-expression is reduced as well as their ability to produce cartilage ECM components. Redifferentiation and thereby restoration 179 DISCUSSION AND FUTURE PERSPECTIVES 9