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is too weak to withstand scar contraction forces after direct subcutaneous implantation, it enables a homogeneous cell distribution and prevents cells from floating out while permitting nutrient diffusion and oxygen transfer to the cells in order to create an environment to form new cartilage matrix with sufficient properties. [89] Therefore, alginate is an excellent cell- carrying gel for cell-based cartilage repair in the head and neck area. Bacterial nanocellulose is the extracellular product of the Gluconacetobacter xylinus bacterium. These gram-negative aerobic bacteria produce pure nanocellulose fibrils in the presence of sugar and oxygen. [90] More recently, medical devices made from bacterial nanocellulose were introduced into the clinic as wound and burns dressings (e.g. Dermafill ® , Bioprocess ® , XCell ® and Biofill ® ), surgical meshes (e.g. Xylos ® , Macro-Porous Surgical Mesh ® and Securian ® ) and dura mater substitutes (Synthecel Dura Repair ® ). Bacterial nanocellulose is extremely hydrophilic and can hold as much as 100 times its dry weight of water. [91] This property, combined with the distinct physical and mechanical properties of bacterial nanocellulose, including its insolubility, rapid biodegradability, tensile strength, elasticity, durability, nontoxic and non-allergenic features, make bacterial nanocellulose a candidate biomaterial for cartilage TE in the head and neck area. [92] Recently, natural acellular ECM scaffolds have become increasingly popular. These acellular ECM scaffolds are acquired by a process called decellularization: a method that requires chemical, physical and/or enzymatic treatments. [93] Decellularized ECM scaffolds provide a 3D ECM structure with immediate functional support without evoking an adaptive immune response upon implantation due to the absence of donor cellular antigens. [94] To date, various cartilaginous structures have already been decellularized including tracheal cartilage [94-99], articular cartilage [100-103], intervertebral discs [104, 105] and meniscal cartilage [106-109]. So far, little research has been executed on decellularized ECM in the head and neck area such as nasal cartilage [106, 110] or ear cartilage. Inductive factors Cartilage development and homeostasis is influenced by several inductive factors that induce, improve or accelerate cartilage regeneration. They include both biochemical and biophysical factors. (Reviewed by Wescoe et al . [111]) Growth factors, especially those from the Transforming Growth Factor beta family, Insulin-like Growth Factors and Fibroblast Growth Factors, are signalling factors most extensively investigated in cartilage tissue engineering. [112-114] These factors regulate cellular migration, adhesion, proliferation, differentiation, and cell survival, and ultimately improve cartilage formation and stability. [115] The easiest and most common way to deliver growth factors to the culture environment is through direct supplementation to culture media. However, the quantity and fast release of such inductive factors may impede cartilage regeneration. In order to more closely replicate the in vivo situation, inductive factors have been more gradually delivered using drug-eluting scaffolds or gene therapy. Still, further research needs to study efficacy and spatiotemporal kinetics of future delivery systems as well as safety and reliability of gene therapy. Recently, the endogenous delivery of inductive factors through co-culture was introduced. Mixed-cell- cultures provide cell populations that secrete trophic factors to regulate local cellular activity for cartilage regeneration more similar to normal cartilage development. [116] 1 GENERAL INTRODUCTION 19