A Microgel–Hydrogel Hybrid for Functional Compensation and Mechanical Stability in 3D Printed Cell-Dense Vascularized Liver Tissue

3D bioprinting of liver tissue with high cell density (HCD) shows great promise for restoring function in cases of acute liver failure, where a substantial number of functional cells are required to perform essential physiological tasks. Direct vascular anastomosis is critical for the successful implantation of these bioprinted vascularized tissues into the host vasculature, allowing for rapid functional compensation and addressing various acute conditions. However, conventional hydrogels used to encapsulate high-density cells often lack the mechanical properties needed to withstand the shear forces of physiological blood flow, often resulting in implantation failure. In this study, a heterogeneous microgel–hydrogel hybrid is developed to carry HCD hepatocytes and support the embedded bioprinting of hierarchical vascular structures. By optimizing the ratio of microgel to biomacromolecule, the covalently crosslinked network offers mechanical integrity and enables direct vascular anastomosis, ensuring efficient nutrient and oxygen exchange. The bioprinted thick, vascularized constructs, containing HCD hepatocytes, are successfully implanted in rats after 85% hepatectomy, leading to swift functional recovery and prolonged survival. This study presents a strategy to enhance regenerative therapy outcomes through advanced bioprinting and vascular integration techniques.