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The creation of multi‐tissue auricular transplants for the treatment of microtia is a challenge due to the complex and layered structure of this anatomical tissue. A novel casting technique for the 3D biofabrication of heterogeneous, multi‐layered, and human‐scale tissue transplants using eluting agarose molds is presented. The molds are generated by casting agarose into custom 3D‐printed containers, termed metamolds, optimized to facilitate the hydrogel casting process based on geometric and topological constraints. Casting yields high resolution (50 µm) and allows for subsequent casting of further hydrogel layers on the transplant. Multi‐layered auricular constructs are fabricated on a cartilage core consisting of a hyaluronic acid‐alginate double network and an adjacent gelatin‐based dermal layer. Bonding between adjacent layers is achieved by orthogonal physical and enzymatic crosslinking of residual functional groups between each layer. Material composition and culture duration are optimized for each layer allowing for maturation into cartilaginous and pre‐vascularized dermal tissues. To demonstrate the scalability of this technique for the biofabrication of human‐sized transplants, bi‐layered human‐sized ears are cast. Overall, this novel casting technique offers a promising approach for the fabrication of complex tissue grafts, overcoming the limitations of other traditional biofabrication methods. [ABSTRACT FROM AUTHOR]

Biofabrication techniques including three-dimensional bioprinting could be used one day to fabricate living, patient-specific tissues and organs for use in regenerative medicine. Compared to traditional casting and molding methods, bioprinted structures can be much more complex, containing for example multiple materials and cell types in controlled spatial arrangement, engineered porosity, reinforcement structures and gradients in mechanical properties. With this complexity and increased function, however, comes the necessity to develop guidelines to standardize the bioprinting process, so printed grafts can safely enter the clinics. The bioink material must firstly fulfil requirements for biocompatibility and flow. Secondly, it is important to understand how process parameters affect the final mechanical properties of the printed graft. Using a gellan-alginate physically crosslinked bioink as an example, we show shear thinning and shear recovery properties which allow good printing resolution. Printed tensile specimens were used to systematically assess effect of line spacing, printing direction and crosslinking conditions. This standardized testing allowed direct comparison between this bioink and three commercially-available products. Bioprinting is a promising, yet complex fabrication method whose outcome is sensitive to a range of process parameters. This study provides the foundation for highly needed best practice guidelines for reproducible and safe bioprinted grafts. [ABSTRACT FROM AUTHOR]