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Cartilage tissue engineering Tissue engineering is described as “the interdisciplinary field that applies the principles of engineering and life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function”. [22] Tissue engineering attempts to mimic functional tissue that has features similar to native tissue. The development of such an engineered tissue requires a careful selection of three major components, also known as the “tissue engineering triad”: (1) cells; (2) a supporting structure or scaffold; and (3) inductive factors that trigger tissue regeneration cascades. (Figure 2) These components are discussed more extensively below. Cell sources Defining an appropriate cell source for cartilage tissue engineering is a major challenge. The ideal cell source is one that is abundantly available, can be easily isolated or expanded, and forms cartilage tissue that is similar to that of native tissue. The most obvious choice are chondrocytes themselves. Therefore, chondrocytes from several anatomical locations (e.g. joint, rib, nose, ear, meniscus) have been investigated for their applicability. [39-60] Typically, autologous chondrocytes are isolated by enzymatic digestion from small cartilage biopsies, to minimize donor site morbidity. However, large numbers of chondrocytes are required to generate a construct of reasonable size. Therefore, after cell-isolation, cells are expanded in vitro until a sufficient cell number is obtained. Unfortunately, culture-expansion results in chondrocyte dedifferentiation: they change phenotypically to a fibroblast-like morphology and lose their chondrogenic gene-expression capacity, which usually results in fibrous and mechanically inferior cartilage. [61] In recent years, considerable progress has been made to remedy current limitations. Multiple biological and biophysical cues have been introduced to inhibit the process of chondrocyte-dedifferentiation and improve chondrocyte redifferentiation, as discussed below. Next to chondrocytes, mesenchymal stem cells (MSCs) have been introduced and demonstrated to be an attractive cell source for cell-based cartilage repair. [62] These cells are easily available from several tissues, including bone marrow, adipose tissue, synovium, peripheral blood, dental pulp, placenta, umbilical cord, and skeletal muscle. [63] Of these MSCs, adipose-tissue-derived MSCs (AMSCs) and bone-marrow-derived MSCs (BMSCs) are best characterized. 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] A potential limitation to their application in cell-based cartilage repair is that differentiated MSCs become hypertrophic, a process called terminal differentiation. Hypertrophic MSCs produce cartilage tissue that 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 yet ideal for cell-based cartilage repair in the head and neck area. As an alternative to the individual use of cells, the concept of co-culture was introduced. [73] It became clear that combination of chondrocytes and MSCs extenuate many disadvantages of individually studied cell types. In particular, co-cultures of chondrocytes and MSCs demonstrated improved chondrogenesis [74] as well as reduced hypertrophy and tissue 1 GENERAL INTRODUCTION 17