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INTRODUCTION Cartilage defects in the head and neck area are a commonly encountered problem in reconstructive surgery. Currently, these defects are reconstructed with autologous cartilage grafts or artificial implants. Although autologous cartilage grafting has been used successfully, the procedure requires a high degree of surgical expertise, is associated with limited availability of autologous cartilage and can cause severe donor site morbidity. Besides, the use of artificial implants as an alternative is questioned in the head and neck area, since implants in this area are prone to induce a foreign body reaction and frequently lead to extrusion. [276] Cartilage tissue engineering (TE) can offer a promising solution for restoring missing or destructed cartilage and has the potential to overcome limitations of current treatments, re- establishing unique biological and functional properties of the tissue. To generate a construct of reasonable size, large numbers of cells are required. Currently, cartilage TE is predominantly based on the use of two distinct cell types: chondrocytes or mesenchymal stem cells (MSCs). Each cell type is however associated with specific disadvantages. Chondrocytes of several anatomical location have been investigated for their applicability. [39, 40, 42, 44, 46-53, 55-60] Yet, to obtain sufficient numbers of autologous cells, culture-expansion seems an inevitable step in chondrocyte-based cartilage repair, resulting in generally more fibrous and mechanically inferior cartilage. [61] MSCs on the contrary, are easily available from several tissues, 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] However, their use is currently debated, as the formed cartilage tissue is unstable and predisposed for tissue mineralisation and ossification in vivo . [69-72] Taken together, the individual use of chondrocytes or MSCs is at present not ideal for cell-based cartilage repair in the head and neck area. At present, the combination of both cell sources holds great promise for cartilage TE as it reduces the required number of chondrocytes and extenuates most disadvantages of both individual cell types. Contiguous thereto, mixed-cell cultures of chondrocytes and MSCs have been demonstrated to improve chondrogenesis [74] as well as to reduce hypertrophy and tissue mineralization [73, 75]. Moreover, by decreasing the amount of chondrocytes (≤ 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] Moreover, by using primary cells, the procedure is more translatable towards a one-step clinical application. To date, most research on mixed-cell-based cartilage repair has been performed with chondrocytes obtained from articular cartilage. So far, little research was executed on mixed- cell cultures of MSCs and non-articular chondrocytes, such as ear (ECs) [77-79] or nasal chondrocytes (NCs) [80]. Nonetheless, the translation of such basic research into a one-step clinical application is yet unfeasible. Primarily as these studies made use of non-optimal culture conditions, such as the use of culture-expanded chondrocytes [77, 78, 80], or the paradoxical use of additional growth factors [77, 80]. Moreover, only few studies have yet evaluated the cartilage-forming capacity of MSC/ECs [77, 79] and MSC/NCs (none) in vivo . In an attempt to translate experimental research towards a one-stage cell-based cartilage repair 109 CO-CULTURE: A PROMISING CELL-BASED THERAPY FOR FACIAL CARTILAGES 6