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of chondrogenic potential can however be facilitated in the presence of induction factors, like biological or biophysical stimuli. [365] However, induction factors can enhance but never emulate the complex process of cartilage regeneration and may have unpredictable effects on future clinical outcome. Multipotent mesenchymal stem cells (MSCs) achieved considerable attention as alternative cells. They can undergo multiple population doublings without losing their chondrogenic potential and have the capacity to differentiate into cartilage tissue under appropriate culture conditions. [64-68] Furthermore, MSCs are easily available from several tissues, including bone marrow and adipose tissue, which makes culture-expansion unnecessary. However, their role in cell-based cartilage repair is currently debated, since MSCs terminally differentiate through the process of endochondral ossification. They produce cartilage ECM that is unstable ( chapter four ) and predisposed to mineralization and ossification in vivo . [69-71, 240, 241] However, significant research is required to understand and predict MSC behavior during chondrogenic differentiation and to prevent terminal differentiation. Therefore, the single use of either chondrocytes or MSCs is being questioned as appropriated cell sources for cell-based cartilage repair in the head and neck area. Co-culture Currently, combining both cell sources holds great promise for cell-based cartilage repair as it reduces the required number of chondrocytes and diminishes many disadvantages of both individual cell types. By decreasing the amount of chondrocytes required (≤ 20% of the total cell mixture), culture-expansion is no longer necessary, which allows the use of freshly isolated primary chondrocytes leading to improved cartilage formation. [76] The attribution of chondrocytes and stem cells are both essential in co-culture and are further discussed below. (1) Chondrocytes As the foundation of plastic reconstructive surgery focuses on replacing ‘like tissue with like tissue’, it seems only logical that for the reconstruction of cartilage defects in the head and neck area, location and type-specific chondrocytes are used. In chapter four we emphasize that only chondrocytes derived from elastic cartilage are able to produce an elastin-rich cartilage matrix and that chondrocytes derived from hyaline cartilage are not. Moreover, the properties of the ECM of location-specific hyaline chondrocytes (i.e. nasal or articular chondrocytes) are mutually different and remarkably related to their origin. Thereby, we further completed former research [56, 366] and conclude that location and type-specific chondrocytes ultimately result in cartilage regeneration of similar molecular nature. This means that for the reconstruction of cartilage defects in the head and neck area, ear and nasal chondrocytes are favorably used to repair ear or nasal cartilage defects respectively. Unfortunately, most co-culture research on cartilage repair has been performed on chondrocytes derived from articular cartilage and only few studies studied the combination of MSCs and non-articular chondrocytes such as ear [77-79, 367, 368] or nasal chondrocytes [80]. In chapter six we demonstrate that cartilage constructs containing a combination of 80 percent MSCs and 20 percent of primary ear or nasal chondrocytes produce similar quantities of cartilage matrix components as constructs containing chondrocytes only. Therefore, 80 180 CHAPTER 9