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Biocompatible polysaccharide scaffolds with controllable pore size, good mechanical properties and without hazardous chemical crosslinkers, are desirable for long-term tissue engineering applications but their production is highly challenging. Herein, we fabricated three-dimensional (3D) scaffolds using a polysaccharide composite ink composed of nanofibrillated cellulose, carboxymethyl cellulose and citric acid, featuring strong shear thinning behavior and adequate printability. Highly porous and mechanically stable scaffolds were produced by combining direct ink writing 3D printing, freeze-drying and dehydrothermal heat-assisted crosslinking techniques. The last heat-assisted step induces reaction of citric acid, which was chosen as it is a non-hazardous and green crosslinker. Degree of crosslinking was controlled by varying the concentration of citric acid (2.5 – 10 wt.%) to tune the chemical, surface, swelling and degradation properties of the scaffolds in the dry and hydrated states. The scaffolds with the highest porosity (86%) and interconnected pores (100-450 µm) were acquired using the lowest citric acid concentration; and the porosity was significantly reduced at higher citric acid concentration as well as at longer hydration time. The compressive strength, elastic modulus and the shape recovery behavior of the crosslinked scaffolds were increased significantly with increasing crosslinker concentration. The prepared crosslinked scaffolds promoted clustered cell adhesion and showed no cytotoxic effects, as determined by a cell viability assay and live/dead staining with human bone tissue derived osteoblast cells. The water-based and non-hazardous crosslinking method reported here can be extended to all polysaccharide-based materials to develop cell-friendly scaffolds with tailormade properties suitable for various tissue engineering applications in general.

Three-dimensional scaffolds (3D) with controlled shape, dual porosity and long-term mechanical and dimensional stability in biofluids are of interest as biotemplates in tissue engineering. Herein, self-standing and lightweight cellulose-based biogenic scaffolds with a spatially structured morphology, macropores and interconnected micropores were fabricated using a combination of direct ink writing 3D printing and freeze-drying techniques. This was achieved by developing a water-based and low-cost bicomponent ink based on commercially available nanofibrillated cellulose (NFC) and carboxymethyl cellulose (CMC). Physical cross-linking through dehydrothermal treatment significantly increased the surface hardness, indentation modulus, compression strength, as well as the dimensional stability of the scaffolds in biofluids, in comparison to untreated materials. However, no differences in the spectra of solid state nuclear magnetic resonance or infrared were observed for dehydrothermal treated samples, suggesting that the increase of mechanical properties and dimensional stability is based on the physical cross-linking of functional groups both at the interface between NFC and CMC. The supramolecular structure of the polymers was well-preserved as disclosed by X-ray diffraction measurements. The cross-linked scaffolds showed high proliferation, viability, and attachment of human bone tissue derived osteoblast cells (hFOB). The simple and straightforward avenue proposed here for the design of cellulose-based fibrous inks and dual porous scaffolds from the commercially available materials and without the need of any additional cross-linkers should pave the way for the development of implantable, degradable scaffolds and cell-laden biomaterials for bone tissue regeneration and 3D bioprinting applications.