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Limitation of this work includes the lack of control of sample thickness during preparation, since perfectly cylindrical samples cannot be obtained. Indentation testing [158] requires a well-defined surface only around the indenter; and since maximizing sample number was key, the sample height was kept to that with only the perichondrium removed. Although significant correlations were observed between thickness and mechanical properties ( R between 0.4 and 0.7, p <0.05, Table 2), sample and indenter geometries were used which limit their bias on measured properties. [177] The test setup could additionally be modeled using an appropriate finite element approach. Since ear cartilage displays a different tissue composition and architecture to articular cartilage, it cannot be assumed that models used for articular cartilage would yield relevant results for ear cartilage. Only very recently, a first model has been proposed for ear cartilage. [24] Furthermore, tests were performed at room (20°C) rather than physiological (37°C) temperature. Literature indicates no change in mechanical properties for articular cartilage between 20°C and 37°C [178], and room temperature is routinely used [179]. Although numerous attempts to develop tissue-engineered ear cartilage have been reported, nearly no data is available on the native mechanical properties. One reason is likely the difficulty accessing fresh tissue. Although samples obtained for this work were collected over four years, it was not possible to obtain equal sample numbers for all groups. Additionally, hydroxyproline content as an indicator of collagen content is not ideal since both collagen and elastin contain hydroxyproline (12.5% and 2% of protein mass respectively [180], therefore a fraction of hydroxyproline measured in ear cartilage is due to elastin. In conclusion, this study establishes the first mechanical and biochemical map of human ear cartilage, enabling reliable assessment of engineered ear cartilage sufficient to sustain daily loading, while also ensuring cartilage grafts are not stiffer than necessary. The extensive elastic fiber network of ear cartilage is a key functional component. Regional variations are demonstrated, and biochemical composition alone does not fully account for observed mechanical variation indicating a probable contribution from local architecture. It would be of interest, in future, to have numerical models for ear cartilage and an understanding of the role of elastin. (Table 3) Acknowledgements The authors would like to thank the donors and their families who enabled this research, and Prof. dr. G.J. Kleinrensink, Y. van Steinvoort and B.J. Korstanje (Department of Anatomy and Neuroscience, Erasmus MC, University Medical Center, Rotterdam, the Netherlands) and dr. N. Rotter (Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany) for their assistance in obtaining human donor tissue. This study was supported by the Swiss National Science Foundation (NRP63) and ERA-NET/EuroNanoMed (EAREG-406340- 131009/1). 40 CHAPTER 2