3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Secondly, the capacity of BNC to match these requirements is assessed. Finally, a biofabrication process to produce patient-specific BNC auricular implants is demonstrated.BNC samples (n = 78) with varying cellulose content (2.5 -15%) were compared using stressrelaxation indentation with human ear cartilage (n = 17, from 4 males, aged 49 -93 years old).Additionally, an auricle from a volunteer was scanned using a 3T MRI with a spoiled gradientecho sequence. A negative ear mold was produced from the MRI data in order to investigate if an ear-shaped BNC prototype could be produced from this mold.The results show that the instantaneous modulus E in , equilibrium modulus E eq , and maximum stress σ max of the BNC samples are correlated to effective cellulose content. Despite significantly different relaxation kinetics, the E in , E eq and σ max of BNC at 14% effective cellulose content reached values equivalent to ear cartilage (for E eq , BNC: 2.4 ± 0.4 MPa and ear cartilage: 3.3 ± 1.3 MPa). Additionally, this work shows that BNC can be fabricated into patient-specific auricular shapes. In conclusion, BNC has the capability to reach mechanical properties of relevance for ear cartilage replacement, and can be produced in patient-specific ear shapes.

Scaffolds are widely used to reconstruct cartilage. Yet, the fabrication of a scaffold with a highly organized microenvironment that closely resembles native cartilage remains a major challenge. Scaffolds derived from acellular extracellular matrices are able to provide such a microenvironment. Currently, no report specifically on decellularization of full thickness ear cartilage has been published. In this study, decellularized ear cartilage scaffolds were prepared and extensively characterized. Cartilage decellularization was optimized to remove cells and cell remnants from elastic cartilage. Following removal of nuclear material, the obtained scaffolds retained their native collagen and elastin contents as well as their architecture and shape. High magnification scanning electron microscopy showed no obvious difference in matrix density after decellularization. However, glycosaminoglycan content was significantly reduced, resulting in a loss of viscoelastic properties. Additionally, in contact with the scaffolds, human bone-marrow-derived mesenchymal stem cells remained viable and are able to differentiate toward the chondrogenic lineage when cultured in vitro. These results, including the ability to decellularize whole human ears, highlight the clinical potential of decellularization as an improved cartilage reconstruction strategy.

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