3D printing of vascularized hepatic tissues with a high cell density and heterogeneous microenvironment

Three-dimensional bioprinting has emerged as an appealing approach for creating functional tissues; however, a lack of suitable bioinks with high cell density and printability has greatly limited our ability to print functional tissues. We address this limitation by developing a granular cell aggregate-based biphasic (GCAB) bioink based on densely packed cell aggregates. The GCAB bioink exhibited the desired shear-thinning and shear-recovery properties for extrusion bioprinting and hyperelastic behaviors postprinting for modeling the mechanical characteristics of soft biological tissues. The GCAB bioink displayed a high cell density (∼1.7 × 10⁸cells cm^-3) without compromising viability (∼83%). We printed dense hepatic tissue constructs with enhanced vascularization and metabolic functions by preorganization of GCAB bioink with a defined heterogeneous microenvironment. By simultaneously printing the GCAB bioink and an endothelial cell-laden gelatin bioink, we successfully produced functional hepatic tissues with a high cell density and a perfusable vascular network. The design of the generalizable GCAB bioink opens new avenues to create functional tissues for therapeutic applications.