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Mechanically Tunable Bioink for 3D Bioprinting of Human CellsAurelien Forget, Andreas Blaeser, Florian Miessmer, Marius Köpf, Daniela F. Duarte Campos, Nicolas H. Voelcker, Anton Blencowe, Horst Fischer,* and V. Prasad Shastri* DOI: 10.1002/adhm.201700255 medium-the bioink. [5] The former approach offers the advantage that the 3D scaffold does not have to be fabricated under cytocompatible conditions. Therefore, a broader range of materials can be employed, for example, thermoplasts, such as poly(caprolactone), [6] and additionally, other alternative scaffold fabrication techniques, such as electrospinning, or pressurized gyration can be combined with subsequent functionalization of the scaffold with proteins. [7] In contrast, the latter approach, that is, direct fabrication of cellloaded constructs by hydrogel molding or 3D printing, places high demands on the cytocompatibility of the material and the fabrication process and the resolution is limited by the size of the extrusion nozzle utilized in the fabrication process. [8] However, the advantage of direct fabrication techniques, especially of 3D bioprinting, is its ability to generate constructs with spatially defined cell and material composition. Moreover, biomaterials that are conventionally used in cell culture such as alginate, [9] Pluronic, [10] gelatin, [11] nanocellulose, [12] self-assembling peptides, [13] and agarose [14] are highly advantageous for direct cell printing as they are soluble in water and hence can be formulated as a cell carrier. There has been extensive effort to build on and improve the properties of watersoluble polymers as bioinks. [15,16] For example, to overcome the limitation of the solubilization of Pluronic and its limited diversity of mechanical properties, blending of Pluronic with alginate [17] and crosslinking using acrylate-modified Pluronic have been explored. [10] Notwithstanding these advances that utilize chemical crosslinking to control the mechanical properties of the bioinks, controlling the shear behavior and mechanical This study introduces a thermogelling bioink based on carboxylated agarose (CA) for bioprinting of mechanically defined microenvironments mimicking natural tissues. In CA system, by adjusting the degree of carboxylation, the elastic modulus of printed gels can be tuned over several orders of magnitudes (5-230 Pa) while ensuring almost no change to the shear viscosity (10-17 mPa) of the bioink solution; thus enabling the fabrication of 3D structures made of different mechanical domains under identical printing parameters and low nozzle shear stress. Human mesenchymal stem cells printed using CA as a bioink show significantly higher survival (95%) in comparison to when printed using native agarose (62%), a commonly used thermogelling hydrogel for 3D-bioprinting applications. This work paves the way toward the printing of complex tissue-like structures composed of a range of mechanically discrete microdomains that could potent...